Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/dailymed/precaution
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| dailymed-drugs:1 | dailymed-instance:precautio... | General: As with all broad���spectrum antibiotics, Cefizox (ceftizoxime for injection, USP) should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. Although Cefizox has not been shown to produce an alteration in renal function, renal status should be evaluated, especially in seriously ill patients receiving maximum dose therapy. As with any antibiotic, prolonged use may result in overgrowth of nonsusceptible organisms. Careful observation is essential; appropriate measures should be taken if superinfection occurs. Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated. Prescribing Cefizox in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.<br/>Drug Interactions: Although the occurrence has not been reported with Cefizox, nephrotoxicity has been reported following concomitant administration of other cephalosporins and aminoglycosides.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long���term studies in animals to evaluate the carcinogenic potential of ceftizoxime have not been conducted. In an in vitro bacterial cell assay (i.e., Ames test), there was no evidence of mutagenicity at ceftizoxime concentrations of 0.001���0.5 mcg/plate. Ceftizoxime did not produce increases in micronuclei in the in vivo mouse micronucleus test when given to animals at doses up to 7500 mg/kg, approximately six times greater than the maximum human daily dose on a mg/Mbasis. Ceftizoxime had no effect on fertility when administered subcutaneously to rats at daily doses of up to 1000 mg/kg/day, approximately two times the maximum human daily dose on a mg/Mbasis. Ceftizoxime produced no histological changes in the sexual organs of male and female dogs when given intravenously for thirteen weeks at a dose of 1000 mg/kg/day, approximately five times greater than the maximum human daily dose on a mg/Mbasis.<br/>Pregnancy::<br/>Teratogenic Effects::<br/>Pregnancy Category B.: Reproduction studies performed in rats and rabbits have revealed no evidence of impaired fertility or harm to the fetus due to Cefizox. There are, however, no adequate and well���controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human effects, this drug should be used during pregnancy only if clearly needed.<br/>Labor and Delivery: Safety of Cefizox use during labor and delivery has not been established.<br/>Nursing Mothers: Cefizox is excreted in human milk in low concentrations. Caution should be exercised when Cefizox is administered to a nursing woman.<br/>Pediatric Use: Safety and efficacy in pediatric patients from birth to six months of age have not been established. In pediatric patients six months of age and older, treatment with Cefizox has been associated with transient elevated levels of eosinophils, AST (SGOT), ALT (SGPT), and CPK (creatine phosphokinase). The CPK elevation may be related to IM administration. The potential for the toxic effect in pediatric patients from chemicals that may leach from the single���dose IV preparation in plastic has not been determined.<br/>Geriatric Use: Clinical studies of ceftizoxime did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.<br/>Information for Patients: Patients should be counseled that antibacterial drugs including Cefizox should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefizox is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be takenexactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Cefizox or other antibacterial drugs in the future. | lld:dailymed |
| dailymed-drugs:2 | dailymed-instance:precautio... | General: Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients (see PRECAUTIONS: Pediatric Use.) During withdrawal from systemically active corticosteroids, some patients may experience symptoms of corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function. Fluticasone propionate will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of FLOVENT DISKUS in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment with fluticasone propionate. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing FLOVENT DISKUS. Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with FLOVENT DISKUS should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when FLOVENT DISKUS is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of FLOVENT DISKUS should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma. The long-term effects of fluticasone propionate in human subjects are not fully known. In particular, the effects resulting from chronic use of fluticasone propionate on developmental or immunologic processes in the mouth, pharynx, trachea, and lung are unknown. Some patients have received inhaled fluticasone propionate on a continuous basis for periods of 3 years or longer. In clinical studies with patients treated for 2 years with inhaled fluticasone propionate, no apparent differences in the type or severity of adverse reactions were observed after long- versus short-term treatment. Rare instances of glaucoma, increased intraocular pressure, and cataracts have been reported in patients following the long term administration of inhaled corticosteroids, including fluticasone propionate. In clinical studies with inhaled fluticasone propionate, the development of localized infections of the pharynx with Candida albicans has occurred. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while remaining on treatment with FLOVENT DISKUS, but at times therapy with FLOVENT DISKUS may need to be interrupted. Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.<br/>Eosinophilic Conditions: In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions, with some patients presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with other inhaled corticosteroids in this clinical setting. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between fluticasone propionate and these underlying conditions has not been established (see ADVERSE REACTIONS: Observed During Clinical Practice: Eosinophilic Conditions).<br/>Information for Patients: Patients being treated with FLOVENT DISKUS should receive the following information and instructions. This information is intended to aid them in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. It is important that patients understand how to use the DISKUS inhalation device appropriately and how it should be used in relation to other asthma medications they are taking. Patients should be given the following information:<br/>Drug Interactions:<br/>Inhibitors of Cytochrome P450: Fluticasone propionate is a substrate of cytochrome P450 3A4. A drug interaction study with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can significantly increase plasma fluticasone propionate concentration, resulting in significantly reduced serum cortisol concentrations (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Drug Interactions). During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Therefore, coadministration of fluticasone propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. In a placebo-controlled crossover study in 8 healthy volunteers, coadministration of a single dose of orally inhaled fluticasone propionate (1,000 mcg) with multiple doses of ketoconazole (200 mg) to steady state resulted in increased plasma fluticasone propionate concentrations, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol. Caution should be exercised when FLOVENT DISKUS is coadministered with ketoconazole and other known potent cytochrome P450 3A4 inhibitors.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 2 times the maximum recommended daily inhalation dose in adults and approximately 10 times the maximum recommended daily inhalation dose in children on a mcg/mbasis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (less than the maximum recommended daily inhalation dose in adults and approximately equal to the maximum recommended daily inhalation dose in children on a mcg/mbasis) for 104 weeks. Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the mouse micronucleus test. No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at subcutaneous doses up to 50 mcg/kg (less than the maximum recommended daily inhalation dose in adults on a mcg/mbasis). Prostate weight was significantly reduced at a subcutaneous dose of 50 mcg/kg.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C. Subcutaneous studies in the mouse and rat at 45 and 100 mcg/kg, respectively (less than the maximum recommended daily inhalation dose in adults on a mcg/mbasis), revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. No teratogenicity was seen in the rat at inhalation doses up to 68.7 mcg/kg (less than the maximum recommended daily inhalation dose in adults on a mcg/mbasis). In the rabbit, fetal weight reduction and cleft palate were observed at a subcutaneous dose of 4 mcg/kg (less than the maximum recommended daily inhalation dose in adults on a mcg/mbasis). However, no teratogenic effects were reported at oral doses up to 300 mcg/kg (approximately 3 times the maximum recommended daily inhalation dose in adults on a mcg/mbasis) of fluticasone propionate. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Absorption). Fluticasone propionate crossed the placenta following administration of a subcutaneous dose of 100 mcg/kg to mice (less than the maximum recommended daily inhalation dose in adults on a mcg/mbasis), a subcutaneous or an oral dose of 100 mcg/kg to rats (less than the maximum recommended daily inhalation dose in adults on a mcg/mbasis), and an oral dose of 300 mcg/kg to rabbits (approximately 3 times the maximum recommended daily inhalation dose in adults on a mcg/mbasis). There are no adequate and well-controlled studies in pregnant women. FLOVENT DISKUS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy.<br/>Nursing Mothers: It is not known whether fluticasone propionate is excreted in human breast milk. However, other corticosteroids have been detected in human milk. Subcutaneous administration to lactating rats of 10 mcg/kg of tritiated fluticasone propionate (less than the maximum recommended daily inhalation dose in adults on a mcg/mbasis) resulted in measurable radioactivity in the milk.Since there are no data from controlled trials on the use of FLOVENT DISKUS by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue FLOVENT DISKUS, taking into account the importance of FLOVENT DISKUS to the mother.<br/>Pediatric Use: Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. A reduction of growth velocity in children or teenagers may occur as a result of poorly controlled asthma or from use of corticosteroids including inhaled corticosteroids. The effects of long-term treatment of children and adolescents with inhaled corticosteroids, including fluticasone propionate, on final adult height are not known. Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth in pediatric patients. In these studies, the mean reduction in growth velocity was approximately 1 cm/year (range, 0.3 to 1.8 cm/year) and appears to depend upon dose and duration of exposure. This effect was observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity isa more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for���catch-up���growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The effects on growth velocity of treatment with orally inhaled corticosteroids for over 1 year, including the impact on final adult height, are unknown. The growth of children and adolescents receiving orally inhaled corticosteroids, including FLOVENT DISKUS, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including FLOVENT DISKUS, each patient should be titrated to the lowest dose that effectively controls his/her symptoms. A 52-week, placebo-controlled study to assess the potential growth effects of fluticasone propionate inhalation powder (FLOVENT ROTADISK) at 50 and 100 mcg twice daily was conducted in the US in 325 prepubescent children (244 males and 81 females) aged 4 to 11 years. The mean growth velocities at 52 weeks observed in the intent-to-treat population were 6.32 cm/year in the placebo group(n = 76), 6.07 cm/year in the 50-mcg group (n = 98), and 5.66 cm/year in the 100-mcg group (n = 89). An imbalance in the proportion of children entering puberty between groups and a higher dropout rate in the placebo group due to poorly controlled asthma may be confounding factors in interpreting these data. A separate subset analysis of children who remained prepubertal during the study revealed growth rates at 52 weeks of 6.10 cm/year in the placebo group (n = 57), 5.91 cm/year in the 50-mcg group (n = 74), and 5.67 cm/year in the 100-mcg group (n = 79). In children 8.5 years of age, the mean age of children in this study, the range for expected growth velocity is: boys���3percentile = 3.8 cm/year, 50percentile = 5.4 cm/year, and 97percentile = 7.0 cm/year; girls���3percentile = 4.2 cm/year, 50percentile =5.7 cm/year, and 97percentile = 7.3 cm/year. The clinical significance of these growth data is not certain. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route, and weigh the benefits of corticosteroid therapy against the possibility of growth suppression if growth appears slowed. Patients should be maintained on the lowest dose of inhaled corticosteroid that effectively controls their asthma. The safety and effectiveness of FLOVENT DISKUS in children below 4 years of age have not been established.<br/>Geriatric Use: Safety data have been collected on 280 patients (FLOVENT DISKUS n = 83, FLOVENT ROTADISK n = 197) 65 years of age or older and 33 patients (FLOVENT DISKUS n = 14, FLOVENT ROTADISK n = 19) 75 years of age or older who have been treated with fluticasone propionate inhalation powder in US and non-US clinical trials. There were no differences in adverse reactions compared to those reported by younger patients. In addition, there were no apparent differences in efficacy between patients 65 years of age or older and younger patients. Fifteen patients 65 years of age or older and 1 patient 75 years of age or older were included in the efficacy evaluation of US clinical studies. | lld:dailymed |
| dailymed-drugs:3 | dailymed-instance:precautio... | Impaired Renal Function: Nadolol should be used with caution in patients with impaired renal function (see DOSAGE AND ADMINISTRATION).<br/>Information for Patients: Patients, especially those with evidence of coronary artery insufficiency, should be warned against interruption or discontinuation of nadolol therapy without the physician's advice. Although cardiac failure rarely occurs in properly selected patients, patients being treated with beta-adrenergic blocking agents should be advised to consult the physician at the first sign or symptom of impending failure. The patient should also be advised of a proper course in the event of an inadvertently missed dose.<br/>Drug Interactions: When administered concurrently, the following drugs may interact with beta-adrenergic receptor blocking agents:<br/>Anesthetics, general: Exaggeration of the hypotension induced by general anesthetics (see WARNINGS, Major Surgery).<br/>Antidiabetic drugs (oral agents and insulin): Hypoglycemia or hyperglycemia; adjust dosage of antidiabetic drug accordingly (see WARNINGS, Diabetes and Hypoglycemia).<br/>Catecholamine-depleting drugs (e.g., reserpine): Additive effect; monitor closely for evidence of hypotension and/or excessive bradycardia (e.g., vertigo, syncope, postural hypotension).<br/>Digitalis glycosides: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.<br/>Response to Treatment for Anaphylactic Reaction: While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In chronic oral toxicologic studies (one to two years) in mice, rats, and dogs, nadolol did not produce any significant toxic effects. In two-year oral carcinogenic studies in rats and mice, nadolol did not produce any neoplastic, preneoplastic, or non-neoplastic pathologic lesions. In fertility and general reproductive performance studies in rats, nadolol caused no adverse effects.<br/>Pregnancy Category C: In animal reproduction studies with nadolol, evidence of embryo- and fetotoxicity was found in rabbits, but not in rats or hamsters, at doses 5 to 10 times greater (on a mg/kg basis) than the maximum indicated human dose. No teratogenic potential was observed in any of these species. There are no adequate and well-controlled studies in pregnant women. Nadolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonates whose mothers are receiving nadolol at parturition have exhibited bradycardia, hypoglycemia, and associated symptoms.<br/>Nursing Mothers: Nadolol is excreted in human milk. Because of the potential for adverse effects in nursing infants, a decision should be made whether to discontinue nursing or to discontinue therapy taking into account the importance of nadolol to the mother.<br/>Pediatric Use: Safety and effectiveness in children have not been established. | lld:dailymed |
| dailymed-drugs:4 | dailymed-instance:precautio... | Potential for Stimulation of Tumor Growth: The safety and efficacy of Kepivance have not been established in patients with non-hematologic malignancies. The effects of Kepivance on stimulation of KGF receptor-expressing, non-hematopoietic tumors in patients are not known. Kepivance has been shown to enhance the growth of human epithelial tumor cell lines in vitro and to increase the rate of tumor cell line growth in a human carcinoma xenograft model .<br/>Information for Patients: Patients should be informed of the possible adverse effects of Kepivance, including muco-cutaneous adverse effects. These include rash, erythema, edema, pruritus, oral/perioral dysesthesia, tongue discoloration, tongue thickening, and alteration of taste. Patients should be instructed to report these adverse effects, or any other adverse reactions, to the prescribing physician . The safety and efficacy of Kepivance have not been established in patients with non-hematologic malignancies. Patients should be informed of the evidence of tumor growth and stimulation in cell culture and in animal models of non-hematopoietic human tumors.<br/>Drug Interactions: In-vitro and in vivo data suggests that palifermin interacts with unfractionated as well as low molecular weight heparins. While the clinical relevance is unclear, heparin should be used with care in patients who are concomitantly administered palifermin. Therefore, if heparin is used to maintain an IV line, saline should be used to rinse the line prior to and after Kepivance administration. Kepivance should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy . In a clinical trial, administration of Kepivance within 24 hours of chemotherapy resulted in increased severity and duration of oral mucositis.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity: In a study to assess potential carcinogenicity in transgenic rasH2 mice, no treatment related increases in the incidence of neoplastic lesions were observed. Mutagenicity: No clastogenic or mutagenic effects of Kepivance were observed in the Ames or mammalian chromosomal aberration assays; however, such studies are generally not informative for biological products. Impairment of Fertility: When Kepivance was administered intravenously daily to male and female rats prior to and during mating, reproductive performance, fertility, and sperm assessment parameters were not affected at doses up to 100 mcg/kg/day. Systemic toxicity (clinical signs of toxicity and/or body weight effects), decreased epididymal sperm counts, and increased post-implantation losses were observed at doses���300 mcg/kg/day (5-fold higher than the recommended human dose). Increased pre-implantation loss and a decreased fertility index were observed at a Kepivance dose of 1000 mcg/kg/day.<br/>Pregnancy Category C: Kepivance has been shown to be embryotoxic in rabbits and rats when given in doses that are 2.5 and 8 times the human dose, respectively. Increased post-implantation loss and decreased fetal body weights were observed when Kepivance was administered to pregnant rabbits from days 6 to 18 of gestation at IV doses���150 mcg/kg/day (2.5-fold higher than the recommended human dose). However, treatment with these doses was also associated with maternal toxicity (clinical signs and reductions in body weight gain/food consumption). No evidence of developmental toxicity was observed in rabbits at doses up to 60 mcg/kg/day. Increased post-implantation loss, decreased fetal body weight, and/or increased skeletal variations were observed when Kepivance was administered to pregnant rats from days 6 to 17 or 19 of gestation at IV doses���500 mcg/kg/day (>8-fold higher than the recommended human dose). Treatment with these doses was also frequently associated with maternal toxicity (clinical signs and body weight effects). No evidence of developmental toxicity was observed in rats at doses up to 300 mcg/kg/day. There are no adequate and well-controlled studies in pregnant women. Kepivance should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.<br/>Lactating Women: It is not known whether Kepivance is excreted in human milk. Because many drugs are excreted in human milk���caution should be exercised when Kepivance is administered to a nursing woman.<br/>Pediatric Use: The safety and effectiveness of Kepivance in pediatric patients have not been established.<br/>Geriatric Use: A single dose IV study of palifermin (90 or 180 mcg/kg) conducted in healthy volunteers age 18-80 indicates that age does not have clinically meaningful effects on the pharmacokinetics of palifermin. | lld:dailymed |
| dailymed-drugs:5 | dailymed-instance:precautio... | General: The safety and effectiveness of local anesthetics depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use. During major regional nerve blocks, the patient should have IV fluids running via an indwelling catheter to assure a functioning intravenous pathway. The lowest dosage of local anesthetic that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. Injections should be made slowly, with frequent aspirations before and during the injection to avoid intravascular injection. Current opinion favors fractional administration with constant attention to the patient, rather than rapid bolus injection. Syringe aspirations should also be performed before and during each supplemental injection in continuous (intermittent) catheter techniques. An intravascular injection is still possible even if aspirations for blood are negative. During the administration of epidural anesthesia, it is recommended that a test dose be administered initially and the effects monitored before the full dose is given. When using a���continuous���catheter technique, test doses should be given prior to both the original and all reinforcing doses, because plastic tubing in the epidural space can migrate into a blood vessel or through the dura. When the clinical conditions permit, an effective test dose should contain epinephrine (10��g to 15��g have been suggested) to serve as a warning of unintended intravascular injection. If injected into a blood vessel, this amount of epinephrine is likely to produce an���epinephrine response���within 45 seconds, consisting of an increase of pulse and blood pressure, circumoral pallor, palpitations, and nervousness in the unsedated patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds. Therefore, following the test dose, the heart rate should be monitored for a heart rate increase. The test dose should also contain 45 mg to 50 mg of mepivacaine hydrochloride to detect an unintended intrathecal administration. This will be evidenced within a few minutes by signs of spinal block (eg, decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk). Injection of repeated doses of local anesthetics may cause significant increases in plasma levels with each repeated dose due to slow accumulation of the drug or its metabolites or to slow metabolic degradation. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients, and acutely ill patients should be given reduced doses commensurate with their age and physical status. Local anesthetics should also be used with caution in patients with severe disturbances of cardiac rhythm, shock, heart block, or hypotension. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs, and the patient's state of consciousness should be performed after each local anesthetic injection. It should be kept in mind at such times that restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression, or drowsiness may be early warning signs of central nervous system toxicity. Local anesthetic solutions containing a vasoconstrictor should be used cautiously and in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply such as digits, nose, external ear, penis. Patients with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result. Mepivacaine should be used with caution in patients with known allergies and sensitivities. Because amide-type local anesthetics such as mepivacaine are metabolized by the liver and excreted by the kidneys, these drugs, especially repeat doses, should be used cautiously in patients with hepatic and renal disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations. Local anesthetics should also be used with caution in patients with impaired cardiovascular function because they may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by these drugs. Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are employed in patients during or following the administration of potent inhalation anesthetics. In deciding whether to use these products concurrently in the same patient, the combined action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should be taken into account. Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Because it is not known whether amide-type local anesthetics may trigger this reaction and because the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for management should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure, and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s), and institution of treatment, including oxygen therapy, indicated supportive measures, and dantrolene. (Consult dantrolene sodium intravenous package insert before using.)<br/>Use in Head and Neck Area: Small doses of local anesthetics injected into the head and neck area may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. The injection procedures require the utmost care. Confusion, convulsions, respiratory depression, and/or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded.<br/>Information for Patients: When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of caudal or epidural anesthesia. Also, when appropriate, the physician should discuss other information including adverse reactions listed in this package insert.<br/>Clinically Significant Drug Interactions: The administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential. Concurrent administration of vasopressor drugs and of ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine.<br/>Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long-term studies in animals of most local anesthetics including mepivacaine to evaluate the carcinogenic potential have not been conducted. Mutagenic potential or the effect on fertility have not been determined. There is no evidence from human data that mepivacaine may be carcinogenic or mutagenic or that it impairs fertility.<br/>Pregnancy Category C: Animal reproduction studies have not been conducted with mepivacaine. There are no adequate and well-controlled studies in pregnant women of the effect of mepivacaine on the developing fetus. Mepivacaine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk tothe fetus. This does not preclude the use of mepivacaine at term for obstetrical anesthesia or analgesia. (See Labor and Delivery.) Mepivacaine has been used for obstetrical analgesia by the epidural, caudal, and paracervical routes without evidence of adverse effects on the fetus when no more than the maximum safe dosages are used and strict adherence to technique is followed.<br/>Labor and Delivery: Local anesthetics rapidly cross the placenta, and when used for epidural, paracervical, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity. The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus, and neonate involve alterations of the central nervous system, peripheral vascular tone, and cardiac function. Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient's legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously and electronic fetal monitoring is highly advisable. Epidural, paracervical, caudal, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. In one study, paracervical block anesthesia was associated with a decrease in the mean duration of first stage labor and facilitation of cervical dilation. Epidural anesthesia has been reportedto prolong the second stage of labor by removing the parturient's reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. The long-term significance of these observations is unknown. Fetal bradycardia may occur in 20 to 30 percent of patients receiving paracervical block anesthesia with the amide-type local anesthetics and may be associated with fetal acidosis. Fetal heart rate should always be monitored during paracervical anesthesia. Added risk appears to be present in prematurity, postmaturity, toxemia of pregnancy, and fetal distress. The physician should weigh the possible advantages against dangers when considering paracervical block in these conditions. Careful adherence to recommended dosage is of the utmost importance in obstetrical paracervical block. Failure to achieve adequate analgesia with recommended doses should arouse suspicion of intravascular or fetal intracranial injection. Cases compatible with unintended fetal intracranial injection of local anesthetic solution have been reported following intended paracervical or pudendal block or both. Babies so affected present with unexplained neonatal depression at birth which correlates with high local anesthetic serum levels and usually manifest seizures within six hours. Prompt use of supportive measures combined with forced urinary excretion of the local anesthetic has been used successfully to manage this complication. Case reports of maternal convulsions and cardiovascular collapse following use of some local anesthetics for paracervical block in early pregnancy (as anesthesia for elective abortion) suggest that systemic absorption under these circumstances may be rapid. The recommended maximum dose of the local anesthetic should not be exceeded. Injection should be made slowly and with frequent aspiration. Allow a five-minute interval between sides. It is extremely important to avoid aortocaval compression by the gravid uterus during administration of regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus position or a blanket roll or sandbag may be placed beneath the right hip and the gravid uterus displaced to the left.<br/>Nursing Mothers: It is not known whether local anesthetic drugs are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when local anesthetics are administered to a nursing woman.<br/>Pediatric Use: Guidelines for the administration of mepivacaine to pediatric patients are presented in DOSAGE AND ADMINISTRATION.<br/>Geriatric Use: Clinical studies and other reported clinical experience indicates that use of the drug in elderly patients requires a decreased dosage. . Mepivacaine and mepivacaine metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. | lld:dailymed |
| dailymed-drugs:6 | dailymed-instance:precautio... | General: This drug is HIGHLY TOXIC and both powder and solution must be handled and administered with care. Since MUSTARGEN is a powerful vesicant, it is intended primarily for intravenous use, and in most cases is given by this route. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Appropriate protective equipment should be worn when handling MUSTARGEN. Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water, for at least 15 minutes while removing contaminated clothing and shoes, followed by 2% sodium thiosulfate solution. Medical attention should be sought immediately. Contaminated clothing should be destroyed. Because of the toxicity of MUSTARGEN, and the unpleasant side effects following its use, the potential risk and discomfort from the use of this drug in patients with inoperable neoplasms or in the terminal stage of the disease must be balanced against the limited gain obtainable. These gains will vary with the nature and the status of the disease under treatment. The routine use of MUSTARGEN in all cases of widely disseminated neoplasms is to be discouraged. The use of MUSTARGEN in patients with leukopenia, thrombocytopenia, and anemia, due to invasion of the bone marrow by tumor carries a greater risk. In such patients a good response to treatment with disappearance of the tumor from the bone marrow may be associated with improvement of bone marrow function. However, in the absence of a good response or in patients who have been previously treated with chemotherapeutic agents, hematopoiesis may be further compromised, and leukopenia, thrombocytopenia and anemia may become more severe and lead to the demise of the patient. Tumors of bone and nervous tissue have responded poorly to therapy. Results are unpredictable in disseminated and malignant tumors of different types.Precautions must be observed with the use of MUSTARGEN and x-ray therapy or other chemotherapy in alternating courses. Hematopoietic function is characteristically depressed by either form of therapy, and neither MUSTARGEN following x-ray therapy nor x-ray therapy subsequent to the drug should be given until bone marrow function has recovered. In particular, irradiation of such areas as sternum, ribs, and vertebrae shortly after a course of nitrogen mustard may lead to hematologic complications. MUSTARGEN has been reported to have immunosuppressive activity. Therefore, it should be borne in mind that use of the drug may predispose the patient to bacterial, viral or fungal infection. Hyperuricemia may develop during therapy with MUSTARGEN. The problem of urate precipitation should be anticipated, particularly in the treatment of the lymphomas, and adequate methods for control of hyperuricemia should be instituted and careful attention directed toward adequate fluid intake before treatment. Since drug toxicity, especially sensitivity to bone marrow failure, seems to be more common in chronic lymphatic leukemia than in other conditions, the drug should be given in this condition with great caution, if at all. Extreme caution must be used in exceeding the average recommended dose.<br/>Laboratory Tests: Many abnormalities of renal, hepatic, and bone marrow function have been reported in patients with neoplastic disease and receiving mechlorethamine. It is advisable to check renal, hepatic, and bone marrow functions frequently.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Therapy with alkylating agents such as MUSTARGEN may be associated with an increased incidence of a second malignant tumor, especially when such therapy is combined with other antineoplastic agents or radiation therapy. The International Agency for Research on Cancer has judged that mechlorethamine is a probable carcinogen in humans. This is supported by limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in animals. Young-adult female RF mice were injected intravenously with four doses of 2.4 mg/kg of mechlorethamine (0.1% solution) at 2-week intervals with observations for up to 2 years. An increased incidence of thymic lymphomas and pulmonary adenomas was observed. Painting mechlorethamine on the skin of mice for periods up to 33 weeks resulted in squamous cell tumors in 9 of 33 mice. Mechlorethamine induced mutations in the Ames test, in E. coli, and Neurospora crassa. Mechlorethamine caused chromosome aberrations in a variety of plant and mammalian cells. Dominant lethal mutations were produced in ICR/Ha Swiss mice. Mechlorethamine impaired fertility in the rat at a daily dose of 500 mg/kg intravenously for two weeks.<br/>Pregnancy: Pregnancy Category D. See WARNINGS.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from MUSTARGEN, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established by well-controlled studies. Use of MUSTARGEN in pediatric patients has been quite limited. MUSTARGEN has been used in Hodgkin's disease, stages III and IV, in combination with other oncolytic agents (MOPP schedule). The MOPP chemotherapy combination includes mechlorethamine, vincristine, procarbazine, and prednisone or prednisolone.<br/>Geriatric Use: Clinical studies of MUSTARGEN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:7 | dailymed-instance:precautio... | General: Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. Most of these reports involved seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory. Fluconazole should be administered with caution to patients with these potentially proarrhythmic conditions.<br/>Drug Interactions: Clinically or potentially significant drug interactions between fluconazole and the following agents/classes have been observed. These are described in greater detail below: Oral hypoglycemics: Clinically significant hypoglycemia may be precipitated by the use of fluconazole with oral hypoglycemic agents; one fatality has been reported from hypoglycemia in association with combined fluconazole and glyburide use. Fluconazole reduces the metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of these agents. When fluconazole is used concomitantly with these or other sulfonylurea oral hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose of the sulfonylurea should be adjusted as necessary. Coumarin-type anticoagulants: Prothrombin time may be increased in patients receiving concomitant fluconazole and coumarin-type anticoagulants. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin time in patients receiving fluconazole and coumarin-type anticoagulants is recommended. Phenytoin: Fluconazole increases the plasma concentrations of phenytoin. Careful monitoring of phenytoin concentrations in patients receiving fluconazole and phenytoin is recommended. Cyclosporine: Fluconazole may significantly increase cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving fluconazole and cyclosporine. Rifampin: Rifampin enhances the metabolism of concurrently administered fluconazole. Depending on clinical circumstances, consideration should be given to increasing the dose of fluconazole when it is administered with rifampin. Theophylline: Fluconazole increases the serum concentrations of theophylline. Careful monitoring of serum theophylline concentrations in patients receiving fluconazole and theophylline is recommended. Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated. The coadministration of fluconazole at doses lower than 400 mg/day with terfenadine should be carefully monitored. Cisapride: There have been reports of cardiac events, including torsade de pointes in patients to whom fluconazole and cisapride were coadministered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. The combined use of fluconazole with cisapride is contraindicated. Astemizole: The use of fluconazole in patients concurrently taking astemizole or other drugs metabolized by the cytochrome P450 system may be associated with elevations in serum levels of these drugs. In the absence of definitive information, caution should be used when coadministering fluconazole. Patients should be carefully monitored. Rifabutin: There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored. Tacrolimus: There have been reports of nephrotoxicity in patients to whom fluconazole and tacrolimus were coadministered. Patients receiving tacrolimus and fluconazole concomitantly should be carefully monitored. Short-acting Benzodiazepines: Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If short-acting benzodiazepines, which are metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored. Fluconazole tablets coadministered with ethinyl estradiol- and levonorgestrel-containing oral contraceptives produced an overall mean increase in ethinyl estradiol and levonorgestrel levels; however, in some patients there were decreases up to 47% and 33% of ethinyl estradiol and levonorgestrel levels. The data presently available indicate that the decreases in some individual ethinyl estradiol and levonorgestrel AUC values with fluconazole treatment are likely the result of random variation. While there is evidence that fluconazole can inhibit the metabolism of ethinyl estradiol and levonorgestrel, there is no evidence that fluconazole is a net inducer of ethinyl estradiol or levonorgestrel metabolism. The clinical significance of these effects is presently unknown. Physicians should be aware that interaction studies with medications other than those listed in the CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may occur.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5 or 10 mg/kg/day (approximately 2 to 7x the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas. Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1000 mcg/mL) showed no evidence of chromosomal mutations. Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10 or 20 mg/kg or with parenteral doses of 5, 25 or 75 mg/kg, although the onset of parturition was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5, 20 and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg (approximately 5 to 15x the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The disturbances in parturition were reflected by a slight increase in the number of still-born pups and decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent with the species specific estrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole.<br/>Pregnancy:<br/>Teratogenic Effects; Pregnancy Category C: Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies, at 5, 10 and 20 mg/kg and at 5, 25, and 75 mg/kg, respectively. Maternal weight gain was impaired at all dose levels, and abortions occurred at 75 mg/kg (approximately 20 to 60x the recommended human dose); no adverse fetal effects were detected. In several studies in which pregnant rats were treated orally with fluconazole during organogenesis, maternal weight gain was impaired and placental weights were increased at 25 mg/kg. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 mg/kg (approximately 20 to 60x the recommended human dose) to 320 mg/kg embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification. These effects are consistent with the inhibition of estrogen synthesis in rats and may be a resultof known effects of lowered estrogen on pregnancy, organogenesis and parturition. There are no adequate and well-controlled studies in pregnant women. There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for 3 or more months with high dose (400 to 800 mg/day) fluconazole therapy for coccidioidomycosis (an unindicated use). The relationship between fluconazole use and these events is unclear. Fluconazole should be used in pregnancy only if the potential benefit justifies the possible risk to the fetus.<br/>Nursing Mothers: Fluconazole is secreted in human milk at concentrations similar to plasma. Therefore, the use of fluconazole in nursing mothers is not recommended.<br/>Pediatric Use: An open-label, randomized, controlled trial has shown fluconazole to be effective in the treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. The use of fluconazole in children with cryptococcal meningitis, Candida esophagitis, or systemic Candida infections is supported by the efficacy shown for these indications in adults and by the results from several small noncomparative pediatric clinical studies. In addition, pharmacokinetic studies in children have established a dose proportionality between children and adults. In a noncomparative study of children with serious systemic fungal infections, most of which were candidemia, the effectiveness of fluconazole was similar to that reported for the treatment of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with baseline symptoms (3 were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients had a mycologic cure at the end of treatment but two of these patients relapsed at 10 and 18 days, respectively, following cessation of therapy. The efficacy of fluconazole for the suppression of cryptococcal meningitis was successful in 4 of 5 children treated in a compassionate-use study of fluconazole for the treatment of life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole for primary treatment of cryptococcal meningitis in children. The safety profile of fluconazole in children has been studied in 577 children ages 1 day to 17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. Efficacy of fluconazole has not been established in infants less than 6 months of age. A small number of patients (29) ranging in age from 1 day to 6 months have been treated safely with fluconazole.<br/>Geriatric Use: In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in fewer patients aged 65 and older (9%, n =339) than for younger patients (14%, n=2240). However, there was no consistent difference between the older and younger patients with respect to individual side effects. Of the most frequently reported (>1%) side effects, rash, vomiting and diarrhea occurred in greater proportions of older patients. Similar proportions of older patients (2.4%) and younger patients (1.5%) discontinued fluconazole therapy because of side effects. In post-marketing experience, spontaneous reports of anemia and acute renal failure were more frequent among patients 65 years of age or older than in those between 12 and 65 years of age. Because of the voluntary nature of the reports and the natural increase in the incidence of anemia and renal failure in theelderly, it is however not possible to establish a casual relationship to drug exposure. Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 65 and older to evaluate whether they respond differently from younger patients in each indication. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients are more likely to have decreased renal function, care should be taken to adjust dose based on creatinine clearance. It may be useful to monitor renal function. | lld:dailymed |
| dailymed-drugs:8 | dailymed-instance:precautio... | General:: The initial prescription and renewal of the medication order beyond 20 milliliters of PRED FORTE suspension should be made by a physician only after examination of the patient with the aid of magnification, such as slit lamp biomicroscopy, and, where appropriate, fluorescein staining. If signs and symptoms fail to improve after 2 days, the patient should be re-evaluated. As fungal infections of the cornea are particularly prone to develop coincidentally with long-term local corticosteroid applications, fungal invasion should be suspected in any persistent corneal ulceration where a corticosteroid has been used or is in use. Fungal cultures should be taken when appropriate. If this product is used for 10 days or longer, intraocular pressure should be monitored .<br/>Information for patients:: If inflammation or pain persists longer than 48 hours or becomes aggravated, the patient should be advised to discontinue use of the medication and consult a physician. This product is sterile when packaged. To prevent contamination, care should be taken to avoid touching the bottle tip to eyelids or to any other surface. The use of this bottle by more than one person may spread infection. Keep bottle tightly closed when not in use. Keep out of the reach of children.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:: No studies have been conducted in animals or in humans to evaluate the potential of these effects.<br/>Pregnancy Category C: Prednisolone has been shown to be teratogenic in mice when given in doses 1-10 times the human dose. There are no adequate well-controlled studies in pregnant women. Prednisolone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Dexamethasone, hydrocortisone, and prednisolone were ocularly applied to both eyes of pregnant mice five times per day on days 10 through 13 of gestation. A significant increase in the incidence of cleft palate was observed in the fetuses of the treated mice.<br/>Nursing Mothers:: It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from prednisolone, a decision should bemade whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use:: Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric Use:: No overall differences in safety or effectiveness have been observed between elderly and younger patients. | lld:dailymed |
| dailymed-drugs:10 | dailymed-instance:precautio... | General: Because of the potential effects of beta-adrenergic blocking agents relative to blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with Betimol, alternative therapy should be considered. There have been reports of bacterial keratitis associated with the use of multiple dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. Muscle Weakness: Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g. diplopia, ptosis, and generalized weakness). Beta-adrenergic blocking agents have been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms. In angle-closure glaucoma, the goal of the treatment is to reopen the angle. This requires constricting the pupil. Betimol has no effect on the pupil. Therefore, if timolol is used in angle-closure glaucoma, it should always be combined with a miotic and not used alone. Anaphylaxis: While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions. The preservative benzalkonium chloride may be absorbed by soft contact lenses. Patients who wear soft contact lenses should wait 5 minutes after instilling Betimol before they insert their lenses.<br/>Information for Patients: Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures. Patients should also be instructed that ocular solutions can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions. Patients requiring concomitant topical ophthalmic medications should be instructed to administer these at least 5 minutes apart. Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second- or third-degree atrioventricular block, or cardiac failure should be advised not to take this product<br/>Drug Interactions: Beta-adrenergic blocking agents: Patients who are receiving a beta-adrenergic blocking agent orally and Betimol should be observed for a potential additive effect either on the intraocular pressure or on the known systemic effects of beta-blockade. Patients should not usually receive two topical ophthalmic beta-adrenergic blocking agents concurrently. Catecholamine-depleting drugs: Close observation of the patient is recommended when a beta-blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may produce vertigo, syncope, or postural hypotension. Calcium antagonists: Caution should be used in the co-administration of beta-adrenergic blocking agents and oral or intravenous calcium antagonists, because of possible atrioventricular conduction disturbances, left ventricular failure, and hypotension. In patients with impaired cardiac function, co-administration should be avoided. Digitalis and calcium antagonists: The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time. Injectable Epinephrine:<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity of timolol (as the maleate) has been studied in mice and rats. In a two-year study orally administrated timolol maleate (300mg/kg/day) (approximately 42,000 times the systemic exposure following the maximum recommended human ophthalmic dose) in male rats caused a significant increase in the incidence of adrenal pheochromocytomas; the lower doses, 25 mg or 100 mg/kg daily did not cause any changes. In a life span study in mice the overall incidence of neoplasms was significantly increased in female mice at 500 mg/kg/day (approximately 71,000 times the systemic exposure following the maximum recommended human ophthalmic dose). Furthermore, significant increases were observed in the incidences of benign and malignant pulmonary tumors, benign uterine polyps, as well as mammary adenocarcinomas. These changes were not seen at the daily dose level of 5 or 50 mg/kg (approximately 700 or 7,000, respectively, times the systemic exposure following the maximum recommended human ophthalmic dose). For comparison, the maximum recommended human oral dose of timolol maleate is 1 mg/kg/day. Mutagenic potential of timolol was evaluated in vivo in the micronucleus test and cytogenetic assay and in vitro in the neoplastic cell transformation assay and Ames test. In the bacterial mutagenicity test (Ames test) high concentrations of timolol maleate (5000 and 10,000 g/plate) statistically significantly increased the number of revertants in Salmonella typhimurium TA100, but not in the other three strains tested. However, no consistent dose-response was observed nor did the number of revertants reach the double of the control value, which is regarded as one of the criteria for a positive result in the Ames test. In vivo genotoxicity tests (the mouse micronucleus test and cytogenetic assay) and in vitro the neoplastic cell transformation assay were negative up to dose levels of 800 mg/kg and 100 g/mL, respectively. No adverse effects on male and female fertility were reported in rats at timolol oral doses of up to 150 mg/kg/day (21,000 times the systemic exposure following the maximum recommended human ophthalmic dose).<br/>PREGNANCY:<br/>Teratogenic effects: Category C: Teratogenicity of timolol (as the maleate) after oral administration was studied in mice and rabbits. No fetal malformations were reported in mice or rabbits at a daily oral dose of 50 mg/kg (7,000 times the systemic exposure following the maximum recommended human ophthalmic dose). Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1000 mg/kg/day (142,000 times the systemic exposure following the maximum recommended human ophthalmic dose) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses of 14,000 times the systemic exposure following the maximum recommended human ophthalmic dose in this case without apparent maternotoxicity. There are no adequate and well-controlled studies in pregnant women. Betimol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing mothers: Because of the potential for serious adverse reactions in nursing infants from timolol, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric use: Safety and efficacy in pediatric patients have not been established. | lld:dailymed |
| dailymed-drugs:11 | dailymed-instance:precautio... | The extent of clinical experience with CHEMET is limited. Therefore, patients should be carefully observed during treatment.<br/>General: Elevated blood lead levels and associated symptoms may return rapidly after discontinuation of CHEMET because of redistribution of lead from bone stores to soft tissues and blood. After therapy, patients should be monitored for rebound of blood lead levels, by measuring blood lead levels at least once weekly until stable. However, the severity of lead intoxication (as measured by the initial blood lead level and the rate and degree of rebound of blood lead) should be used as a guide for more frequent blood lead monitoring. All patients undergoing treatment should be adequately hydrated. Caution should be exercised in using CHEMET therapy in patients with compromised renal function. Limited data suggests that CHEMET is dialyzable, but that the lead chelates are not. Transient mild elevations of serum transaminases have been observed in 6-10% of patients during the course of succimer therapy. Serum transaminases should be monitored before the start of therapy and at least weekly during therapy. Patients with a history of liver disease should be monitored closely. No data are available regarding the metabolism of succimer in patients with liver disease. Clinical experience with repeated courses is limited. The safety of uninterrupted dosing longer than three weeks has not been established and it is not recommended. The possibility of allergic or other mucocutaneous reactions to the drug must be borne in mind on readministration (as well as during initial courses). Patients requiring repeated courses of CHEMET should be monitored during each treatment course. One patient experienced recurrent mucocutaneous vesicular eruptions of increasing severity affecting the oral mucosa, the external urethral meatus and the perianal area on the third, fourth and fifth courses of the drug. The reaction resolved between courses and upon discontinuation of therapy.<br/>Information for Patients: Patients should be instructed to maintain adequate fluid intake. If rash occurs, patients should consult their physician. Patients should be instructed to promptly report any indication of infection, which may be a sign of neutropenia . In young pediatric patients unable to swallow capsules, the contents of the capsule can be administered in a small amount of food .<br/>Drug Interaction: CHEMET is not known to interact with other drugs including iron supplements; interactions have not been systematically studied. Concomitant administration of CHEMET with other chelation therapy, such as CaNaEDTA is not recommended.<br/>Drug/Laboratory Tests Interaction: Succimer may interfere with serum and urinary laboratory tests. In vitro studies have shown succimer to cause false positive results for ketones in urine using nitroprusside reagents such as Ketostix and falsely decreased measurements of serum uric acid and CPK.<br/>Carcinogenesis, Mutagenesis and Impairment of Fertility: CHEMET has not been tested for carcinogenic potential in long-term animal studies. CHEMET has not been tested in animals for its effect on fertility and reproductive performance in males and females. It was not mutagenic in the Ames bacterial assay and in the mammalian cell forward gene mutation assay.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C. CHEMET has been shown to be teratogenic and fetotoxic in pregnant mice when given subcutaneously in a dose range of 410 to 1640 mg/kg/day during the period of organogenesis. There are no adequate and well controlled studies in pregnant women. CHEMET should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs and heavy metals are excreted in human milk, nursing mothers requiring CHEMET therapy should be discouraged from nursing their infants.<br/>Pediatric Use: Refer to the INDICATIONS and DOSAGE AND ADMINISTRATION sections. Safety and efficacy in pediatric patients less than 12 months of age have not been established. | lld:dailymed |
| dailymed-drugs:12 | dailymed-instance:precautio... | General:<br/>Somnolence: In US controlled studies, somnolence was reported in 54% of patients treated with REMERON' (mirtazapine) Tablets, compared to 18% for placebo and 60% for amitriptyline. In these studies, somnolence resulted in discontinuation for 10.4% of REMERON'-treated patients, compared to 2.2% for placebo. It is unclear whether or not tolerance develops to the somnolent effects of REMERON'. Because of REMERON''s potentially significant effects on impairment of performance, patients should be cautioned about engaging in activities requiring alertness until they have been able to assess the drug's effect on their own psychomotor performance (see Information for Patients).<br/>Dizziness: In US controlled studies, dizziness was reported in 7% of patients treated with REMERON', compared to 3% for placebo and 14% for amitriptyline. It is unclear whether or not tolerance develops to the dizziness observed in association with the use of REMERON'.<br/>Increased Appetite/Weight Gain: In US controlled studies, appetite increase was reported in 17% of patients treated with REMERON', compared to 2% for placebo and 6% for amitriptyline. In these same trials, weight gain of���7% of body weight was reported in 7.5% of patients treated with mirtazapine, compared to 0% for placebo and 5.9% for amitriptyline. In a pool of premarketing US studies, including many patients for long-term, open-label treatment, 8% of patients receiving REMERON' discontinued for weight gain. In an 8-week long pediatric clinical trial of doses between 15���45 mg/day, 49% of REMERON'-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients (see PRECAUTIONS: Pediatric Use).<br/>Cholesterol/Triglycerides: In US controlled studies, nonfasting cholesterol increases to���20% above the upper limits of normal were observed in 15% of patients treated with REMERON', compared to 7% for placebo and 8% for amitriptyline. In these same studies, nonfasting triglyceride increases to���500 mg/dL were observed in 6% of patients treated with mirtazapine, compared to 3% for placebo and 3% for amitriptyline.<br/>Transaminase Elevations: Clinically significant ALT (SGPT) elevations (���3 times the upper limit of the normal range) were observed in 2.0% (8/424) of patients exposed to REMERON' in a pool of short-term US controlled trials, compared to 0.3% (1/328) of placebo patients and 2.0% (3/181) of amitriptyline patients. Most of these patients with ALT increases did not developsigns or symptoms associated with compromised liver function. While some patients were discontinued for the ALT increases, in other cases, the enzyme levels returned to normal despite continued REMERON' treatment. REMERON' should be used with caution in patients with impaired hepatic function (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).<br/>Activation of Mania/Hypomania: Mania/hypomania occurred in approximately 0.2% (3/1299 patients) of REMERON'-treated patients in US studies. Although the incidence of mania/hypomania was very low during treatment with mirtazapine, it should be used carefully in patients with a history of mania/hypomania.<br/>Seizure: In premarketing clinical trials, only one seizure was reported among the 2796 US and non-US patients treated with REMERON'. However, no controlled studies have been carried out in patients with a history of seizures. Therefore, care should be exercised when mirtazapine is used in these patients.<br/>Use in Patients with Concomitant Illness: Clinical experience with REMERON' in patients with concomitant systemic illness is limited. Accordingly, care is advisable in prescribing mirtazapine for patients with diseases or conditions that affect metabolism or hemodynamic responses. REMERON' has not been systematically evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or other significant heart disease. REMERON' was associated with significant orthostatic hypotension in early clinical pharmacology trials with normal volunteers. Orthostatic hypotension was infrequently observed in clinical trials with depressed patients. REMERON' should be used with caution in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension (history of myocardial infarction, angina, or ischemic stroke) and conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medication). Mirtazapine clearance is decreased in patients with moderate [glomerular filtration rate (GFR) = 11���39 mL/min/1.73 m] and severe [GFR<10 mL/min/1.73 m] renal impairment, and also in patients with hepatic impairment. Caution is indicated in administering REMERON' to such patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).<br/>Information for Patients: Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with REMERON' (mirtazapine) Tablets and should counsel them in its appropriate use. A patient Medication Guide about���Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions���is available for REMERON'. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking REMERON'.<br/>Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.<br/>Agranulocytosis: Patients who are to receive REMERON' should be warned about the risk of developing agranulocytosis. Patients should be advised to contact their physician if they experience any indication of infection such as fever, chills, sore throat, mucous membrane ulceration or other possible signs of infection. Particular attention should be paid to any flu-like complaints or other symptoms that might suggest infection.<br/>Interference with Cognitive and Motor Performance: REMERON' may impair judgement, thinking, and particularly, motor skills, because of its prominent sedative effect. The drowsiness associated with mirtazapine use may impair a patient's ability to drive, use machines or perform tasks that require alertness. Thus, patients should be cautioned about engaging in hazardous activities until they are reasonably certain that REMERON' therapy does not adversely affect their ability to engage in such activities.<br/>Completing Course of Therapy: While patients may notice improvement with REMERON' therapy in 1���4 weeks, they should be advised to continue therapy as directed.<br/>Concomitant Medication: Patients should be advised to inform their physician if they are taking, or intend to take, any prescription or over-the-counter drugs since there is a potential for REMERON' to interact with other drugs.<br/>Alcohol: The impairment of cognitive and motor skills produced by REMERON' has been shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking mirtazapine.<br/>Pregnancy: Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during REMERON' therapy.<br/>Nursing: Patients should be advised to notify their physician if they are breast-feeding an infant.<br/>Laboratory Tests: There are no routine laboratory tests recommended.<br/>Drug Interactions: As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility (see CLINICAL PHARMACOLOGY).<br/>Drugs Affecting Hepatic Metabolism: The metabolism and pharmacokinetics of REMERON' (mirtazapine) Tablets may be affected by the induction or inhibition of drug-metabolizing enzymes.<br/>Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes: Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERON' with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON'with such drugs.<br/>Alcohol: Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON' were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking REMERON'.<br/>Diazepam: Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON' has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON'.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis: Carcinogenicity studies were conducted with mirtazapine given in the diet at doses of 2, 20, and 200 mg/kg/day to mice and 2, 20, and 60 mg/kg/day to rats. The highest doses used are approximately 20 and 12 times the maximum recommended human dose (MRHD) of 45 mg/day on a mg/mbasis in mice and rats, respectively. There was an increased incidence of hepatocellular adenoma and carcinoma in male mice at the high dose. In rats, there was an increase in hepatocellular adenoma in females at the mid and high doses and in hepatocellular tumors and thyroid follicular adenoma/cystadenoma and carcinoma in males at the high dose. The data suggest that the above effects could possibly be mediated by non-genotoxic mechanisms, the relevance of which to humans is not known. The doses used in the mouse study may not have been high enough to fully characterize the carcinogenic potential of REMERON' (mirtazapine) Tablets.<br/>Mutagenesis: Mirtazapine was not mutagenic or clastogenic and did not induce general DNA damage as determined in several genotoxicity tests: Ames test, in vitro gene mutation assay in Chinese hamster V 79 cells, in vitro sister chromatid exchange assay in cultured rabbit lymphocytes, in vivo bone marrow micronucleus test in rats, and unscheduled DNA synthesis assay in HeLa cells.<br/>Impairment of Fertility: In a fertility study in rats, mirtazapine was given at doses up to 100 mg/kg [20 times the maximum recommended human dose (MRHD) on a mg/mbasis]. Mating and conception were not affected by the drug, but estrous cycling was disrupted at doses that were 3 or more times the MRHD and pre-implantation losses occurred at 20 times the MRHD.<br/>Pregnancy:<br/>Teratogenic Effects���Pregnancy Category C: Reproduction studies in pregnant rats and rabbits at doses up to 100 mg/kg and 40 mg/kg, respectively [20 and 17 times the maximum recommended human dose (MRHD) on a mg/mbasis, respectively], have revealed no evidence of teratogenic effects. However, in rats, there was an increase in post-implantation losses in dams treated with mirtazapine. There was an increase in pup deaths during the first 3 days of lactation and a decrease in pup birth weights. The cause of these deaths is not known. The effects occurred at doses that were 20 times the MRHD, but not at 3 times the MRHD, on a mg/mbasis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.<br/>Nursing Mothers: It is not known whether mirtazapine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when REMERON' (mirtazapine) Tablets are administered to nursing women.<br/>Pediatric Use: Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS���Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 258 pediatric patients with MDD have been conducted with REMERON' (mirtazapine) Tablets, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of REMERON' in a child or adolescent must balance the potential risks with the clinical need. In an 8-week long pediatric clinical trial of doses between 15���45 mg/day, 49% of REMERON'-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients. The mean increase in weight was 4 kg (2 kg SD) for REMERON'-treated patients versus 1 kg (2 kg SD) for placebo-treated patients (see PRECAUTIONS���Increased Appetite/Weight Gain).<br/>Geriatric Use: Approximately 190 elderly individuals (���65 years of age) participated in clinical studies with REMERON' (mirtazapine) Tablets. This drug is known to be substantially excreted by the kidney (75%), and the risk of decreased clearance of this drug is greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Sedating drugs may cause confusion and over-sedation in the elderly. No unusual adverse age-related phenomena were identified in this group. Pharmacokinetic studies revealed a decreased clearance in the elderly. Caution is indicated in administering REMERON' to elderly patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). | lld:dailymed |
| dailymed-drugs:14 | dailymed-instance:precautio... | General: For dermatological use only; not for ophthalmic use. Concomitant topical acne therapy should be used with caution because a possible cumulative irritancy effect may occur, especially with the use of peeling, desquamating, or abrasive agents. The use of antibiotic agents may be associated with the overgrowth of nonsusceptible organisms including fungi. If this occurs, discontinue use of this medication and take appropriate measures. Avoid contact with eyes and mucous membranes. Clindamycin and erythromycin containing products should not be used in combination. In vitro studies have shown antagonism between these two antimicrobials. The clinical significance of this in vitro antagonism is not known.<br/>Information for Patients: Patients using BenzaClin Topical Gel should receive the following information and instructions:<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Benzoyl peroxide has been shown to be a tumor promoter and progression agent in a number of animal studies. The clinical significance of this is unknown. Benzoyl peroxide in acetone at doses of 5 and 10 mg administered twice per week induced skin tumors in transgenic Tg.AC mice in a study using 20 weeks of topical treatment. In a 52 week dermal photocarcinogenicity study in hairless mice, the median time to onset of skin tumor formation was decreased and the number of tumors per mouse increased following chronic concurrent topical administration of BenzaClin Topical Gel with exposure to ultraviolet radiation (40 weeks of treatment followed by 12 weeks ofobservation). In a 2-year dermal carcinogenicity study in rats, treatment with BenzaClin Topical Gel at doses of 100, 500, and 2000 mg/kg/day caused a dose-dependent increase in the incidence of keratoacanthoma at the treated skin site of male rats. The incidence of keratoacanthoma at the treated site of males treated with 2000 mg/kg/day (8 times the highest recommended adult dose of 2.5 g BenzaClin Topical Gel, based on mg/m2) was statistically significantly higher than that in the sham-and vehicle-controls. Genotoxicity studies were not conducted with BenzaClin Topical Gel. Clindamycin phosphate was not genotoxic in Salmonella typhimurium or in a rat micronucleus test. Clindamycin phosphate sulfoxide, an oxidative degradation product of clindamycin phosphate and benzoyl peroxide, was not clastogenic in a mouse micronucleus test. Benzoyl peroxide has been found to cause DNA strand breaks in a variety of mammalian cell types, to be mutagenic in S. typhimurium tests by some but not all investigators, and to cause sister chromatid exchanges in Chinese hamster ovary cells. Studies have not been performed with BenzaClin Topical Gel or benzoyl peroxide to evaluate the effect on fertility. Fertility studies in rats treated orally with up to 300 mg/kg/day of clindamycin (approximately 120 times the amount of clindamycin in the highest recommended adult human dose of 2.5 g BenzaClin Topical Gel, based on mg/m) revealed no effects on fertility or mating ability.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C Animal reproductive/developmental toxicity studies have not been conducted with BenzaClin Topical Gel or benzoyl peroxide. Developmental toxicity studies performed in rats and mice using oral doses of clindamycin up to 600 mg/kg/day (240 and 120 times amount of clindamycin in the highest recommended adult human dose based on mg/m, respectively) or subcutaneous doses of clindamycin up to 250 mg/kg/day (100 and 50 times the amount of clindamycin in the highest recommended adult human dose based on mg/m, respectively) revealed no evidence of teratogenicity. There are no well-controlled trials in pregnant women treated with BenzaClin Topical Gel. It also is not known whether BenzaClin Topical Gel can cause fetal harm when administered to a pregnant woman.<br/>Nursing Women: It is not known whether BenzaClin Topical Gel is excreted in human milk after topical application. However, orally and parenterally administered clindamycin has been reported to appear in breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness of this product in pediatric patients below the age of 12 have not been established. | lld:dailymed |
| dailymed-drugs:15 | dailymed-instance:precautio... | General: Penicillin should be used with caution in individuals with histories of significant allergies and/or asthma. Care should be taken to avoid intravenous or intra-arterial administration, or injection into or near major peripheral nerves or blood vessels, since such injection may produce neurovascular damage. Prolonged use of antibiotics may promote the overgrowth of nonsusceptible organisms, including fungi. Should superinfection occur, appropriate measures should be taken. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.<br/>Laboratory Tests: In streptococcal infections, therapy must be sufficient to eliminate the organism; otherwise, the sequelae of streptococcal disease may occur. Cultures should be taken following completion of treatment to determine whether streptococci have been eradicated.<br/>Drug Interactions: Tetracycline, a bacteriostatic antibiotic, may antagonize the bactericidal effect of penicillin, and concurrent use of these drugs should be avoided. Concurrent administration of penicillin and probenecid increases and prolongs serum penicillin levels by decreasing the apparent volume of distribution and slowing the rate of excretion by competitively inhibiting renal tubular secretion of penicillin.<br/>Pregnancy Category B: Reproduction studies performed in the mouse, rat, and rabbit have revealed no evidence of impaired fertility or harm to the fetus due to penicillin G. Human experience with the penicillins during pregnancy has not shown any positive evidence of adverse effects on the fetus. There are, however, no adequate and well-controlled studies in pregnant women showing conclusively that harmful effects of these drugs on the fetus can be excluded. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.<br/>Nursing Mothers: Soluble penicillin G is excreted in breast milk. Caution should be exercised when penicillin G benzathine is administered to a nursing woman.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term animal studies have been conducted with this drug.<br/>Pediatric Use:<br/>Geriatric Use: Clinical studies of penicillin G benzathine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function . Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, andit may be useful to monitor renal function. | lld:dailymed |
| dailymed-drugs:16 | dailymed-instance:precautio... | General: Do not connect flexible plastic containers of intravenous solutions in series connections. Such use could result in air embolism due to residual air being drawn from one container before administration of the fluid from a secondary container is completed. Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers. For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus.<br/>Laboratory Tests: Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation.<br/>Drug Interactions: Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP.<br/>Carcinogenesis and Mutagenesis and Impairment of Fertility: Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Labor and Delivery: Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother.<br/>Pediatric Use: Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. Dextrose is safe and effective for the stated indications in pediatric patients (see INDICATIONS AND USAGE). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants.<br/>Geriatric Use: Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in the responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. | lld:dailymed |
| dailymed-drugs:17 | dailymed-instance:precautio... | Amantadine Hydrochloride should not be discontinued abruptly in patients with Parkinson's disease since a few patients have experienced a parkinsonian crisis, i.e., a sudden marked clinical deterioration, when this medication was suddenly stopped. The dose of anticholinergic drugs or of Amantadine Hydrochloride should be reduced if atropine-like effects appear when these drugs are used concurrently. Abrupt discontinuation may also precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech.<br/>Neuroleptic Malignant Syndrome (NMS): Sporadic cases of possible Neuroleptic Malignant Syndrome (NMS) have been reported in association with dose reduction or withdrawal of Amantadine Hydrochloride therapy. Therefore, patients should be observed carefully when the dosage of Amantadine Hydrochloride is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics. NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia; neurologic findings including muscle rigidity, involuntary movements, altered consciousness; mental status changes; other disturbances such as autonomic dysfunction, tachycardia, tachypnea, hyper - or hypotension; laboratory findings such as creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin. The early diagnosis of this condition is important for the appropriate management of these patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic infection, etc.) is essential. This may be especially complex if the clinical presentation includes both serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include: 1) intense symptomatic treatment and medical monitoring, and 2) treatment of any concomitant serious medical problems for which specific treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene are often used in the treatment of NMS, however, their effectiveness has not been demonstrated in controlled studies.<br/>Renal Disease: Because Amantadine Hydrochloride is mainly excreted in the urine, it accumulates in the plasma and in the body when renal function declines. Thus, the dose of Amantadine Hydrochloride should be reduced in patients with renal impairment and in individuals who are 65 years of age or older .<br/>Liver Disease: Care should be exercised when administering Amantadine Hydrochloride to patients with liver disease. Rare instances of reversible elevation of liver enzymes have been reported in patients receiving Amantadine Hydrochloride, though a specific relationship between the drug and such changes has not been established.<br/>Other: The dose of Amantadine Hydrochloride may need careful adjustment in patients with congestive heart failure, peripheral edema, or orthostatic hypotension. Care should be exercised when administering Amantadine Hydrochloride to patients with a history of recurrent eczematoid rash, or to patients with psychosis or severe psychoneurosis not controlled by chemotherapeutic agents. Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. Amantadine Hydrochloride has not been shown to prevent such complications.<br/>Information for Patients: Patients should be advised of the following information: Blurry vision and/or impaired mental acuity may occur. Gradually increase physical activity as the symptoms of Parkinson's disease improve. Avoid excessive alcohol usage, since it may increase the potential for CNS effects such as dizziness, confusion, lightheadedness and orthostatic hypotension. Avoid getting up suddenly from a sitting or lying position. If dizziness or lightheadedness occurs, notify physician. Notify physician if mood/mental changes, swelling of extremities, difficulty urinating and/or shortness of breath occur. Do not take more medication than prescribed because of the risk of overdose. If there is no improvement in a few days, or if medication appears less effective after a few weeks, discuss with a physician. Consult physician before discontinuing medication. Seek medical attention immediately if it is suspected that an overdose of medication has been taken.<br/>Drug Interactions: Careful observation is required when Amantadine Hydrochloride is administered concurrently with central nervous system stimulants. Agents with anticholinergic properties may potentiate the anticholinergic-like side effects of amantadine. Coadministration of thioridazine has been reported to worsen the tremor in elderly patients with Parkinson's disease, however, it is not known if other phenothiazines produce a similar response. Coadministration of Dyazide (triamterene/hydrochlorothiazide) resulted in a higher plasma amantadine concentration in a 61-year-old man receiving Amantadine Hydrochloride 100 mg TID for Parkinson's disease.It is not known which of the components of Dyazide contributed to the observation or if related drugs produce a similar response. Coadministration of quinine or quinidine with amantadine was shown to reduce the renal clearance of amantadine by about 30%.<br/>Carcinogenesis and Mutagenesis: Long-term in vivo animals studies designed to evaluate the carcinogenic potential of Amantadine Hydrochloride have not been performed. In several in vitro assays for gene mutation, Amantadine Hydrochloride did not increase the number of spontaneously observed mutations in four strains of Salmonella typhimurium (Ames Test) or in a mammalian cell line (Chinese Hamster Ovary cells) when incubations were performed either with or without a liver metabolic activation extract. Further, there was no evidence of chromosome damage observed in an in vitro test using freshly derived and stimulated human peripheral blood lymphocytes (with and without metabolic activation) or in an in vivo mouse bone marrow micronucleus test (140-550 mg/kg; estimated human equivalent doses of 11.7-45.8 mg/kg based on body surface area conversion).<br/>Impairment of Fertility: The effect of amantadine on fertility has not been adequately tested, that is, in a study conducted under Good Laboratory Practices (GLP) and according to current recommended methodology. In a three litter, non-GLP, reproduction study in rats, Amantadine Hydrochloride at a dose of 32 mg/kg/day (equal to the maximum recommended human dose on a mg/mbasis) administered to both males and females slightly impaired fertility. There were no effects on fertility at a dose level of 10 mg/kg/day (or 0.3 times the maximum recommended human dose on a mg/mbasis); intermediate doses were not tested. Failed fertility has been reported during human in vitro fertilization (IVF) when the sperm donor ingested amantadine 2 weeks prior to, and during the IVF cycle.<br/>Pregnancy Category C: The effect of amantadine on embryofetal and peri-postnatal development has not been adequately tested, that is, in studies conducted under Good Laboratory Practice (GLP) and according to current recommended methodology. However, in two non-GLP studies in rats in which females were dosed from 5 days prior to mating to Day 6 of gestation or on Days 7-14 of gestation, Amantadine Hydrochloride produced increases in embryonic death at an oral dose of 100 mg/kg (or 3 times the maximum recommended human dose on a mg/mbasis). In the non-GLP rat study in which females were dosed on Days 7-14 of gestation, there was a marked increase in severe visceral and skeletal malformations at oral doses of 50 and 100 mg/kg (or 1.5 and 3 times, respectively, the maximum recommended human dose on a mg/mbasis). The no-effect dose for teratogenicity was 37 mg/kg (equal to the maximum recommended human dose on a mg/mbasis). The safety margins reported may not accurately reflect the risk considering the questionable quality of the study on which they are based. There are no adequate and well- controlled studies in pregnant women. Human data regarding teratogenicity after maternal use of amantadine is scarce. Tetralogy of Fallot and tibial hemimelia (normal karyotype) occurred in an infant exposed to amantadine during the first trimester of pregnancy (100 mg P.O. for 7 days during the 6th and 7th week of gestation). Cardiovascular maldevelopment (single ventricle with pulmonary atresia) was associated with maternal exposure to amantadine (100 mg/d) administered during the first 2 weeks of pregnancy. Amantadine Hydrochloride should be used during pregnancy only ifthe potential benefit justifies the potential risk to the embryo or fetus.<br/>Nursing Mothers: Amantadine Hydrochloride is excreted in human milk. Use is not recommended in nursing mothers.<br/>Pediatric Use: The safety and efficacy of Amantadine Hydrochloride in newborn infants and infants below the age of 1 year have not been established.<br/>Usage in the Elderly: Because Amantadine Hydrochloride is primarily excreted in the urine, it accumulates in the plasma and in the body when renal function declines. Thus, the dose of Amantadine Hydrochloride should be reduced in patients with renal impairment and in individuals who are 65 years of age or older. The dose of Amantadine Hydrochloride may need reduction in patients with congestive heart failure, peripheral edema, or orthostatic hypotension . | lld:dailymed |
| dailymed-drugs:18 | dailymed-instance:precautio... | General: Coronary Artery Disease: Dipyridamole has a vasodilatory effect and should be used with caution in patients with severe coronary artery disease (e.g., unstable angina or recently sustained myocardial infarction). Chest pain may be aggravated in patients with underlying coronary artery disease who are receiving dipyridamole. Hepatic Insufficiency: Elevations of hepatic enzymes and hepatic failure have been reported in association with dipyridamole administration. Hypotension: Dipyridamole should be used with caution in patients with hypotension since it can produce peripheral vasodilation.<br/>Laboratory Tests: Dipyridamole has been associated with elevated hepatic enzymes.<br/>Drug Interactions: No pharmacokinetic drug-drug interaction studies were conducted with dipyridamole USP Tablets. The following information was obtained from the literature. Adenosine: Dipyridamole has been reported to increase the plasma levels and cardiovascular effects of adenosine. Adjustment of adenosine dosage may be necessary. Cholinesterase Inhibitors: Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors, thereby potentially aggravating myasthenia gravis.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In studies in which dipyridamole was administered in the feed to mice (up to 111 weeks in males and females) and rats (up to 128 weeks in males and up to 142 weeks in females), there was no evidence of drug-related carcinogenesis. The highest dose administered in these studies (75 mg/kg/day) was, on a mg/mbasis, about equivalent to the maximum recommended daily human oral dose (MRHD) in mice and about twice the MRHD in rats. Mutagenicity tests of dipyridamole with bacterial and mammalian cell systems were negative. There was no evidence of impaired fertility when dipyridamole was administered to male and female rats at oral doses up to 500 mg/kg/day (about 12 times the MRHD on a mg/mbasis). A significant reduction in number of corpora lutea with consequent reduction in implantations and live fetuses was, however, observed at 1250 mg/kg (more than 30 times the MRHD on a mg/mbasis).<br/>Pregnancy: Teratogenic Effects: PREGNANCY CATEGORY BReproduction studies have been performed in mice, rabbits and rats at oral dipyridamole doses of up to 125 mg/kg, 40 mg/kg and 1000 mg/kg, respectively (about 1��, 2 and 25 times the maximum recommended daily human oral dose, respectively, on a mg/mbasis) and have revealed no evidence of harm to the fetus due to dipyridamole. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, dipyridamole USP should be used during pregnancy only if clearly needed.<br/>Nursing Mothers: As dipyridamole is excreted in human milk, caution should be exercised when dipyridamole USP tablets are administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in the pediatric population below the age of 12 years have not been established. | lld:dailymed |
| dailymed-drugs:19 | dailymed-instance:precautio... | General: Penicillin should be used with caution in individuals with histories of significant allergies and/or asthma. Care should be taken to avoid intravenous or intra-arterial administration, or injection into or near major peripheral nerves or blood vessels, since such injections may produce neurovascular damage. A small percentage of patients are sensitive to procaine. If there is a history of sensitivity, make the usual test: Inject intradermally 0.1 mL of a 1 to 2 percent procaine solution. Development of an erythema, wheal, flare, or eruption indicates procaine sensitivity. Sensitivity should be treated by the usual methods, including barbiturates, and procaine penicillin preparations should not be used. Antihistaminics appear beneficial in treatment of procaine reactions. The use of antibiotics may result in overgrowth of nonsusceptible organisms. Constant observation of the patient is essential. If new infections due to bacteria or fungi appear during therapy, the drug should be discontinued and appropriate measures taken. Whenever allergic reactions occur, penicillin should be withdrawn unless, in the opinion of the physician, the condition being treated is life-threatening and amenable only to penicillin therapy.<br/>Laboratory Tests: In suspected staphylococcal infections, proper laboratory studies, including susceptibility tests, should be performed. In prolonged therapy with penicillin, and particularly with high-dosage schedules, periodic evaluation of the renal and hematopoietic systems is recommended. In such situations, use of penicillin for more than 2 weeks may be associated with an increased risk of neutropenia and an increased incidence of serum sickness-like reactions. When treating gonococcal infections in which primary or secondary syphilis may be suspected, proper diagnostic procedures, including dark-field examinations, should be done. In all cases in which concomitant syphilis is suspected, monthly serological tests should be made for at least four months.<br/>Drug Interactions: Tetracycline, a bacteriostatic antibiotic, may antagonize the bactericidal effect of penicillin and concurrent use of these drugs should be avoided. Concurrent administration of penicillin and probenecid increases and prolongs serum penicillin levels by decreasing the apparent volume of distribution and slowing the rate of excretion by competitively inhibiting renal tubular secretion of penicillin.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term animal studies have been conducted with these drugs.<br/>Pregnancy: Teratogenic effects���Pregnancy Category B: Reproduction studies performed in the mouse, rat, and rabbit have revealed no evidence of impaired fertility or harm to the fetus due to penicillin G. Human experience with the penicillins during pregnancy has not shown any positive evidence of adverse effects on the fetus. There are, however, no adequate and well-controlled studies in pregnant women showing conclusively that harmful effects of these drugs on the fetus can be excluded. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.<br/>Nursing Mothers: Penicillins are excreted in human milk. Caution should be exercised when penicillins are administered to a nursing woman.<br/>Pediatric Use: Because of incompletely developed renal function in newborns, penicillin elimination may be delayed. Guidelines for administration of this drug to pediatric patients are presented in DOSAGE AND ADMINISTRATION. | lld:dailymed |
| dailymed-drugs:20 | dailymed-instance:precautio... | General:<br/>Impaired renal function:: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including quinapril hydrochloride, may be associated with oliguria and/or progressive azotemia and rarely acute renal failure and/or death. In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy. Some patients with hypertension or heart failure with no apparent preexisting renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when quinapril hydrochloride has been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting renal impairment. Dosage reduction and/or discontinuation of any diuretic and/or quinapril hydrochloride may be required. Evaluation of patients should always include assessment of renal function (see DOSAGE AND ADMINISTRATION).<br/>Hyperkalemia and potassium-sparing diuretics:: In clinical trials, hyperkalemia (serum potassium���5.8 mmol/L) occurred in approximately 2% of patients receiving quinapril hydrochloride. In most cases, elevated serum potassium levels were isolated values which resolved despite continued therapy. Less than 0.1% of patients discontinued therapy due to hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with quinapril hydrochloride (see PRECAUTIONS, Drug Interactions).<br/>Cough:: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent non-productive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.<br/>Surgery/anesthesia:: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, quinapril hydrochloride will block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.<br/>Information for patients:<br/>Pregnancy:: Female patients of childbearing age should be told about the consequences of second-and third-trimester exposure to ACE inhibitors, and they should also be told that these consequences do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.<br/>Angioedema:: Angioedema, including laryngeal edema can occur with treatment with ACE inhibitors, especially following the first dose. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to stop taking the drug until they have consulted with their physician (see WARNINGS).<br/>Symptomatic hypotension:: Patients should be cautioned that lightheadedness can occur, especially during the first few days of quinapril hydrochloride therapy, and that it should be reported to a physician. If actual syncope occurs, patients should be told to not take the drug until they have consulted with their physician (see WARNINGS). All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure because of reduction in fluid volume, with the same consequences of lightheadedness and possible syncope. Patients planning to undergo any surgery and/or anesthesia should be told to inform their physician that they are taking an ACE inhibitor.<br/>Hyperkalemia:: Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting their physician (see PRECAUTIONS).<br/>Neutropenia:: Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which could be a sign of neutropenia. NOTE: As with many other drugs, certain advice to patients being treated with quinapril hydrochloride is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.<br/>Drug interactions:<br/>Concomitant diuretic therapy:: As with other ACE inhibitors, patients on diuretics, especially those on recently instituted diuretic therapy, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with quinapril hydrochloride. The possibility of hypotensive effects with quinapril hydrochloride may be minimized by either discontinuing the diuretic or cautiously increasing salt intake priorto initiation of treatment with quinapril hydrochloride. If it is not possible to discontinue the diuretic, the starting dose of quinapril should be reduced (see DOSAGE AND ADMINISTRATION).<br/>Agents increasing serum potassium:: Quinapril can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone. If concomitant therapy of quinapril hydrochloride with potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes is indicated, they should be used with caution along with appropriate monitoring of serum potassium (see PRECAUTIONS).<br/>Tetracycline and other drugs that interact with magnesium:: Simultaneous administration of tetracycline with quinapril hydrochloride reduced the absorption of tetracycline by approximately 28% to 37%, possibly due to the high magnesium content in quinapril tablets. This interaction should be considered if coprescribing quinapril hydrochloride and tetracycline or other drugs that interact with magnesium.<br/>Lithium:: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, it may increase the risk of lithium toxicity.<br/>Other agents:: Drug interaction studies of quinapril hydrochloride with other agents showed:<br/>Carcinogenesis, mutagenesis, impairment of fertility: Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or 100 mg/kg/day (50 to 60 times the maximum human daily dose, respectively, on an mg/kg basis and 3.8 to 10 times the maximum human daily dose when based on an mg/mbasis) for 104 weeks. Female rats given the highest dose level had an increased incidence of mesenteric lymph node hemangiomas and skin/subcutaneous lipomas. Neither quinapril nor quinaprilat were mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also negative in the following genetic toxicology studies: in vitro mammalian cell point mutation, sister chromatid exchange in cultured mammalian cells, micronucleus test with mice, in vitro chromosome aberration with V79 cultured lung cells, and in an in vivo cytogenetic study with rat bone marrow. There were no adverse effects on fertility or reproduction in rats at doses up to 100 mg/kg/day (60 and 10 times the maximum daily human dose when based on mg/kg and mg/m, respectively).<br/>Pregnancy: Pregnancy Categories C (first trimester) and D (second and third trimesters): See WARNINGS, Fetal/Neonatal Morbidity and Mortality.<br/>Nursing mothers: Because quinapril hydrochloride is secreted in human milk, caution should be exercised when this drug is administered to a nursing woman.<br/>Pediatric use: The safety and effectiveness of quinapril hydrochloride in pediatric patients have not been established.<br/>Geriatric use: Clinical studies of quinapril did not include sufficient numbers of subjects ages 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Elderly patients exhibited increased area under the plasma concentration time curve and peak levels for quinaprilat compared to values observed in younger patients; this appeared to relate to decreased renal function rather than to age itself. | lld:dailymed |
| dailymed-drugs:21 | dailymed-instance:precautio... | General: Aphakic Patients: Macular edema has been shown to occur in up to 30% of aphakic patients treated with epinephrine. Discontinuation of epinephrine generally results in reversal of the maculopathy.<br/>Information for patients: To avoid contamination, do not touch tip of container to the eye, eyelid, or any surface.<br/>Pregnancy: Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at daily oral doses up to 10 mg/kg body weight (5 mg/kg in teratogenicity studies), and have revealed no evidence of impaired fertility or harm to the fetus due to dipivefrin. There are, however, no adequate and well-controlled studies in pregnant women. Because animalreproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when dipivefrin hydrochloride is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.<br/>Animal Studies: Rabbit studies indicated a dose-related incidence of meibomiam gland retention cysts following topical administration of both dipivefrin and epinephrine. | lld:dailymed |
| dailymed-drugs:22 | dailymed-instance:precautio... | General: Extraordinary electrolytes losses such as may occur during protracted nasogastric suction, vomiting, diarrhea or gastrointestinal fistula drainage may necessitate additional electrolyte supplementation. Sodium-containing solutions should be administered with caution to patients receiving corticosteroids or corticotropin, or to other salt-retaining patients. Potassium therapy should be guided primarily by serial electrocardiograms, especially in patients receiving digitalis. Serum potassium levels are not necessarily indicative of tissue potassium levels. Care should be exercised in administering solutions containing sodium or potassium to patients with renal or cardiovascular insufficiency, with or without congestive heart failure, particularly if they are postoperative or elderly. Solutions containing potassium or calcium should be used with caution in the presence of cardiac disease, particularly in the presence of renal disease. Parenteral calcium should be administered with extreme caution to patients receiving digitalis preparations. To minimize the risk of possible incompatibilities arising from mixing this solution with other additives that may be prescribed, the final infusate should be inspected for cloudiness or precipitation immediately after mixing, prior to administration, and periodically during administration. Do not use plastic container in series connection. If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result. This solution is intended for intravenous administration using sterile equipment. It is recommended that intravenous administration apparatus be replaced at least once every 24 hours. Use only if solution is clear and container and seals are intact.<br/>Laboratory Tests: Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid-base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Significant deviations from normal concentrations may require the use of additional electrolyte supplements, or the use of electrolyte-free dextrose solutions to which individualized electrolyte supplements may be added.<br/>Drug Interactions: Some additives may be incompatible. Consult with pharmacist. When introducing additives, use aseptic techniques. Mix thoroughly. Do not store.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with Ringer's Injection USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Labor and Delivery: As reported in the literature, Ringer's Injection USP has been administered during labor and delivery. Caution should be exercised, and the fluid balance, glucose and electrolyte concentrations, and acid-base balance, of both mother and fetus should be evaluated periodically or whenever warranted by the condition of the patient or fetus.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Ringer's Injection USP is administered to a nursing mother.<br/>Pediatric Use: Safety and effectiveness of Ringer's Injection USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The warnings, precautions, and adverse reactions identified in the label copy should be observed in the pediatric population.<br/>Geriatric Use: Clinical studies of Ringer's Injection USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:23 | dailymed-instance:precautio... | 1. SEXUALLY TRANSMITTED DISEASES Women should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.<br/>2. PHYSICAL EXAMINATION AND FOLLOW-UP: It is routine medical practice for women using NuvaRing', as for all women, to have an annual medical evaluation including physical examination and relevant laboratory tests. The physical examination should include special reference to blood pressure, breasts, abdomen, pelvic organs and vagina (including cervical cytology). In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a family history of breast cancer or who have breast nodules should be monitored with particular care.<br/>3. LIPID DISORDERS: Women who are being treated for hyperlipidemias should be followed closely if they elect to use NuvaRing'. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. In women with familial defects of lipoprotein metabolism receiving estrogen-containing preparations, there have been case reports of significant elevations of plasma triglycerides leading to pancreatitis.<br/>4. LIVER FUNCTION: If jaundice develops in any woman using NuvaRing', product use should be discontinued. The hormones in NuvaRing' may be poorly metabolized in women with impaired liver function.<br/>5. FLUID RETENTION: Steroid hormones like those in NuvaRing', may cause some degree of fluid retention. NuvaRing' should be prescribed with caution, and only with careful monitoring, in women with conditions which might be aggravated by fluid retention.<br/>6. EMOTIONAL DISORDERS: Women becoming significantly depressed while taking hormonal contraceptives should stop the medication and use an alternate method of contraception in an attempt to determine whether the symptom is drug related. Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.<br/>7. TAMPON USE: On rare occasions, NuvaRing' may be expelled while removing a tampon . Pharmacokinetic data show that the use of tampons has no effect on the systemic absorption of the hormones released by NuvaRing'.<br/>8. TOXIC SHOCK SYNDROME (TSS): Cases of toxic shock syndrome have been associated with tampons and certain barrier contraceptives. Very rare cases of TSS have been reported by NuvaRing' users; in some cases the women were also using tampons. No causal relationship between the use of NuvaRing' and TSS has been established. If a patient exhibits signs or symptoms of TSS, the possibility of this diagnosis should not be excluded and appropriate medical evaluation and treatment initiated.<br/>9. CONTACT LENSES: Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.<br/>10. DRUG INTERACTIONS:<br/>Changes in contraceptive effectiveness associated with co-administration of other drugs:: a. Anti-infective agents and anticonvulsants Contraceptive effectiveness may be reduced when hormonal contraceptives are co-administered with some antifungals, anticonvulsants, and other drugs that increase metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include barbiturates, griseofulvin,rifampin, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, and modafinil. Women may need to use an additional contraceptive method when taking such medications. b. Anti-HIV protease inhibitors Several of the anti-HIV protease inhibitors have been studied with co-administration of oral combination hormonal contraceptives; significant changes (increases and decreases) in the plasma levels of the estrogen and progestin have been noted in some cases. The efficacy and safety of hormonal contraceptive products may be affected with co-administration of anti-HIV protease inhibitors. Healthcare providers should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information. c. Herbal products Herbal products containing St. John's Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding.<br/>Increase in plasma hormone levels associated with co-administered drugs:: Co-administration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP 3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels. Co-administration of vaginal miconazole nitrate and NuvaRing' increases the serum concentrations of etonogestrel and ethinyl estradiol by up to 40%.<br/>Changes in plasma levels of co-administered drugs:: Combination hormonal contraceptives containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. In addition, oral contraceptives may induce the conjugation of other compounds. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine and clofibric acid have been noted when these drugs were administered with oral contraceptives.<br/>11. INTERACTIONS WITH LABORATORY TESTS: Certain endocrine and liver function tests and blood components may be affected by combined hormonal contraceptives:<br/>12. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: In a 24-month carcinogenicity study in rats with subdermal implants releasing 10 and 20��g etonogestrel per day, (approximately 0.3 and 0.6 times the systemic steady-state exposure of women using NuvaRing'), no drug-related carcinogenic potential was observed. Etonogestrel was not genotoxic in the in vitro Ames/Salmonella reverse mutation assay, the chromosomal aberration assay in Chinese hamster ovary cells or in the in vivo mouse micronucleus test. Fertility returned after withdrawal from treatment (see WARNINGS).<br/>13. PREGNANCY: Pregnancy Category X . Teratology studies have been performed in rats and rabbits using the oral route of administration at doses up to 130 and 260 times, respectively, the human NuvaRing' dose (based on body surface area) and have revealed no evidence of harm to the fetus due to etonogestrel.<br/>14. NURSING MOTHERS: The effects of NuvaRing' in nursing mothers have not been evaluated and are unknown. Small amounts of contraceptive steroids have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, contraceptive steroids given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. Long-term follow-up of children whose mothers used combination hormonal contraceptives while breast-feeding has shown no deleterious effects on infants. However, women who are breast-feeding should be advised not to use NuvaRing' but to use other forms of contraception until the child is weaned.<br/>15. PEDIATRIC USE: Safety and efficacy of NuvaRing' have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.<br/>16. GERIATRIC USE: This product has not been studied in women over 65 years of age and is not indicated in this population.<br/>17. VAGINAL USE: NuvaRing' may not be suitable for women with conditions that make the vagina more susceptible to vaginal irritation or ulceration. Vaginal/cervical erosion or ulceration in women using NuvaRing' has been rarely reported. In some cases, the ring adhered to vaginal tissue, necessitating removal by a healthcare provider. Some women are aware of the ring at random times during the 21 days of use or during intercourse. During intercourse some sexual partners may feel NuvaRing' in the vagina. However, clinical studies revealed that 90% of couples did not find this to be a problem. NuvaRing' may interfere with the correct placement and position of a diaphragm. A diaphragm is therefore not recommended as a back-up method with NuvaRing' use.<br/>18. URINARY BLADDER INSERTION: There have been rare reports of inadvertent insertions of NuvaRing' into the urinary bladder, which required cystoscopic removal. Healthcare providers should assess for ring insertion into the urinary bladder in NuvaRing' users who present with persistent urinary symptoms and are unable to locate the ring.<br/>19. EXPULSION: NuvaRing' can be accidentally expelled, for example, while removing a tampon, during intercourse, or with straining during a bowel movement. NuvaRing' should be left in the vagina for a continuous period of three weeks. If the ring is accidentally expelled and is left outside of the vagina for less than three hours contraceptive efficacy is not reduced. NuvaRing' can be rinsed with cool to lukewarm (not hot) water and reinserted as soon as possible, but at the latest within three hours. If NuvaRing' is lost, a new vaginal ring should be inserted and the regimen should be continued without alteration. If NuvaRing' is out of the vagina for more than three continuous hours: During Weeks 1 and 2: If NuvaRing' has been out of the vagina for more than three continuous hours during the 1st or 2nd week of use, contraceptive efficacy may be reduced. The woman should reinsert the ring as soon as she remembers. A barrier method such as condoms or spermicides must be used until the ring has been used continuously for seven days. During Week 3: If NuvaRing' has been out of the vagina for more than three continuous hours during the 3rd week of the three-week use period, the woman should discard that ring. One of the following two options should be chosen: A barrier method such as condoms or spermicides must be used until the new ring has been used continuously for seven days.<br/>20. DISCONNECTED RING: There have been reported cases of NuvaRing' disconnecting at the weld joint. This is not expected to affect the contraceptive effectiveness of NuvaRing'. In the event of a disconnected ring, vaginal discomfort or expulsion (slipping out) is more likely to occur . If a woman discovers that her NuvaRing' has disconnected, she should discard the ring and replace it with a new ring. | lld:dailymed |
| dailymed-drugs:24 | dailymed-instance:precautio... | Should a reaction of hypersensitivity occur the drug should be immediately withdrawn and appropriate measures taken. This preparation is not for ophthalmic use. | lld:dailymed |
| dailymed-drugs:2598 | dailymed-instance:precautio... | Should a reaction of hypersensitivity occur the drug should be immediately withdrawn and appropriate measures taken. This preparation is not for ophthalmic use. | lld:dailymed |
| dailymed-drugs:25 | dailymed-instance:precautio... | General: The possibility of suicide is inherent in any severely depressed patient and persists until a significant remission occurs. When a patient with a serious suicidal potential is not hospitalized, the prescription should be for the smallest amount feasible. In schizophrenic patients activation of the psychosis may occur and require reduction of dosage or the addition of a major tranquilizer to the therapeutic regime. Manic or hypomanic episodes may occur in some patients, in particular those with cyclic-type disorders. In some cases therapy with Surmontil must be discontinued until the episode is relieved, after which therapy may be reinstituted at lower dosages if still required. Concurrent administration of Surmontil and electroshock therapy may increase the hazards of therapy. Such treatment should be limited to those patients for whom it is essential. When possible, discontinue the drug for several days prior to elective surgery. Surmontil should be used with caution in patients with impaired liver function. Chronic animal studies showed occasional occurrence of hepatic congestion, fatty infiltration, or increased serum liver enzymes at the highest dose of 60 mg/kg/day. Both elevation and lowering of blood sugar have been reported with tricyclic antidepressants.<br/>Information for Patients: Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Surmontil and should counsel them in its appropriate use. A patient Medication Guide about���Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions���is available for Surmontil. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Surmontil. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need forvery close monitoring and possibly changes in the medication.<br/>Drug Interactions:<br/>Cimetidine: There is evidence that cimetidine inhibits the elimination of tricyclic antidepressants. Downward adjustment of Surmontil dosage may be required if cimetidine therapy is initiated; upward adjustment if cimetidine therapy is discontinued.<br/>Alcohol: Patients should be warned that the concomitant use of alcoholic beverages may be associated with exaggerated effects.<br/>Catecholamines/Anticholinergics: It has been reported that tricyclic antidepressants can potentiate the effects of catecholamines. Similarly, atropinelike effects may be more pronounced in patients receiving anticholinergic therapy. Therefore, particular care should be exercised when it is necessary to administer tricyclic antidepressants with sympathomimetic amines, local decongestants, local anesthetics containing epinephrine, atropine or drugs with an anticholinergic effect. In resistant cases of depression in adults, a dose of 2.5 mg/kg/day may have to be exceeded. If a higher dose is needed, ECG monitoring should be maintained during the initiation of therapy and at appropriate intervals during stabilization of dose.<br/>Drugs Metabolized by P450 2D6: The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7-10% of caucasians are so called���poor metabolizers���); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of the isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selectiveserotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Semen studies in man (four schizophrenics and nine normal volunteers) revealed no significant changes in sperm morphology. It is recognized that drugs having a parasympathetic effect, including tricyclic antidepressants, may alter the ejaculatory response. Chronic animal studies showed occasional evidence of degeneration of seminiferous tubules at the highest dose of 60 mg/kg/day.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C Surmontil has shown evidence of embryotoxicity and/or increased incidence of major anomalies in rats or rabbits at doses 20 times the human dose. There are no adequate and well-controlled studies in pregnant women. Surmontil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Pediatric Use: Safety and effectiveness in the pediatric population have not been established . Anyone considering the use of Surmontil in a child or adolescent must balance the potential risks with the clinical need.<br/>Geriatric Use: Clinical studies of Surmontil (trimipramine maleate) were not adequate to determine whether subjects aged 65 and over respond differently from younger subjects. The pharmacokinetics of trimipramine were not substantially altered in the elderly . Surmontil is known to be substantially excreted by the kidney. Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered . Greater sensitivity (e.g., confusional states, sedation) of some older individuals cannot be ruled out . In general, dose selection for an elderly patient should be cautious, usually starting at a lower dose . | lld:dailymed |
| dailymed-drugs:27 | dailymed-instance:precautio... | General:<br/>Activation of Mania/Hypomania:<br/>Weight Loss:<br/>Seizure:<br/>Discontinuation of Treatment with Sertraline Hydrochloride:<br/>Abnormal Bleeding: SSRIs and SNRIs, including sertraline hydrochloride, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of sertraline hydrochloride and NSAIDs, aspirin, or other drugs that affect coagulation.<br/>Weak Uricosuric Effect:<br/>Use in Patients with Concomitant Illness:<br/>Interference with Cognitive and Motor Performance:<br/>Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including sertraline hydrochloride. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see Geriatric Use). Discontinuation of sertraline hydrochloride should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.<br/>Platelet Function:<br/>Information for Patients: Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with sertraline hydrochloride and should counsel them in its appropriate use. A patient Medication Guide About���Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions���is available for sertraline hydrochloride oral concentrate. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking sertraline hydrochloride.<br/>Clinical Worsening and Suicide Risk:<br/>Laboratory Tests:<br/>Drug Interactions:<br/>Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins: Because sertraline is tightly bound to plasma protein, the administration of sertraline hydrochloride to a patient taking another drug which is tightly bound to protein (e.g., warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein bound sertraline hydrochloride by other tightly bound drugs.In a study comparing prothrombin time AUC (0 to 120 hr) following dosing with warfarin (0.75 mg/kg) before and after 21 days of dosing with either sertraline hydrochloride (50 to 200 mg/day) or placebo, there was a mean increase in prothrombin time of 8% relative to baseline for sertraline hydrochloride compared to a 1% decrease for placebo (p<0.02). The normalization of prothrombin time for the sertraline hydrochloride group was delayed compared to the placebo group. The clinical significance of this change is unknown. Accordingly, prothrombin time should be carefully monitored when sertraline hydrochloride therapy is initiated or stopped.<br/>Monoamine Oxidase Inhibitors:<br/>Drugs Metabolized by P450 3A4:<br/>Drugs Metabolized by P450 2D6:<br/>Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs, including sertraline hydrochloride, and the potential for serotonin syndrome, caution is advised when SNRIs and SSRIs, including sertraline hydrochloride, are coadministered with other drugs that may affect the serotonergic neutrotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John's Wort . The concomitant use of sertraline hydrochloride with other SSRIs, SNRIs or tryptophan is not recommended .<br/>Triptans: There have been rare post marketing reports of serotonin syndrome with use of an SNRI or an SSRI and a triptan. If concomitant treatment of SNRIs and SSRIs, including sertraline hydrochloride, with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases .<br/>Sumatriptan:<br/>Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder (TCAs):<br/>Hypoglycemic Drugs:<br/>Atenolol:<br/>Digoxin:<br/>Microsomal Enzyme Induction:<br/>Drugs That Interfere With Hemostasis (Non-selective NSAIDs, Aspirin, Warfarin, etc.):<br/>Electroconvulsive Therapy:<br/>Alcohol:<br/>Carcinogenesis:<br/>Mutagenesis:<br/>Impairment of Fertility:<br/>Pregnancy:<br/>Pregnancy-Nonteratogenic Effects:<br/>Labor and Delivery:<br/>Nursing Mothers:<br/>Pediatric Use:<br/>Geriatric Use: SSRIs and SNRIs, including sertraline hydrochloride, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event . | lld:dailymed |
| dailymed-drugs:28 | dailymed-instance:precautio... | 14.6% Sodium Chloride Injection, USP Additive Solution must be diluted before infusion to avoid a sudden increase in the level of plasma sodium. Too rapid administration should be avoided. Special caution should be used in administering sodium containing solutions to patients with severe renal impairment, cirrhosis of the liver, cardiac failure, or other edematous or sodium-retaining states. Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid-base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Caution must be exercised in the administration of parenteral fluids, especially those containing sodium ions, to patients receiving corticosteroids or corticotropin. Do not use unless the solution is clear and seal is intact. Discard unused portion.<br/>Pregnancy Category C.: Animal reproduction studies have not been conducted with sodium chloride. It is also not known whether sodium chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium chloride should be given to a pregnant woman only if clearly needed.<br/>Geriatric Use: An evaluation of current literature revealed no clinical experience identifying differences in response between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.<br/>Pediatric Use: The safety and effectiveness of 14.6% Sodium Chloride Injection, USP Additive Solution have not been established. Its limited use in pediatric patients has been inadequate to fully define proper dosage and limitations for use. | lld:dailymed |
| dailymed-drugs:29 | dailymed-instance:precautio... | General���Propoxyphene should be administered with caution to patients with hepatic or renal impairment since higher serum concentrations or delayed elimination may occur. Drug Interactions���The CNS-depressant effect of propoxyphene is additive with that of other CNS depressants, including alcohol. As is the case with many medicinal agents, propoxyphene may slow the metabolism of a concomitantly administered drug. Should this occur, the higher serum concentrations of that drug may result in increased pharmacologic or adverse effects of that drug. Such occurrences have been reported when propoxyphene was administered to patients on antidepressants, anticonvulsants, or warfarin-like drugs. Severe neurologic signs, including coma, have occurred with concurrent use of carbamazepine. Usage in Pregnancy���Safe use in pregnancy has not been established relative to possible adverse effects on fetal development. Instances of withdrawal symptoms in the neonate have been reported following usage during pregnancy. Therefore, propoxyphene should not be used in pregnant women unless, in the judgment of the physician, the potential benefits outweigh the possible hazards. Usage in Nursing Mothers���Low levels of propoxyphene have been detected in human milk. In postpartum studies involving nursing mothers who were given propoxyphene, no adverse effects were noted in infants receiving mother's milk. Usage in Pediatric Patients���Safety and effectiveness in pediatric patients have not been established. Usage in the Elderly���The rate of propoxyphene metabolism may be reduced in some patients. Increased dosing interval should be considered. A Patient Information Sheet is available for this product. See text following���How Supplied���section below. | lld:dailymed |
| dailymed-drugs:2140 | dailymed-instance:precautio... | General���Propoxyphene should be administered with caution to patients with hepatic or renal impairment since higher serum concentrations or delayed elimination may occur. Drug Interactions���The CNS-depressant effect of propoxyphene is additive with that of other CNS depressants, including alcohol. As is the case with many medicinal agents, propoxyphene may slow the metabolism of a concomitantly administered drug. Should this occur, the higher serum concentrations of that drug may result in increased pharmacologic or adverse effects of that drug. Such occurrences have been reported when propoxyphene was administered to patients on antidepressants, anticonvulsants, or warfarin-like drugs. Severe neurologic signs, including coma, have occurred with concurrent use of carbamazepine. Usage in Pregnancy���Safe use in pregnancy has not been established relative to possible adverse effects on fetal development. Instances of withdrawal symptoms in the neonate have been reported following usage during pregnancy. Therefore, propoxyphene should not be used in pregnant women unless, in the judgment of the physician, the potential benefits outweigh the possible hazards. Usage in Nursing Mothers���Low levels of propoxyphene have been detected in human milk. In postpartum studies involving nursing mothers who were given propoxyphene, no adverse effects were noted in infants receiving mother's milk. Usage in Pediatric Patients���Safety and effectiveness in pediatric patients have not been established. Usage in the Elderly���The rate of propoxyphene metabolism may be reduced in some patients. Increased dosing interval should be considered. A Patient Information Sheet is available for this product. See text following���How Supplied���section below. | lld:dailymed |
| dailymed-drugs:30 | dailymed-instance:precautio... | General: PLAVIX prolongs the bleeding time and therefore should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other pathological conditions (particularly gastrointestinal and intraocular). If a patient is to undergo elective surgery and an antiplatelet effect is not desired, PLAVIX should be discontinued 5 days prior to surgery. Due to the risk of bleeding and undesirable hematological effects, blood cell count determination and/or other appropriate testing should be promptly considered, whenever such suspected clinical symptoms arise during the course of treatment . In patients with recent TIA or stroke who are at high risk of recurrent ischemic events, the combination of aspirin and PLAVIX has not been shown to be more effective than PLAVIX alone, but the combination has been shown to increase major bleeding.<br/>GI Bleeding:: In CAPRIE, PLAVIX was associated with a rate of gastrointestinal bleeding of 2.0%, vs. 2.7% on aspirin. In CURE, the incidence of major gastrointestinal bleeding was 1.3% vs 0.7% (PLAVIX + aspirin vs. placebo + aspirin, respectively). PLAVIX should be used with caution in patients who have lesions with a propensity to bleed (such as ulcers). Drugs that might induce such lesions should be used with caution in patients taking PLAVIX.<br/>Use in Hepatically Impaired Patients:: Experience is limited in patients with severe hepatic disease, who may have bleeding diatheses. PLAVIX should be used with caution in this population.<br/>Use in Renally-impaired Patients:: Experience is limited in patients with severe renal impairment. PLAVIX should be used with caution in this population.<br/>Information For Patients: Patients should be told that it may take them longer than usual to stop bleeding, that they may bruise and/or bleed more easily when they take PLAVIX or PLAVIX combined with aspirin, and that they should report any unusual bleeding to their physician. Patients should inform physicians and dentists that they are taking PLAVIX and/or any other product known to affect bleeding before any surgery is scheduled and before any new drug is taken.<br/>Drug Interactions: Study of specific drug interactions yielded the following results:<br/>Aspirin:: Aspirin did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation. Concomitant administration of 500 mg of aspirin twice a day for 1 day did not significantly increase the prolongation of bleeding time induced by PLAVIX. PLAVIX potentiated the effect of aspirin on collagen-induced platelet aggregation. PLAVIX and aspirin have been administered together for up to one year.<br/>Heparin:: In a study in healthy volunteers, PLAVIX did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Coadministration of heparin had no effect on inhibition of platelet aggregation induced by PLAVIX.<br/>Nonsteroidal Anti-Inflammatory Drugs (NSAIDs):: In healthy volunteers receiving naproxen, concomitant administration of PLAVIX was associated with increased occult gastrointestinal blood loss. NSAIDs and PLAVIX should be coadministered with caution.<br/>Warfarin:: Because of the increased risk of bleeding, the concomitant administration of warfarin with PLAVIX should be undertaken with caution.<br/>Other Concomitant Therapy:: No clinically significant pharmacodynamic interactions were observed when PLAVIX was coadministered with atenolol, nifedipine, or both atenolol and nifedipine. The pharmacodynamic activity of PLAVIX was also not significantly influenced by the coadministration of phenobarbital, cimetidine or estrogen. The pharmacokinetics of digoxin or theophylline were not modified by the coadministration of PLAVIX (clopidogrel bisulfate). At high concentrations in vitro, clopidogrel inhibits P(2C9). Accordingly, PLAVIX may interfere with the metabolism of phenytoin, tamoxifen, tolbutamide, warfarin, torsemide, fluvastatin, and many non-steroidal anti-inflammatory agents, but there are no data with which to predict the magnitude of these interactions. Caution should be used when any of these drugs is coadministered with PLAVIX. In addition to the above specific interaction studies, patients entered into clinical trials with PLAVIX received a variety of concomitant medications including diuretics, beta-blocking agents, angiotensin converting enzyme inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), thrombolytics, heparins (unfractionated and LMWH), GPIIb/IIIa antagonists, antiepileptic agents and hormone replacement therapy without evidence of clinically significant adverse interactions. There are no data on the concomitant use of oral anticoagulants, non study oral anti-platelet drugs and chronic NSAIDs with clopidogrel.<br/>Drug/Laboratory Test Interactions: None known.<br/>Carcinogenesis, Mutagenesis, Impairment Of Fertility: There was no evidence of tumorigenicity when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats at dosages up to 77 mg/kg per day, which afforded plasma exposures>25 times that in humans at the recommended daily dose of 75 mg. Clopidogrel was not genotoxic in four in vitro tests (Ames test, DNA-repair test in rat hepatocytes, gene mutation assay in Chinese hamster fibroblasts, and metaphase chromosome analysis of human lymphocytes) and in one in vivo test (micronucleus test by oral route in mice). Clopidogrel was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg per day (52 times the recommended human dose on a mg/mbasis).<br/>Pregnancy: Pregnancy Category B. Reproduction studies performed in rats and rabbits at doses up to 500 and 300 mg/kg/day (respectively, 65 and 78 times the recommended daily human dose on a mg/mbasis), revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, PLAVIX should be used during pregnancy only if clearly needed.<br/>Nursing Mothers: Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be madewhether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the nursing woman.<br/>Pediatric Use: Safety and effectiveness in the pediatric population have not been established.<br/>Geriatric Use: Of the total number of subjects in the CAPRIE, CURE and CLARITY controlled clinical studies, approximately 50% of patients treated with PLAVIX were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with PLAVIX were 60 years and older, 26% of whom were 70 years and older. The observed risk of thrombotic events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Figures 3 and 6 for the CURE and COMMIT trials, respectively . The observed risk of bleeding events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Tables 5 and 6 for the CURE and COMMIT trials, respectively . | lld:dailymed |
| dailymed-drugs:31 | dailymed-instance:precautio... | General: Nyamyc���(Nystatin Topical Powder, USP) should not be used for the treatment of systemic, oral, intravaginal or ophthalmic infections. If irritation or sensitization develops, treatment should be discontinued and appropriate measures taken as indicated. It is recommended that KOH smears, cultures, or other diagnostic methods be used to confirm the diagnosis of cutaneous or mucocutaneous candidiasis and to rule out infection caused by other pathogens. | lld:dailymed |
| dailymed-drugs:32 | dailymed-instance:precautio... | Amiodarone hydrochloride injection should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment.<br/>Liver Enzyme Elevations: Elevations of blood hepatic enzyme values-alanine aminotransferase (ALT), aspartate amino���transferase (AST), and gamma-glutamyl transferase (GGT)-are seen commonly in patients with immediately life-threatening VT/VF. Interpreting elevated AST activity can be difficult because the values may be elevated in patients who have had recent myocardial infarction, congestive heart failure, or multiple electrical defibrillations. Approximately 54% of patients receiving amiodarone in clinical studies had baseline liver enzyme elevations, and 13% had clinically significant elevations. In 81% of patients with both baseline and on-therapy data available, the liver enzyme elevations either improved during therapy or remained at baseline levels. Baseline abnormalities in hepatic enzymes are not a contraindication to treatment. Rare cases of fatal hepatocellular necrosis after treatment with amiodarone have been reported. Two patients, one 28 years of age and the other 60 years of age, were treated for atrial arrhythmias with an initial infusion of 1500 mg over 5 hours, a rate much higher than recommended. Both patients developed hepatic and renal failure within 24 hours after the start of amiodarone treatment and died on day 14 and day 4, respectively. Because these episodes of hepatic necrosis may have been due to the rapid rate of infusion with possible rate-related hypotension, the initial rate of infusion should be monitored closely and should not exceed that prescribed in DOSAGE AND ADMINISTRATION. In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of amiodarone therapy, but patients receiving amiodarone should be monitored carefully for evidence of progressive hepatic injury. Consideration should be given to reducing the rate of administration or withdrawing amiodarone in such cases.<br/>Proarrhythmia: Like all antiarrhythmic agents, amiodarone may cause a worsening of existing arrhythmias or precipitate a new arrhythmia. Proarrhythmia, primarily torsades de pointes (TdP), has been associated with prolongation by amiodarone of the QTc interval to 500 ms or greater. Although QTc prolongation occurred frequently in patients receiving amiodarone, torsades de pointes or new-onset VF occurred infrequently (less than 2%). Patients should be monitored for QTc prolongation during infusion with amiodarone. Combination of amiodarone with other antiarrhythmic therapy that prolongs the QTc should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients takingamiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. (See Drug Interactions, Other reported interactions with amiodarone.) The need to co-administer amiodarone with any other drug known to prolong the QTc interval must be based on a careful assessment of the potential risks and benefits of doing so for each patient. A careful assessment of the potential risks and benefits of administering amiodarone must be made in patients with thyroid dysfunction due to the possibility of arrhythmia breakthrough or exacerbation of arrhythmia, which may result in death, in these patients.<br/>Pulmonary Disorders:<br/>Early-onset pulmonary toxicity: There have been postmarketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with amiodarone Findings have included pulmonary infiltrates on X-ray, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure and/or death.<br/>ARDS: Two percent (2%) of patients were reported to have adult respiratory distress syndrome (ARDS) during clinical studies involving 48 hours of therapy. ARDS is a disorder characterized by bilateral, diffuse pulmonary infiltrates with pulmonary edema and varying degrees of respiratory insufficiency. The clinical and radiographic picture can arise after a variety of lung injuries, such as those resulting from trauma, shock, prolonged cardiopulmonary resuscitation, and aspiration pneumonia, conditions present in many of the patients enrolled in the clinical studies. There have been postmarketing reports of ARDS in amiodarone patients. Amiodarone may play a role in causing or exacerbating pulmonary disorders in those patients. Postoperatively, occurrences of ARDS have been reported in patients receiving oral amiodarone therapy who have undergone either cardiac or noncardiac surgery. Although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. Until further studies have been performed, it is recommended that FiOand the determinants of oxygen delivery to the tissues (e.g., SaO, PaO) be closely monitored in patients on amiodarone.<br/>Pulmonary fibrosis: Only 1 of more than 1000 patients treated with amiodarone in clinical studies developed pulmonary fibrosis. In that patient, the condition was diagnosed 3 months after treatment with amiodarone, during which time she received oral amiodarone. Pulmonary toxicity is a well-recognized complication of long-term amiodarone use (see labeling for oral amiodarone).<br/>Surgery: Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction defects of halogenated inhalational anesthetics.<br/>Drug Interactions: Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochromes P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines . Amiodarone is also known to be an inhibitor of CYP3A4. Therefore, amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors or inducers of CYP3A4. While only a limited number of in vivo drug-drug interactions with amiodarone have been reported, chiefly with the oral formulation, the potential for other interactions should be anticipated. This is especially important for drugs associated with serious toxicity, such as other antiarrhythmics. If such drugs are needed, their dose should be reassessed and, where appropriate, plasma concentration measured. In view of the long and variable half-life of amiodarone, potential for drug interactions exists not only with concomitant medication but also with drugs administered after discontinuation of amiodarone. Since amiodarone is a substrate for CYP3A4 and CYP2C8, drugs/substances that inhibit these isoenzymes may decrease the metabolism and increase serum concentration of amiodarone. Reported examples include the following: Amiodarone may suppress certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A4. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes. Reported examples of this interaction include the following: Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A4 (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in efficacy. Reported examples of this interaction include the following:<br/>Electrolyte Disturbance: Patients with hypokalemia or hypomagnesemia should have the condition corrected whenever possible before being treated with amiodarone, as these disorders can exaggerate the degree of QTc prolongation and increase the potential for torsades de pointes. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics.<br/>Carcinogenesis, Mutagenesis, Impairment Of Fertility: No carcinogenicity studies were conducted with amiodarone. However, oral amiodarone caused a statistically significant, dose-related increase in the incidence of thyroid tumors (follicular adenoma and/or carcinoma) in rats. The incidence of thyroid tumors in rats was greater than the incidence in controls even at the lowest dose level tested, i.e., 5mg/kg/day (approximately 0.08 times the maximum recommended human maintenance dose). Mutagenicity studies conducted with amiodarone HCl (Ames, micronucleus, and lysogenic induction tests) were negative. No fertility studies were conducted with amiodarone I.V. However, in a study in which oral amiodarone HCl was administered to male and female rats, beginning 9 weeks prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately 1.4 times the maximum recommended human maintenance dose).<br/>Pregnancy:<br/>Category D: See WARNINGS and Neonatal Hypo- or Hyperthyroidism. In addition to causing infrequent congenital goiter/hypothyroidism and hyperthyroidism, amiodarone has caused a variety of adverse effects in animals. In a reproductive study in which amiodarone was given intravenously to rabbits at dosages of 5, 10, or 25 mg/kg per day (about 0.1, 0.3, and 0.7 times the maximum recommended human dose [MRHD] on a body surface area basis), maternal deaths occurred in all groups, including controls. Embroyotoxicity (as manifested by fewer full-term fetuses and increased resorptions with concomitantly lower litter weights) occurred at dosages of 10 mg/kg and above. No evidence of embryotoxicity was observed at 5 mg/kg and no teratogenicity was observed at any dosages. In a teratology study in which amiodarone was administered by continuous i.v. infusion to rats at dosages of 25, 50, or 100 mg/kg per day (about 0.4, 0.7, and 1.4 times the MRHD when compared on a body surface area basis), maternal toxicity (as evidenced by reduced weight gain and food consumption) and embryotoxicity (as evidenced by increased resorptions, decreased live litter size, reduced body weights, and retarded sternumand metacarpal ossification) were observed in the 100 mg/kg group. Amiodarone should be used during pregnancy only if the potential benefit to the mother justifies the risk to the fetus.<br/>Nursing Mothers: Amiodarone and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered amiodarone have demonstrated reduced viability and reduced body weight gains. The risk of exposing the infant to amiodarone should be weighed against the potential benefit of arrhythmia suppression in the mother. The mother should be advised to discontinue nursing.<br/>Labor and Delivery: It is not known whether the use of amiodarone during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect on the duration of gestation or on parturition.<br/>Pediatric Usage: The safety and efficacy of amiodarone in the pediatric population have not been established; therefore, its use in pediatric patients is not recommended. In a pediatric trial of 61 patients, aged 30 days to 15 years, hypotension (36%), bradycardia (20%), and atrio-ventricular block (15%) were common dose-related adverse events and were severe or life-threatening in some cases. Injection site reactions were seen in 5 (25%) of the 20 patients receiving amiodarone through a peripheral vein irrespective of dose regimen. Amiodarone contains the preservative benzyl alcohol . There have been reports of fatal "gasping syndrome" in neonates (children less than one month of age) following the administration of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse.<br/>Geriatric Use: Clinical studies of amiodarone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:33 | dailymed-instance:precautio... | General: This medication is not to be used for the treatment of systemic mycoses. Discontinue treatment if sensitization or irritation is reported during use.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term animal studies have been performed to evaluate carcinogenic potential. There also have been no studies to determine mutagenicity or whether this medication affects fertility in males or females.<br/>Pregnancy:<br/>Teratogenic Effects Category C: Animal reproduction studies have not been conducted with nystatin oral suspension. It is also not known whether nystatin oral suspension can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Nystatin oral suspension should be given to a pregnant woman only if clearly needed.<br/>Nursing Mothers: It is not known whether nystatin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nystatin is administered to a nursing woman.<br/>Pediatric Use: See DOSAGE AND ADMINISTRATION. | lld:dailymed |
| dailymed-drugs:3629 | dailymed-instance:precautio... | General: This medication is not to be used for the treatment of systemic mycoses. Discontinue treatment if sensitization or irritation is reported during use.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term animal studies have been performed to evaluate carcinogenic potential. There also have been no studies to determine mutagenicity or whether this medication affects fertility in males or females.<br/>Pregnancy:<br/>Teratogenic Effects Category C: Animal reproduction studies have not been conducted with nystatin oral suspension. It is also not known whether nystatin oral suspension can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Nystatin oral suspension should be given to a pregnant woman only if clearly needed.<br/>Nursing Mothers: It is not known whether nystatin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nystatin is administered to a nursing woman.<br/>Pediatric Use: See DOSAGE AND ADMINISTRATION. | lld:dailymed |
| dailymed-drugs:34 | dailymed-instance:precautio... | General:<br/>Laboratory Tests:<br/>Drug Interactions:<br/>Drug/Laboratory Test Interactions:<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Pregnancy:<br/>Teratogenic effects:<br/>Nonteratogenic effects:<br/>Nursing Mothers:<br/>Pediatric Use: | lld:dailymed |
| dailymed-drugs:35 | dailymed-instance:precautio... | General: Etodolac cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered solely if a decision is made to discontinue corticosteroids. The pharmacological activity of etodolac in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.<br/>Hepatic Effects: Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including etodolac. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure, some of them with fatal outcomes, have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with etodolac. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), etodolac should be discontinued.<br/>Hematological Effects: Anemia is sometimes seen in patients receiving NSAIDs including etodolac. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including etodolac, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving etodolac who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.<br/>Preexisting Asthma: Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthmas has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, etodolac should not be administered to patients with this form of aspirin sensitivity and should be used with caution in all patients with pre-existing asthma.<br/>Information for patients: Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.<br/>Laboratory tests: Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically for signs or symptoms of anemia. Appropriate measures should be taken in case such signs of anemia occur. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, etodolac should be discontinued.<br/>Drug interactions:<br/>ACE-inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors (see WARNINGS).<br/>Antacids: The concomitant administration of antacids has no apparent effect on the extent of absorption of etodolac. However, antacids can decrease the peak concentration reached by 15% to 20% but have no detectable effect on the time-to-peak.<br/>Aspirin: When etodolac is administered with aspirin, its protein binding is reduced, although the clearance of free etodolac is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of etodolac and aspirin is not generally recommended because of the potential of increased adverse effects.<br/>Cyclosporine, Digoxin, Methotrexate: Etodolac, like other NSAIDs, through effects on renal prostaglandins, may cause changes in the elimination of these drugs leading to elevated serum levels of cyclosporine, digoxin, methotrexate, and increased toxicity. Nephrotoxicity associated with cyclosporine may also be enhanced. Patients receiving these drugs who are given etodolac, or any other NSAID, and particularly those patients with altered renal function, should be observed for the development of the specific toxicities of these drugs. NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be usedwhen NSAIDs are administered concomitantly with methotrexate.<br/>Diuretics: Etodolac has no apparent pharmacokinetic interaction when administered with furosemide or hydrochlorothiazide. Nevertheless, clinical studies, as well as postmarketing observations have shown that etodolac can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy.<br/>Glyburide: Etodolac has no apparent pharmacokinetic interaction when administered with glyburide.<br/>Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.<br/>Phenylbutazone: Phenylbutazone causes increase (by about 80%) in the free fraction of etodolac. Although in vivo studies have not been done to see if etodolac clearance is changed by coadministration of phenylbutazone, it is not recommended that they be coadministered.<br/>Phenytoin: Etodolac has no apparent pharmacokinetic interaction when administered with phenytoin.<br/>Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than that of users of either drug alone. Short-term pharmacokinetic studies have demonstrated that concomitant administration of warfarin and etodolac capsules and tablets results in reduced protein binding of warfarin, but there was no change in the clearance of free warfarin. There was no significant difference in the pharmacodynamic effect of warfarin administered alone and warfarin administered with etodolac as measured by prothrombin time. Thus, concomitant therapy with warfarin and etodolac should not require dosage adjustment of either drug. However, caution should be exercised because there have been a few spontaneous reports of prolonged prothrombin times, with or without bleeding, in etodolac-treated patients receiving concomitant warfarin therapy.<br/>Drug/Laboratory Test Interactions: The urine of patients who take etodolac can give a false-positive reaction for urinary bilirubin (urobilin) due to the presence of phenolic metabolites of etodolac. Diagnostic dip-stick methodology, used to detect ketone bodies in urine, has resulted in false-positive findings in some patients treated with etodolac. Generally, this phenomenon has not been associated with other clinically significant events. No dose relationship has been observed. Etodolac treatment is associated with a small decrease in serum uric acid levels. In clinical trials, mean decreases of 1 to 2 mg/dL were observed in arthritic patients receiving etodolac (600 mg to 1000 mg/day) after 4 weeks of therapy. These levels then remained stable for up to 1 year of therapy.<br/>Cacinogenesis, mutagenesis, impairment of fertility: No carcinogenic effect of etodolac was observed in mice or rats receiving oral doses of 15 mg/kg/day (45 to 89 mg/m, respectively) or less for periods of 2 years or 18 months, respectively. Etodolac was not mutagenic in in vitro tests performed with S. typhimurium and mouse lymphoma cells as well as in an in vivo mouse micronucleus test. However, data from the in vitro human peripheral lymphocyte test showed an increase in the number of gaps (3.0 to 5.3% unstained regions in the chromatid without dislocation) among the etodolac-treated cultures (50 to 200��g/mL) compared to negative controls (2.0%); no other difference was noted between the controls and drug-treated groups. Etodolac showed no impairment of fertility in male and female rats up to oral doses of 16 mg/kg (94 mg/m). However, reduced implantation of fertilized eggs occurred in the 8 mg/kg group.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nonteratogenic Effects: Etodolac should be used during pregnancy only if the potential benefits justify the potential risk to the fetus. Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of the ductus arteriosus), use during pregnancy (particularly during the third trimester) should be avoided.<br/>Labor and delivery: In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of etodolac on labor and delivery in pregnant women are unknown.<br/>Nursing mothers: It is not known whether etodolac is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from etodolac, a decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother.<br/>Pediatric use: Safety and effectiveness in pediatric patients below the age of 18 years have not been established.<br/>Geriatric use: As with any NSAID, caution should be exercised in treating the elderly (65 years and older) and when increasing the dose (see WARNINGS). In etodolac clinical studies, no overall differences in safety or effectiveness were observed between these patients and younger patients. In pharmacokinetic studies, age was shown not to have any effect on etodolac half-life or protein binding, and there was no change in expected drug accumulation. Therefore, no dosage adjustment is generally necessary in the elderly on the basis of pharmacokinetics (see CLINICAL PHARMACOLOGY, Special Populations). Elderly patients may be more sensitive to the antiprostaglandin effects of NSAIDs (on the gastrointestinal tract and kidneys) than younger patients (see WARNINGS). In particular, elderly or debilitated patients who receive NSAID therapy seem to tolerate gastrointestinal ulceration or bleeding less well than other individuals, and most spontaneous reports of fatal GI events are in this population. Etodolac is eliminated primarily by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see WARNINGS, Renal Effects). | lld:dailymed |
| dailymed-drugs:36 | dailymed-instance:precautio... | General: As with any penicillin preparation, an allergic response, including anaphylaxis, may occur particularly in a hypersensitive individual. Long term use of Geocillin may result in the overgrowth of nonsusceptible organisms. If superinfection occurs during therapy, appropriate measures should be taken. Since carbenicillin is primarily excreted by the kidney, patients with severe renal impairment (creatinine clearance of less than 10 ml/min) will not achieve therapeutic urine levels of carbenicillin. In patients with creatinine clearance of 10���20 ml/min it may be necessary to adjust dosage to prevent accumulation of drug. Prescribing Geocillin in the absence of proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.<br/>Information For Patients: Patients should be counseled that antibacterial drugs including Geocillin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Geocillin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Geocillin or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.<br/>Laboratory Tests: As with other penicillins, periodic assessment of organ system function including renal, hepatic, and hematopoietic systems is recommended during prolonged therapy.<br/>Drug Interactions: Geocillin (carbenicillin indanyl sodium) blood levels may be increased and prolonged by concurrent administration of probenecid.<br/>Carcinogenesis, Mutagenesis, Impairment Of Fertility: There are no long-term animal or human studies to evaluate carcinogenic potential. Rats fed 250���1000 mg/kg/day for 18 months developed mild liver pathology (e.g., bile duct hyperplasia) at all dose levels, but there was no evidence of drug-related neoplasia. Geocillin administered at daily doses ranging to 1000 mg/kg had no apparent effect on the fertility or reproductive performance of rats.<br/>Pregnancy Category B: Reproduction studies have been performed at dose levels of 1000 or 500 mg/kg in rats, 200 mg/kg in mice, and at 500 mg/kg in monkeys with no harm to fetus due to Geocillin. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.<br/>Labor And Delivery: It is not known whether the use of Geocillin in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary.<br/>Nursing Mothers: Carbenicillin class antibiotics are excreted in milk although the amounts excreted are unknown; therefore, caution should be exercised if administered to a nursing woman.<br/>Pediatric Use: Since only limited clinical data is available to date in children, the safety of Geocillin administration in this age group has not yet been established. | lld:dailymed |
| dailymed-drugs:37 | dailymed-instance:precautio... | General:<br/>Somnolence: In U.S. controlled studies, somnolence was reported in 54% of patients treated with mirtazapine, compared to 18% for placebo and 60% for amitriptyline. In these studies, somnolence resulted in discontinuation for 10.4% of mirtazapine treated patients, compared to 2.2% for placebo. It is unclear whether or not tolerance develops to the somnolent effects of mirtazapine. Because of mirtazapine's potentially significant effects on impairment of performance, patients should be cautioned about engaging in activities requiring alertness until they have been able to assess the drug's effect on their own psychomotor performance (see Information for Patients).<br/>Dizziness: In U.S. controlled studies, dizziness was reported in 7% of patients treated with mirtazapine, compared to 3% for placebo and 14% for amitriptyline. It is unclear whether or not tolerance develops to the dizziness observed in association with the use of mirtazapine.<br/>Increased Appetite/Weight Gain: In U.S. controlled studies, appetite increase was reported in 17% of patients treated with mirtazapine, compared to 2% for placebo and 6% for amitriptyline. In these same trials, weight gain of���7% of body weight was reported in 7.5% of patients treated with mirtazapine, compared to 0% for placebo and 5.9% for amitriptyline. In a pool of premarketing U.S. studies, including many patients for long-term, open label treatment, 8% of patients receiving mirtazapine discontinued for weight gain. In an 8-week long pediatric clinical trial of doses between 15-45 mg/day, 49% of mirtazapine-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo treated patients .<br/>Cholesterol/Triglycerides: In U.S. controlled studies, nonfasting cholesterol increases to���20% above the upper limits of normal were observed in 15% of patients treated with mirtazapine compared to 7% for placebo and 8% for amitriptyline. In these same studies, nonfasting triglyceride increases to>500 mg/dL were observed in 6% of patients treated with mirtazapine, compared to 3% for placebo and 3% for amitriptyline.<br/>Transaminase Elevations: Clinically significant ALT (SGPT) elevations (���3 times the upper limit of the normal range) were observed in 2.0% (8/424) of patients exposed to mirtazapine in a pool of short-term U.S. controlled trials, compared to 0.3% (1/328) of placebo patients and 2.0% (3/181) of amitriptyline patients. Most of these patients with ALT increases did not develop signs or symptoms associated with compromised liver function. While some patients were discontinued for the ALT increases, in other cases, the enzyme levels returned to normal despite continued mirtazapine treatment. Mirtazapine should be used with caution in patients with impaired hepatic function .<br/>Activation of Mania/Hypomania: Mania/hypomania occurred in approximately 0.2% (3/1,299 patients) of mirtazapine treated patients in U.S. studies. Although the incidence of mania/hypomania was very low during treatment with mirtazapine, it should be used carefully in patients with a history of mania/hypomania.<br/>Seizure: In premarketing clinical trials only one seizure was reported among the 2,796 U.S. and non-U.S. patients treated with mirtazapine. However, no controlled studies have been carried out in patients with a history of seizures. Therefore, care should be exercised when mirtazapine is used in these patients.<br/>Use in Patients with Concomitant Illness: Clinical experience with mirtazapine in patients with concomitant systemic illness is limited. Accordingly, care is advisable in prescribing mirtazapine for patients with diseases or conditions that affect metabolism or hemodynamic responses. Mirtazapine has not been systematically evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or other significant heart disease. Mirtazapine was associated with significant orthostatic hypotension in early clinical pharmacology trials with normal volunteers. Orthostatic hypotension was infrequently observed in clinical trials with depressed patients. Mirtazapine should be used with caution in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension (history of myocardial infarction, angina, or ischemic stroke) and conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medication). Mirtazapine clearance is decreased in patients with moderate [glomerular filtration rate (GFR) = 11-39 mL/min/1.73 m] and severe [GFR<10 mL/min/1.73 m] renal impairment, and also in patients with hepatic impairment. Caution is indicated in administering mirtazapine to such patients .<br/>Information for Patients: Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with mirtazapine and should counsel them in its appropriate use. A patient Medication Guide about "Anti-depressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions" is available for mirtazapine. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking mirtazapine. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.<br/>Agranulocytosis: Patients who are to receive mirtazapine should be warned about the risk of developing agranulocytosis. Patients should be advised to contact their physician if they experience any indication of infection such as fever, chills, sore throat, mucous membrane ulceration or other possible signs of infection. Particular attention should be paid to any flu-likecomplaints or other symptoms that might suggest infection.<br/>Interference with Cognitive and Motor Performance: Mirtazapine may impair judgment, thinking, and particularly, motor skills, because of its prominent sedative effect. The drowsiness associated with mirtazapine use may impair a patient's ability to drive, use machines or perform tasks that require alertness. Thus, patients should be cautioned about engaging in hazardous activities until they are reasonably certain that mirtazapine therapy does not adversely affect their ability to engage in such activities.<br/>Completing Course of Therapy: While patients may notice improvement with mirtazapine therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.<br/>Concomitant Medication: Patients should be advised to inform their physician if they are taking, or intend to take, any prescription or over-the-counter drugs since there is a potential for mirtazapine to interact with other drugs.<br/>Alcohol: The impairment of cognitive and motor skills produced by mirtazapine has been shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking mirtazapine.<br/>Pregnancy: Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during mirtazapine therapy.<br/>Nursing: Patients should be advised to notify their physician if they are breast-feeding an infant.<br/>Laboratory Tests: There are no routine laboratory tests recommended.<br/>Drug Interactions: As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility .<br/>Drugs Affecting Hepatic Metabolism: The metabolism and pharmacokinetics of mirtazapine may be affected by the induction or inhibition of drug-metabolizing enzymes.<br/>Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes: Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6,1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of mirtazapine with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of mirtazapine with such drugs.<br/>Alcohol: Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by mirtazapine were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking mirtazapine.<br/>Diazepam: Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by mirtazapine has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking mirtazapine.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis: Carcinogenicity studies were conducted with mirtazapine given in the diet at doses of 2, 20, and 200 mg/kg/day to mice and 2, 20, and 60 mg/kg/day to rats. The highest doses used are approximately 20 and 12 times the maximum recommended human dose (MRHD) of 45 mg/day on a mg/mbasis in mice and rats, respectively. There was an increased incidence of hepatocellular adenoma and carcinoma in male mice at the high dose. In rats, there was an increase in hepatocellular adenoma in females at the mid and high doses and in hepatocellular tumors and thyroid follicular adenoma/cystadenoma and carcinoma in males at the high dose. The data suggest that the above effects could possibly bemediated by non-genotoxic mechanisms, the relevance of which to humans is not known. The doses used in the mouse study may not have been high enough to fully characterize the carcinogenic potential of mirtazapine tablets.<br/>Mutagenesis: Mirtazapine was not mutagenic or clastogenic and did not induce general DNA damage as determined in several genotoxicity tests: Ames test, in vitro gene mutation assay in Chinese hamster V 79 cells, in vitro sister chromatid exchange assay in cultured rabbit lymphocytes, in vivo bone marrow micronucleus test in rats, and unscheduled DNA synthesis assay in HeLa cells.<br/>Impairment of Fertility: In a fertility study in rats, mirtazapine was given at doses up to 100 mg/kg (20 times the maximum recommended human dose (MRHD) on a mg/mbasis). Mating and conception were not affected by the drug, but estrous cycling was disrupted at doses that were 3 or more times the MRHD and pre-implantation losses occurred at 20 times the MRHD.<br/>Pregnancy:<br/>Teratogenic Effects - Pregnancy Category C: Reproduction studies in pregnant rats and rabbits at doses up to 100 mg/kg and 40 mg/kg, respectively (20 and 17 times the maximum recommended human dose (MRHD) on a mg/mbasis, respectively), have revealed no evidence of teratogenic effects. However, in rats, there was an increase in post-implantation losses in dams treated with mirtazapine. There was an increase in pup deaths during the first 3 days of lactation and a decrease in pup birth weights. The cause of these deaths is not known. These effects occurred at doses that were 20 times the MRHD, but not at 3 times the MRHD, on a mg/mbasis. There are no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.<br/>Nursing Mothers: It is not known whether mirtazapine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when mirtazapine is administered to nursing women.<br/>Pediatric Use: Safety and effectiveness in the pediatric population have not been established . Two placebo-controlled trials in 258 pediatric patients with MDD have been conducted with Mirtazapine, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Mirtazapine in a child or adolescent must balance the potential risks with the clinical need.<br/>Geriatric Use: Approximately 190 elderly individuals (���65 years of age) participated in clinical studies with mirtazapine. This drug is known to be substantially excreted by the kidney (75%), and the risk of decreased clearance of this drug is greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Sedating drugs may cause confusion and over-sedation in the elderly. No unusual adverse age-related phenomena were identified in this group. Pharmacokinetic studies revealed a decreased clearance in the elderly. Caution is indicated in administering mirtazapine to elderly patients . | lld:dailymed |
| dailymed-drugs:38 | dailymed-instance:precautio... | General: Care of Intravenous Site: Irinotecan Hydrochloride Injection is administered by Intravenous infusion. Care should be taken to avoid extravasation, and the infusion site should be monitored for signs of inflammation. Should extravasation occur, flushing the site with sterile water and applications of ice are recommended. Premedication with Antiemetics: Irinotecan is emetigenic. It is recommended that patients receive premedication with antiemetic agents. In clinical studies of the weekly dosage schedule, the majority of patients received 10 mg of dexamethasone given in conjunction with another type of antiemetic agent, such as a 5-HTblocker (e.g., ondansetron or granisetron). Antiemetic agents should be given on the day of treatment, starting at least 30 minutes before administration of Irinotecan Hydrochloride Injection. Physicians should also consider providing patients with an antiemetic regimen (e.g., prochlorperazine) for subsequent use as needed. Treatment of Cholinergic Symptoms: Prophylactic or therapeutic administration of 0.25 to 1 mg of intravenous or subcutaneous atropine should be considered (unless clinically contraindicated) in patients experiencing rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, abdominal cramping, or diarrhea (occurringduring or shortly after infusion of Irinotecan Hydrochloride Injection). These symptoms are expected to occur more frequently with higher irinotecan doses. Patients at Particular Risk:The use of Irinotecan Hydrochloride Injection in patients with significant hepatic dysfunction has not been established. In clinical trials of either dosing schedule, irinotecan was not administered to patients with serum bilirubin>2.0 mg/dL, or transaminase>3 times the upper limit of normal if no liver metastasis, or transaminase>5 times the upper limit of normal with liver metastasis. In clinical trials of the weekly dosage schedule, patients with modestly elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dL) had a significantly greater likelihood of experiencing first-cycle, grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL (50% [19/38] versus 18% [47/226]; p<0.001). Also see CLINICAL PHARMACOLOGY: Pharmacokinetics in Special Populations: Hepatic Insufficiency. Patients with deficient glucuronidation of bilirubin, such as those with Gilbert's syndrome, may be at greater risk of myelosuppression when receiving therapy with Irinotecan Hydrochloride Injection. Ketoconazole, enzyme-inducing anticonvulsants and St. John's Wort are known to have drug-drug interactions with irinotecan therapy. Irinotecan commonly causes neutropenia, leucopenia, and anemia, any of which may be severe and therefore should not be used in patients with severe bone marrow failure.Patients must not be treated with irinotecan until resolution of the bowel obstruction. Patients with hereditary fructose intolerance should not be given Irinotecan Hydrochloride Injection, as this product contains sorbitol.<br/>Information for Patients: Patients and patients' caregivers should be informed of the expected toxic effects of Irinotecan Hydrochloride Injection, particularly of its gastrointestinal complications, such as nausea, vomiting, abdominal cramping, diarrhea, and infection. Each patient should be instructed to have loperamide readily available and to begin treatment for late diarrhea (generally occurring morethan 24 hours after administration of Irinotecan Hydrochloride Injection) at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than normally expected for the patient. One dosage regimen for loperamide used in clinical trials consisted of the following (Note: This dosage regimen exceeds the usual dosage recommendations for loperamide.): 4 mg at the first onset of late diarrhea and then 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus. During the night, the patient may take 4 mg of loperamide every 4 hours. Premedication with loperamide is not recommended. The use of drugs with laxative properties should be avoided because of the potential for exacerbation of diarrhea. Patients should be advised to contact their physician to discuss any laxative use. Patients should be instructed to contact their physician or nurse if any of the following occur: diarrhea for the first time during treatment; black or bloody stools; symptoms of dehydration such as lightheadedness, dizziness, or faintness; inability to take fluids by mouth due to nausea or vomiting; inability to get diarrhea under control within 24 hours; or fever or evidence of infection. Patients should be warned about the potential for dizziness or visual disturbances which may occur within 24 hours following the administration of Irinotecan Hydrochloride Injection, and advised not to drive or operate machinery if these symptoms occur. Patients should be alerted to the possibility of alopecia.<br/>Laboratory Tests: Careful monitoring of the white blood cell count with differential, hemoglobin, and platelet count is recommended before each dose of Irinotecan Hydrochloride Injection.<br/>Drug Interactions: The adverse effects of Irinotecan Hydrochloride Injection, such as myelosuppression and diarrhea, would be expected to be exacerbated by other antineoplastic agents having similar adverse effects. Patients who have previously received pelvic/ abdominal irradiation are at increased risk of severe myelosuppression following the administration of Irinotecan Hydrochloride Injection. The concurrent administration of Irinotecan Hydrochloride Injection with irradiation has not been adequately studied and is not recommended. Lymphocytopenia has been reported in patients receiving Irinotecan Hydrochloride Injection, and it is possible that the administration of dexamethasone as antiemetic prophylaxis may have enhanced the likelihood of this effect. However, serious opportunistic infections have not been observed, and no complications have specifically been attributed to lymphocytopenia. Hyperglycemia has also been reported in patients receiving Irinotecan Hydrochloride Injection. Usually, this has been observed in patients with a history of diabetes mellitus or evidence of glucose intolerance prior to administration of Irinotecan Hydrochloride Injection. It is probable that dexamethasone, given as antiemetic prophylaxis, contributed to hyperglycemia in some patients. The incidence of akathisia in clinical trials of the weekly dosage schedule was greater(8.5%, 4/47 patients) when prochlorperazine was administered on the same day as Irinotecan Hydrochloride Injection than when these drugs were given on separate days (1.3%, 1/80 patients). The 8.5% incidence of akathisia, however, is within the range reported for use of prochlorperazine when given as a premedication for other chemotherapies. It would be expected that laxative use during therapy with Irinotecan Hydrochloride Injection would worsen the incidence or severity of diarrhea, but this has not been studied. In view of the potential risk of dehydration secondary to vomiting and/or diarrhea induced by Irinotecan Hydrochloride Injection, the physician may wish to withhold diuretics during dosing with Irinotecan Hydrochloride Injection and, certainly, during periods of active vomiting or diarrhea.<br/>Drug-Laboratory Test Interactions: There are no known interactions between Irinotecan Hydrochloride Injection and laboratory tests.<br/>Carcinogenesis, Mutagenesis&Impairment of Fertility: Long-term carcinogenicity studies with irinotecan were not conducted. Rats were, however, administered intravenous doses of 2 mg/kg or 25 mg/kg irinotecan once per week for 13 weeks (in separate studies, the 25 mg/kg dose produced an irinotecan Cand AUC that were about 7.0 times and 1.3 times the respective values in patients administered 125 mg/mweekly) and were then allowed to recover for 91 weeks. Under these conditions, there was a significant linear trend with dose for the incidence of combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas. Neither irinotecan nor SN-38 was mutagenic in the in vitro Ames assay. Irinotecan was clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (micronucleus test in mice). No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of irinotecan in doses of up to 6 mg/kg/day to rats and rabbits. However, atrophy of male reproductive organs was observed after multiple daily irinotecan doses both in rodents at 20 mg/kg (which in separate studies produced an irinotecan Cand AUC about 5 and 1 times, respectively, the corresponding values in patients administered 125 mg/mweekly) and dogs at 0.4 mg/kg (which in separate studies produced an irinotecan Cand AUC about one-half and 1/15th, respectively, the corresponding values in patients administered 125 mg/mweekly).<br/>Pregnancy: Pregnancy Category D���see WARNINGS.<br/>Nursing Mothers: Radioactivity appeared in rat milk within 5 minutes of intravenous administration of radiolabeled irinotecan and was concentrated up to 65-fold at 4 hours after administration relative to plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommendedthat nursing be discontinued when receiving therapy with Irinotecan Hydrochloride Injection.<br/>Pediatric Use: The effectiveness of irinotecan in pediatric patients has not been established. Results from two open-label, single arm studies were evaluated. One hundred and seventy children with refractory solid tumors were enrolled in one phase 2 trial in which 50 mg/mof irinotecan was infused for 5 consecutive days every 3 weeks. Grade 3-4 neutropenia was experienced by 54 (31.8%) patients. Neutropenia was complicated by fever in 15 (8.8%) patients. Grade 3-4 diarrhea was observed in 35 (20.6%) patients. This adverse event profile was comparable to that observed in adults. In the second phase 2 trial of 21 children with previously untreated rhabdomyosarcoma, 20 mg/mof irinotecan was infused for 5 consecutive days on weeks 0, 1, 3 and 4. This single agent therapy was followed by multimodal therapy. Accrual to the single agent irinotecan phase was halted due to the high rate (28.6%) of progressive disease and the early deaths (14%). The adverse event profile was different in this study from that observed in adults; the most significant grade 3 or 4 adverse events were dehydration experienced by 6 patients (28.6%) associated with severe hypokalemia in 5 patients (23.8%) and hyponatremia in 3 patients (14.3%); in addition Grade 3-4 infection was reported in 5 patients (23.8%) (across all courses of therapy and irrespective of causal relationship). Pharmacokinetic parameters for irinotecan and SN-38 were determined in 2 pediatric solid-tumor trials at dose levels of 50 mg/m(60-min infusion, n=48) and 125 mg/m(90-min infusion, n=6). Irinotecan clearance (mean��S.D.) was 17.3��6.7 L/h/mfor the 50mg/mdose and 16.2��4.6 L/h/mfor the 125 mg/mdose, which is comparable to that in adults. Dose-normalized SN-38 AUC values were comparable between adults and children. Minimal accumulation of irinotecan and SN-38 was observed in children on daily dosing regimens [daily x 5 every 3 weeks or (daily x 5) x 2 weeks every 3 weeks].<br/>Geriatric Use: Patients greater than 65 years of age should be closely monitored because of a greater risk of late diarrhea in this population . The starting dose of Irinotecan Hydrochloride Injection inpatients 70 years and older for the once-every-3-week-dosage schedule should be 300 mg/m. | lld:dailymed |
| dailymed-drugs:39 | dailymed-instance:precautio... | Use of estrogens with a progestin may increase the risk of breast cancer compared to estrogen alone.<br/>Ovarian Cancer: The CE/MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA vs. placebo was 1.58 (95% confidence interval 0.77���3.24) but was not statistically significant. The absolute risk for CE/MPA vs. placebo was 4.2 vs. 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen alone, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.<br/>General:<br/>Information for the Patient: See accompanying Patient Insert. General: This product contains peanut oil and should not be used if you are allergic to peanuts.<br/>Drug/Laboratory Test Interactions: The following laboratory results may be altered by the use of estrogen-progestin combination drugs: Fasting and 2-hour plasma insulin and glucose levels following an oral glucose tolerance test (OGTT) and fibrinogen levels were measured in patients receiving PROMETRIUM Capsules at a dose of 200 mg/day for 12 days per 28-day cycle in combination with conjugated estrogens 0.625 mg/day (n=120). Table 7 summarizes these data. Plasma insulin levels 2 hours post-OGTT were decreased from baseline. The fasting plasma glucose and fasting plasma insulin levels were also decreased from baseline. Glucose levels 2 hours post-OGTT were increased slightly. There was no effect on fibrinogen levels. For information on changes in lipid profile, see the Clinical Studies subsection, Table 5.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Progesterone has not been tested for carcinogenicity in animals by the oral route of administration. When implanted into female mice, progesterone produced mammary carcinomas, ovarian granulosa cell tumors and endometrial stromal sarcomas. In dogs, long-term intramuscular injections produced nodular hyperplasia and benign and malignant mammary tumors. Subcutaneous or intramuscular injections of progesterone decreased the latency period and increased the incidence of mammary tumors in rats previously treated with a chemicalcarcinogen. Progesterone did not show evidence of genotoxicity in in vitro studies for point mutations or for chromosomal damage. In vivo studies for chromosome damage have yielded positive results in mice at oral doses of 1000 mg/kg and 2000 mg/kg. Exogenously administered progesterone has been shown to inhibit ovulation in a number of species and it is expected that high doses given for an extended duration would impair fertility until the cessation of treatment.<br/>Pregnancy Category B: Reproductive studies have been performed in mice at doses up to 9 times the human oral dose, in rats at doses up to 44 times the human oral dose, in rabbits at a dose of 10 mcg/day delivered locally within the uterus by an implanted device, in guinea pigs at doses of approximately one-half the human oral dose and in rhesus monkeys at doses approximately the human dose, all based on body surface area, and have revealed little or no evidence of impaired fertility or harm to the fetus due to progesterone. Rare cases of congenital anomalies including cleft palate, cleft lip, hypospadia, ventricular septal defect, patent ductus arteriosus, and other congenital heart defects have been reported in the infants of women using progesterone, including PROMETRIUM Capsules, in early pregnancy. Definitive causality has not been established. Rare instances of fetal death and spontaneous abortion have been reported in pregnant women prescribed PROMETRIUM Capsules for unapproved indications including the prevention of such outcomes. Studies in humans cannot rule out the possibility of harm. Therefore, PROMETRIUM Capsules should be used during pregnancy only if indicated.<br/>Nursing Mothers: The administration of any drug to nursing mothers should be done only when clearly necessary since many drugs are excreted in human milk. Detectable amounts of progestin have been identified in the milk of nursing mothers receiving progestins. Caution should be exercised when PROMETRIUM Capsules are administered to a nursing woman.<br/>Pediatric Use: PROMETRIUM Capsules are not indicated in children.<br/>Geriatric Use: Clinical studies of PROMETRIUM Capsules did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In the Women's Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n = 3,729) were 65 to 74 while 18% (n = 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer's disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70. | lld:dailymed |
| dailymed-drugs:41 | dailymed-instance:precautio... | Special care must be taken when administering glucose to provide calories in diabetic or prediabetic patients. Feeding regimens which include amino acids should be used with caution in patients with history of renal disease, pulmonary disease, or with cardiac insufficiency so as to avoid excessive fluid accumulation. The effect of infusion of amino acids, without dextrose, upon carbohydrate metabolism of children is not known at this time. Nitrogen intake should be carefully monitored in patients with impaired renal function. For long-term total nutrition, or if a patient has inadequate fat stores, it is essential to provide adequate exogenous calories concurrently with the amino acids. Concentrated dextrose solutions are an effective source of such calories. Such strongly hypertonic nutrient solutions should be administered through an indwellingintravenous catheter with the tip located in the superior vena cava. SPECIAL PRECAUTIONS FOR CENTRAL INFUSIONS ADMINISTRATION BY CENTRAL VENOUS CATHETER SHOULD BE USED ONLY BY THOSE FAMILIAR WITH THIS TECHNIQUE AND ITS COMPLICATIONS. Central vein infusion (with added concentrated carbohydrate solutions) of amino acid solutions requires a knowledge of nutrition as well as clinical expertise in recognition and treatment of complications. Attention must be given to solution preparation, administration and patient monitoring. IT IS ESSENTIAL THAT A CAREFULLY PREPARED PROTOCOL BASED ON CURRENT MEDICAL PRACTICES BE FOLLOWED, PREFERABLY BY AN EXPERIENCED TEAM. SUMMARY HIGHLIGHTS OF COMPLICATIONS (consult current medical literature).<br/>Pregnancy Category C: Animal reproduction studies have not been conducted with Aminosyn. It is not known whether Aminosyn, Sulfite-Free, (a crystalline amino acid solution) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Aminosyn should be given to a pregnant woman only if clearly needed.<br/>Geriatric Use: Clinical studies of Aminosyn 3.5% have not been performed to determine whether patients over 65 years respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal functions. CLINICAL EVALUATION AND LABORATORY DETERMINATIONS, AT THE DISCRETION OF THE ATTENDING PHYSICIAN, ARE NECESSARY FOR PROPER MONITORING DURING ADMINISTRATION. Do not withdraw venous blood for blood chemistries through the peripheral infusion site, as interference with estimations of nitrogen containing substances may occur. Blood studies should include glucose, urea nitrogen, serum electrolytes, ammonia, cholesterol, acid-base balance, serum proteins, kidney and liver function tests, osmolarity and hemogram. White blood count and blood cultures are to be determined if indicated. Urinary osmolality and glucose should be determined as necessary. Aminosyn contains no more than 25 mcg/L of aluminum.<br/>Drug Interactions: Because of its antianabolic activity, concurrent administration of tetracycline may reduce the potential anabolic effects of amino acids infused with dextrose as part of a parenteral feeding regimen. Additives may be incompatible. Consult with pharmacist if available. When introducing additives, use aseptic technique, mix thoroughly and do not store. | lld:dailymed |
| dailymed-drugs:42 | dailymed-instance:precautio... | General: This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial. Following prolonged therapy, withdrawal of corticosteroids may result in symptoms of the corticosteroid withdrawal syndrome including fever, myalgia, arthralgia and malaise. This may occur in patients even without evidence of adrenal insufficiency. There is an enhanced effect of corticosteroids in patients with hypothyroidism and in those with cirrhosis. Corticosteroids should be used cautiously in patients with ocular herpes simplex for fear of corneal perforation. The lowest possible dose of corticosteroid should be used to control the condition under treatment, and when reduction in dosage is possible, the reduction must be gradual. Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. Steroids should be used with caution in nonspecific ulcerative colitis, if there is a probability of impending perforation, abscess, or other pyogenic infection, also in diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer, renal insufficiency, hypertension, osteoporosis and myasthenia gravis. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving large doses of corticosteroids may be minimal or absent. Fat embolism has been reported as a possible complication of hypercortisonism. When large doses are given, some authorities advise that antacids be administered between meals to help prevent peptic ulcer. Growth and development of infants and children on prolonged corticosteroid therapy should be carefully followed. Steroids may increase or decrease motility and number of spermatozoa in some patients. Phenytoin, phenobarbital, ephedrine and rifampin may enhance the metabolic clearance of corticosteroids resulting in decreased blood levels and lessened physiologic activity, thus requiring adjustment in corticosteroid dosage. These interactions may interfere with dexamethasone suppression tests which should be interpreted with caution during administration of these drugs. False negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported. Thus, results of the DST should be interpreted with caution in these patients. The prothrombin time should be checked frequently in patients who are receiving corticosteroids and coumarin anticoagulants at the same time because of reports that corticosteroids have altered the response to these anticoagulants. Studies have shown that the usual effect produced by adding corticosteroids is inhibition of response to coumarins, although there have been some conflicting reports of potentiation not substantiated by studies. When corticosteroids are administered concomitantly with potassium-depleting diuretics, patients should be observed closely for development of hypokalemia. Intra-articular injection of a corticosteroid may produce systemic as well as local effects. Appropriate examination of any joint fluid present is necessary to exclude a septic process. A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever and malaise is suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted. Injection of a steroid into an infected site is to be avoided. Corticosteroids should not be injected into unstable joints. Patients should be impressed strongly with the importance of not overusing joints in which symptomatic benefit has been obtained as long as the inflammatory process remains active. Frequent intra-articular injection may result in damage to joint tissues. The slower rate of absorption by intramuscular administration should be recognized.<br/>Information for Patients: Persons who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay. | lld:dailymed |
| dailymed-drugs:43 | dailymed-instance:precautio... | General:: The safety and effectiveness of local anesthetics depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use. (See WARNINGS, ADVERSE REACTIONS, and OVERDOSAGE.) During major regional nerve blocks, the patient should have IV fluids running via an indwelling catheter to assure a functioning intravenous pathway. The lowest dosage of local anesthetic that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. The rapid injection of a large volume of local anesthetic solution should be avoided and fractional (incremental) doses should be used when feasible. Epidural Anesthesia: During epidural administration of Bupivacaine Hydrochloride, 0.5% and 0.75% solutions should be administered in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. Injections should be made slowly, with frequent aspirations before and during the injection to avoid intravascular injection. Syringe aspirations should also be performed before and during each supplemental injection in continuous (intermittent) catheter techniques. An intravascular injection is still possible even if aspirations for blood are negative. During the administration of epidural anesthesia, it is recommended that a test dose be administered initially and the effects monitored before the full dose is given. When using a���continuous���catheter technique, test doses should be given prior to both the original and all reinforcing doses, because plastic tubing in the epidural space can migrate into a blood vessel or through the dura. When clinical conditions permit, the test dose should contain epinephrine (10 mcg to 15 mcg has been suggested) to serve as a warning of unintended intravascular injection. If injected into a blood vessel, this amount of epinephrine is likely to produce a transient���epinephrine response���within 45 seconds, consisting of an increase in heart rate and/or systolic blood pressure, circumoral pallor, palpitations, and nervousness in the unsedated patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds. Therefore, following the test dose, the heart rate should be monitored for a heart rate increase. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring can detect a transient rise in systolic blood pressure. The test dose should also contain 10 mg to 15 mg of Bupivacaine Hydrochloride or an equivalent amount of another local anesthetic to detect an unintended intrathecal administration. This will be evidenced within a few minutes by signs of spinal block (e.g., decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk). The Test Dose formulation of Bupivacaine Hydrochloride contains 15 mg of bupivacaine and 15 mcg of epinephrine in a volume of 3 mL. An intravascular or subarachnoid injection is still possible even if results of the test dose are negative. The test dose itself may produce a systemic toxic reaction, high spinal or epinephrine-induced cardiovascular effects. Injection of repeated doses of local anesthetics may cause significant increases in plasma levels with each repeated dose due to slow accumulation of the drug or its metabolites, or to slow metabolic degradation. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients and acutely ill patients should be given reduced doses commensurate with their age and physical status. Local anesthetics should also be used with caution in patients with hypotension or heartblock. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient's state of consciousness should be performed after each local anesthetic injection. It should be kept in mind at such times that restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression, or drowsiness may be early warning signs of central nervous system toxicity. Local anesthetic solutions containing a vasoconstrictor should be used cautiously and in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply such as digits, nose, external ear, or penis. Patients with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result. Because amide-local anesthetics such as Bupivacaine Hydrochloride are metabolized by the liver, these drugs, especially repeat doses, should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations. Local anesthetics should also be used with caution in patients with impaired cardiovascular function because they may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by these drugs. Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are employed in patients during or following the administration of potent inhalation anesthetics. In deciding whether to use these products concurrently in the same patient, the combined action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should be taken into account. Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Because it is not known whether amide-type local anesthetics may trigger this reaction and because the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for management should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure, and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s) and prompt institution of treatment, including oxygen therapy, indicated supportive measures and dantrolene. (Consult dantrolene sodium intravenous package insert before using.) Use in Head and Neck Area: Small doses of local anesthetics injected into the head and neck area, including retrobulbar, dental, and stellate ganglion blocks, may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. The injection procedures require the utmost care. Confusion, convulsions, respiratory depression, and/or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. They may also be due to puncture of the dural sheath of the optic nerve during retrobulbar block with diffusion of any local anesthetic along the subdural space to the midbrain. Patients receiving these blocks should have theircirculation and respiration monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded. (See DOSAGE AND ADMINISTRATION.) Use in Ophthalmic Surgery: Clinicians who perform retrobulbar blocks should be aware that there have been reports of respiratory arrest following local anesthetic injection. Prior to retrobulbar block, as with all other regional procedures, the immediate availability of equipment, drugs, and personnel to manage respiratory arrest or depression, convulsions, and cardiac stimulation or depression should be assured (see also WARNINGS and Use In Head and Neck Area, above). As with other anesthetic procedures, patients should be constantly monitored following ophthalmic blocks for signs of these adverse reactions, which may occur following relatively low total doses. A concentration of 0.75% bupivacaine is indicated for retrobulbar block; however, this concentration is not indicated for any other peripheral nerve block, including the facial nerve, and not indicated for local infiltration, including the conjunctiva (see INDICATIONS and PRECAUTIONS, General). Mixing Bupivacaine Hydrochloride with other local anesthetics is not recommended because of insufficient data on the clinical use of such mixtures. When Bupivacaine Hydrochloride 0.75% is used for retrobulbar block, complete corneal anesthesia usually precedes onset of clinically acceptable external ocular muscle akinesia. Therefore, presence of akinesia rather than anesthesia alone should determine readiness of the patient for surgery.<br/>Information for Patients:: When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of caudal or epidural anesthesia. Also, when appropriate, the physician should discuss other information including adverse reactions in the package insert of Bupivacaine Hydrochloride.<br/>Clinically Significant Drug Interactions:: The administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential. Concurrent administration of vasopressor drugs and of ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:: Long-term studies in animals of most local anesthetics including bupivacaine to evaluate the carcinogenic potential have not been conducted. Mutagenic potential or the effect on fertility has not been determined. There is no evidence from human data that Bupivacaine Hydrochloride may be carcinogenic or mutagenic or that it impairs fertility.<br/>Pregnancy Category C:: Decreased pup survival in rats and an embryocidal effect in rabbits have been observed when bupivacaine hydrochloride was administered to these species in doses comparable to nine and five times respectively the maximum recommended daily human dose (400 mg). There are no adequate and well-controlled studies in pregnant women of the effect of bupivacaine on the developing fetus. Bupivacaine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. This does not exclude the use of Bupivacaine Hydrochloride at term for obstetrical anesthesia or analgesia. (See Labor and Delivery.)<br/>Labor and Delivery:: SEE BOXED WARNING REGARDING OBSTETRlCAL USE OF 0.75% BUPIVACAINE HYDROCHLORIDE. Bupivacaine Hydrochloride is contraindicated for obstetrical paracervical block anesthesia. Local anesthetics rapidly cross the placenta, and when used for epidural, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity. (See Pharmacokinetics in CLINICAL PHARMACOLOGY.) The incidence and degree of toxicity depend upon the procedure performed, the type, and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus, and neonate involve alterations of the central nervous system, peripheral vascular tone, and cardiac function. Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient's legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously and electronic fetal monitoring is highlyadvisable. Epidural, caudal, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. Epidural anesthesia has been reported to prolong the second stage of labor by removing the parturient's reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. This has not been reported with bupivacaine. It is extremely important to avoid aortocaval compression by the gravid uterus during administration of regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus position or a blanket roll or sandbag may be placed beneath the right hip and gravid uterus displaced to the left.<br/>Nursing Mothers:: Bupivacaine has been reported to be excreted in human milk suggesting that the nursing infant could be theoretically exposed to a dose of the drug. Because of the potential for serious adverse reactions in nursing infants from bupivacaine, a decision should be made whether to discontinue nursing or not administer bupivacaine, taking into account the importance of the drug to the mother.<br/>Pediatric Use:: Until further experience is gained in pediatric patients younger than 12 years, administration of Bupivacaine Hydrochloride in this age group is not recommended. Continuous infusions of bupivacaine in children have been reported to result in high systemic levels of bupivacaine and seizures; high plasma levels may also be associated with cardiovascular abnormalities. (See WARNINGS, PRECAUTIONS, and OVERDOSAGE.)<br/>Geriatric Use:: Patients over 65 years, particularly those with hypertension, may be at increased risk for developing hypotension while undergoing anesthesia with Bupivacaine Hydrochloride. (See ADVERSE REACTIONS.) Elderly patients may require lower doses of Bupivacaine Hydrochloride. (See PRECAUTIONS, Epidural Anesthesia and DOSAGE AND ADMINISTRATION.) In clinical studies, differences in various pharmacokinetic parameters have been observed between elderly and younger patients. (See CLINICAL PHARMACOLOGY.) This product is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY.) | lld:dailymed |
| dailymed-drugs:46 | dailymed-instance:precautio... | Granisetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of granisetron in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distention.<br/>Drug Interactions: Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system in vitro. There have been no definitive drug-drug interaction studies to examine pharmacokinetic or pharmacodynamic interaction with other drugs; however, in humans, granisetron hydrochloride injection has been safely administered with drugs representing benzodiazepines, neuroleptics, and anti-ulcer medications commonly prescribed with antiemetic treatments. Granisetron hydrochloride injection also does not appear to interact with emetogenic cancer chemotherapies. Because granisetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of granisetron. No specific interaction studies have been conducted in anesthetized patients. In addition, the activity of the cytochrome P-450 subfamily 3A4 (involved in the metabolism of some of the main narcotic analgesic agents) is not modified by granisetron in vitro. In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of granisetron. However, the clinical significance of in vivo pharmacokinetic interactions with ketoconazole is not known. In a human pharmacokinetic study, hepatic enzyme induction with phenobarbital resulted in a 25% increase in total plasma clearance of intravenous granisetron. The clinical significance of this change is not known.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 24 month carcinogenicity study, rats were treated orally with granisetron 1, 5 or 50 mg/kg/ day (6, 30 or 300 mg/m/day). The 50 mg/kg/day dose was reduced to 25 mg/kg/day (150 mg/m/day) during week 59 due to toxicity. For a 50 kg person of average height (1.46 mbody surface area), these doses represent 4, 20, and 101 times the recommended clinical dose (1.48 mg/m, oral) on a body surface area basis. There was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in males treated with 5 mg/kg/day (30 mg/m/day, 20 times the recommended human dose based on body surface area) and above, and in females treated with 25 mg/kg/day (150 mg/m/day, 101 times the recommended human dose based on body surface area). No increase in liver tumors was observed at a dose of 1 mg/kg/day (6 mg/m/day, 4 times the recommended human dose based on body surface area) in males and 5 mg/kg/day (30 mg/m/day, 20 times the recommended human dose based on body surface area) in females. In a 12 month oral toxicity study, treatment with granisetron 100 mg/kg/day (600 mg/m/day, 405 times the recommended human dose based on body surface area) produced hepatocellular adenomas in male and female rats while no such tumors were found in the control rats. A 24 month mouse carcinogenicity study of granisetron did not show a statistically significant increase in tumor incidence, but the study was not conclusive. Because of the tumor findings in rat studies, granisetron hydrochloride should be prescribed only at the dose and for the indication recommended (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION). Granisetron was not mutagenic in in vitro Ames test and mouse lymphoma cell forward mutation assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat hepatocyte UDS assays. It, however, produced a significant increase in UDS in HeLa cells in vitro and a significant increased incidence of cells with polyploidy in an in vitro human lymphocyte chromosomal aberration test. Granisetron at oral doses up to 100 mg/kg/day (600 mg/m/day, 405 times the recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: It is not known whether granisetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when granisetron hydrochloride is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric Use: During clinical trials, 325 patients 65 years of age or older received granisetron hydrochloride tablets; 298 were 65 to 74 years of age, and 27 were 75 years of age or older. Efficacy and safety were maintained with increasing age. | lld:dailymed |
| dailymed-drugs:47 | dailymed-instance:precautio... | See PRECAUTIONS���General. Some clinicians consider multiple myeloma a contraindication to excretory urography because of the great possibility of producing transient to fatal renal failure. Others believe that the risk of causing anuria is definite but small. If excretory urography is performed in the presence of multiple myeloma, dehydration should be avoided since it favors protein precipitation in renal tubules. Although azotemia is not considered a contraindication, care is required in patients with advanced renal failure. The usual preparatory dehydration should be omitted, and urinary output should be observed for one to two days in these patients. Adequate visualization may be difficult or impossible to attain in patients with severely impaired renal and/or hepatic function. Use with extreme caution in patients with concomitant hepatorenal disease.<br/>Preparatory Dehydration: Preparatory dehydration is dangerous in infants, young children, the elderly, and azotemic patients (especially those with polyuria, oliguria, diabetes, advanced vascular disease, or preexisting dehydration). The undesirable dehydration in these patients may be accentuated by the osmotic diuretic action of the medium. Dehydration may improve image quality in patients with adequate renal function particularly if a low dose is used. Dehydration, however, will not improve contrast quality in patients with substantial renal insufficiencies and will increase risk of contrast induced renal damage. Dehydration in these patients is therefore contraindicated. | lld:dailymed |
| dailymed-drugs:48 | dailymed-instance:precautio... | General: 1. Symptomatic response to nizatidine therapy does not preclude the presence of gastric malignancy. 2. Because nizatidine is excreted primarily by the kidney, dosage should be reduced in patients with moderate to severe renal insufficiency (see Dosage and Administration). 3. Pharmacokinetic studies in patients with hepatorenal syndrome have not been done. Part of the dose of nizatidine is metabolized in the liver. In patients with normal renal function and uncomplicated hepatic dysfunction, the disposition of nizatidine is similar to that in normal subjects.<br/>Laboratory tests: False-positive tests for urobilinogen with Multistix' may occur during therapy with nizatidine.<br/>Interactions:<br/>Drug interactions: No interactions have been observed between Axid and theophylline, chlordiazepoxide, lorazepam, lidocaine, phenytoin, and warfarin. Axid does not inhibit the cytochrome P-450-linked drug-metabolizing enzyme system; therefore, drug interactions mediated by inhibition of hepatic metabolism are not expected to occur. In patients given very high doses (3,900 mg) of aspirin daily, increases in serum salicylate levels were seen when nizatidine, 150 mg b.i.d., was administered concurrently.<br/>Carcinogenesis, mutagenesis, impairment of fertility: A 2���year oral carcinogenicity study in rats with doses as high as 500 mg/kg/day (about 80 times the recommended daily therapeutic dose) showed no evidence of a carcinogenic effect. There was a dose-related increase in the density of enterochromaffin-like (ECL) cells in the gastric oxyntic mucosa. In a 2-year study in mice, there was no evidence of a carcinogenic effect in male mice; although hyperplastic nodules of the liver were increased in the high-dose males as compared with placebo. Female mice given the high dose of Axid (2,000 mg/kg/day, about 330 times the human dose) showed marginally statistically significant increases in hepatic carcinoma and hepatic nodular hyperplasia with no numerical increase seen in any of the other dose groups. The rate of hepatic carcinoma in the high-dose animals was within the historical control limits seen for the strain of mice used. The female mice were given a dose larger than the maximum tolerated dose, as indicated by excessive (30%) weight decrement as compared with concurrent controls and evidence of mild liver injury (transaminase elevations). The occurrence of a marginal finding at high dose only in animals given an excessive and somewhat hepatotoxic dose, with no evidence of a carcinogenic effect in rats, male mice, and female mice (given up to 360 mg/kg/day, about 60 times the human dose), and a negative mutagenicity battery are not considered evidence of a carcinogenic potential for Axid. Axid was not mutagenic in a battery of tests performed to evaluate its potential genetic toxicity, including bacterial mutation tests, unscheduled DNA synthesis, sister chromatid exchange, mouse lymphoma assay, chromosome aberration tests, and a micronucleus test. In a 2-generation, perinatal and postnatal fertility study in rats, doses of nizatidine up to 650 mg/kg/day produced no adverse effects on the reproductive performance of parental animals or their progeny.<br/>Pregnancy:<br/>Teratogenic effects Pregnancy Category B: Oral reproduction studies in pregnant rats at doses up to 1500 mg/kg/day (9000 mg/m/day, 40.5 times the recommended human dose based on body surface area) and in pregnant rabbits at doses up to 275 mg/kg/day (3245 mg/m/day, 14.6 times the recommended human dose based on body surface area) have revealed no evidence of impaired fertility or harm to the fetus due to nizatidine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, thisdrug should be used during pregnancy only if clearly needed.<br/>Nursing mothers: Studies conducted in lactating women have shown that 0.1% of the administered oral dose of nizatidine is secreted in human milk in proportion to plasma concentrations. Because of the growth depression in pups reared by lactating rats treated with nizatidine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric use: Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric use: Of the 955 patients in clinical studies who were treated with nizatidine, 337 (35.3%) were 65 and older. No overall differences in safety or effectiveness were observed between these and younger subjects. Other reported clinical experience has not identified differences and responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see Dosage and Administration). | lld:dailymed |
| dailymed-drugs:49 | dailymed-instance:precautio... | Administration of hypertonic dextrose and amino acid solutions via central venous catheter may be associated with complications which can be prevented or minimized by careful attention to all aspects of the procedure. This includes attention to solution preparation, administration and patient monitoring. It is essential that carefully prepared protocol, based upon current medical practice, be followed, preferably by an experienced team. The package insert of the protein (nitrogen) source should be consulted for dosage and all precautionary information. Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentration, and acid base balance during prolonged parenteral therapy or whenever the conditions of the patient warrants such evaluation. Care should be taken to avoid circulatory overload, particularly in patients with cardiac insufficiency. Caution must be exercised in the administration of these injections to patients receiving corticosteroids or corticotropin. These injections should be used with caution in patients with overt or subclinical diabetes mellitus. Drug product contains no more than 25��g//L of aluminum.<br/>Carcinogenesis and Mutagenesis and Impairment of Fertility: Studies with 50% and 70% Dextrose Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: Caution should be exercised when 50% and 70% Dextrose Injection, USP is administered to a nursing woman<br/>Pediatric Use: Dextrose is safe and effective for the stated indications in pediatric patients (see INDICATIONS AND USAGE). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. Because of their hypertonicity, 50% and 70% Dextrose Injections mustbe diluted prior to administration. | lld:dailymed |
| dailymed-drugs:52 | dailymed-instance:precautio... | General: The addition of Phenytoin Sodium Injection to intravenous infusion is not recommended due to lack of solubility and resultant precipitation. Phenytoin Sodium Injection should be injected slowly (not exceeding 50 mg per minute in adults), directly into a large vein through a large-gauge needle or intravenous catheter. Each injection of intravenous Phenytoin Sodium Injection should be followed by an injection of sterile saline through the same needleor intravenous catheter to avoid local venous irritation due to the alkalinity of the solution. Continuous infusion should be avoided. Soft tissue irritation and inflammation has occurred at the site of injection with and without extravasation of intravenous phenytoin. Soft tissue irritation may vary from slight tenderness to extensive necrosis, sloughing, and in rare instances has led to amputation. Improper administration including subcutaneous or perivascular injection should be avoided to help prevent the possibility of the above. Edema, discoloration and pain of the distal limb (described as���purple glove syndrome���) have been reported following peripheral intravenous phenytoin sodium injection. This may or may not be associated with extravasation. Although resolution of symptoms may be spontaneous, skin necrosis and limb ischemia have occurred and required such interventions as fasciotomies, skin grafting and amputation. Therefore, Phenytoin Sodium Injection should be administered as described above. The liver is the site of biotransformation. Patients with impaired liver function, elderly patients, or those who are gravely ill may show early toxicity. A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined. Phenytoin should be discontinued if a skin rash appears (see WARNINGS section regarding drug discontinuation). If the rash is exfoliative, purpuric, or bullous or if lupus erythematosus or Stevens-Johnson syndrome is suspected, use of this drug should not be resumed and alternative therapy should be considered. If the rash is of a milder type (measles-like or scarlatiniform), therapy may be resumed after the rash has completely disappeared. If the rash recurs upon reinstitution of therapy, further phenytoin medication is contraindicated. Hyperglycemia, resulting from the drug's inhibitory effects on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients. Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated. Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence (petit mal) seizures are present, combined drug therapy is needed. Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as���delirium,������psychosis,���or���encephalopathy,���or rarely irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, plasma levels are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended.<br/>Laboratory Tests: Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments.<br/>Drug Interactions: There are many drugs which may increase or decrease phenytoin levels or which phenytoin may affect. The most commonly occurring drug interactions are listed below: Serum level determinations are especially helpful when possible drug interactions are suspected.<br/>Drug and/or Laboratory Test Interactions: Phenytoin may cause decreased serum levels of protein-bound iodine (PBI). It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose, alkaline phosphatase and gamma glutamyl transpeptidase (GGT).<br/>Carcinogenesis: See WARNINGS section for information on carcinogenesis.<br/>Pregnancy: See WARNINGS.<br/>Nursing Mothers: Infant breast feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk. | lld:dailymed |
| dailymed-drugs:54 | dailymed-instance:precautio... | General: Prescribing rifampin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. For the treatment of tuberculosis, rifampin is usually administered on a daily basis. Doses of rifampin greater than 600 mg given once or twice weekly have resulted in a higher incidence of adverse reactions, including the "flu syndrome" (fever, chills and malaise), hematopoietic reactions (leukopenia, thrombocytopenia, or acute hemolytic anemia), cutaneous, gastrointestinal, and hepatic reactions, shortness of breath, shock, anaphylaxis, and renal failure. Recent studies indicate that regimens using twice-weekly doses of rifampin 600 mg plus isoniazid 15 mg/kg are much better tolerated. Intermittent therapy may be used if the patient cannot (or will not) self-administer drugs on a daily basis. Patients on intermittent therapy should be closely monitored for compliance and cautioned against intentional or accidental interruption of prescribed therapy, because of the increased risk of serious adverse reactions. Rifampin has enzyme induction properties that can enhance the metabolism of endogenous substrates including adrenal hormones, thyroid hormones, and vitamin D. Rifampin and isoniazid have been reported to alter vitamin D metabolism. In some cases, reduced levels of circulating 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D have been accompanied by reduced serum calcium and phosphate, and elevated parathyroid hormone.<br/>RIFADIN IV: For intravenous infusion only. Must not be administered by intramuscular or subcutaneous route. Avoid extravasation during injection: local irritation and inflammation due to extravascular infiltration of the infusion have been observed. If these occur, the infusion should be discontinued and restarted at another site.<br/>Information for Patients: Patients should be counseled that antibacterial drugs including rifampin should only be used to treat bacterial infections. They do not treat viral infections (eg, the common cold). When rifampin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by rifampin or other antibacterial drugs in the future. The patient should be told that rifampin may produce a reddish coloration of the urine, sweat, sputum, and tears, and the patient should be forewarned of this. Soft contact lenses may be permanently stained. The patient should be advised that the reliability of oral or other systemic hormonal contraceptives may be affected; consideration should be given to using alternative contraceptive measures. Patients should be instructed to take rifampin either 1 hour before or 2 hours after a meal with a full glass of water. Patients should be instructed to notify their physicians promptly if they experience any of the following: fever, loss of appetite, malaise, nausea and vomiting, darkened urine, yellowish discoloration of the skin and eyes, and pain or swelling of the joints. Compliance with the full course of therapy must be emphasized, and the importance of not missing any doses must be stressed.<br/>Laboratory Tests: Adults treated for tuberculosis with rifampin should have baseline measurements of hepatic enzymes, bilirubin, serum creatinine, a complete blood count, and a platelet count (or estimate). Baseline tests are unnecessary in pediatric patients unless a complicating condition is known or clinically suspected. Patients should be seen at least monthly during therapy and should be specifically questioned concerning symptoms associated with adverse reactions. All patients with abnormalities should have follow-up, including laboratory testing, if necessary. Routine laboratory monitoring for toxicity in people with normal baseline measurements is generally not necessary.<br/>Drug Interactions:<br/>ENZYME INDUCTION: Rifampin is known to induce certain cytochrome P���450 enzymes. Administration of rifampin with drugs that undergo biotransformation through these metabolic pathways may accelerate elimination of coadministered drugs. To maintain optimum therapeutic blood levels, dosages of drugs metabolized by these enzymes may require adjustment when starting or stopping concomitantly administered rifampin. Rifampin has been reported to accelerate the metabolism of the following drugs: anticonvulsants (eg, phenytoin), antiarrhythmics (eg, disopyramide, mexiletine, quinidine, tocainide), oral anticoagulants, antifungals (eg, fluconazole, itraconazole, ketoconazole), barbiturates, beta-blockers, calcium channel blockers (eg, diltiazem, nifedipine, verapamil), chloramphenicol, clarithromycin, corticosteroids, cyclosporine, cardiac glycoside preparations, clofibrate, oral or other systemic hormonal contraceptives, dapsone, diazepam, doxycycline, fluoroquinolones (eg, ciprofloxacin), haloperidol, oral hypoglycemic agents (sulfonylureas), levothyroxine, methadone, narcotic analgesics, nortriptyline, progestins, quinine, tacrolimus, theophylline tricyclic antidepressants (eg, amitriptyline, nortriptyline) and zidovudine. It may be necessary to adjust the dosages of these drugs if they are given concurrently with rifampin. Patients using oral or other systemic hormonal contraceptives should be advised to change to nonhormonal methods of birth control during rifampin therapy. Rifampin has been observed to increase the requirements for anticoagulant drugs of the coumarin type. In patients receiving anticoagulants and rifampin concurrently, it is recommended that the prothrombin time be performed daily or as frequently as necessary to establish and maintain the required dose of anticoagulant. Diabetes may become more difficult to control.<br/>OTHER INTERACTIONS: When the two drugs were taken concomitantly, decreased concentrations of atovaquone and increased concentrations of rifampin were observed. Concurrent use of ketoconazole and rifampin has resulted in decreased serum concentrations of both drugs. Concurrent use of rifampin and enalapril has resulted in decreased concentrations of enalaprilat, the active metabolite of enalapril. Dosage adjustments should be made if indicated by the patient's clinical condition. Concomitant antacid administration may reduce the absorption of rifampin. Daily doses of rifampin should be given at least 1 hour before the ingestion of antacids. Probenecid and cotrimoxazole have been reported to increase the blood level of rifampin. When rifampin is given concomitantly with either halothane or isoniazid, the potential for hepatotoxicity is increased. The concomitant use of rifampin and halothane should be avoided. Patients receiving both rifampin and isoniazid should be monitored close for hepatotoxicity. Plasma concentrations of sulfapyridine may be reduced following the concomitant administration of sulfasalazine and rifampin. This finding may be the result of alteration in the colonic bacteria responsible for the reduction of sulfasalazine to sulfapyridine and mesalamine.<br/>Drug/Laboratory Interactions: Cross-reactivity and false-positive urine screening tests for opiates have been reported in patients receiving rifampin when using the KIMS (Kinetic Interaction of Microparticles in Solution) method (eg, Abuscreen OnLine opiates assay; Roche Diagnostic Systems). Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish rifampin from opiates. Therapeutic levels of rifampin have been shown to inhibit standard microbiological assays for serum folate and vitamin B. Thus, alternate assay methods should be considered. Transient abnormalities in liver function tests (eg, elevation in serum bilirubin, alkaline phosphatase, and serum transaminases) and reduced biliary excretion of contrast media used for visualization of the gallbladder have also been observed. Therefore, these tests should be performed before the morning dose of rifampin.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: There are no known human data on long-term potential for carcinogenicity, mutagenicity, or impairment of fertility. A few cases of accelerated growth of lung carcinoma have been reported in man, but a causal relationship with the drug has not been established. An increase in the incidence of hepatomas in female mice (of a strain known to be particularly susceptible to the spontaneous development of hepatomas) was observed when rifampin was administered in doses 2 to 10 times the average daily human dose for 60 weeks, followed by an observation period of 46 weeks. No evidence of carcinogenicity was found in male mice of the same strain, mice of a different strain, or rats under similar experimental conditions. Rifampin has been reported to possess immunosuppressive potential in rabbits, mice, rats, guinea pigs, human lymphocytes in vitro, and humans. Antitumor activity in vitro has also been shown with rifampin. There was no evidence of mutagenicity in bacteria, Drosophila melanogaster, or mice. An increase in chromatid breaks was noted when whole blood cell cultures were treated with rifampin. Increased frequency of chromosomal aberrations was observed in vitro in lymphocytes obtained from patients treated with combinations of rifampin, isoniazid, and pyrazinamide and combinations of streptomycin, rifampin, isoniazid, and pyrazinamide.<br/>Pregnancy���Teratogenic Effects: Category C Rifampin has been shown to be teratogenic in rodents given oral doses of rifampin 15 to 25 times the human dose. Although rifampin has been reported to cross the placental barrier and appear in cord blood, the effect of RIFADIN, alone or in combination with other antituberculosis drugs, on the human fetus is not known. Neonates of rifampin-treated mothers should be carefully observed for any evidence of adverse effects.Isolated cases of fetal malformations have been reported; however, there are no adequate and well-controlled studies in pregnant women. Rifampin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Rifampin in oral doses of 150 to 250 mg/kg produced teratogenic effects in mice and rats. Malformations were primarily cleft palate in the mouse and spina bifida in the rat. The incidence of these anomalies was dose-dependent. When rifampin was given to pregnantrabbits in doses up to 20 times the usual daily human dose, imperfect osteogenesis and embryotoxicity were reported.<br/>Pregnancy���Non-Teratogenic Effects: When administered during the last few weeks of pregnancy, rifampin can cause post-natal hemorrhages in the mother and infant for which treatment with vitamin K may be indicated.<br/>Nursing Mothers: Because of the potential for tumorigenicity shown for rifampin in animal studies, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: See CLINICAL PHARMACOLOGY���Pediatrics; see also DOSAGE AND ADMINISTRATION.<br/>Geriatric Use: Clinical studies of RIFADIN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Caution should therefore be observed in using rifampin in elderly patients. . | lld:dailymed |
| dailymed-drugs:55 | dailymed-instance:precautio... | General: Prescribing Cephalexin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Patients should be followed carefully so that any side effects or unusual manifestations of drug idiosyncrasy may be detected. If an allergic reaction to Cephalexin Capsules, USP occurs, the drug should be discontinued and the patient treated with the usual agents (eg, epinephrine or other pressor amines, antihistamines, or corticosteroids). Prolonged use of Cephalexin Capsules, USP may result in the overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken. Positive direct Coombs' tests have been reported during treatment with the cephalosporin antibiotics. In hematologic studies or in transfusion cross-matching procedures when antiglobulin tests are performed on the minor side or in Coombs' testing of newborns whose mothers have received cephalosporin antibiotics before parturition, it should be recognized that a positive Coombs' test may be due to the drug. Cephalexin Capsules, USP should be administered with caution in the presence of markedly impaired renal function. Under such conditions, careful clinical observation and laboratory studies should be made because safe dosage may be lower than that usually recommended. Indicated surgical procedures should be performed in conjunction with antibiotic therapy. As a result of administration of Cephalexin Capsules, USP, a false-positive reaction for glucose in the urine may occur. This has been observed with Benedict's and Fehling's solutions and also with Clinitest tablets. Broad-spectrum antibiotics should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.<br/>Information for Patients:: Patients should be counseled that antibacterial drugs including Cephalexin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cephalexin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Cephalexin or other antibacterial drugs in the future.<br/>Drug Interactions: Metformin���In healthy subjects given single 500 mg doses of cephalexin and metformin, plasma metformin mean Cmax and AUC increased by an average of 34% and 24%, respectively, and metformin mean renal clearance decreased by 14%. No information is available about the interaction of cephalexin and metformin following multiple doses of either drug. Although not observed in this study, adverse effects could potentially arise from co-administration of cephalexin and metformin by inhibition of tubular secretion via organic cationic transporter systems. Accordingly, careful patient monitoring and dose adjustment of metformin is recommended in patients concomitantly taking cephalexin and metformin. Probenecid���As with other��-lactams, the renal excretion of cephalexin is inhibited by probenecid. Usage in Pregnancy Pregnancy Category B���The daily oral administration of cephalexin to rats in doses of 250 or 500 mg/kg prior to and during pregnancy, or to rats and mice during the period of organogenesis only, had no adverse effect on fertility, fetal viability, fetal weight, or litter size. Note that the safety of cephalexin during pregnancy in humans has not been established. Cephalexin showed no enhanced toxicity in weanling and newborn rats as compared with adult animals. Nevertheless, because the studies in humans cannot rule out the possibility of harm, Cephalexin Capsules, USP should be used during pregnancy only if clearly needed.<br/>Nursing Mothers: The excretion of cephalexin in the milk increased up to 4 hours after a 500-mg dose; the drug reached a maximum level of 4 mcg/mL, then decreased gradually, and had disappeared 8 hours after administration. Caution should be exercised when Cephalexin Capsules, USP is administered to a nursing woman.<br/>Geriatric Use: Of the 701 subjects in 3 published clinical studies of cephalexin, 433 (62%) were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function . | lld:dailymed |
| dailymed-drugs:58 | dailymed-instance:precautio... | General:<br/>Glipizide and Metformin Hydrochloride Tablets:<br/>Glipizide:<br/>Metformin Hydrochloride:<br/>Information for Patients:<br/>Glipizide and Metformin Hydrochloride Tablets: Patients should be informed of the potential risks and benefits of glipizide and metformin hydrochloride tablets and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters. The risks of lactic acidosis associated with metformin therapy, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue glipizide and metformin hydrochloride tablets immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of glipizide and metformin hydrochloride tablets, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving glipizide and metformin hydrochloride tablets. (See Patient Information printed below.)<br/>Laboratory Tests: Periodic fasting blood glucose and glycosylated hemoglobin (HbA) measurements should be performed to monitor therapeutic response. Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, Vitamin Bdeficiency should be excluded.<br/>Drug Interactions:<br/>Glipizide and Metformin Hydrochloride Tablets: Certain drugs tend to produce hyperglycemia and may lead to loss of blood glucose control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving glipizide and metformin hydrochloride tablets, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving glipizide and metformin hydrochloride tablets, the patient should be observed closelyfor hypoglycemia. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid as compared to sulfonylureas, which are extensively bound to serum proteins.<br/>Glipizide: The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents, some azoles, and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such drugs are administered to a patient receiving glipizide and metformin hydrochloride tablets, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving glipizide and metformin hydrochloride tablets, the patient should be observed closely for loss of blood glucose control. In vitro binding studies with human serum proteins indicate that glipizide binds differently than tolbutamide and does not interact with salicylate or dicumarol. However, caution mustbe exercised in extrapolating these findings to the clinical situation and in the use of glipizide and metformin hydrochloride tablets with these drugs. A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known. The effect of concomitant administration of fluconazole and glipizide has been demonstrated in a placebo-controlled crossover study in normal volunteers. All subjects received glipizide alone and following treatment with 100 mg of fluconazole as a single oral daily dose for 7 days, the mean percent increase in the glipizide AUC after fluconazole administration was 56.9% (range: 35 to 81%).<br/>Metformin Hydrochloride:<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No animal studies have been conducted with the combined products in glipizide and metformin hydrochloride tablets. The following data are based on findings in studies performed with the individual products.<br/>Glipizide: A 20 month study in rats and an 18 month study in mice at doses up to 75 times the maximum human dose revealed no evidence of drug-related carcinogenicity. Bacterial and in vivo mutagenicity tests were uniformly negative. Studies in rats of both sexes at doses up to 75 times the human dose showed no effects on fertility.<br/>Metformin Hydrochloride: Long-term carcinogenicity studies were performed with metformin alone in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately four times the maximum recommended human daily dose of 2000 mg of the metformin component of glipizide and metformin hydrochloride tablets based on body surface area comparisons. No evidence of carcinogenicity with metformin alone was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin alone in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day of metformin alone. There was no evidence of a mutagenic potential of metformin alone in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin alone when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose of the metformin component of glipizide and metformin hydrochloride tablets based on body surface area comparisons.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. It is not recommended that glipizideand metformin hydrochloride tablets be used during pregnancy. However, if it is used, glipizide and metformin hydrochloride tablets should be discontinued at least one month before the expected delivery date. (See Pregnancy, Teratogenic Effects, Pregnancy category C.)<br/>Nursing Mothers: Although it is not known whether glipizide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue glipizide and metformin hydrochloride tablets, taking into account the importance of the drug to the mother. If glipizide and metformin hydrochloride tablets are discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.<br/>Pediatric Use: Safety and effectiveness of glipizide and metformin hydrochloride tablets in pediatric patients have not been established.<br/>Geriatric Use: Of the 345 patients who received glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg and 2.5 mg/500 mg in the initial therapy trial, 67 (19.4%) were aged 65 and older while 5 (1.4%) were aged 75 and older. Of the 87 patients who received glipizide and metformin hydrochloride tablets in the second-line therapy trial, 17 (19.5%) were aged 65 and older while one (1.1%) was at least aged 75. No overall differences in effectiveness or safety were observed between these patients and younger patients in either the initial therapy trial or the second-line therapy trial, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Metformin hydrochloride is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, glipizide and metformin hydrochloride tablets should only be used in patients with normal renal function (see CONTRAINDICATIONS, WARNINGS, and CLINICAL PHARMACOLOGY, Pharmacokinetics). Because aging is associated with reduced renal function, glipizide and metformin hydrochloride tablets should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of glipizide and metformin hydrochloride tablets (see also WARNINGS and DOSAGE AND ADMINISTRATION). | lld:dailymed |
| dailymed-drugs:59 | dailymed-instance:precautio... | Hematologic: At the recommended dosage of BUSULFEX (busulfan) Injection, profound myelosuppression is universal, and can manifest as neutropenia, thrombocytopenia, anemia, or a combination thereof. Patients should be monitored for signs of local or systemic infection or bleeding. Their hematologic status should be evaluated frequently.<br/>Information for Patients: The increased risk of a second malignancy should be explained to the patient.<br/>Laboratory Tests: Patients receiving BUSULFEX should be monitored daily with a complete blood count, including differential count and quantitative platelet count, until engraftment has been demonstrated. To detect hepatotoxicity, which may herald the onset of hepatic venoocclusive disease, serum transaminases, alkaline phosphatase, and bilirubin should be evaluated daily through BMT Day +28.<br/>Drug Interactions: Itraconazole decreases busulfan clearance by up to 25%, and may produce an AUC>1500��M���min in some patients. Fluconazole, and the 5-HT3 antiemetics odansetron (Zofran') and granisetron (Kytril') have all been used with BUSULFEX. Phenytoin increases the clearance of busulfan by 15% or more, possibly due to the induction of glutathione-S-transferase. Since the pharmacokinetics of BUSULFEX were studied in patients treated with phenytoin, the clearance of BUSULFEX at the recommended dose may be lower and exposure (AUC) higher in patients not treated with phenytoin. Because busulfan is eliminated from the body via conjugation with glutathione, use of acetaminophen prior to (<72 hours) or concurrent with BUSULFEX may result in reduced busulfan clearance based upon the known property of acetaminophen to decrease glutathione levels in the blood and tissues.<br/>Pregnancy: Pregnancy Category D. See WARNINGS.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorgenicity shown for busulfan in human and animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Special Populations: Pediatric:The effectiveness of BUSULFEX in the treatment of CML has not been specifically studied in pediatric patients. An open-label, uncontrolled study evaluated the pharmacokinetics of BUSULFEX in 24 pediatric patients receiving BUSULFEX as part of a conditioning regimen administered prior to hematopoietic progenitor cell transplantation for a variety of malignant hematologic (N=15) or non-malignant diseases (N=9). Patients ranged in age from 5 months to 16 years (median 3 years). BUSULFEX dosing was targeted to achieve an area under the plasma concentration curve (AUC) of 900-1350��M���min with an initial dose of 0.8 mg/kg or 1.0 mg/kg (based on ABW) if the patient was>4 or���4 years, respectively. The dose was adjusted based on plasma concentration after completion of dose 1. Patients received BUSULFEX doses every six hours as a two-hour infusion over four days for a total of 16 doses, followed by cyclophosphamide 50 mg/kg once daily for four days. After one rest day, hematopoietic progenitor cells were infused. All patients received phenytoin as seizure prophylaxis. The target AUC (900-1350��5%��M���min) for BUSULFEX was achieved at dose 1 in 71% (17/24) of patients. Steady state pharmacokinetic testing was performed at dose 9 and 13. BUSULFEX levels were within the target range for 21 of 23 evaluable patients. All 24 patients experienced neutropenia (absolute neutrophil count<0.5 x 10/L) and thrombocytopenia (platelet transfusions or platelet count<20,000/mm). Seventy-nine percent (19/24) of patients experienced lymphopenia (absolute lymphocyte count<0.1 x 10). In 23 patients, the ANC recovered to>0.5 x 10/L (median time to recovery = BMT day +13; range = BMT day +9 to +22). One patient who died on day +20 had not recovered to an ANC>0.5 x 10/L. Four (17%) patients died during the study. Two patients died within 28 days of transplant; one with pneumonia and capillary leak syndrome, and the other with pneumonia and veno-occlusive disease. Two patients died prior to day 100; one due to progressive disease and one due to multi-organ failure. Adverse events were reported in all 24 patients during the study period (BMT day -10 through BMT day +28) or post-study surveillance period (day +29 through +100). These included vomiting (100%), nausea (83%), stomatitis (79%), hepatic veno-occlusive disease (HVOD) (21%), graft-versus host disease (GVHD) (25%), and pneumonia (21%). Based on the results of this 24-patient clinical trial, a suggested dosing regimen of BUSULFEX in pediatric patients is shown in the following dosing nomogram: Simulations based on a pediatric population pharmacokinetic model indicate that approximately 60% of pediatric patients will achieve a target BUSULFEX exposure (AUC) between 900 to 1350��M���min with the first dose of BUSULFEX using this dosing nomogram. Therapeutic drug monitoring and dose adjustment following the first dose of BUSULFEX is recommended. Dose Adjustment Based on Therapeutic Drug Monitoring Instructions for measuring the AUC of busulfan at dose 1 (see Blood Sample Collection for AUC Determination), and the formula for adjustment of subsequent doses to achieve the desired target AUC (1125��M���min), are provided below. Adjusted dose (mg) = Actual Dose (mg) x Target AUC (��M���min)/Actual AUC (��M���min) For example, if a patient received a dose of 11 mg busulfan and if the corresponding AUC measured was 800��M���min, for a target AUC of 1125��M���min, the target mg dose would be: Mg dose = 11 mg x 1125��M���min / 800��M���min = 15.5 mg Busulfex dose adjustment may be made using this formula and instructions below. Blood Sample Collection for AUC Determination: Calculate the AUC (��M���min) based on blood samples collected at the following time points: For dose 1: 2 hr (end of infusion), 4 hr and 6 hr (immediately prior to the next scheduled BUSULFEX administration). Actual sampling times should be recorded. For doses other than dose 1: Pre-infusion (baseline), 2 hr (end of infusion), 4 hr and 6 hr (immediately prior to the next scheduled BUSULFEX administration). AUC calculations based on fewer than the three specified samples may result in inaccurate AUC determinations. For each scheduled blood sample, collect one to three mL of blood into heparinized (Na or Li heparin) Vacutainer' tubes. The blood samples should be placed on wet ice immediately after collection and should be centrifuged (at 4��C) within one hour. The plasma, harvested into appropriate cryovial storage tubes, is to be frozen immediately at -20��C. All plasma samples are to be sent in a frozen state (i.e., on dry ice) to the assay laboratory for the determination of plasma busulfan concentrations. Calculation of AUC: BUSULFEX AUC calculations may be made using the following instructions and appropriate standard pharmacokinetic formula: Dose 1 AUCCalculation: AUC= AUC+ AUC, where AUCis to be estimated using the linear trapezoidal rule and AUC extrapolated can be computed by taking the ratio of the busulfan concentration at Hour 6 and the terminal elimination rate constant, z. The z must be calculated from the terminal elimination phase of the busulfan concentration vs. time curve. A������pre-dose busulfan concentration should be assumed, and used in the calculation of AUC. If the AUC is assessed subsequent to Dose 1, steady-state AUC(AUC) is to be estimated from the trough, 2 hr, 4 hr and 6 hr concentrations using the linear trapezoidal rule. Instructions for Drug Administration and Blood Sample Collection for Therapeutic Drug Monitoring: An administration set with minimal residual hold up (priming) volume (1-3 mL) should be used for drug infusion to ensure accurate delivery of the entire prescribed dose and to ensure accurate collection of blood samples for therapeutic drug monitoring and dose adjustment. Prime the administration set tubing with drug solution to allow accurate documentation of the start time of BUSULFEX infusion. Collect the blood sample from a peripheral IV line to avoid contamination with infusing drug. If the blood sample is taken directly from the existing central venous catheter (CVC), DO NOT COLLECT THE BLOOD SAMPLE WHILE THE DRUG IS INFUSINGto ensure that the end of infusion sample is not contaminated with any residual drug. At the end of infusion (2 hr), disconnect the administration tubing and flush the CVC line with 5 cc of normal saline prior to the collection of the end of infusion sample from the CVC port. Collect the blood samples from a different port than that used for the BUSULFEX infusion. When recording the BUSULFEX infusion stop time, do not include the time required to flush the indwelling catheter line. Discard the administration tubing at the end of thetwo-hour infusion. See Preparation for Intravenous Administration section for detailed instructions on drug preparation. Geriatric:Five of sixty-one patients treated in the BUSULFEX clinical trial were over the age of 55 (range 57-64). All achieved myeloablation and engraftment. Gender, Race:Adjusting BUSULFEX dosage based on gender or race has not been adequately studied. Renal Insufficiency:BUSULFEX has not been studied in patients with renal impairment. Hepatic Insufficiency:BUSULFEX has not been administered to patients with hepatic insufficiency. Other:Busulfan may cause cellular dysplasia in many organs. Cytologic abnormalities characterized by giant, hyperchromatic nuclei have been reported in lymph nodes, pancreas, thyroid, adrenal glands, liver, lungs and bone marrow. This cytologic dysplasia may be severe enough to cause difficulty in the interpretation of exfoliative cytologic examinations of the lungs, bladder, breast and the uterine cervix. | lld:dailymed |
| dailymed-drugs:60 | dailymed-instance:precautio... | Because magnesium is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL every four hours. Monitoring serum magnesium levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). Serum magnesium levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when serum magnesium levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of magnesium intoxication in eclampsia. Magnesium Sulfate in 5% Dextrose Injection, USP should be administered slowly to avoid producing hypermagnesemia.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:: Studies with Magnesium Sulfate in 5% Dextrose Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.<br/>Pregnancy Category A.: Studies in pregnant women have not shown that magnesium sulfate injection increases the risk of fetal abnormalities if administered during all trimesters of pregnancy. If this drug is used during pregnancy, the possibility of fetal harm appears remote. However, because studies cannot rule out the possibility of harm, magnesium sulfate solution should be used during pregnancy only if clearly needed. When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in toxemic mothers, the newborn may show signs of magnesium toxicity, including neuromuscular or respiratory depression. See OVERDOSAGE.<br/>Nursing Mothers:: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Magnesium Sulfate in 5% Dextrose Injection, USP is administered to a nursing woman. | lld:dailymed |
| dailymed-drugs:61 | dailymed-instance:precautio... | General:<br/>Activation of Mania/Hypomania: During premarketing testing, hypomania or mania occurred in approximately 1.0% of unipolar patients treated with paroxetine hydrochloride compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. In a subset of patients classified as bipolar, the rate of manic episodes was 2.2% for paroxetine hydrochloride and 11.6% for the combined active-control groups. As with all drugs effective in the treatment of major depressive disorder, paroxetine hydrochloride should be used cautiously in patients with a history of mania.<br/>Seizures: During premarketing testing, seizures occurred in 0.1% of patients treated with paroxetine hydrochloride, a rate similar to that associated with other drugs effective in the treatment of major depressive disorder. Paroxetine hydrochloride should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures.<br/>Discontinuation of Treatment With Paroxetine Tablets: Recent clinical trials supporting the various approved indications for paroxetine hydrochloride employed a taper-phase regimen, rather than an abrupt discontinuation of treatment. The taper-phase regimen used in GAD and other clinical trials involved an incremental decrease in the daily dose by 10 mg/day atweekly intervals. When a daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before treatment was stopped. With this regimen in those studies, the following adverse events were reported at an incidence of 2% or greater for paroxetine hydrochloride and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness. In the majority of patients, these events were mild to moderate andwere self-limiting and did not require medical intervention. During marketing of paroxetine hydrochloride and other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring, upon the discontinuation of these drugs (particularly when abrupt), including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with paroxetine tablets. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION). See also PRECAUTIONS, Pediatric Use, for adverse events reported upon discontinuation of treatment with paroxetine tablets in pediatric patients.<br/>Akathisia: The use of paroxetine or other SSRIs has been associated with the development of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation such as an inability to sit or stand still usually associated with subjective distress. This is most likely to occur within the first few weeks of treatment.<br/>Hyponatremia: Several cases of hyponatremia have been reported. The hyponatremia appeared to be reversible when paroxetine hydrochloride was discontinued. The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume depleted.<br/>Abnormal Bleeding: Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic agents that interfere with serotonin reuptake. Subsequent epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In 2 studies, concurrent use of a non-steroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding (see Drug Interactions). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding associatedwith the concomitant use of paroxetine with NSAIDs, aspirin, or other drugs that affect coagulation.<br/>Use in Patients With Concomitant Illness: Clinical experience with paroxetine hydrochloride in patients with certain concomitant systemic illness is limited. Caution is advisable in using paroxetine tablets in patients with diseases or conditions that could affect metabolism or hemodynamic responses. As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with paroxetine hydrochloride. A few cases of acute angle closure glaucoma associated with paroxetine therapy have been reported in the literature. As mydriasis can cause acute angle closure in patients with narrow angle glaucoma, caution should be used when paroxetine tablets are prescribed for patients with narrow angle glaucoma. Paroxetine hydrochloride has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product's premarket testing. Evaluation of electrocardiograms of 682 patients who received paroxetine hydrochloride in double-blind, placebo-controlled trials, however, did not indicate that paroxetine hydrochloride is associated with the development of significant ECG abnormalities. Similarly, paroxetine hydrochloride does not cause any clinically important changes in heart rate or blood pressure. Increased plasma concentrations of paroxetine occur in patients with severe renal impairment (creatinine clearance<30 mL/min.) or severe hepatic impairment. A lower starting dose should be used in such patients (see DOSAGE AND ADMINISTRATION).<br/>Information for Patients: Paroxetine tablets should not be chewed or crushed, and should be swallowed whole. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of paroxetine and triptans, tramadol, or other serotonergic agents. Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with paroxetine tablets and should counsel them in its appropriate use. A patient Medication Guide about���Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions���is available for paroxetine tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking paroxetine tablets.<br/>Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possiblychanges in the medication.<br/>Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.): Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding.<br/>Interference With Cognitive and Motor Performance: Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies paroxetine hydrochloride has not been shown to impair psychomotor performance, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with paroxetine hydrochloride does not affect their ability to engage in such activities.<br/>Completing Course of Therapy: While patients may notice improvement with treatment with paroxetine hydrochloride in 1 to 4 weeks, they should be advised to continue therapy as directed.<br/>Concomitant Medication: Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.<br/>Alcohol: Although paroxetine hydrochloride has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine tablets.<br/>Pregnancy: Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy (see WARNINGS, Usage in Pregnancy, Teratogenic effects and Nonteratogeniceffects).<br/>Nursing: Patients should be advised to notify their physician if they are breast-feeding an infant (see PRECAUTIONS, Nursing Mothers).<br/>Laboratory Tests: There are no specific laboratory tests recommended.<br/>Drug Interactions:<br/>Tryptophan: As with other serotonin reuptake inhibitors, an interaction between paroxetine and tryptophan may occur when they are coadministered. Adverse experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been reported when tryptophan was administered to patients taking paroxetine tablets. Consequently, concomitant use of paroxetine hydrochloride with tryptophan is not recommended (see WARNINGS, Serotonin Syndrome).<br/>Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.<br/>Pimozide: In a controlled study of healthy volunteers, after paroxetine hydrochloride was titrated to 60 mg daily, coadministration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and Cof 62%, compared to pimozide administered alone. Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and paroxetine hydrochloride is contraindicated (see CONTRAINDICATIONS).<br/>Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs, including paroxetine hydrochloride, and the potential for serotonin syndrome, caution is advised when paroxetine is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John's Wort (see WARNINGS, Serotonin Syndrome). The concomitant use of paroxetine with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS, Drug Interactions, Tryptophan).<br/>Thioridazine: See CONTRAINDICATIONS and WARNINGS.<br/>Warfarin: Preliminary data suggest that there may be a pharmacodynamic interaction (that causes an increased bleeding diathesis in the face of unaltered prothrombin time) between paroxetine and warfarin. Since there is little clinical experience, the concomitant administration of paroxetine tablets and warfarin should be undertaken with caution (see Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.)).<br/>Triptans: There have been rare postmarketing reports of serotonin syndrome with the use of an SSRI and a triptan. If concomitant use of paroxetine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome).<br/>Drugs Affecting Hepatic Metabolism: The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.<br/>Cimetidine: Cimetidine inhibits many cytochrome P(oxidative) enzymes. In a study where paroxetine hydrochloride (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during coadministration with oral cimetidine (300 mg three times daily) for the final week. Therefore, when these drugs are administered concurrently, dosage adjustment of paroxetine tablets after the 20 mg starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine's pharmacokinetics was not studied.<br/>Phenobarbital: Phenobarbital induces many cytochrome P(oxidative) enzymes. When a single oral 30 mg dose of paroxetine hydrochloride was administered at phenobarbital steady state (100 mg once daily for 14 days), paroxetine AUC and Twere reduced (by an average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. Since paroxetine hydrochloride exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustment of paroxetine tablets is considered necessarywhen coadministered with phenobarbital; any subsequent adjustment should be guided by clinical effect.<br/>Phenytoin: When a single oral 30 mg dose of paroxetine hydrochloride was administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and Twere reduced (by an average of 50% and 35%, respectively) compared to paroxetine hydrochloride administered alone. In a separate study, when a single oral 300 mg dose of phenytoin was administered at paroxetine steady state (30 mg once daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustments are considered necessary when these drugs are coadministered; any subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS, Postmarketing Reports).<br/>Drugs Metabolized by CYP2D6: Many drugs, including most drugs effective in the treatment of major depressive disorder (paroxetine, other SSRIs and many tricyclics), are metabolized by the cytochrome Pisozyme CYP2D6. Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients (>90%), this CYP2D6 isozyme is saturated early during dosing with paroxetine hydrochloride. In 1 study, daily dosing of paroxetine hydrochloride (20 mg once daily) under steady-state conditions increased single dose desipramine (100 mg) C, AUC, and Tby an average of approximately 2, 5, and 3 fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4 fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4 fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steadystate. In healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady state atomoxetine AUC values that were 6 to 8 fold greater and in atomoxetine Cvalues that were 3 to 4 fold greater than when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be initiated at a reduced dose when it is given with paroxetine. Concomitant use of paroxetine hydrochloride with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either paroxetine hydrochloride or the other drug. Therefore, coadministration of paroxetine tablets with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution. However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be coadministered (see CONTRAINDICATIONS and WARNINGS). At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by alternative Pisozymes that, unlike CYP2D6, show no evidence of saturation (see PRECAUTIONS, Tricyclic Antidepressants (TCAs)).<br/>Drugs Metabolized by Cytochrome CYP3A4: An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine. Based on the assumption that the relationship between paroxetine's in vitro Kand its lack of effect on terfenadine's in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine's extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.<br/>Tricyclic Antidepressants (TCAs): Caution is indicated in the coadministration of tricyclic antidepressants (TCAs) with paroxetine hydrochloride, because paroxetine may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is coadministered with paroxetine tablets (see PRECAUTIONS, Drugs Metabolized by CYP2D6).<br/>Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma protein, administration of paroxetine tablets to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of paroxetine by other highly bound drugs.<br/>Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.): Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin potentiated the risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with paroxetine.<br/>Alcohol: Although paroxetine hydrochloride does not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine tablets.<br/>Lithium: A multiple-dose study has shown that there is no pharmacokinetic interaction between paroxetine hydrochloride and lithium carbonate. However, due to the potential for serotonin syndrome, caution is advised when paroxetine tablets are coadministered with lithium.<br/>Digoxin: The steady-state pharmacokinetics of paroxetine was not altered when administered with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the presence of paroxetine. Since there is little clinical experience, the concurrent administration of paroxetine and digoxin should be undertaken with caution.<br/>Diazepam: Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of paroxetine on diazepam were not evaluated.<br/>Procyclidine: Daily oral dosing of paroxetine hydrochloride (30 mg once daily) increased steady-state AUC, C, and Cvalues of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%, respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen, the dose of procyclidine should be reduced.<br/>Beta-Blockers: In a study where propranolol (80 mg twice daily) was dosed orally for 18 days, the established steady-state plasma concentrations of propranolol were unaltered during coadministration with paroxetine hydrochloride (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS, Postmarketing Reports).<br/>Theophylline: Reports of elevated theophylline levels associated with treatment with paroxetine hydrochloride have been reported. While this interaction has not been formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered.<br/>Fosamprenavir/Ritonavir: Coadministration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy).<br/>Electroconvulsive Therapy (ECT): There are no clinical studies of the combined use of ECT and paroxetine hydrochloride.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis: Two-year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2.4 (mouse) and 3.9 (rat) times the maximum recommended human dose (MRHD) for major depressive disorder, social anxiety disorder, and GAD on a mg/mbasis. Because the MRHD for major depressive disorder is slightly less than that for OCD (50 mg versus 60 mg), the doses used in these carcinogenicity studies were only 2.0 (mouse) and 3.2 (rat) times the MRHD for OCD. There was a significantly greater number of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose-related increase in the number of tumors in mice, there was no drug-related increase in the number of mice with tumors. The relevance of these findings to humans is unknown.<br/>Mutagenesis: Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests for cytogenic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats.<br/>Impairment of Fertility: A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/kg/day, which is 2.9 times the MRHD for major depressive disorder, social anxiety disorder, and GAD or 2.4 times the MRHD for OCD on a mg/mbasis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times the MRHD for major depressive disorder, social anxiety disorder, and GAD; 8.2 and 4.1 times the MRHD for OCD and PD on a mg/mbasis).<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Labor and Delivery: The effect of paroxetine on labor and delivery in humans is unknown.<br/>Nursing Mothers: Like many other drugs, paroxetine is secreted in human milk, and caution should be exercised when paroxetine tablets are administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in the pediatric population have not been established (see BOXWARNING and WARNINGS, Clinical Worsening and Suicide Risk). Three placebo-controlled trials in 752 pediatric patients with MDD have been conducted with paroxetine hydrochloride, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of paroxetine tablets in a child or adolescent must balance the potential risks with the clinical need. In placebo-controlled clinical trials conducted with pediatric patients, the following adverse events were reported in at least 2% of pediatric patients treated with paroxetine and occurred at a rate at least twice that for pediatric patients receiving placebo: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesias, and agitation. Events reported upon discontinuation of treatment with paroxetine in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients who received paroxetine hydrochloride and which occurred at a rate at least twice that of placebo, were: emotional lability (including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and abdominal pain (see Discontinuation of Treatment With Paroxetine Tablets).<br/>Geriatric Use: In worldwide premarketing clinical trials with paroxetine hydrochloride, 17% of patients treated with paroxetine hydrochloride (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended; there were, however, no overall differences in the adverse event profile between elderly and younger patients, and effectiveness was similar in younger and older patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). | lld:dailymed |
| dailymed-drugs:63 | dailymed-instance:precautio... | General:<br/>Activation of Mania/Hypomania: During premarketing testing, hypomania or mania occurred in approximately 1.0% of unipolar patients treated with paroxetine compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. In a subset of patients classified as bipolar, the rate of manic episodes was 2.2% for paroxetine and 11.6% for the combined active-control groups. As with all drugs effective in the treatment of major depressive disorder, paroxetine should be used cautiously in patients with a history of mania.<br/>Seizures: During premarketing testing, seizures occurred in 0.1% of patients treated with paroxetine, a rate similar to that associated with other drugs effective in the treatment of major depressive disorder. Paroxetine should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures.<br/>Discontinuation of Treatment with Paroxetine: Recent clinical trials supporting the various approved indications for paroxetine employed a taper-phase regimen, rather than an abrupt discontinuation of treatment. The taper-phase regimen used in GAD and PTSD clinical trials involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before treatment was stopped. With this regimen in those studies, the following adverse events were reported at an incidence of 2% or greater for paroxetine and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness. In the majority of patients, these events were mild to moderate and were self-limiting and did not require medical intervention. During marketing of paroxetine and other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring, upon the discontinuation of these drugs (particularly when abrupt), including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with paroxetine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (seeDOSAGE AND ADMINISTRATION). See also PRECAUTIONS - Pediatric Use, for adverse events reported upon discontinuation of treatment with paroxetine in pediatric patients.<br/>Akathisia: The use of paroxetine or other SSRIs has been associated with the development of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation such as an inability to sit or stand still usually associated with subjective distress. This is most likely to occur within the first few weeks of treatment.<br/>Hyponatremia: Several cases of hyponatremia have been reported. The hyponatremia appeared to be reversible when paroxetine was discontinued. The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume depleted.<br/>Abnormal Bleeding: Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic agents that interfere with serotonin reuptake. Subsequent epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In 2 studies, concurrent use of a nonsteroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding (see Drug Interactions). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding associated with the concomitant use of paroxetine with NSAIDs, aspirin, or other drugs that affect coagulation.<br/>Use in Patients With Concomitant Illness: Clinical experience with paroxetine in patients with certain concomitant systemic illness is limited. Caution is advisable in using paroxetine in patients with diseases or conditions that could affect metabolism or hemodynamic responses. As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with paroxetine. A few cases of acute angle closure glaucoma associated with paroxetine therapy have been reported in the literature. As mydriasis can cause acute angle closure in patients with narrow angle glaucoma, caution should be used when paroxetine is prescribed for patients with narrow angle glaucoma. Paroxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product's premarket testing. Evaluation of electrocardiograms of 682 patients who received paroxetine in double-blind, placebo-controlled trials, however, did not indicate that paroxetine is associated with the development of significant ECG abnormalities. Similarly, paroxetine does not cause any clinically important changes in heart rate or blood pressure. Increased plasma concentrations of paroxetine occur in patients with severe renal impairment (creatinine clearance<30 mL/min.) or severe hepatic impairment. A lower starting dose should be used in such patients (see DOSAGE AND ADMINISTRATION).<br/>Information for Patients: Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of paroxetine and triptans, tramadol, or other serotonergic agents. Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with paroxetine and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions" is available for paroxetine. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The Medication Guide is provided with this Prescribing Information. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking paroxetine.<br/>Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.<br/>Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.): Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.<br/>Interference With Cognitive and Motor Performance: Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies paroxetine has not been shown to impair psychomotor performance, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with paroxetine does not affect their ability to engage in such activities.<br/>Completing Course of Therapy: While patients may notice improvement with treatment with paroxetine in 1 to 4 weeks, they should be advised to continue therapy as directed.<br/>Concomitant Medication: Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.<br/>Alcohol: Although paroxetine has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine.<br/>Pregnancy: Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy (see WARNINGS - Usage in Pregnancy: Teratogenic and Nonteratogenic Effects).<br/>Nursing: Patients should be advised to notify their physician if they are breast-feeding an infant (see PRECAUTIONS - Nursing Mothers).<br/>Laboratory Tests: There are no specific laboratory tests recommended.<br/>Drug Interactions:<br/>Tryptophan: As with other serotonin reuptake inhibitors, an interaction between paroxetine and tryptophan may occur when they are coadministered. Adverse experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been reported when tryptophan was administered to patients taking paroxetine. Consequently, concomitant use of paroxetine with tryptophan is not recommended (see S erotonin Syndrome).<br/>Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.<br/>Pimozide: In a controlled study of healthy volunteers, after paroxetine was titrated to 60 mg daily, coadministration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and Cof 62%, compared to pimozide administered alone. Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and paroxetine is contraindicated (see CONTRAINDICATIONS).<br/>Serotonergic Drugs: Based on the mechanism of action of paroxetine hydrochloride and the potential for serotonin syndrome, caution is advised when paroxetine is coadministered with other drugs or agents that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John's Wort (see WARNINGS - Serotonin Syndrome). The concomitant use of paroxetine with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS - Drug Interactions, Tryptophan).<br/>Thioridazine: See CONTRAINDICATIONS and WARNINGS.<br/>Warfarin: Preliminary data suggest that there may be a pharmacodynamic interaction (that causes an increased bleeding diathesis in the face of unaltered prothrombin time) between paroxetine and warfarin. Since there is little clinical experience, the concomitant administration of paroxetine and warfarin should be undertaken with caution (see Drugs That Interfere With Hemostasis ).<br/>Triptans: There have been rare postmarketing reports of serotonin syndrome with the use of an SSRI and a triptan. If concomitant use of paroxetine with a triptan is warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS - Serotonin Syndrome).<br/>Drugs Affecting Hepatic Metabolism: The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.<br/>Cimetidine: Cimetidine inhibits many cytochrome P(oxidative) enzymes. In a study where paroxetine (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during coadministration with oral cimetidine (300 mg three times daily) for the final week. Therefore, when these drugs are administered concurrently, dosage adjustment of paroxetine after the 20-mg starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine'spharmacokinetics was not studied.<br/>Phenobarbital: Phenobarbital induces many cytochrome P(oxidative) enzymes. When a single oral 30-mg dose of paroxetine was administered at phenobarbital steady state (100 mg once daily for 14 days), paroxetine AUC and T��were reduced (by an average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. Since paroxetine exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustment of paroxetine is considered necessary when coadministered with phenobarbital; any subsequent adjustment should be guided by clinical effect.<br/>Phenytoin: When a single oral 30-mg dose of paroxetine was administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and Twere reduced (by an average of 50% and 35%, respectively) compared to paroxetine administered alone. In a separate study, when a single oral 300-mg dose of phenytoin was administered at paroxetine steady state (30 mg once daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustments are considered necessary when these drugs are coadministered; any subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS - Postmarketing Reports).<br/>Drugs Metabolized by CYP2D6: Many drugs, including most drugs effective in the treatment of major depressive disorder (paroxetine, other SSRIs and many tricyclics), are metabolized by the cytochrome Pisozyme CYP2D6. Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients (>90%), this CYP2D6 isozyme is saturated early during dosing with paroxetine. In 1 study, daily dosing of paroxetine (20 mg once daily) under steady-state conditions increased single dose desipramine (100 mg) C, AUC, and Tby an average of approximately 2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine Cvalues that were 3- to 4-fold greater than when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be initiated at a reduced dose when it is given with paroxetine. Concomitant use of paroxetine with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either paroxetine or the other drug. Therefore, co-administration of paroxetine with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution. However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be coadministered (see CONTRAINDICATIONS and WARNINGS). At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by alternative Pisozymes that, unlike CYP2D6, show no evidence of saturation (see PRECAUTIONS - Tricyclic Antidepressants).<br/>Drugs Metabolized by Cytochrome CYP3A4: An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine. Based on the assumption that the relationship between paroxetine's in vitro Kand its lack of effect on terfenadine's in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine's extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.<br/>Tricyclic Antidepressants (TCAs): Caution is indicated in the co-administration of tricyclic antidepressants (TCAs) with paroxetine, because paroxetine may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is co-administered with paroxetine (see PRECAUTIONS - Drugs Metabolized by Cytochrome CYP2D6).<br/>Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma protein, administration of paroxetine to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of paroxetine by other highly bound drugs.<br/>Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.): Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin potentiated the risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with paroxetine.<br/>Alcohol: Although paroxetine does not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine.<br/>Lithium: A multiple-dose study has shown that there is no pharmacokinetic interaction between paroxetine and lithium carbonate. However, due to the potential for serotonin syndrome, caution is advised when paroxetine is coadministered with lithium.<br/>Digoxin: The steady-state pharmacokinetics of paroxetine was not altered when administered with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the presence of paroxetine. Since there is little clinical experience, the concurrent administration of paroxetine and digoxin should be undertaken with caution.<br/>Diazepam: Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of paroxetine on diazepam were not evaluated.<br/>Procyclidine: Daily oral dosing of paroxetine (30 mg once daily) increased steady-state AUC, C, and Cvalues of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%, respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen, the dose of procyclidine should be reduced.<br/>Beta-Blockers: In a study where propranolol (80 mg twice daily) was dosed orally for 18 days, the established steady-state plasma concentrations of propranolol were unaltered during co-administration with paroxetine (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS - Postmarketing Reports).<br/>Fosamprenavir/Ritonavir: Coadministration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy).<br/>Theophylline: Reports of elevated theophylline levels associated with treatment with paroxetine have been reported. While this interaction has not been formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered.<br/>Electroconvulsive Therapy (ECT): There are no clinical studies of the combined use of ECT and paroxetine.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis: Two-year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2.4 (mouse) and 3.9 (rat) times the maximum recommended human dose (MRHD) for major depressive disorder, social anxiety disorder, GAD, and PTSD on a mg/mbasis. Because the MRHD for major depressive disorder is slightly less than that for OCD (50 mg versus 60 mg), the doses used in these carcinogenicity studies were only 2.0 (mouse) and 3.2 (rat) times the MRHD for OCD. There was a significantly greater number of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose-related increase in the number of tumors in mice, there was no drug-related increase in the number of mice with tumors. The relevance of these findings to humans is unknown.<br/>Mutagenesis: Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats.<br/>Impairment of Fertility: A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/kg/day, which is 2.9 times the MRHD for major depressive disorder, social anxiety disorder, GAD, and PTSD or 2.4 times the MRHD for OCD on a mg/mbasis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times the MRHD for major depressive disorder, social anxiety disorder, and GAD; 8.2 and 4.1 times the MRHD for OCD and PD on a mg/mbasis).<br/>Pregnancy: Pregnancy Category D. See WARNINGS���Usage in Pregnancy: Teratogenic and Nonteratogenic Effects.<br/>Labor and Delivery: The effect of paroxetine on labor and delivery in humans is unknown.<br/>Nursing Mothers: Like many other drugs, paroxetine is secreted in human milk, and caution should be exercised when paroxetine is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS - Clinical Worsening and Suicide Risk). Three placebo-controlled trials in 752 pediatric patients with MDD have been conducted with paroxetine, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of paroxetine in achild or adolescent must balance the potential risks with the clinical need. In placebo-controlled clinical trials conducted with pediatric patients, the following adverse events were reported in at least 2% of pediatric patients treated with paroxetine and occurred at a rate at least twice that for pediatric patients receiving placebo: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased appetite, tremor,sweating, hyperkinesia, and agitation. Events reported upon discontinuation of treatment with paroxetine in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients who received paroxetine and which occurred at a rate at least twice that of placebo, were: emotional lability (including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and abdominal pain (see Discontinuation of Treatment With Paroxetine).<br/>Geriatric Use: In worldwide premarketing clinical trials with paroxetine, 17% of patients treated with paroxetine (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended; there were, however, no overall differences in the adverse event profile between elderly and younger patients, and effectiveness was similar in younger and older patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). | lld:dailymed |
| dailymed-drugs:64 | dailymed-instance:precautio... | General:: a. White Clot Syndrome: It has been reported that patients on heparin may develop new thrombus formation in association with thrombocytopenia resulting from irreversible aggregation of platelets induced by heparin, the so-called���white clot syndrome���. The process may lead to severe thromboembolic complications like skin necrosis, gangrene of the extremities that may lead to amputation, myocardial infarction, pulmonary embolism, stroke, and possibly death. Therefore, heparin administration should be promptly discontinued if a patient develops new thrombosis in association with thrombocytopenia. b. Heparin Resistance: Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer and in postsurgical patients. c. Increased Risk to Older Patients, Especially Women: A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age.<br/>Laboratory Tests:: Periodic platelet counts, hematocrits and tests for occult blood in stool are recommended during the entire course of heparin therapy, regardless of the route of administration (see DOSAGE AND ADMINISTRATION).<br/>Drug Interactions:: Oral anticoagulants: Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose should elapse before blood is drawn if a valid PROTHROMBIN time is to be obtained. Platelet inhibitors: Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine and others that interfere with platelet-aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium. Other interactions: Digitalis, tetracyclines, nicotine, or antihistamines may partially counteract the anticoagulant action of heparin sodium.<br/>Drug/Laboratory Test Interactions:: Hyperaminotransferasemia: Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT]) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin. Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease, and pulmonary emboli, rises that might be caused by drugs (like heparin) should be interpreted with caution.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:: No long-term studies in animals have been performed to evaluate carcinogenic potential of heparin. Also, no reproduction studies in animals have been performed concerning mutagenesis or impairment of fertility.<br/>Pregnancy:: Teratogenic Effects:Pregnancy Category C. Animal reproduction studies have not been conducted with heparin sodium or sodium chloride. It is also not known whether heparin sodium or sodium chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Heparin sodium or sodium chloride should be given to a pregnant woman only if clearly needed. Nonteratogenic Effects: Heparin does not cross the placental barrier.<br/>Nursing Mothers:: Heparin is not excreted in human milk.<br/>Pediatric Use:: See DOSAGE AND ADMINISTRATION.<br/>Geriatric Use:: A higher incidence of bleeding has been reported in patients over 60 years of age, especially women (see PRECAUTIONS, General). Clinical studies indicate that lower doses of heparin may be indicated in these patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). | lld:dailymed |
| dailymed-drugs:65 | dailymed-instance:precautio... | Carcinogenesis, Mutagenesis, Impairment of Fertility: Mutagenicity tests performed in Salmonella typhimurium, Saccharomyces cerevisiae, and Schizosaccharomyces pombe indicate that levocarnitine is not mutagenic. No long-term animal studies have been performed to evaluate the carcinogenic potential of levocarnitine.<br/>Pregnancy:<br/>Teratogenic Effects - Pregnancy Category B: Reproductive studies have been performed in rats and rabbits at doses up to 3.8 times the human dose on the basis of surface area and have revealed no evidence of impaired fertility or harm to the fetus due to levocarnitine. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.<br/>Nursing Mothers: Levocarnitine supplementation in nursing mothers has not been specifically studied. Studies in dairy cows indicate that the concentration of levocarnitine in milk is increased following exogenous administration of levocarnitine. In nursing mothers receiving levocarnitine, any risks to the child of excess carnitine intake need to be weighed against the benefits of levocarnitine supplementation to the mother. Consideration may be given to discontinuation of nursing or of levocarnitine treatment.<br/>Pediatric Use: See DOSAGE AND ADMINISTRATION. | lld:dailymed |
| dailymed-drugs:66 | dailymed-instance:precautio... | General: Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid-base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Significant deviations from normal concentrations may require the use of additional electrolyte supplements. Strongly hypertonic nutrient solutions should be administered through an indwelling intravenous catheter with the tip located in the superior vena cava. Special care must be taken when giving hypertonic dextrose to a diabetic or prediabetic patient. To prevent severe hyperglycemia in such patients, insulin may be required. Peripheral intravenous administration of Aminosyn-HF 8% (amino acid injection 8%) requires appropriate dilution and provision of adequate calories. Care should be taken to assure proper placement of the needle within the lumen of the vein. The venipuncture site should be inspected frequently for signs of infiltration. If venous thrombosis or phlebitis occurs,discontinue infusions or change infusion site and initiate appropriate treatment. Care should be taken to avoid circulatory overload, particularly in patients with cardiac insufficiency. In patients with myocardial infarct, infusion of amino acids should always be accompanied by dextrose since in anoxia, free fatty acids cannot be utilized by the myocardium, and energy must be produced anaerobically from glycogen or glucose. Infusion of Aminosyn-HF 8% may not affect the clinical course of patients with fulminant hepatitis who have a poor prognosis and are generally unresponsive to treatment. It has been shown that the abnormal plasma amino acid pattern in fulminant hepatitis differs from that in chronic liver disease. Extraordinary electrolyte losses such as may occur during protracted nasogastric suction, vomiting, diarrhea, or gastrointestinal fistula drainage may necessitate additional electrolyte supplementation. Administration of glucose at a rate exceeding the patient's utilization rate may lead to hyperglycemia, coma, and death. Metabolic acidosis can be prevented or readily controlled by adding a portion of the cations in the electrolyte mixture as acetate salts and in the case of hyperchloremic acidosis, by keeping the total chloride content of the infusate to a minimum. Aminosyn-HF 8% contains no more than 25 mcg/L of aluminum. Aminosyn-HF 8% contains less than 3 mEq chloride per liter. Aminosyn-HF 8% contains 10 mMol of phosphate/liter. Some patients, especially those with hypophosphatemia, may require additional phosphate. To prevent hypocalcemia, calcium supplementation should always accompany phosphate administration. To assure adequate intake, serum levels should be monitored frequently. Aminosyn-HF 8% has not been adequately studied in pregnant women and children; therefore, its safe use in such patients has not been demonstrated. To minimize the risk of possible incompatibilities arising from mixing this solution with other additives that may be prescribed, the final infusate should be inspected for cloudiness or precipitation immediately after mixing, prior to administration, and periodically during administration. Use only if solution is clear and container is undamaged. Must not be used in series connections.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:: Studies with Aminosyn-HF 8% have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.<br/>Pregnancy:: Teratogenic Effects: Pregnancy Category C: Animal reproduction studies have not been conducted with Aminosyn���HF 8%. It is also not known whether Aminosyn���HF 8% can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Aminosyn���HF 8% should be given to a pregnant woman only if clearly needed.<br/>Nursing Mothers: Caution should be exercised when Aminosyn���HF 8% is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric Use: Clinical studies of Aminosyn���HF 8% have not been performed to determine whether patients over 65 years respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renalfunction. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal functions. SPECIAL PRECAUTIONS FOR CENTRAL VENOUS NUTRITION ADMINISTRATION BY CENTRAL VENOUS CATHETER SHOULD BE USED ONLY BY THOSE FAMILIAR WITH THIS TECHNIQUE AND ITS COMPLICATIONS. Central venous nutrition may be associated with complications which can be prevented or minimized by careful attention to all aspects of the procedure, including solution preparation, administration, and patient monitoring. IT IS ESSENTIAL THAT A CAREFULLY PREPARED PROTOCOL, BASED ON CURRENT MEDICAL PRACTICES, BE FOLLOWED, PREFERABLY BY AN EXPERIENCED TEAM. Although a detailed discussion of the complications is beyond the scope of this insert, the following summary lists those based on current literature. | lld:dailymed |
| dailymed-drugs:67 | dailymed-instance:precautio... | General: Rare cases of serious hepatotoxicity have been observed with SPORANOX treatment, including some cases within the first week. In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with SPORANOX is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. Liver function monitoring should be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications and should be considered in all patients receiving SPORANOX. Treatment should be stopped immediately and liverfunction testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction. If neuropathy occurs that may be attributable to SPORANOX Injection, the treatment should be discontinued. As severe renal impairment prolongs the elimination rate of hydroxypropyl-��-cyclodextrin, SPORANOX (itraconazole) Injection should not be used in patients with severe renal dysfunction (creatinine clearance<30 mL/min).<br/>Information for Patients: SPORANOX Injection contains the excipient hydroxypropyl-��-cyclodextrin which produced pancreatic adenocarcinomas in a rat carcinogenicity study. These findings were not observed in a similar mouse carcinogenicity study. The clinical relevance of these findings is unknown.<br/>Drug Interactions: Itraconazole and its major metabolite, hydroxyitraconazole, are inhibitors of CYP3A4. Therefore, the following drug interactions may occur (See Table 1 below and the following drug class subheadings that follow):<br/>Antiarrhythmics: The class IA antiarrhythmic quinidine and class III antiarrhythmic dofetilide are known to prolong the QT interval. Coadministration of quinidine or dofetilide with SPORANOX may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX and quinidine or dofetilide is contraindicated. The class IA antiarrhythmic disopyramide has the potential to increase the QT interval at high plasma concentrations. Caution is advised when SPORANOX and disopyramide are administered concomitantly. Concomitant administration of digoxin and SPORANOX has led to increased plasma concentrations of digoxin.<br/>Anticonvulsants: Reduced plasma concentrations of itraconazole were reported when SPORANOX was administered concomitantly with phenytoin. Carbamazepine, phenobarbital, and phenytoin are all inducers of CYP3A4. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of SPORANOX and these drugs would be expected to result in decreased plasma concentrations of itraconazole. In addition, in vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX and carbamazepine may inhibit the metabolism of carbamazepine.<br/>Antimycobacterials: Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. SPORANOX may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of SPORANOX could be substantially reduced if given concomitantly with one of these agents. Coadministration is not recommended.<br/>Antineoplastics: SPORANOX may inhibit the metabolism of busulfan, docetaxel, and vinca alkaloids.<br/>Antipsychotics: Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Coadministration of pimozide with SPORANOX could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX and pimozide is contraindicated.<br/>Benzodiazepines: Concomitant administration of SPORANOX and alprazolam, diazepam, oral midazolam, or triazolam could lead to increased plasma concentrations of these benzodiazepines. Increased plasma concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant administration of SPORANOX and oral midazolam or triazolam is contraindicated. If midazolam is administered parenterally, special precaution and patient monitoring is required since the sedative effect may be prolonged.<br/>Calcium Channel Blockers: Edema has been reported in patients concomitantly receiving SPORANOX and dihydropyridine calcium channel blockers. Appropriate dosage adjustment may be necessary. Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole; itraconazole can inhibit the metabolism of calcium channel blockers such as dihydropyridines (e.g., nifedipine and felodipine) and verapamil. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers.<br/>Gastrointestinal Motility Agents: Coadministration of SPORANOX with cisapride can elevate plasma cisapride concentrations which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX with cisapride is contraindicated.<br/>HMG CoA-Reductase Inhibitors: Human pharmacokinetic data suggest that SPORANOX inhibits the metabolism of atorvastatin, cerivastatin, lovastatin, and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of SPORANOX with HMG CoA-reductase inhibitors, such as lovastatin and simvastatin, is contraindicated.<br/>Immunosuppressants: Concomitant administration of SPORANOX and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Concomitant administration of SPORANOX and sirolimus could increase plasma concentrations of sirolimus.<br/>Macrolide Antibiotics: Erythromycin and clarithromycin are known inhibitors of CYP3A4 (See Table 1) and may increase plasma concentrations of itraconazole. In a small pharmacokinetic study involving HIV infected patients, clarithromycin was shown to increase plasma concentrations of itraconazole. Similarly, following administration of 1 gram of erythromycin ethyl succinate and 200 mg itraconazole as single doses, the mean Cand AUCof itraconazole increased by 44% (90% CI: 119���175%) and 36% (90% Cl:108���171%), respectively.<br/>Oral Hypoglycemic Agents: Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents. Blood glucose concentrations should be carefully monitored when SPORANOX and oral hypoglycemic agents are coadministered.<br/>Polyenes: Prior treatment with itraconazole, like other azoles, may reduce or inhibit the activity of polyenes such as amphotericin B. However, the clinical significance of this drug effect has not been clearly defined.<br/>Protease Inhibitors: Concomitant administration of SPORANOX and protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir, and saquinavir, may increase plasma concentrations of these protease inhibitors. In addition, concomitant administration of SPORANOX and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole. Caution is advised when SPORANOX and protease inhibitors must be given concomitantly.<br/>Reverse Transcriptase Inhibitors: Nevirapine is an inducer of CYP3A4. In vivo studies have shown that nevirapine induces the metabolism of ketoconazole, significantly reducing the bioavailability of ketoconazole. Studies involving nevirapine and itraconazole have not been conducted. However, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX and nevirapine is not recommended. In a clinical study, when 8 HIV-infected subjects were treated concomitantly with SPORANOX Capsules 100 mg twice daily and the nucleoside reverse transcriptase inhibitor zidovudine 8��0.4 mg/kg/day, the pharmacokinetics of zidovudine were not affected. Other nucleoside reverse transcriptase inhibitors have not been studied.<br/>Other:<br/>Carcinogenesis, Mutagenesis and Impairment of Fertility: Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels up to 80 mg/kg/day (approximately 10��the maximum recommended human dose [MRHD]). Male rats treated with 25 mg/kg/day (3.1��MRHD) had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolemia, which is a response of rats, but not dogs or humans, to chronic itraconazole administration. Female rats treated with 50 mg/kg/day (6.25��MRHD) had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant. Hydroxypropyl-��-cyclodextrin (HP-��-CD), the solubilizing excipient used in SPORANOX Injection and Oral Solution, was found to produce pancreatic exocrine hyperplasia and neoplasia when administered orally to rats at doses of 500, 2000 or 5000 mg/kg/day for 25 months. Adenocarcinomas of the exocrine pancreas produced in the treated animals were not seen in the untreated group and are not reported in the historical controls. Development of these tumors may be related to a mitogenic action of cholecystokinin. This finding was not observed in the mouse carcinogenicity study at doses of 500, 2000 or 5000 mg/kg/day for 22���23 months; however, the clinical relevance of these findings is unknown. Based on body surface area comparisons, the exposure to humans of HP-��-CD at the recommended clinical dose of SPORANOX Oral Solution, is approximately equivalent to 1.7 times the exposure at the lowest dose in the rat study. The relevance of the findings with orally administered HP-��-CD to potential carcinogenic effects for SPORANOX Injection is uncertain. Itraconazole produced no mutagenic effects when assayed in a DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests with Salmonella typhimurium (6 strains) and Escherichia coli, in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethal mutation (Drosophila melanogaster) test, in chromosome aberration tests in human lymphocytes, in a cell transformation test with C3H/10T��C18 mouse embryo fibroblasts cells, in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats. Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of up to 40 mg/kg/day (5��MRHD), even though parental toxicity was present at this dosage level. More severe signs of parental toxicity, including death, were present in the next higher dosage level, 160 mg/kg/day (20��MRHD).<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants.<br/>Pediatric Use: The efficacy and safety of SPORANOX have not been established in pediatric patients. No pharmacokinetic data on SPORANOX Capsules or Injection are available in children. A small number of patients ages 3 to 16 years have been treated with 100 mg/day of itraconazole capsules for systemic fungal infections, and no serious unexpected adverse effects have been reported. SPORANOX Oral Solution (5 mg/kg/day) has been administered to pediatric patients (N=26, ages 6 months to 12 years) for 2 weeks and no serious unexpected adverse events were reported. The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (2.5��MRHD). The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility. At a dosage level of 80 mg/kg/day (10��MRHD) over 1 year or 160 mg/kg/day (20��MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats. No such bone toxicity has been reported in adult patients.<br/>Geriatric Use: Clinical studies of SPORANOX Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:70 | dailymed-instance:precautio... | General: Since Coly-Mycin M Parenteral is eliminated mainly by renal excretion, it should be used with caution when the possibility of impaired renal function exists. The decline in renal function with advanced age should be considered. When actual renal impairment is present, Coly-Mycin M Parenteral may be used, but the greatest caution should be exercised and the dosage should be reduced in proportion to the extent of the impairment. Administration of amounts of Coly-Mycin M Parenteral in excess of renal excretory capacity will lead to high serum levels and can result in further impairment of renal function, initiating a cycle which, if not recognized, can lead to acute renal insufficiency, renal shutdown, and further concentration of the antibiotic to toxic levels in the body. At this point, interference of nerve transmission at neuromuscular junctions may occur and result in muscle weakness and apnea . Signs indicating the development of impaired renal function include: diminishing urine output, rising BUN and serum creatinine and decreased creatinine clearance. Therapy with Coly-Mycin M Parenteral should be discontinued immediately if signs of impaired renal function occur. However, if it is necessary to reinstate the drug, dosing should be adjusted accordingly after drug plasma levels have fallen . Prescribing Coly-Mycin M in absence of a proven or strongly suspected bacterial infection or prophylactic indication is unlikely provide benefit to the patient increases the risk of the development of drug-resistant bacteria.<br/>Drug Interactions: Certain other antibiotics (aminoglycosides and polymyxin) have also been reported to interfere with the nerve transmission at the neuromuscular junction. Based on this reported activity, they should not be given concomitantly with Coly-Mycin M Parenteral except with the greatest caution. Curariform muscle relaxants (e.g., tubocurarine) and other drugs, including ether, succinylcholine, gallamine, decamethonium and sodium citrate, potentiate the neuromuscular blocking effect and should be used with extreme caution in patients being treated with Coly-Mycin M Parenteral. Sodium cephalothin may enhance the nephrotoxicity of Coly-Mycin M Parenteral. The concomitant use of sodium cephalothin and Coly-Mycin M Parenteral should be avoided.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal carcinogenicity studies and genetic toxicology studies have not been performed with colistimethate sodium. There were no adverse effects on fertility or reproduction in rats at doses of 9.3 mg/kg/day (0.30 times the maximum daily human dose when based on mg/m).<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C: Colistimethate sodium given intramuscularly during organogenesis to rabbits at 4.15 and 9.3 mg/kg resulted in talipes varus in 2.6% and 2.9% of fetuses, respectively. These doses are 0.25 and 0.55 times the maximum daily human dose based on mg/m. In addition, increased resorption occurred at 9.3 mg/kg. Colistimethate sodium was not teratogenic in rats at 4.15 or 9.3 mg/kg. These doses are 0.13 and 0.30 times the maximum daily human dose based on mg/m. There are no adequate and well-controlled studies in pregnant women. Since colistimethate sodium is transferred across the placental barrier in humans, it should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: It is not known whether colistimethate sodium is excreted in human breast milk. However, colistin sulphate is excreted in human breast milk. Therefore, caution should be exercised when colistimethate sodium is administered to nursing women.<br/>Geriatric Use: Clinical studies of colistemethate sodium did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.<br/>Pediatric Use: In clinical studies, colistimethate sodium was administered to the pediatric population (neonates, infants, children and adolescents). Although adverse reactions appear to be similar in the adult and pediatric populations, subjective symptoms of toxicity may not be reported by pediatric patients. Close clinical monitoring of pediatric patients is recommended.<br/>Information for Patients: Patients should be counseled that antibacterial drugs including Coly-Mycin M should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Coly-Mycin M is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full courseof therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Coly-Mycin M or other antibacterial drugs in the future. | lld:dailymed |
| dailymed-drugs:71 | dailymed-instance:precautio... | General: Discontinuation of Treatment with Citalopram During marketing of citalopram and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with citalopram. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate . Abnormal Bleeding SSRIs and SNRIs, including citalopram, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to the risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of citalopram and NSAIDs, aspirin, or other drugs that affect coagulation. Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including citalopram. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and was reversible when citalopram was discontinued. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see Geriatric Use). Discontinuation of citalopram should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Activation of Mania/Hypomania In placebo-controlled trials of citalopram, some of which included patients with bipolar disorder, activation of mania/hypomania was reported in 0.2% of 1063 patients treated with citalopram and in none of the 446 patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorderstreated with other marketed antidepressants. As with all antidepressants, citalopram should be used cautiously in patients with a history of mania. Seizures Although anticonvulsant effects of citalopram have been observed in animal studies, citalopram has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product's premarketing testing. In clinical trials of citalopram, seizures occurred in 0.3% of patients treated with citalopram (a rate of one patient per 98 years of exposure) and 0.5% of patients treated with placebo (a rate of one patient per 50 years of exposure). Like other antidepressants, citalopram should be introduced with care in patients with a history of seizure disorder. Interference with Cognitive and Motor Performance In studies in normal volunteers, citalopram in doses of 40 mg/day did not produce impairment of intellectual function or psychomotor performance. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that citalopram therapy does not affect their ability to engage in such activities. Use in Patients with Concomitant Illness Clinical experience with citalopram in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using citalopram in patients with diseases or conditions that produce altered metabolism or hemodynamic responses. Citalopram has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical studies during the product's premarketing testing. However, the electrocardiograms of 1116 patients who received citalopram in clinical trials were evaluated and the data indicate that citalopram is not associated with the development of clinically significant ECG abnormalities. In subjects with hepatic impairment, citalopram clearance was decreased and plasma concentrations were increased. The use of citalopram in hepatically impaired patients should be approached with caution and a lower maximum dosage is recommended . Because citalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with citalopram, however, it should be used with caution in such patients .<br/>Information for Patients: Physicians are advised to discuss the following issues with patients for whom they prescribe citalopram. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of citalopram and triptans, tramadol or other serotonergic agents. Although in controlled studies citalopram has not been shown to impair psychomotor performance, any psychoactive drug may impair judgment, thinking, or motor skills, so patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that citalopram therapy does not affect their ability to engage in such activities. Patients should be told that, although citalopram has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of citalopram and alcohol in depressed patients is not advised. Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions. Patients should be cautioned about the concomitant use of citalopram and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physician if they are breastfeeding an infant. While patients may notice improvement with citalopram therapy in 1 to 4 weeks, they should be advised to continue therapy as directed. Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with citalopram and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions" is available for citalopram. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking citalopram. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.<br/>Laboratory Tests: There are no specific laboratory tests recommended.<br/>Drug Interactions: Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs including citalopram, and the potential for serotonin syndrome, caution is advised when citalopram is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John's Wort . The concomitant use of citalopram with other SSRIs, SNRIs or tryptophan is not recommended . Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of citalopram with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases . CNS Drugs - Given the primary CNS effects of citalopram, caution should be used when it is taken in combination with other centrally acting drugs. Alcohol - Although citalopram did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by depressed patients taking citalopram is not recommended. Monoamine Oxidase Inhibitors (MAOIs) - See CONTRAINDICATIONS and WARNINGS. Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.)- Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate the risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when citalopram is initiated ordiscontinued. Cimetidine - In subjects who had received 21 days of 40 mg/day citalopram, combined administration of 400 mg/day cimetidine for 8 days resulted in an increase in citalopram AUC and Cof 43% and 39%, respectively. The clinical significance of these findings is unknown. Digoxin - In subjects who had received 21 days of 40 mg/day citalopram, combined administration of citalopram and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin. Lithium - Coadministration of citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of citalopram, caution should be exercised when citalopram and lithium are coadministered. Pimozide - In a controlled study, a single dose of pimozide 2 mg co-administered with citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Citalopram did not alter the mean AUC or Cof pimozide. The mechanism of this pharmacodynamic interaction is not known. Theophylline - Combined administration of citalopram (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline. The effect of theophylline on the pharmacokinetics of citalopram was not evaluated. Sumatriptan - There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram) is clinically warranted, appropriate observation of the patient is advised. Warfarin - Administration of 40 mg/day citalopram for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance of which is unknown. Carbamazepine - Combined administration of citalopram (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of citalopram should be considered if the two drugs are coadministered. Triazolam - Combined administration of citalopram (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam. Ketoconazole - Combined administration of citalopram (40 mg) and ketoconazole (200 mg) decreased the Cand AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram. CYP3A4 and 2C19 Inhibitors - In vitro studies indicated that CYP3A4 and 2C19 are the primary enzymes involved in the metabolism of citalopram. However, coadministration of citalopram (40 mg) and ketoconazole (200 mg), a potent inhibitor of CYP3A4, did not significantly affect the pharmacokinetics of citalopram. Because citalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease citalopram clearance. Metoprolol - Administration of 40 mg/day citalopram for 22 days resulted in a two-fold increase in the plasma levels of the betaadrenergic blocker metoprolol. Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Coadministration of citalopram and metoprolol had no clinically significant effects on blood pressure or heart rate. Imipramine and Other Tricyclic Antidepressants (TCAs) - In vitro studies suggest that citalopram is a relatively weak inhibitor of CYP2D6. Coadministration of citalopram (40 mg/day for 10 days) with the TCA imipramine (single dose of 100 mg), a substrate for CYP2D6, did not significantly affect the plasma concentrations ofimipramine or citalopram. However, the concentration of the imipramine metabolite desipramine was increased by approximately 50%. The clinical significance of the desipramine change is unknown. Nevertheless, caution is indicated in the coadministration of TCAs with citalopram. Electroconvulsive Therapy (ECT) - There are no clinical studies of the combined use of electroconvulsive therapy (ECT) and citalopram.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis Citalopram was administered in the diet to NMRI/BOM strain mice and COBS WI strain rats for 18 and 24 months, respectively. There was no evidence for carcinogenicity of citalopram in mice receiving up to 240 mg/kg/day, which is equivalent to 20 times the maximum recommended human daily dose (MRHD) of 60 mg on a surface area (mg/m) basis. There was an increased incidence of small intestine carcinoma in rats receiving 8 or 24 mg/kg/day, doses which are approximately 1.3 and 4 times the MRHD, respectively, on a mg/mbasis. A no-effect dose for this finding was not established. The relevance of these findings to humans is unknown. Mutagenesis Citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Citalopram was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in a coupled in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. It was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays. Impairment of Fertility When citalopram was administered orally to 16 male and 24 female rats prior to and throughout mating and gestation at doses of 32, 48, and 72 mg/kg/day, mating was decreased at all doses, and fertility was decreased at doses���32 mg/kg/day, approximately 5 times the MRHD of 60 mg/day on a body surface area (mg/m) basis. Gestation duration was increased at 48 mg/kg/day, approximately 8 times the MRHD.<br/>Pregnancy: Pregnancy Category C In animal reproduction studies, citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at doses greater than human therapeutic doses. In two rat embryo/fetal development studies, oral administration of citalopram (32, 56, or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose, which is approximately 18 times the MRHD of 60 mg/day on a body surface area (mg/m) basis. This dose was also associated with maternal toxicity (clinical signs, decreased body weight gain). The developmental, no-effect dose of 56 mg/kg/day is approximately 9 times the MRHD on a mg/mbasis. In a rabbit study, no adverse effects on embryo/fetal development were observed at doses of up to 16 mg/kg/day, or approximately 5 times the MRHD on a mg/mbasis. Thus, teratogenic effects were observed at a maternally toxic dose in the rat and were not observed in the rabbit. When female rats were treated with citalopram (4.8, 12.8, or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at the highest dose, which is approximately 5 times the MRHD on a mg/mbasis. The no-effect dose of 12.8 mg/kg/day is approximately 2 times the MRHD on a mg/mbasis. Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses���24 mg/kg/day, approximately 4 times the MRHD on a mg/mbasis. A no-effect dose was not determined in that study. There are no adequate and well-controlled studies in pregnant women; therefore, citalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Pregnancy-Nonteratogenic Effects: Neonates exposed to citalopram and other SSRIs or SNRIs, late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome . Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective, case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy.There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. When treating a pregnant woman with citalopram during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment . Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.<br/>Labor and Delivery: The effect of citalopram on labor and delivery in humans is unknown.<br/>Nursing Mothers: As has been found to occur with many other drugs, citalopram is excreted in human breast milk. There have been two reports of infants experiencing excessive somnolence, decreased feeding, and weight loss in association with breastfeeding from a citalopram-treated mother; in one case, the infant was reported to recover completely upon discontinuation of citalopram by its mother and in the second case, no follow-up information was available. The decision whether to continue or discontinue either nursing or citalopram therapy should take into account the risks of citalopram exposure for the infant and the benefits of citalopram treatment for the mother.<br/>Pediatric Use: Safety and effectiveness in the pediatric population have not been established . Two placebo-controlled trials in 407 pediatric patients with MDD have been conducted with citalopram, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of citalopram in a child or adolescent must balance the potential risks with the clinical need.<br/>Geriatric Use: Of 4422 patients in clinical studies of citalopram, 1357 were 60 and over, 1034 were 65 and over, and 457 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Most elderly patients treated with citalopram in clinical trials received daily doses between 20 and 40 mg . SSRIs and SNRIs, including citalopram, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event . In two pharmacokinetic studies, citalopram AUC was increased by 23% and 30%, respectively, in elderly subjects as compared to younger subjects, and its half-life was increased by 30% and 50%, respectively . 20 mg/day is the recommended dose for most elderly patients . | lld:dailymed |
| dailymed-drugs:72 | dailymed-instance:precautio... | General: Drugs having anticholinergic properties should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, stenosing peptic ulcer, pyloroduodenal obstruction, and bladder-neck obstruction. Promethazine HCl suppositories should be used cautiously in persons with cardiovascular disease or with impairment of liver function.<br/>Information for Patients: Promethazine HCl suppositories may cause marked drowsiness or impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. The use of alcohol or other central-nervous-system depressants such as sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers, may enhance impairment . Pediatric patients should be supervised to avoid potential harm in bike riding or in other hazardous activities. Patients should be advised to report any involuntary muscle movements. Avoid prolonged exposure to the sun.<br/>Drug Interactions:<br/>CNS Depressants: Promethazine HCl suppositories may increase, prolong, or intensify the sedative action of other central-nervous-system depressants, such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore, such agents should be avoided or administered in reduced dosage to patients receiving promethazine HCl. When given concomitantly with promethazine HCl suppositories, the dose of barbituates should be reduced by one-half, and the dose of narcotics should be reduced by one-quarter to one-half. Dosage must be individualized. Excessive amounts of promethazine HCl relative to a narcotic may lead to restlessness and motor hyperactivity in the patient with pain; these symptoms usually disappear with adequate control of the pain.<br/>Epinephrine: Because of the potential for promethazine HCl to reverse epinephrine's vasopressor effect, epinephrine should NOT be used to treat hypotension associated with promethazine HCl suppositories overdose.<br/>Anticholinergics: Concomitant use of other agents with anticholinergic properties should be undertaken with caution.<br/>Monoamine Oxidase Inhibitors (MAOI): Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAOI and phenothiazines are used concomitantly. This possibility should be considered with promethazine HCl suppositories.<br/>Drug/Laboratory Test Interactions: The following laboratory tests may be affected in patients who are receiving therapy with promethazine HCl:<br/>Pregnancy tests: Diagnostic pregnancy tests based on immunological reactions between HCG and anti-HCG may result in false-negative or false-positive interpretations.<br/>Glucose Tolerance Test: An increase in blood glucose has been reported in patients receiving promethazine HCl.<br/>Carcinogenesis, Mutagenesis, Impairment Of Fertility: Long-term animal studies have not been performed to assess the carcinogenic potential of promethazine, nor are there other animal or human data concerning carcinogenicity, mutagenicity, or impairment of fertility with this drug. Promethazine was nonmutagenic in the Salmonella test system of Ames.<br/>Pregnancy:<br/>Teratogenic Effects-Pregnancy Category C: Teratogenic effects have not been demonstrated in rat-feeding studies at doses of 6.25 and 12.5 mg/kg of promethazine HCl. These doses are from approximately 2.1 to 4.2 times the maximum recommended total daily dose of promethazine for a 50-kg subject, depending upon the indication for which the drug is prescribed. Daily doses of 25 mg/kg intraperitoneally have been found to produce fetal mortality in rats. Specific studies to test the action of the drug on parturition, lactation, and development of the animal neonate were not done, but a general preliminary study in rats indicated no effect on these parameters. Although antihistamines have been found to produce fetal mortality in rodents, the pharmacological effects of histamine in the rodent do not parallel those in man. There are no adequate and well-controlled studies of promethazine HCl suppositories in pregnant women. Promethazine HCl suppositories should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nonteratogenic Effects: Promethazine HCl suppositories administered to a pregnant woman within two weeks of delivery may inhibit platelet aggregation in the newborn.<br/>Labor and Delivery: Promethazine HCl may be used alone or as an adjunct to narcotic analgesics during labor . Limited data suggest that use of promethazine HCl during labor and delivery does not have an appreciable effect on the duration of labor or delivery and does not increase the risk of need for intervention in the newborn. The effect on later growth and development of the newborn is unknown (See also Nonteratogenic Effects).<br/>Nursing Mothers: It is not known whether promethazine HCl is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from promethazine HCl suppositories, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: PROMETHAZINE HCL SUPPOSITORIES ARE CONTRAINDICATED FOR USE IN PEDIATRIC PATIENTS LESS THAN TWO YEARS OF AGE (see WARNINGS-Black Box Warning and Use in Pediatric Patients ). Promethazine HCl suppositories should be used with caution in pediatric patients 2 years of age and older .<br/>Geriatric Use: Clinical studies of promethazine HCl formulations did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of promethazine HCl suppositories and observed closely. | lld:dailymed |
| dailymed-drugs:73 | dailymed-instance:precautio... | Carcinogenesis: Studies in animals to evaluate the carcinogenic potential have not been conducted.<br/>Pregnancy: Category C.: There are no adequate and well controlled studies in pregnant women. Carbastat should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: It is not known if this medication is excreted in breast milk. Exercise caution when administering to a nursing woman.<br/>Pediatric Use: Safety and efficacy in pediatric patients have not been established. | lld:dailymed |
| dailymed-drugs:75 | dailymed-instance:precautio... | General: Ethionamide may potentiate the adverse effects of the other antituberculous drugs administered concomitantly (see Drug Interactions). Ophthalmologic examinations (including ophthalmoscopy) should be performed before and periodically during therapy with Trecator.<br/>Information For Patients: Patients should be advised to consult their physician should blurred vision or any loss of vision, with or without eye pain, occur during treatment. Excessive ethanol ingestion should be avoided because a psychotic reaction has been reported.<br/>Laboratory Tests: Determination of serum transaminases (SGOT, SGPT) should be made prior to initiation of therapy and should be monitored monthly. If serum transaminases become elevated during therapy, ethionamide and the companion antituberculosis drug or drugs may be discontinued temporarily until the laboratory abnormalities have resolved. Ethionamide and the companion antituberculosis medication(s) then should be reintroduced sequentially to determine which drug (or drugs) is (are) responsible for the hepatotoxicity. Blood glucose determinations should be made prior to and periodically throughout therapy with Trecator. Diabetic patients should be particularly alert for episodes of hypoglycemia. Periodic monitoring of thyroid function tests is recommended as hypothyroidism, with or without goiter, has been reported with ethionamide therapy.<br/>Drug Interactions: Trecator has been found to temporarily raise serum concentrations of isoniazid. Trecator may potentiate the adverse effects of other antituberculous drugs administered concomitantly. In particular, convulsions have been reported when ethionamide is administered with cycloserine and special care should be taken when the treatment regimen includes both of these drugs. Excessive ethanol ingestion should be avoided because a psychotic reaction has been reported.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Teratogenic Effects: Pregnancy Category C: Animal studies conducted with Trecator indicate that the drug has teratogenic potential in rabbits and rats. The doses used in these studies on a mg/kg basis were considerably in excess of those recommended in humans. There are no adequate and well-controlled studies in pregnant women. Because of these animal studies, however, it must be recommended that Trecator be withheld from women who are pregnant, or who are likely to become pregnant while under therapy, unless the prescribing physician considers it to be an essential part of the treatment.<br/>Labor and Delivery: The effect of Trecator on labor and delivery in pregnant women is unknown.<br/>Nursing Mothers: Because no information is available on the excretion of ethionamide in human milk, Trecator should be administered to nursing mothers only if the benefits outweigh the risks. Newborns who are breast-fed by mothers who are taking Trecator should be monitored for adverse effects.<br/>Pediatric Use: Due to the fact that pulmonary tuberculosis resistant to primary therapy is rarely found in neonates, infants, and children, investigations have been limited in these age groups. At present, the drug should not be used in pediatric patients under 12 years of age except when the organisms are definitely resistant to primary therapy and systemic dissemination of the disease, or other life-threatening complications of tuberculosis, is judged to be imminent. | lld:dailymed |
| dailymed-drugs:76 | dailymed-instance:precautio... | General: ZOVIRAX Cream is intended for cutaneous use only and should not be used in the eye or inside the mouth or nose. ZOVIRAX Cream should only be used on herpes labialis on the affected external aspects of the lips and face. Because no data are available, application to human mucous membranes is not recommended. ZOVIRAX Cream has a potential for irritation and contact sensitization (see ADVERSE REACTIONS). The effect of ZOVIRAX Cream has not been established in immunocompromised patients.<br/>Information for Patients: Please see Patient Information About ZOVIRAX Cream.<br/>Drug Interactions: Clinical experience has identified no interactions resulting from topical or systemic administration of other drugs concomitantly with ZOVIRAX Cream.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Systemic exposure following topical administration of acyclovir is minimal. Dermal carcinogenicity studies were not conducted. Results from the studies of carcinogenesis, mutagenesis and fertility are not included in the full prescribing information for ZOVIRAX Cream due to the minimal exposures of acyclovir that result from dermal application. Information on these studies is available in the full prescribing information for ZOVIRAX Capsules, Tablets, and Suspension and ZOVIRAX for Injection.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category B. Acyclovir was not teratogenic in the mouse, rabbit, or rat at exposures greatly in excess of human exposure. There are no adequate and well-controlled studies of systemic acyclovir in pregnant women. A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses. Systemic acyclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: It is not known whether topically applied acyclovir is excreted in breast milk. Systemic exposure following topical administration is minimal. After oral administration of ZOVIRAX, acyclovir concentrations have been documented in breast milk in 2 women and ranged from 0.6 to 4.1 times the corresponding plasma levels. These concentrations would potentially expose the nursing infant to a dose of acyclovir up to 0.3 mg/kg/day. Nursing mothers who have active herpetic lesions near or on the breast should avoid nursing.<br/>Geriatric Use: Clinical studies of acyclovir cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Systemic absorption of acyclovir after topical administration is minimal (see CLINICAL PHARMACOLOGY).<br/>Pediatric Use: Safety and effectiveness in pediatric patients less than 12 years of age have not been established. | lld:dailymed |
| dailymed-drugs:77 | dailymed-instance:precautio... | General: Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria in some patients. Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids. Pediatric patients may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity. . If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted. In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled.<br/>Information for the Patient: Patients using topical corticosteroids should receive the following information and instructions:<br/>Laboratory Tests: The following tests may be helpful in evaluating the hypothalamic-pituitary-adrenal (HPA) axis suppression:<br/>Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of desoximetasone. Desoximetasone was nonmutagenic in the Ames test. Studies to determine mutagenicity with prednisolone and hydrocortisone have revealed negative results. Desoximetasone did not show potential for mutagenic activity in vitro in the Ames microbial mutagen test with or without metabolic activation.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant. Nevertheless, caution should be exercised when topical corticosteroids are administered to a nursing woman.<br/>Pediatric Use: Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced HPA axis suppression and Cushing's syndrome than mature patients because of a larger skin surface area to body weight ratio. HPA axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Administration of topical corticosteroids to pediatric patients should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of pediatric patients. | lld:dailymed |
| dailymed-drugs:78 | dailymed-instance:precautio... | General: Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal from treatment. Manifestations of Cushing's syndrome, hyperglycemia and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment. Patients applying a topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA axis suppression. This may be done by using the ACTH stimulation, A.M. plasma cortisol, and urinary free cortisol tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid. Recovery of HPA axis function is generally prompt upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur, requiring supplemental systemic corticosteroids. For information on systemic supplementation, see prescribing information for those products. A concentrated fluticasone propionate ointment, 0.05% (10 times that of the marketed fluticasone propionate ointment, 0.005%) suppressed 24-hour urinary free cortisol levels in 2 of 6 patients when used at a dose of 30 g/day for a week in patients with psoriasis or atopic eczema. No suppression of A.M. plasma cortisol was observed. In a second study of the same concentrated formulation of fluticasone propionate ointment, 0.05%, depression of A.M. plasma cortisol levels was noted in 2 of 8 normal volunteers when applied at doses of 50 g/day for 21 days. Morning plasma levels returned to normal levels within 4 days upon discontinuation of fluticasone propionate. In this study there was no corresponding decrease in 24-hour urinary free cortisol levels. Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios. . Fluticasone propionate ointment, 0.005% may cause local cutaneous adverse reactions . If irritation develops, fluticasone propionate ointment should be discontinued and appropriate therapy instituted. Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation as with most topical products not containing corticosteroids. Such an observation should be corroborated with appropriate diagnostic patch testing. If concomitant skin infections are present or develop, an appropriate antifungal or antibacterial agent should be used. If a favorable response does not occur promptly, use of fluticasone propionate ointment should be discontinued until the infection has been adequately controlled. Fluticasone propionate ointment should not be used in the presence of preexisting skin atrophy and should not be used where infection is present at the treatment site. Fluticasone propionate ointment should not be used in the treatment of rosacea and perioral dermatitis.<br/>Information for Patients: Patients using topical corticosteroids should receive the following information and instructions: Laboratory Tests: The following tests may be helpful in evaluating patients for HPA axis suppression: ACTH stimulation test A.M. plasma cortisol test Urinary free cortisol test<br/>Carcinogenesis, Mutagenesis and Impairment of Fertility: Two 18-month studies were performed in mice to evaluate the carcinogenic potential of fluticasone propionate when given topically (as an 0.05% ointment) and orally. No evidence of carcinogenicity was found in either study. Fluticasone propionate was not mutagenic in the standard Ames test, E. coli fluctuation test, S. cerevisiae gene conversion test or Chinese Hamster ovarian cell assay. It was not clastogenic in mouse micronucleus or cultured human lymphocyte tests. In a fertility and general reproductive performance study in rats, fluticasone propionate administered subcutaneously to females at up to 50 mcg/kg per day and to males at up to 100 mcg/kg per day (later reduced to 50 mcg/kg per day) had no effect upon mating performance or fertility. These doses are approximately 150 and 300 times, respectively, the human systemic exposure following use of the recommended human topical dose of fluticasone propionate ointment, 0.005%, assuming human percutaneous absorption of approximately 3% and the use in a 70-kg person of 15 g/day. Pregnancy:Teratogenic Effects: Pregnancy Category C. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. Teratology studies in the mouse demonstrated fluticasone propionate to be teratogenic (cleft palate) when administered subcutaneously in doses of 45 mcg/kg per day and 150 mcg/kg per day. This dose is approximately 140 and 450 times, respectively, the human topical dose of fluticasone propionate ointment, 0.005%. There are no adequate and well-controlled studies in pregnant women. Fluticasone propionate ointment should be used during pregnancy only if the potential benefit justifies the potentialrisk to the fetus. Nursing Mothers: Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when fluticasone propionate ointment is administered to a nursing woman. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of HPA axis suppression and Cushing's syndrome when they are treated with topical corticosteroids. They are therefore also at greater risk of adrenal insufficiency during or after withdrawal of treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in pediatric patients. HPA axis suppression, Cushing's Syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteriods. Manifestations of adrenal suppression in pediatric patients include low plasma cortisol levels and an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, andbilateral papilledema. Geriatric Use: A limited number of patients above 65 years of age (n=203) have been treated with fluticasone propionate ointment in US and non-US clinical trials. While the number of patients is too small to permit separate analysis of efficacy and safety, the adverse reactions reported in this population were similar to those reported by younger patients. Based on available data, no adjustment of dosage of fluticasone in geriatric patients is warranted. | lld:dailymed |
| dailymed-drugs:79 | dailymed-instance:precautio... | The safety and efficacy of REBETOL'/INTRON' A and PegIntron���therapy for the treatment of HIV infection, adenovirus, RSV, parainfluenza, or influenza infections have not been established. REBETOL Capsules should not be used for these indications. Ribavirin for inhalation has a separate package insert, which should be consulted if ribavirin inhalation therapy is being considered. The safety and efficacy of REBETOL/INTRON A therapy has not been established in liver or other organ transplant patients, patients with decompensated liver disease due to hepatitis C infection, patients who are non-responders to interferon therapy, or patients coinfected with HBV or HIV.<br/>Information for Patients: Patients must be informed that REBETOL Capsules and Oral Solution may cause birth defects and/or death of the exposed fetus. REBETOL must not be used by women who are pregnant or by men whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking REBETOL. REBETOL should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Patients must perform a pregnancy test monthly during therapy and for 6 months posttherapy. Women of childbearing potential must be counseled about use of effective contraception (two reliable forms) prior to initiating therapy. Patients (male and female) must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during REBETOL and for6 months posttherapy. Patients (male and female) should be advised to notify the physician immediately in the event of a pregnancy . If pregnancy does occur during treatment or during 6 months posttherapy, the patient must be advised of the teratogenic risk of REBETOL therapy to the fetus. Patients, or partners of patients, should immediately report any pregnancy that occurs during treatment or within 6 months after treatment cessation to their physician. Physicians should report such cases by calling 1-800-593-2214. Patients receiving REBETOL Capsules should be informed of the benefits and risks associated with treatment, directed in its appropriate use, and referred to the patient MEDICATION GUIDE. Patients should be informed that the effect of treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of the hepatitis C virus should be taken. The most common adverse experience occurring with REBETOL Capsules is anemia, which may be severe . Patients should be advised that laboratory evaluations are required prior to starting therapy and periodically thereafter . It is advised that patients be well hydrated, especially during the initial stages of treatment.<br/>Laboratory Tests: The following laboratory tests are recommended for all patients treated with REBETOL Capsules, prior to beginning treatment and then periodically thereafter.<br/>Carcinogenesis and Mutagenesis: Ribavirin did not cause an increase in any tumor type when administered for 6 months in the transgenic p53 deficient mouse model at doses up to 300 mg/kg (estimated human equivalent of 25 mg/kg based on body surface area adjustment for a 60 kg adult; approximately 1.9 times the maximum recommended human daily dose). Ribavirin was non-carcinogenic when administered for 2 years to rats at doses up to 40 mg/kg (estimated human equivalent of 5.71 mg/kg based on body surface area adjustment for a 60 kg adult). However, this dose wasless than the maximum tolerated dose, and therefore the study was not adequate to fully characterize the carcinogenic potential of ribavirin. Ribavirin demonstrated increased incidences of mutation and cell transformation in multiple genotoxicity assays. Ribavirin was active in the Balb/3T3 In Vitro Cell Transformation Assay. Mutagenic activity was observed in the mouse lymphoma assay, and at doses of 20���200 mg/kg (estimated human equivalent of 1.67���16.7 mg/kg, based on body surface area adjustment for a 60 kg adult; 0.1���1��the maximum recommended human 24-hour dose of ribavirin) in a mouse micronucleus assay. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes.<br/>Impairment of Fertility: Ribavirin demonstrated significant embryocidal and/or teratogenic effects at doses well below the recommended human dose in all animal species in which adequate studies have been conducted. Fertile women and partners of fertile women should not receive REBETOL unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple-dose half-life (t) of ribavirin of 12 days, effective contraception must be utilized for 6 months posttherapy (e.g., 15 half-lives of clearance for ribavirin). REBETOL should be used with caution in fertile men. In studies in mice to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of 15 to 150 mg/kg/day (estimated human equivalent of 1.25���12.5 mg/kg/day, based on body surface area adjustment for a 60 kg adult; 0.1���0.8��the maximum human 24-hour dose of ribavirin) administered for 3 or 6 months, abnormalities in sperm occurred. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenesis cycles.<br/>Animal Toxicology: Long-term studies in the mouse and rat (18���24 months; doses of 20���75 and 10���40 mg/kg/day, respectively {estimated human equivalent doses of 1.67���6.25 and 1.43���5.71 mg/kg/day, respectively, based on body surface area adjustment for a 60 kg adult; approximately 0.1���0.4��the maximum human 24-hour dose of ribavirin}) have demonstrated a relationship between chronic ribavirin exposure and increased incidences of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence was increased in ribavirin-treated rats. In a study in which rat pups were dosed postnatally with ribavirin at doses of 10, 25 and 50 mg/kg/day, drug-related deaths occurred at 50 mg/kg (at rat pup plasma concentrations below human plasma concentrations at the human therapeutic dose) between study days 13 and 48. Rat pups dosed from postnatal day 7 through 63 demonstrated a minor, dose-related decrease in overall growth at all doses, which was subsequently manifested as slight decreases in body weight, crown-rump length and bone length. These effects showed evidence of reversibility, and no histopathological effects on bone were observed. No ribavirin effects were observed regarding neurobehavioral or reproductive development.<br/>Pregnancy Category X: Ribavirin produced significant embryocidal and/or teratogenic effects in all animal species in which adequate studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of fetuses and offspring was reduced. In conventional embryotoxicity/teratogenicity studies in rats and rabbits, observed no effect dose levels were well below those for proposed clinical use (0.3 mg/kg/day for both the rat and rabbit; approximately 0.06��the recommended human 24-hour dose of ribavirin). No maternal toxicity or effects on offspring were observed in a peri/postnatal toxicity study in rats dosed orally at up to 1 mg/kg/day (estimated human equivalent dose of 0.17 mg/kg based on body surface area adjustment for a 60 kg adult; approximately 0.01��the maximum recommended human 24-hour dose of ribavirin).<br/>Treatment and Posttreatment: Potential Risk to the Fetus: Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether ribavirin contained in sperm will exert a potential teratogenic effect upon fertilization of the ova. In a study in rats, it was concluded that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg for 5 days (estimated human equivalent doses of 7.14���28.6 mg/kg, based on body surface area adjustment for a 60 kg adult; up to 1.7��the maximum recommended human dose of ribavirin). However, because of the potential human teratogenic effects of ribavirin, male patients should be advised to take every precaution to avoid risk of pregnancy for their female partners. Women of childbearing potential should not receive REBETOL unless they are using effective contraception (two reliable forms) during the therapy period. In addition, effective contraception should be utilized for 6 months posttherapy based on a multiple-dose half-life (t) of ribavirin of 12 days. Male patients and their female partners must practice effective contraception (two reliable forms) during treatment with REBETOL and for the 6-month posttherapy period (e.g., 15 half-lives for ribavirin clearance from the body). Ribavirin Pregnancy Registry: A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for six months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214.<br/>Nursing Mothers: It is not known whether the REBETOL product is excreted in human milk. Because of the potential for serious adverse reactions from the drug in nursing infants, a decision should be made whether to discontinue nursing or to delay or discontinue REBETOL.<br/>Geriatric Use: Clinical studies of REBETOL/INTRON A or PegIntron therapy did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently from younger subjects. REBETOL is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients often have decreased renal function, care should be taken in dose selection. Renal function should be monitored and dosage adjustments should be made accordingly. REBETOL should not be used in patients with creatinine clearance<50 mL/min . In general, REBETOL Capsules should be administered to elderly patients cautiously, starting at the lower end of the dosing range, reflecting the greater frequency of decreased hepatic and/or cardiac function, and of concomitant disease or other drug therapy. In clinical trials, elderly subjects had a higher frequency of anemia (67%) than did younger patients (28%) .<br/>Pediatric Use: Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% versus 1%) during treatment and off-therapy follow-up . As in adult patients, pediatric patients experienced other psychiatric adverse events (e.g., depression, emotional lability, somnolence), anemia, and neutropenia . During a 48-week course of therapy there was a decrease in the rate of linear growth (mean percentile assignment decrease of 9%) and a decrease in the rate of weight gain (mean percentile assignment decrease of 13%). A general reversal of these trends was noted during the 24-week posttreatment period.<br/>Drug Interactions:<br/>Didanosine: Co-administration of REBETOL Capsules or Oral Solution and didanosine is not recommended. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactactemia/lactic acidosis have been reported in clinical trials .<br/>Stavudine and Zidovudine: Ribavirin may antagonize the in vitro antiviral activity of stavudine and zidovudine against HIV. Therefore, concomitant use of ribavirin with either of these drugs should be used with caution . | lld:dailymed |
| dailymed-drugs:80 | dailymed-instance:precautio... | Cognitive/Neuropsychiatric Adverse Events: Use of oxcarbazepine has been associated with central nervous system-related adverse events. The most significant of these can be classified into three general categories: 1) cognitive symptoms including psychomotor slowing, difficulty with concentration, and speech or language problems, 2) somnolence or fatigue, and 3) coordination abnormalities, including ataxia and gait disturbances.<br/>Adult Patients: In one large, fixed-dose study, oxcarbazepine was added to existing AED therapy (up to three concomitant AEDs). By protocol, the dosage of the concomitant AEDs could not be reduced as oxcarbazepine was added, reduction in oxcarbazepine dosage was not allowed if intolerance developed, and patients were discontinued if unable to tolerate their highest target maintenance doses. In this trial, 65% of patients were discontinued because they could not tolerate the2400 mg/day dose of oxcarbazepine on top of existing AEDs. The adverse events seen in this study were primarily CNS related and the risk for discontinuation was dose related. In this trial, 7.1% of oxcarbazepine-treated patients and 4% of placebo-treated patients experienced a cognitive adverse event. The risk of discontinuation for these events was about 6.5 times greater on oxcarbazepine than on placebo. In addition, 26% of oxcarbazepine-treated patients and 12% of placebo-treated patients experienced somnolence. The risk of discontinuation for somnolence was about 10 times greater on oxcarbazepine than on placebo. Finally, 28.7% of oxcarbazepine-treated patients and 6.4% of placebo-treated patients experienced ataxia or gait disturbances. The risk for discontinuation for these events was about seven times greater on oxcarbazepine than on placebo. In a single placebo-controlled monotherapy trial evaluating 2400 mg/day of oxcarbazepine, no patients in either treatment group discontinued double-blind treatment because of cognitive adverse events, somnolence, ataxia, or gait disturbance. In the two dose-controlled conversion to monotherapy trials comparing 2400 mg/day and 300 mg/day oxcarbazepine, 1.1% of patients in the 2400 mg/day group discontinued double-blind treatment because of somnolence or cognitive adverse events compared to 0% in the 300 mg/day group. In these trials, no patients discontinued because of ataxia or gait disturbances in either treatment group.<br/>Pediatric Patients: A study was conducted in pediatric patients (3 to 17 years old) with inadequately controlled partial seizures in which oxcarbazepine was added to existing AED therapy (up to two concomitant AEDs). By protocol, the dosage of concomitant AEDs could not be reduced as oxcarbazepine was added. Oxcarbazepine was titrated to reach a target dose ranging from 30 mg/kg to 46 mg/kg (based on a patient's body weight with fixed doses for pre-defined weight ranges). Cognitive adverse events occurred in 5.8% of oxcarbazepine treated patients (the single most common event being concentration impairment, 4 of 138 patients) and in 3.1% of patients treated with placebo. In addition, 34.8% of oxcarbazepine-treated patients and 14.0% of placebo-treated patients experienced somnolence. (No patient discontinued due to a cognitive adverse event or somnolence.). Finally, 23.2% of oxcarbazepine-treated patients and 7.0% of placebo-treated patients experienced ataxia or gait disturbances. Two (1.4%) oxcarbazepine-treated patients and 1 (0.8%) placebo-treated patient discontinued due to ataxia or gait disturbances.<br/>Multi-Organ Hypersensitivity: Multi-organ hypersensitivity reactions have occurred in close temporal association (median time to detection 13 days: range 4 to 60) to the initiation of oxcarbazepine therapy in adult and pediatric patients. Although there have been a limited number of reports, many of these cases resulted in hospitalization and some were considered life threatening. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations included lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepatorenal syndrome, arthralgia and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, oxcarbazepine should be discontinued and an alternative treatment started. Although there are no case reports to indicate cross sensitivity with other drugs that produce this syndrome, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility (see WARNINGS, Patients with a Past History of Hypersensitivity Reaction to Carbamazepine).<br/>Information for Patients: Anaphylactic reactions and angioedema may occur during treatment with oxcarbazepine. Patients should be advised to report immediately signs and symptoms suggesting angioedema (swelling of the face, eyes, lips, tongue or difficulty in swallowing or breathing) and to stop taking the drug until they have consulted with their physician (see WARNINGS, Anaphylactic Reactions and Angioedema). Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25% to 30% of these patients may experience hypersensitivity reactions with oxcarbazepine. Patients should be advised that if they experience a hypersensitivity reaction while taking oxcarbazepine they should consult with their physician immediately (see WARNINGS, Patients with a Past History of Hypersensitivity Reaction to Carbamazepine). Patients should be advised that serious skin reactions have been reported in association with oxcarbazepine. In the event a skin reaction should occur while taking oxcarbazepine, patients should consult with their physician immediately (see WARNINGS, Serious Dermatological Reactions). Patients should be instructed that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug related and should be reported to the physician immediately (see PRECAUTIONS, Multi-Organ Hypersensitivity). Female patients of childbearing age should be warned that the concurrent use of oxcarbazepine with hormonal contraceptives may render this method of contraception less effective (see Drug Interactions). Additional non-hormonal forms of contraception are recommended when using oxcarbazepine. Caution should be exercised if alcohol is taken in combination with oxcarbazepine therapy, due to a possible additive sedative effect. Patients should be advised that oxcarbazepine may cause dizziness and somnolence. Accordingly, patients should be advised not to drive or operate machinery until they have gained sufficient experience on oxcarbazepine to gauge whether it adversely affects their ability to drive or operate machinery.<br/>Laboratory Tests: Serum sodium levels below 125 mmol/L have been observed in patients treated with oxcarbazepine (see WARNINGS). Experience from clinical trials indicates that serum sodium levels return toward normal when the oxcarbazepine dosage is reduced or discontinued, or when the patient was treated conservatively (e.g., fluid restriction). Laboratory data from clinical trials suggest that oxcarbazepine use was associated with decreases in T, without changes in Tor TSH.<br/>Drug Interactions: Oxcarbazepine can inhibit CYP2C19 and induce CYP3A4/5 with potentially important effects on plasma concentrations of other drugs. In addition, several AEDs that are cytochrome P450 inducers can decrease plasma concentrations of oxcarbazepine and MHD. Oxcarbazepine was evaluated in human liver microsomes to determine its capacity to inhibit the major cytochrome P450 enzymes responsible for the metabolism of other drugs. Results demonstrate that oxcarbazepine and its pharmacologically active 10-monohydroxy metabolite (MHD) have little or no capacity to function as inhibitors for most of the human cytochrome P450 enzymes evaluated (CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP4A9 and CYP4A11) with the exception of CYP2C19 and CYP3A4/5. Although inhibition of CYP3A4/5 by oxcarbazepine and MHD did occur at high concentrations, it is not likely to be of clinical significance. The inhibition of CYP2C19 by oxcarbazepine and MHD, however, is clinically relevant (see below). In vitro, the UDP-glucuronyl transferase level was increased, indicating induction of this enzyme. Increases of 22% with MHD and 47% with oxcarbazepine were observed. As MHD, the predominant plasma substrate, is only a weak inducer of UDP-glucuronyl transferase, it is unlikely to have an effect on drugs that are mainly eliminated by conjugation through UDP-glucuronyl transferase (e.g., valproic acid, lamotrigine). In addition, oxcarbazepine and MHD induce a subgroup of the cytochrome P450 3A family (CYP3A4 and CYP3A5) responsible for the metabolism of dihydropyridine calcium antagonists and oral contraceptives, resulting in a lower plasma concentration of these drugs. As binding of MHD to plasma proteins is low (40%), clinically significant interactions with other drugs through competition for protein binding sites are unlikely.<br/>Antiepileptic Drugs: Potential interactions between oxcarbazepine and other AEDs were assessed in clinical studies. The effect of these interactions on mean AUCs and Care summarized in Table 2. In vivo, the plasma levels of phenytoin increased by up to 40% when oxcarbazepine was given at doses above 1200 mg/day. Therefore, when using doses of oxcarbazepine greater than 1200 mg/day during adjunctive therapy, a decrease in the dose of phenytoin may be required. The increase of phenobarbital level, however, is small (15%) when given with oxcarbazepine. Strong inducers of cytochrome P450 enzymes (i.e., carbamazepine, phenytoin and phenobarbital) have been shown to decrease the plasma levels of MHD (29% to 40%). No autoinduction has been observed with oxcarbazepine.<br/>Hormonal Contraceptives: Coadministration of oxcarbazepine with an oral contraceptive has been shown to influence the plasma concentrations of the two hormonal components, ethinylestradiol (EE) and levonorgestrel (LNG). The mean AUC values of EE were decreased by 48% [90% CI: 22 to 65] in one study and 52% [90% CI: 38 to 52] in another study. The mean AUC values of LNG were decreased by 32% [90% CI: 20 to 45] in one study and 52% [90% CI: 42 to 52] in another study. Therefore, concurrent use of oxcarbazepine with hormonal contraceptives may render these contraceptives less effective (see Drug Interactions). Studies with other oral or implant contraceptives have not been conducted.<br/>Calcium Antagonists: After repeated coadministration of oxcarbazepine, the AUC of felodipine was lowered by 28% [90% CI: 20 to 33]. Verapamil produced a decrease of 20% [90% CI: 18 to 27] of the plasma levels of MHD.<br/>Other Drug Interactions: Cimetidine, erythromycin and dextropropoxyphene had no effect on the pharmacokinetics of MHD. Results with warfarin show no evidence of interaction with either single or repeated doses of oxcarbazepine.<br/>Drug/Laboratory Test Interactions: There are no known interactions of oxcarbazepine with commonly used laboratory tests.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In two-year carcinogenicity studies, oxcarbazepine was administered in the diet at doses of up to 100 mg/kg/day to mice and by gavage at doses of up to 250 mg/kg to rats, and the pharmacologically active 10-hydroxy metabolite (MHD) was administered orally at doses of up to 600 mg/kg/day to rats. In mice, a dose-related increase in the incidence of hepatocellular adenomas was observed at oxcarbazepine doses���70 mg/kg/day or approximately 0.1 times the maximum recommended human dose (MRHD) on a mg/mbasis. In rats, the incidence of hepatocellular carcinomas was increased in females treated with oxcarbazepine at doses���25 mg/kg/day (0.1 times the MRHD on a mg/mbasis), and incidences of hepatocellular adenomas and/or carcinomas were increased in males and females treated with MHD at doses of 600 mg/kg/day (2.4 times the MRHD on a mg/mbasis) and���250 mg/kg/day (equivalent to the MRHD on a mg/mbasis), respectively. There was an increase in the incidence of benign testicular interstitial cell tumors in rats at 250 mg oxcarbazepine/kg/day and at���250 mg MHD/kg/day, and an increase in the incidence of granular cell tumors in the cervix and vagina in rats at 600 mg MHD/kg/day. Oxcarbazepine increased mutation frequencies in the Ames test in vitro in the absence of metabolic activation in one of five bacterial strains. Both oxcarbazepine and MHD produced increases in chromosomal aberrations and polyploidy in the Chinese hamster ovary assay in vitro in the absence of metabolic activation. MHD was negative in the Ames test and no mutagenic or clastogenic activity was found with either oxcarbazepine or MHD in V79 Chinese hamster cells in vitro. Oxcarbazepine and MHD were both negative for clastogenic or aneugenic effects (micronucleus formation) in an in vivo rat bone marrow assay. In a fertility study in which rats were administered MHD (50, 150, or 450 mg/kg) orally prior to and during mating and early gestation, estrous cyclicity was disrupted and numbers of corpora lutea, implantations, and live embryos were reduced in females receiving the highest dose (approximately two times the MRHD on a mg/mbasis).<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Labor and Delivery: The effect of oxcarbazepine on labor and delivery in humans has not been evaluated.<br/>Nursing Mothers: Oxcarbazepine and its active metabolite (MHD) are excreted in human breast milk. A milk-to-plasma concentration ratio of 0.5 was found for both. Because of the potential for serious adverse reactions to oxcarbazepine in nursing infants, a decision should be made about whether to discontinue nursing or to discontinue the drug in nursing women, taking into account the importance of the drug to the mother.<br/>Patients with Renal Impairment: In renally-impaired patients (creatinine clearance<30 mL/min), the elimination half-life of MHD is prolonged with a corresponding two-fold increase in AUC (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Oxcarbazepine therapy should be initiated at one-half the usual starting dose and increased, if necessary, at a slower than usual rate until the desired clinical response is achieved.<br/>Pediatric Use: Oxcarbazepine is indicated for use as adjunctive therapy for partial seizures in patients aged 4 to 16 years. Oxcarbazepine is also indicated as monotherapy for partial seizures in patients aged 4 to 16 years. Oxcarbazepine has been given to 770 patients between the ages of 3 to 17 years in controlled clinical trials (332 treated as monotherapy) and about 615 patients between the ages of 3 to 17 years in other trials. (See ADVERSE REACTIONS for a description of the adverse events associated with oxcarbazepine use in this population.) Additional pediatric use information in patients ages 2 to 4 years is approved for Novartis Pharmaceuticals Corporation's oxcarbazepine tablets and oral suspension. However due to Novartis' marketing exclusivity rights, this drug product is not labeled for this pediatric age group.<br/>Geriatric Use: There were 52 patients over age 65 in controlled clinical trials and 565 patients over the age of 65 in other trials. Following administration of single (300 mg) and multiple (600 mg/day) doses of oxcarbazepine in elderly volunteers (60 to 82 years of age), the maximum plasma concentrations and AUC values of MHD were 30% to 60% higher than in younger volunteers (18 to 32 years of age). Comparisons of creatinine clearance in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance. | lld:dailymed |
| dailymed-drugs:81 | dailymed-instance:precautio... | General: Therapy with hydroxyurea requires close supervision. The complete status of the blood, including bone marrow examination, if indicated, as well as kidney function and liver function should be determined prior to, and repeatedly during, treatment. The determination of the hemoglobin level, total leukocyte counts, and platelet counts should be performed at least once a week throughout the course of hydroxyurea therapy. If the white blood cell count decreases to less than 2500/mm, or the platelet count to less than 100,000/mm, therapy should be interrupted until the values rise significantly toward normal levels. Severe anemia, if it occurs, should be managed without interrupting hydroxyurea therapy. Hydroxyurea should be used with caution in patients with marked renal dysfunction. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION.) Hydroxyurea is not indicated for the treatment of HIV infection; however, if HIV-infected patients are treated with hydroxyurea, and in particular, in combination with didanosine and/or stavudine, close monitoring for signs and symptoms of pancreatitis is recommended. Patients who develop signs and symptoms of pancreatitis should permanently discontinue therapy with hydroxyurea. (See WARNINGS and ADVERSE REACTIONS.) An increased risk of hepatotoxicity, which may be fatal, may occur in patients treated with hydroxyurea, and in particular, in combination with didanosine and stavudine. This combination should be avoided.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS for Carcinogenesis and Mutagenesis information. Impairment of Fertility: Hydroxyurea administered to male rats at 60 mg/kg/day (about 0.3 times the maximum recommended human daily dose on an mg/mbasis) produced testicular atrophy, decreased spermatogenesis, and significantly reduced their ability to impregnate females.<br/>Pregnancy: Pregnancy Category D.<br/>Nursing Mothers: Hydroxyurea is excreted in human milk. Because of the potential for serious adverse reactions with hydroxyurea, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric Use: Elderly patients may be more sensitive to the effects of hydroxyurea, and may require a lower dose regimen. This drug is known to be excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION: Renal Insufficiency).<br/>Drug Interactions: Prospective studies on the potential for hydroxyurea to interact with other drugs have not been performed. Concurrent use of hydroxyurea and other myelosuppressive agents or radiation therapy may increase the likelihood of bone marrow depression or other adverse events. Since hydroxyurea may raise the serum uric acid level, dosage adjustment of uricosuric medication may be necessary.<br/>Information for Patients: HYDREA is a medication that must be handled with care. People who are not taking HYDREA should not be exposed to it. To decrease the risk of exposure, wear disposable gloves when handling HYDREA or bottles containing HYDREA. Anyone handling HYDREA should wash their hands before and after contact with the bottle or capsules. If the powder from the capsule is spilled, it should be wiped up immediately with a damp disposable towel and discarded in a closed container, such as a plastic bag. The medication should be kept away from children and pets. Contact your doctor for instructions on how to dispose of outdated capsules. | lld:dailymed |
| dailymed-drugs:83 | dailymed-instance:precautio... | General:: Patients may experience a transient stinging or burning sensation following application of cromolyn sodium ophthalmic solution, USP 4%. The recommended frequency of administration should not be exceeded .<br/>Information for Patients:: Patients should be advised to follow the patient instructions listed on the Information for Patients sheet. Users of contact lenses should refrain from wearing lenses while exhibiting the signs and symptoms of vernal keratoconjunctivitis, vernal conjunctivitis, or vernal keratitis. Do not wear contact lenses during treatment with cromolyn sodium ophthalmic solution, USP 4%.<br/>Carcinogenesis, Mutagenesis, and Impairment of Fertility:: Long term studies of cromolyn sodium in mice (12 months intraperitoneal administration at doses up to 150 mg/kg three days per week), hamsters (intraperitoneal administration at doses up to 52.6 mg/kg three days per week for 15 weeks followed by 17.5 mg/kg three days per week for 37 weeks), and rats (18 months subcutaneous administration at doses up to 75 mg/kg six days per week) showed no neoplastic effects. The average daily maximum dose levels administered in these studies were 192.9 mg/mfor mice, 47.2 mg/mfor hamsters and 385.8 mg/mfor rats. These doses correspond to approximately 6.8, 1.7, and 14 times the maximum daily human dose of 28 mg/m. Cromolyn sodium showed no mutagenic potential in the Ames Salmonella/microsome plate assays, mitotic gene conversion in Saccharomyces cerevisiae and in an in vitro cytogenetic study in human peripheral lymphocytes. No evidence of impaired fertility was shown in laboratory reproduction studies conducted subcutaneously in rats at the highest doses tested, 175 mg/kg/day (1050 mg/m) in males and 100 mg/kg/day (600 mg/m) in females. These doses are approximately 37 and 21 times the maximum daily human dose, respectively, based on mg/m.<br/>Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies with cromolyn sodium administered subcutaneously to pregnant mice and rats at maximum daily doses of 540 mg/kg (1620 mg/m) and 164 mg/kg (984 mg/m), respectively, and intravenously to rabbits at a maximum daily dose of 485 mg/kg (5820 mg/m) produced no evidence of fetal malformation. These doses represent approximately 57, 35, and 205 times the maximum daily human dose, respectively, on a mg/mbasis. Adverse fetal effects (increased resorption and decreased fetal weight) were noted only at the very high parenteral doses that produced maternal toxicity. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.<br/>Nursing Mothers:: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when cromolyn sodium ophthalmic solution, USP 4% is administered to a nursing woman.<br/>Pediatric use:: Safety and effectiveness in children below the age of 4 years have not been established.<br/>Geriatric use:: No overall differences in safety or effectiveness have been observed between elderly and younger patients. | lld:dailymed |
| dailymed-drugs:87 | dailymed-instance:precautio... | General:<br/>Suicide: Since depression is a commonly associated feature of OCD, the risk of suicide must be considered. Prescriptions for ClomiPRAMINE hydrochloride should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.<br/>Cardiovascular Effects: Modest orthostatic decreases in blood pressure and modest tachycardia were each seen in approximately 20% of patients taking ClomiPRAMINE in clinical trials; but patients were frequently asymptomatic. Among approximately 1400 patients treated with ClomiPRAMINE in the premarketing experience who had ECGs, 1.5% developed abnormalities during treatment, compared with 3.1% of patients receiving active control drugs and 0.7% of patients receiving placebo. The most common ECG changes were PVCs, ST-T wave changes, and intraventricular conduction abnormalities. These changes were rarely associated with significant clinical symptoms. Nevertheless, caution is necessary in treating patients with known cardiovascular disease, and gradual dose titration is recommended.<br/>Psychosis, Confusion, and Other Neuropsychiatric Phenomena: Patients treated with ClomiPRAMINE have been reported to show a variety of neuropsychiatric signs and symptoms including delusions, hallucinations, psychotic episodes, confusion, and paranoia. Because of the uncontrolled nature of many of the studies, it is impossible to provide a precise estimate ofthe extent of risk imposed by treatment with ClomiPRAMINE. As with tricyclic antidepressants to which it is closely related, ClomiPRAMINE may precipitate an acute psychotic episode in patients with unrecognized schizophrenia.<br/>Mania/Hypomania: During premarketing testing of ClomiPRAMINE in patients with affective disorder, hypomania or mania was precipitated in several patients. Activation of mania or hypomania has also been reported in a small proportion of patients with affective disorder treated with marketed tricyclic antidepressants, which are closely related to ClomiPRAMINE.<br/>Hepatic Changes: During premarketing testing, ClomiPRAMINE was occasionally associated with elevations in SGOT and SGPT (pooled incidence of approximately 1% and 3%, respectively) of potential clinical importance (i.e., values greater than 3 times the upper limit of normal). In the vast majority of instances, these enzyme increases were not associated with other clinical findings suggestive of hepatic injury; moreover, none were jaundiced. Rare reports of more severe liver injury, some fatal, have been recorded in foreign postmarketing experience. Caution is indicated in treating patients with known liver disease, and periodic monitoring of hepatic enzyme levels is recommended in such patients.<br/>Hematologic Changes: Although no instances of severe hematologic toxicity were seen in the premarketing experience with ClomiPRAMINE, there have been postmarketing reports of leukopenia, agranulocytosis, thrombocytopenia, anemia, and pancytopenia in association with ClomiPRAMINE hydrochloride capsules USP use. As is the case with tricyclic antidepressants to which ClomiPRAMINE is closely related, leukocyte and differential blood counts should be obtained in patients who develop fever and sore throat during treatment with ClomiPRAMINE.<br/>Central Nervous System: More than 30 cases of hyperthermia have been recorded by nondomestic postmarketing surveillance systems. Most cases occurred when ClomiPRAMINE was used in combination with other drugs. When ClomiPRAMINE and a neuroleptic were used concomitantly, the cases were sometimes considered to be examples of a neuroleptic malignant syndrome.<br/>Sexual Dysfunction: The rate of sexual dysfunction in male patients with OCD who were treated with ClomiPRAMINE in the premarketing experience was markedly increased compared with placebo controls (i.e., 42% experienced ejaculatory failure and 20% experienced impotence, compared with 2.0% and 2.6%, respectively, in the placebo group). Approximately 85% of males with sexual dysfunction chose to continue treatment.<br/>Weight Changes: In controlled studies of OCD, weight gain was reported in 18% of patients receiving ClomiPRAMINE, compared with 1% of patients receiving placebo. In these studies, 28% of patients receiving ClomiPRAMINE had a weight gain of at least 7% of their initial body weight, compared with 4% of patients receiving placebo. Several patients had weight gains in excess of 25% of their initial body weight. Conversely, 5% of patients receiving ClomiPRAMINE and 1% receiving placebo had weight losses of at least 7% of their initial body weight.<br/>Electroconvulsive Therapy: As with closely related tricyclic antidepressants, concurrent administration of ClomiPRAMINE with electroconvulsive therapy may increase the risks; such treatment should be limited to those patients for whom it is essential, since there is limited clinical experience.<br/>Surgery: Prior to elective surgery with general anesthetics, therapy with ClomiPRAMINE hydrochloride should be discontinued for as long as is clinically feasible, and the anesthetist should be advised.<br/>Use in Concomitant Illness: As with closely related tricyclic antidepressants, ClomiPRAMINE should be used with caution in the following:<br/>Withdrawal Symptoms: A variety of withdrawal symptoms have been reported in association with abrupt discontinuation of ClomiPRAMINE, including dizziness, nausea, vomiting, headache, malaise, sleep disturbance, hyperthermia, and irritability. In addition, such patients may experience a worsening of psychiatric status. While the withdrawal effects of ClomiPRAMINE have not been systematically evaluated in controlled trials, they are well known with closely related tricyclic antidepressants, and it is recommended that the dosage be tapered gradually and the patient monitored carefully during discontinuation (see DRUG ABUSE AND DEPENDENCE).<br/>Information for Patients: Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with ClomiPRAMINE hydrochloride capsules and should counsel them in its appropriate use. A patient Medication Guide about���Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions���is available for ClomiPRAMINE hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking ClomiPRAMINE hydrochloride.<br/>Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Physicians are advised to discuss the following issues with patients for whom they prescribe ClomiPRAMINE hydrochloride.<br/>Drug Interactions: The risks of using ClomiPRAMINE in combination with other drugs have not been systematically evaluated. Given the primary CNS effects of ClomiPRAMINE, caution is advised in using it concomitantly with other CNS-active drugs (see PRECAUTIONS, Information for Patients). ClomiPRAMINE should not be used with MAO inhibitors (see CONTRAINDICATIONS). Close supervision and careful adjustment of dosage are required when ClomiPRAMINE is administered with anticholinergic or sympathomimetic drugs. Several tricyclic antidepressants have been reported to block the pharmacologic effects of guanethidine, clonidine, or similar agents, and such an effect may be anticipated with ClomiPRAMINE because of its structural similarity to other tricyclic antidepressants. The plasma concentration of ClomiPRAMINE has been reported to be increased by the concomitant administration of haloperidol; plasma levels of several closely related tricyclic antidepressants have been reported to be increased by the concomitant administration of methylphenidate or hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and decreased by the concomitant administration of hepatic enzyme inducers (e.g., barbiturates, phenytoin), and such an effect may be anticipated with ClomiPRAMINE as well. Administration of ClomiPRAMINE has been reported to increase the plasma levels of phenobarbital, ifgiven concomitantly (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Interactions).<br/>Drugs Metabolized by P450 2D6: The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so-called���poor metabolizers���); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may besmall, or quite large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, paroxetine, and fluvoxamine, inhibit P450 2D6, they may vary in the extent of inhibition. Fluvoxamine has also been shown to inhibit P450 1A2, an isoform also involved in TCA metabolism. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of agents in the tricyclic antidepressant class (which includes ClomiPRAMINE) with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant agent or the other drug. Furthermore, whenever one of these drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant agent may be required. It is desirable to monitor TCA plasma levels whenever an agent of the tricyclic antidepressant class including ClomiPRAMINE is going to be coadministered with another drug known to be an inhibitor of P450 2D6 (and/or P450 1A2). Because ClomiPRAMINE is highly bound to serum protein, the administration of ClomiPRAMINE to patients taking other drugs that are highly bound to protein (e.g., warfarin, digoxin) may cause an increase in plasma concentrations of these drugs, potentially resulting in adverse effects. Conversely, adverse effects may result from displacement of protein-bound ClomiPRAMINE by other highly bound drugs (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Distribution).<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of carcinogenicity was found in two 2 year bioassays in rats at doses up to 100 mg/kg, which is 24 and 4 times the maximum recommended human daily dose (MRHD) on a mg/kg and mg/mbasis, respectively, or in a 2 year bioassay in mice at doses up to 80 mg/kg, which is 20 and 1.5 times the MRHD on a mg/kg and mg/mbasis, respectively. In reproduction studies, no effects on fertility were found in rats given up to 24 mg/kg, which is 6 times, and approximately equal to, the MRHD on a mg/kg and mg/mbasis, respectively.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: ClomiPRAMINE hydrochloride capsules USP have been found in human milk. Because of the potential for adverse reactions, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone considering the use of ClomiPRAMINE hydrochloride capsules in a child or adolescent must balance the potential risks with the clinical need. In a controlled clinical trial in children and adolescents (10 to 17 years of age), 46 outpatients received ClomiPRAMINE for up to 8 weeks. In addition, 150 adolescent patients have received ClomiPRAMINE in open-label protocols for periods of several months to several years. Of the 196 adolescents studied, 50 were 13 years of age or less and 146 were 14 to 17 years of age. The adverse reaction profile in this age group (see ADVERSE REACTIONS) is similar to that observed in adults. The risks, if any, that may be associated with ClomiPRAMINE's extended use in children and adolescents with OCD have not been systematically assessed. The evidence supporting the conclusion that ClomiPRAMINE is safe for use in children and adolescents is derived from relatively short term clinical studies and from extrapolation of experience gained with adult patients. In particular, there are no studies that directly evaluate the effects of long term ClomiPRAMINE use on the growth, development, and maturation of children and adolescents. Although there is no evidence to suggest that ClomiPRAMINE adversely affects growth, development or maturation, the absence of such findings is not adequate to rule out a potential for such effects in chronic use. The safety and effectiveness in pediatric patients below the age of 10 have not been established. Therefore, specific recommendations cannot be made for the use of ClomiPRAMINE in pediatric patients under the age of 10.<br/>Geriatric Use: Clinical studies of ClomiPRAMINE hydrochloride did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects; 152 patients at least 60 years of age participating in various U.S. clinical trials received ClomiPRAMINE hydrochloride for periods of several months to several years. No unusual age-related adverse events were identified in this population. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:88 | dailymed-instance:precautio... | General: INDOCIN (Indomethacin) may mask the usual signs and symptoms of infection. Therefore, the physician must be continually on the alert for this and should use the drug with extra care in the presence of existing controlled infection. Severe hepatic reactions have been reported in adults treated chronically with oral indomethacin for arthritic disorders. [For further information, see package insert for Capsules INDOCIN (Indomethacin).] If clinical signs and symptoms consistent with liver disease develop in the neonate, or if systemic manifestations occur, INDOCIN I.V. should be discontinued. INDOCIN I.V. may inhibit platelet aggregation. In one small study, platelet aggregation was grossly abnormal after indomethacin therapy (given orally to premature infants to close the ductus arteriosus). Platelet aggregation returned to normal by the tenth day. Premature infants should be observed for signs of bleeding. The drug should be administered carefully to avoid extravascular injection or leakage as the solution may be irritating to tissue.<br/>Drug Interactions: Since renal function may be reduced by INDOCIN I.V., consideration should be given to reduction in dosage of those medications that rely on adequate renal function for their elimination. Because the half-life of digitalis (given frequently to pre-term infants with patent ductus arteriosus and associated cardiac failure) may be prolonged when given concomitantly with indomethacin, the neonate should be observed closely; frequent ECGs and serum digitalis levels may be required to prevent or detect digitalis toxicity early. Furthermore, in one study of premature infants treated with INDOCIN I.V. and also receiving either gentamicin or amikacin, both peak and trough levelsof these aminoglycosides were significantly elevated. Therapy with indomethacin may blunt the natriuretic effect of furosemide. This response has been attributed to inhibition of prostaglandin synthesis by non-steroidal anti-inflammatory drugs. In a study of 19 premature infants with patent ductus arteriosus treated with either INDOCIN I.V. alone or a combination of INDOCIN I.V. and furosemide, results showed that neonates receiving both INDOCIN I.V. and furosemide had significantlyhigher urinary output, higher levels of sodium and chloride excretion, and higher glomerular filtration rates than did those receiving INDOCIN I.V. alone. In this study, the data suggested that therapy with furosemide helped to maintain renal function in the premature infant when INDOCIN I.V. was added to the treatment of patent ductus arteriosus. Indomethacin usually does not influence the hypoprothrombinemia produced by anticoagulants. When indomethacin is added to anticoagulants, prothrombin time should be monitored closely. In post marketing experience, bleeding has been reported in patients on concomitant treatment with anticoagulants and INDOCIN I.V. Caution should be exercised when INDOCIN I.V. and anticoagulants are administered concomitantly. In some patients with compromised renal function, the co-administration of an NSAID and an ACE inhibitor or angiotensin II antagonist may result in further deterioration of renal function,including possible acute renal failure, which is usually reversible.<br/>Neonatal Effects: In rats and mice, oral indomethacin 4.0 mg/kg/day given during the last three days of gestation caused a decrease in maternal weight gain and some maternal and fetal deaths. An increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses was observed. At 2.0 mg/kg/day, no increase in neuronal necrosis was observed as compared to the control groups. Administration of 0.5 or 4.0 mg/kg/day during the first three days of life did not cause an increase in neuronal necrosis at either dose level. Pregnant rats, given 2.0 mg/kg/day and 4.0 mg/kg/day during the last trimester of gestation, delivered offspring whose pulmonary blood vessels were both reduced in number and excessively muscularized. These findings are similar to those observed in the syndrome of persistent pulmonary hypertension of the neonate. | lld:dailymed |
| dailymed-drugs:89 | dailymed-instance:precautio... | General: During the course of acute febrile illness, encephalitides, gastroenteritis, dehydration and electrolyte imbalance, especially in children and the elderly or debilitated, CNS reactions such as opisthotonos, convulsions, coma and extrapyramidal symptoms have been reported with and without use of Tigan (trimethobenzamide hydrochloride) or other antiemetic agents. In such disorders caution should be exercised in administering Tigan, particularly to patients who have recently received other CNS-acting agents (phenothiazines, barbiturates, belladonna derivatives). Primary emphasis should be directed toward the restoration of body���uids and electrolyte balance, the relief of fever and relief of the causative disease process. Overhydration should be avoided since it may result in cerebral edema. The antiemetic effects of Tigan may render diagnosis more dif���cult in such conditions as appendicitis and obscure signs of toxicity due to overdosage of other drugs. | lld:dailymed |
| dailymed-drugs:91 | dailymed-instance:precautio... | General: Therapy with Cystadane should be directed by physicians knowledgeable in the management of patients with homocystinuria.<br/>Hypermethioninemia: Patients with homocystinuria due to cystathionine beta-synthase (CBS) deficiency may also have elevated plasma methionine concentrations. Treatment with Cystadane may further increase methionine concentrations due to the remethylation of homocysteine to methionine. Cerebral edema has been reported in patients with hypermethioninemia, including a few patients treated with Cystadane. Plasma methionine concentrations should be monitored in patients with CBS deficiency. Plasmamethionine concentrations should be kept below 1,000 umol/L through dietary modification and, if necessary, a reduction of Cystadane dose.<br/>Information for patients: Always replace the cap tightly after using. Protect from moisture.<br/>Carcinogenesis, mutagenesis, impairment of fertility: Long-term carcinogenicity and fertility studies have not been conducted on betaine. No evidence of genotoxicity was demonstrated in the following tests: Metaphase Analysis of Human Lymphocytes; Bacterial Reverse Mutation Assay; and Mouse Micronucleus Test.<br/>Pregnancy: Pregnancy Category C. Animal reproduction studies have not been conducted with betaine. It is also not known whether betaine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Cystadane (betaine anhydrous for oral solution) should be given to a pregnant woman only if clearly needed.<br/>Nursing mothers: It is not known whether betaine is excreted in human milk (although its metabolic precursor, choline, occurs at high levels in human milk). Because many drugs are excreted in human milk, caution should be exercised when Cystadane is administered to a nursing woman.<br/>Pediatric use: The majority of case studies of homocystinuria patients treated with betaine have been pediatric patients. The disorder, in its most severe form, can be manifested within the first months or years of life by lethargy, failure to thrive, developmental delays, seizures, or optic lens displacement. Patients have been treated successfully without adverse effects within the first months or years of life with dosages of 6 grams per day or moreof betaine with resultant biochemical and clinical improvement. However, dosage titration may be preferable in pediatric patients . | lld:dailymed |
| dailymed-drugs:92 | dailymed-instance:precautio... | General: Review of experience to date suggests that a subgroup of older patients with associated severe illness may tolerate diarrhea less well. When clindamycin is indicated in these patients, they should be carefully monitored for change in bowel frequency. CLEOCIN PHOSPHATE products should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. CLEOCIN PHOSPHATE should be prescribed with caution in atopic individuals. Certain infections may require incision and drainage or other indicated surgical procedures in addition to antibiotic therapy. The use of CLEOCIN PHOSPHATE may result in overgrowth of nonsusceptible organisms���particularly yeasts. Should superinfections occur, appropriate measures should be taken as indicated by the clinical situation. CLEOCIN PHOSPHATE should not be injected intravenously undiluted as a bolus, but should be infused over at least 10���60 minutes as directed in the DOSAGE AND ADMINISTRATION section. Clindamycin dosage modification may not be necessary in patients with renal disease. In patients with moderate to severe liver disease, prolongation of clindamycin half-life has been found. However, it was postulated from studies that when given every eight hours, accumulation should rarely occur. Therefore, dosage modification in patients with liver disease may not be necessary. However, periodic liver enzyme determinations should be made when treating patients with severe liver disease. Prescribing CLEOCIN PHOSPHATE in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.<br/>Information for Patients: Patients should be counseled that antibacterial drugs including CLEOCIN PHOSPHATE should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When CLEOCIN PHOSPHATE is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by CLEOCIN PHOSPHATE or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. Ifthis occurs, patients should contact their physician as soon as possible.<br/>Laboratory Tests: During prolonged therapy periodic liver and kidney function tests and blood counts should be performed.<br/>Drug Interactions: Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, it should be used with caution in patients receiving such agents. Antagonism has been demonstrated between clindamycin and erythromycin in vitro. Because of possible clinical significance, the two drugs should not be administered concurrently.<br/>Carcinogenesis, Mutagenesis, Impairment Of Fertility: Long term studies in animals have not been performed with clindamycin to evaluate carcinogenic potential. Genotoxicity tests performed included a rat micronucleus test and an Ames Salmonella reversion test. Both tests were negative. Fertility studies in rats treated orally with up to 300 mg/kg/day (approximately 1.1 times the highest recommended adult human dose based on mg/m) revealed no effects on fertility or mating ability.<br/>Pregnancy:<br/>Teratogenic effects:<br/>Nursing Mothers: Clindamycin has been reported to appear in breast milk in the range of 0.7 to 3.8 mcg/mL at dosages of 150 mg orally to 600 mg intravenously. Because of the potential for adverse reactions due to clindamycin in neonates (see Pediatric Use), the decision to discontinue the drug should be made, taking into account the importance of the drug to the mother.<br/>Pediatric Use: When CLEOCIN PHOSPHATE Sterile Solution is administered to the pediatric population (birth to 16 years) appropriate monitoring of organ system functions is desirable.<br/>Usage in Newborns and Infants: This product contains benzyl alcohol as a preservative. Benzyl alcohol has been associated with a fatal "Gasping Syndrome" in premature infants. The potential for the toxic effect in the pediatric population from chemicals that may leach from the single dose premixed IV preparation in plastic has not been evaluated.<br/>Geriatric Use: Clinical studies of clindamycin did not include sufficient numbers of patients age 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experience indicates that antibiotic-associated colitis and diarrhea (due to Clostridium difficile) seen in association with most antibiotics occur more frequently in the elderly (>60 years) and may be more severe. These patients should be carefully monitored for the development of diarrhea. Pharmacokinetic studies with clindamycin have shown no clinically important differences between young and elderly subjects with normal hepatic function and normal (age-adjusted) renal function after oral or intravenous administration. | lld:dailymed |
| dailymed-drugs:93 | dailymed-instance:precautio... | General: Hypersensitivity reactions ranging from mild cutaneous events to anaphylaxis cannot be predicted. In patients with epilepsy, mefloquine may increase the risk of convulsions. The drug should therefore be prescribed only for curative treatment in such patients and only if there are compelling medical reasons for its use . Caution should be exercised with regard to activities requiring alertness and fine motor coordination such as driving, piloting aircraft, operating machinery, and deep-sea diving, as dizziness, a loss of balance, or other disorders of the central or peripheral nervous system have been reported during and following the use of mefloquine. These effects may occur after therapy is discontinued due to the long half-life of the drug. Mefloquine should be used with caution in patients with psychiatric disturbances because mefloquine use has been associated with emotional disturbances . In patients with impaired liver function the elimination of mefloquine may be prolonged, leading to higher plasma levels. This drug has been administered for longer than 1 year. If the drug is to be administered for a prolonged period, periodic evaluations including liver function tests should be performed. Although retinal abnormalities seen in humans with long-term chloroquine use have not been observed with mefloquine use, long-term feeding of mefloquine to rats resulted in dose-related ocular lesions (retinal degeneration, retinal edema and lenticular opacity at 12.5 mg/kg/day and higher) . Therefore, periodic ophthalmic examinations are recommended. Parenteral studies in animals show that mefloquine, a myocardial depressant, possesses 20% of the antifibrillatory action of quinidine and produces 50% of the increase in the PR interval reported with quinine. The effect of mefloquine on the compromised cardiovascular system has not been evaluated. However, transitory and clinically silent ECG alterations have been reported during the use of mefloquine. Alterations included sinus bradycardia, sinus arrhythmia, first degree AV-block, prolongation of the QTc interval and abnormal T waves . The benefits of mefloquine therapy should be weighed against the possibility of adverse effects in patients with cardiac disease.<br/>Laboratory Tests: Periodic evaluation of hepatic function should be performed during prolonged prophylaxis.<br/>Information for Patients: Medication Guide: As required by law, a Mefloquine Medication Guide is supplied to patients when mefloqine is dispensed. Patients should be instructed to read the MedGuide when mefloquine is received. The complete text of the MedGuide is reprinted at the end of this document. Patients should be advised:<br/>Drug Interactions: Drug-drug interactions with mefloquine have not been explored in detail. There is one report of cardiopulmonary arrest, with full recovery, in a patient who was taking a beta blocker (propranolol) . The effects of mefloquine on the compromised cardiovascular system have not been evaluated. The benefits of mefloquine therapy should be weighed against the possibility of adverse effects in patients with cardiac disease. Because of the danger of a potentially fatal prolongation of the QTc interval, halofantrine must not be given simultaneously with or subsequent to mefloquine . Concomitant administration of mefloquine and other related compounds (eg, quinine, quinidine and chloroquine) may produce electrocardiographic abnormalities and increase the risk of convulsions . If these drugs are to be used in the initial treatment of severe malaria, mefloquine administration should be delayed at least 12 hours after the last dose. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Clinically significant QTc prolongation has not been found with mefloquine alone. This appears to be the only clinically relevant interaction of this kind with mefloquine, although theoretically, coadministration of other drugs known to alter cardiac conduction (eg, anti-arrhythmic or beta-adrenergic blocking agents, calcium channel blockers, antihistamines or H-blocking agents, tricyclic antidepressants and phenothiazines) might also contribute to a prolongation of the QTc interval. There are no data that conclusively establish whether the concomitant administration of mefloquine and the above listed agents has an effect on cardiac function. In patients taking an anticonvulsant (eg, valproic acid, carbamazepine, phenobarbital or phenytoin), the concomitant use of mefloquine may reduce seizure control by lowering the plasma levels of the anticonvulsant. Therefore, patients concurrently taking antiseizure medication and mefloquine should have the blood level of their antiseizure medication monitored and the dosage adjusted appropriately . When mefloquine is taken concurrently with oral live typhoid vaccines, attenuation of immunization cannot be excluded. Vaccinations with attenuated live bacteria should therefore be completed at least 3 days before the first dose of mefloquine hydrochloride tablets. No other drug interactions are known. Nevertheless, the effects of mefloquine on travelers receiving comedication, particularly diabetics or patients using anticoagulants, should be checked before departure. In clinical trials, the concomitant administration of sulfadoxine and pyrimethamine did not alter the adverse reaction profile.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis: The carcinogenic potential of mefloquine was studied in rats and mice in 2-year feeding studies at doses of up to 30 mg/kg/day. No treatment-related increases in tumors of any type were noted.<br/>Mutagenesis: The mutagenic potential of mefloquine was studied in a variety of assay systems including: Ames test, a host-mediated assay in mice, fluctuation tests and a mouse micronucleus assay. Several of these assays were performed with and without prior metabolic activation. In no instance was evidence obtained for the mutagenicity of mefloquine.<br/>Impairment of Fertility: Fertility studies in rats at doses of 5, 20, and 50 mg/kg/day of mefloquine have demonstrated adverse effects on fertility in the male at the high dose of 50 mg/kg/day, and in the female at doses of 20 and 50 mg/kg/day. Histopathological lesions were noted in the epididymides from male rats at doses of 20 and 50 mg/kg/day. Administration of 250 mg/week of mefloquine (base) in adult males for 22 weeks failed to reveal any deleterious effects on human spermatozoa.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: Mefloquine is excreted in human milk in small amounts, the activity which is unknown. Based on a study in a few subjects, low concentrations (3% to 4%) of mefloquine were excreted in human milk following a dose equivalent to 250 mg of the free base. Because of the potential for serious adverse reactions in nursing infants from mefloquine, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Use of mefloquine to treat acute, uncomplicated P. falciparum malaria in pediatric patients is supported by evidence from adequate and well-controlled studies of mefloquine in adults with additional data from published open-label and comparative trials using mefloquine to treat malaria caused by P. falciparum in patients younger than 16 years of age. The safety and effectiveness of mefloquine for the treatment of malaria in pediatric patients below the age of 6 months have notbeen established. In several studies, the administration of mefloquine for the treatment of malaria was associated with early vomiting in pediatric patients. Early vomiting was cited in some reports as a possible cause of treatment failure. If a second dose is not tolerated, the patient should be monitored closely and alternative malaria treatment considered if improvement is not observed within a reasonable period of time .<br/>Geriatric Use: Clinical studies of mefloquine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Since electrocardiographic abnormalities have been observed in individuals treated with mefloquine and underlying cardiac disease is more prevalent in elderly than in younger patients, the benefits of mefloquine therapy should be weighed against the possibility of adverse cardiac effects in elderly patients. | lld:dailymed |
| dailymed-drugs:94 | dailymed-instance:precautio... | General: ARIXTRA Injection should be administered according to the recommended regimen, especially with respect to the timing of the first dose after surgery. In the hip fracture, hip replacement, knee replacement, or abdominal surgery clinical studies, the administration of ARIXTRA before 6 hours after surgery has been associated with an increased risk of major bleeding (see ADVERSE REACTIONS: Hemorrhage and DOSAGE AND ADMINISTRATION). ARIXTRA Injection should be used with care in patients with a bleeding diathesis, uncontrolled arterial hypertension, or a history of recent gastrointestinal ulceration, diabetic retinopathy, and hemorrhage. ARIXTRA Injection should be used with caution in elderly patients (see PRECAUTIONS: Geriatric Use). ARIXTRA should be used with caution in patients with a low body weight (<50 kg) for the treatment of PE and DVT. The needle guard of the prefilled syringe of ARIXTRA contains dry natural latex rubber that may cause allergic reactions in latex sensitive individuals. ARIXTRA Injection should not be mixed with other injections or infusions. If thrombotic events occur despite prophylaxis with ARIXTRA, appropriate therapy should be initiated.<br/>Laboratory Tests: Periodic routine complete blood counts (including platelet count), serum creatinine level, and stool occult blood tests are recommended during the course of treatment with ARIXTRA Injection. When administered at the recommended doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) are relatively insensitive measures of ARIXTRA activity, and are therefore, unsuitable for monitoring. The anti-Factor Xa activity of fondaparinux sodium can be measured by anti-Xa assay using the appropriate calibrator (fondaparinux). Since the international standards of heparin or LMWH are not appropriate calibrators, the activity of fondaparinux sodium is expressed in milligrams (mg) of the fondaparinux and cannot be compared with activities of heparin or low molecular weight heparins (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Pharmacokinetics and WARNINGS: Laboratory Testing).<br/>Drug Interactions: In clinical studies performed with ARIXTRA, the concomitant use of oral anticoagulants (warfarin), platelet inhibitors (acetylsalicylic acid), NSAIDs (piroxicam), and digoxin did not significantly affect the pharmacokinetics/pharmacodynamics of fondaparinux sodium. In addition, ARIXTRA neither influenced the pharmacodynamics of warfarin, acetylsalicylic acid, piroxicam, and digoxin, nor the pharmacokinetics of digoxin at steady state. Agents that may enhance the risk of hemorrhage should be discontinued prior to initiation of therapy with ARIXTRA. If co-administration is essential, close monitoring may be appropriate. In an in vitro study in human liver microsomes, inhibition of CYP2A6 hydroxylation of coumarin by fondaparinux (200��M i.e., 350 mg/L) was 17-28%. Inhibition of the other isozymes evaluated (CYPs 2A1, 2C9, 2C19, 2D6, 3A4, and 3E1) was 0-16%. Since fondaparinux does not markedly inhibit CYP450s (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4) in vitro,fondaparinux sodium is not expected to significantly interact with other drugs in vivo by inhibition of metabolism mediated by these isozymes. Since fondaparinux sodium does not bind significantly to plasma proteins other than ATIII, no drug interactions by protein-binding displacement are expected.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term studies in animals have been performed to evaluate the carcinogenic potential of fondaparinux sodium. Fondaparinux sodium was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK) forward mutation test, the human lymphocyte chromosome aberration test, the rat hepatocyte unscheduled DNA synthesis (UDS) test, or the rat micronucleus test. At subcutaneous doses up to 10 mg/kg/day (about 32 times the recommended human dose based on body surface area), fondaparinux sodium was found to have no effect on fertility and reproductive performance of male and female rats.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in pregnant rats at subcutaneous doses up to 10 mg/kg/day (about 32 times the recommended human dose based on body surface area) and pregnant rabbits at subcutaneous doses up to 10 mg/kg/day (about 65 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to fondaparinux sodium. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.<br/>Nursing Mothers: Fondaparinux sodium was found to be excreted in the milk of lactating rats. However, it is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when fondaparinux sodium is administered to a nursing mother.<br/>Pediatric Use: Safety and effectiveness of ARIXTRA in pediatric patients have not been established.<br/>Geriatric Use: ARIXTRA should be used with caution in elderly patients. Over 3,000 patients, 65 years and older, have received ARIXTRA 2.5 mg in randomized clinical trials. Over 1,200 patients, 65 years and older, have received the ARIXTRA treatment regimen in the DVT and PE treatment clinical trials. The efficacy of ARIXTRA in the elderly (equal to or older than 65 years) was similar to that seen in younger patients (younger than65 years). In the peri-operative hip fracture, hip replacement, or knee replacement surgery clinical trials with patients receiving ARIXTRA 2.5 mg, the risk of major bleeding associated with use of ARIXTRA increased with age: 1.8% (23/1,253) in patients<65 years, 2.2% (24/1,111) in those 65-74 years, and 2.7% (33/1,227) in those���75 years. Serious adverse events increased with age for patients receiving ARIXTRA. In patients undergoing 3 weeks of extended prophylaxis following one week of peri-operative prophylaxis after hip fracture surgery, the incidence of major bleeding was: 1.9% (1/52) in patients<65 years, 1.4% (1/71) in those 65-74 years, and 2.9% (6/204) in those���75 years. In the abdominal surgery clinical trial, the risk of major bleeding associated with use of ARIXTRA increased with age: 3.0% (19/644) in patients<65 years, 3.2% (16/507) in those 65-74 years, and 5.0% (14/282) in those���75 years. In the DVT and PE treatment clinical trials with patients receiving the ARIXTRA treatment regimen, the risk of major bleeding associated with ARIXTRA increased with age: 0.6% (7/1,151) in patients<65 years, 1.6% (9/560) in those 65-74 years, and 2.1% (12/583) in those���75 years. Careful attention to dosing directions and concomitant medications (especially anti-platelet medication) is advised (see CLINICAL PHARMACOLOGY and PRECAUTIONS: General). Fondaparinux sodium is substantially excreted by the kidney, and the risk of toxic reactions to ARIXTRA may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function (see CONTRAINDICATIONS and WARNINGS: Renal Impairment). | lld:dailymed |
| dailymed-drugs:95 | dailymed-instance:precautio... | General: The safety of concomitant use of Ridaura (auranofin) with injectable gold, hydroxychloroquine, penicillamine, immunosuppressive agents (e.g., cyclophosphamide, azathioprine, or methotrexate) or high doses of corticosteroids has not been established. Medical problems that might affect the signs or symptoms used to detect Ridaura toxicity should be under control before starting Ridaura (auranofin). The potential benefits of using Ridaura in patients with progressive renal disease, significant hepatocellular disease, inflammatory bowel disease, skin rash or history of bone marrow depression should be weighed against 1) the potential risks of gold toxicity on organ systems previously compromised or with decreased reserve, and 2) the difficulty in quickly detecting and correctly attributing the toxic effect. The following adverse reactions have been reported with the use of gold preparations and require modification of Ridaura treatment or additional monitoring. See ADVERSE REACTIONS for the approximate incidence of those reactions specifically reported with Ridaura. Gastrointestinal Reactions: Gastrointestinal reactions reported with gold therapy include diarrhea/loose stools, nausea, vomiting, anorexia and abdominal cramps. The most common reaction to Ridaura is diarrhea/ loose stools reported in approximately 50% of the patients. This is generally manageable by reducing the dosage (e.g., from 6 mg daily to 3 mg) and in only 6% of the patients is it necessary to discontinue Ridaura (auranofin) permanently. Ulcerative enterocolitis is a rare serious gold reaction. Therefore, patients with gastrointestinal symptoms should be monitored for the appearance of gastrointestinal bleeding. Cutaneous Reactions: Dermatitis is the most common reaction to injectable gold therapy and the second most common reaction to Ridaura. Any eruption, especially if pruritic, that develops during treatment should be considered a gold reaction until proven otherwise. Pruritus often exists before dermatitis becomes apparent, and therefore should be considered to be a warning signal of a cutaneous reaction. Gold dermatitis may be aggravated by exposure to sunlight or an actinic rash may develop. The most serious form of cutaneous reaction reported with injectable gold is generalized exfoliative dermatitis. Mucous Membrane Reactions: Stomatitis, another common gold reaction, may be manifested by shallow ulcers on the buccal membranes, on the borders of the tongue, and on the palate or in the pharynx. Stomatitis may occur as the only adverse reaction or with a dermatitis. Sometimes diffuse glossitis or gingivitis develops. A metallic taste may precede these oral mucous membrane reactions and should be considered a warning signal. Renal Reactions: Gold can produce a nephrotic syndrome or glomerulitis with proteinuria and hematuria. These renal reactions are usually relatively mild and subside completely if recognized early and treatment is discontinued. They may become severe and chronic if treatment is continued after the onset of the reaction. Therefore it is important to perform urinalyses regularly and to discontinue treatment promptly if proteinuria or hematuria develops. Hematologic Reactions: Blood dyscrasias including leukopenia, granulocytopenia, thrombocytopenia and aplastic anemia have all been reported as reactions to injectable gold and Ridaura. These reactions may occur separately or in combination at anytime during treatment. Because they have potentially serious consequences, blood dyscrasias should be constantly watched for through regular monitoring (at least monthly) of the formed elements of the blood throughout treatment. Miscellaneous Reactions: Rare reactions attributed to gold include cholestatic jaundice; gold bronchitis and interstitial pneumonitis and fibrosis; peripheral neuropathy; partial or complete hair loss; fever. Information for Patients: Patients should be advised of the possibility of toxicity from Ridaura and of the signs and symptoms that they should report promptly. (Patient information sheets are available.) Women of childbearing potential should be warned of the potential risks of Ridaura therapy during pregnancy . Laboratory Tests: CBC with differential, platelet count, urinalysis, and renal and liver function tests should be performed prior to Ridaura (auranofin) therapy to establish a baseline and to identify any preexisting conditions. CBC with differential, platelet count and urinalysis should then be monitored at least monthly; other parameters should be monitored as appropriate. Drug Interactions: In a single patient-report, there is the suggestion that concurrent administration of Ridaura and phenytoin may have increased phenytoin blood levels. Carcinogenesis/Mutagenesis: In a 24-month study in rats, animals treated with auranofin at 0.4, 1.0 or 2.5 mg/kg/day orally (3, 8 or 21 times the human dose) or gold sodium thiomalate at 2 or 6 mg/kg injected twice weekly (4 or 12 times the human dose) were compared to untreated control animals. There was a significant increase in the frequency of renal tubular cell karyomegaly and cytomegaly and renal adenoma in the animals treated with 1.0 or 2.5 mg/kg/day of auranofin and 2 or 6 mg/kg twice weekly of gold sodium thiomalate. Malignant renal epithelial tumors were seen in the 1.0 mg/kg/day and the 2.5 mg/kg/dayauranofin and in the 6 mg/kg twice weekly gold sodium thiomalate���treated animals. In a 12-month study, rats treated with auranofin at 23 mg/kg/day (192 times the human dose) developed tumors of the renal tubular epithelium, whereas those treated with 3.6 mg/ kg/day (30 times the human dose) did not. In an 18-month study in mice given oral auranofin at doses of 1, 3 and 9 mg/kg/day (8, 24 and 72 times the human dose), there was no statistically significant increase above controls in the instances of tumors. In the mouse lymphoma forward mutation assay, auranofin at high concentrations (313 to 700 ng/mL) induced increases in the mutation frequencies in the presence of a rat liver microsomal preparation. Auranofin produced no mutation effects in the Ames test (Salmonella), in the in vitro assay (Forward and Reverse Mutation Inducement Assay with Saccharomyces), in the in vitro transformation of BALB/T3 cell mouse assay or in the Dominant Lethal Assay. Pregnancy: Teratogenic Effects���Pregnancy Category C. Use of Ridaura (auranofin) by pregnant women is not recommended. Furthermore, women of childbearing potential should be warned of the potential risks of Ridaura therapy during pregnancy. (See below.) Pregnant rabbits given auranofin at doses of 0.5, 3 or 6 mg/kg/day (4.2 to 50 times the human dose) had impaired food intake, decreased maternal weights, decreased fetal weights and an increase above controls in the incidence of resorptions, abortions and congenital abnormalities, mainly abdominal defects such as gastroschisis and umbilical hernia. Pregnant rats given auranofin at a dose of 5 mg/kg/day (42 times the human dose) had an increase above controls in the incidence of resorptions and a decrease in litter size and weight linked to maternal toxicity. No such effects were found in rats given 2.5 mg/kg/day (21 times the human dose). Pregnant mice given auranofin at a dose of 5 mg/kg/day (42 times the human dose) had no teratogenic effects. There are no adequate and well-controlled Ridaura studies in pregnant women. Nursing Mothers: Nursing during Ridaura therapy is not recommended. Following auranofin administration to rats and mice, gold is excreted in milk. Following the administration of injectable gold, gold appears in the milk of nursing women; human data on auranofin are not available. Pediatric Use: Riduara (auranofin) is not recommended for use in pediatric patients because its safety and effectiveness have not been established. | lld:dailymed |
| dailymed-drugs:96 | dailymed-instance:precautio... | General: Ipratropium Bromide Nasal Spray 0.03% should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, or bladder neck obstruction, particularly if they are receiving an anticholinergic by another route. Cases of precipitation or worsening of narrow-angle glaucoma and acute eye pain have been reported with direct eye contact of ipratropium bromide administered by oral inhalation.<br/>Information for Patients: Patients should be advised that temporary blurring of vision, precipitation or worsening of narrow-angle glaucoma, or eye pain may result if Ipratropium Bromide Nasal Spray 0.03% comes into direct contact with the eyes. Patients should be instructed to avoid spraying Ipratropium Bromide Nasal Spray 0.03% in or around their eyes. Patients who experience eye pain, blurred vision, excessive nasal dryness, or episodes of nasal bleeding should be instructed to contact their doctor. Patients should be reminded to carefully read and follow the accompanying Patient's Instructions for Use.<br/>Drug Interactions: No controlled clinical trials were conducted to investigate drug-drug interactions. Ipratropium Bromide Nasal Spray 0.03% is minimally absorbed into the systemic circulation; nonetheless, there is some potential for an additive interaction with other concomitantly administered anticholinergic medications, including Ipratropium Bromide for oral inhalation.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In two-year carcinogenicity studies in rats and mice, ipratropium bromide at oral doses up to 6 mg/kg (approximately 190 and 95 times the maximum recommended daily intranasal dose in adults, respectively, and approximately 110 and 60 times the maximum recommended daily intranasal dose in children, respectively, on a mg/mbasis) showed no carcinogenic activity. Results of various mutagenicity studies (Ames test, mouse dominant lethal test, mouse micronucleus test, and chromosome aberration of bone marrow in Chinese hamsters) were negative. Fertility of male or female rats was unaffected by ipratropium bromide at oral doses up to 50 mg/kg (approximately 1,600 times the maximum recommended daily intranasal dose in adults on a mg/mbasis). At an oral dose of 500 mg/kg (approximately 16,000 times the maximum recommended daily intranasal dose in adults on a mg/mbasis), ipratropium bromide produced a decrease in the conception rate.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: It is known that some ipratropium bromide is systemically absorbed following nasal administration; however the portion which may be excreted in human milk is unknown. Although lipid-insoluble quaternary bases pass into breast milk, the minimal systemic absorption makes it unlikely that ipratropium bromide would reach the infant in an amount sufficient to cause a clinical effect. However, because many drugs are excreted in human milk, caution should be exercised when Ipratropium Bromide Nasal Spray 0.03% is administered to a nursing woman.<br/>Pediatric Use: The safety of Ipratropium Bromide Nasal Spray 0.03% at a dose of two sprays (42 mcg) per nostril two or three times daily (total dose 168 to 252 mcg/day) has been demonstrated in 77 pediatric patients 6-12 years of age in placebo-controlled, 4-week trials and in 55 pediatric patients in active-controlled, 6 month trials. The effectiveness of Ipratropium Bromide Nasal Spray 0.03% for the treatment of rhinorrhea associated with allergic and nonallergic perennial rhinitis in this pediatric age group is based on an extrapolation of the demonstrated efficacy of Ipratropium Bromide Nasal Spray 0.03% in adults with these conditions and the likelihood that the disease course, pathophysiology, and the drug's effects are substantially similar to that of the adults. The recommended dose for the pediatric population is based on within and cross-study comparisons of the efficacy of Ipratropium Bromide Nasal Spray 0.03% in adults and pediatric patients and on its safety profile in both adults and pediatric patients. The safety and effectiveness of Ipratropium Bromide Nasal Spray 0.03% in patients under 6 years of age have not been established. | lld:dailymed |
| dailymed-drugs:97 | dailymed-instance:precautio... | General: Serum potassium should be measured periodically and potassium supplements or potassium-sparing diuretics added if necessary. Periodic determinations of other electrolytes are advised in patients treated with high doses or for prolonged periods, particularly in those on low salt diets. Hyperuricemia may occur; it has been asymptomatic in cases reported to date. Reversible elevations of the BUN and creatinine may also occur, especially in association with dehydration and particularly in patients with renal insufficiency. Bumetanide may increase urinary calcium excretion with resultant hypocalcemia. Diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.<br/>Laboratory Tests: Studies in normal subjects receiving bumetanide revealed no adverse effects on glucose tolerance, plasma insulin, glucagon and growth hormone levels, but the possibility of an effect on glucose metabolism exists. Periodic determinations of blood sugar should be done, particularly in patients with diabetes or suspected latent diabetes. Patients under treatment should be observed regularly for possible occurrence of blood dyscrasias, liver damage or idiosyncratic reactions, which have been reported occasionally in foreign marketing experience. The relationship of these occurrences to bumetanide use is not certain.<br/>Drug Interactions: 1. Drugs with ototoxic potential : Especially in the presence of impaired renal function, the use of parenterally administered bumetanide in patients to whom aminoglycoside antibiotics are also being given should be avoided, except in life-threatening conditions. 2. Drugs with nephrotoxic potential: There has been no experience with the concurrent use of bumetanide with drugs known to have a nephrotoxic potential. Therefore, the simultaneous administration of these drugs should be avoided. 3. Lithium: Lithium should generally not be given with diuretics (such as bumetanide) because they reduce its renal clearance and add a high risk of lithium toxicity. 4. Probenecid: Pretreatment with probenecid reduces both the natriuresis and hyperreninemia produced by bumetanide. This antagonistic effect of probenecid on bumetanide natriuresis is not due to a direct action on sodium excretion but is probably secondary to its inhibitory effect on renal tubular secretion of bumetanide. Thus, probenecid should not be administered concurrently with bumetanide. 5. Indomethacin: Indomethacin blunts the increases in urine volume and sodium excretion seen during bumetanide treatment and inhibits the bumetanide-induced increase in plasma renin activity. Concurrent therapy with bumetanide is thus not recommended. 6. Antihypertensives: Bumetanide may potentiate the effect of various antihypertensive drugs, necessitating a reduction in the dosage of these drugs. 7. Digoxin: Interaction studies in humans have shown no effect on digoxin blood levels. 8. Anticoagulants: Interaction studies in humans have shown bumetanide to have no effect on warfarin metabolism or on plasma prothrombin activity.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Bumetanide was devoid of mutagenic activity in various strains of Salmonella typhimurium when tested in the presence or absence of an in vitro metabolic activation system. An 18-month study showed an increase in mammary adenomas of questionable significance in female rats receiving oral doses of 60 mg/kg/day (2000 times a 2-mg human dose). A repeat study at the same doses failed to duplicate this finding. Reproduction studies were performed to evaluate general reproductive performance and fertility in rats at oral dose levels of 10, 30, 60 or 100 mg/kg/day. The pregnancy rate was slightly decreased in the treated animals; however, the differences were small and not statistically significant.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. As a general rule, nursing should not be undertaken while the patient is on bumetanide since it may be excreted in human milk.<br/>Pediatric Use: Safety and effectiveness in pediatric patients below the age of 18 have not been established. In vitro studies using pooled sera from critically ill neonates have shown bumetanide to be a potent displacer of bilirubin . The administration of bumetanide could present a particular concern if given to critically ill or jaundiced neonates at risk for kernicterus.<br/>Geriatric Use: Clinical studies of bumetanide did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. | lld:dailymed |
| dailymed-drugs:100 | dailymed-instance:precautio... | Macrovascular Outcome: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Riomet or any other anti-diabetic drug.<br/>Monitoring of renal function: Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive RIOMET. In patients with advanced age, RIOMET should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those���80 years of age, renal function should be monitored regularly and, generally, RIOMET should not be titrated to the maximum dose (see WARNINGS and DOSAGE AND ADMINISTRATION). Before initiation of RIOMET therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and RIOMET discontinued if evidence of renal impairment is present.<br/>Information for Patients: Patients should be informed of the potential risks and benefits of RIOMET and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters. The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue RIOMET immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of RIOMET, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. Patients should be counselled against excessive alcohol intake, either acute or chronic, while receiving RIOMET. Metformin alone does not usually cause hypoglycemia, although it may occur when metformin is used in conjunction with oral sulfonylureas and insulin. When initiating combination therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members.<br/>Laboratory Tests: Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control (see also DOSAGE AND ADMINISTRATION). Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, Vitamin Bdeficiency should be excluded.<br/>Drug Interactions (clinical evaluation of drug interactions done with metformin):<br/>Glyburide: In a single-dose interaction study in type 2 diabetes patients, co-administration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cwere observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain (see DOSAGE AND ADMINISTRATION: Concomitant Metformin and Oral Sulfonylurea Therapy).<br/>Furosemide: A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood Cby 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cand AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically.<br/>Nifedipine: A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cand AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tand half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.<br/>Cationic drugs: Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of RIOMET and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.<br/>Other: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, andisoniazid. When such drugs are administered to a patient receiving RIOMET, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving RIOMET, the patient should be observed closely for hypoglycemia. In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when co-administered in single-dose interaction studies. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.<br/>Carcinogenesis and Mutagenesis and Impairment of Fertility: Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks), at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately 4X the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. However, there was an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. Results in Ames test, gene mutation test (mouse lymphoma cells), chromosomal aberrations test (human lymphocytes), and in vivo mouse micronucleus tests were negative. Fertility of male and female rats was not affected by metformin when administered at doses of 600 mg/kg/day, which is approximately 3X the maximum recommended human daily dose based on body surface area comparisons.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category B: Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Because animal reproduction studies are not always predictive of human response, RIOMET should not be used during pregnancy unless clearly needed. There are no adequate and well-controlled studies in pregnant women with metformin. Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day, which is 2X and 6X the maximum recommended human daily dose of 2000 mg based on body surface area comparison for rats and rabbits, respectively. However, because animal reproduction studies are not always predictive of humanresponse, RIOMET should not be used during pregnancy unless clearly needed. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.<br/>Nursing Mothers: Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. It is not known whether this drug is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from metformin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If RIOMET is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.<br/>Pediatric Use: The safety and effectiveness of metformin for the treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years). Use of metformin in this age group is supported by evidence from adequate and well-controlled studies of metformin in adults withadditional data from a controlled clinical study in pediatric patients ages 10-16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults. (See CLINICAL PHARMACOLOGY: Pediatric Clinical Studies.) In this study, adverse effects were similar to those described in adults. (See ADVERSE REACTIONS: Pediatric Patients.) A maximum daily dose of 2000 mg is recommended. (see DOSAGE AND ADMINISTRATION: Recommended Dosing Schedule: Pediatrics.)<br/>Geriatric Use: Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, RIOMET should only be used in patients with normal renal function (see CONTRAINDICATIONS, WARNINGS, and CLINICAL PHARMACOLOGY: Pharmacokinetics). Because aging is associated with reduced renal function, RIOMET should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of RIOMET (see also WARNINGS and DOSAGE AND ADMINISTRATION). | lld:dailymed |
| dailymed-drugs:101 | dailymed-instance:precautio... | General: Intranasal DDAVP at high dosage has infrequently produced a slight elevation of blood pressure, which disappeared with a reduction in dosage. The drug should be used with caution in patients with coronary artery insufficiency and/or hypertensive cardiovascular disease because of possible rise in blood pressure. DDAVP should be used with caution in patients with conditions associated with fluid and electrolyte imbalance, such as cystic fibrosis, heart failure and renal disorders because these patients are prone to hyponatremia. Rare severe allergic reactions have been reported with DDAVP. Anaphylaxis has been reported rarely with intravenous and intranasal administration of DDAVP.<br/>Central Cranial Diabetes Insipidus: Since DDAVP is used intranasally, changes in the nasal mucosa such as scarring, edema, or other disease may cause erratic, unreliable absorption in which case intranasal DDAVP should not be used. For such situations, DDAVP Injection should be considered.<br/>Information for Patients: Ensure that in children administration is under adult supervision in order to control the dose intake. Patients should be informed that the DDAVP Nasal Spray bottle accurately delivers 50 doses of 10 mcg each. Any solution remaining after 50 doses should be discarded since the amount delivered thereafter may be substantially less than 10 mcg of drug. No attempt should be made to transfer remaining solution to another bottle. Patients should be instructed to read accompanying directions onuse of the spray pump carefully before use. Fluid intake should be adjusted downward based upon discussion with the physician.<br/>Laboratory Tests: Laboratory tests for following the patient with central cranial diabetes insipidus or post-surgical or head trauma-related polyuria and polydipsia include urine volume and osmolality. In some cases plasma osmolality measurements may be required.<br/>Drug Interactions: Although the pressor activity of DDAVP is very low compared to the antidiuretic activity, use of large doses of intranasal DDAVP with other pressor agents should only be done with careful patient monitoring. The concomitant administration of drugs that may increase the risk of water intoxication with hyponatremia, (e.g., tricyclic antidepressants, selective serotonin re-uptake inhibitors, chlorpromazine, opiate analgesics, NSAIDs, lamotrigine and carbamazepine) should be performed with caution.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with DDAVP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.<br/>Pregnancy: Category B: Fertility studies have not been done. Teratology studies in rats and rabbits at doses from 0.05 to 10 mcg/kg/day (approximately 0.1 times the maximum systemic human exposure in rats and up to 38 times the maximum systemic human exposure in rabbits based on surface area, mg/m) revealed no harm to the fetus due to DDAVP (desmopressin acetate). There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Several publications of desmopressin acetate's use in the management of diabetes insipidus during pregnancy are available; these include a few anecdotal reports of congenital anomalies and low birth weight babies. However, no causal connection between these events and desmopressin acetate has been established. A fifteen year Swedish epidemiologic study of the use of desmopressin acetate in pregnant women with diabetes insipidus found the rate of birth defects to be no greater than that in the general population; however, the statistical power of this study is low. As opposed to preparations containing natural hormones, desmopressin acetate in antidiuretic doses has no uterotonic action and the physician will have to weigh the therapeutic advantages against the possible risks in each case.<br/>Nursing Mothers: There have been no controlled studies in nursing mothers. A single study in a post-partum woman demonstrated a marked change in plasma, but little if any change in assayable DDAVP in breast milk following an intranasal dose of 10 mcg. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution shouldbe exercised when DDAVP is administered to a nursing woman.<br/>Pediatric Use:<br/>Central Cranial Diabetes Insipidus: DDAVP Nasal Spray has been used in children with diabetes insipidus. Use in infants and children will require careful fluid intake restriction to prevent possible hyponatremia and water intoxication. The dose must be individually adjusted to the patient with attention in the very young to the danger of an extreme decrease in plasma osmolality with resulting convulsions. Dose should start at 0.05 mL or less. Since the spray cannot deliver less than 0.1 mL (10 mcg), smaller doses should be administered using the rhinal tube delivery system. Do not use the nasal spray in pediatric patients requiring less than 0.1 mL (10 mcg) per dose.<br/>Geriatric Use: Clinical studies of DDAVP Nasal Spray did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. DDAVP is contraindicated in patients withmoderate to severe renal impairment (defined as a creatinine clearance below 50ml/min). Use of DDAVP Nasal Spray in geriatric patients will require careful fluid intake restriction to prevent possible hyponatremia and water intoxication. . There are reports of an occasional change in response with time, usually greater than 6 months. Some patients may show a decreased responsiveness, others a shortened duration of effect. There is no evidence this effect is due to the development of binding antibodies but may be due to a local inactivation of the peptide. | lld:dailymed |
| dailymed-drugs:102 | dailymed-instance:precautio... | Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Potassium Chloride in Lactated Ringer's and 5% Dextrose Injection, USP should be used with caution. Excess administration may result in metabolic alkalosis. Caution must be exercised in the administration of Potassium Chloride in Lactated Ringer's and 5% Dextrose Injection, USP to patients receiving corticosteroids or corticotropin. Potassium Chloride in Lactated Ringer's and 5% Dextrose Injection, USP should be used with caution in patients with overt or subclinical diabetes mellitus.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Pediatric Use: Safety and effectiveness of Potassium Chloride in Lactated Ringer's and 5% Dextrose Injection, USP in pediatric patients have not been established by adequate and well-controlled studies. However, the use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is referenced in the medical literature. Dextrose is safe and effective for the stated indications in pediatric patients (see INDICATIONS AND USAGE). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants.<br/>Geriatric Use: Clinical studies of Potassium Chloride in Lactated Ringer's and 5% Dextrose Injection, USP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and ofconcomitant disease or drug therapy. For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of serum potassium levels and serial EKGs are recommended. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with Potassium Chloride in Lactated Ringer's and 5% Dextrose Injection, USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Potassium Chloride in Lactated Ringer's and 5% Dextrose Injection, USP is administered to a nursing mother. Do not administer unless solution is clear and seal is intact. | lld:dailymed |
| dailymed-drugs:104 | dailymed-instance:precautio... | General: Prolonged use of Cefazolin for Injection, USP may result in the overgrowth of nonsusceptible organisms. Careful clinical observation of the patient is essential. When Cefazolin for Injection, USP is administered to patients with low urinary output because of impaired renal function, lower daily dosage is required . As with other beta-lactam antibiotics, seizures may occur if inappropriately high doses are administered to patients with impaired renal function . Cefazolin for Injection, USP, as with all cephalosporins should be prescribed with caution in individuals with history of gastrointestinal disease, particularly colitis. Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated. Prescribing Cefazolin for Injection, USP in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development drug-resistant bacteria.<br/>Information for Patients: Patients should be counseled that antibacterial drugs including Cefazolin for Injection, USP, should only be used lo treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefazolin for Injection, USP is prescribed lo treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Cefazolin for Injection, USP or other antibacterial drugs in the future.<br/>Drug Interactions: Probenecid may decrease renal tubular secretion of cephalosporins when used concurrently, resulting in increased and more prolonged cephalosporin blood concentrations.<br/>Drug/Laboratory Test Interactions: A false positive reaction for glucose in the urine may occur with Benedict's solution, Fehling's solution or with Clinitest tablets, but not with enzyme-based tests such as Clinistix. Positive direct and indirect antiglobulin (Coombs) tests have occurred; these may also occur in neonates whose mothers received cephalosporins before delivery.<br/>Carcinogenesis/Mutagenesis: Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of Cefazolin for Injection, USP have not been performed.<br/>Pregnancy - Teratogenic Effects-Pregnancy Category B.: Reproduction studies have been performed in rats, mice, and rabbits at doses up lo 25 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to cefazolin. There are however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.<br/>Labor and Delivery: When cefazolin has been administered prior to caesarean section, drug concentrations in cord blood have been approximately one quarter to one third of maternal drug concentrations. The drug appears to have no adverse effect on the fetus.<br/>Nursing Mothers: Cefazolin is present in very low concentrations in the milk of nursing mothers. Caution should be exercised when Cefazolin for Injection, USP is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness for use in premature infants and neonates have not been established. See DOSAGE AND ADMINISTRATION for recommended dosage in pediatric patients over 1 month.<br/>Geriatric Use: Of the 920 subjects who received cefazolin in clinical studies, 313 (34%) were 65 years and over, while 138 (15%) were 75 years and over. No overall differences in safety or effectiveness were observed between these subject and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients; but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renat function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may he useful to monitor renal function . | lld:dailymed |
| dailymed-drugs:105 | dailymed-instance:precautio... | General: All topical nonsteroidal anti-inflammatory drugs (NSAIDs) may slow or delay healing. Topical corticosteroids are also known to slow or delay healing. Concomitant use of topical NSAIDs and topical steroids may increase the potential for healing problems. Use of topical NSAIDs may result in keratitis. In some susceptible patients continued use of topical NSAIDs may result in epithelial breakdown, corneal thinning, corneal infiltrates, corneal erosion, corneal ulceration, and corneal perforation. These events may be sight threatening. Patients with evidence of corneal epithelial breakdown should immediately discontinue use of topical NSAIDs and should be closely monitored for corneal health. Postmarketing experience with topical NSAIDs suggests that patients experiencing complicated ocular surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface disease (e.g., dry eye syndrome), rheumatoid arthritis, or repeat ocular surgeries within a short period of time may be at increased risk for corneal adverse events, which may become sight threatening. Topical NSAIDs should be used with caution in these patients. Postmarketing experience with topical NSAIDs also suggests that use more than 24 hours prior to surgery or use beyond 14 days post surgery may increase patient risk for occurrence and severity of corneal adverse events. It is recommended that diclofenac sodium ophthalmic solution, like other NSAIDs, be used with caution in patients with known bleeding tendencies or who are receiving other medications which may prolong bleeding time. Results from clinical studies indicate that diclofenac sodium ophthalmic solution has no significant effect upon ocular pressure. However, elevations in intraocular pressure may occur following cataract surgery.<br/>Information for Patients: Except for the use of a bandage hydrogel soft contact lens during the first 3 days following refractive surgery, diclofenac sodium ophthalmic solution should not be used by patients currently wearing soft contact lenses due to adverse events that have occurred in other circumstances.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term carcinogenicity studies in rats given diclofenac sodium in oral doses up to 2 mg/kg/day (approximately 500 times the human topical ophthalmic dose) revealed no significant increases in tumor incidence. A 2 year carcinogenicity study conducted in mice employing oral diclofenac sodium up to 2 mg/kg/day did not reveal any oncogenic potential. Diclofenac sodium did not show mutagenic potential in various mutagenicity studies including the Ames test. Diclofenac sodium administered to male and female rats at 4 mg/kg/day (approximately 1000 times the human topical ophthalmic dose) did not affect fertility.<br/>Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and younger adult patients.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C.: Reproduction studies performed in mice at oral doses up to 5,000 times (20 mg/kg/day) and in rats and rabbits at oral doses up to 2,500 times (10 mg/kg/day) the human topical dose have revealed no evidence of teratogenicity due to diclofenac sodium despite the induction of maternal toxicity and fetal toxicity. In rats, maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac sodium has been shown to cross the placental barrier in mice and rats. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.<br/>Non-teratogenic Effects: Because of the known effects of prostaglandin biosynthesis-inhibiting drugs on the fetal cardiovascular system (closure of ductus arteriosus), the use of diclofenac sodium ophthalmic solution during late pregnancy should be avoided.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established. | lld:dailymed |
| dailymed-drugs:106 | dailymed-instance:precautio... | General: The use of antimicrobial agents may be associated with the overgrowth of non-susceptible organisms including fungi; in such a case, antibiotic administration should be stopped and appropriate measures taken.<br/>Information for patients: Avoid contaminating the tip of container with material from the eye, fingers or other source.<br/>Carcinogenesis, mutagenesis, impairment of fertility: Avoid contaminating the tip of container with material from the eye, fingers or other source.<br/>Pregnancy:<br/>Pregnancy Category B: Reproduction studies have been performed in rats, mice, and rabbits using erythromycin and its various salts and esters, at doses that were several multiples of the usual human dose. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, the erythromycins should be used during pregnancy only if clearly needed.<br/>Nursing mothers: Caution should be exercised when erythromycin is administered to a nursing woman.<br/>Pediatric use: See Indications and Usage and Dosage and Administration. | lld:dailymed |
| dailymed-drugs:108 | dailymed-instance:precautio... | General: In clinical trials of COREG CR in patients with hypertension (338 subjects) and in patients with left ventricular dysfunction following a myocardial infarction or heart failure (187 subjects), the profile of adverse events observed with carvedilol phosphate was generally similar to that observed with the administration of immediate-release carvedilol. Therefore, the information included within this section is based on data from controlled clinical trials with COREG CR as well as immediate-release carvedilol. In clinical trials with immediate-release carvedilol, bradycardia was reported in about 2% of hypertensive patients, 9% of heart failure patients, and 6.5% of myocardial infarction patients with left ventricular dysfunction. Bradycardia was reported in 0.5% of patients receiving COREG CR in a study of heart failure patients and myocardial infarction patients with left ventricular dysfunction. There were no reports of bradycardia in the clinical trial of COREG CR in hypertension. However, if pulse rate drops below 55 beats/minute, the dosage of COREG CR should be reduced. In clinical trials of primarily mild-to-moderate heart failure with immediate-release carvedilol, hypotension and postural hypotension occurred in 9.7% and syncope in 3.4% of patients receiving carvedilol compared to 3.6% and 2.5% of placebo patients, respectively. The risk for these events was highest during the first 30 days of dosing, corresponding to the up-titration period and was a cause for discontinuation of therapy in 0.7% of carvedilol patients, compared to 0.4% of placebo patients. In a long-term, placebo-controlled trial in severe heart failure (COPERNICUS), hypotension and postural hypotension occurred in 15.1% and syncope in 2.9% of heart failure patients receiving carvedilol compared to 8.7% and 2.3% of placebo patients, respectively. These events were a cause for discontinuation of therapy in 1.1% of carvedilol patients, compared to 0.8% of placebo patients. In the clinical trial of COREG CR in hypertensive patients, syncope was reported in 0.3% of patients receiving COREG CR compared to 0% of patients receiving placebo. There were no reports of postural hypotension in this trial. Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive patients receiving immediate-release carvedilol, primarily following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy in 1% of patients. In the CAPRICORN study of survivors of an acute myocardial infarction with left ventricular dysfunction, hypotension or postural hypotension occurred in 20.2% of patients receiving carvedilol compared to 12.6% of placebo patients. Syncope was reported in 3.9% and 1.9% of patients, respectively. These events were a cause for discontinuation of therapy in 2.5% of patients receiving carvedilol, compared to 0.2% of placebo patients. To decrease the likelihood of syncope or excessive hypotension, treatment with COREG CR should be initiated with 10 mg once daily for heart failure patients, and at 20 mg once daily for hypertensive patients and survivors of an acute myocardial infarction with left ventricular dysfunction. Dosage should then be increased slowly, according to recommendations in the DOSAGEAND ADMINISTRATION section, and the drug should be taken with food. During initiation of therapy, the patient should be cautioned to avoid situations such as driving or hazardous tasks, where injury could result should syncope occur. Rarely, use of carvedilol in patients with heart failure has resulted in deterioration of renal function. Patients at risk appear to be those with low blood pressure (systolic blood pressure<100 mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. Renal function has returned to baseline when carvedilol was stopped. In patients with these risk factors it is recommended that renal function be monitored during up-titration of COREG CR and the drug discontinued or dosage reduced if worsening of renal function occurs. Worsening heart failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, diuretics should be increased and the dose of COREG CR should not be advanced until clinical stability resumes (see DOSAGE AND ADMINISTRATION). Occasionally it is necessary to lower the dose of COREG CR or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of, or a favorable response to, COREG CR. In a placebo-controlled trial of patients with severe heart failure, worsening heart failure during the first 3 months was reported to a similar degree with immediate-release carvedilol and with placebo. When treatment was maintained beyond 3 months, worsening heart failure was reported less frequently in patients treated with carvedilol than with placebo. Worsening heart failure observed during long-term therapy is more likely to be related to the patients' underlying disease than to treatment with carvedilol. In patients with pheochromocytoma, an��-blocking agent should be initiated prior to the use of any��-blocking agent. Although carvedilol has both��- and��-blocking pharmacologic activities, there has been no experience with its use in this condition. Therefore, caution should be taken in the administration of carvedilol to patients suspected of having pheochromocytoma. Agents with non-selective��-blocking activity may provoke chest pain in patients with Prinzmetal's variant angina. There has been no clinical experience with carvedilol in these patients although the��-blocking activity may prevent such symptoms. However, caution should be taken in the administration of COREG CR to patients suspected of having Prinzmetal's variant angina.<br/>Effects on Glycemic Control in Type 2 Diabetic Patients: In heart failure patients with diabetes, carvedilol therapy may lead to worsening hyperglycemia, which responds to intensification of hypoglycemic therapy. It is recommended that blood glucose be monitored when dosing with COREG CR is initiated, adjusted, or discontinued. Studies designed to examine the effects of carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted. In a study designed to examine the effects of immediate-release carvedilol on glycemic control in a population with mild-to-moderate hypertension and well-controlled type 2 diabetes mellitus, carvedilol had no adverse effect on glycemic control, based on HbA1c measurements (see CLINICAL TRIALS, Hypertensive Patients with Type 2 Diabetes Mellitus [GEMINI]).<br/>Risk of Anaphylactic Reaction: While taking��-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.<br/>Nonallergic Bronchospasm (e.g., chronic bronchitis and emphysema): Patients with bronchospastic disease should, in general, not receive��-blockers. COREG CR may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if COREG CR is used, to use the smallest effective dose, so that inhibition of endogenous or exogenous��-agonists is minimized. In clinical trials of patients with heart failure, patients with bronchospastic disease were enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In such patients, it is recommended that COREG CR be used with caution. The dosing recommendations should be followed closely and the dose should be lowered if any evidence of bronchospasm is observed during up-titration.<br/>Information for Patients: Patients taking COREG CR should be advised of the following:<br/>Drug Interactions: (Also see CLINICAL PHARMACOLOGY, Pharmacokinetic Drug-Drug Interactions.)<br/>Inhibitors of CYP2D6: poor metabolizers of debrisoquin: Interactions of carvedilol with strong inhibitors of CYP2D6 (such as quinidine, fluoxetine, paroxetine, and propafenone) have not been studied, but these drugs would be expected to increase blood levels of the R(+) enantiomer of carvedilol (see CLINICAL PHARMACOLOGY). Retrospective analysis of side effects in clinical trials showed that poor 2D6 metabolizers had a higher rate of dizziness during up-titration, presumably resulting from vasodilating effects of the higher concentrations of the��-blocking R(+) enantiomer.<br/>Catecholamine-depleting agents: Patients taking both agents with��-blocking properties and a drug that can deplete catecholamines (e.g., reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia.<br/>Clonidine: Concomitant administration of clonidine with agents with��-blocking properties may potentiate blood-pressure- andheart-rate-lowering effects. When concomitant treatment with agents with��-blocking properties and clonidine is to be terminated, the��-blocking agent should be discontinued first. Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage.<br/>Cyclosporine: Modest increases in mean trough cyclosporine concentrations were observed following initiation of carvedilol treatment in 21 renal transplant patients suffering from chronic vascular rejection. In about 30% of patients, the dose of cyclosporine had to be reduced in order to maintain cyclosporine concentrations within the therapeutic range, while in the remainder no adjustment was needed. On the average for the group, the dose of cyclosporine was reduced about 20% in these patients. Due to wide interindividual variability in the dose adjustment required, it is recommended that cyclosporine concentrations be monitored closely after initiation of carvedilol therapy and that the dose of cyclosporine be adjusted as appropriate.<br/>Digitalis Glycosides: Both digitalis glycosides and��-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly. Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing COREG CR (see CLINICAL PHARMACOLOGY, Pharmacokinetic Drug-Drug Interactions).<br/>Inducers and inhibitors of hepatic metabolism: Rifampin reduced plasma concentrations of carvedilol by about 70%. Cimetidine increased AUC by about 30% but caused no change in C.<br/>Calcium channel blockers: Isolated cases of conduction disturbance (rarely with hemodynamic compromise) have been observed when carvedilol is co-administered with diltiazem. As with other agents with��-blocking properties, if COREG CR is to be administered orally with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored.<br/>Insulin or oral hypoglycemics: Agents with��-blocking properties may enhance the blood-sugar-reducing effect of insulin and oral hypoglycemics. Therefore, in patients taking insulin or oral hypoglycemics, regular monitoring of blood glucose is recommended.<br/>Proton Pump Inhibitors: There is no clinically meaningful increase in AUC and Cwith concomitant administration of carvedilol extended-release capsules with pantoprazole.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In 2-year studies conducted in rats given carvedilol at doses up to 75 mg/kg/day (12 times the maximum recommended human dose [MRHD] when compared on a mg/mbasis) or in mice given up to 200 mg/kg/day (16 times the MRHD on a mg/mbasis), carvedilol had no carcinogenic effect. Carvedilol was negative when tested in a battery of genotoxicity assays, including the Ames and the CHO/HGPRT assays for mutagenicity and the in vitro hamster micronucleus and in vivo human lymphocyte cell tests for clastogenicity. At doses���200 mg/kg/day (���32 times the MRHD as mg/m) carvedilol was toxic to adult rats (sedation, reduced weight gain) and was associated with a reduced number of successful matings, prolonged mating time, significantly fewer corpora lutea and implants per dam, and complete resorption of 18% of the litters. The no-observed-effect dose level for overt toxicity and impairment of fertility was 60 mg/kg/day (10 times the MRHD as mg/m).<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C. Studies performed in pregnant rats and rabbits given carvedilol revealed increased post-implantation loss in rats at doses of 300 mg/kg/day (50 times the MRHD as mg/m) and in rabbits at doses of 75 mg/kg/day (25 times the MRHD as mg/m). In the rats, there was also a decrease in fetal body weight at the maternally toxic dose of 300 mg/kg/day (50 times the MRHD as mg/m), which was accompanied by an elevation in the frequency of fetuses with delayed skeletal development (missing or stunted 13th rib). In rats the no-observed-effect level for developmental toxicity was 60 mg/kg/day (10 times the MRHD as mg/m); in rabbits it was 15 mg/kg/day (5 times the MRHD as mg/m). There are no adequate and well-controlled studies in pregnant women. COREG CR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Studies in rats have shown that carvedilol and/or its metabolites (as well as other��-blockers) cross the placental barrier and are excreted in breast milk. There was increased mortality at one week post partum in neonates from rats treated with 60 mg/kg/day (10 times the MRHD as mg/m) and above during the last trimester through day 22 of lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from��-blockers, especially bradycardia, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The effects of other��- and��-blocking agents have included perinatal and neonatal distress.<br/>Pediatric Use: Effectiveness of carvedilol in patients younger than 18 years of age has not been established. In a double-blind trial, 161 children (mean age 6 years, range 2 months to 17 years; 45% less than 2 years old) with chronic heart failure [NYHA class II-IV, left ventricular ejection fraction<40% for children with a systemic left ventricle (LV), and moderate-severe ventricular dysfunction qualitatively by echo for those with a systemic ventricle that was not an LV] who were receiving standard background treatment were randomized to placebo or to 2 dose levels of carvedilol. These dose levels produced placebo-corrected heart rate reduction of 4-6 heart beats per minute, indicative of��-blockade activity. Exposure appeared to be lower in pediatric subjects than adults. After 8 months of follow-up, there was no significant effect of treatment on clinical outcomes. Adverse reactions in this trial that occurred in greater than 10% of patients treated with immediate-release carvedilol and at twice the rate of placebo-treated patients included chest pain (17% versus 6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%).<br/>Geriatric Use: The clinical studies of COREG CR in patients with hypertension, heart failure, and left ventricular dysfunction following myocardial infarction did not include sufficient numbers of subjects 65 years of age or older to determine whether they respond differently from younger patients. The following information is available for trials with immediate-release carvedilol. Of the 765 patients with heart failure randomized to carvedilol in US clinical trials, 31% (235) were 65 years of age or older, and 7.3% (56) were 75 years of age or older. Of the 1,156 patients randomized to carvedilol in a long-term, placebo-controlled trial in severe heart failure, 47% (547) were 65 years of age or older, and 15% (174) were 75 years of age or older. Of 3,025 patients receiving carvedilol in heart failure trials worldwide, 42% were 65 years of age or older. Of the 975 myocardial infarction patients randomized to carvedilol in the CAPRICORN trial, 48% (468) were 65 years of age or older, and 11% (111) were 75 years of age or older. Of the 2,065 hypertensive patients in US clinical trials of efficacy or safety who were treatedwith carvedilol, 21% (436) were 65 years of age or older. Of 3,722 patients receiving immediate-release carvedilol in hypertension clinical trials conducted worldwide, 24% were 65 years of age or older. With the exception of dizziness in hypertensive patients (incidence 8.8% in the elderly vs. 6% in younger patients), no overall differences in the safety or effectiveness (see Figures 2 and 4) were observed between the older subjects and younger subjects in each of these populations. Similarly, other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. | lld:dailymed |
| dailymed-drugs:109 | dailymed-instance:precautio... | 1. General: Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.<br/>2. PHYSICAL EXAMINATION AND FOLLOW-UP: A periodic personal and family medical history and complete physical examination are appropriate for all women, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special referenceto blood pressure, breasts, abdomen and pelvic organs, including cervical cytology and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.<br/>3. LIPID DISORDERS: Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. (See WARNINGS Dose-related risk of vascular disease from oral contraceptives .) In patients with familial defects of lipoprotein metabolism receiving estrogen-containing preparations, there have been case reports of significant elevations of plasma triglycerides leading to pancreatitis.<br/>4. LIVER FUNCTION: If jaundice develops in any woman receiving oral contraceptives, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.<br/>5. FLUID RETENTION: Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.<br/>6. EMOTIONAL DISORDERS: Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree. Patients becoming significantly depressed while taking oral contraceptives should stop the medication and use an alternate method of contraception in an attempt to determine whether the symptom is drug related.<br/>7. CONTACT LENSES: Contact-lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.<br/>8. DRUG INTERACTIONS:<br/>Effects of Other Drugs on Combined Hormonal Contraceptives: Rifampin: Metabolism of ethinyl estradiol and some progestins (e.g., norethindrone) is increased by rifampin. A reduction in contraceptive effectiveness and an increase in menstrual irregularities have been associated with concomitant use of rifampin. Anticonvulsants: Anticonvulsants such as phenobarbital, phenytoin, and carbamazepine have been shown to increase the metabolism of ethinyl estradiol and/or some progestins, which could result in a reduction of contraceptive effectiveness. Antibiotics: Pregnancy while taking combined hormonal contraceptives has been reported when the combined hormonal contraceptives were administered with antimicrobials such as ampicillin, tetracycline, and griseofulvin. However, clinical pharmacokinetic studies have not demonstrated any consistent effects ofantibiotics (other than rifampin) on plasma concentrations of synthetic steroids. Atorvastatin: Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%, respectively. St. John's Wort: Herbal products containing St. John's Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of oral contraceptives and emergency contraceptive pills. This may also result in breakthrough bleeding. Other: Ascorbic acid and acetaminophen may increase plasma concentrations of some synthetic estrogens, possibly by inhibition of conjugation.<br/>Effects of Drospirenone on Other Drugs:<br/>Effects of Combined Hormonal Contraceptives on Other Drugs: Combined oral contraceptives containing ethinyl estradiol may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. In addition, oral contraceptives may induce the conjugation of other compounds. Decreased plasma concentrations of acetaminophen and increased clearance on temazepam, salicylic acid, morphine, and clofibric acid have been noted when these drugs were administered with oral contraceptives.<br/>9. INTERACTIONS WITH LABORATORY TESTS: Certain endocrine- and liver-function tests and blood components may be affected by oral contraceptives: a. Increased prothrombin and factors VII, VIII, IX and X; decreased antithrombin 3; increased norepinephrine induced platelet aggregability. b. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG, free T4 concentration is unaltered. c. Other binding proteins may be elevated in serum. d. Sex-hormone-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged. e. Triglycerides may be increased. f. Glucose tolerance may be decreased. g. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.<br/>10. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: In a 24 month oral carcinogenicity study in mice dosed with 10 mg/kg/day drospirenone alone or 1 + 0.01, 3 + 0.03 and 10 + 0.1 mg/kg/day of drospirenone and ethinyl estradiol, 0.1 to 2 times the exposure (AUC of drospirenone) of women taking a contraceptive dose, there was an increase in carcinomas of the harderian gland in the group that received thehigh dose of drospirenone alone. In a similar study in rats given 10 mg/kg/day drospirenone alone or 0.3 + 0.003, 3 + 0.03 and 10 + 0.1 mg/kg/day drospirenone and ethinyl estradiol, 0.8 to 10 times the exposure of women taking a contraceptive dose, there was an increased incidence of benign and total (benign and malignant) adrenal gland pheochromocytomas in the group receiving the high dose of drospirenone. Drospirenone was not mutagenic in a number of in vitro (Ames, Chinese Hamster Lung gene mutation andchromosomal damage in human lymphocytes) and in vivo (mouse micronucleus) genotoxicity tests. Drospirenone increased unscheduled DNA synthesis in rat hepatocytes and formed adducts with rodent liver DNA but not with human liver DNA. SeeWARNINGS.<br/>11. PREGNANCY:<br/>Pregnancy category X: Estrogens and progestins should not be used during pregnancy. Fourteen pregnancies that occurred during exposure with 3 mg DRSP/0.03 mg EE tablets in utero (none with more than a single cycle of exposure) have been identified. One infant was born with esophageal atresia. A causal association with the 3 mg DRSP/0.03 mg EE tablet is unknown. Twelve pregnancies that occurred with YAZ exposure in utero (none with more than a single cycle of exposure) have been identified. There were no known cases of congenital anomalies. A teratology study in pregnant rats given drospirenone orally at doses of 5, 15 and 45 mg/kg/day, 6 to 50 times the human exposure based on AUC of drospirenone, resulted in an increased number of fetuses with delayed ossification of bones of the feet in the two higher doses. A similar study in rabbits dosed orally with 1, 30 and 100 mg/kg/day drospirenone, 2 to 27 times the human exposure, resulted in an increase in fetal loss and retardation of fetal development (delayed ossification of small bones, multiple fusions of ribs) at the high dose only. When drospirenone was administered with ethinyl estradiol (100:1) during late pregnancy (the period of genital development) at doses of 5, 15 and 45 mg/kg, there was a dose dependent increase in feminization of male rat fetuses. In a study in 36 cynomolgous monkeys, no teratogenic or feminization effects were observed with orally administered drospirenone and ethinyl estradiol (100:1) at doses up to 10 mg/kg/day drospirenone, 30 times the human exposure.<br/>12. NURSING MOTHERS: Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers, and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child. After oral administration of 3 mg DRSP/0.03 mg EE tablets about 0.02% of the drospirenone dose was excreted into the breast milk of postpartum women within 24 hours. This results in a maximal daily dose of about 3 mcg drospirenone in an infant.<br/>13. PEDIATRIC USAGE: Safety and efficacy of YAZ has been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.<br/>INFORMATION FOR THE PATIENT: See "Patient Labeling" printed below. | lld:dailymed |
| dailymed-drugs:110 | dailymed-instance:precautio... | General:<br/>Renal Function: Telbivudine is eliminated primarily by renal excretion, therefore dose interval adjustment is recommended in patients with creatinine clearance<50 mL/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). In addition, co-administration of TYZEKA(telbivudine) with drugs that affect renal function may alter plasma concentrations of telbivudine and/or the co-administered drug .<br/>Patients Resistant to Antiviral Drugs for Hepatitis B: There are no adequate and well controlled studies for telbivudine treatment of patients with established lamivudine-resistant hepatitis B virus infection. In cell culture, telbivudine is not active against HBV encoding amino acid substitutions M204I or M204V/L180M. Telbivudine retains wild-type phenotypic activity against the lamivudine resistance-associated substitution rtM204V alone; however, the efficacy of telbivudine against HBV harboring the rtM204V mutation has not been established in clinical trials. There are no adequate and well controlled studies for telbivudine treatment of patients with established adefovir-resistant hepatitis B virus infection. HBV encoding the adefovir resistance-associated substitution rtN236T remains susceptible to telbivudine, while HBV encoding an A181V amino acid substitution showed 3- to 5-fold reduced susceptibility to telbivudine in cell culture.<br/>Liver Transplant Recipients: The safety and efficacy of telbivudine in liver transplant recipients are unknown. The steady-state pharmacokinetics of telbivudine was not altered following multiple dose administration in combination with cyclosporine. If telbivudine treatment is determined to be necessary for a liver transplant recipient who has received or is receiving an immunosuppressant that may affect renal function, such as cyclosporine or tacrolimus, renal function should be monitored both before and during treatment with TYZEKA .<br/>Information for Patients: A patient package insert (PPI) for TYZEKA is available for patient information. Patients should remain under the care of a physician while taking TYZEKA. They should discuss any new symptoms or concurrent medications with their physician. Patients should be advised to report promptly unexplained muscle weakness, tenderness or pain. Patients should be advised that TYZEKA is not a cure for hepatitis B, that the long-term treatment benefits of telbivudine are unknown at this time and in particular, that the relationship of initial treatment response to outcomes such as hepatocellular carcinoma and decompensated cirrhosis is unknown. Patients should be informed that deterioration of liver disease may occur in some cases if treatment is discontinued, and that they should discuss any change in regimen with their physician. Patients should be advised that treatment with TYZEKA has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination .<br/>Drug Interactions: Telbivudine is excreted mainly by passive diffusion so the potential for interactions between telbivudine and other drugs eliminated by renal excretion is low. However, because telbivudine is eliminated primarily by renal excretion, co-administration of telbivudine with drugs that alter renal function may alter plasma concentrations of telbivudine.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Telbivudine has shown no carcinogenic potential. Long term oral carcinogenicity studies with telbivudine were negative in mice and rats at exposures up to 14 times those observed in humans at the therapeutic dose of 600 mg/day. There was no evidence of genotoxicity based on in vitro or in vivo tests. Telbivudine was not mutagenic in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains with or without metabolic activation. Telbivudine was not clastogenic in mammalian-cell gene mutation assays, including human lymphocyte cultures and an assay with Chinese hamster ovary cells with or without metabolic activation. Furthermore, telbivudine showed no effect in an in vivo micronucleus study in mice. In reproductive toxicology studies, no evidence of impaired fertility was seen in male or female rats at systemic exposures approximately 14 times that achieved in humans at the therapeutic dose.<br/>Pregnancy Category B: Telbivudine is not teratogenic and has shown no adverse effects in developing embryos and fetuses in preclinical studies. Studies in pregnant rats and rabbits showed that telbivudine crosses the placenta. Developmental toxicity studies revealed no evidence of harm to the fetus in rats and rabbits at doses up to 1000 mg/kg/day, providing exposure levels 6- and 37-times higher, respectively, than those observed with the 600 mg/day dose in humans. There are no adequate and well-controlled studies of telbivudine in pregnant women. Because animal reproductive toxicity studies are not always predictive of human response, telbivudine should be used during pregnancy only if potential benefits outweigh the risks. Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to telbivudine, healthcare providers are encouraged to register such patients in the AntiRetroviral Pregnancy Registry by calling 1-800-258-4263.<br/>Labor and Delivery: There are no studies in pregnant women and no data on the effect of telbivudine on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV infection.<br/>Nursing Mothers: Telbivudine is excreted in the milk of rats. It is not known whether telbivudine is excreted in human milk. Mothers should be instructed not to breastfeed if they are receiving TYZEKA.<br/>Pediatric Use: Safety and effectiveness of telbivudine in pediatric patients have not been established.<br/>Geriatric Use: Clinical studies of telbivudine did not include sufficient numbers of patients���65 years of age to determine whether they respond differently from younger subjects. In general, caution should be exercised when prescribing TYZEKA to elderly patients, considering the greater frequency of decreased renal function due to concomitant disease or other drug therapy. Renal function should be monitored in elderly patients, and dosage adjustments should be made accordingly.<br/>Special Populations: Telbivudine has not been investigated in co-infected hepatitis B patients (e.g., patients co-infected with HIV, HCV or HDV). | lld:dailymed |
| dailymed-drugs:111 | dailymed-instance:precautio... | General: Cevimeline toxicity is characterized by an exaggeration of its parasympathomimetic effects. These may include: headache, visual disturbance, lacrimation, sweating, respiratory distress, gastrointestinal spasm, nausea, vomiting, diarrhea, atrioventricular block, tachycardia, bradycardia, hypotension, hypertension, shock, mental confusion, cardiac arrhythmia, and tremors. Cevimeline should be administered with caution to patients with a history of nephrolithiasis or cholelithiasis. Contractions of the gallbladder or biliary smooth muscle could precipitate complications such as cholecystitis, cholangitis and biliary obstruction. An increase in the ureteral smooth muscle tone could theoretically precipitate renal colic or ureteral reflux in patients with nephrolithiasis.<br/>Information for Patients: Patients should be informed that cevimeline may cause visual disturbances, especially at night, that could impair their ability to drive safely. If a patient sweats excessively while taking cevimeline, dehydration may develop. The patient should drink extra water and consult a health care provider.<br/>Drug Interactions: Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with cevimeline can be expected to have additive effects. Cevimeline might interfere with desirable antimuscarinic effects of drugs used concomitantly. Drugs which inhibit CYP2D6 and CYP3A3/4 also inhibit the metabolism of cevimeline. Cevimeline should be used with caution in individuals known or suspected to be deficient in CYP2D6 activity, based on previous experience, as they may be at a higher risk of adverse events. In an in vitro study, cytochromeP450 isozymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 were not inhibited by exposure to cevimeline.<br/>Carcinogenesis, Mutagenesis and Impairment of Fertility: Lifetime carcinogenicity studies were conducted in CD-1 mice and F-344 rats. A statistically significant increase in the incidence of adenocarcinomas of the uterus was observed in female rats that received cevimeline at a dosage of 100 mg/kg/day (approximately 8 times the maximum human exposure based on comparison of AUC data). No other significant differences in tumor incidence were observed in either mice or rats. Cevimeline exhibited no evidence of mutagenicity or clastogenicity in a battery of assays that included an Ames test, an in vitro chromosomal aberration study in mammalian cells, a mouse lymphoma study in L5178Y cells, or a micronucleus assay conducted in vivo in ICR mice. Cevimeline did not adversely affect the reproductive performance or fertility of male Sprague-Dawley rats when administered for 63 days prior to mating and throughout the period of mating at dosages up to 45 mg/kg/day (approximately 5 times the maximum recommended dose for a 60 kg human following normalization of the data on the basis of body surface area estimates). Females that were treated with cevimeline at dosages up to 45 mg/kg/day from 14 days prior to mating through day seven of gestation exhibited a statistically significantly smaller number of implantations than did control animals.<br/>Pregnancy:<br/>Pregnancy Category C.: Cevimeline was associated with a reduction in the mean number of implantations when given to pregnant Sprague-Dawley rats from 14 days prior to mating through day seven of gestation at a dosage of 45 mg/kg/day (approximately 5 times the maximum recommended dose for a 60 kg human when compared on the basis of body surface area estimates). This effect may have been secondary to maternal toxicity. There are no adequate and well-controlled studies in pregnant women. Cevimeline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: It is not known whether this drug is secreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from EVOXAC', a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric Use: Although clinical studies of cevimeline included subjects over the age of 65, the numbers were not sufficient to determine whether they respond differently from younger subjects. Special care should be exercised when cevimeline treatment is initiated in an elderly patient, considering the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in the elderly. | lld:dailymed |
| dailymed-drugs:112 | dailymed-instance:precautio... | General: As with other anti-infectives, prolonged use may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, discontinue use and institute alternative therapy. Whenever clinical judgment dictates, the patient should be examined with the aid of magnification, such as slit-lamp biomicroscopy, and, where appropriate, fluorescein staining. Patients should be advised not to wear contact lenses if they have signs and symptoms of corneal ulcer.<br/>Information for Patients: Avoid contaminating the applicator tip with material from the eye, fingers or other source. Systemic quinolones have been associated with hypersensitivity reactions, even following a single dose. Discontinue use immediately and contact your physician at the first sign of a rash or allergic reaction.<br/>Drug Interactions: Specific drug interaction studies have not been conducted with IQUIX. However, the systemic administration of some quinolones has been shown to elevate plasma concentrations of theophylline, interfere with the metabolism of caffeine, and enhance the effects of the oral anticoagulant warfarin and its derivatives, and has been associated with transient elevations in serum creatinine in patients receiving systemic cyclosporine concomitantly.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In a long term carcinogenicity study in rats, levofloxacin exhibited no carcinogenic or tumorigenic potential following daily dietary administration for 2 years; the highest dose (100 mg/kg/day) was 100 times the highest recommended human ophthalmic dose. Levofloxacin was not mutagenic in the following assays: Ames bacterial mutation assay (S. typhimurium and E. coli), CHO/HGPRT forward mutation assay, mouse micronucleus test, mouse dominant lethal test, rat unscheduled DNA synthesis assay, and the in vivo mouse sister chromatid exchange assay. It was positive in the in vitro chromosomal aberration (CHL cell line) and in vitro sister chromatid exchange (CHL/IU cell line) assays. Levofloxacin caused no impairment of fertility or reproduction in rats at oral doses as high as 360 mg/kg/day, corresponding to 400 times the highest recommended human ophthalmic dose.<br/>Pregnancy::<br/>Teratogenic Effects: Pregnancy Category C: Levofloxacin at oral doses of 810 mg/kg/day in rats, which corresponds to approximately 1000 times the highest recommended human ophthalmic dose, caused decreased fetal body weight and increased fetal mortality. No teratogenic effect was observed when rabbits were dosed orally as high as 50 mg/kg/day, which corresponds to approximately 60 times the highest recommended maximum human ophthalmic dose, or when dosed intravenously as high as 25 mg/kg/day, corresponding to approximately 30 times the highest recommended human ophthalmic dose. There are, however, no adequate and well-controlled studies in pregnant women. Levofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: Levofloxacin has not been measured in human milk. Based upon data from ofloxacin, it can be presumed that levofloxacin is excreted in human milk. Caution should be exercised when IQUIX is administered to a nursing mother.<br/>Pediatric Use: Safety and effectiveness in children below the age of six years have not been established. Oral administration of systemic quinolones has been shown to cause arthropathy in immature animals. There is no evidence that the ophthalmic administration of levofloxacin has any effect on weight bearing joints.<br/>Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and other adult patients. | lld:dailymed |
| dailymed-drugs:113 | dailymed-instance:precautio... | General:: Meloxicam cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of meloxicam in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.<br/>Hepatic Effects:: Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including meloxicam. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with meloxicam. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), meloxicam should be discontinued.<br/>Renal Effects:: Caution should be used when initiating treatment with meloxicam in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with meloxicam. Caution is also recommended in patients with pre-existing kidney disease (see WARNINGS , Renal Effectsand Advanced Renal Disease). The extent to which metabolites may accumulate in patients with renal failure has not been studied with meloxicam. Because some meloxicam metabolites are excreted by the kidney, patients with significantly impaired renal function should be more closely monitored.<br/>Hematological Effects:: Anemia is sometimes seen in patients receiving NSAIDs, including meloxicam. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including meloxicam, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. Drugs which inhibit the biosynthesis of prostaglandins may interfere to some extent with platelet function and vascular responses to bleeding. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving meloxicam who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.<br/>Pre-existing Asthma:: Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, meloxicam should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma.<br/>Information for Patients:: Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.<br/>Laboratory Tests:: Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, meloxicam should be discontinued.<br/>Drug Interactions::<br/>ACE-inhibitors:: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors.<br/>Aspirin:: When meloxicam is administered with aspirin (1000 mg TID) to healthy volunteers, it tended to increase the AUC (10%) and C(24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with meloxicam may result in an increased rate of GI ulceration or other complications, compared to use of meloxicam alone. Meloxicam is not a substitute for aspirin for cardiovascular prophylaxis.<br/>Cholestyramine:: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established.<br/>Cimetidine:: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam.<br/>Digoxin:: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after (-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam.<br/>Furosemide:: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with meloxicam, patients should be observed closely for signs of declining renal failure , as well as to assure diuretic efficacy.<br/>Lithium:: In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by meloxicam. Patients on lithium treatment should be closely monitored for signs of lithium toxicity when meloxicam is introduced, adjusted, or withdrawn.<br/>Methotrexate:: NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites.<br/>Warfarin:: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing meloxicam therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering meloxicam with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:: No carcinogenic effect of meloxicam was observed in rats given oral doses up to 0.8 mg/kg/day (approximately 0.4-fold the human dose at 15 mg/day for a 50 kg adult based on body surface area conversion) for 104 weeks or in mice given oral doses up to 8.0 mg/kg/day (approximately 2.2-fold the human dose, as noted above) for 99 weeks. Meloxicam was not mutagenic in an Ames assay, or clastogenic in a chromosome aberration assay with human lymphocytes and an in vivo micronucleus test in mouse bone marrow. Meloxicam did not impair male and female fertility in rats at oral doses up to 9 and 5 mg/kg/day, respectively (4.9-fold and 2.5-fold the human dose, as noted above). However, an increased incidence of embryolethality at oral doses (1 mg/kg/day (0.5-fold the human dose, as noted above) was observed in rats when dams were given meloxicam 2 weeks prior to mating and during early embryonic development.<br/>Pregnancy::<br/>Teratogenic Effects: Pregnancy Category C.:: Meloxicam caused an increased incidence of septal defect of the heart, a rare event, at an oral dose of 60 mg/kg/day (64.5-fold the human dose at 15 mg/day for a 50 kg adult based on body surface area conversion) and embryolethality at oral doses (5( mg/kg/day (5.4-fold the human dose, as noted above) when rabbits were treated throughout organogenesis. Meloxicam was not teratogenic in rats up to an oral dose of 4 mg/kg/day (approximately 2.2-fold the human dose, as noted above) throughout organogenesis. An increased incidence of stillbirths was observed when rats were given oral doses (1 mg/kg/day throughout organogenesis. Meloxicam crosses the( placental barrier. There are no adequate and well-controlled studies in pregnant women. Meloxicam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nonteratogenic Effects:: Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Meloxicam caused a reduction in birth index, live births, and neonatal survival at oral doses (0.125 mg/kg/day (approximately 0.07-fold the human dose at 15 mg/day for a 50 kg adult based on body surface area conversion) when rats were treated during the late gestation and lactation period. No studies have been conducted to evaluatethe effect of meloxicam on the closure of the ductus arteriosus in humans; use of meloxicam during the third trimester of pregnancy should be avoided.<br/>Labor and Delivery:: Studies in rats with meloxicam, as with other drugs known to inhibit prostaglandin synthesis, showed an increased incidence of stillbirths, prolonged delivery, and delayed parturition at oral dosages (1( mg/kg/day (approximately 0.5-fold the human dose at 15 mg/day for a 50 kg adult based on body surface area conversion), and decreased pup survival at an oral dose of 4 mg/kg/day (approximately 2.1-fold the human dose, as noted above) throughout organogenesis. Similar findings were observed in rats receiving oral dosages (0.125( mg/kg/day (approximately 0.07-fold the human dose, as noted above) during late gestation and the lactation period. The effects of meloxicam on labor and delivery in pregnant women are unknown.<br/>Nursing Mothers:: It is not known whether this drug is excreted in human milk however, meloxicam was excreted in the milk of lactating rats at concentrations higher than those in plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from meloxicam, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use:: Use of this drug for a pediatric indication is protected by marketing exclusivity.<br/>Geriatric Use:: As with any NSAID, caution should be exercised in treating the elderly (65 years and older). | lld:dailymed |
| dailymed-drugs:115 | dailymed-instance:precautio... | General: Dihydroergotamine mesylate injection may cause coronary artery vasospasm; patients who experience signs or symptoms suggestive of angina following its administration should, therefore, be evaluated for the presence of CAD or a predisposition to variant angina before receiving additional doses. Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud's syndrome following the use of any 5-HT agonist are candidates for further evaluation.<br/>Fibrotic Complications: See WARNINGS: Fibrotic Complications.<br/>Information for Patients: The text of a patient information sheet is printed at the end of this insert. To assure safe and effective use of dihydroergotamine mesylate injection, the information and instructions provided in the patient information sheet should be discussed with patients. Patients should be advised to report to the physician immediately any of the following: numbness or tingling in the fingers and toes, muscle pain in the arms and legs, weakness in the legs, pain in the chest, temporary speeding or slowing of the heart rate, swelling, or itching. Prior to the initial use of the product by a patient, the prescriber should take steps to ensure that the patient understands how to use the product as provided. (See Patient Information Sheet and product packaging.) Administration of dihydroergotamine mesylate injection should not exceed the dosing guidelines and should not be used for chronic daily administration<br/>Drug Interactions:<br/>Vasoconstrictors: Dihydroergotamine mesylate injection should not be used with peripheral vasoconstrictors because the combination may cause synergistic elevation of blood pressure.<br/>Sumatriptan: Sumatriptan has been reported to cause coronary artery vasospasm, and its effect could be additive with dihydroergotamine mesylate injection. Sumatriptan and dihydroergotamine mesylate injection should not be taken within 24 hours of each other.<br/>Beta Blockers: Although the results of a clinical study did not indicate a safety problem associated with the administration of dihydroergotamine mesylate injection to subjects already receiving propranolol, there have been reports that propranolol may potentiate the vasoconstrictive action of ergotamine by blocking the vasodilating property of epinephrine.<br/>Nicotine: Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy.<br/>CYP 3A4 Inhibitors: (e.g. Macrolide Antibiotics and Protease Inhibitors) See CONTRAINDICATIONS and WARNINGS.<br/>SSRI's: Weakness, hyperreflexia, and incoordination have been reported rarely when 5-HTagonists have been co-administered with SSRI's (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline). There have been no reported cases from spontaneous reports of drug interaction between SSRI's and dihydroergotamine mesylate injection.<br/>Oral Contraceptives: The effect of oral contraceptives on the pharmacokinetics of dihydroergotamine mesylate injection has not been studied.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis: Assessment of the carcinogenic potential of dihydroergotamine mesylate in mice and rats is ongoing.<br/>Mutagenesis: Dihydroergotamine mesylate was clastogenic in two in vitro chromosomal aberration assays, the V79 Chinese hamster cell assay with metabolic activation and the cultured human peripheral blood lymphocyte assay. There was no evidence of mutagenic potential when dihydroergotamine mesylate was tested in the presence or absence of metabolic activation in two gene mutation assays (the Ames test and the in vitro mammalian Chinese hamster V79/HGPRT assay) and in an assay for DNA damage (the rat hepatocyte unscheduled DNA synthesis test). Dihydroergotamine was not clastogenic in the in vivo mouse and hamster micronucleus tests.<br/>Impairment of Fertility: Impairment of fertility was not evaluated for dihydroergotamine mesylate injection. There was no evidence of impairment of fertility in rats given intranasal doses of Migranal' Nasal Spray up to 1.6 mg/day (associated with mean plasma dihydroergotamine mesylate exposures [AUC] approximately 9 to 11 times those in humans receiving the MRDD of 4 mg).<br/>Pregnancy:<br/>Teratogenic Effects; Pregnancy Category X: See CONTRAINDICATIONS.<br/>Nursing Mothers: Ergot drugs are known to inhibit prolactin. It is likely that dihydroergotamine mesylate injection is excreted in human milk, but there are no data on the concentration of dihydroergotamine in human milk. It is known that ergotamine is excreted in breast milk and may cause vomiting, diarrhea, weak pulse, and unstable blood pressure in nursing infants. Because of the potential for these serious adverse events in nursing infants exposed to dihydroergotamine mesylate injection nursing should not be undertaken with the use of dihydroergotamine mesylate injection.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established. | lld:dailymed |
| dailymed-drugs:116 | dailymed-instance:precautio... | General: Symptomatic response to cimetidine therapy does not preclude the presence of a gastric malignancy. There have been rare reports of transient healing of gastric ulcers despite subsequently documented malignancy. Reversible confusional states have been observed on occasion, predominantly, but not exclusively, in severely ill patients. Advancing age (50 or more years) and preexisting liver and/or renal disease appear to be contributing factors. In some patients these confusional states have been mild and have not required discontinuation of cimetidine therapy. In cases where discontinuation was judged necessary, the condition usually cleared with 3 to 4 days of drug withdrawal.<br/>Drug Interactions: Cimetidine, apparently through an effect on certain microsomal enzyme systems, has been reported to reduce the hepatic metabolism of warfarin-type anticoagulants, phenytoin, propranolol, nifedipine, chlordiazepoxide, diazepam, certain tricyclic antidepressants, lidocaine, theophylline and metronidazole, thereby delaying elimination and increasing blood levels of these drugs. Clinically significant effects have been reported with the warfarin anticoagulants; therefore, close monitoring of prothrombin time is recommended, and adjustment of the anticoagulant dose may be necessary when cimetidine is administered concomitantly. Interaction with phenytoin, lidocaine and theophylline has also been reported to produce adverse clinical effects. However, a crossover study in healthy subjects receiving either cimetidine 300 mg q.i.d. or 800 mg h.s. concomitantly with a 300 mg b.i.d. dosage of theophylline extended-release tablets demonstrated less alteration in steady-state theophylline peak serum levels with the 800 mg h.s. regimen, particularly in subjects aged 54 years and older. Data beyond ten days are not available. (Note: All patients receiving theophylline should be monitored appropriately,regardless of concomitant drug therapy.) Dosage of the drugs mentioned above and other similarly metabolized drugs, particularly those of low therapeutic ratio or in patients with renal and/or hepatic impairment, may require adjustment when starting or stopping concomitantly administered cimetidine to maintain optimum therapeutic blood levels. Alteration of pH may affect absorption of certain drugs (e.g., ketoconazole). If these products are needed, they should be given at least 2 hours before cimetidine administration. Additional clinical experience may reveal other drugs affected by the concomitant administration of cimetidine.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 24-month toxicity study conducted in rats, at dose levels of 150, 378 and 950 mg/kg/day (approximately 8 to 48 times the recommended human dose), there was a small increase in the incidence of benign Leydig cell tumors in each dose group; when the combined drug-treated groups and control groups were compared, this increase reached statistical significance. In a subsequent 24-month study,there were no differences between the rats receiving 150 mg/kg/day and the untreated controls. However, a statistically significant increase in benign Leydig cell tumor incidence was seen in the rats that received 378 and 950 mg/kg/day. These tumors were common in control groups as well as treated groups and the difference became apparent only in aged rats. Cimetidine has demonstrated a weak antiandrogenic effect. In animal studies this was manifested as reduced prostate and seminal vesicle weights. However, there was no impairment of mating performance or fertility, nor any harm to the fetus in these animals at doses 8 to 48 times the full therapeutic dose of cimetidine, as compared with controls. The cases of gynecomastia seen in patients treated for one month or longer may be related to this effect. In human studies, cimetidine has been shown to have no effect on spermatogenesis, sperm count, motility, morphology or in vitro fertilizing capacity.<br/>Pregnancy:<br/>Teratogenic Effects. Pregnancy Category B: Reproduction studies have been performed in rats, rabbits and mice at doses up to 40 times the normal human dose and have revealed no evidence of impaired fertility or harm to the fetus due to cimetidine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.<br/>Nursing Mothers: Cimetidine is secreted in human milk and, as a general rule, nursing should not be undertaken while patient is on a drug.<br/>Pediatric Use: Clinical experience in pediatric patients is limited. Therefore, cimetidine therapy cannot be recommended for pediatric patients under 16, unless, in the judgement of the physician, anticipated benefits outweigh the potential risks. In very limited experience, doses of 20 to 40 mg/kg per day have been used.<br/>Immunocompromised Patients: In immunocompromised patients, decreased gastric acidity, including that produced by acid-suppressing agents such as cimetidine, may increase the possibility of a hyperinfection of strongyloidiasis. | lld:dailymed |
| dailymed-drugs:118 | dailymed-instance:precautio... | General: INDOCIN cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of INDOCIN in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.<br/>Hepatic Effects: Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including INDOCIN. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with INDOCIN. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), INDOCIN should be discontinued.<br/>Hematological Effects: Anemia is sometimes seen in patients receiving NSAIDs, including INDOCIN. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including INDOCIN, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving INDOCIN who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.<br/>Preexisting Asthma: Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, INDOCIN should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.<br/>Information for Patients: Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.<br/>Laboratory Tests: Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, INDOCIN should be discontinued.<br/>Drug Interactions:<br/>ACE-Inhibitors and Angiotensin II Antagonists: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors and angiotensin II antagonists. INDOCIN can reduce the antihypertensive effects of captopril and losartan. These interactions should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors or angiotensin II antagonists. In some patients with compromised renal function, the co-administration of an NSAID and an ACE-inhibitor or an angiotensin II antagonist may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible.<br/>Aspirin: When INDOCIN is administered with aspirin, its protein binding is reduced, although the clearance of free INDOCIN is not altered. The clinical significance of this interaction is not known. The use of INDOCIN in conjunction with aspirin or other salicylates is not recommended. Controlled clinical studies have shown that the combined use of INDOCIN and aspirin does not produce any greater therapeutic effect than the use of INDOCIN alone. In a clinical study of the combined use of INDOCIN and aspirin, the incidence of gastrointestinal side effects was significantly increased with combined therapy. In a study in normal volunteers, itwas found that chronic concurrent administration of 3.6 g of aspirin per day decreases indomethacin blood levels approximately 20%.<br/>Beta-adrenoceptor blocking agents: Blunting of the antihypertensive effect of beta���adrenoceptor blocking agents by non-steroidal anti-inflammatory drugs including INDOCIN has been reported. Therefore, when using these blocking agents to treat hypertension, patients should be observed carefully in order to confirm that the desired therapeutic effect has been obtained.<br/>Cyclosporine: Administration of non-steroidal anti-inflammatory drugs concomitantly with cyclosporine has been associated with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of renal prostacyclin. NSAIDs should be used with caution in patients taking cyclosporine, and renal function should be carefully monitored.<br/>Diflunisal: In normal volunteers receiving indomethacin, the administration of diflunisal decreased the renal clearance and significantly increased the plasma levels of indomethacin. In some patients, combined use of INDOCIN and diflunisal has been associated with fatal gastrointestinal hemorrhage. Therefore, diflunisal and INDOCIN should not be used concomitantly.<br/>Digoxin: INDOCIN given concomitantly with digoxin has been reported to increase the serum concentration and prolong the half���life of digoxin. Therefore, when INDOCIN and digoxin are used concomitantly, serum digoxin levels should be closely monitored.<br/>Diuretics: In some patients, the administration of INDOCIN can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. This response has been attributed to inhibition of renal prostaglandin synthesis. INDOCIN reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients. It has been reported that the addition of triamterene to a maintenance schedule of INDOCIN resulted in reversible acute renal failure in two of four healthy volunteers. INDOCIN and triamterene should not be administered together. INDOCIN and potassium-sparing diuretics each may be associated with increased serum potassium levels. The potential effects of INDOCIN and potassium-sparing diuretics on potassium kinetics and renal function should be considered when these agents are administered concurrently. Most of the above effects concerning diuretics have been attributed, at least in part, to mechanisms involving inhibition of prostaglandin synthesis by INDOCIN. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy.<br/>Lithium: Capsules INDOCIN 50 mg t.i.d. produced a clinically relevant elevation of plasma lithium and reduction in renal lithium clearance in psychiatric patients and normal subjects with steady state plasma lithium concentrations. This effect has been attributed to inhibition of prostaglandin synthesis. As a consequence, when NSAIDs and lithium are given concomitantly, the patient should be carefully observed for signs of lithium toxicity. (Read circulars for lithium preparations before use of such concomitant therapy.) In addition, the frequency of monitoring serum lithium concentration should be increased at the outset of such combination drug treatment.<br/>Methotrexate: NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.<br/>NSAIDs: The concomitant use of INDOCIN with other NSAIDs is not recommended due to the increased possibility of gastrointestinal toxicity, with little or no increase in efficacy.<br/>Oral anticoagulants: Clinical studies have shown that INDOCIN does not influence the hypoprothrombinemia produced by anticoagulants. However, when any additional drug, including INDOCIN, is added to the treatment of patients on anticoagulant therapy, the patients should be observed for alterations of the prothrombin time. In post-marketing experience, bleeding has been reported in patients on concomitant treatment with anticoagulants and INDOCIN. Caution should be exercised when INDOCIN and anticoagulants are administered concomitantly. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.<br/>Probenecid: When INDOCIN is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. Therefore, a lower total daily dosage of INDOCIN may produce a satisfactory therapeutic effect. When increases in the dose of INDOCIN are made, they should be made carefully and in small increments.<br/>Drug/Laboratory Test Interactions: False-negative results in the dexamethasone suppression test (DST) in patients being treated with INDOCIN have been reported. Thus, results of the DST should be interpreted with caution in these patients.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In an 81���week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day, indomethacin had no tumorigenic effect. Indomethacin produced no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat (dosing period 73-110 weeks) and the mouse (dosing period 62-88 weeks) at doses up to 1.5 mg/kg/day. Indomethacin did not have any mutagenic effect in in vitro bacterial tests (Ames test and E. coli with or without metabolic activation) and a series of in vivo tests including the host-mediated assay, sex-linked recessive lethals in Drosophila, and the micronucleus test in mice. Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two generation reproduction study or a two litter reproduction study in rats.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nonteratogenic Effects: Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. The known effects of indomethacin and other drugs of this class on the human fetus during the third trimester of pregnancy include: constriction of the ductus arteriosus prenatally, tricuspid incompetence, and pulmonary hypertension; non-closure of the ductus arteriosus postnatally which may be resistant to medical management; myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or failure, renal injury/dysgenesis which may result in prolonged or permanent renal failure, oligohydramnios, gastrointestinal bleeding or perforation, and increased risk of necrotizing enterocolitis. In rats and mice, 4.0 mg/kg/day given during the last three days of gestation caused a decrease in maternal weight gain and some maternal and fetal deaths. An increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses was observed. At 2.0 mg/kg/day, no increase in neuronal necrosis was observed as compared to the control groups. Administration of 0.5 or 4.0 mg/kg/day during the first three days of life did not cause an increase in neuronal necrosis at either dose level.<br/>Labor and Delivery: In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of INDOCIN on labor and delivery in pregnant women are unknown.<br/>Use in Nursing Mothers: Indomethacin is excreted in the milk of lactating mothers. INDOCIN is not recommended for use in nursing mothers.<br/>Pediatric Use: Safety and effectiveness in pediatric patients 14 years of age and younger has not been established. INDOCIN should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk. In experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with Capsules INDOCIN, side effects in pediatric patients were comparable to those reported in adults. Experience in pediatric patients has been confined to the use of Capsules INDOCIN. If a decision is made to use indomethacin for pediatric patients two years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. There have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, a suggested starting dose is 1-2 mg/kg/day given in divided doses. Maximum daily dosage should not exceed 3 mg/kg/day or 150���200 mg/day, whichever is less. Limited data are available to support the use of a maximum daily dosage of 4 mg/kg/day or 150-200 mg/day, whichever is less. As symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms, or the drug should be discontinued.<br/>Geriatric Use: As with any NSAID, caution should be exercised in treating the elderly (65 years and older) since advancing age appears to increase the possibility of adverse reactions (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation and DOSAGE AND ADMINISTRATION). Elderly patients seem to tolerate ulceration or bleeding less well than other individuals and many spontaneous reports of fatal GI events arein this population (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation). Indomethacin may cause confusion or, rarely, psychosis ; physicians should remain alert to the possibility of such adverse effects in the elderly. This drug is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function (see WARNINGS, Renal Effects). | lld:dailymed |
| dailymed-drugs:120 | dailymed-instance:precautio... | General: Most drug-related adverse events of Vinorelbine are reversible. If severe adverse events occur, Vinorelbine should be reduced in dosage or discontinued and appropriate corrective measures taken. Reinstitution of therapy with Vinorelbine should be carried out with caution and alertness as to possible recurrence of toxicity. Vinorelbine should be used with extreme caution in patients whose bone marrow reserve may have been compromised by prior irradiation or chemotherapy, or whose marrow function is recovering from the effects of previous chemotherapy (see DOSAGE AND ADMINISTRATION). Administration of Vinorelbine to patients with prior radiation therapy may result in radiation recall reactions (see ADVERSE REACTIONS and Drug Interactions). Patients with a prior history or pre-existing neuropathy, regardless of etiology, should be monitored for new or worsening signs and symptoms of neuropathy while receiving Vinorelbine. Care must be taken to avoid contamination of the eye with concentrations of Vinorelbine used clinically. Severe irritation of the eye has been reported with accidental exposure to another vinca alkaloid. If exposure occurs, the eye should immediately be thoroughly flushed with water.<br/>Information for Patients: Patients should be informed that the major acute toxicities of Vinorelbine are related to bone marrow toxicity, specifically granulocytopenia with increased susceptibility to infection. They should be advised to report fever or chills immediately. Women of childbearing potential should be advised to avoid becoming pregnant during treatment. Patients should be advised to contact their physician if they experience increased shortness of breath, cough, or other new pulmonary symptoms, or if they experience symptoms of abdominal pain or constipation.<br/>Laboratory Tests: Since dose-limiting clinical toxicity is the result of depression of the white blood cell count, it is imperative that complete blood counts with differentials be obtained and reviewed on the day of treatment prior to each dose of Vinorelbine (see ADVERSE REACTIONS: Hematologic).<br/>Hepatic: There is no evidence that the toxicity of Vinorelbine is enhanced in patients with elevated liver enzymes. No data are available for patients with severe baseline cholestasis, but the liver plays an important role in the metabolism of Vinorelbine. Because clinical experience in patients with severe liver disease is limited, caution should be exercised when administering Vinorelbine to patients with severe hepatic injury or impairment (see DOSAGE AND ADMINISTRATION).<br/>Drug Interactions: Acute pulmonary reactions have been reported with Vinorelbine and other anticancer vinca alkaloids used in conjunction with mitomycin. Although the pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin, the incidence of granulocytopenia with Vinorelbine used in combination with cisplatin is significantly higher than with single-agent Vinorelbine. Patients who receive Vinorelbine and paclitaxel, either concomitantly or sequentially, should be monitored for signs and symptoms of neuropathy. Administration of Vinorelbine to patients with prior or concomitant radiation therapy may result in radiosensitizing effects. Caution should be exercised in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily, or in patients with hepatic dysfunction. Concurrent administration of vinorelbine tartrate with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of side effects.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of Vinorelbine has not been studied. Vinorelbine has been shown to affect chromosome number and possibly structure in vivo (polyploidy in bone marrow cells from Chinese hamsters and a positive micronucleus test in mice). It was not mutagenic in the Ames test and gave inconclusive results in the mouselymphoma TK Locus assay. The significance of these or other short-term test results for human risk is unknown. Vinorelbine did not affect fertility to a statistically significant extent when administered to rats on either a once-weekly (9 mg/m, approximately one third the human dose) or alternate-day schedule (4.2 mg/m, approximately one seventh the human dose) prior to and during mating. However, biweekly administration for 13 or 26 weeks in the rat at 2.1 and 7.2 mg/m(approximately one fifteenth and one fourth the human dose) resulted in decreased spermatogenesis and prostate/seminal vesicle secretion.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category D: See WARNINGS section.<br/>Nursing Mothers: It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Vinorelbine, it is recommended that nursing be discontinued in women who are receiving therapy with Vinorelbine.<br/>Pediatric Use: Safety and effectiveness of Vinorelbine in pediatric patients have not been established. Data from a single-arm study in 46 patients with recurrent solid malignant tumors, including rhabdomyosarcoma/undifferentiated sarcoma, neuroblastoma, and CNS tumors, at doses similar to those used in adults, showed no meaningful clinical activity. Toxicities were similar to those reported in adults.<br/>Geriatric Use: Of the total number of patients in North American clinical studies of IV Vinorelbine, approximately one third were 65 years of age or greater. No overall differences in effectiveness or safety were observed between these patients and younger adult patients. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out. The pharmacokinetics of vinorelbine in elderly and younger adult patients are similar (see CLINICAL PHARMACOLOGY). | lld:dailymed |
| dailymed-drugs:122 | dailymed-instance:precautio... | General:: When Reversal of Naltrexone Blockade is Required: In an emergency situation in patients receiving fully blocking doses of naltrexone, a suggested plan of management is regional analgesia, conscious sedation with a benzodiazepine, use of non-opioid analgesics or general anesthesia. In a situation requiring opioid analgesia, the amount of opioid required may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged. A rapidly acting opioid analgesic which minimizes the duration of respiratory depression is preferred. The amount of analgesic administered should be titrated to the needs of the patient. Non-receptor mediated actions may occur and should be expected (e.g., facial swelling, itching, generalized erythema, or bronchoconstriction) presumably due to histamine release. Irrespective of the drug chosen to reverse naltrexone blockade, the patient should be monitored closely by appropriately trained personnel in a setting equipped and staffed for cardiopulmonary resuscitation. Accidentally Precipitated Withdrawal: Severe opioid withdrawal syndromes precipitated by the accidental ingestion of naltrexone have been reported in opioid-dependent individuals. Symptoms of withdrawal have usually appeared within five minutes of ingestion of naltrexone and have lasted for up to 48 hours. Mental status changes including confusion, somnolence and visual hallucinations have occurred. Significant fluid losses from vomiting and diarrhea have required intravenous fluid administration. In all cases patients were closely monitored and therapy with non-opioid medications was tailored to meet individual requirements. Use of naltrexone does not eliminate or diminish withdrawal symptoms. If naltrexone is initiated early in the abstinence process, it will not preclude the patient's experience of the full range of signs and symptoms that would be experienced if naltrexone had not been started. Numerous adverse events are known to be associated with withdrawal.<br/>Special Risk Patients:: Information for Patients: It is recommended that the prescribing physician relate the following information to patients being treated with naltrexone: You have been prescribed naltrexone hydrochloride as part of the comprehensive treatment for your alcoholism or drug dependence. You should carry identification to alert medical personnel to the fact that you are taking naltrexone. A naltrexone medication card may be obtained from your physician and can be used for this purpose. Carrying the identification card should help to ensure that you can obtain adequate treatment in an emergency. If you require medical treatment, be sure to tell the treating physician that you are receiving naltrexone therapy. You should take naltrexone as directed by your physician. If you attempt to self-administer heroin or any other opiate drug, in small doses while on naltrexone, you will not perceive any effect. Most important, however, if you attempt to self-administer large doses of heroin or any other opioid (including methadone or LAAM) while on naltrexone, you may die or sustain serious injury, including coma. Naltrexone is well-tolerated in the recommended doses, but may cause liver injury when taken in excess or in people who develop liver disease from other causes. If you develop abdominal pain lasting more than a few days, white bowel movements, dark urine, or yellowing of your eyes, you should stop taking naltrexone immediately and see your doctor as soon as possible. Laboratory Tests: A high index of suspicion for drug-related hepatic injury is critical if the occurrence of liver damage induced by naltrexone is to be detected at the earliest possible time. Evaluations, using appropriate batteries of tests to detect liver injury are recommended at a frequency appropriate to the clinical situation and the dose of naltrexone. Naltrexone does not interfere with thin-layer, gas-liquid, and high pressure liquid chromatographic methods which may be used for the separation and detection of morphine, methadone or quinine in the urine. Naltrexone may or may not interfere with enzymatic methods for the detection of opioids depending on the specificityof the test. Please consult the test manufacturer for specific details. Drug Interactions: Studies to evaluate possible interactions between naltrexone and drugs other than opiates have not been performed. Consequently, caution is advised if the concomitant administration of naltrexone and other drugs is required. The safety and efficacy of concomitant use of naltrexone and disulfiram is unknown, and the concomitant use of two potentially hepatotoxic medications is not ordinarily recommended unless the probable benefits outweigh the known risks. Lethargy and somnolence have been reported following doses of naltrexone and thioridazine. Patients taking naltrexone may not benefit from opioid containing medicines, such as cough and cold preparations, antidiarrheal preparations, and opioid analgesics. In an emergency situation when opioid analgesia must be administered to a patient receiving naltrexone, the amount of opioid required may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged . Carcinogenesis, Mutagenesis and Impairment of Fertility: The following statements are based on the results of experiments in mice and rats. The potential carcinogenic, mutagenic and fertility effects of the metabolite 6-��-naltrexol are unknown. In a two-year carcinogenicity study in rats, there were small increases in the numbers of testicular mesotheliomas in males and tumors of vascular origin in males and females. The incidence of mesothelioma in males given naltrexone at a dietary dose of 100 mg/kg/day (600 mg/m/day; 16 times the recommended therapeutic dose, based on body surface area) was 6%, compared with a maximum historical incidence of 4%. The incidence of vascular tumors in males and females given dietary doses of 100 mg/kg/day (600 mg/m/day) was 4%, but only the incidence in females was increased compared with a maximum historical control incidence of 2%. There was no evidence of carcinogenicity in a two-year dietary study with naltrexone in male and female mice. There was limited evidence of a weak genotoxic effect of naltrexone in one gene mutation assay in a mammalian cell line, in the Drosophila recessive lethal assay, and in non-specific DNA repair tests with E. coli. However, no evidence of genotoxic potential was observed in a range of other in vitro tests, including assays for gene mutation in bacteria, yeast, or in a second mammalian cell line, a chromosomal aberration assay, and an assay for DNA damage in human cells. Naltrexone did not exhibit clastogenicity in an in vivo mouse micronucleus assay. Naltrexone (100 mg/kg/day [600 mg/m/day] PO; 16 times the recommended therapeutic dose, based on body surface area) caused a significant increase in pseudopregnancy in the rat. A decrease in the pregnancy rate of mated female rats also occurred. There was no effect on male fertility at this dose level. The relevance of these observations to human fertility is not known. Pregnancy: Category C. Naltrexone has been shown to increase the incidence of early fetal loss when given to rats at doses���30 mg/kg/day (180 mg/m/day; 5 times the recommended therapeutic dose, based on body surface area) and to rabbits at oral doses���60 mg/kg/day (720 mg/m/day; 18 times the recommended therapeutic dose, based on body surface area). There was no evidence of teratogenicity when naltrexone was administered orally to rats and rabbits during the period of major organogenesis at doses up to 200 mg/kg/day (32 and 65 times the recommended therapeutic dose, respectively, based on body surface area). Rats do not form appreciable quantities of the major human metabolite, 6-��-naltrexol; therefore, the potential reproductive toxicity of the metabolite in rats is not known. There are no adequate and well-controlled studies in pregnant women. Naltrexone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor And Delivery: Whether or not naltrexone affects the duration of labor and delivery is unknown. Nursing Mothers: In animal studies, naltrexone and 6-��-naltrexol were excreted in the milk of lactating rats dosed orally with naltrexone. Whether or not naltrexone is excreted in human milk is unknown. Because many drugs are excreted in human milk, caution should be exercised when naltrexone is administered to a nursing woman. Pediatric Use: The safe use of naltrexone in pediatric patients younger than 18 years old has not been established. | lld:dailymed |
| dailymed-drugs:123 | dailymed-instance:precautio... | General: Totect���is a cytotoxic drug. When administered to patients receiving anthracycline-containing cytotoxic therapy, additive cytotoxicity may occur. Treatment with Totect���is associated with leukopenia, neutropenia, and thrombocytopenia. Hematological monitoring should be performed. Reversible elevations of liver enzymes may occur with dexrazoxane.<br/>Patients with Moderate or Severe Renal Insufficiency: Greater exposure to dexrazoxane may occur in patients with compromised renal function. The Totect���dose should be reduced by 50% in patients with creatinine clearance values<40 mL/min . Dimethylsulfoxide (DMSO) should not be used in patients who are receiving dexrazoxane to treat anthracycline-induced extravasation.<br/>Information for Patients: Women of who have the potential to become pregnant should be advised that Totect���might cause fetal harm.<br/>Laboratory Tests: Blood counts and liver enzymes should be monitored.<br/>Drug Interactions: None known.<br/>Carcinogenesis/Mutagenesis/Impairment of Fertility: No carcinogenicity studies have been done with Totect���in animals. The carcinogenic potential of dexrazoxane has not been investigated. Nevertheless, a study by the National Cancer Institute has reported that long term dosing with razoxane (the racemic mixture of dexrazoxane, ICRF-187, and its enantiomer ICRF-186) is associated with the development of malignancies in rats and possibly in mice. Dexrazoxane was not mutagenic to bacteria in vitro (Ames assay), but caused significant chromosomal aberrations in mammalian cells in vitro. It also increased the formation of micronucleated polychromatic erythrocytes in mice. Thus, dexrazoxane is mutagenic and clastogenic. The possible adverse effects of Totect���on the fertility of humans and experimental animals, male or female, have not been adequately studied. Testicular atrophy was seen with dexrazoxane administration at doses as low as 30 mg/kg weekly for 6 weeks in rats (about 1/5 the human dose on a mg/mbasis) and as low as 20 mg/kg weekly for 13 weeks in dogs (about half the human dose on a mg/mbasis).<br/>Pregnancy: Category D. See WARNINGS section.<br/>Labor and Delivery: The effect of dexrazoxane on labor and delivery in humans has not been studied.<br/>Nursing Mothers: It is not known whether dexrazoxane or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from dexrazoxane, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: The safety and effectiveness of Totect���in pediatric patients have not been established.<br/>Geriatric Use: In total, 21% of the patients treated with Totect���were age 65 years or older, and 9 % were 75 and older. No differences in safety or efficacy were observed between older and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function . | lld:dailymed |
| dailymed-drugs:125 | dailymed-instance:precautio... | General: As with all sympathomimetic drugs, DUO-MEDIHALER should be used with great caution in the presence of coronary insufficiency, hypertension, hyperthyroidism, and diabetes. Information for Patients: Patients who are being treated with DUO��-MEDIHALER should be informed adequately of the dangers of overusage, tolerance and rebound bronchospasm . They should be instructed to take no more than two inhalations at any one time, nor more than six in any one hour during a 24-hour period, unless advised by the physician . Isoproterenol may cause the patient's saliva to turn pinkish to red in color. Proper use of DUO-MEDIHALER oral inhaler should be demonstrated and discussed. Patient Instructions for Use are available with the package insert and should be provided when the medication is dispensed. As with any drug, patients should be advised against the ingestion of alcohol during treatment. Drug Interactions: A monoamine oxidase (MAO) inhibitor, a tricyclic antidepressant, or guanethidine may increase the cardiac and pressor effects of phenylephrine and isoproterenol; however, normal volunteers given isoproterenol by inhalation along with an MAO inhibitor or a tricyclic antidepressant had no adverse cardio��vascular effects. Arrhythmias may result from the concurrent administration of isoproterenol or phenylephrine to patients who are receiving digitalis, epinephrine, cyclopropane, or halogenated hydrocarbon anesthetics. Beta-adrenergic blocking drugs such as propranolol antagonize the cardiac, bronchodilating, and vasodilating effects of isoproterenol and the stimulating effects of phenylephrine. Ergot alkaloids may increase blood pressure in patients receiving iso��proterenol or phenylephrine. Phentolamine mesylate (Regitine), an alpha-adrenergic blocker, may decrease the pressor response to phenylephrine. Phenothiazine drugs have some alpha-adrenergic blocking activity and may reduce the pressor effects and duration of action of phenylephrine. Drug/Laboratory Test Interactions: Isoproterenol causes false elevations of bilirubin as measured in vitro by sequential multiple analyzer. An effect on serum bilirubin determinations in patients receiving the drug has not been determined. One case of surrepti��tious self-administration of a 500 mg subcutaneous dose of isopro��terenol resulted in increased urinary excretion of epinephrine, norepinephrine, and vanilmandelic acid. Isoproterenol inhalation may result in enough absorption of the drug to produce increased values for urinary epinephrine. This effect is probably small with standard doses, but is likely to increase with larger doses. Carcinogencity, Mutagenesis, and Impairment of Fertility: Isoproterenol hydrochloride, phenylephrine bitartrate, or DUO-��MEDIHALER have not been evaluated for carcinogenicity, muta��genicity or impairment of fertility. Pregnancy: Teratogenic Effects - Pregnancy Category C: Repro��duction studies have not been done with DUO-MEDIHALER or phenylephrine. Reproduction studies with isoproterenol have been performed in rats and rabbits with aerosol doses (30 minutes per day for 12 days) up to 15 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus. It is also not known whether DUO-MEDIHALER can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. DUO-MEDIHALER should be given to a pregnant woman only if clearly needed. Labor and Delivery: DUO-MEDIHALER has no recognized use during labor and delivery. Phenylephrine administration during late pregnancy or labor may cause fetal anoxia and bradycardia by increasing uterine contractility and decreasing uterine blood flow. Nursing Mothers: It is not known whether isoproterenol or phenyl��ephrine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when DUO��MEDIHALER is administered to a nursing woman. Pediatric Use: Safe and effective use of DUO-MEDIHALER in children below the age of 12 has not been established. Geriatric Use: Lower doses in elderly patients may be required due to increased sympathomimetic sensitivity . | lld:dailymed |
| dailymed-drugs:126 | dailymed-instance:precautio... | GENERAL: Blood Pressure:Because Cardene I.V. decreases peripheral resistance, monitoring of blood pressure during administration is required. Cardene I.V., like other calcium channel blockers, may occasionally produce symptomatic hypotension. Caution is advised to avoid systemic hypotension when administering the drug to patients who have sustained an acute cerebral infarction or hemorrhage. Use in Patients with Impaired Hepatic Function:Since nicardipine is metabolized in the liver, the drug should be used with caution in patients with impaired liver function or reduced hepatic blood flow. The use of lower dosages should be considered. Nicardipine administered intravenously has been reported to increase hepatic venous pressure gradient by 4 mmHg in cirrhotic patients at high doses (5 mg/20 min). Cardene I.V. should therefore be used with caution in patients with portal hypertension. Use in Patients with Impaired Renal Function:When Cardene I.V. was given to mild to moderate hypertensive patients with moderate renal impairment, a significantly lower systemic clearance and higher AUC was observed. These results are consistent with those seen after oral administration of nicardipine. Careful dose titration is advised when treating renal impaired patients.<br/>DRUG INTERACTIONS: Since Cardene I.V. may be administered to patients already being treated with other medications, including other antihypertensive agents, careful monitoring of these patients is necessary to detect and promptly treat any undesired effects from concomitant administration.<br/>BETA-BLOCKERS: In most patients, Cardene I.V. can safely be used concomitantly with beta-blockers. However, caution should be exercised when using Cardene I.V. in combination with a beta-blocker in congestive heart failure patients (see���Warnings���).<br/>CIMETIDINE: Cimetidine has been shown to increase nicardipine plasma concentrations with Cardene capsule administration. Patients receiving the two drugs concomitantly should be carefully monitored. Data with other histamine-2 antagonists are not available.<br/>DIGOXIN: Studies have shown that Cardene capsules usually do not alter digoxin plasma concentrations. However, as a precaution, digoxin levels should be evaluated when concomitant therapy with Cardene I.V. is initiated.<br/>FENTANYL ANESTHESIA: Hypotension has been reported during fentanyl anesthesia with concomitant use of a beta-blocker and a calcium channel blocker. Even though such interactions were not seen during clinical studies with Cardene I.V. (nicardipine hydrochloride), an increased volume of circulating fluids might be required if such an interaction were to occur.<br/>CYCLOSPORINE: Concomitant administration of Cardene capsules and cyclosporine results in elevated plasma cyclosporine levels. Plasma concentrations of cyclosporine should therefore be closely monitored during Cardene I.V. administration, and the dose of cyclosporine reduced accordingly.<br/>IN VITRO INTERACTION: The plasma protein binding of nicardipine was not altered when therapeutic concentrations of furosemide, propranolol, dipyridamole, warfarin, quinidine, or naproxen were added to human plasma in vitro.<br/>CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: Rats treated with nicardipine in the diet (at concentrations calculated to provide daily dosage levels of 5, 15, or 45 mg/kg/day) for two years showed a dose-dependent increase in thyroid hyperplasia and neoplasia (follicular adenoma/carcinoma). One- and three-month studies in the rat have suggested that these results are linked to a nicardipine-induced reduction in plasma thyroxine (T4) levels with a consequent increase in plasma levels of thyroid stimulating hormone (TSH). Chronic elevation of TSH is known to cause hyperstimulation of the thyroid. In rats on an iodine deficient diet, nicardipine administration for one month was associated with thyroid hyperplasia that was prevented by T4 supplementation. Mice treated with nicardipine in the diet (at concentrations calculated to provide daily dosage levels of up to 100 mg/kg/day) for up to 18 months showed no evidence of neoplasia of any tissue and no evidence of thyroid changes. There was no evidence of thyroid pathology in dogs treated with up to 25 mg nicardipine/kg/day for one year and no evidence of effects of nicardipine on thyroid function (plasma T4 and TSH) in man. There was no evidence of a mutagenic potential of nicardipine in a battery of genotoxicity tests conducted on microbial indicator organisms, in micronucleus tests in mice and hamsters, or in a sister chromatid exchange study in hamsters. No impairment of fertility was seen in male or female rats administered nicardipine at oral doses as high as 100 mg/kg/day (50 times the 40 mg TlD maximum recommended dose in man, assuming a patient weightof 60 kg).<br/>Pregnancy Category C: Cardene' I.V. at doses up to 5 mg/kg/day to pregnant rats and up to 0.5 mg/kg/day to pregnant rabbits produced no embryotoxicity or teratogenicity. Embryotoxicity was seen at 10 mg/kg/day in rats and at 1 mg/kg/day in rabbits, but no teratogenicity was observed at these doses. Nicardipine was embryocidal when administered orally to pregnant Japanese White rabbits, during organogenesis, at 150 mg/kg/day (a dose associated with marked body weight gain suppression in the treated doe), but not at 50 mg/kg/day (25 times the maximum recommended dose in man). No adverse effects on the fetus were observed when New Zealand albino rabbits were treated, during organogenesis, with up to 100 mg nicardipine/kg/day (a dose associated with significant mortality in the treated doe). In pregnant rats administered nicardipine orally at up to 100 mg/kg/day (50 times the maximum recommended human dose) there was no evidence of embryolethality or teratogenicity. However, dystocia, reduced birth weights, reduced neonatal survival, and reduced neonatal weight gain were noted. There are no adequate and well-controlled studies in pregnant women. Cardene should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>NURSING MOTHERS: Studies in rats have shown significant concentrations of nicardipine in maternal milk. For this reason, it is recommended that women who wish to breastfeed should not be given this drug.<br/>PEDIATRIC USE: Safety and efficacy in patients under the age of 18 have not been established.<br/>USE IN THE ELDERLY: No significant difference has been observed in the antihypertensive effect of Cardene I.V. in elderly patients (���65 years) compared with other adult patients in clinical studies. | lld:dailymed |
| dailymed-drugs:128 | dailymed-instance:precautio... | In patients with depression, a possibility for suicide should be borne in mind; benzodiazepines should not be used in such patients without adequate anti-depressant therapy. Lorazepam should be used with caution in patients with compromised respiratory function (e.g. COPD, sleep apnea syndrome). Elderly or debilitated patients may be more susceptible to the sedative effects of lorazepam. Therefore, these patients should be monitored frequently and have their dosage adjusted carefully according to patient response; the initial dosage should not exceed 2 mg. Paradoxical reactions have been occasionally reported during benzodiazepine use. Such reactions may be more likely to occur in children and the elderly. Should these occur, use of the drug should be discontinued. The usual precautions for treating patients with impaired renal or hepatic function should be observed. As with all benzodiazepines, the use of lorazepam may worsen hepatic encephalopathy; therefore, lorazepam should be used with caution in patients with severe hepatic insufficiency and/or encephalopathy. Dosage for patients with severe hepatic insufficiency should be adjusted carefullyaccording to patient response; lower doses may be sufficient in such patients. In patients where gastrointestinal or cardiovascular disorders coexist with anxiety, it should be noted that lorazepam has not been shown to be of significant benefit in treating the gastrointestinal or cardiovascular component. Esophageal dilation occurred in rats treated with lorazepam for more than one year at 6 mg/kg/day. The no-effect dose was 1.25 mg/kg/day (approximately 6 times the maximum human therapeutic dose of 10 mg per day). The effect was reversible only when the treatment was withdrawn within two months of first observation of the phenomenon. The clinical significance of this is unknown. However, use of lorazepam for prolonged periods and in geriatric patients requires caution, and there should be frequent monitoring for symptoms of upper G.I. disease. Safety and effectiveness of Ativan (lorazepam) in children of less than 12 years have not been established.<br/>Information for Patients: To assure the safe and effective use of Ativan (lorazepam), patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is advisable that they consult with their physician before either increasing the dose or abruptly discontinuing this drug.<br/>Essential Laboratory Tests: Some patients on Ativan (lorazepam) have developed leukopenia, and some have had elevations of LDH. As with other benzodiazepines, periodic blood counts and liver-function tests are recommended for patients on long-term therapy.<br/>Clinically Significant Drug Interactions: The benzodiazepines, including Ativan (lorazepam), produce increased CNS-depressant effects when administered with other CNS depressants such as alcohol, barbiturates, antipsychotics, sedative/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants, and anesthetics. Concomitant use of clozapine and lorazepam may produce marked sedation, excessive salivation, hypotension, ataxia, delirium, and respiratory arrest. Concurrent administration of lorazepam with valproate results in increased plasma concentrations and reduced clearance of lorazepam. Lorazepam dosage should be reduced to approximately 50% when coadministered with valproate. Concurrent administration of lorazepam with probenecid may results in a more rapid onset or prolonged effect of lorazepam due to increased half-life and decreased total clearance. Lorazepam dosage needs to be reduced by approximately 50% when coadministered with probenecid. The effects of probenecid and valproate on lorazepam may be due to inhibition of glucuronidation. Administration of theophylline or aminophylline may reduce the sedative effects of benzodiazepines, including lorazepam.<br/>Carcinogenesis and Mutagenesis: No evidence of carcinogenic potential emerged in rats during an 18-month study with Ativan (lorazepam). No studies regarding mutagenesis have been performed.<br/>Pregnancy: Reproductive studies in animals were performed in mice, rats, and two strains of rabbits. Occasional anomalies (reduction of tarsals, tibia, metatarsals, malrotated limbs, gastroschisis, malformed skull, and microphthalmia) were seen in drug-treated rabbits without relationship to dosage. Although all of these anomalies were not present in the concurrent control group, they have been reported to occur randomly in historical controls. At doses of 40 mg/kg and higher, there was evidence of fetal resorption and increased fetal loss in rabbits which was not seen at lower doses. The clinical significance of the above findings is not known. However, an increased risk of congenital malformations associated with the use of minor tranquilizers (chlordiazepoxide, diazepam, and meprobamate) during the first trimester of pregnancy has been suggested in several studies. Because the use of these drugs is rarely a matter of urgency, the use of lorazepam during this period should be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant, they should communicate with their physician about the desirability of discontinuing the drug. In humans, blood levels obtained from umbilical cord blood indicate placental transfer of lorazepam and lorazepam glucuronide. Infants of mothers who ingested benzodiazepines for several weeks or more preceding delivery have been reported to havewithdrawal symptoms during the postnatal period. Symptoms such as hypoactivity, hypotonia, hypothermia, respiratory depression, apnea, feeding problems, and impaired metabolic response to cold stress have been reported in neonates born of mothers who have received benzodiazepines during the late phase of pregnancy or at delivery.<br/>Nursing Mothers: Lorazepam has been detected in human breast milk; therefore, it should not be administered to breast-feeding women, unless the expected benefit to the woman outweighs the potential risk to the infant. Sedation and inability to suckle have occurred in neonates of lactating mothers taking benzodiazepines. Infants of lactating mothers should be observed for pharmacological effects (including sedation and irritability).<br/>Geriatric Use: Clinical studies of Ativan generally were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects; however, the incidence of sedation and unsteadiness was observed to increase with age . Age does not appear to have a significant effect on lorazepam kinetics . Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered. Greater sensitivity (e.g., sedation) of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious, and lower doses may be sufficient in these patients . | lld:dailymed |
| dailymed-drugs:129 | dailymed-instance:precautio... | General: ERTACZO Cream, 2%, is for use on the skin only. If irritation or sensitivity develops with the use of ERTACZO Cream, 2%, treatment should be discontinued and appropriate therapy instituted. Diagnosis of the disease should be confirmed either by direct microscopic examination of infected superficial epidermal tissue in a solution of potassium hydroxide or by culture on an appropriate medium. Physicians should exercise caution when prescribing ERTACZO Cream, 2%, to patients known to be sensitive to imidazole antifungals, since cross-reactivity may occur. Information for Patients: The patient should be instructed to: Drug/Laboratory Test Interactions: Potential interactions between ERTACZO Cream, 2%, and other drugs or laboratory tests have not been systematically evaluated. Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies to evaluate the carcinogenic potential of sertaconazole nitrate have not been conducted. No clastogenic potential was observed in a mouse micronucleus test. Sertaconazole nitrate was considered negative for sister chromatid exchange (SCE) in the in vivo mouse bone marrow SCE assay. There was no evidence that sertaconazole nitrate induced unscheduled DNA synthesis in rat primary hepatocyte cultures. Sertaconazole nitrate exhibited no toxicity or adverse effects on reproductive performance or fertility of male or female rats given up to 60 mg/kg/day orally by gastric intubation (16 times the maximum recommended human dose based on a body surface area comparison). Pregnancy: Teratogenic Effects. Pregnancy Category C: Oral reproduction studies in rats and rabbits did not produce any evidence of maternal toxicity, embryotoxicity or teratogenicity of sertaconazole nitrate at an oral dose of 160 mg/kg/day (40 times (rats) and 80 times (rabbits) the maximum recommended human dose on a body surface area comparison). In an oral peri-postnatal study in rats, a reduction in live birth indices and an increase in the number of still-born pups was seen at 80 and 160 mg/kg/day. There are no adequate and well-controlled studies that have been conducted on topically applied ERTACZO Cream, 2%, in pregnant women. Because animal reproduction studies are not always predictive of human response, ERTACZO Cream, 2%, should be used during pregnancy only if clearly needed. Nursing Mothers: It is not known if sertaconazole is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when prescribing ERTACZO Cream, 2%, to a nursing woman. Pediatric Use: The efficacy and safety of ERTACZO Cream, 2%, have not been established in pediatric patients below the age of 12 years. Geriatric Use: Clinical studies of ERTACZO Cream, 2%, did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. | lld:dailymed |
| dailymed-drugs:131 | dailymed-instance:precautio... | General: If a reaction suggesting sensitivity or chemical irritation should occur, use of the medication should be discontinued. Hepatitis (1:10,000 reported incidence) and, at high doses, lowered testosterone and ACTH induced corticosteroid serum levels have been seen with orally administered ketoconazole; these effects have not been seen with topical ketoconazole.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: A long-term feeding study in Swiss Albino mice and in Wistar rats showed no evidence of oncogenic activity. The dominant lethal mutation test in male and female mice revealed that single oral doses of ketoconazole as high as 80 mg/kg produced no mutation in any stage of germ cell development. The Ames'Salmonella microsomal activator assay was also negative.<br/>Pregnancy:<br/>Teratogenic effects:<br/>Nursing Mothers: It is not known whether ketoconazole cream, 2% administered topically could result in sufficient systemic absorption to produce detectable quantities in breast milk. Nevertheless, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in children have not been established. | lld:dailymed |
| dailymed-drugs:132 | dailymed-instance:precautio... | Impaired Renal or Hepatic Function: Beta-blocking agents should be used with caution in patients with impaired hepatic or renal function. Poor renal function has only minor effects on Visken (pindolol) clearance, but poor hepatic function may cause blood levels of Visken (pindolol) to increase substantially.<br/>Information for Patients: Patients, especially those with evidence of coronary artery insufficiency, should be warned against interruption or discontinuation of Visken (pindolol) therapy without the physician's advice. Although cardiac failure rarely occurs in properly selected patients, patients being treated with beta-adrenergic blocking agents should be advised to consult the physician at the first sign or symptom of impending failure.<br/>Drug Interactions: Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients receiving Visken (pindolol) plus a catecholamine-depleting agent should, therefore, be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope, or postural hypotension. Visken (pindolol) has been used with a variety of antihypertensive agents, including hydrochlorothiazide, hydralazine, and guanethidine without unexpected adverse interactions. Visken (pindolol) has been shown to increase serum thioridazine levels when both drugs are co-administered. Visken (pindolol) levels may also be increased with this combination.<br/>Risk of Anaphylactic Reaction:: While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In chronic oral toxicologic studies (1-2 years) in mice, rats, and dogs, Visken (pindolol) did not produce any significant toxic effects. In 2-year oral carcinogenicity studies in rats and mice in doses as high as 59 mg/kg/day and 124 mg/kg/day (50 and 100 times the maximum recommended human dose), respectively, Visken (pindolol) did not produce any neoplastic, preneoplastic, or nonneoplastic pathologic lesions. In fertility and general reproductive performance studies in rats, Visken (pindolol) caused no adverse effects at a dose of 10 mg/kg. In the male fertility and general reproductive performance test in rats, definite toxicity characterized by mortality and decreased weight gain was observed in the group given 100 mg/kg/day. At 30 mg/kg/day, decreased mating was associated with testicular atrophy and/or decreased spermatogenesis. This response is not clearly drug related, however, as there was no dose response relationship within this experiment and no similar effect on testes of rats administered Visken (pindolol) as a dietary admixture for 104 weeks. There appeared to be an increase in prenatal mortality in males given 100 mg/kg but development of offspring was not impaired. In females administered Visken (pindolol) prior to mating through day 21 of lactation, mating behavior was decreased at 100 mg/kg and 30 mg/kg. At these dosages there also was increased mortality of offspring. Prenatal mortality was increased at 10 mg/kg but there was not a clear dose response relationshipin this experiment. There was an increased resorption rate at 100 mg/kg observed in females necropsied on the 15th day of gestation.<br/>Pregnancy:<br/>Category B:: Studies in rats and rabbits exceeding 100 times the maximum recommended human doses, revealed no embryotoxicity or teratogenicity. Since there are no adequate and well-controlled studies in pregnant women, and since animal reproduction studies are not always predictive of human response, Visken (pindolol), as with any drug, should be employed during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: Since Visken (pindolol) is secreted in human milk, nursing should not be undertaken by mothers receiving the drug.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established. | lld:dailymed |
| dailymed-drugs:134 | dailymed-instance:precautio... | General:<br/>Information for Patients:<br/>Phenylketonurics: ZANTAC 25 EFFERdose Tablets contain phenylalanine 2.81 mg per 25 mg of ranitidine. ZANTAC EFFERdose Tablets should not be chewed, swallowed whole, or dissolved on the tongue.<br/>Laboratory Tests: False-positive tests for urine protein with MULTISTIX may occur during ZANTAC therapy, and therefore testing with sulfosalicylic acid is recommended.<br/>Drug Interactions: Ranitidine has the potential to affect the absorption, metabolism, or renal excretion of other drugs. The altered pharmacokinetics may necessitate dosage adjustment of the affected drug or discontinuation of ranitidine. Interactions may occur by several mechanisms including: Inhibition of Cytochrome P450-linked Mixed Function Oxygenase System: Ranitidine at usual therapeutic doses does not potentiate the actions of drugs which are inactivated by this enzyme system such as diazepam, lidocaine, phenytoin, propranolol, and theophylline. There have been reports of altered prothrombin time with coumarin anticoagulants (e.g., warfarin). Due to the narrow therapeutic index, close monitoring of increased or decreased prothrombin time is recommended during concurrent treatment with ranitidine. Competition for Renal Tubular Secretion: Since ranitidine is partially eliminated by the cationic system, it may affect the clearance of other drugs eliminated by this route. High doses of ranitidine (such as those used in the treatment of Zollinger-Ellison syndrome) may reduce the excretion of procainamide and N-acetylprocainamide resulting in increased plasma levels of these drugs. Alteration of Gastric pH: The bioavailability of certain drugs may be affected. This can result in either an increase in absorption (e.g., triazolam, midazolam) or a decrease in absorption (e.g., ketoconazole, atazanavir, glipizide, delaviridine, gefitnib). In a ranitidine-triazolam drug-drug interaction study, triazolam plasma concentrations were higher during b.i.d. dosing of ranitidine than triazolam given alone. The mean area under the triazolam concentration-time curve (AUC) values in 18- to 60-year-old subjects were 10% and 28% higher following administration of 75-mg and 150-mg ranitidine tablets, respectively, than triazolam given alone. In subjects older than 60 years of age, the mean AUC values were approximately 30% higher following administration of 75-mg and 150-mg ranitidine tablets. It appears that there were no changes in pharmacokinetics of triazolam and��-hydroxytriazolam, a major metabolite, and in their elimination. Reduced gastric acidity due to ranitidine may have resulted in an increase in the availability of triazolam. The clinical significance of this triazolam and ranitidine pharmacokinetic interaction is unknown.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: There was no indication of tumorigenic or carcinogenic effects in life-span studies in mice and rats at dosages up to 2,000 mg/kg per day. Ranitidine was not mutagenic in standard bacterial tests (Salmonella, Escherichia coli) for mutagenicity at concentrations up to the maximum recommended for these assays. In a dominant lethal assay, a single oral dose of 1,000 mg/kg to male rats was without effect on the outcome of 2 matings per week for the next 9 weeks.<br/>Pregnancy:<br/>Teratogenic Effects:: Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses up to 160 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to ZANTAC. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.<br/>Nursing Mothers: ZANTAC is secreted in human milk. Caution should be exercised when ZANTAC is administered to a nursing mother.<br/>Pediatric Use: The safety and effectiveness of ZANTAC have been established in the age-group of 1 month to 16 years for the treatment of duodenal and gastric ulcers, gastroesophageal reflux disease and erosive esophagitis, and the maintenance of healed duodenal and gastric ulcer. Use of ZANTAC in this age-group is supported by adequate and well-controlled studies in adults, as well as additional pharmacokinetic data in pediatric patients and an analysis of the published literature (see CLINICAL PHARMACOLOGY: Pediatrics and DOSAGE AND ADMINISTRATION: Pediatric Use). Safety and effectiveness in pediatric patients for the treatment of pathological hypersecretory conditions or the maintenance of healing of erosive esophagitis have not been established. Safety and effectiveness in neonates (less than 1 month of age) have not been established (see CLINICAL PHARMACOLOGY: Pediatrics).<br/>Geriatric Use: Of the total number of subjects enrolled in US and foreign controlled clinical trials of oral formulations of ZANTAC, for which there were subgroup analyses, 4,197 were 65 and over, while 899 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, caution should be exercised in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Geriatrics and DOSAGE AND ADMINISTRATION: Dosage Adjustment for Patients With Impaired Renal Function). | lld:dailymed |
| dailymed-drugs:135 | dailymed-instance:precautio... | General: Symptomatic response to therapy with pantoprazole does not preclude the presence of gastric malignancy. Owing to the chronic nature of erosive esophagitis, there may be a potential for prolonged administration of pantoprazole. In long-term rodent studies, pantoprazole was carcinogenic and caused rare types of gastrointestinal tumors. The relevance of these findings to tumor development in humans is unknown. Generally, daily treatment with any acid-suppressing medications over a long period of time (eg, longer than 3 years) may lead to malabsorption of cyanocobalamin (Vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This possibility should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed. Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with pantoprazole, particularly in patients who were H. pylori positive.<br/>Information for Patients: Patients should be cautioned that PROTONIX Delayed-Release Tablets SHOULD NOT BE SPLIT, CRUSHED, OR CHEWED. PROTONIX Delayed-Release Tablets should be swallowed whole, with or without food in the stomach. Concomitant administration of antacids does not affect the absorption of PROTONIX Delayed-Release Tablets. (See the Dosage and Administration Section, Administration Options subsection)<br/>Drug Interactions: Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and to a minor extent the CYP3A4 isozymes, and subsequently undergoes Phase II conjugation (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions). Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol),metoprolol, nifedipine, phenytoin, warfarin (see below), midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time inpatients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Concomitant use of atazanavir and proton pump inhibitors is not recommended. Coadministration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and thereby reduce its therapeutic effect. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts).<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 24-month carcinogenicity study, Sprague-Dawley rats were treated orally with doses of 0.5 to 200 mg/kg/day, about 0.1 to 40 times the exposure on a body surface area basis of a 50-kg person dosed at 40 mg/day. In the gastric fundus, treatment at 0.5 to 200 mg/kg/day produced enterochromaffin-like (ECL) cell hyperplasia and benign and malignant neuroendocrine cell tumors in a dose-related manner. In the forestomach, treatment at 50 and 200 mg/kg/day (about 10 and 40 times the recommended human dose on a body surface area basis) produced benign squamous cell papillomas and malignant squamous cell carcinomas. Rare gastrointestinal tumors associated with pantoprazole treatment included an adenocarcinoma of the duodenum at 50 mg/kg/day, and benign polyps and adenocarcinomas of the gastric fundus at 200 mg/kg/day. In the liver, treatment at 0.5 to 200 mg/kg/day produced dose-related increases in the incidences of hepatocellular adenomas and carcinomas. In the thyroid gland, treatment at 200 mg/kg/day produced increased incidences of follicular cell adenomas and carcinomas for both male and female rats. Sporadic occurrences of hepatocellular adenomas and a hepatocellular carcinoma were observed in Sprague-Dawley rats exposed to pantoprazole in 6-month and 12-month toxicity studies. In a 24-month carcinogenicity study, Fischer 344 rats were treated orally with doses of 5 to 50 mg/kg/day, approximately 1 to 10 times the recommended human dose based on body surface area. In the gastric fundus, treatment at 5 to 50 mg/kg/day produced enterochromaffin-like (ECL) cell hyperplasia and benign and malignant neuroendocrine cell tumors. Dose selection for this study may not have been adequate to comprehensively evaluate the carcinogenic potential of pantoprazole. In a 24-month carcinogenicity study, B6C3F1 mice were treated orally with doses of 5 to 150 mg/kg/day, 0.5 to 15 times the recommended human dose based on body surface area. In the liver, treatment at 150 mg/kg/day produced increased incidences of hepatocellular adenomas and carcinomas in female mice. Treatment at 5 to 150 mg/kg/day also produced gastric fundic ECL cell hyperplasia. A 26-week p53 +/- transgenic mouse carcinogenicity study was not positive. Pantoprazole was positive in the in vitro human lymphocyte chromosomal aberration assays, in one of two mouse micronucleus tests for clastogenic effects, and in the in vitro Chinese hamster ovarian cell/HGPRT forward mutation assay for mutagenic effects. Equivocal results were observed in the in vivo rat liver DNA covalent binding assay. Pantoprazole was negative in the in vitro Ames mutation assay, the in vitro unscheduled DNA synthesis (UDS) assay with rat hepatocytes, the in vitro AS52/GPT mammalian cell-forward gene mutation assay, the in vitro thymidine kinase mutation test with mouse lymphoma L5178Y cells, and the in vivo rat bone marrow cell chromosomal aberration assay. Pantoprazole at oral doses up to 500 mg/kg/day in male rats (98 times the recommended human dose based on body surface area) and 450 mg/kg/day in female rats (88 times the recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: Pantoprazole and its metabolites are excreted in the milk of rats. Pantoprazole excretion in human milk has been detected in a study of a single nursing mother after a single 40 mg oral dose. The clinical relevance of this finding is not known. Many drugs which are excreted in human milk have a potential for serious adverse reactions in nursing infants.Based on the potential for tumorigenicity shown for pantoprazole in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the benefit of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.<br/>Use in Women: Erosive esophagitis healing rates in the 221 women treated with PROTONIX Delayed-Release Tablets in U.S. clinical trials were similar to those found in men. In the 122 women treated long-term with PROTONIX 40 mg or 20 mg, healing was maintained at a rate similar to that in men. The incidence rates of adverse events were also similar for men and women.<br/>Use in Elderly: In short-term U.S. clinical trials, erosive esophagitis healing rates in the 107 elderly patients (���65 years old) treated with PROTONIX were similar to those found in patients under the age of 65. The incidence rates of adverse events and laboratory abnormalities in patients aged 65 years and older were similar to those associated with patients younger than 65 years of age.<br/>Laboratory Tests: There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | lld:dailymed |
| dailymed-drugs:136 | dailymed-instance:precautio... | General:<br/>Suicide: As with other psychotropic medications, the usual precautions with respect to administration of the drug and size of the prescription are indicated for severely depressed patients or those in whom there is reason to expect concealed suicidal ideation or plans. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients.<br/>Mania: Episodes of hypomania and mania have been reported in association with the use of alprazolam tablets in patients with depression.<br/>Uricosuric Effect: Alprazolam has a weak uricosuric effect. Although other medications with weak uricosuric effect have been reported to cause acute renal failure, there have been no reported instances of acute renal failure attributable to therapy with alprazolam.<br/>Use in Patients with Concomitant Illness: It is recommended that the dosage be limited to the smallest effective dose to preclude the development of ataxia or oversedation which may be a particular problem in elderly or debilitated patients . The usual precautions in treating patients with impaired renal, hepatic, or pulmonary function should be observed. There have been rare reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam tablets. Adecreased systemic alprazolam elimination rate (e.g., increased plasma half-life) has been observed in both alcoholic liver disease patients and obese patients receiving alprazolam tablets .<br/>Information for Patients:: To assure safe and effective use of alprazolam extended-release tablets, the physician should provide the patient with the following guidance.<br/>Laboratory Tests: Laboratory tests are not ordinarily required in otherwise healthy patients. However, when treatment is protracted, periodic blood counts, urinalysis, and blood chemistry analyses are advisable in keeping with good medical practice.<br/>Drug Interactions::<br/>Use with Other CNS Depressants: If alprazolam extended-release tablets are to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed, particularly with compounds which might potentiate the action of benzodiazepines. The benzodiazepines, including alprazolam, produce additive CNS depressant effects when co-administered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS depression.<br/>Use with Imipramine and Desipramine: The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of alprazolam tablets in doses up to 4 mg/day. The clinical significance of these changes is unknown.<br/>Drugs that inhibit alprazolam metabolism via cytochrome P450 3A: The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam . Drugs demonstrated to be CYP3A inhibitors of possible clinical significance on the basis of clinical studies involving alprazolam (caution is recommended during co-administration with alprazolam) Fluoxetine: Co-administration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased half-life by 17%, and decreased measured psychomotor performance. Propoxyphene: Co-administration of propoxyphene decreased the maximum plasma concentration of alprazolam by 6%, decreased clearance by 38%, and increased half-life by 58%. Oral Contraceptives: Co-administration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased half-life by 29%. Drugs and other substances demonstrated to be CYP3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to alprazolam or on the basis of in vitro studies with alprazolam or other benzodiazepines (caution is recommended during co-administration with alprazolam) Available data from clinical studies of benzodiazepines other than alprazolam suggest a possible drug interaction with alprazolam for the following: diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin, and grapefruit juice. Data from in vitro studies of alprazolam suggest a possible drug interaction with alprazolam for the following: sertraline and paroxetine. However, data from an in vivo drug interaction study involving a single dose of alprazolam 1 mg and steady state doses of sertraline (50 to 150 mg/day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. Data from in vitro studies of benzodiazepines other than alprazolam suggest a possible drug interaction for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. Caution is recommended during the co-administration of any of these with alprazolam .<br/>Drugs demonstrated to be inducers of CYP3A: Carbamazepine can increase alprazolam metabolism and therefore can decrease plasma levels of alprazolam.<br/>Drug/Laboratory Test Interactions: Although interactions between benzodiazepines and commonly employed clinical laboratory tests have occasionally been reported, there is no consistent pattern for a specific drug or specific test.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of carcinogenic potential was observed during 2-year bioassay studies of alprazolam in rats at doses up to 30 mg/kg/day (150 times the maximum recommended daily human dose of 10 mg/day) and in mice at doses up to 10 mg/kg/day (50 times the maximum recommended daily human dose). Alprazolam was not mutagenic in the rat micronucleus test at doses up to 100 mg/kg, which is 500 times the maximum recommended daily human dose of 10 mg/day. Alprazolam also was not mutagenic in vitro in the DNA Damage/Alkaline Elution Assay or the Ames Assay. Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg/day, which is 25 times the maximum recommended daily human dose of 10 mg/day.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category D: .<br/>Nonteratogenic Effects: It should be considered that the child born of a mother who is receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines.<br/>Labor and Delivery: Alprazolam has no established use in labor or delivery.<br/>Nursing Mothers: Benzodiazepines are known to be excreted in human milk. It should be assumed that alprazolam is as well. Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight. As a general rule, nursing should not be undertaken by mothers who must use alprazolam.<br/>Pediatric Use: Safety and effectiveness of alprazolam in individuals below 18 years of age have not been established.<br/>Geriatric Use: The elderly may be more sensitive to the effects of benzodiazepines. They exhibit higher plasma alprazolam concentrations due to reduced clearance of the drug as compared with a younger population receiving the same doses. The smallest effective dose of alprazolam should be used in the elderly to preclude the development of ataxia and oversedation . | lld:dailymed |
| dailymed-drugs:137 | dailymed-instance:precautio... | General:<br/>Activation of Mania/Hypomania: During premarketing testing, hypomania or mania occurred in approximately 1.0% of unipolar patients treated with paroxetine compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. In a subset of patients classified as bipolar, the rate of manic episodes was 2.2% for paroxetine and 11.6% for the combined active-control groups. As with all drugs effective in the treatment of major depressive disorder, paroxetine should be used cautiously in patients with a history of mania.<br/>Seizures: During premarketing testing, seizures occurred in 0.1% of patients treated with paroxetine, a rate similar to that associated with other drugs effective in the treatment of major depressive disorder. Paroxetine should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures.<br/>Discontinuation of Treatment With Paroxetine: Recent clinical trials supporting the various approved indications for paroxetine employed a taper-phase regimen, rather than an abrupt discontinuation of treatment. The taper-phase regimen used in GAD clinical trials involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before treatment was stopped. With this regimen in those studies, the following adverse events were reported at an incidence of 2% or greater for paroxetine and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness. In the majority of patients, these events were mild to moderate and were self-limiting and did not require medical intervention. During marketing of paroxetine and other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring, upon the discontinuation of these drugs (particularly when abrupt), including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. Whilethese events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with paroxetine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION). See also PRECAUTIONS���Pediatric Use, for adverse events reported upon discontinuation of treatment with paroxetine in pediatric patients.<br/>Akathisia: The use of paroxetine or other SSRIs has been associated with the development of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation such as an inability to sit or stand still usually associated with subjective distress. This is most likely to occur within the first few weeks of treatment.<br/>Hyponatremia: Several cases of hyponatremia have been reported. The hyponatremia appeared to be reversible when paroxetine was discontinued. The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume depleted.<br/>Abnormal Bleeding: Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic agents that interfere with serotonin reuptake. Subsequent epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In 2 studies, concurrent use of a nonsteroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding (see Drug Interactions). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding associated with the concomitant use of paroxetine with NSAIDs, aspirin, or other drugs that affect coagulation.<br/>Use in Patients With Concomitant Illness: Clinical experience with paroxetine in patients with certain concomitant systemic illness is limited. Caution is advisable in using paroxetine in patients with diseases or conditions that could affect metabolism or hemodynamic responses. As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with paroxetine. A few cases of acute angle closure glaucoma associated with paroxetine therapy have been reported in the literature. As mydriasis can cause acute angle closure in patients with narrow angle glaucoma, caution should be used when paroxetine is prescribed for patients with narrow angle glaucoma. Paroxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product's premarket testing. Evaluation of electrocardiograms of 682 patients who received paroxetine in double-blind, placebo-controlled trials, however, did not indicate that paroxetine is associated with the development of significant ECG abnormalities. Similarly, paroxetine does not cause any clinically important changes in heart rate or blood pressure. Increased plasma concentrations of paroxetine occur in patients with severe renal impairment (creatinine clearance<30 mL/min.) or severe hepatic impairment. A lower starting dose should be used in such patients (see DOSAGE AND ADMINISTRATION).<br/>Information for Patients: Paroxetine tablets USP should not be chewed or crushed, and should be swallowed whole. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of paroxetine and triptans, tramadol, or other serotonergic agents. Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with paroxetine and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions" is available for paroxetine tablets USP. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking paroxetine tablets USP.<br/>Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presentingsymptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.<br/>Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.): Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.<br/>Interference With Cognitive and Motor Performance: Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies paroxetine has not been shown to impair psychomotor performance, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with paroxetine does not affect their ability to engage in such activities.<br/>Completing Course of Therapy: While patients may notice improvement with treatment with paroxetine in 1 to 4 weeks, they should be advised to continue therapy as directed.<br/>Concomitant Medication: Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.<br/>Alcohol: Although paroxetine has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine.<br/>Pregnancy: Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. (See WARNINGS���Usage in Pregnancy: Teratogenic and Nonteratogenic Effects).<br/>Nursing: Patients should be advised to notify their physician if they are breast-feeding an infant (see PRECAUTIONS���Nursing Mothers).<br/>Laboratory Tests: There are no specific laboratory tests recommended.<br/>Drug Interactions:<br/>Tryptophan: As with other serotonin reuptake inhibitors, an interaction between paroxetine and tryptophan may occur when they are coadministered. Adverse experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been reported when tryptophan was administered to patients taking paroxetine. Consequently, concomitant use of paroxetine with tryptophan is not recommended (see WARNINGS���Serotonin Syndrome).<br/>Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.<br/>Pimozide: In a controlled study of healthy volunteers, after paroxetine was titrated to 60 mg daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and Cof 62%, compared to pimozide administered alone. Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and paroxetine is contraindicated (see CONTRAINDICATIONS).<br/>Serotonergic Drugs: Based on the mechanism of action of paroxetine hydrochloride and the potential for serotonin syndrome, caution is advised when paroxetine is coadministered with other drugs or agents that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John's Wort (see WARNINGS���Serotonin Syndrome). The concomitant use of paroxetine with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS���Drug Interactions, Tryptophan).<br/>Thioridazine: See CONTRAINDICATIONS and WARNINGS.<br/>Warfarin: Preliminary data suggest that there may be a pharmacodynamic interaction (that causes an increased bleeding diathesis in the face of unaltered prothrombin time) between paroxetine and warfarin. Since there is little clinical experience, the concomitant administration of paroxetine and warfarin should be undertaken with caution (see Drugs That Interfere With Hemostasis).<br/>Triptans: There have been rare postmarketing reports of serotonin syndrome with the use of an SSRI and a triptan. If concomitant use of paroxetine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS���Serotonin Syndrome).<br/>Drugs Affecting Hepatic Metabolism: The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.<br/>Cimetidine: Cimetidine inhibits many cytochrome P(oxidative) enzymes. In a study where paroxetine (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during coadministration with oral cimetidine (300 mg three times daily) for the final week. Therefore, when these drugs are administered concurrently, dosage adjustment of paroxetine after the 20-mg starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine's pharmacokinetics was not studied.<br/>Phenobarbital: Phenobarbital induces many cytochrome P(oxidative) enzymes. When a single oral 30-mg dose of paroxetine was administered at phenobarbital steady state (100 mg once daily for 14 days), paroxetine AUC and T��were reduced (by an average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. Since paroxetine exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustment of paroxetine is considered necessary when coadministered with phenobarbital; any subsequent adjustment should be guided by clinical effect.<br/>Phenytoin: When a single oral 30-mg dose of paroxetine was administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and T��were reduced (by an average of 50% and 35%, respectively) compared to paroxetine administered alone. In a separate study, when a single oral 300-mg dose of phenytoin was administered at paroxetine steady state (30 mg once daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustments are considered necessary when these drugs are coadministered; any subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS���Postmarketing Reports).<br/>Drugs Metabolized by CYP2D6: Many drugs, including most drugs effective in the treatment of major depressive disorder (paroxetine, other SSRIs and many tricyclics), are metabolized by the cytochrome Pisozyme CYP2D6. Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients (>90%), this CYP2D6 isozyme is saturated early during dosing with paroxetine. In 1 study, daily dosing of paroxetine (20 mg once daily) under steady-state conditions increased single dose desipramine (100 mg) C, AUC, and Tby an average of approximately 2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, andincreased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine Cvalues that were 3- to 4-fold greater than when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be initiated at a reduced dose when it is given with paroxetine. Concomitant use of paroxetine with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either paroxetine or the other drug. Therefore, coadministration of paroxetine with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution. However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be coadministered (see CONTRAINDICATIONS and WARNINGS). At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by alternative Pisozymes that, unlike CYP2D6, show no evidence of saturation (see PRECAUTIONS���Tricyclic Antidepressants).<br/>Drugs Metabolized by Cytochrome CYP3A4: An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine. Based on the assumption that the relationship between paroxetine's in vitro Kand its lack of effect on terfenadine's in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine's extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.<br/>Tricyclic Antidepressants (TCAs): Caution is indicated in the coadministration of tricyclic antidepressants (TCAs) with paroxetine, because paroxetine may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is coadministered with paroxetine (see PRECAUTIONS���Drugs Metabolized by Cytochrome CYP2D6).<br/>Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma protein, administration of paroxetine to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of paroxetine by other highly bound drugs.<br/>Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.): Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin potentiated the risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with paroxetine.<br/>Alcohol: Although paroxetine does not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine.<br/>Lithium: A multiple-dose study has shown that there is no pharmacokinetic interaction between paroxetine and lithium carbonate. However, due to the potential for serotonin syndrome, caution is advised when paroxetine is coadministered with lithium.<br/>Digoxin: The steady-state pharmacokinetics of paroxetine was not altered when administered with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the presence of paroxetine. Since there is little clinical experience, the concurrent administration of paroxetine and digoxin should be undertaken with caution.<br/>Diazepam: Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of paroxetine on diazepam were not evaluated.<br/>Procyclidine: Daily oral dosing of paroxetine (30 mg once daily) increased steady-state AUC, C, and Cvalues of procyclidine (5 mg oral once daily) by 35%, 37% and 67%, respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen, the dose of procyclidine should be reduced.<br/>Beta-Blockers: In a study where propranolol (80 mg twice daily) was dosed orally for 18 days, the established steady-state plasma concentrations of propranolol were unaltered during coadministration with paroxetine (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS���Postmarketing Reports).<br/>Theophylline: Reports of elevated theophylline levels associated with treatment with paroxetine have been reported. While this interaction has not been formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered.<br/>Fosamprenavir/Ritonavir: Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy).<br/>Electroconvulsive Therapy (ECT): There are no clinical studies of the combined use of ECT and paroxetine.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis: Two-year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2.4 (mouse) and 3.9 (rat) times the maximum recommended human dose (MRHD) for major depressive disorder, social anxiety disorder, and GAD on a mg/mbasis. Because the MRHD for major depressive disorder is slightly less than that for OCD (50 mg versus 60 mg), the doses used in these carcinogenicity studies were only 2.0 (mouse) and 3.2 (rat) times the MRHD for OCD. There was a significantly greater number of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose-related increase in the number of tumors in mice, there was no drug-related increase in the number of mice with tumors. The relevance of these findings to humans is unknown.<br/>Mutagenesis: Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats.<br/>Impairment of Fertility: A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/kg/day, which is 2.9 times the MRHD for major depressive disorder, social anxiety disorder, and GAD or 2.4 times the MRHD for OCD on a mg/mbasis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times the MRHD for major depressive disorder, social anxiety disorder, and GAD; 8.2 and 4.1 times the MRHD for OCD and PD on a mg/mbasis).<br/>Pregnancy:<br/>Pregnancy Category D: See WARNINGS-Usage in Pregnancy: Teratogenic and Nonteratogenic Effects.<br/>Labor and Delivery: The effect of paroxetine on labor and delivery in humans is unknown.<br/>Nursing Mothers: Like many other drugs, paroxetine is secreted in human milk, and caution should be exercised when paroxetine is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS���Clinical Worsening and Suicide Risk). Three placebo-controlled trials in 752 pediatric patients with MDD have been conducted with paroxetine, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of paroxetine in a child or adolescent must balance the potential risks with the clinical need. In placebo-controlled clinical trials conducted with pediatric patients, the following adverse events were reported in at least 2% of pediatric patients treated with paroxetine and occurred at a rate at least twice that for pediatric patients receiving placebo: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation. Events reported upon discontinuation of treatment with paroxetine in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients who received paroxetine and which occurred at a rate at least twice that of placebo, were: emotional lability (including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and abdominal pain (see Discontinuation of Treatment With Paroxetine).<br/>Geriatric Use: In worldwide premarketing clinical trials with paroxetine, 17% of patients treated with paroxetine (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended; there were, however, no overall differences in the adverse event profile between elderly and younger patients, and effectiveness was similar in younger and older patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). | lld:dailymed |
| dailymed-drugs:139 | dailymed-instance:precautio... | General: Prescribing polymyxin B in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely benefit to the patient and increase of the development of drug-resistant bacteria. See WARNING box. Baseline renal function should be done prior to therapy, with frequent monitoring of renal function and blood levels of the drug during parenteral therapy. Avoid concurrent use of a curariform muscle relaxant and other neurotoxic drugs (ether, tubocurarine, succinylcholine, gallamine, decamethonium and sodium citrate) which may precipitate respiratory depression. If signs of respiratory paralysis appear, respiration should be assisted as required, and the drug discontinued. As with other antibiotics, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be instituted.<br/>Information for Patients: Patients should be counseled that antibacterial drugs including polymyxin B should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold).When polymyxin B is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by polymyxin B or other antibacterial drugs in the future. | lld:dailymed |
| dailymed-drugs:141 | dailymed-instance:precautio... | General: Because of the possibility of cross-sensitivity, fluphenazine hydrochloride should be used cautiously in patients who have developed cholestatic jaundice, dermatoses or other allergic reactions to phenothiazine derivatives. Psychotic patients on large doses of a phenothiazine drug who are undergoing surgery should be watched carefully for possible hypotensive phenomena. Moreover, it should be remembered that reduced amounts of anesthetics or central nervous system depressants may be necessary. The effects of atropine may be potentiated in some patients receiving fluphenazine because of added anticholinergic effects. Fluphenazine hydrochloride should be used cautiously in patients exposed to extreme heat or phosphorous insecticides; in patients with a history of convulsive disorders, since grand mal convulsions have been known to occur; and in patients with special medical disorders such as mitral insufficiency or other cardiovascular diseases and pheochromocytoma. The possibility of liver damage, pigmentary retinopathy, lenticular and corneal deposits, and development of irreversible dyskinesia should be remembered when patients are on prolonged therapy. Neuroleptic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of neuroleptic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time.<br/>Information for Patients: Given the likelihood that some patients exposed chronically to neuroleptics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided.<br/>Abrupt Withdrawal: In general, phenothiazines do not produce psychic dependence; however, gastritis, nausea and vomiting, dizziness, and tremulousness have been reported following abrupt cessation of high dose therapy. Reports suggest that these symptoms can be reduced if concomitant antiparkinsonian agents are continued for several weeks after the phenothiazine is withdrawn. Facilities should be available for periodic checking of hepatic function, renal function and the blood picture. Renal function of patients on long-term therapy should be monitored; if BUN (blood urea nitrogen) becomes abnormal, treatment should be discontinued. As with any phenothiazine, the physician should be alert to the possible development of���silent pneumonias���in patients under treatment with fluphenazine hydrochloride. | lld:dailymed |
| dailymed-drugs:142 | dailymed-instance:precautio... | General: Prescribing Cefaclor Extended-Release Tablets USP in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Superinfection (overgrowth by non-susceptible organisms) should always be considered a possibility in a patient being treated with a broad spectrum antimicrobial. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.<br/>Information for Patients: Patients should be counseled that antibacterial drugs including Cefaclor Extended-Release Tablets USP should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefaclor Extended-Release Tablets USP are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Cefaclor Extended-Release Tablets USP or other antibacterial drugs in the future.<br/>Drug Interactions:<br/>Antacids: The extent of absorption of cefaclor extended-release tablets is diminished if magnesium or aluminum hydroxide-containing antacids are taken within 1 hour of administration; Hblockers do not alter either the rate or the extent of absorption of cefaclor extended-release tablets.<br/>Probenecid: The renal excretion of cefaclor is inhibited by probenecid.<br/>Warfarin: There have been rare reports of increased prothrombin time with or without clinical bleeding in patients receiving cefaclor and warfarin concomitantly. No specific studies have been performed to rule in or rule out this potential drug/drug interaction.<br/>Laboratory Test Interactions: Administration of cefaclor extended-release tablets may result in a false-positive reaction for glucose in the urine. This phenomenon has been seen in patients taking cephalosporin antibiotics when the test is performed using Benedict's and Fehling's solutions and also with Clinitesttablets.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies in animals have not been performed to evaluate the carcinogenic or mutagenic potential for cefaclor. Reproduction studies have revealed no evidence of impaired fertility.<br/>Usage in Pregnancy:<br/>Teratogenic Effect:<br/>Labor and Delivery: Cefaclor extended-release tablets have not been studied for use during labor and delivery. Treatment should be given only if clearly needed.<br/>Nursing Mothers: No studies in lactating women have been performed with cefaclor extended-release tablets. Small amounts of cefaclor (���0.21��g/mL) have been detected in human milk following administration of single 500-mg doses of cefaclor extended-release tablets. The effect on nursing infants is not known. Caution should be exercised when cefaclor extended-release tablets are administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness of cefaclor extended-release tablets in pediatric patients less than 16 years of age have not been established.<br/>Geriatric Use: Healthy geriatric volunteers (>65 years old) who received a single 750-mg dose of cefaclor extended-release tablets had 40%-50% higher AUC and 20% lower renal clearance values when compared to healthy adult volunteers less than 45 years of age. These differences are considered to be primarily a result of age-related decreases in renal function. In clinical studies when geriatric patients received the usual recommended adult doses, clinical efficacy and safety were comparable to results in non-geriatric adult patients. No dosage changes are recommended for healthy geriatric patients. | lld:dailymed |
| dailymed-drugs:144 | dailymed-instance:precautio... | The safety and efficacy of ribavirin tablets and peginterferon alfa-2a therapy for the treatment of adenovirus, RSV, parainfluenza or influenza infections have not been established. Ribavirin tablets should not be used for these indications. Ribavirin for inhalation has a separate package insert, which should be consulted if ribavirin inhalation therapy is being considered. The safety and efficacy of ribavirin tablets and peginterferon alfa-2a therapy have not been established in liver or other organ transplant patients, patients with decompensated liver disease due to hepatitis C virus infection, patients who are non-responders to interferon therapy or patients coinfected with HBV or HIV and a CD4+ cell count<100 cells/��L.<br/>Information for Patients: Patients must be informed that ribavirin may cause birth defects and/or death of the exposed fetus. Ribavirin tablets therapy must not be used by women who are pregnant or by men whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking ribavirin tablets therapy and for 6 months posttherapy. Ribavirin tablets therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Patients must performa pregnancy test monthly during therapy and for 6 months posttherapy. Female patients of childbearing potential and male patients with female partners of childbearing potential must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during ribavirin tablets therapy and for 6 months posttherapy. Patients should be advised to notify the healthcare provider immediately in the event of a pregnancy . The most common adverse event associated with ribavirin is anemia, which may be severe . Patients should be advised that laboratory evaluations are required prior to starting ribavirin tablets therapy and periodically thereafter (see Laboratory Tests ). It is advised that patients be well hydrated, especially during the initial stages of treatment. Patients who develop dizziness, confusion, somnolence, and fatigue should be cautioned to avoid driving or operating machinery. Patients should be informed regarding the potential benefits and risks attendant to the use of ribavirin tablets. Instructions on appropriate use should be given, including review of the contents of the enclosed MEDICATION GUIDE, which is not a disclosure of all or possible adverse effects. Patients should be advised to take ribavirin tablets with food.<br/>Laboratory Tests: Before beginning ribavirin tablets therapy, standard hematological and biochemical laboratory tests must be conducted for all patients. Pregnancy screening for women of childbearing potential must be done. After initiation of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy. Monthly pregnancy testing should be done during combination therapy and for 6 months after discontinuing therapy. The entrance criteria used for the clinical studies of ribavirin tablets and peginterferon alfa-2a combination therapy may be considered as a guideline to acceptable baseline values for initiation of treatment: The maximum drop in hemoglobin usually occurred during the first 8 weeks of initiation of ribavirin tablets therapy. Because of this initial acute drop in hemoglobin, it is advised that a complete blood count should be obtained pretreatment and at week 2 and week 4 of therapy or more frequently if clinically indicated. Additional testing should be performed periodically during therapy. Patients should then be followed as clinically appropriate.<br/>Drug Interactions: Results from a pharmacokinetic sub-study demonstrated no pharmacokinetic interaction between peginterferon alfa-2a and ribavirin. Nucleoside Analogues NRTIs In Study NR15961 among the CHC/HIV coinfected cirrhotic patients receiving NRTIs cases of hepatic decompensation (some fatal) were observed . Patients receiving peginterferon alfa-2a/ribavirin tablets and NRTIs should be closely monitored for treatment associated toxicities. Physicians should refer to prescribing information for the respective NRTIs for guidance regarding toxicity management. In addition, dose reduction or discontinuation of peginterferon alfa-2a, ribavirin tablets or both should also be considered if worsening toxicities are observed . Didanosine Co-administration of ribavirin tablets and didanosine is not recommended. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials . Zidovudine In Study NR15961, patients who were administered zidovudine in combination with peginterferon alfa-2a/ribavirin tablets developed severe neutropenia (ANC<500) and severe anemia (hemoglobin<8 g/dL) more frequently than similar patients not receiving zidovudine (neutropenia 15% vs. 9%) (anemia 5% vs. 1%). Lamivudine, Stavudine, and Zidovudine In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogs such as lamivudine, stavudine, and zidovudine. No evidence of a pharmacokinetic or pharmacodynamic interaction was seen when ribavirin was co-administered with lamivudine, stavudine, and/or zidovudine in HIV/HCV coinfected patients .<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis: In a p53 (+/-) mouse carcinogenicity study and a rat 2-year carcinogenicity study at doses up to the maximum tolerated doses of 100 mg/kg/day and 60 mg/kg/day, respectively, ribavirin was not oncogenic. On a body surface area basis, these doses are approximately 0.5 and 0.6 times the maximum recommended human 24-hour dose of ribavirin.<br/>Mutagenesis: Ribavirin demonstrated mutagenic activity in the in vitro mouse lymphoma assay. No clastogenic activity was observed in an in vivo mouse micronucleus assay at doses up to 2000 mg/kg. However, results from studies published in the literature show clastogenic activity in the in vivo mouse micronucleus assay at oral doses up to 2000 mg/kg. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes. However, potential carcinogenic risk to humans cannot be excluded.<br/>Impairment of Fertility: In a fertility study in rats, ribavirin showed a marginal reduction in sperm counts at the dose of 100 mg/kg/day with no effect on fertility. Upon cessation of treatment, total recovery occurred after 1 spermatogenesis cycle. Abnormalities in sperm were observed in studies in mice designed to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of 15 to 150 mg/kg/day (approximately 0.1 to 0.8 times the maximum recommended human 24-hour dose of ribavirin) administered for 3 to 6 months. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenic cycles. Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive ribavirin tablets unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half-life (t) of ribavirin of 12 days, effective contraception must be utilized for 6 months posttherapy (i.e., 15 half-lives of clearance for ribavirin). No reproductive toxicology studies have been performed using peginterferon alfa-2a in combination with ribavirin tablets. However, peginterferon alfa-2a and ribavirin when administered separately, each has adverse effects on reproduction. It should be assumed that the effects produced by either agent alone would also be caused by the combination of the two agents.<br/>Pregnancy: Pregnancy: Category X Ribavirin produced significant embryocidal and/or teratogenic effects in all animal species in which adequate studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of fetuses and offspring was reduced. In conventional embryotoxicity/teratogenicity studies in rats and rabbits, observed no-effect dose levels were well below those for proposed clinical use (0.3 mg/kg/day for both the rat and rabbit; approximately 0.06 times the recommended human 24-hour dose of ribavirin). No maternal toxicity or effects on offspring were observed in a peri/postnatal toxicity study in rats dosed orally at up to 1 mg/kg/day (approximately 0.01 times the maximum recommended human 24-hour dose of ribavirin). Treatment and Posttreatment: Potential Risk to the Fetus Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether ribavirin is contained in sperm, and if so, will exert a potential teratogenic effect upon fertilization of the ova. In a study in rats, it was concluded that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg for 5 days (up to 1.7 times the maximum recommended human dose of ribavirin). However, because of the potential human teratogenic effects of ribavirin, male patients should be advised to take every precaution to avoid risk of pregnancy for their female partners. Ribavirin tablets should not be used by pregnant women or by men whose female partners are pregnant. Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive ribavirin tablets unless the patient and his/her partner are using effective contraception (two reliable forms) during therapy and for 6 months posttherapy. Ribavirin Pregnancy Registry A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies of female patients and female partners of male patients exposed to ribavirin during treatment and for six months following cessation of treatment. Healthcare providers and patients are encouraged toreport such cases by calling 1-800-593-2214. Animal Toxicology Long-term study in the mouse and rat (18 to 24 months; dose 20 to 75 and 10 to 40 mg/kg/day, respectively, approximately 0.1 to 0.4 times the maximum human daily dose of ribavirin) have demonstrated a relationship between chronic ribavirin exposure and an increased incidence of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence wasincreased in ribavirin-treated rats.<br/>Nursing Mothers: It is not known whether ribavirin is excreted in human milk. Because many drugs are excreted in human milk and to avoid any potential for serious adverse reactions in nursing infants from ribavirin, a decision should be made either to discontinue nursing or therapy with ribavirin tablets, based on the importance of the therapy to the mother.<br/>Pediatric Use: Safety and effectiveness of ribavirin tablets have not been established in patients below the age of 18.<br/>Geriatric Use: Clinical studies of ribavirin tablets and peginterferon alfa-2a did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Specific pharmacokinetic evaluations for ribavirin in the elderly have not been performed. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. Ribavirin tablets should not be administered to patients with creatinine clearance<50 mL/min. .<br/>Effect of Gender: No clinically significant differences in the pharmacokinetics of ribavirin were observed between male and female subjects. | lld:dailymed |
| dailymed-drugs:145 | dailymed-instance:precautio... | Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations and acid-base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Caution must be exercised in the administration of parenteral fluids, especially those containing sodium ions to patients receiving corticosteroids or corticotropin. Do not administer unless solution is clear and container is undamaged. Discard unused portion.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:: Studies have not been performed with Sodium Chloride Injection, USP to evaluate the potential for carcinogenesis, mutagenesis or impairment of fertility.<br/>Pregnancy:: Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with sodium chloride. It is also not known whether sodium chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium chloride should be given to a pregnant woman only if clearly needed.<br/>Nursing Mothers:: Caution should be exercised when Sodium Chloride Injection, USP is administered to a nursing woman.<br/>Pediatric Use:: The safety and effectiveness in the pediatric population are based on the similarity of the clinical conditions of the pediatric and adult populations. In neonates or very small infants the volume of fluid may affect fluid and electrolyte balance. | lld:dailymed |
| dailymed-drugs:148 | dailymed-instance:precautio... | General:<br/>Discontinuation of Treatment with Citalopram: During marketing of citalopram and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with citalopram. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose maybe considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION).<br/>Abnormal Bleeding: Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic drugs that interfere with serotonin reuptake. Subsequent epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of a nonsteroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding (see Drug Interactions). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding associated with the concomitant use of citalopram with NSAIDs, aspirin, or other drugs that affect coagulation.<br/>Hyponatremia: Cases of hyponatremia and SIADH (syndrome of inappropriate antidiuretic hormone secretion) have been reported in association with citalopram treatment. All patients with these events have recovered with discontinuation of citalopram and/or medical intervention. Hyponatremia and SIADH have also been reported in association with other marketed drugs effective in the treatment of major depressive disorder.<br/>Activation of Mania/Hypomania: In placebo-controlled trials of citalopram, some of which included patients with bipolar disorder, activation of mania/hypomania was reported in 0.2% of 1,063 patients treated with citalopram and in none of the 446 patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorderstreated with other marketed antidepressants. As with all antidepressants, citalopram should be used cautiously in patients with a history of mania.<br/>Seizures: Although anticonvulsant effects of citalopram have been observed in animal studies, citalopram has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product's premarketing testing. In clinical trials of citalopram, seizures occurred in 0.3% of patients treated with citalopram (a rate of one patient per 98 years of exposure) and 0.5% of patients treated with placebo (a rate of one patient per 50 years of exposure). Like other antidepressants, citalopram should be introduced with care in patients with a history of seizure disorder.<br/>Interference with Cognitive and Motor Performance: In studies in normal volunteers, citalopram in doses of 40 mg/day did not produce impairment of intellectual function or psychomotor performance. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that citalopram therapy does not affect theirability to engage in such activities.<br/>Use in Patients with Concomitant Illness: Clinical experience with citalopram in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using citalopram in patients with diseases or conditions that produce altered metabolism or hemodynamic responses. Citalopram has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical studies during the product's premarketing testing. However, the electrocardiograms of 1,116 patients who received citalopram in clinical trials were evaluated and the data indicate that citalopram is not associated with the development of clinically significant ECG abnormalities. In subjects with hepatic impairment, citalopram clearance was decreased and plasma concentrations were increased. The use of citalopram in hepatically impaired patients should be approached with caution and a lower maximum dosage is recommended (see DOSAGE AND ADMINISTRATION). Because citalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with citalopram, however, it should be used with caution in such patients (see DOSAGE AND ADMINISTRATION).<br/>Information for Patients: Physicians are advised to discuss the following issues with patients for whom they prescribe citalopram. Although in controlled studies citalopram has not been shown to impair psychomotor performance, any psychoactive drug may impair judgment, thinking or motor skills, so patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that citalopram therapy does not affect their ability to engage in such activities. Patients should be told that, although citalopram has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of citalopram and alcohol in depressed patients is not advised. Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions. Patients should be cautioned about the concomitant use of citalopram and NSAIDs, aspirin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physician if they are breastfeeding an infant. While patients may notice improvement with citalopram therapy in 1 to 4 weeks, they should be advised to continue therapy as directed. Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with citalopram and should counsel them in its appropriate use. A patient Medication Guide about���Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions���is available for citalopram. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking citalopram.<br/>Clinical Worsening and Suicide Risk:: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or healthprofessional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.<br/>Laboratory Tests: There are no specific laboratory tests recommended.<br/>Drug Interactions: CNS Drugs - Given the primary CNS effects of citalopram, caution should be used when it is taken in combination with other centrally acting drugs. Alcohol - Although citalopram did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by depressed patients taking citalopram is not recommended. Monoamine Oxidase Inhibitors (MAOIs) - See CONTRAINDICATIONS and WARNINGS. Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.) - Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrenceof upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin potentiated the risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with citalopram. Cimetidine - In subjects who had received 21 days of 40 mg/day citalopram, combined administration of 400 mg/day cimetidine for 8 days resulted in an increase in citalopram AUC and Cof 43% and 39%, respectively. The clinical significance of these findings is unknown. Digoxin - In subjects who had received 21 days of 40 mg/day citalopram, combined administration of citalopram and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin. Lithium - Coadministration of citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of citalopram, caution should be exercised when citalopram and lithium are coadministered. Pimozide - In a controlled study, a single dose of pimozide 2 mg coadministered with citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Citalopram did not alter the mean AUC or Cof pimozide. The mechanism of this pharmacodynamic interaction is not known. Theophylline - Combined administration of citalopram (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline. The effect of theophylline on the pharmacokinetics of citalopram was not evaluated. Sumatriptan - There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram) is clinically warranted, appropriate observation of the patient is advised. Warfarin - Administration of 40 mg/day citalopram for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance of which is unknown. Carbamazepine - Combined administration of citalopram (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of citalopram should be considered if the two drugs are coadministered. Triazolam - Combined administration of citalopram (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam. Ketoconazole - Combined administration of citalopram (40 mg) and ketoconazole (200 mg) decreased the Cand AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram. CYP3A4 and 2C19 Inhibitors - In vitro studies indicated that CYP3A4 and 2C19 are the primary enzymes involved in the metabolism of citalopram. However, coadministration of citalopram (40 mg) and ketoconazole (200 mg), a potent inhibitor of CYP3A4, did not significantly affect the pharmacokinetics of citalopram. Because citalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease citalopram clearance. Metoprolol - Administration of 40 mg/day citalopram for 22 days resulted in a two-fold increase in the plasma levels of the beta-adrenergic blocker metoprolol. Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Coadministration of citalopram and metoprolol had no clinically significant effects on blood pressure or heart rate. Imipramine and Other Tricyclic Antidepressants (TCAs) - In vitro studies suggest that citalopram is a relatively weak inhibitor of CYP2D6. Coadministration of citalopram (40 mg/day for 10 days) with the TCA imipramine (single dose of 100 mg), a substrate for CYP2D6, did not significantly affect the plasma concentrations of imipramine or citalopram. However, the concentration of the imipramine metabolite desipramine was increased by approximately 50%. The clinical significance of the desipramine change is unknown. Nevertheless, caution is indicated in the coadministration of TCAs with citalopram. Electroconvulsive Therapy (ECT) -There are no clinical studies of the combined use of electroconvulsive therapy (ECT) and citalopram.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis: Citalopram was administered in the diet to NMRI/BOM strain mice and COBS WI strain rats for 18 and 24 months, respectively. There was no evidence for carcinogenicity of citalopram in mice receiving up to 240 mg/kg/day, which is equivalent to 20 times the maximum recommended human daily dose (MRHD) of 60 mg on a surface area (mg/m) basis. There was an increased incidence of small intestine carcinoma in rats receiving 8 or 24 mg/kg/day, doses which are approximately 1.3 and 4 times the MRHD, respectively, on a mg/mbasis. A no-effect dose for this finding was not established. The relevance of these findings to humans is unknown.<br/>Mutagenesis: Citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Citalopram was not mutagenicin the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in a coupled in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. It was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays.<br/>Impairment of Fertility: When citalopram was administered orally to 16 male and 24 female rats prior to and throughout mating and gestation at doses of 32, 48, and 72 mg/kg/day, mating was decreased at all doses, and fertility was decreased at doses���32 mg/kg/day, approximately 5 times the MRHD of 60 mg/day on a body surface area (mg/m) basis. Gestation duration was increased at 48 mg/kg/day, approximately 8 times the MRHD.<br/>Pregnancy:<br/>Pregnancy Category C: In animal reproduction studies, citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at doses greater than human therapeutic doses. In two rat embryo/fetal development studies, oral administration of citalopram (32, 56, or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose, which is approximately 18 times the MRHD of 60 mg/day on a body surface area (mg/m) basis. This dose was also associated with maternal toxicity (clinical signs, decreased body weight gain). The developmental, no-effect dose of 56 mg/kg/day is approximately 9 times the MRHD on a mg/mbasis. In a rabbit study, no adverse effects on embryo/fetal development were observed at doses of up to 16 mg/kg/day, or approximately 5 times the MRHD on a mg/mbasis. Thus, teratogenic effects were observed at a maternally toxic dose in the rat and were not observed in the rabbit. When female rats were treated with citalopram (4.8, 12.8, or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at the highest dose, which is approximately 5 times the MRHD on a mg/mbasis. The no-effect dose of 12.8 mg/kg/day is approximately 2 times the MRHD on a mg/mbasis. Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses���24 mg/kg/day, approximately 4 times the MRHD on a mg/mbasis. A no-effect dose was not determined in that study. There are no adequate and well-controlled studies in pregnant women; therefore, citalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Pregnancy - Nonteratogenic Effects: Neonates exposed to citalopram and other SSRIs or SNRIs, late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a directtoxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS). When treating a pregnant woman with citalopram during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION).<br/>Labor and Delivery: The effect of citalopram on labor and delivery in humans is unknown.<br/>Nursing Mothers: As has been found to occur with many other drugs, citalopram is excreted in human breast milk. There have been two reports of infants experiencing excessive somnolence, decreased feeding, and weight loss in association with breastfeeding from a citalopram-treated mother; in one case, the infant was reported to recover completely upon discontinuation of citalopram by its mother, and in the second case, no follow-up information was available. The decision whether to continue or discontinue either nursing or citalopram therapy should take into account the risks of citalopram exposure for the infant and the benefits of citalopram treatment for the mother.<br/>Pediatric Use: Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS - Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 407 pediatric patients with MDD have been conducted with citalopram, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of citalopram in a child or adolescent must balance the potential risks with the clinical need.<br/>Geriatric Use: Of 4,422 patients in clinical studies of citalopram, 1,357 were 60 and over, 1,034 were 65 and over, and 457 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Most elderly patients treated with citalopram in clinical trials received daily doses between 20 and 40 mg (see DOSAGE AND ADMINISTRATION). In two pharmacokinetic studies, citalopram AUC was increased by 23% and 30%, respectively, in elderly subjects as compared to younger subjects, and its half-life was increased by 30% and 50%, respectively (see CLINICAL PHARMACOLOGY). 20 mg/day is the recommended dose for most elderly patients (see DOSAGE AND ADMINISTRATION). | lld:dailymed |
| dailymed-drugs:150 | dailymed-instance:precautio... | General:: Solutions containing dextrose should be used with caution in patients with known subclinical or overt diabetes mellitus. Fluid and Electrolyte Balance: Excess administration of potassium-free solutions may result in significant hypokalemia. The intravenous administration of these solutions can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. Careful Monitoring Required: Close monitoring of the following indices���urine flow, cardiac output and blood pressure���during dopamine infusion is necessary as in the case of any adrenergic agent. Hypoxia, Hypercapnia, Acidosis: These conditions, which may also reduce the effectiveness and/or increase the incidence of adverse effects of dopamine, must be identified and corrected prior to, or concurrently with, administration of dopamine HCl. Ventricular Arrhythmias: If an increased number of ectopic beats are observed the dose should be reduced if possible. Hypotension: At lower infusion rates, if hypotension occurs, the infusion rate should be rapidly increased until adequate blood pressure is obtained. If hypotension persists, dopamine HCl should be discontinued and a more potent vasoconstrictor agent such as norepinephrine should be administered. Occlusive Vascular Disease: Patients with a history of occlusive vascular disease (e.g., arteriosclerosis, arterial embolism, Raynaud's disease, cold injury such as frostbite, diabetic endarteritis, and Buerger's disease) should be closely monitored for any changes in color or temperature of the skin of the extremities. If a change in skin color or temperature occurs and is thought to be the result of compromised circulation to the extremities, the benefits of continued dopamine infusion should be weighed against the risk of possible necrosis. These changes may be reversed by decreasing the rate or discontinuing the infusion entirely. Extravasation: Dopamine Hydrochloride in 5% Dextrose Injection, USP should be infused into a large vein whenever possible to prevent the possibility of infiltration of perivascular tissue adjacent to the infusion site. Extravasation may cause necrosis and sloughing of surrounding tissue. Large veins of the antecubital fossa are preferred to veins of the dorsum of the hand or ankle. Administration into an umbilical arterial catheter is not recommended. Less suitable infusion sites should be used only when larger veins are unavailable and the patient's condition requires immediate attention. The physician should switch to a more suitable site as soon as possible and the infusion site in use should be continuously monitored for free flow.<br/>Laboratory Tests:: Infusion of dopamine suppresses pituitary secretion of thyroid���stimulating hormone, growth hormone, and prolactin. Weaning: When discontinuing the infusion, it may be necessary to gradually decrease the dose of dopamine HCl while expanding blood volume with IV fluids. Sudden cessation may result in marked hypotension.<br/>Drug Interactions:: Cyclopropane or halogenated hydrocarbon anesthetics increase cardiac autonomic irritability and may sensitize the myocardium to the action of certain intravenously administered catecholamines, such as dopamine. This interaction appears to be related both to pressor activity and to the��-adrenergic stimulating properties of these catecholamines, and may produce ventricular arrhythmias and hypertension. Therefore, EXTREME CAUTION should be exercised when administering dopamine HCl to patients receiving cyclopropane or halogenated hydrocarbon anesthetics. Results of studies in animals indicate that dopamine-induced ventricular arrhythmias during anesthesia can be reversed by propranolol. Because dopamine is metabolized by monoamine oxidase (MAO), inhibition of this enzyme prolongs and potentiates the effect of dopamine. Patients who have been treated with MAO inhibitors within two to three weeks prior to the administration of dopamine should receive initial doses of dopamine hydrochloride no greater than one-tenth (1/10) of the usual dose. Concurrent administration of low-dose dopamine HCl and diuretic agents may produce an additive or potentiating effect on urine flow. Tricyclic antidepressants may potentiate the cardiovascular effects of adrenergic agents. Cardiac effects of dopamine are antagonized by��-adrenergic blocking agents, such as propranolol and metoprolol. The peripheral vasoconstriction caused by high doses of dopamine HCl is antagonized by��-adrenergic blocking agents. Dopamine-induced renal and mesenteric vasodilation is not antagonized by either��- or��-adrenergic blocking agents. Butyrophenones (such as haloperidol) and phenothiazines can suppress the dopaminergic renal and mesenteric vasodilation induced with low-dose dopamine infusion. The concomitant use of vasopressors, vasoconstricting agents (such as ergonovine) and some oxytocic drugs may result in severe hypertension. Administration of phenytoin to patients receiving dopamine HCl has been reported to lead to hypotension and bradycardia. It is suggested that in patients receiving dopamine HCl, alternatives to phenytoin should be considered if anticonvulsant therapy is needed.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:: Long term animal studies have not been performed to evaluate the carcinogenic potential of dopamine HCl. Dopamine HCl at doses approaching maximal solubility showed no clear genotoxic potential in the Ames test. Although there was a reproducible dose-dependent increase in the number of revertant colonies with strains TA100 and TA98, both with and without metabolic activation, the small increase was considered inconclusive evidence of mutagenicity. In the L5178Y TKmouse lymphoma assay, dopamine HCl at the highest concentrations used of 750��g/mL without metabolic activation, and 3000��g/mL with activation, was toxic and associated with increases in mutant frequencies when compared to untreated and solvent controls; at the lower concentrations no increases over controls were noted. No clear evidence of clastogenic potential was reported in the in vivo mouse or male rat bone marrow micronucleus test when the animals were treated intravenously with up to 224 mg/kg and 30 mg/kg of dopamine HCl, respectively.<br/>Pregnancy:: Pregnancy Category C: Teratogenic Effects: Teratogenicity studies in rats and rabbits at dopamine HCl dosages up to 6 mg/kg/day intravenously during organogenesis produced no detectable teratogenic or embryotoxic effects, although maternal toxicity consisting of mortalities, decreased body weight gain, and pharmacotoxic signs were observed in rats. In a published study, dopamine HCl administered at 10 mg/kg subcutaneously for 30 days, markedly prolonged metestrus and increased mean pituitary and ovary weights in female rats. Similar administration to pregnant rats throughout gestation or for 5 days starting on gestation day 10 or 15 resulted in decreased body weight gains, increased mortalities and slight increases in cataract formation among the offspring. There are no adequate and well-controlled studies in pregnant women, and it is not known if dopamine HCl crosses the placental barrier. Dopamine HCl should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Labor and Delivery:: In obstetrics, if vasopressor drugs are used to correct hypotension or are added to a local anesthetic solution the interaction with some oxytocic drugs may cause severe hypertension.<br/>Nursing Mothers:: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when dopamine HCl is administered to a nursing mother.<br/>Pediatric Use:: Dopamine infusions have been used in patients of every age from birth onwards. There are scattered reports of infusion rates in neonates up to 125 mcg/kg/min, but most reports in pediatric patients describe dosing that is similar (on a mcg/kg/min basis) to that used in adults. Except for vasoconstrictive effects caused by inadvertent infusion of dopamine into the umbilical artery, adverse effects unique to the pediatric population have not been identified, nor have adverse effects identified in adults been found to be more common in pediatric patients.<br/>Geriatric Use:: Clinical studies of dopamine injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:153 | dailymed-instance:precautio... | Laboratory Tests: Serum potassium levels are not necessarily indicative of tissue potassium levels. Solutions containing potassium should be used with caution in the presence of cardiac or renal disease. Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid-base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Significant deviations from normal concentrations may require the use of additional electrolyte supplements, or the use of electrolyte-free dextrose solutions to which individualized electrolyte supplements may be added.<br/>Pregnancy:<br/>Pregnancy Category C: Animal reproduction studies have not been conducted with potassium chloride. It is also not known whether potassium chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium chloride should be given to a pregnant woman only if clearly needed.<br/>Pediatric Use: These products should not be used in children at this time. Do not administer unless solution is clear and seal is intact. | lld:dailymed |
| dailymed-drugs:154 | dailymed-instance:precautio... | Special care must be taken when administering glucose to provide calories in diabetic or prediabetic patients. Feeding regimens which include amino acids should be used with caution in patients with history of renal disease, pulmonary disease, or with cardiac insufficiency so as to avoid excessive fluid accumulation. The effect of infusion of amino acids, without dextrose, upon carbohydrate metabolism of children is not known at this time. Nitrogen intake should be carefully monitored in patients with impaired renal function. For long-term total nutrition, or if a patient has inadequate fat stores, it is essential to provide adequate exogenous calories concurrently with the amino acids. Concentrated dextrose solutions are an effective source of such calories. Such strongly hypertonic nutrient solutions should be administered through an indwelling intravenous catheter with the tip located in the superior vena cava. Central vein infusion (with added concentrated carbohydrate solutions) of amino acid solutions requires a knowledge of nutrition as well as clinical expertise in recognition and treatment of complications. Attention must be given to solution preparation, administration and patient monitoring. IT IS ESSENTIAL THAT A CAREFULLY PREPARED PROTOCOL BASED ON CURRENT MEDICAL PRACTICES BE FOLLOWED, PREFERABLY BY AN EXPERIENCED TEAM. SUMMARY HIGHLIGHTS OF COMPLICATIONS (consult current medical literature).<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:: Studies with solutions from flexible plastic containers have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.<br/>Pregnancy Category C.: Animal reproduction studies have not been conducted with Aminosyn II (an amino acid injection). It is not known whether Aminosyn II can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Aminosyn II should be given to a pregnant woman only if clearly needed.<br/>Nursing Mothers:: Caution should be exercised when solutions from flexible plastic containers are administered to a nursing mother.<br/>Geriatric Use: Clinical Studies of Aminosyn II have not been performed to determine whether patients over 65 years of age respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, andof concomitant disease or other drug therapy. This drug is known to be substantially excreted by kidney, and the risk for adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.<br/>Pediatric Use:: Safety and effectiveness of solutions from flexible plastic containers in pediatric patients have not been well established. CLINICAL EVALUATION AND LABORATORY DETERMINATIONS, AT THE DISCRETION OF THE ATTENDING PHYSICIAN, ARE NECESSARY FOR PROPER MONITORING DURING ADMINISTRATION. Do not withdraw venous blood for blood chemistries through the peripheral infusion site, as interference with estimations of nitrogen containing substances may occur. Blood studies should include glucose, urea nitrogen, serum electrolytes, ammonia, cholesterol, acid-base balance, serum proteins, kidney and liver function tests, osmolarity and hemogram. White blood count and blood cultures are to be determined if indicated. Urinary osmolality and glucose should be determined as necessary.<br/>Drug Interactions: Because of its antianabolic activity, concurrent administration of tetracycline may reduce the potential effects of amino acids infused with dextrose as part of a parenteral feeding regimen. | lld:dailymed |
| dailymed-drugs:155 | dailymed-instance:precautio... | Information for Patients: Patients should be instructed to take gabapentin only as prescribed. Patients should be advised that gabapentin may cause dizziness, somnolence and other symptoms and signs of CNS depression. Accordingly, they should be advised neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on gabapentin to gauge whether or not it affects their mental and/or motor performance adversely. Patients who require concomitant treatment with morphine may experience increases in gabapentin concentrations. Patients should be carefully observed for signs of CNS depression, such as somnolence, and the dose of gabapentin or morphine should be reduced appropriately (see Drug Interactions).<br/>Laboratory Tests: Clinical trials data do not indicate that routine monitoring of clinical laboratory parameters is necessary for the safe use of gabapentin. The value of monitoring gabapentin blood concentrations has not been established. Gabapentin may be used in combination with other antiepileptic drugs without concern for alteration of the blood concentrations of gabapentin or of other antiepileptic drugs.<br/>Drug Interactions: In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker substrates and human liver microsomal preparations. Only at the highest concentration tested (171 mcg/mL; 1 mM) was a slight degree of inhibition (14% to 30%) of isoform CYP2A6 observed. No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to 171 mcg /mL (approximately 15 times the Cat 3600 mg/day). Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of commonly coadministered antiepileptic drugs. The drug interaction data described in this section were obtained from studies involving healthy adults and adult patients with epilepsy. Phenytoin: In a single (400 mg) and multiple dose (400 mg TID) study of gabapentin in epileptic patients (N = 8) maintained on phenytoin monotherapy for at least 2 months, gabapentin had no effect on the steady-state trough plasma concentrations of phenytoin and phenytoin had no effect on gabapentin pharmacokinetics. Carbamazepine: Steady-state trough plasma carbamazepine and carbamazepine 10, 11 epoxide concentrations were not affected by concomitant gabapentin (400 mg TID; N = 12) administration. Likewise, gabapentin pharmacokinetics were unaltered by carbamazepine administration. Valproic Acid: The mean steady-state trough serum valproic acid concentrations prior to and during concomitant gabapentin administration (400 mg TID; N = 17) were not different and neither were gabapentin pharmacokinetic parameters affected by valproic acid. Phenobarbital: Estimates of steady-state pharmacokinetic parameters for phenobarbital or gabapentin (300 mg TID; N = 12) are identical whether the drugs are administered alone or together. Naproxen: Coadministration (N = 18) of naproxen sodium capsules (250 mg) with gabapentin (125 mg) appears to increase the amount of gabapentin absorbed by 12% to 15%. Gabapentin had no effect on naproxen pharmacokinetic parameters. These doses are lower than the therapeutic doses for both drugs. The magnitude of interaction withinthe recommended dose ranges of either drug is not known. Hydrocodone: Coadministration of gabapentin (125 to 500 mg; N = 48) decreases hydrocodone (10 mg; N = 50) Cand AUC values in a dose-dependent manner relative to administration of hydrocodone alone; Cand AUC values are 3% to 4% lower, respectively, after administration of 125 mg gabapentin and 21% to 22% lower, respectively, after administration of 500 mg gabapentin. The mechanism for this interaction is unknown. Hydrocodone increases gabapentin AUC values by 14%. The magnitude of interaction at other doses is not known. Morphine: A literature article reported that when a 60 mg controlled-release morphine capsule was administered 2 hours prior to a 600 mg gabapentin capsule dose (N = 12), mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine (see PRECAUTIONS). Morphine pharmacokinetic parameter values were not affected by administration of gabapentin 2 hours after morphine. The magnitude of interaction at other doses is not known. Cimetidine: In the presence of cimetidine at 300 mg QID (N = 12) the mean apparent oral clearance of gabapentin fell by 14% and creatinine clearance fell by 10%. Thus cimetidine appeared to alter the renal excretion of both gabapentin and creatinine, an endogenous marker of renal function. This small decrease in excretion of gabapentin by cimetidine is not expected to be of clinical importance. The effect of gabapentin on cimetidine was not evaluated. Oral Contraceptive: Based on AUC and half-life, multiple-dose pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of tablets containing 2.5 mg of norethindrone acetate and 50 mcg of ethinyl estradiol were similar with and without coadministration of gabapentin (400 mg TID; N = 13). The Cof norethindrone was 13% higher when it was coadministered with gabapentin; this interaction is not expected to be of clinical importance. Antacid (Maalox)*: Maalox reduced the bioavailability of gabapentin (N = 16) by about 20%. This decrease in bioavailability was about 5% when gabapentin was administered 2 hours after Maalox. It is recommended that gabapentin be taken at least 2 hours following Maalox administration. Effect of Probenecid: Probenecid is a blocker of renal tubular secretion. Gabapentin pharmacokinetic parameters without and with probenecid were comparable. This indicates that gabapentin does not undergo renal tubular secretion by the pathway that is blocked by probenecid.<br/>Drug/Laboratory Tests Interactions: Because false positive readings were reported with the Ames N-Multistix SG dipstick test for urinary protein when gabapentin was added to other antiepileptic drugs, the more specific sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine protein.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to rats at 250, 1000, and 2000 mg/kg/day for 2 years. A statistically significant increase in the incidence of pancreatic acinar cell adenomas and carcinomas was found in male rats receiving the high dose; the no-effect dose for the occurrence of carcinomas was 1000 mg/kg/day. Peak plasma concentrations of gabapentin in rats receiving the high dose of 2000 mg/kg were 10 times higher than plasma concentrations in humans receiving 3600 mg per day, and in rats receiving 1000 mg/kg/day peak plasma concentrations were 6.5 times higher than in humans receiving 3600 mg/day. The pancreatic acinar cell carcinomas did not affect survival, did not metastasize and were not locally invasive. The relevance of this finding to carcinogenic risk in humans isunclear. Studies designed to investigate the mechanism of gabapentin-induced pancreatic carcinogenesis in rats indicate that gabapentin stimulates DNA synthesis in rat pancreatic acinar cells in vitro and, thus, may be acting as a tumor promoter by enhancing mitogenic activity. It is not known whether gabapentin has the ability to increase cell proliferation in other cell types or in other species, including humans. Gabapentin did not demonstrate mutagenic or genotoxic potential in three in vitro and four in vivo assays. It was negative in the Ames test and the in vitro HGPRT forward mutation assay in Chinese hamster lung cells; it did not produce significant increases in chromosomal aberrations in the in vitro Chinese hamster lung cell assay; it was negative in the in vivo chromosomal aberration assay and in the in vivo micronucleus test in Chinese hamster bone marrow; it was negative in the in vivo mouse micronucleus assay; and it did not induce unscheduled DNA synthesis in hepatocytes from rats given gabapentin. No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg (approximately 5 times the maximum recommended human dose on a mg/mbasis).<br/>Pregnancy: Pregnancy Category C: Gabapentin has been shown to be fetotoxic in rodents, causing delayed ossification of several bones in the skull, vertebrae, forelimbs, and hindlimbs. These effects occurred when pregnant mice received oral doses of 1000 or 3000 mg/kg/day during the period of organogenesis, or approximately 1 to 4 times the maximum dose of 3600 mg/day given to epileptic patients on a mg/mbasis. The no-effect level was 500 mg/kg/day or approximately��of the human dose on a mg/mbasis. When rats were dosed prior to and during mating, and throughout gestation, pups from all dose groups (500, 1000 and 2000 mg/kg/day) were affected. These doses are equivalent to less than approximately 1 to 5 times the maximum human dose on a mg/mbasis. There was an increased incidence of hydroureter and/or hydronephrosis in rats in a study of fertility and general reproductive performance at 2000 mg/kg/day with no effect at 1000 mg/kg/day, in a teratology study at 1500 mg/kg/day with no effect at 300 mg/kg/day, and in a perinatal and postnatal study at all doses studied (500, 1000 and 2000 mg/kg/day). The doses at which the effects occurred are approximately 1 to 5 times the maximum human dose of 3600 mg/day on a mg/mbasis; the no-effect doses were approximately 3 times (Fertility and General Reproductive Performance study) and approximately equal to (Teratogenicity study) the maximum human dose on a mg/mbasis. Other than hydroureter and hydronephrosis, the etiologies of which are unclear, the incidence of malformations was not increased compared to controls in offspring of mice, rats, or rabbits given doses up to 50 times (mice), 30 times (rats), and 25 times (rabbits) the human daily dose on a mg/kg basis, or 4 times (mice), 5 times (rats), or 8 times (rabbits) the human daily dose on a mg/mbasis. In a teratology study in rabbits, an increased incidence of postimplantation fetal loss occurred in dams exposed to 60, 300, and 1500 mg/kg/day, or less than approximately��to 8 times the maximum human dose on a mg/mbasis. There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Use in Nursing Mothers: Gabapentin is secreted into human milk following oral administration. A nursed infant could be exposed to a maximum dose of approximately 1 mg/kg/day of gabapentin. Because the effect on the nursing infant is unknown, gabapentin should be used in women who are nursing only if the benefits clearly outweigh the risks.<br/>Pediatric Use: Safety and effectiveness of gabapentin in the management of postherpetic neuralgia in pediatric patients have not been established. Effectiveness as adjunctive therapy in the treatment of partial seizures in pediatric patients below the age of 3 years has not been established. (see CLINICAL PHARMACOLOGY, Clinical Studies).<br/>Geriatric Use: The total number of patients treated with gabapentin in controlled clinical trials in patients with postherpetic neuralgia was 336, of which 102 (30%) were 65 to 74 years of age, and 168 (50%) were 75 years of age and older. There was a larger treatment effect in patients 75 years of age and older compared with younger patients who received the same dosage. Since gabapentin is almost exclusively eliminated by renal excretion, the larger treatment effect observed in patients���75 years may be a consequence of increased gabapentin exposure for a given dose that results from an age-related decrease in renal function. However, other factors cannot be excluded. The types and incidence of adverse events were similar across age groups except for peripheral edema and ataxia, which tended to increase in incidence with age. Clinical studies of gabapentin in epilepsy did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and dose should be adjusted based on creatinine clearance values in these patients (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION sections). | lld:dailymed |
| dailymed-drugs:158 | dailymed-instance:precautio... | General:<br/>Impaired Hepatic Function: Labetalol HCI injection should be used with caution in patients with impaired hepatic function since metabolism of the drug may be diminished.<br/>Hypotension: Symptomatic postural hypotension (incidence, 58%) is likely to occur if patients are tilted or allowed to assume the upright position within 3 hours of receiving labetalol HCl injection. Therefore, the patient's ability to tolerate an upright position should be established before permitting any ambulation.<br/>Following Coronary Artery Bypass Surgery: In one uncontrolled study, patients with low cardiac indices and elevated systemic vascular resistance following intravenous labetalol HCl treatment experienced significant declines in cardiac output with little change in systemic vascular resistance. One of these patients developed hypotension following labetalol treatment. Therefore, use of labetalol HCl should be avoided in such patients.<br/>High Dose Labetalol HCl: Administration of up to 3 g per day as an infusion for up to 2 to 3 days has been anecdotally reported; several patients have experienced hypotension or bradycardia. .<br/>Jaundice or Hepatic Dysfunction: .<br/>Information for Patients: he following information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. During and immediately following (for up to 3 hours) labetalol HCl injection, the patient should remain supine. Subsequently, the patient should be advised on how to proceed gradually to become ambulatory and should be observed at the time of first ambulation. When the patient is started on labetalol HCl tablets following adequate control of blood pressure with labetalol HCl injection, appropriate directions for titration of dosage should be provided . As with all drugs with beta-blocking activity, certain advice to patients being treated with labetalol HCl is warranted. While no incident of the abrupt withdrawal phenomenon (exacerbation of angina pectoris) has been reported with labetalol HCl, dosing with labetalol HCl tablets should not be interrupted or discontinued without a physician's advice. Patients being treated with labetalol HCl tablets should consult a physician at any signs or symptoms of impending cardiac failure or hepatic dysfunction . Also, transient scalp tingling may occur, usually when treatment with labetalol HCl tablets is initiated .<br/>Laboratory Tests: Routine laboratory tests are ordinarily not required before or after intravenous labetalol. In patients with concomitant illnesses, such as impaired renal function, appropriate tests should be done to monitor these conditions.<br/>Drug Interactions: Since labetalol HCl may be administered to patients already being treated with other medications, including other antihypertensive agents, careful monitoring of these patients is necessary to detect and treat promptly any undesired effect from concomitant administration. In one survey, 2.3% of patients taking labetalol orally in combination with tricyclic antidepressants experienced tremor as compared to 0.7% reported to occur with labetalol alone. The contribution of each of the treatments to this adverse reaction is unknown, but the possibility of a drug interaction cannot be excluded. Drug possessing beta-blocking properties can blunt the bronchodilator effect of beta-receptor agonist drugs in patients with bronchospasm; therefore, doses greater than the normal antiasthmatic dose of beta-agonist bronchodilator drugs may be required. Cimetidine has been shown to increase the bioavailability of labetalol administered orally. Since this could be explained either by enhanced absorption or by an alteration of hepatic metabolism of labetalol, special care should be used in establishing the dose required for blood pressure control in such patients. Synergism has been shown between halothane anesthesia and intravenously administered labetalol. During controlled hypotensive anesthesia using labetalol in association with halothane, high concentrations (3% or above) of halothane should not be used because the degree of hypotension will be increased and because of the possibility of a large reduction in cardiac output and an increase in central venous pressure. The anesthesiologist should be informed when a patient is receiving labetalol. Labetalol blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effect. If labetalol is used with nitroglycerin in patients with angina pectoris, additional antihypertensive effects may occur. Care should be taken if labetalol is used concomitantly with calcium antagonists of the verapamil type.<br/>Risk of Anaphylactic Reaction: While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.<br/>Drug/Laboratory Test Interactions: The presence of labetalol metabolites in the urine may result in falsely elevated levels of urinary catecholamines, metanephrine, normetanephrine, and vanillylmandelic acid (VMA) when measured by fluorimetric or photometric methods. In screening patients suspected of having a pheochromocytoma and being treated with labetalol, a specific method, such as a high performance liquid chromatographic assay with solid phase extraction (e.g., J Chromatogr 385:241, 1987) should be employed in determining levels of catecholamines. Labetalol has also been reported to produce a false-positive test for amphetamine when screening urine for the presence of drugs using the commercially available assay methods Toxi-Lab A (thin-layer chromatographic assay) and Emit-d.a.u. (radioenzymatic assay). When patients being treated with labetalol have a positive urine test for amphetamine using these techniques, confirmation should be made by using more specific methods, such as a gas chromatographic-mass spectrometer technique.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term oral dosing studies with labetalol for 18 months in mice and for 2 years in rats showed no evidence of carcinogenesis. Studies with labetalol using dominant lethal assays in rats and mice and exposing microoganisms according to modified Ames tests showed no evidence of mutagenesis.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C: Teratogenic studies were performed with labetalol in rats and rabbits at oral doses up to approximately six and four times the maximum recommended human dose (MRHD), respectively. No reproducible evidence of fetal malformations was observed. Increased fetal resorptions were seen in both species at doses approximating the MRHD. A teratology study performed with labetalol in rabbits at intravenous doses up to 1.7 times the MRHD revealed no evidence of drug-related harm to the fetus. There are no adequate and well-controlled studies in pregnant women. Labetalol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nonteratogenic Effects: Hypotension, bradycardia, hypoglycemia, and respiratory depression have been reported in infants of mothers who were treated with labetalol for hypertension during pregnancy. Oral administration of labetalol to rats during late gestation through weaning at doses of two to four times the MRHD caused a decrease in neonatal survival.<br/>Labor and Delivery: Labetalol given to pregnant women with hypertension did not appear to affect the usual course of labor and delivery.<br/>Nursing Mothers: Small amounts of labetalol (approximately 0.004% of the maternal dose) are excreted in human milk. Caution should be exercised when labetalol HCl is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established. | lld:dailymed |
| dailymed-drugs:159 | dailymed-instance:precautio... | General:<br/>Prostate Cancer: Carcinoma of the prostate causes many of the symptoms associated with BPH and the two disorders frequently co-exist. Carcinoma of the prostate should therefore be ruled out prior to commencing therapy with doxazosin mesylate.<br/>Cataract Surgery: Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on or previously treated with alphablockers. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient's surgeon should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alphablocker therapy prior to cataract surgery.<br/>Orthostatic Hypotension: While syncope is the most severe orthostatic effect of doxazosin mesylate, other symptoms of lowered blood pressure, such as dizziness, lightheadedness, or vertigo can occur, especially at initiation of therapy or at the time of dose increases.<br/>Information for Patients (See Patient Package Insert): Patients should be made aware of the possibility of syncopal and orthostatic symptoms, especially at the initiation of therapy, and urged to avoid driving or hazardous tasks for 24 hours after the first dose, after a dosage increase, and after interruption of therapy when treatment is resumed. They should be cautioned to avoid situations where injury could result should syncope occur during initiation of doxazosin therapy. They should also be advised of the need to sit or lie down when symptoms of lowered blood pressure occur, although these symptoms are not always orthostatic, and to be careful when rising from a sitting or lying position. If dizziness, lightheadedness, or palpitations are bothersome they should be reported to the physician, so that dose adjustment can be considered. Patients should also be told that drowsiness or somnolence can occur with doxazosin mesylate, or any selective alphaadrenoceptor antagonist, requiring caution in people who must drive or operate heavy machinery. Patients should be advised about the possibility of priapism as a result of treatment with alphaantagonists. Patients should know that this adverse event is very rare. If they experience priapism, it should be brought to immediate medical attention for if not treated promptly it can lead to permanent erectile dysfunction (impotence).<br/>Drug/Laboratory Test Interactions: Doxazosin mesylate does not affect the plasma concentration of prostate specific antigen in patients treated for up to 3 years. Both doxazosin, an alphainhibitor, and finaseride, a 5-alpha reductase inhibitor, are highly protein bound and hepatically metabolized. There is no definitive controlled clinical experience on the concomitant use of alphainhibitors and 5-alpha reductase inhibitors at this time.<br/>Impaired Liver Function: Doxazosin mesylate should be administered with caution to patients with evidence of impaired hepatic function or to patients receiving drugs known to influence hepatic metabolism (see CLINICAL PHARMACOLOGY).<br/>Leukopenia/Neutropenia: Analysis of hematologic data from hypertensive patients receiving doxazosin mesylate in controlled hypertension clinical trials showed that the mean WBC (N = 474) and mean neutrophil counts (N = 419) were decreased by 2.4% and 1.0% respectively, compared to placebo, a phenomenon seen with other alpha blocking drugs. In BPH patients the incidence of clinically significant WBC abnormalities was 0.4% (2/459) with doxazosin mesylate and 0% (0/147) with placebo, with no statistically significant difference between the two treatment groups. A search through a data base of 2400 hypertensive patients and 665 BPH patientsrevealed 4 hypertensives in which drug-related neutropenia could not be ruled out and one BPH patient in which drug related leukopenia could not be ruled out. Two hypertensives had a single low value on the last day of treatment. Two hypertensives had stable, non-progressive neutrophil counts in the 1000/mmrange over periods of 20 and 40 weeks. One BPH patient had a decrease from WBC count of 4800/mmto 2700/mmat the end of the study; there was no evidence of clinical impairment. In cases where follow-up was available the WBCs and neutrophil counts returned to normal after discontinuation of doxazosin mesylate. No patients became symptomatic as a result of the low WBC or neutrophil counts.<br/>Drug Interactions: Most (98%) of plasma doxazosin is protein bound. In vitro data in human plasma indicate that doxazosin mesylate has no effect on protein binding of digoxin, warfarin, phenytoin, or indomethacin. There is no information on the effect of other highly plasma protein bound drugs on doxazosin binding. Doxazosin mesylate has been administered without any evidence of an adverse drug interaction to patients receiving thiazide diuretics, beta-blocking agents, and non-steroidal anti-inflammatory drugs. In a placebo-controlled trial in normal volunteers, the administration of a single 1 mg dose of doxazosin on day 1 of a four-day regimen of oral cimetidine (400 mg twice daily) resulted in a 10% increase in mean AUC of doxazosin (p = 0.006), and a slight but not statistically significant increase in mean Cand mean half-life of doxazosin. The clinical significance of this increase in doxazosin AUC is unknown. In clinical trials, doxazosin mesylate tablets have been administered to patients on a variety of concomitant medications; while no formal interaction studies have been conducted, no interactions were observed. Doxazosin mesylate tablets have been used with the following drugs or drug classes: 1) analgesic/anti-inflammatory (e.g., acetaminophen, aspirin, codeine and codeine combinations, ibuprofen, indomethacin); 2) antibiotics (e.g., erythromycin, trimethoprim and sulfamethoxazole, amoxicillin); 3) antihistamines (e.g., chlorpheniramine); 4) cardiovascular agents (e.g., atenolol, hydrochlorothiazide, propranolol); 5) corticosteroids; 6) gastrointestinal agents (e.g., antacids); 7) hypoglycemics and endocrine drugs; 8) sedatives and tranquilizers (e.g., diazepam); 9)cold and flu remedies.<br/>Cardiac Toxicity in Animals: An increased incidence of myocardial necrosis or fibrosis was displayed by Sprague-Dawley rats after 6 months of dietary administration at concentrations calculated to provide 80 mg doxazosin/kg/day and after 12 months of dietary administration at concentrations calculated to provide 40 mg doxazosin/kg/day (AUC exposure in rats 8 times the human AUC exposure with a 12 mg/day therapeutic dose). Myocardial fibrosis was observed in both rats and mice treated in the same manner with 40 mg doxazosin/kg/day for 18 months (exposure 8 times human AUC exposure in rats and somewhat equivalent to human Cexposure in mice). No cardiotoxicity was observed at lower doses (up to 10 or 20 mg/kg/day, depending on the study) in either species. These lesions were not observed after 12 months of oral dosing in dogs at maximum doses of 20 mg/kg/day [maximum plasma concentrations (C) in dogs 14 times the Cexposure in humans receiving a 12 mg/day therapeutic dose] and in Wistar rats at doses of 100 mg/kg/day (Cexposures 15 times human Cexposure with a 12 mg/day therapeutic dose). There is no evidence that similar lesions occur in humans.<br/>Carcinogenesis and Mutagenesis and Impairment of Fertility: Chronic dietary administration (up to 24 months) of doxazosin mesylate at maximally tolerated doses of 40 mg/kg/day in rats and 120 mg/kg/day in mice revealed no evidence of carcinogenic potential. The highest doses evaluated in the rat and mouse studies are associated with AUCs (a measure of systemic exposure) that are 8 times and 4 times, respectively, the human AUC at a dose of 16 mg/day. Mutagenicity studies revealed no drug- or metabolite-related effects at either chromosomal or subchromosomal levels. Studies in rats showed reduced fertility in males treated with doxazosin at oral doses of 20 (but not 5 or 10) mg/kg/day, about 4 times the AUC exposures obtained with a 12 mg/day human dose. This effect was reversible within two weeks of drug withdrawal. There have been no reports of any effects of doxazosin on male fertility in humans.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nonteratogenic Effects: In peri-postnatal studies in rats, postnatal development at maternal doses of 40 or 50 mg/kg/day of doxazosin (8 times human AUC exposure with a 12 mg/day therapeutic dose) was delayed as evidenced by slower body weight gain and a slightly later appearance of anatomical features and reflexes.<br/>Nursing Mothers: Studies in lactating rats given a single oral dose of 1 mg/kg of [2-C]-doxazosin mesylate indicate that doxazosin accumulates in rat breast milk with a maximum concentration about 20 times greater than the maternal plasma concentration. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when doxazosin mesylate is administered to a nursing mother.<br/>Pediatric Use: The safety and effectiveness of doxazosin mesylate as an antihypertensive agent have not been established in children.<br/>Geriatric Use: The safety and effectiveness profile of doxazosin mesylate in BPH was similar in the elderly (age���65 years) and younger (age<65 years) patients. Clinical studies of doxazosin mesylate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:161 | dailymed-instance:precautio... | General:<br/>Discontinuation of Treatment with Citalopram Hydrobromide: During marketing of citalopram hydrobromide and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with citalopram hydrobromide. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate .<br/>Abnormal Bleeding: Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic drugs that interfere with serotonin reuptake. Subsequent epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of a nonsteroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding . Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding associated with the concomitant use of citalopram hydrobromide with NSAIDs, aspirin, or other drugs that affect coagulation.<br/>Hyponatremia: Cases of hyponatremia and SIADH (syndrome of inappropriate antidiuretic hormone secretion) have been reported in association with citalopram hydrobromide treatment. All patients with these events have recovered with discontinuation of citalopram hydrobromide and/or medical intervention. Hyponatremia and SIADH have also been reported in association with other marketed drugs effective in the treatment of major depressive disorder.<br/>Activation of Mania/Hypomania: In placebo-controlled trials of citalopram hydrobromide, some of which included patients with bipolar disorder, activation of mania/hypomania was reported in 0.2% of 1063 patients treated with citalopram hydrobromide and in none of the 446 patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with other marketed antidepressants. As with all antidepressants, citalopram hydrobromide should be used cautiously in patients with a history of mania.<br/>Seizures: Although anticonvulsant effects of citalopram have been observed in animal studies, citalopram hydrobromide has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product's premarketing testing. In clinical trials of citalopram hydrobromide, seizures occurred in 0.3% of patients treated with citalopram hydrobromide (a rate of one patient per 98 years of exposure) and 0.5% of patients treated with placebo (a rate of one patient per 50 years of exposure). Like other antidepressants, citalopram hydrobromide should be introduced with care in patients with a history of seizure disorder.<br/>Interference with Cognitive and Motor Performance: In studies in normal volunteers, citalopram hydrobromide in doses of 40 mg/day did not produce impairment of intellectual function or psychomotor performance. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that citalopram hydrobromide therapy does not affect their ability to engage in such activities.<br/>Use in Patients with Concomitant Illness: Clinical experience with citalopram hydrobromide in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using citalopram hydrobromide in patients with diseases or conditions that produce altered metabolism or hemodynamic responses. Citalopram hydrobromide has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical studies during the products premarketing testing. However, the electrocardiograms of 1116 patients who received citalopram hydrobromide in clinical trials were evaluated and the data indicate that citalopram hydrobromide is not associated with the development of clinically significant ECG abnormalities. In subjects with hepatic impairment, citalopram clearance was decreased and plasma concentrations were increased. The use of citalopram hydrobromide in hepatically impaired patients should be approached with caution and a lower maximum dosage is recommended . Because citalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with citalopram hydrobromide, however, it should be used with caution in such patients .<br/>Information for Patients: Physicians are advised to discuss the following issues with patients for whom they prescribe citalopram hydrobromide: Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of citalopram hydrobromide and triptans, tramadol or other serotonergic agents. Although in controlled studies citalopram hydrobromide has not been shown to impair psychomotor performance, any psychoactive drug may impair judgment, thinking or motor skills, so patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that citalopram hydrobromide therapy does not affect their ability to engage in such activities. Patients should be told that, although citalopram hydrobromide has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of citalopram hydrobromide and alcohol in depressed patients is not advised. Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions. Patients should be cautioned about the concomitant use of citalopram hydrobromide and NSAIDs, aspirin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents had been associated with an increased risk of bleeding. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physician if they are breast-feeding an infant. While patients may notice improvement with citalopram hydrobromide therapy in 1 to 4 weeks, they should be advised to continue therapy as directed. Prescribers or other health professionals should inform patients, their families and their caregivers about the benefits and risks associated with treatment with citalopram hydrobromide tablets and should counsel them in its appropriate use. A patient Medication Guide about���Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions���is available for citalopram hydrobromide tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking citalopram hydrobromide tablets. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of citalopram and triptans, tramadol or other serotonergic agents.<br/>Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk forsuicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.<br/>Laboratory Tests: There are no specific laboratory tests recommended.<br/>Interactions:<br/>Drug Interactions:<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis: Citalopram was administered in the diet to NMRI/BOM strain mice and COBS WI strain rats for 18 months and 24 months, respectively. There was no evidence for carcinogenicity of citalopram in mice receiving up to 240 mg/kg/day, which is equivalent to 20 times the maximum recommended human daily dose (MRHD) of 60 mg on a surface area (mg/m) basis. There was an increased incidence of small intestine carcinoma in rats receiving 8 mg/kg/day or 24 mg/kg/day, doses which are approximately 1.3 times and 4 times the MRHD, respectively, on a mg/mbasis. A no-effect dose for this finding was not established. The relevance of these findings to humans is unknown.<br/>Mutagenesis: Citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Citalopram was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in a coupled invitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. It was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays.<br/>Impairment of Fertility: When citalopram was administered orally to 16 male and 24 female rats prior to and throughout mating and gestation at doses of 32 mg/kg/day, 48mg/kg/day and 72 mg/kg/day, mating was decreased at all doses, and fertility was decreased at doses���32 mg/kg/day, approximately 5 times the MRHD of 60 mg/day on a body surface area (mg/m) basis. Gestation duration was increased at 48 mg/kg/day, approximately 8 times the MRHD.<br/>Pregnancy:<br/>Pregnancy Category C: In animal reproduction studies, citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at doses greater than human therapeutic doses. In two rat embryo/fetal development studies, oral administration of citalopram (32 mg/kg/day, 56mg/kg/day or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose, which is approximately 18 times the MRHD of 60 mg/day on a body surface area (mg/m) basis. This dose was also associated with maternal toxicity (clinical signs, decreased body weight gain). The developmental, no-effect dose of 56 mg/kg/day is approximately 9 times the MRHD on a mg/mbasis. In a rabbit study, no adverse effects on embryo/fetal development were observed at doses of up to 16 mg/kg/day, or approximately 5 times the MRHD on a mg/mbasis. Thus, teratogenic effects were observed at a maternally toxic dose in the rat and were not observed in the rabbit. When female rats were treated with citalopram (4.8 mg/kg/day, 12.8 mg/kg/day or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at the highest dose, which is approximately 5 times the MRHD on a mg/mbasis. The no effect dose of 12.8 mg/kg/day is approximately 2 times the MRHD on a mg/mbasis. Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses���24 mg/kg/day, approximately 4 times the MRHD on a mg/mbasis. A no effect dose was not determined in that study. There are no adequate and well-controlled studies in pregnant women; therefore, citalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nonteratogenic Effects: Neonates exposed to citalopram hydrobromide and other SSRIs or SNRIs, late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture isconsistent with serotonin syndrome . Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective, case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. When treating a pregnant woman with citalopram hydrobromide during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment . Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.<br/>Labor and Delivery: The effect of citalopram hydrobromide on labor and delivery in humans is unknown.<br/>Nursing Mothers: As has been found to occur with many other drugs, citalopram is excreted in human breast milk. There have been two reports of infants experiencing excessive somnolence, decreased feeding, and weight loss in association with breast feeding from a citalopram-treated mother; in one case, the infant was reported to recover completely upon discontinuation of citalopram by its mother and in the second case, no follow-up information was available. The decision whether to continue or discontinue either nursing or citalopram hydrobromide therapy should take into account the risks of citalopram exposurefor the infant and the benefits of citalopram hydrobromide treatment for the mother.<br/>Pediatric Use: Safety and effectiveness in the pediatric population have not been established . Two placebo-controlled trials in 407 pediatric patients with MDD have been conducted with citalopram hydrobromide tablets, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of citalopram hydrobromide tablets in a child or adolescent must balance the potential risks with the clinical need.<br/>Geriatric Use: Of 4422 patients in clinical studies of citalopram hydrobromide, 1357 were 60 and over, 1034 were 65 and over, and 457 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Most elderly patients treated with citalopram hydrobromide in clinical trials received daily doses between 20 mg and 40 mg . In two pharmacokinetic studies, citalopram AUC was increased by 23% and 30%, respectively, in elderly subjects as compared to younger subjects, and its half-life was increased by 30% and 50%, respectively . 20 mg/day is the recommended dose for most elderly patients . | lld:dailymed |
| dailymed-drugs:162 | dailymed-instance:precautio... | General: As with other antibiotic preparations, prolonged use may result in overgrowth of nonsusceptible organisms, including fungi. Treatment should not be continued for longer than 7 days. If the infection is not improved after 1 week, cultures and susceptibility tests should be repeated to verify the identity of the organism and to determine whether therapy should be changed. Allergic cross-reactions may occur which could prevent the use of any or all of the aminoglycoside antibiotics for the treatment of future infections. Use of steroids on infected areas should be supervised with care as anti-inflammatory steroids may encourage spread of infections. If this occurs, steroid therapy should be stopped and appropriate antibacterial drugs used. Generalized dermatological conditions may require systemic corticosteroid therapy. Signs and symptoms of exogenous hyperadrenocorticism can occur with the use of topical corticosteroids, including adrenal suppression. Systemic absorption of topically applied steroids will be increased if extensive body surface areas are treated or if occlusive dressings are used. Under these circumstances, suitable precautions should be taken when long-term use is anticipated.<br/>Information for Patients: If redness, irritation, swelling, or pain persists or increases, discontinue use and notify physician. Do not use in the eyes.<br/>Laboratory Tests: Systemic effects of excessive levels of hydrocortisone may include a reduction in the number of circulating eosinophils and a decrease in urinary excretion of 17-hydroxycorticosteroids.<br/>Carcinogenesis and Mutagenesis and Impairment of Fertility: Long-term studies in animals (rats, rabbits, mice) showed no evidence of carcinogenicity attributable to oral administration of corticosteroids.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C. Corticosteroids have been shown to be teratogenic in rabbits when applied topically at concentrations of 0.5% on days 6 to 18 of gestation and in mice when applied topically at a concentration of 15% on days 10 to 13 of gestation. There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: Hydrocortisone appears in human milk following oral administration of the drug. Since systemic absorption of hydrocortisone may occur when applied topically, caution should be exercised when CORTISPORIN Ointment is used by a nursing woman.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Sufficient percutaneous absorption of hydrocortisone can occur in infants and children during prolonged use to cause cessation of growth, as well as other signs and symptoms of hyperadrenocorticism.<br/>Geriatric Use: Clinical studies of Cortisporin Ointment did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. | lld:dailymed |
| dailymed-drugs:163 | dailymed-instance:precautio... | General: Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria in some patients. Conditions that augment systemic absorption include application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings . Therefore, patients receiving a large dose of any potent topical steroid applied to large surface area should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests, and for impairment of thermal homeostasis. If HPA axis suppression or elevation of the body temperature occurs, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function and thermal homeostasis are generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids. Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity . If irritation or hypersensitivity develops with the combination nystatin and triamcinolone acetonide, treatment should be discontinued and appropriate therapy instituted.<br/>Information for the Patient: Patients using this medication should receive the following information and instructions:<br/>Laboratory Test: If there is a lack of therapeutic response, appropriate microbiological studies (e.g., KOH smears and/or cultures) should be repeated to confirm the diagnosis and rule out other pathogens, before instituting another course of therapy. A urinary free cortisol test and ACTH stimulation test may be helpful in evaluating hypothalamic-pituitary-adrenal (HPA) axis suppression due to corticosteroid.<br/>Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long-term animal studies have not been performed to evaluate carcinogenic or mutagenic potential, or possible impairment of fertility in males or females.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C: There are no teratogenic studies with combined nystatin and triamcinolone acetonide. Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. Therefore, any topical corticosteroid preparation should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Topical preparations containing corticosteroids should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time.<br/>Nursing Mothers: It is not known whether any component of this preparation is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised during use of this preparation by a nursing woman.<br/>Pediatric Use: In clinical studies of limited number number of pediatric patients ranging in age from two months through 12 years, MYCOLOG-II cleared or significantly ameliorated the disease state in most patients. Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced hypothalamic-pituitary-adrenal (HPA) axis suppression and Cushing's syndrome than mature patients because of a larger skin surface area to body weight ratio. HPA axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of children. | lld:dailymed |
| dailymed-drugs:164 | dailymed-instance:precautio... | General: As with other anti-infectives, prolonged use may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, discontinue use and institute alternative therapy. Whenever clinical judgment dictates, the patient should be examined with the aid of magnification, such as slit-lamp biomicroscopy, and, where appropriate, fluorescein staining. Patients should be advised not to wear contact lenses if they have signs and symptoms of bacterial conjunctivitis.<br/>Information for Patients: Avoid contaminating the applicator tip with material from the eye, fingers or other source. Systemic quinolones have been associated with hypersensitivity reactions, even following a single dose. Discontinue use immediately and contact your physician at the first sign of a rash or allergic reaction.<br/>Drug Interactions: Specific drug interaction studies have not been conducted with QUIXIN. However, the systemic administration of some quinolones has been shown to elevate plasma concentrations of theophylline, interfere with the metabolism of caffeine, and enhance the effects of the oral anticoagulant warfarin and its derivatives, and has been associated with transient elevations in serum creatinine in patients receiving systemic cyclosporine concomitantly.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In a long term carcinogenicity study in rats, levofloxacin exhibited no carcinogenic or tumorigenic potential following daily dietary administration for 2 years; the highest dose (100 mg/kg/day) was 875 times the highest recommended human ophthalmic dose. Levofloxacin was not mutagenic in the following assays: Ames bacterial mutation assay (S. typhimurium and E. coli), CHO/HGPRT forward mutation assay, mouse micronucleus test, mouse dominant lethal test, rat unscheduled DNA synthesis assay, and the in vivo mouse sister chromatid exchange assay. It was positive in the in vitro chromosomal aberration (CHL cell line) and in vitro sister chromatid exchange (CHL/IU cell line) assays. Levofloxacin caused no impairment of fertility or reproduction in rats at oral doses as high as 360 mg/kg/day, corresponding to 3,150 times the highest recommended human ophthalmic dose.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C:Levofloxacin at oral doses of 810 mg/kg/day in rats, which corresponds to approximately 7,000 times the highest recommended human ophthalmic dose, caused decreased fetal body weight and increased fetal mortality. No teratogenic effect was observed when rabbits were dosed orally as high as 50 mg/kg/day, which corresponds to approximately 400 times the highest recommended maximum human ophthalmic dose, or when dosed intravenously as high as 25 mg/kg/day, corresponding to approximately 200 times the highest recommended human ophthalmic dose. There are, however, no adequate and well-controlled studies in pregnant women. Levofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: Levofloxacin has not been measured in human milk. Based upon data from ofloxacin, it can be presumed that levofloxacin is excreted in human milk. Caution should be exercised when QUIXIN is administered to a nursing mother.<br/>Pediatric Use: Safety and effectiveness in infants below the age of one year have not been established. Oral administration of quinolones has been shown to cause arthropathy in immature animals. There is no evidence that the ophthalmic administration of levofloxacin has any effect on weight bearing joints.<br/>Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and other adult patients. | lld:dailymed |
| dailymed-drugs:165 | dailymed-instance:precautio... | General: Women should be observed for signs of virilization which is usual following androgen use at high doses. Discontinuation of drug therapy at the time of evidence of mild virilism is necessary to prevent irreversible virilization. A decision may be made by the patient and the physician that some virilization will be tolerated during treatment for breast carcinoma. Patients with benign prostatic hypertrophy may develop acute urethral obstruction. Priapism or excessive sexual stimulation may develop. Oligospermia may occur after prolonged administration or excessive dosage. If any of these effects appear, the androgen should be stopped and if restarted, a lower dosage should be utilized. This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.<br/>Information for patients: Patients should be instructed to report any of the following: nausea, vomiting, changes in skin color, and ankle swelling. Males should be instructed to report too frequent or persistent erections of the penis and females any hoarseness, acne, changes in menstrual periods or increase in facial hair.<br/>Laboratory tests: Women with disseminated breast carcinoma should have frequent determination of urine and serum calcium levels during the course of androgen therapy . Because of the hepatotoxicity associated with the use of 17-alpha-alkylated androgens, liver function tests should be obtained periodically. Periodic (every six months) X-ray examinations of bone age should be made during treatment of prepubertal males to determine the rate of bone maturation and the effects of androgen therapy on the epiphyseal centers. Hemoglobin and hematocrit levels (to detect polycythemia) should be checked periodically in patients receiving long-term androgen administration. Serum cholesterol may increase during androgen therapy.<br/>Drug interactions: Androgens may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may require reduction in order to maintain satisfactory therapeutic hypoprothrombinemia. Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, insulin requirements.<br/>Drug/Laboratory test interferences: Androgens may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.<br/>Carcinogenesis, mutagenesis, impairment Of Fertility: Animal data: Testosterone has been tested by subcutaneous injection and implantation in mice and rats. The implant induced cervical-uterine tumors in mice, which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically-induced carcinomas of the liver in rats. Human data: There are rare reports of hepatocellular carcinoma in patients receiving long-term therapy with androgens in high doses. Withdrawal of the drugs did not lead to regression of the tumors in all cases. Geriatric patients treated with androgens may be at an increased risk of developing prostatic hypertrophy and prostatic carcinoma although conclusive evidence to support this concept is lacking. This compound has not been tested for mutagenic potential. However, as noted above, carcinogenic effects have been attributed to treatment with androgenic hormones. The potential carcinogenic effects likely occur through a hormonal mechanism rather than by a direct chemical interaction mechanism. Impairment of fertility was not tested directly in animal species. However, as noted below under Adverse Reactions, oligospermia in males and amenorrhea in females are potential adverse effects of treatment with HALOTESTIN Tablets. Therefore, impairment of fertility is a possible outcome of treatment with HALOTESTIN.<br/>Pregnancy:<br/>Teratogenic effects: Pregnancy Category X.<br/>Nursing mothers: HALOTESTIN is not recommended for use in nursing mothers.<br/>Pediatric use: Androgen therapy should be used very cautiously in children and only by specialists aware of the adverse effects on bone maturation. Skeletal maturation must be monitored every six months by an X-ray of the hand and wrist . | lld:dailymed |
| dailymed-drugs:166 | dailymed-instance:precautio... | Although seizures may be brought under control promptly, a significant proportion of patients experience a return to seizure activity, presumably due to the short-lived effect of diazepam after IV administration. The physician should be prepared to readminister the drug. However, diazepam is not recommended for maintenance, and once seizures are brought under control, consideration should be given to the administration of agents useful in longer term control of seizures. If diazepam is to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed, particularly with known compounds which may potentiate the action of diazepam, such as phenothiazines, narcotics, barbiturates, MAO inhibitors, and other antidepressants. In highly anxious patients with evidence of accompanying depression, particularly those who may have suicidal tendencies, protective measures may be necessary. The usual precautions in treating patients with impaired hepatic function should be observed. Metabolites of diazepam are excreted by the kidney; to avoid their excess accumulation, caution should be exercised in the administration to patients with compromised kidney function. Since an increase in cough reflex and laryngospasm may occur with peroral endoscopic procedures, the use of a topical anesthetic agent, and the availability of necessary countermeasures are recommended. Until additional information is available, diazepam injection is not recommended for obstetrical use. Diazepam injection has produced hypotension or muscular weakness in some patients particularly when used with narcotics, barbiturates, or alcohol. Lower doses (usually 2 mg to 5 mg) should be used for elderly and debilitated patients. The clearance of diazepam and certain other benzodiazepines can be delayed in association with Tagamet (cimetidine) administration. The clinical significance of this is unclear. | lld:dailymed |
| dailymed-drugs:168 | dailymed-instance:precautio... | General: Patients with an element of agitation may react adversely; discontinue therapy if necessary. Periodic CBC, differential, and platelet counts are advised during prolonged therapy. Drug treatment is not indicated in all cases of this behavioral syndrome and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe Methylin should depend on the physician's assessment of the chronicity and severity of the child's symptoms and their appropriateness for his/her age. Prescription should not depend solely on the presence of one or more of the behavioral characteristics. When these symptoms are associated with acute stress reactions, treatment with Methylin is usually not indicated. Long-term effects of Methylin in children have not been well established.<br/>Information for Patients: Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with methylphenidate and should counsel them in its appropriate use. A patient Medication Guide is available for Methylin' Chewable Tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The completetext of the Medication Guide is reprinted at the end of this document. Physicians are advised to discuss the following issues with patients for whom they prescribe Methylin: Choking���Taking this product without adequate fluid may cause it to swell and block your throat or esophagus and may cause choking. Do not take this product if you have difficulty in swallowing. If you experience chest pain, vomiting, or difficulty in swallowing or breathing after taking this product, seek immediate medical attention. Directions���Take this product (child or adult dose) with at least 8 ounces (a full glass) of water or other fluid. Taking this product without enough liquid may cause choking. See choking warning. Phenylketonurics���Phenylalanine is a component of aspartame. Each 2.5 mg Methylin Chewable Tablet contains 0.42 mg of phenylalanine; each 5.0 mg Methylin Chewable Tablet contains 0.84 mg of phenylalanine and each 10.0 mg Methylin Chewable Tablet contains 1.68 mg of phenylalanine.<br/>Drug Interactions: Methylin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Methylin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Methylin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 30 times and 2.5 times the maximum recommended human dose on a mg/kg and mg/mbasis, respectively. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which approximately 22 times and 4 times the maximum recommended human dose on a mg/kg and mg/mbasis, respectively. Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. The genotoxic potential of methylphenidate has not been evaluated in an in vivo assay.<br/>Usage in Pregnancy: Adequate animal reproduction studies to establish safe use of Methylin during pregnancy have not been conducted. However, in a recently conducted study, methylphenidate has been shown to have teratogenic effects in rabbits when given in doses of 200 mg/kg/day, which is approximately 167 times and 78 times the maximum recommended human dose on a mg/kg and a mg/mbasis, respectively. In rats, teratogenic effects were not seen when the drug was given in doses of 75 mg/kg/day, which is approximately 62.5 and 13.5 times the maximum recommended human dose on a mg/kg and a mg/mbasis, respectively. Therefore, until more information is available, methylphenidate should not be prescribed for women of childbearing age unless, in the opinion of the physician, the potential benefits outweigh the possible risks. | lld:dailymed |
| dailymed-drugs:171 | dailymed-instance:precautio... | General: Therapy with idarubicin requires close observation of the patient and careful laboratory monitoring. Hyperuricemia secondary to rapid lysis of leukemic cells may be induced. Appropriate measures must be taken to prevent hyperuricemia and to control any systemic infection before beginning therapy. Extravasation of idarubicin can cause severe local tissue necrosis. Extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If signs or symptoms of extravasation occur the injection or infusion should be terminated immediately and restarted in another vein.<br/>Laboratory Tests: Frequent complete blood counts and monitoring of hepatic and renal function tests are recommended.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Formal long-term carcinogenicity studies have not been conducted with idarubicin. Idarubicin and related compounds have been shown to have mutagenic and carcinogenic properties when tested in experimental models (including bacterial systems, mammalian cells in culture and female Sprague-Dawley rats). In male dogs given 1.8 mg/m/day 3 times/week (about one seventh the weekly human dose on a mg/mbasis) for 13 weeks, or 3 times the human dose, testicular atrophy was observed with inhibition of spermatogenesis and sperm maturation with few or no mature sperm. These effects were not readily reversed after a recovery of 8 weeks.<br/>Pregnancy Category D:<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from idarubicin, mothers should discontinue nursing prior to taking this drug.<br/>Pediatric Use: Safety and effectiveness in children have not been established.<br/>Geriatric Use: Patients over 60 years of age who were undergoing induction therapy experienced congestive heart failure, serious arrhythmias, chest pain, myocardial infarction, and asymptomatic declines in LVEF more frequently than younger patients . | lld:dailymed |
| dailymed-drugs:172 | dailymed-instance:precautio... | 1. General: Patients should be counseled that oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. Scheduled withdrawal bleeding does not occur with the use of LYBREL, therefore, the absence of withdrawal bleeding cannot be used as a sign of an unexpected pregnancy and as such, unexpected pregnancy may be difficult to recognize. Although pregnancy is unlikely if LYBREL is taken as directed, if for any reason, pregnancy is suspected in a woman using LYBREL, a pregnancy test should be performed.<br/>2. Physical Examination and Follow-Up: A periodic personal and family medical history and complete physical examination are appropriate for all women, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen, and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent, or recurrent abnormal vaginal bleeding, appropriate diagnostic measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.<br/>3. Lipid Disorders: Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. (See WARNINGS, 1a., 1d., and 8.) A small proportion of women will have adverse lipid changes while taking oral contraceptives. Nonhormonal contraception should be considered in women with uncontrolled dyslipidemias. Persistent hypertriglyceridemia may occur in a small population of combination oral contraceptive users. Elevations of plasma triglycerides may lead to pancreatitis and other complications.<br/>4. Liver Function: If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.<br/>5. Fluid Retention: Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.<br/>6. Emotional Disorders: Patients becoming significantly depressed while taking oral contraceptives should stop the medication and use an alternate method of contraception in an attempt to determine whether the symptom is drug related. Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.<br/>7. Contact Lenses: Contact-lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.<br/>8. Gastrointestinal: Diarrhea and/or vomiting may reduce hormone absorption resulting in decreased serum concentrations.<br/>9. Drug Interactions:<br/>Changes in Contraceptive Effectiveness Associated with Coadministration of Other Products:: Contraceptive effectiveness may be reduced when hormonal contraceptives are coadministered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or unscheduled bleeding. Examples include rifampin, rifabutin, barbiturates, primidone, phenylbutazone, phenytoin, dexamethasone, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin, and modafinil. In such cases a nonhormonal back-up method of birth control should be considered. Several cases of contraceptive failure and unscheduled bleeding have been reported in the literature with concomitant administration of antibiotics such as ampicillin and other penicillins, and tetracyclines. However, clinical pharmacology studies investigating drug interactions between combined oral contraceptives and these antibiotics have reported inconsistent results. Enterohepatic recirculation of estrogens may also be decreased by substances that reduce gut transit time. Several of the anti-HIV protease inhibitors have been studied with coadministration of oral combination hormonal contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The safety and efficacy of oral contraceptive products may be affected with coadministration of anti-HIV protease inhibitors. Health care professionals should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information. Herbal products containing St. John's Wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in unscheduled bleeding.<br/>Increase in Plasma Levels Associated with Coadministered Drugs:: Coadministration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increases AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen increase the bioavailability of ethinyl estradiol since these drugs act as competitive inhibitors for sulfation of ethinyl estradiol in the gastrointestinal wall, a known pathway of elimination for ethinyl estradiol. CYP 3A4 inhibitors such as indinavir, itraconazole, ketoconazole, fluconazole, and troleandomycin may increase plasma hormone levels. Troleandomycin may also increase the risk of intrahepatic cholestasis during coadministration with combination oral contraceptives.<br/>Changes in Plasma Levels of Coadministered Drugs:: Combination hormonal contraceptives containing some synthetic estrogens (eg, ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone and other corticosteroids, and theophylline have been reported with concomitant administration of oral contraceptives. Decreased plasma concentrations of acetaminophen and lamotrigine, and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid, due to induction of conjugation (particularly glucuronidation), have been noted when these drugs were administered with oral contraceptives. The prescribing information of concomitant medications should be consulted to identify potential interactions.<br/>10. Interactions with Laboratory Tests: Certain endocrine- and liver-function tests and blood components may be affected by oral contraceptives:<br/>11. Carcinogenesis: See WARNINGS section.<br/>12. Pregnancy: Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS sections.<br/>13. Nursing Mothers: Small amounts of oral contraceptive steroids and/or metabolites have been identified in the milk of nursing mothers, and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, combination oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use combination oral contraceptives, but to use other forms of contraception until she has completely weaned her child.<br/>14. Pediatric Use: Safety and efficacy of LYBREL tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.<br/>15. Geriatric Use: This product has not been studied in women over 65 years of age and is not indicated in this population.<br/>16. Information for the Patient: See DETAILED PATIENT LABELING printed below. | lld:dailymed |
| dailymed-drugs:174 | dailymed-instance:precautio... | General: Patients on ELITEK should receive intravenous hydration according to standard medical practice for the management of plasma uric acid in patients at risk for tumor lysis syndrome.<br/>Drug Interactions: No studies of interactions with other drugs have been conducted in humans. Rasburicase does not metabolize allopurinol, cytarabine, methylprednisolone, methotrexate, 6-mercaptopurine, thioguanine, etoposide, daunorubicin, cyclophosphamide or vincristine in vitro. No metabolic-based drug interactions are therefore anticipated with these agents in patients. In preclinical in vivo studies, rasburicase did not affect the activity of isoenzymes CYP1A, CYP2A, CYP2B, CYP2C, CYP2E, and CYP3A, suggesting no induction nor inhibition potential. Clinically relevant P450-mediated drug-drug interactions are therefore not anticipated in patients treated with the recommended ELITEK dose and dosing schedule.<br/>Laboratory Test Interactions: At room temperature, ELITEK causes enzymatic degradation of the uric acid in blood/plasma/serum samples potentially resulting in spuriously low plasma uric acid assay readings. The following special sample handling procedure must be followed to avoid ex vivo uric acid degradation. Uric acid must be analyzed in plasma. Blood must be collected into pre-chilled tubes containing heparin anticoagulant. Samples must be immediately immersed in an ice water bath. Plasma samples must be prepared by centrifugation in a pre-cooled centrifuge (4��C). Finally, the plasma must be maintained in an ice water bath and analyzed for uric acid within four hours of collection (see BOXED WARNINGS, Interference with Uric Acid Measurements).<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals to evaluate carcinogenic potential have not been performed. ELITEK was non-genotoxic in the Ames, unscheduled DNA synthesis, chromosome analysis, mouse lymphoma, and micronucleus tests. ELITEK did not affect reproductive performance or fertility in male or female rats at doses 8-fold higher than the human dose when corrected for differences in body surface area.<br/>Pregnancy Category C: Rasburicase is teratogenic in rabbits and rats. Pregnant rabbits were dosed with rasburicase at levels of 2, 10 or 20 mg/kg (equivalent to 10, 50 and 100 times the human equivalent dose). Mortality occurred at 2 and 20 mg/kg, abortions at 10 mg/kg and clinical signs of toxicity appeared at all dose levels. At doses equal to or greater than 10 mg/kg, decreases were observed in uterine weight and viable fetuses while increases were observed in the number of fetal resorptions and post-implantation loss. Additionally, fetal body weights were decreased while increases occurred in heart and great vessel malformation at all doses levels. In offspring of pregnant rats given 50 mg/kg (equivalent to 250 times the human dose), multiple heart and great vessel malformations were observed. There are no adequate and well-controlled studies in pregnant women. Because animal studies are not always predictive of human response, ELITEK should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue ELITEK, taking into account the importance of the drug to the mother.<br/>Pediatric Use: The efficacy and safety of ELITEK was studied in 246 pediatric patients ranging in age from 1 month to 17 years. There were an insufficient number of patients in the 0���6 months age group (n=7) to determine whether they respond differently from older children. These patients were pooled into the<2 years of age group (n=24). Children<2 years of age had a higher mean uric acid AUCthan those age 2���17 years (150��s.e. 16 mg���hr/dL vs. 108��s.e. 4 mg���hr/dL, respectively). In addition, the data suggest that children<2 years of age had a lower rate of success at achieving maintenance uric acid concentration by 48 hours [83% (95% CI of 62 to 95) vs. 93% (95% CI of 89 to 95), respectively]. Children<2 years old also experienced more toxicity. The following adverse events were observed more frequently in children less than 2 years of age compared to those age 2���17 years respectively: vomiting (75% vs. 55%), diarrhea (63% vs. 20%), fever (50% vs. 38%), and rash (38% vs. 10%).<br/>Geriatric Use: Five of the 19 adults among the 265 patients enrolled in clinical studies of ELITEK, were age 65 or greater. Therefore, there are insufficient data to determine whether geriatric subjects, or adults in general, respond differently from pediatric subjects. | lld:dailymed |
| dailymed-drugs:177 | dailymed-instance:precautio... | General: The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following a complete medical assessment. Before prescribing VIAGRA, it is important to note the following: Caution is advised when Phosphodiesterase Type 5 (PDE5) inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including VIAGRA, and alpha-adrenergic blocking agents are both vasodilators with blood pressure lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly (see Drug Interactions) leading to symptomatic hypotension (e.g. dizziness, lightheadedness, fainting). Consideration should be given to the following: Viagra has systemic vasodilatory properties and may augment the blood pressure lowering effect of other anti-hypertensive medications. Patients on multiple antihypertensive medications were included in the pivotal clinical trials for VIAGRA. In a separate drug interaction study, when amlodipine, 5 mg or 10 mg, and VIAGRA, 100 mg were orally administered concomitantly to hypertensive patients mean additional blood pressure reduction of 8 mmHg systolic and 7 mmHg diastolicwere noted (see Drug Interactions). The safety of VIAGRA is unknown in patients with bleeding disorders and patients with active peptic ulceration. VIAGRA should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia). The safety and efficacy of combinations of VIAGRA with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended. In humans, VIAGRA has no effect on bleeding time when taken alone or with aspirin. In vitro studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor). The combination of heparin and VIAGRA had an additive effect on bleeding time in the anesthetized rabbit, but this interaction has not been studied in humans.<br/>Information for Patients: Physicians should discuss with patients the contraindication of VIAGRA with regular and/or intermittent use of organic nitrates. Physicians should advise patients of the potential for VIAGRA to augment the blood pressure lowering effect of alpha-blockers and anti-hypertensive medications. Concomitant administration of VIAGRA and an alpha-blocker may lead to symptomatic hypotension in some patients. Therefore, when VIAGRA is co-administered with alpha-blockers, patients should be stable on alpha-blocker therapy prior to initiating VIAGRA treatment and VIAGRA should be initiated at the lowest dose. Physicians should discuss with patients the potential cardiac risk of sexual activity in patients with preexisting cardiovascular risk factors. Patients who experience symptoms (e.g., angina pectoris, dizziness, nausea) upon initiation of sexual activity should be advised to refrain from further activity and should discuss the episode with their physician. Physicians should advise patients to stop use of all PDE5 inhibitors, including VIAGRA, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Physicians shouldalso discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE5 inhibitors . Physicians should advise patients to stop taking PDE5 inhibitors, including VIAGRA, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including VIAGRA. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors . Physicians should warn patients that prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of VIAGRA. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result. The use of VIAGRA offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), may be considered.<br/>Drug Interactions:<br/>Effects of Other Drugs on VIAGRA:<br/>Effects of VIAGRA on Other Drugs:<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 29- and 42-times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18���21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.6 times the MRHD on a mg/mbasis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC. There was no effect on sperm motility or morphology after single 100 mg oral doses of VIAGRA in healthy volunteers.<br/>Pregnancy, Nursing Mothers and Pediatric Use: VIAGRA is not indicated for use in newborns, children, or women.<br/>Pregnancy Category B: No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received up to 200 mg/kg/day during organogenesis. These doses represent, respectively, about 20 and 40 times the MRHD on a mg/mbasis in a 50 kg subject. In the rat pre- and postnatal development study, the no observed adverse effect dose was 30 mg/kg/day given for 36 days. In the nonpregnant rat the AUC at this dose was about 20 times human AUC. There are no adequate and well-controlled studies of sildenafil in pregnant women.<br/>Geriatric Use: Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil . Since higher plasma levels may increase both the efficacy and incidence of adverse events, a starting dose of 25 mg should be considered . | lld:dailymed |
| dailymed-drugs:179 | dailymed-instance:precautio... | General: As with levodopa alone, periodic evaluations of hepatic, hematopoietic, cardiovascular, and renal function are recommended during extended concomitant therapy with LODOSYN and levodopa, or with LODOSYN and SINEMET (Carbidopa-Levodopa), or any combination of these drugs. Patients with chronic wide-angle glaucoma may be treated cautiously with LODOSYN and levodopa or SINEMET, or any combination of these drugs, just as with levodopa alone, provided the intraocular pressure is well controlled and the patient is monitored carefully for changes in intraocular pressure during therapy.<br/>Laboratory Tests: Abnormalities in laboratory tests may include elevations of liver function tests such as alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, and bilirubin. Abnormalities in blood urea nitrogen and positive Coombs test have also been reported. Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during concomitant administration of carbidopa and levodopa than with levodopa alone. Levodopa and carbidopa-levodopa combination products may cause a false-positive reaction for urinary ketone bodies when a test tape is used for determination of ketonuria. This reaction will not be altered by boiling the urine specimen. False-negative tests may result with the use of glucose-oxidase methods of testing for glucosuria.<br/>Drug Interactions: Caution should be exercised when the following drugs are administered concomitantly with LODOSYN (Carbidopa) given with levodopa or carbidopa-levodopa combination products. Symptomatic postural hypotension has occurred when LODOSYN, given with levodopa or carbidopa-levodopa combination products, was added to the treatment of a patient receiving antihypertensive drugs. Therefore, when therapy with LODOSYN, given with or without levodopa or carbidopa-levodopa combination products, is started, dosage adjustment of the antihypertensive drug may be required. For patients receiving monoamine oxidase inhibitors, see CONTRAINDICATIONS. Concomitant therapy with selegiline and carbidopa-levodopa may be associated with severe orthostatic hypotension not attributable to carbidopa-levodopa alone . There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and carbidopa-levodopa preparations. Dopamine Dreceptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and isoniazid may reduce the therapeutic effects of levodopa. In addition, the beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by phenytoin and papaverine. Patients taking these drugs with LODOSYN and levodopa or carbidopa-levodopa combination products should be carefully observed for loss of therapeutic response. Iron salts may reduce the bioavailability of carbidopa and levodopa. The clinical relevance is unclear. Although metoclopramide may increase the bioavailability of levodopa by increasing gastric emptying, metoclopramide may also adversely affect disease control by its dopamine receptor antagonistic properties.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis: There were no significant differences between treated and control rats with respect to mortality or neoplasia in a 96-week study of carbidopa at oral doses of 25, 45, or 135 mg/kg/day. Combinations of carbidopa and levodopa (10-20, 10-50, 10-100 mg/kg/day) were given orally to rats for 106 weeks. No effect on mortality or incidence and type of neoplasia was seen when compared to concurrent controls.<br/>Mutagenesis: Mutagenicity studies have not been performed with either carbidopa or the combination of carbidopa and levodopa.<br/>Fertility: Carbidopa had no effect on the mating performance, fertility, or survival of the young when administered orally to rats at doses of 30, 60, or 120 mg/kg/day. The highest dose caused a moderate decrease in body weight gain in males. The administration of carbidopa-levodopa at dose levels of 10-20, 10-50, or 10-100 mg/kg/day did not adversely affect the fertility of male or female rats, their reproductive performance, or the growth and survival of the young.<br/>Pregnancy:<br/>Pregnancy Category C: There are no adequate and well-controlled studies with LODOSYN in pregnant women. It has been reported from individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized. Carbidopa concentrations in fetal tissue appeared to be minimal. LODOSYN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Carbidopa, at doses as high as 120 mg/kg/day, was without teratogenic effects in the mouse or rabbit. In the rabbit, but not in the mouse, carbidopa-levodopa produced visceral anomalies, similar to those seen with levodopa alone, at approximately 7 times the maximum recommended human dose. The teratogenic effect of levodopa in rabbits was unchanged by the concomitant administration of carbidopa.<br/>Nursing Mothers: It is not known whether carbidopa is excreted in human milk. Because many drugs are excreted in human milk, and because of their potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the nursing woman.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established, and use of the drug in patients below the age of 18 is not recommended. | lld:dailymed |
| dailymed-drugs:180 | dailymed-instance:precautio... | General: Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria in some patients. Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids. Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity . If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted. In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled. Information for Patients: Patients using topical corticosteroids should receive the following information and instructions: Laboratory tests: The following tests may be helpful in evaluating the HPA axis suppression: Carcinogenesis, Mutagenesis and Impairment of Fertility: Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of topical corticosteroids. Studies to determine mutagenicity with prednisolone and hydrocortisone have revealed negative results. Pregnancy: Teratogenic Effects���Pregnancy Category C. Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids. Therefore, topical corticosteroids should be used during pregnancy only if the potential benefit justifies thepotential risk to the fetus. Drugs of this class should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time. Nursing Mothers: It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant. Nevertheless, caution should be exercised when topical corticosteroids are administered to a nursing woman. Pediatric Use: Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced HPA axis suppression and Cushing's syndrome than mature patients because of a larger skin surface area to body weight ratio. Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Administration of topical corticosteroids to pediatric patients should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of children. | lld:dailymed |
| dailymed-drugs:182 | dailymed-instance:precautio... | General:: Prolonged use of topical antibiotics may give rise to overgrowth of nonsusceptible microorganisms, including fungi. Bacterial resistance to gentamicin may also develop. If purulent discharge, inflammation or pain becomes aggravated, the patient should discontinue use of the medication and consult a physician. If irritation or hypersensitivity to any component of the drug develops, the patient should discontinue use of this preparation and appropriate therapy should be instituted.<br/>Information for Patients:: To avoid contamination, do not touch tip of container to the eye, eyelid or any surface.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:: There are no published carcinogenicity or impairment of fertility studies on gentamicin. Aminoglycoside antibiotics have been found to be non-mutagenic.<br/>Pregnancy:: Pregnancy Category C: Gentamicin has been shown to depress body weights, kidney weights and median glomerular counts in newborn rats when administered systemically to pregnant rats in daily doses approximately 500 times the maximum recommended ophthalmic human dose. There are no adequate and well-controlled studies in pregnant women. Gentamicin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Pediatric Use:: Safety and effectiveness in neonates have not been established. | lld:dailymed |
| dailymed-drugs:186 | dailymed-instance:precautio... | Amiodarone I.V. should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment.<br/>Thyroid Abnormalities: Amiodarone inhibits peripheral conversion of thyroxine (T) to triiodothyronine (T) and may cause increased thyroxine levels, decreased Tlevels, and increased levels of inactive reverse T(rT) in clinically euthyroid patients. It is also a potential source of large amounts of inorganic iodine. Because of its release of inorganic iodine, or perhaps for other reasons, amiodarone can cause either hypothyroidism or hyperthyroidism. Thyroid function should be monitored prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of amiodarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid-function tests may persist for several weeks or even months following amiodarone withdrawal. Hypothyroidism has been reported in 2 to 4% of patients in most series, but in 8 to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Hypothyroidism is best managed by amiodarone dose reduction and/or thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue amiodarone tablets in some patients. Hyperthyroidism occurs in about 2% of patients receiving amiodarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and/or arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED. Hyperthyroidism is best identified by relevant clinical symptoms and signs, accompanied usually by abnormally elevated levels of serum TRIA, and further elevations of serum T, and a subnormal serum TSH level (using a sufficiently sensitive TSH assay). The finding of a flat TSH response to TRH is confirmatory of hyperthyroidism and may be sought in equivocal cases. Since arrhythmia breakthroughs may accompany amiodarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of amiodarone. The institution of antithyroid drugs,��-adrenergic blockers and/or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. There have been reports of death associated with amiodarone-induced thyrotoxicosis. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. Amiodarone-induced hyperthyroidism may be followed by a transient period of hypothyroidism (see WARNINGS, Thyrotoxicosis). When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning. There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with amiodarone. In some instances hyperthyroidism was also present .<br/>Surgery: Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction defects of halogenated inhalational anesthetics.<br/>Corneal Refractive Laser Surgery: Patients should be advised that most manufacturers of corneal refractive laser surgery devices contraindicate that procedure in patients taking amiodarone I.V.<br/>Interactions:<br/>Drug interactions: Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines . Amiodarone is an inhibitor of CYP3A4 and p-glycoprotein. Therefore, amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors or inducers of CYP3A4 and substrates of p-glycoprotein. While only a limited number of in vivo drug-drug interactions with amiodarone have been reported, chiefly with the oral formulation, the potential for other interactions should be anticipated. This is especially important for drugs associated with serious toxicity, such as other antiarrhythmics. If such drugs are needed, their dose should be reassessed and, where appropriate, plasma concentration measured. In view of the long and variable half-life of amiodarone, potential for drug interactions exists not only with concomitant medication but also with drugs administered after discontinuation of amiodarone. Since amiodarone is a substrate for CYP3A4 and CYP2C8, drugs/substances that inhibit these isoenzymes may decrease the metabolism and increase serum concentration of amiodarone. Reported examples include the following:<br/>Electrolyte Disturbances: Patients with hypokalemia or hypomagnesemia should have the condition corrected whenever possible before being treated with amiodarone I.V., as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics.<br/>Carcinogenesis, mutagenesis, impairment of fertility: No carcinogenicity studies were conducted with amiodarone I.V. However, oral amiodarone caused a statistically significant, dose-related increase in the incidence of thyroid tumors (follicular adenoma and/or carcinoma) in rats. The incidence of thyroid tumors in rats was greater than the incidence in controls even at the lowest dose level tested, i.e., 5 mg/kg/day (approximately 0.08 times the maximum recommended human maintenance dose*). Mutagenicity studies conducted with amiodarone HCI (Ames, micronucleus, and lysogenic induction tests) were negative. No fertility studies were conducted with amiodarone I.V. However, in a study in which amiodarone HCI was orally administered to male and female rats, beginning 9 weeks prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately 1.4 times the maximum recommended human maintenance dose*). *600 mg in a 50 kg patient (dose compared on a body surface area basis).<br/>Pregnancy:<br/>Teratogenic effects:<br/>Nursing mothers: Amiodarone and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk, suggesting that breastfeeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered amiodarone have demonstrated reduced viability and reduced body weight gains. The risk of exposing the infant to amiodarone should be weighed against the potential benefit of arrhythmia suppression in the mother. The mother should be advised to discontinue nursing.<br/>Labor and delivery: It is not known whether the use of amiodarone during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect on the duration of gestation or on parturition.<br/>Pediatric use: The safety and efficacy of amiodarone in the pediatric population have not been established; therefore, its use in pediatric patients is not recommended. In a pediatric trial of 61 patients, aged 30 days to 15 years, hypotension (36%), bradycardia (20%), and atrio-ventricular block (15%) were common dose-related adverse events and were severe or life-threatening in some cases. Injection site reactions were seen in 5 (25%) of the 20 patients receiving amiodarone I.V. through a peripheral vein irrespective of dose regimen. Amiodarone I.V. contains the preservative benzyl alcohol . There have been reports of fatal "gasping syndrome" in neonates (children less than one month of age) following the administration of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse.<br/>Geriatric use: Clinical studies of amiodarone I.V. did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:187 | dailymed-instance:precautio... | General: Prescribing rifampin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. For the treatment of tuberculosis, rifampin is usually administered on a daily basis. Doses of rifampin greater than 600 mg given once or twice weekly have resulted in a high incidence of adverse reactions, including the���flu syndrome���(fever, chills and malaise), hematopoietic reactions (leukopenia, thrombocytopenia, or acute hemolytic anemia), cutaneous, gastrointestinal, and hepatic reactions, shortness of breath, shock, anaphylaxis, and renal failure. Recent studies indicate that regimens using twice-weekly doses of rifampin 600 mg plus isoniazid 15 mg/kg are much better tolerated. Intermittent therapy may be used if the patient cannot (or will not) self-administer drugs on a daily basis. Patients on intermittent therapy should be closely monitored for compliance and cautioned against intentional or accidental interruption of prescribed therapy, because of the increased risk of serious adverse reactions. Rifampin has enzyme induction properties that can enhance the metabolism of endogenous substrates including adrenal hormones, thyroid hormones, and vitamin D. Rifampin and isoniazid have been reported to alter vitamin D metabolism. In some cases, reduced levels of circulating 25-hydroxy vitamin D and 1, 25-dihydroxy vitamin D have been accompanied by reduced serum calcium and phosphate, and elevated parathyroid hormone.<br/>Rifampin IV: For intravenous infusion only. Must not be administered by intramuscular or subcutaneous route. Avoid extravasation during injection: local irritation and inflammation due to extravascular infiltration of the infusion have been observed. If these occur, the infusion should be discontinued and restarted at another site.<br/>Information for Patients: Patients should be counseled that antibacterial drugs including rifampin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When rifampin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by rifampin or other antibacterial drugs in the future. The patient should be told that rifampin may produce a reddish coloration of the urine, sweat, sputum, and tears, and the patient should be forewarned of this. Soft contact lenses may be permanently stained. The patient should be advised that the reliability of oral or other systemic hormonal contraceptives may be affected; consideration should be given to using alternative contraceptive measures. Patients should be instructed to notify their physicians promptly if they experience any of the following: fever, loss of appetite, malaise, nausea and vomiting, darkened urine, yellowish discoloration of the skin and eyes, and pain or swelling of the joints. Compliance with the full course of therapy must be emphasized, and the importance of not missing any doses must be stressed.<br/>Laboratory Tests: Adults treated for tuberculosis with rifampin should have baseline measurements of hepatic enzymes, bilirubin, serum creatinine, a complete blood count, and a platelet count (or estimate). Baseline tests are unnecessary in pediatric patients unless a complicating condition is known or clinically suspected. Patients should be seen at least monthly during therapy and should be specifically questioned concerning symptoms associated with adverse reactions. All patients with abnormalities should have follow-up, including laboratory testing, if necessary. Routine laboratory monitoring for toxicity in people with normal baseline measurements is generally not necessary.<br/>Drug Interactions: Enzyme Induction: Rifampin is known to induce certain cytochrome P-450 enzymes. Administration of rifampin with drugs that undergo biotransformation through these metabolic pathways may accelerate elimination of coadministered drugs. To maintain optimum therapeutic blood levels, dosages of drugs metabolized by these enzymes may require adjustment when starting or stopping concomitantly administered rifampin. Rifampin has been reported to accelerate the metabolism of the following drugs: anticonvulsants (eg, phenytoin), antiarrhythmics (eg, disopyramide, mexiletine, quinidine, tocainide), oral anticoagulants, antifungals (eg, fluconazole, itraconazole, ketoconazole), barbiturates, beta-blockers, calcium channel blockers (eg, diltiazem, nifedipine, verapamil), chloramphenicol, clarithromycin, corticosteroids, cyclosporine, cardiac glycoside preparations, clofibrate, oral or other systemic hormonal contraceptives, dapsone, diazepam, doxycycline, fluoroquinolones (eg, ciprofloxacin), haloperidol, oral hypoglycemic agents (sulfonylureas), levothyroxine, methadone, narcotic analgesics, nortriptyline, progestins, quinine, tacrolimus, theophylline, tricyclic antidepressants (eg, amitriptyline, nortriptyline), and zidovudine. It may be necessary to adjust the dosages of these drugs if they are given concurrently with rifampin. Patients using oral or other systemic hormonal contraceptives should be advised to change to nonhormonal methods of birth control during rifampin therapy. Rifampin has been observed to increase the requirements for anticoagulant drugs of the coumarin type. In patients receiving anticoagulants and rifampin concurrently, it is recommended that the prothrombin time be performed daily or as frequently as necessary to establish and maintain the required dose of anticoagulant. Diabetes may become more difficult to control. Concurrent use of ketoconazole and rifampin has resulted in decreased serum concentrations of both drugs. Concurrent use of rifampin and enalapril has resulted in decreased concentrations of enalaprilat, the active metabolite of enalapril. Dosage adjustments should be made if indicated by the patient's clinical condition. Other Interactions: When the two drugs were taken concomitantly, decreased concentrations of atovaquone and increased concentrations of rifampin were observed. Concurrent use of ketoconazole and rifampin has resulted in decreased serum concentrations of both drugs. Concurrent use of rifampin and enalapril has resulted in decreased concentrations of enalaprilat, the active metabolite of enalapril. Dosage adjustments should be made if indicated by the patient's clinical condition. Concomitant antacid administration may reduce the absorption of rifampin. Daily doses of rifampin should be given at least 1 hour before the ingestion of antacids. Probenecid and cotrimoxazole have been reported to increase the blood levels of rifampin. When rifampin is given concomitantly with either halothane or isoniazid, the potential for hepatotoxicity is increased. The concomitant use of rifampin and halothane should be avoided. Patients receiving both rifampin and isoniazid should be monitored close for hepatotoxicity. Plasma concentrations of sulfapyridine may be reduced following the concomitant administration of sulfasalazine and rifampin. This finding may be the result of alteration in the colonic bacteria responsible for the reduction of sulfasalazine to sulfapyridine and mesalamine.<br/>Drug/Laboratory Interactions: Cross-reactivity and false-positive urine screening tests for opiates have been reported in patients receiving rifampin when using the KIMS (Kinetic Interaction of Microparticles in Solution) method (eg, Abuscreen OnLine opiates assay; Roche Diagnostic Systems). Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish rifampin from opiates. Therapeutic levels of rifampin have been shown to inhibit standard microbiological assays for serum folate and Vitamin B. Thus, alternate assay methods should be considered. Transient abnormalities in liver function tests (eg, elevation in serum bilirubin, alkaline phosphatase, and serum transaminases) and reduced biliary excretion of contrast media used for visualization of the gallbladder have also been observed. Therefore, these tests should be performed before the morning dose of rifampin.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: There are no known human data on long-term potential for carcinogenicity, mutagenicity, or impairment of fertility. A few cases of accelerated growth of lung carcinoma have been reported in man, but a causal relationship with the drug has not been established. An increase in the incidence of hepatomas in female mice (of a strain known to be particularly susceptible to thespontaneous development of hepatomas) was observed when rifampin was administered in doses 2 to 10 times the average daily human dose for 60 weeks, followed by an observation period of 46 weeks. No evidence of carcinogenicity was found in male mice of the same strain, mice of a different strain, or rats, under similar experimental conditions. Rifampin has been reported to possess immunosuppressive potential in rabbits, mice, rats, guinea pigs, human lymphocytes in vitro, and humans. Antitumor activity in vitro has also been shown with rifampin. There was no evidence of mutagenicity in bacteria, Drosophila melanogaster, or mice. An increase in chromatid breaks was noted when whole blood cell cultures were treated with rifampin. Increased frequency of chromosomal aberrations was observed in vitro in lymphocytes obtained from patients treated with combinations of rifampin, isoniazid, and pyrazinamide and combinations of streptomycin, rifampin, isoniazid, and pyrazinamide.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy - Category C: Rifampin has been shown to be teratogenic in rodents given oral doses of rifampin 15 to 25 times the human dose. Although rifampin has been reported to cross the placental barrier and appear in cord blood, the effect of rifampin for injection, alone or in combination with other antituberculosis drugs, on the human fetus is not known. Neonates of rifampin-treated mothers should be carefully observed for any evidence of adverse effects. Isolated cases of fetal malformations have been reported; however, there are no adequate and well-controlled studies in pregnant women. Rifampin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Rifampin in oral doses of 150 to 250 mg/kg produced teratogenic effects in mice and rats. Malformations were primarily cleft palate in the mouse and spina bifida in the rat. The incidence of these anomalies was dose-dependent. When rifampin was given to pregnant rabbits in doses up to 20 times the usual daily human dose, imperfect osteogenesis and embryotoxicity were reported.<br/>Pregnancy:<br/>Non-Teratogenic Effects: When administered during the last few weeks of pregnancy, rifampin can cause post-natal hemorrhages in the mother and infant for which treatment with Vitamin K may be indicated.<br/>Nursing Mothers: Because of the potential for tumorigenicity shown for rifampin in animal studies, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: See CLINICAL PHARMACOLOGY - Pediatrics; see also DOSAGE AND ADMINISTRATION.<br/>Geriatric Use: Clinical studies of rifampin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Caution should therefore be observed in using rifampin in elderly patients. | lld:dailymed |
| dailymed-drugs:188 | dailymed-instance:precautio... | General: Severe hypotension, particularly with upright posture, may occur with even small doses of isosorbide mononitrate. This drug should therefore be used with caution in patients who may be volume depleted or who, for whatever reason, are already hypotensive. Hypotension induced by isosorbide mononitrate may be accompanied by paradoxical bradycardia and increased angina pectoris. Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy. In industrial workers who have had long-term exposure to unknown (presumably high) doses of organic nitrates, tolerance clearly occurs. Chest pain, acute myocardial infarction, and even sudden death have occurred during temporary withdrawal of nitrates from these workers, demonstrating the existence of true physical dependence. The importance of these observations to the routine, clinical use of oral isosorbide mononitrate is not known. Information for Patients: Patients should be told that the antianginal efficacy of Isosorbide Mononitrate Tablets can be maintained by carefully following the prescribed schedule of dosing. For most patients, this can be accomplished by taking the dose on arising. As with other nitrates, daily headaches sometimes accompany treatment with isosorbide mononitrate. In patients who get these headaches, the headaches are a marker of the activity of the drug. Patients should resist the temptation to avoid headaches by altering the schedule of their treatment with isosorbide mononitrate, since loss of headache may be associated with simultaneous loss of antianginal efficacy. Aspirin or acetaminophen often successfully relieves isosorbide mononitrate-induced headaches with no deleterious effect on isosorbide mononitrate's antianginal efficacy. Treatment with isosorbide mononitrate may be associated with lightheadedness on standing, especially just after rising from a recumbent or seated position. This effect may be more frequent in patients who have also consumed alcohol. Drug Interactions: The vasodilating effects of isosorbide mononitrate may be additive with those of other vasodilators. Alcohol, in particular, has been found to exhibit additive effects of this variety. Marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination. Dose adjustments of either class of agents may be necessary. Drug/Laboratory Test Interactions: Nitrates and nitrites may interfere with the Zlatkis-Zak color reaction, causing falsely low readings in serum cholesterol determinations. Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of carcinogenicity was observed in rats exposed to isosorbide mononitrate in their diets at doses of up to 900 mg/kg/day for the first 6 months and 500 mg/kg/day for the remaining duration of a study in which males were dosed for up to 121 weeks and females were dosed for up to 137 weeks. No evidence of carcinogenicity was observed in mice exposed to isosorbide mononitrate in their diets for up to 104 weeks at doses of up to 900 mg/kg/day. Isosorbide mononitrate did not produce gene mutations (Ames test, mouse lymphoma test) or chromosome aberrations (human lymphocyte and mouse micronucleus tests) at biologically relevant concentrations. No effects on fertility were observed in a study in which male and female rats were administered doses of up to 750 mg/kg/day beginning, in males, 9 weeks prior to mating, and in females, 2 weeks prior to mating. Pregnancy Teratogenic Effects:Pregnancy Category B In studies designed to detect effects of isosorbide mononitrate on embryo-fetal development, doses of up to 240 or 248 mg/kg/day, administered to pregnant rats and rabbits, were unassociated with evidence of such effects. These animal doses are about 100 times the maximum recommended human dose (120 mg in a 50 kg woman) when comparison is based on body weight; when comparison is based on body surface area,the rat dose is about 17 times the human dose and the rabbit dose is about 38 times the human dose. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Isosorbide Mononitrate Tablets should be used during pregnancy only if clearly needed. Nonteratogenic Effects: Neonatal survival and development and incidence of stillbirths were adversely affected when pregnant rats were administered oral doses of 750 (but not 300) mg isosorbide mononitrate/kg/day during late gestation and lactation. This dose (about 312 times the human dose when comparison is based on body weight and 54 times the human dose when comparison is based on body surface area) was associated with decreases in maternal weight gain and motor activity and evidence of impaired lactation. Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ISMN is administered to a nursing mother. Pediatric Use: The safety and effectiveness of ISMN in pediatric patients have not been established. Geriatric Use: Clinical studies of Isosorbide Mononitrate Tablets did not include sufficient information on patients age 65 and over to determine if they respond differently from younger patients. Other reported clinical experience for Isosorbide Mononitrate Tablets has not identified differences in response between elderly and younger patients. Clinical experience for organic nitrates reported in the literature identified a potential for severe hypotension and increased sensitivity to nitrates in the elderly. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients may have reduced baroreceptor function and may develop severe orthostatic hypotension when vasodilators are used. Isosorbide Mononitrate should therefore be used with caution in elderly patients who may be volume depleted, on multiple medications, or who, for whatever reason, are already hypotensive. Hypotension induced by isosorbide mononitrate may be accompanied by paradoxical bradycardia and increased angina pectoris. Elderly patients may be more susceptible to hypotension and may be at a greater risk of falling at therapeutic doses of nitroglycerin. Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy, particularly in the elderly. | lld:dailymed |
| dailymed-drugs:189 | dailymed-instance:precautio... | 1. Physical Examination: It is good medical practice for all women to have annual history and physical examinations, including women using DEPO-PROVERA Sterile Aqueous Suspension. The physical examination, however, may be deferred until after initiation of DEPO-PROVERA if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.<br/>2. Fluid Retention: Because progestational drugs may cause some degree of fluid retention, conditions which might be influenced by this condition, such as epilepsy, migraine, asthma, cardiac or renal dysfunction, require careful observation.<br/>3. Vaginal Bleeding: In cases of breakthrough bleeding, as in all cases of irregular bleeding per vaginum, nonfunctional causes should be borne in mind and adequate diagnostic measures undertaken.<br/>4. Depression: Patients who have a history of psychic depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.<br/>5. Masking of Climacteric: The age of the patient constitutes no absolute limiting factor although treatment with progestin may mask the onset of the climacteric.<br/>6. Use with Estrogen: Studies of the addition of a progestin product to an estrogen replacement regimen for seven or more days of a cycle of estrogen administration have reported a lowered incidence of endometrial hyperplasia. Morphological and biochemical studies of endometrial suggest that 10���13 days of a progestin are needed to provide maximal maturation of the endometrium and to eliminate any hyperplastic changes. Whether this will provide protection from endometrial carcinoma has not been clearly established. There are possible risks which may be associated with the inclusion of progestin in estrogen replacement regimen, including adverse effects on carbohydrate and lipid metabolism. The dosage used may be important in minimizing these adverse effects. A decrease in glucose tolerance has been observed in a small percentage of patients on estrogen-progestin combination treatment. The mechanism of this decrease is obscure. For this reason, diabetic patients should be carefully observed while receiving such therapy.<br/>7. Prolonged Use: The effect of prolonged use of DEPO-PROVERA Sterile Aqueous Suspension at the recommended doses on pituitary, ovarian, adrenal, hepatic, and uterine function is not known.<br/>8. Multi-dose Use: When multi-dose vials are used, special care to prevent contamination of the contents is essential. There is some evidence that benzalkonium chloride is not an adequate antiseptic for sterilizing DEPO-PROVERA Sterile Aqueous Suspension multi-dose vials. A povidone-iodine solution or similar product is recommended to cleanse the vial top prior to aspiration of contents.<br/>DRUG INTERACTIONS: Aminoglutethimide administered concomitantly with DEPO-PROVERA Sterile Aqueous Suspension may significantly depress the serum concentrations of medroxyprogesterone acetate. DEPO-PROVERA users should be warned of the possibility of decreased efficacy with the use of this or any related drugs.<br/>LABORATORY TEST INTERACTIONS: The pathologist should be advised of progestin therapy when relevant specimens are submitted. The following laboratory tests may be affected by progestins including DEPO-PROVERA Sterile Aqueous Suspension:<br/>CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: Long-term intramuscular administration of Medroxyprogesterone acetate (MPA) has been shown to produce mammary tumors in beagle dogs. There is no evidence of a carcinogenic effect associated with the oral administration of MPA to rats and mice. Medroxyprogesterone acetate was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays. Medroxyprogesterone acetate at high doses is an anti-fertility drug and high doses would be expected to impair fertility until the cessation of treatment.<br/>INFORMATION FOR THE PATIENT: See Patient Information at end of insert. | lld:dailymed |
| dailymed-drugs:190 | dailymed-instance:precautio... | General: Abnormal Bleeding���SSRIs and SNRIs, including fluoxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of SARAFEM and NSAIDs, aspirin, or other drugs that affect coagulation (see Drug Interactions). Anxiety and Insomnia���In 2 placebo���controlled trials of fluoxetine in PMDD, treatment���emergent adverse events were assessed. Rates were as follows for SARAFEM 20 mg (the recommended dose) continuous and intermittent pooled, SARAFEM 60 mg continuous, and pooled placebo, respectively: anxiety (3%, 9%, and 4%); nervousness (5%, 9%, and 3%); and insomnia (9%, 26%, and 7%). For individual rates for SARAFEM 20 mg given as continuous and intermittent dosing, see Table 2 and accompanying footnote under ADVERSE REACTIONS. Events associated with discontinuation for SARAFEM 20 mg continuous and intermittent pooled, SARAFEM 60 mg continuous, and pooled placebo, respectively, were: anxiety (0%, 6%, and 1%); nervousness (1%, 0%, and 0.5%); and insomnia (1%, 4%, and 0.5%). In US placebo���controlled clinical trials of fluoxetine for other approved indications, anxiety, nervousness, and insomnia have been among the most commonly reported adverse events . Altered Appetite and Weight���In 2 placebo���controlled trials of fluoxetine in PMDD, rates for anorexia were as follows for SARAFEM 20 mg (the recommended dose) continuous and intermittent pooled, SARAFEM 60 mg continuous, and pooled placebo, respectively: 4%, 13%, and 2%. For individual rates for SARAFEM 20 mg continuous and intermittent, see footnote accompanying Table 2 under ADVERSE REACTIONS. In 2 placebo���controlled trials (only one of which included a dose of 60 mg/day), potentially clinically significant weight gain (���7%) occurred in 8% of patients on SARAFEM 20 mg, 6% of patients on SARAFEM 60 mg, and 1% of patients on placebo. Potentially clinically significant weight loss (���7%) occurred in 7% of patients on SARAFEM 20 mg, 12% of patients on SARAFEM 60 mg, and 3% of patients on placebo. In US placebo���controlled clinical trials of fluoxetine for other approved indications, changes in appetite and weight have also been reported (see Table 3 and Other events observed in US clinical trials under ADVERSE REACTIONS). Activation of Mania/Hypomania���No patients treated with SARAFEM in 4 PMDD clinical trials (N=415) reported mania/hypomania. In all US fluoxetine clinical trials for conditions other than PMDD, 0.7% of 10,782 patients reported mania/hypomania. Activation of mania/hypomania may occur with medications used to treat depression, especially in patients predisposed to Bipolar Affective Disorder.<br/>Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including fluoxetine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when SARAFEM was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of fluoxetine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death. Seizures���No patients treated with SARAFEM in 4 PMDD clinical trials (N=415) reported seizures. In all US fluoxetine clinical trials for conditions other than PMDD, 0.2% of 10,782 patients reported seizures. Antidepressant medication should be introduced with care in patients with a history of seizures. The Long Elimination Half���Lives of Fluoxetine and its Metabolites���Because of the long elimination half���lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment . Use in Patients with Concomitant Illness���Clinical experience with fluoxetine in patients with concomitant systemic illness is limited. Caution is advisable in using fluoxetine in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product's premarket testing. However, the electrocardiograms of 312 patients who received fluoxetine in double���blind trials for a condition other than PMDD were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min. In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half���lives of these substances . A lower or less frequent dose should be used in patients with cirrhosis . Studies in depressed patients on dialysis did not reveal excessive accumulation of fluoxetine or norfluoxetine in plasma . Use of a lower or less frequent dose for renally impaired patients is not routinely necessary . In patients with diabetes, fluoxetine may alter glycemic control. Hypoglycemia has occurred during therapy with fluoxetine, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic dosage may need to be adjusted when therapy with fluoxetine is instituted or discontinued. Discontinuation of Treatment with SARAFEM���During marketing of SARAFEM and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self���limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with SARAFEM. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy, which may minimize the risk of discontinuation symptoms with this drug . Interference with Cognitive and Motor Performance���Any psychoactive drug may impair judgment, thinking, or motor skills, and patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely.<br/>Information for Patients: Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with SARAFEM and should counsel them in its appropriate use. A patient Medication Guide about���Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions���is available for SARAFEM. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking SARAFEM. Abnormal Bleeding���Patients should be cautioned about the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding . Clinical Worsening and Suicide Risk���Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day���to���day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Serotonin Syndrome���Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of SARAFEM and triptans, tramadol or other serotonergic agents.<br/>Laboratory Tests: There are no specific laboratory tests recommended.<br/>Drug Interactions: As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility . Drugs metabolized by CYP2D6���Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued . Drugs metabolized by CYP3A4���In an in vivo interaction study involving coadministration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine's extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. CNS active drugs���The risk of using fluoxetine in combination with other CNS active drugs has not been systematically evaluated. Nonetheless, caution is advised if the concomitant administration of fluoxetine and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status . Anticonvulsants���Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. Antipsychotics���Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between serotonin specific reuptake inhibitors (SSRIs) and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QTprolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QTprolongation warrants restricting the concurrent use of pimozide and fluoxetine. Concomitant use of fluoxetine and pimozide is contraindicated . For thioridazine, see CONTRAINDICATIONS and WARNINGS. Benzodiazepines���The half���life of concurrently administered diazepam may be prolonged in some patients . Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. Lithium���There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly. Tryptophan���Five patients receiving fluoxetine in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress. Monoamine oxidase inhibitors���See CONTRAINDICATIONS. Antidepressants���In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2���to 10���fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCA may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued . Serotonergic drugs���Based on the mechanism of action of SNRIs and SSRIs, including SARAFEM, and the potential for serotonin syndrome, caution is advised when SARAFEM is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non���selective MAOI), lithium, tramadol, or St. John's Wort . The concomitant use of SARAFEM with other SSRIs, SNRIs or tryptophan is not recommended (see Tryptophan). Triptans���There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of SARAFEM with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases . Potential effects of coadministration of drugs tightly bound to plasma proteins���Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein���bound fluoxetine by other tightly bound drugs . Drugs that interfere with hemostasis (e.g., NSAIDs, Aspirin, Warfarin)���Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued. Electroconvulsive therapy (ECT)���There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: There is no evidence of carcinogenicity or mutagenicity from in vitro or animal studies. Impairment of fertility in adult animals at doses up to 12.5 mg/kg/day (approximately 1.5 times the MRHD on a mg/mbasis) was not observed. Carcinogenicity���The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively [approximately 1.2 and 0.7 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/mbasis], produced no evidence of carcinogenicity. Mutagenicity���Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells. Impairment of fertility���Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/mbasis) indicated that fluoxetine had no adverse effects on fertility (see Pediatric Use).<br/>Pregnancy:<br/>Pregnancy Category C: In embryo���fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg on a mg/mbasis), throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/mbasis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/mbasis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no���effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/mbasis). Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nonteratogenic Effects: Neonates exposed to fluoxetine and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome . Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1���2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case���control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six���fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. When treating a pregnant woman with fluoxetine during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment . Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.<br/>Labor and Delivery: The effect of fluoxetine on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended. In one breast���milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother's plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools. The infant's plasma drug levelswere 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding.<br/>Pediatric Use: Safety and effectiveness in the pediatric population have not been established . Anyone considering the use of SARAFEM in a child or adolescent must balance the potential risks with the clinical need. Significant toxicity, including myotoxicity, long���term neurobehavioral and reproductive toxicity, and impaired bone development, has been observed following exposure of juvenile animals to fluoxetine. Some of these effects occurred at clinically relevant exposures. In a study in which fluoxetine (3, 10, or 30 mg/kg) was orally administered to young rats from weaning (Postnatal Day 21) through adulthood (Day 90), male and female sexual development was delayed at all doses, and growth (body weight gain, femur length) was decreased during the dosing period in animals receiving the highest dose. At the end of the treatment period, serum levels of creatine kinase (marker of muscle damage) were increased at the intermediate and high doses, and abnormal muscle and reproductive organ histopathology (skeletal muscle degeneration and necrosis, testicular degeneration and necrosis, epididymal vacuolation and hypospermia) was observed at the high dose. When animals were evaluated after a recovery period (up to 11 weeks after cessation of dosing), neurobehavioral abnormalities (decreased reactivity at all doses and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose) were seen; in addition, testicular and epididymal microscopic lesions anddecreased sperm concentrations were found in the high dose group, indicating that the reproductive organ effects seen at the end of treatment were irreversible. The reversibility of fluoxetine���induced muscle damage was not assessed. Adverse effects similar to those observed in rats treated with fluoxetine during the juvenile period have not been reported after administration of fluoxetine to adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving the low, intermediate, and highdose in this study were approximately 0.1���0.2, 1���2, and 5���10 times, respectively, the average exposure in pediatric patients receiving the maximum recommended dose (MRD) of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, were approximately 0.3���0.8, 1���8, and 3���20 times, respectively, pediatric exposure at the MRD. A specific effect of fluoxetine on bone development has been reported in mice treated with fluoxetine during the juvenile period. When mice were treated with fluoxetine (5 or 20 mg/kg, intraperitoneal) for 4 weeks starting at 4 weeks of age, bone formation was reduced resulting in decreased bone mineral content and density. These doses did not affect overall growth (body weight gain or femoral length). The doses administered to juvenile mice in this study are approximately 0.5 and 2 times the MRD for pediatric patients on a body surface area (mg/m) basis. In another mouse study, administration of fluoxetine (10 mg/kg intraperitoneal) during early postnatal development (Postnatal Days 4 to 21) produced abnormal emotional behaviors (decreased exploratory behavior in elevated plus���maze, increased shock avoidance latency) in adulthood (12 weeks of age). The dose used in this study is approximately equal to the pediatric MRD on a mg/mbasis. Because of the early dosing period in this study, the significance of these findings to the approved pediatric use in humans is uncertain.<br/>Geriatric Use: The diagnosis of PMDD is not applicable to postmenopausal women. | lld:dailymed |
| dailymed-drugs:191 | dailymed-instance:precautio... | General: Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid-base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Significant deviations from normal concentrations may require the use of additional electrolyte supplements. Strongly hypertonic nutrient solutions should be administered through an indwelling intravenous catheter with the tip located in the superior vena cava. Special care must be taken when giving hypertonic dextrose to a diabetic or prediabetic patient. To prevent severe hyperglycemia in such patients, insulin may be required. Peripheral intravenous administration of 8% Hepatasol (Amino Acid) Injection requires appropriate dilution and provision of adequate calories. Care should be taken to assure proper placement of the needle within the lumen of the vein. The venipuncture site should be inspected frequently for signs of infiltration. If venous thrombosis or phlebitis occurs, discontinue infusions or change infusion site and initiate appropriate treatment. Care should be taken to avoid circulatory overload, particularly in patients with cardiac insufficiency. In patients with myocardial infarct, infusion of amino acids should always be accompanied by dextrose since in anoxia, free fatty acids cannot be utilized by the myocardium and energy must be produced anaerobically from glycogen or glucose. Infusion of this amino acid formulation may not affect the clinical course of patients with fulminant hepatitis who have a poor prognosis and are generally unresponsive to treatment. It has been shown that the abnormal plasma amino acid pattern in fulminant hepatitis differs from that in chronic liver disease. Extraordinary electrolyte losses such as may occur during protracted nasogastric suction, vomiting, diarrhea, or gastrointestinal fistula drainage may necessitate additional electrolyte supplementation. Administration of glucose at a rate exceeding the patient's utilization rate may lead to hyperglycemia, coma, and death. Metabolic acidosis can be prevented or readily controlled by adding a portion of the cations in the electrolyte mixture as acetate salts and in the case of hyperchloremic acidosis, by keeping the total chloride content of the infusate to a minimum. 8% Hepatasol (Amino Acid) Injection contains less than 3 mEq chloride per liter. 8% Hepatasol (Amino Acid) Injection contains 10 mmoles/Liter of phosphate. Some patients, especially those with hypophosphatemia, may require additional phosphate. To prevent hypocalcemia, calcium supplementation should always accompany phosphate administration. To assure adequate intake, serum levels should be monitored frequently. 8% Hepatasol (Amino Acid) Injection has not been adequately studied in pregnant women and children; therefore, its safe use in such patients has not been demonstrated. To minimize the risk of possible incompatibilities arising from mixing this solution with other additives that may be prescribed, the final infusate should be inspected for cloudiness or precipitation immediately after mixing, prior to administration, and periodically during administration. Use 8% Hepatasol (Amino Acid) Injection only if solution is clear, the seal unbroken, and vacuum is present. Carcinogenesis, mutagenesis, impairment of fertility: Studies with 8% Hepatasol (Amino Acid) have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.<br/>Usage in Pregnancy:<br/>Pregnancy Category C.: Animal reproduction studies have not been conducted with 8% Hepatasol (Amino Acid) Injection. It is also not known whether 8% Hepatasol (Amino Acid) Injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 8% Hepatasol (Amino Acid) Injection should be given to a pregnant woman only if clearly needed.<br/>Nursing Mothers:: Caution should be exercised when 8% Hepatasol (Amino Acid) is administered to a nursing woman.<br/>Pediatric Use:: Safety and effectiveness of 8% Hepatasol (Amino Acid) Injection in pediatric patients have not been established by adequate and well-controlled studies. However, the use of amino acid injections in pediatric patients as an adjunct in the offsetting of nitrogen loss or in the treatment of negative nitrogen balance is referenced in the medical literature. See DOSAGE AND ADMINISTRATION.<br/>Special Precautions for Central Venous Nutrition: Administration by central venous catheter should be used only by those familiar with this technique and its complications. Central venous nutrition may be associated with complications which can be prevented or minimized by careful attention to all aspects of the procedure, including solution preparation, administration, and patient monitoring. It is essential that a carefully prepared protocol, based on current medical practices, be followed, preferably by an experienced team. Although a detailed discussion of the complications is beyond the scope of this insert, the following summary lists those based on current literature.<br/>Technical.: The placement of a central venous catheter should be regarded as a surgical procedure. One should be fully acquainted with various techniques of catheter insertion as well as recognition and treatment of complications. For details of techniques and placement sites, consult the medical literature. X-ray is the best means of verifying catheter placement. Complications known to occur from the placement of central venous catheters are pneumothorax, hemothorax, hydrothorax, artery puncture and transection, injury to the brachial plexus, malposition of the catheter, formation of arterio-venous fistula, phlebitis, thrombosis, pericardial tamponade, and air and catheter embolus.<br/>Septic.: The constant risk of sepsis is present during total parenteral nutrition. Since contaminated solutions and infusion catheters are potential sources of infection, it is imperative that the preparation of solutions and the placement and care of catheters be accomplished under controlled aseptic conditions. Solutions should ideally be prepared in the hospital pharmacy in a laminar flow hood. The key factor in their preparation is careful aseptic technique to avoid inadvertent touch contamination during mixing of solutions and subsequent admixtures. Solutions should be used promptly after mixing. Any storage should be under refrigeration for as brief a time as possible. Administration time for a single bottle and set should never exceed 24 hours. Consult the medical literature for a discussion of the management of sepsis. In brief, typical management includes replacing the solution being administered with a fresh container and set, and culturing the contents for bacterial or fungal contamination. If sepsis persists and another source of infection is not identified, the catheter is removed, the proximal tip cultured, and a new catheter reinserted when the fever has subsided. Non-specific, prophylactic antibiotic treatment is not recommended. Clinical experience indicates that the catheter is likely to be the prime source of infection as opposed to aseptically prepared and properly stored solutions.<br/>Metabolic.: The following metabolic complications have been reported during the use of central venous nutrition: metabolic acidosis, hypophosphatemia, alkalosis, hyperglycemia and glycosuria, osmotic diuresis and dehydration, rebound hypoglycemia, elevated liver enzymes, hypo- and hyper-vitaminosis, electrolyte imbalances and hyperammonemia in children. Frequent clinical evaluation and laboratory determinations are necessary, especially during the first few days of therapy to prevent or minimize these complications. | lld:dailymed |
| dailymed-drugs:192 | dailymed-instance:precautio... | General: Metoprolol tartrate should be used with caution in patients with impaired hepatic function.<br/>Drug Interactions: Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients treated with metoprolol tartrate plus a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.<br/>Risk of Anaphylactic Reaction: While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.<br/>General Anesthetics: Some inhalation anesthetics may enhance the cardiodepressant effect of beta-blockers .<br/>CYP2D6 Inhibitors: Potent inhibitors of the CYP2D6 enzyme may increase the plasma concentration of metoprolol tartrate. Strong inhibition of CYP2D6 would mimic the pharmacokinetics of CYP2D6 poor metabolizer (see Pharmacokinetics section). Caution should therefore be exercised when co-administering potent CYP2D6 inhibitors with metoprolol tartrate. Known clinically significant potent inhibitors of CYP2D6 are antidepressants such as fluoxetine, paroxetine or bupropion, antipsychotics such as thioridazine, antiarrhythmics such as quinidine or propafenone, antiretrovirals such as ritonavir, antihistamines such as diphenhydramine, antimalarials such as hydroxychloroquine or quinidine, antifungals such as terbinafine and medications for stomach ulcers such as cimetidine.<br/>Clonidine: If a patient is treated with clonidine and metoprolol tartrate concurrently, and clonidine treatment is to be discontinued, metoprolol tartrate should be stopped several days before clonidine is withdrawn. Rebound hypertension that can follow withdrawal of clonidine may be increased in patients receiving concurrent beta-blocker treatment.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have been conducted to evaluate carcinogenic potential. In a 2-year study in rats at three oral dosage levels of up to 800 mg/kg per day, there was no increase in the development of spontaneously occurring benign or malignant neoplasms of any type. The only histologic changes that appeared to be drug related were an increased incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg per day, benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (benign plus malignant) lung tumors, or in the overall incidence of tumors or malignant tumors. This21-month study was repeated in CD-1 mice, and no statistically or biologically significant differences were observed between treated and control mice of either sex for any type of tumor. All mutagenicity tests performed (a dominant lethal study in mice, chromosome studies in somatic cells, a Salmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly test in somatic interphase nuclei) were negative. No evidence of impaired fertility due to metoprolol tartrate was observed in a study performed in rats at doses up to 55.5 times the maximum daily human dose of 450 mg.<br/>Pregnancy:<br/>Category C: Metoprolol tartrate has been shown to increase postimplantation loss and decrease neonatal survival in rats at doses up to 55.5 times the maximum daily human dose of 450 mg. Distribution studies in mice confirm exposure of the fetus when metoprolol tartrate is administered to the pregnant animal. These studies have revealed no evidence of impaired fertility or teratogenicity. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.<br/>Nursing Mothers: Metoprolol tartrate is excreted in breast milk in a very small quantity. An infant consuming 1 liter of breast milk daily would receive a dose of less than 1 mg of the drug. Caution should be exercised when metoprolol tartrate is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric Use: Clinical trials of metoprolol tartrate in hypertension did not include sufficient numbers of elderly patients to determine whether patients over 65 years of age differ from younger subjects in their response to metoprolol tartrate. Other reported clinical experience in elderly hypertensive patients has not identified any difference in response from younger patients. In worldwide clinical trials of metoprolol tartrate in myocardial infarction, where approximately 478 patients were over 65 years of age (0 over 75 years of age), no age-related differences in safety and effectiveness were found. Other reported clinical experience in myocardial infarction has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some elderly individuals taking metoprolol tartrate cannot be categorically ruled out. Therefore, in general, it is recommended that dosing proceed with caution in this population. | lld:dailymed |
| dailymed-drugs:193 | dailymed-instance:precautio... | General: Vitamin D administration from fortified foods, dietary supplements, self-administered and prescription drug sources should be evaluated. Therapeutic dosage should be readjusted as soon as there is clinical improvement. Dosage levels must be individualized and great care exercised to prevent serious toxic effects. IN VITAMIN D RESISTANT RICKETS THE RANGE BETWEEN THERAPEUTIC AND TOXIC DOSES IS NARROW. When high therapeutic doses are used progress should be followed with frequent blood calcium determinations. In the treatment of hypoparathyroidism, intravenous calcium, parathyroid hormone, and/or dihydrotachysterol may be required. Maintenance of a normal serum phosphorus level by dietary phosphate restriction and/or administration of aluminum gels as intestinal phosphate binders in those patients with hyperphosphatemia as frequently seen in renal osteodystrophy is essential to prevent metastatic calcification. Adequate dietary calcium is necessary for clinical response to vitamin D therapy. This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. Protect from light.<br/>Drug Interactions: Mineral oil interferes with the absorption of fat-soluble vitamins, including vitamin D preparations. Administration of thiazide diuretics to hypoparathyroid patients who are concurrently being treated with DRISDOL may cause hypercalcemia.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term animal studies have been performed to evaluate the drug's potential in these areas.<br/>Pregnancy Category C: Animal reproduction studies have shown fetal abnormalities in several species associated with hypervitaminosis D. These are similar to the supravalvular aortic stenosis syndrome described in infants by Black in England (1963). This syndrome was characterized by supravalvular aortic stenosis, elfin facies, and mental retardation. For the protection of the fetus, therefore, the use of vitamin D in excess of the recommended dietary allowance during normal pregnancy should be avoided unless, in the judgment of the physician, potential benefits in a specific, unique case outweigh the significant hazards involved. The safety in excess of 400 IU of vitamin D daily during pregnancy has not been established.<br/>Nursing Mothers: Caution should be exercised when DRISDOL is administered to a nursing woman. In a mother given large doses of vitamin D, 25-hydroxycholecalciferol appeared in the milk and caused hypercalcemia in her child. Monitoring of the infant's serum calcium concentration is required in that case (Goldberg, 1972).<br/>Pediatric Use: Pediatric doses must be individualized .<br/>Geriatric Use: Clinical studies of DRISDOL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. A few published reports have suggested that the absorption of orally administered vitamin D may be attenuated in elderly compared to younger, individuals. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreasedhepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:194 | dailymed-instance:precautio... | General: Aminocaproic acid inhibits both the action of plasminogen activators and, to a lesser degree, plasmin activity. The drug should NOT be administered without a definite diagnosis and/or laboratory finding indicative of hyperfibrinolysis (hyperplasminemia).* Inhibition of fibrinolysis by aminocaproic acid may theoretically result in clotting or thrombosis. However, there is no definite evidence that administration of aminocaproic acid has been responsible for the few reported cases of intravascular clotting which followed this treatment. Rather, it appears that such intravascular clotting was most likely due to the patient's preexisting clinical condition, e.g., the presence of DIC. It has been postulated that extravascular clots formed in vivo may not undergo spontaneous lysisas do normal clots. Reports have appeared in the literature of an increased incidence of certain neurological deficits such as hydrocephalus, cerebral ischemia, or cerebral vasospasm associated with the use of antifibrinolytic agents in the treatment of subarachnoid hemorrhage (SAH). All of these events have also been described as part of the natural course of SAH, or as a consequence of diagnostic procedures such as angiography. Drug relatedness remains unclear. Thrombosis with severe sequelae (acute myocardial infarction, gangrene) has been rarely reported in patients with hemophilia receiving combined treatment with Factor IX concentrate and aminocaproic acid. Aminocaproic acid should not be administered concomitantly with prothrombin complex concentrates or with activated prothrombin concentrates unless the increased risk of thrombosis is outweighed by the anticipated clinical benefit.<br/>Laboratory Tests: The use of aminocaproic acid should be accompanied by tests designed to determine the amount of fibrinolysis present. There are presently available (a) general tests such as those for the determination of the lysis of a clot of blood or plasma and (b) more specific tests for the study of various phases of the fibrinolytic mechanisms. These latter tests include both semiquantitative and quantitative techniques for the determination of profibrinolysin, fibrinolysin, and antifibrinolysin.<br/>Drug/Laboratory Test Interactions: Prolongation of the template bleeding time has been reported during continuous intravenous infusion of aminocaproic acid at dosages exceeding 24 g/day. Platelet function studies in these patients have not demonstrated any significant platelet dysfunction. However, in vitro studies have shown that at high concentrations (7.4 mMol/L or 0.97 mg/mL and greater) EACA inhibits ADP and collagen-induced platelet aggregation, the release of ATP and serotonin, and the binding of fibrinogen to the platelets in a concentration response manner. Following a 10 g bolus of aminocaproic acid injection, transient peak plasma concentrations of 4.6 mMol/L or 0.60 mg/mL have been obtained. The concentration of aminocaproic acid necessary to maintain inhibition of fibrinolysis is 0.99 mMol/L or 0.13 mg/mL. Administration of a 5 g bolus followed by 1 to 1.25 g/hr should achieve and sustain plasma levels of 0.13 mg/mL. Thus, concentrations which have been obtained in vivo clinically in patients with normal renal function are considerably lower than the in vitro concentrations found to induce abnormalities in platelet function tests. However, higher plasma concentrations of aminocaproic acid may occur in patients with severe renal failure.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals to evaluate the carcinogenic potential of aminocaproic acid and studies to evaluate its mutagenic potential have not been conducted. Dietary administration of an equivalent of the maximum human therapeutic dose of aminocaproic acid to rats of both sexes impaired fertility as evidenced by decreased implantations, litter sizes and number of pups born.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C.: Animal teratological studies have not been conducted with aminocaproic acid. It is also not known whether aminocaproic acid can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Aminocaproic acid should be given to a pregnant woman only if clearly needed.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when aminocaproic acid is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established. | lld:dailymed |
| dailymed-drugs:196 | dailymed-instance:precautio... | Radionuclide Precautions: Iodine I 131 Tositumomab is radioactive. Care should be taken, consistent with the institutional radiation safety practices and applicable federal guidelines, to minimize exposure of medical personnel and other patients.<br/>Renal Function: Iodine I 131 Tositumomab and Iodine-131 are excreted primarily by the kidneys. Impaired renal function may decrease the rate of excretion of the radiolabeled iodine and increase patient exposure to the radioactive component of the BEXXAR therapeutic regimen. There are no data regarding the safety of administration of the BEXXAR therapeutic regimen in patients with impaired renal function.<br/>Immunization: The safety of immunization with live viral vaccines following administration of the BEXXAR therapeutic regimen has not been studied. The ability of patients who have received the BEXXAR therapeutic regimen to generate a primary or anamnestic humoral response to any vaccine has not been studied.<br/>Information for Patients: Prior to administration of the BEXXAR therapeutic regimen, patients should be advised that they will have a radioactive material in their body for several days upon their release from the hospital or clinic. After discharge, patients should be provided with both oral and written instructions for minimizing exposure of family members, friends and the general public. Patients should be given a copy of the written instructions for use as a reference for the recommended precautionary actions. The pregnancy status of women of childbearing potential should be assessed and these women should be advised of the potential risks to the fetus (see CONTRAINDICATIONS). Women who are breastfeeding should be instructed to discontinue breastfeeding and should be apprised of the resultant potential harmful effects to the infant if these instructions are not followed. Patients should be advised of the potential risk of toxic effects on the male and female gonads following the BEXXAR therapeutic regimen, and be instructed to use effective contraceptive methods during treatment and for 12 months following the administration of the BEXXAR therapeutic regimen. Patients should be informed of the risks of hypothyroidism and be advised of the importance of compliance with thyroid blocking agents and need for life-long monitoring. Patients should be informed of the possibility of developing a HAMA immune response and that HAMA may affect the results of in vitro and in vivo diagnostic tests as well as results of therapies that rely on murine antibody technology. Patients should be informed of the risks of cytopenias and symptoms associated with cytopenia, the need for frequent monitoring for up to 12 weeks after treatment, and the potential for persistent cytopenias beyond 12 weeks. Patients should be informed that MDS, secondary leukemia, and solid tumors have also been observed in patients receiving the BEXXAR therapeutic regimen. Due to lack of controlled clinical studies, and high background incidence in the heavily pretreated patient population, the relative risk of development of myelodysplastic syndrome/acute leukemia and solid tumors due to the BEXXAR therapeutic regimen cannot be determined.<br/>Laboratory Monitoring: A complete blood count (CBC) with differential and platelet count should be obtained prior to, and at least weekly following administration of the BEXXAR therapeutic regimen. Weekly monitoring of blood counts should continue for a minimum of 10 weeks or, if persistent, until severe cytopenias have completely resolved. More frequent monitoring is indicated in patients with evidence of moderate or more severe cytopenias (see BOXED WARNINGS and WARNINGS). Thyroid stimulating hormone (TSH) level should be monitored before treatment and annually thereafter. Serum creatinine levels should be measured immediately prior to administration of the BEXXAR therapeutic regimen.<br/>Drug Interactions: No formal drug interaction studies have been performed. Due to the frequent occurrence of severe and prolonged thrombocytopenia, the potential benefits of medications that interfere with platelet function and/or anticoagulation should be weighed against the potential increased risk of bleeding and hemorrhage.<br/>Drug/Laboratory Test Interactions: Administration of the BEXXAR therapeutic regimen may result in the development of HAMA. The presence of HAMA may affect the accuracy of the results of in vitro and in vivo diagnostic tests and may affect the toxicity profile and efficacy of therapeutic agents that rely on murine antibody technology. Patients who are HAMA positive may be at increased risk for serious allergic reactions and other side effects if they undergo in vivo diagnostic testing or treatment with murine monoclonal antibodies.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of the BEXXAR therapeutic regimen or to determine its effects on fertility in males or females. However, radiation is a potential carcinogen and mutagen. Administration of the BEXXAR therapeutic regimen results in delivery of a significant radiation dose to the testes. The radiation dose to the ovaries has not been established. There have been no studies to evaluate whether administration of the BEXXAR therapeutic regimen causes hypogonadism, premature menopause, azoospermia and/or mutagenic alterations to germ cells. There is a potential risk that the BEXXAR therapeutic regimen may cause toxic effects on the male and female gonads. Effective contraceptive methods should be used during treatment and for 12 months following administration of the BEXXAR therapeutic regimen.<br/>Pregnancy Category X: (See CONTRAINDICATIONS; WARNINGS.)<br/>Nursing Mothers: Radioiodine is excreted in breast milk and may reach concentrations equal to or greater than maternal plasma concentrations. Immunoglobulins are also known to be excreted in breast milk. The absorption potential and potential for adverse effects of the monoclonal antibody component (Tositumomab) in the infant are not known. Therefore, formula feedings should be substituted for breast feedings before starting treatment. Women should be advised to discontinue nursing.<br/>Pediatric Use: The safety and effectiveness of the BEXXAR therapeutic regimen in children have not been established.<br/>Geriatric Use: Clinical studies of the BEXXAR therapeutic regimen did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In clinical studies, 230 patients received the BEXXAR therapeutic regimen at the recommended dose. Of these, 27% (61 patients) were age 65 or older and 4% (10 patients) were age 75 or older. Across all studies, the overall response rate was lower in patients age 65 and over (41% vs. 61%) and the duration of responses was shorter (10 months vs. 16 months); however, these findings are primarily derived from 2 of the 5 studies. While the incidence of severe hematologic toxicity was lower, the duration of severe hematologic toxicity was longer in those age 65 or older as compared to patients less than 65 years ofage. Due to the limited experience greater sensitivity of some older individuals cannot be ruled out. | lld:dailymed |
| dailymed-drugs:197 | dailymed-instance:precautio... | The cardiovascular status of the patient should be carefully evaluated before rapidly administering mannitol since sudden expansion of the extracellular fluid may lead to fulminating congestive heart failure. Shift of sodium free intracellular fluid into the extracellular compartment following mannitol infusion may lower serum sodium concentration and aggravate preexisting hyponatremia. By sustaining diuresis, mannitol administration may obscure and intensify inadequate hydration or hypovolemia. Electrolyte free mannitol injections should not be given conjointly with blood. If it is essential that blood be given simultaneously, at least 20 mEq of sodium chloride should be added to each liter of mannitol solution to avoid pseudoagglutination. When exposed to low temperatures, solutions of mannitol may crystallize. Concentrations greater than 15% have a greater tendency to crystallization. Inspect for crystals prior to administration. If crystals are visible, redissolve by warming the solution up to 70��C, with agitation. Allow the solution to cool to room temperature before reinspection for crystals. Administer intravenously using sterile, filter-type administration set.<br/>Laboratory Tests: Although blood levels of mannitol can be measured, there is little if any clinical virtue in doing so. The appropriate monitoring of blood levels of sodium and potassium; degree of hemoconcentration or hemodilution, if any; indices of renal, cardiac and pulmonary function are paramount in avoiding excessive fluid and electrolyte shifts. The routine features of physical examination and clinical chemistries suffice in achieving an adequate degree of appropriate patient monitoring.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when mannitol is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in children below the age of 12 have not been established.<br/>Usage in Children: Dosage requirements for patients 12 years of age and under have not been established.<br/>Geriatric Use: Clinical studies of OSMITROL Injection (Mannitol Injection, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low endof the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. | lld:dailymed |
| dailymed-drugs:198 | dailymed-instance:precautio... | General: Intranasal corticosteroids may cause a reduction in growth velocity when administered to pediatric patients . Rarely, immediate hypersensitivity reactions or contact dermatitis may occur after the administration of Fluticasone Propionate Nasal Spray. Rare instances of wheezing, nasal septum perforation, cataracts, glaucoma, and increased intraocular pressure have been reported following the intranasal application of corticosteroids, including fluticasone propionate. Use of excessive doses of corticosteroids may lead to signs or symptoms of hypercorticism and/or suppression of HPA function. Although systemic effects have been minimal with recommended doses of Fluticasone Propionate Nasal Spray, potential risk increases with larger doses. Therefore, larger than recommended doses of Fluticasone Propionate Nasal Spray should be avoided. When used at higher than recommended doses or in rare individuals at recommended doses, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of Fluticasone Propionate Nasal Spray should be discontinued slowly consistent with accepted procedures for discontinuing oral corticosteroid therapy. In clinical studies with fluticasone propionate administered intranasally, the development of localized infections of the nose and pharynx with Candida albicans has occurred only rarely. When such an infection develops, it may require treatment with appropriate local therapy and discontinuation of treatment with Fluticasone Propionate Nasal Spray. Patients using Fluticasone Propionate Nasal Spray over several months or longer should be examined periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa. Intranasal corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract; untreated local or systemic fungal or bacterial infections; systemic viral or parasitic infections; or ocular herpes simplex. Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal septal ulcers, nasal surgery, or nasal trauma should not use a nasal corticosteroid until healing has occurred.<br/>Information for Patients: Patients being treated with Fluticasone Propionate Nasal Spray should receive the following information and instructions. This information is intended to aid them in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. Patients should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Patients should use Fluticasone Propionate Nasal Spray at regular intervals for optimal effect. A decrease in nasal symptoms may occur as soon as 12 hours after starting therapy with Fluticasone Propionate Nasal Spray. Results in several clinical trials indicate statistically significant improvement within the first day or two of treatment; however, the full benefit of Fluticasone Propionate Nasal Spray may not be achieved until treatment has been administered for several days. The patient should not increase the prescribed dosage but should contact the physician if symptoms do not improve or if the condition worsens. For the proper use of Fluticasone Propionate Nasal Spray and to attain maximum improvement, the patient should read and follow carefully the patient's instructions accompanying the product.<br/>Drug Interactions: Fluticasone propionate is a substrate of cytochrome P450 3A4. A drug interaction study with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations . During postmarketing use, therehave been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Therefore, coadministration of fluticasone propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. In a placebo-controlled, crossover study in 8 healthy volunteers, coadministration of a single dose of orally inhaled fluticasone propionate (1,000 mcg; 5 times the maximum daily intranasal dose) with multiple doses of ketoconazole (200 mg) to steady state resulted in increased plasma fluticasone propionate exposure, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol. Caution should be exercised when Fluticasone Propionate Nasal Spray is coadministered with ketoconazole and other known potent cytochrome P450 3A4 inhibitors.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 20 times the maximum recommended daily intranasal dose in adults and approximately 10 times the maximum recommended daily intranasal dose in children on a mcg/mbasis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (approximately 2 times the maximum recommended daily intranasal dose in adults and approximately equivalent to the maximum recommended daily intranasal dose in children on a mcg/mbasis) for 104 weeks. Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the mouse micronucleus test. No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at subcutaneous doses up to 50 mcg/kg (approximately 2 times the maximum recommended daily intranasal dose in adults on a mcg/mbasis). Prostate weight was significantly reduced at a subcutaneous dose of 50 mcg/kg.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: It is not known whether fluticasone propionate is excreted in human breast milk. However, other corticosteroids have been detected in human milk. Subcutaneous administration to lactating rats of 10 mcg/kg or tritiated fluticasone propionate (less than the maximum recommended daily intranasal dose in adults on a mcg/mbasis) resulted in measurable radioactivity in the milk. Since there are no data from controlled trials on the use of intranasal fluticasone propionate by nursing mothers, caution should be exercised when Fluticasone Propionate Nasal Spray is administered to a nursing woman.<br/>Pediatric Use: Five hundred (500) patients aged 4 to 11 years and 440 patients aged 12 to 17 years were studied in US clinical trials with fluticasone propionate nasal spray. The safety and effectiveness of Fluticasone Propionate Nasal Spray in children below 4 years of age have not been established. Controlled clinical studies have shown that intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for���catch-up���growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids, including Fluticasone Propionate Nasal Spray, should be monitored routinely (e.g. via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks/benefits of treatment alternatives. To minimize the systemic effects of intranasal corticosteroids, including Fluticasone Propionate Nasal Spray, each patient should be titrated to the lowest dose that effectively controls his/her symptoms. Pediatric use information on the results of a long term longitudinal growth study is approved for GlaxoSmithKline's Fluticasone Propionate Nasal Spray. However, due to GlaxoSmithKline's marketing exclusivity rights, this drug product is not labeled with that pediatric information.<br/>Geriatric Use: A limited number of patients above 65 years of age and older (N=129) or 75 years of age and older (N=11) have been treated with Fluticasone Propionate Nasal Spray in US and non-US clinical trials. While the number of patients is too small to permit separate analysis of efficacy and safety, the adverse reactions reported in this population were similar to those reported by younger patients. | lld:dailymed |
| dailymed-drugs:200 | dailymed-instance:precautio... | General: Impaired Hepatic Function: As the majority of valsartan is eliminated in the bile, patients with mild-to-moderate hepatic impairment, including patients with biliary obstructive disorders, showed lower valsartan clearance (higher AUCs). Care should be exercised in administering Diovan to these patients. Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with Diovan. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported. In a 4-day trial of valsartan in 12 patients with unilateral renal artery stenosis, no significant increases in serum creatinine or blood urea nitrogen were observed. There has been no long-term use of Diovan in patients with unilateral or bilateral renal artery stenosis, but an effect similar tothat seen with ACE inhibitors should be anticipated.<br/>Information for Patients: Pregnancy: Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to drugs that act on the renin-angiotensin system, and they should also be told that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.<br/>Drug Interactions: No clinically significant pharmacokinetic interactions were observed when valsartan was coadministered with amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide, hydrochlorothiazide, or indomethacin. The valsartan-atenolol combination was more antihypertensive than either component, but it did not lower the heart rate more than atenolol alone. Coadministration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-course of the anticoagulant properties of warfarin. CYP 450 Interactions: The enzyme(s) responsible for valsartan metabolism have not been identified but do not seem to be CYP 450 isozymes. The inhibitory or induction potential of valsartan on CYP 450 is also unknown.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to 2 years at doses up to 160 and 200 mg/kg/day, respectively. These doses in mice and rats are about 2.6 and 6 times, respectively, the maximum recommended human dose on a mg/mbasis. (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.) Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella (Ames) and E coli; a gene mutation test with Chinese hamster V79 cells; a cytogenetic test with Chinese hamster ovary cells; anda rat micronucleus test. Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day. This dose is 6 times the maximum recommended human dose on a mg/mbasis. (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)<br/>Pregnancy Categories C (first trimester) and D (second and third trimesters): See WARNINGS, Fetal/Neonatal Morbidity and Mortality.<br/>Nursing Mothers: It is not known whether valsartan is excreted in human milk, but valsartan was excreted in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric Use: In the controlled clinical trials of valsartan, 1214 (36.2%) of patients treated with valsartan were���65 years and 265 (7.9%) were���75 years. No overall difference in the efficacy or safety of valsartan was observed in this patient population, but greater sensitivity of some older individuals cannot be ruled out. | lld:dailymed |
| dailymed-drugs:201 | dailymed-instance:precautio... | General: Ethosuximide, when used alone in mixed types of epilepsy, may increase the frequency of grand mal seizures in some patients. As with other anticonvulsants, it is important to proceed slowly when increasing or decreasing dosage, as well as when adding or eliminating other medication. Abrupt withdrawal of anticonvulsant medication may precipitate absence (petit mal) status.<br/>Information for Patients: Ethosuximide may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a motor vehicle or other such activity requiring alertness; therefore, the patient should be cautioned accordingly. Patients taking ethosuximide should be advised of the importance of adhering strictly to the prescribed dosage regimen. Patients should be instructed to promptly contact their physician if they develop signs and/or symptoms (eg, sore throat, fever), suggesting an infection.<br/>Drug Interactions: Since Zarontin (ethosuximide) may interact with concurrently administered antiepileptic drugs, periodic serum level determinations of these drugs may be necessary (eg, ethosuximide may elevate phenytoin serum levels and valproic acid has been reported to both increase and decrease ethosuximide levels).<br/>Pregnancy: See WARNINGS.<br/>Pediatric Use: Safety and effectiveness in pediatric patients below the age of 3 years have not been established. | lld:dailymed |
| dailymed-drugs:202 | dailymed-instance:precautio... | General: Lovastatin may elevate creatine phosphokinase and transaminase levels (see WARNINGS and ADVERSE REACTIONS). This should be considered in the differential diagnosis of chest pain in a patient on therapy with lovastatin.<br/>Homozygous Familial Hypercholesterolemia: Lovastatin is less effective in patients with the rare homozygous familial hypercholesterolemia, possibly because these patients have no functional LDL receptors. Lovastatin appears to be more likely to raise serum transaminases (see ADVERSE REACTIONS) in these homozygous patients.<br/>Information for Patients: Patients should be advised about substances they should not take concomitantly with lovastatin and be advised to report promptly unexplained muscle pain, tenderness, or weakness (see list below and WARNINGS, Myopathy/Rhabdomyolysis). Patients should also be advised to inform other physicians prescribing a new medication that they are taking lovastatin.<br/>Drug Interactions:<br/>CYP3A4 Interactions: Lovastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Potent inhibitors of CYP3A4 (below) increase the risk of myopathy by reducing the elimination of lovastatin. See WARNINGS, Myopathy/Rhabdomyolysis and CLINICAL PHARMACOLOGY, Pharmacokinetics. Itraconazole Ketoconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Nefazodone Large quantities of grapefruit juice (>1 quart daily)<br/>Interactions with Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone: The risk of myopathy is also increased by the following lipid-lowering drugs that are not potent CYP3A4 inhibitors, but which can cause myopathy when given alone. See WARNINGS, Myopathy/Rhabdomyolysis. Gemfibrozil Other fibrates Niacin (nicotinic acid) (���1 g/day)<br/>Other Drug Interactions:<br/>Endocrine Function: HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt adrenal and/or gonadal steroid production. Results of clinical trials with drugs in this class have been inconsistent with regard to drug effects on basal and reserve steroid levels. However, clinical studies have shown that lovastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve, and does not reduce basal plasma testosterone concentration. Another HMG-CoA reductase inhibitor has been shown to reduce the plasma testosterone response to HCG. In the same study, the mean testosterone response to HCG was slightly but not significantly reduced after treatment with lovastatin 40 mg daily for 16 weeks in 21 men. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of male patients. The effects, if any, on the pituitary-gonadal axis in pre-menopausal women are unknown. Patients treated with lovastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that may decrease the levels or activity of endogenous steroid hormones.<br/>CNS Toxicity: Lovastatin produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose (as measured by total enzymeinhibitory activity). Vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis were also seen in dogs treated for 14 weeks at 180 mg/kg/day, a dose which resulted in mean plasma drug level (C) similar to that seen with the 60 mg/kg/day dose. CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels, were seen in dogs treated with lovastatin at a dose of 180 mg/kg/day, a dose which produced plasma drug levels (C) which were about 30 times higher than the mean values in humans taking 80 mg/day. Similar optic nerve and CNS vascular lesions have been observed with other drugs of this class. Cataracts were seen in dogs treated for 11 and 28 weeks at 180 mg/kg/day and 1 year at 60 mg/kg/day.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 21 month carcinogenic study in mice, there was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in both males and females at 500 mg/kg/day. This dose produced a total plasma drug exposure 3 to 4 times that of humans given the highest recommended dose of lovastatin (drug exposure was measured as total HMG-CoA reductase inhibitory activity in extracted plasma). Tumor increases were not seen at 20 and 100 mg/kg/day, doses that produced drug exposures of 0.3 to 2 times that of humans at the 80 mg/day dose. A statistically significant increase in pulmonary adenomas was seen in female mice at approximately 4 times the human drug exposure. (Although mice were given 300 times the human dose [HD] on a mg/kg body weight basis, plasma levels of total inhibitory activity were only 4 times higher in mice than in humans given 80 mg of lovastatin.) There was an increase in incidence of papilloma in the non-glandular mucosa of the stomach of mice beginning at exposures of 1 to 2 times that of humans. The glandular mucosa was not affected. The human stomach contains only glandular mucosa. In a 24 month carcinogenicity study in rats, there was a positive dose response relationship for hepatocellular carcinogenicity in males at drug exposures between 2 to 7 times that of human exposure at 80 mg/day (doses in rats were 5, 30 and 180 mg/kg/day). An increased incidence of thyroid neoplasms in rats appears to be a response that has been seen with other HMG-CoA reductase inhibitors. A chemically similar drug in this class was administered to mice for 72 weeks at 25, 100, and 400 mg/kg body weight, which resulted in mean serum drug levels approximately 3, 15, and 33 times higher than the mean human serum drug concentration (as total inhibitory activity) after a 40 mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males, with a maximum incidence of 90 percent in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of mutagenicity was observed in a microbial mutagen test using mutant strains of Salmonella typhimurium with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat or mouse hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow. Drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation were seen in dogs starting at 20 mg/kg/day. Similar findings were seen with another drug in this class. No drug-related effects on fertility were found in studies with lovastatin in rats. However, in studies with a similar drug in this class, there was decreased fertility in male rats treated for 34 weeks at 25 mg/kg body weight, although this effect was not observed in a subsequent fertility study when this same dose was administered for 11 weeks (the entire cycle of spermatogenesis, including epididymal maturation). In rats treated with this same reductase inhibitorat 180 mg/kg/day, seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. No microscopic changes were observed in the testes from rats of either study. The clinical significance of these findings is unclear.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: It is not known whether lovastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human breast milk and because of the potential for serious adverse reactions in nursing infants, women taking lovastatin should not nurse their infants (see CONTRAINDICATIONS).<br/>Pediatric Use: Safety and effectiveness in patients 10 to 17 years of age with heFH have been evaluated in controlled clinical trials of 48 weeks duration in adolescent boys and controlled clinical trials of 24 weeks duration in girls who were at least 1 year post-menarche. Patients treated with lovastatin had an adverse experience profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In these limited controlled studies, there was no detectable effect on growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls. See CLINICAL PHARMACOLOGY, Clinical Studies in Adolescent Patients; ADVERSE REACTIONS, Adolescent Patients; and DOSAGEAND ADMINISTRATION, Adolescent Patients (10 to 17 years of age) with Heterozygous Familial Hypercholesterolemia. Adolescent females should be counseled on appropriate contraceptive methods while on lovastatin therapy (see CONTRAINDICATIONS and PRECAUTIONS, Pregnancy). Lovastatin has not been studied in pre-pubertal patients or patients younger than 10 years of age.<br/>Geriatric Use: A pharmacokinetic study with lovastatin showed the mean plasma level of HMG-CoA reductase inhibitory activity to be approximately 45% higher in elderly patients between 70 to 78 years of age compared with patients between 18 to 30 years of age; however, clinical study experience in the elderly indicates that dosage adjustment based on this age-related pharmacokinetic difference is not needed. In the two large clinical studies conducted with lovastatin (EXCEL and AFCAPS/TexCAPS), 21% (3,094/14,850) of patients were���65 years of age. Lipid-lowering efficacy with lovastatin was at least as great in elderly patients compared with younger patients, and there were no overall differences in safety over the 20 to 80 mg/day dosage range (see CLINICAL PHARMACOLOGY). | lld:dailymed |
| dailymed-drugs:203 | dailymed-instance:precautio... | General: Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal from treatment. Manifestations of Cushing's syndrome, hyperglycemia and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment. Patients applying a potent topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA axis suppression. This may be done by using the ACTH stimulation, A.M. plasma cortisol, and urinary free cortisol tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function is generally prompt upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur requiring supplemental systemic corticosteroids. For information on systemic supplementation, see prescribing information for those products. Fluticasone propionate cream, 0.05% caused depression of A.M. plasma cortisol levels in 1 of 6 adult patients when used daily for 7 days in patients with psoriasis or eczema involving at least 30% of the body surface. After 2 days of treatment, this patient developed a 60% decrease from pretreatment values in the A.M. plasma cortisol level. There was some evidence of corresponding decrease in the 24-hour urinary free cortisol levels. The A.M. plasma cortisol level remained slightly depressed for 48 hours but recovered by day 6 of treatment. Fluticasone propionate cream, 0.05%, caused HPA axis suppression in 2 of 43 pediatric patients, ages 2 and 5 years old, who were treated for 4 weeks covering at least 35% of the body surface area. Follow-up testing 12 days after treatment discontinuation, available for 1 of the 2 subjects, demonstrated a normally responsive HPA axis . Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios . Fluticasone propionate cream, 0.05%, may cause local cutaneous adverse reactions . If irritation develops, Fluticasone Propionate Cream, 0.05% should be discontinued and appropriate therapy instituted. Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation as with most topical products not containing corticosteroids. Such an observation should be corroborated with appropriate diagnostic patch testing. If concomitant skin infections are present or develop, an appropriate antifungal or antibacterial agent should be used. If a favorable response does not occur promptly, use of Fluticasone Propionate Cream, 0.05% should be discontinued until the infection has been adequately controlled. Fluticasone Propionate Cream, 0.05% should not be used in the presence of preexisting skin atrophy and should not be used where infection is present at the treatment site. Fluticasone Propionate Cream, 0.05% should not be used in the treatment of rosacea and perioral dermatitis. Information for Patients: Patients using topical corticosteroids should receive the following information and instructions: Laboratory Tests: The following tests may be helpful in evaluating patients for HPA axis suppression: ���ACTH stimulation test���A.M. plasma cortisol test���Urinary free cortisol test Carcinogenesis, Mutagenesis and Impairment of Fertility: Two 18-month studies were performed in mice to evaluate the carcinogenic potential of fluticasone propionate when given topically (as a 0.05% ointment) and orally. No evidence of carcinogenicity was found in either study. Fluticasone propionate was not mutagenic in the standard Ames test, E. coli fluctuation test, S. cerevisiae gene conversion test or Chinese Hamster ovarian cell assay. It was not clastogenic in mouse micronucleus or cultured human lymphocyte tests. In a fertility and general reproductive performance study in rats, fluticasone propionate administered subcutaneously to females at up to 50 mcg/kg per day and to males at up to 100 mcg/kg per day (later reduced to 50 mcg/kg per day) had no effect upon mating performance or fertility. These doses are approximately 15 and 30 times respectively the human systemic exposure following use of the recommended human topical dose of fluticasone propionate cream, 0.05%, assuming human percutaneous absorption of approximately 3% and the use in a 70-kg person of 15 g/day. Pregnancy:Teratogenic Effects: Pregnancy Category C. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. Teratology studies in the mouse demonstrated fluticasone propionate to be teratogenic (cleft palate) when administered subcutaneously in doses of 45 mcg/kg per day and 150 mcg/kg per day. This dose is approximately 14 and 45 times, respectively, the human topical dose of fluticasone propionate cream, 0.05%. There are no adequate and well-controlled studies in pregnant women. Fluticasone Propionate Cream, 0.05% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when Fluticasone Propionate Cream, 0.05% is administered to a nursing woman. Pediatric Use: Fluticasone Propionate Cream, 0.05% may be used with caution in pediatric patients as young as 3 months of age. The safety and efficacy of drug use for longer than 4 weeks in this population have not been established. The safety and efficacy of Fluticasone Propionate Cream, 0.05% in pediatric patients below 3 months of age have not been established. Fluticasone propionate cream, 0.05%, caused HPA axis suppression in 2 of 43 pediatric patients, ages 2 and 5 years old, who were treated for 4 weeks covering at least 35% of the body surface area. Follow-up testing 12 days after treatment discontinuation, available for 1 of the 2 subjects, demonstrated a normally responsive HPA axis . Adverse effects including striae have been reported with use of topical corticosteroids in pediatric patients. HPA axis suppression, Cushing's syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteriods. Manifestations of adrenal suppression in pediatric patients include low plasma cortisol levels to an absence of response to ACTHstimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Geriatric Use: A limited number of patients above 65 years of age (n=126) have been treated with fluticasone propionate cream in US and non-US clinical trials. While the number of patients is too small to permit separate analysis of efficacy and safety, the adverse reactions reported in this population were similar to those reported by younger patients. Based on available data, no adjustment of dosage of fluticasone propionate cream in geriatric patient warranted. | lld:dailymed |
| dailymed-drugs:204 | dailymed-instance:precautio... | General:: The initial prescription and renewal of the medication order beyond 20 milliliters of the suspension should be made by a physician only after examination of the patient with the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. If signs and symptoms fail to improve after two days, the patient should be re-evaluated. The possibility of fungal infections of the cornea should be considered after prolonged corticosteroid dosing. Use with caution in patients with severe dry eye. Fungal cultures should be taken when appropriate. The p-aminobenzoic acid present in purulent exudates competes with sulfonamides and can reduce their effectiveness.<br/>Information for Patients:: If inflammation or pain persists longer than 48 hours or becomes aggravated, the patient should be advised to discontinue use of the medication and consult a physician . Contact lenses should not be worn during the use of this product. This product is sterile when packaged. To prevent contamination, care should be taken to avoid touching the applicator tip to eyelids or to any other surface. The use of this bottle by more than one person may spread infection. Keep bottle tightly closed when not in use. Protect from light. Sulfonamide solutions darken on prolonged standing and exposure to heat and light. Do not use if solution has darkened. Yellowing does not affect activity. Keep out of the reach of children.<br/>Laboratory Tests:: Eyelid cultures and tests to determine the susceptibility of organisms to sulfacetamide may be indicated if signs and symptoms persist or recur in spite of the recommended course of treatment with BLEPHAMIDE ophthalmic suspension.<br/>Drug Interactions:: BLEPHAMIDE ophthalmic suspension is incompatible with silver preparations. Local anesthetics related to p-aminobenzoic acid may antagonize the action of the sulfonamides.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:: Prednisolone has been reported to be noncarcinogenic. Long-term animal studies for carcinogenic potential have not been performed with sulfacetamide. One author detected chromosomal nondisjunction in the yeast Saccharomyces cerevisiae following application of sulfacetamide sodium. The significance of this finding to topical ophthalmic use of sulfacetamide sodium in the human is unknown. Mutagenic studies with prednisolone have been negative. Studies on reproduction and fertility have not been performed with sulfacetamide. A long-term chronic toxicity study in dogs showed that high oral doses of prednisolone prevented estrus. A decrease in fertility was seen in male and female rats that were mated following oral dosing with another glucocorticosteroid.<br/>Pregnancy:: Teratogenic Effects: Pregnancy Category C. Animal reproduction studies have not been conducted with sulfacetamide sodium. Prednisolone has been shown to be teratogenic in rabbits, hamsters, and mice. In mice, prednisolone has been shown to be teratogenic when given in doses 1 to 10 times the human ocular dose. Dexamethasone, hydrocortisone and prednisolone were ocularly applied to both eyes of pregnant mice five times per day on days 10 through 13 of gestation. A significant increase in the incidence of cleft palate was observed in the fetuses of the treated mice. There are no adequate well-controlled studies in pregnant women dosed with corticosteroids. Kernicterus may be precipitated in infants by sulfonamides being given systemically during the third trimester of pregnancy. It is not known whether sulfacetamide sodium can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity. BLEPHAMIDE ophthalmic suspension should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers:: It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Systemically administered sulfonamides are capable of producing kernicterus in infants of lactating women. Because of the potential for serious adverse reactions in nursing infants from sulfacetamide sodium and prednisolone acetate ophthalmic suspensions, a decision should be made whether to discontinue nursing or to discontinue the medication.<br/>Pediatric Use:: Safety and effectiveness in pediatric patients below the age of six have not been established. | lld:dailymed |
| dailymed-drugs:205 | dailymed-instance:precautio... | General:<br/>Aortic Stenosis/Hypertrophic Cardiomyopathy:<br/>Impaired Renal Function:<br/>Hyperkalemia:<br/>Cough:<br/>Surgery/Anesthesia:<br/>Information for Patients:<br/>Angioedema:<br/>Symptomatic Hypotension:<br/>Hyperkalemia:<br/>Hypoglycemia:<br/>Leukopenia/Neutropenia:<br/>Pregnancy:<br/>Drug Interactions:<br/>Hypotension - Patients on Diuretic Therapy:<br/>Antidiabetics:<br/>Non-steroidal Anti-inflammatory Agents:<br/>Other Agents:<br/>Agents Increasing Serum Potassium:<br/>Lithium:<br/>Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including lisinopril.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Pregnancy:<br/>Nursing Mothers:<br/>Pediatric Use:<br/>Geriatric Use: | lld:dailymed |
| dailymed-drugs:206 | dailymed-instance:precautio... | General: As with other anti-infectives, prolonged use may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, discontinue use and institute alternative therapy. Whenever clinical judgment dictates, the patient should be examined with the aid of magnification, such as slit-lamp biomicroscopy, and, where appropriate, fluorescein staining. Patients should be advised not to wear contact lenses if they have signs and symptoms of bacterial conjunctivitis.<br/>Information for Patients: Avoid contaminating the applicator tip with material from the eye, fingers or other source. Systemically administered quinolones including moxifloxacin have been associated with hypersensitivity reactions, even following a single dose. Discontinue use immediately and contact your physician at the first sign of a rash or allergic reaction.<br/>Drug Interactions: Drug-drug interaction studies have not been conducted with VIGAMOX' solution. In vitrostudies indicate that moxifloxacin does not inhibit CYP3A4, CYP2D6, CYP2C9, CYP2C19, or CYP1A2 indicating that moxifloxacin is unlikely to alter the pharmacokinetics of drugs metabolized by these cytochrome P450 isozymes.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long term studies in animals to determine the carcinogenic potential of moxifloxacin have not been performed. However, in an accelerated study with initiators and promoters, moxifloxacin was not carcinogenic in rats following up to 38 weeks of oral dosing at 500 mg/kg/day (approximately 21,700 times the highest recommended total daily human ophthalmic dose for a 50 kg person, on a mg/kg basis). Moxifloxacin was not mutagenic in four bacterial strains used in the Ames Salmonellareversion assay. As with other quinolones, the positive response observed with moxifloxacin in strain TA 102 using the same assay may be due to the inhibition of DNA gyrase. Moxifloxacin was not mutagenic in the CHO/HGPRT mammalian cell gene mutation assay. An equivocal result was obtained in the same assay when v79 cells were used. Moxifloxacin was clastogenic in the v79 chromosome aberration assay, but it did not induce unscheduled DNA synthesis in cultured rat hepatocytes. There was no evidence of genotoxicity in vivoin a micronucleus test or a dominant lethal test in mice. Moxifloxacin had no effect on fertility in male and female rats at oral doses as high as 500 mg/kg/day, approximately 21,700 times the highest recommended total daily human ophthalmic dose. At 500 mg/kg orally there were slight effects on sperm morphology (head-tail separation) in male rats and on the estrous cycle in female rats.<br/>Pregnancy:<br/>Teratogenic Effects.:<br/>Nursing Mothers: Moxifloxacin has not been measured in human milk, although it can be presumed to be excreted in human milk. Caution should be exercised when VIGAMOX' solution is administered to a nursing mother.<br/>Pediatric Use: The safety and effectiveness of VIGAMOX' solution in infants below 1 year of age have not been established. There is no evidence that the ophthalmic administration of VIGAMOX' has any effect on weight bearing joints, even though oral administration of some quinolones has been shown to cause arthropathy in immature animals.<br/>Geriatric Use: No overall differences in safety and effectiveness have been observed between elderly and younger patients. | lld:dailymed |
| dailymed-drugs:207 | dailymed-instance:precautio... | Impairment of Vision:<br/>Optic Neuropathy and/or Neuritis: Cases of optic neuropathy and optic neuritis have been reported (see WARNINGS).<br/>Corneal Microdeposits: Corneal microdeposits appear in the majority of adults treated with amiodarone. They are usually discernible only by slit-lamp examination, but give rise to symptoms such as visual halos or blurred vision in as many as 10% of patients. Corneal microdeposits are reversible upon reduction of dose or termination of treatment. Asymptomatic microdeposits alone are not a reason to reduce dose or discontinue treatment (see ADVERSE REACTIONS).<br/>Neurologic: Chronic administration of oral amiodarone in rare instances may lead to the development of peripheral neuropathy that may resolve when amiodarone is discontinued, but this resolution has been slow and incomplete.<br/>Photosensitivity: Amiodarone has induced photosensitization in about 10% of patients; some protection may be afforded by the use of sun-barrier creams or protective clothing. During long-term treatment, a blue-gray discoloration of the exposed skin may occur. The risk may be increased in patients of fair complexion or those with excessive sun exposure, and may be related to cumulative dose and duration of therapy.<br/>Thyroid Abnormalities: Amiodarone inhibits peripheral conversion of thyroxine (T) to triiodothyronine (T) and may cause increased thyroxine levels, decreased Tlevels, and increased levels of inactive reverse T(rT) in clinically euthyroid patients. It is also a potential source of large amounts of inorganic iodine. Because of its release of inorganic iodine, or perhaps for other reasons, amiodarone can cause either hypothyroidism or hyperthyroidism. Thyroid function should be monitored prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of amiodarone and its metabolites, high plasma iodide levels, altered thyroid function and abnormal thyroid-function tests may persist for several weeks or even months following amiodarone withdrawal. Hypothyroidism has been reported in 2 to 4% of patients in most series, but in 8 to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Hypothyroidism is best managed by amiodarone dose reduction and/or thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue amiodarone hydrochloride tablets in some patients. Hyperthyroidism occurs in about 2% of patients receiving amiodarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and/or arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IFANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED. Hyperthyroidism is best identified by relevant clinical symptoms and signs, accompanied usually by abnormally elevated levels of serum TRIA, and further elevations of serum T, and a subnormal serum TSH level (using a sufficiently sensitive TSH assay). The finding of a flat TSH response to TRH is confirmatory of hyperthyroidism and may be sought in equivocal cases. Since arrhythmia breakthroughs may accompany amiodarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of amiodarone. The institution of antithyroid drugs,��-adrenergic blockers and/or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. Amiodarone-induced hyperthyroidism may be followed by a transient period of hypothyroidism (see WARNINGS, Thyrotoxicosis). When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning. There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with amiodarone. In some instances hyperthyroidism was also present (see WARNINGS and ADVERSE REACTIONS).<br/>Surgery:<br/>Volatile Anesthetic Agents: Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalational anesthetics.<br/>Hypotension Postbypass: Rare occurrences of hypotension upon discontinuation of cardiopulmonary bypass during open-heart surgery in patients receiving amiodarone have been reported. The relationship of this event to amiodarone therapy is unknown.<br/>Adult Respiratory Distress Syndrome (ARDS): Postoperatively, occurrences of ARDS have been reported in patients receiving amiodarone therapy who have undergone either cardiac or noncardiac surgery. Although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. Until further studies have been performed, it is recommended that FiOand the determinants of oxygen delivery to the tissues (e.g., SaO, PaO) be closely monitored in patients on amiodarone.<br/>Corneal Refractive Laser Surgery: Patients should be advised that most manufacturers of corneal refractive laser surgery devices contraindicate that procedure in patients taking amiodarone.<br/>Information for Patients: Patients should be instructed to read the accompanying Medication Guide each time they refill their prescription. The complete text of the Medication Guide is reprinted at the end of this document.<br/>Laboratory Tests: Elevations in liver enzymes (SGOT and SGPT) can occur. Liver enzymes in patients on relatively high maintenance doses should be monitored on a regular basis. Persistent significant elevations in the liver enzymes or hepatomegaly should alert the physician to consider reducing the maintenance dose of amiodarone or discontinuing therapy. Amiodarone alters the results of thyroid-function tests, causing an increase in serum Tand serum reverse T, and a decline in serum Tlevels. Despite these biochemical changes, most patients remain clinically euthyroid.<br/>Drug Interactions: Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. This CYP3A4 isoenzyme is present in both the liver and intestines (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Amiodarone is an inhibitor of CYP3A4 and p-glycoprotein. Therefore, amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors or inducers of CYP3A4 and substrates of p-glycoprotein. While only a limited number of in vivo drug-drug interactions with amiodarone have been reported, the potential for other interactions should be anticipated. This is especially important for drugs associated with serious toxicity, such as other antiarrhythmics. If such drugs are needed, their dose should be reassessed and, where appropriate, plasma concentration measured. In view of thelong and variable half-life of amiodarone, potential for drug interactions exists, not only with concomitant medication but also with drugs administered after discontinuation of amiodarone. Since amiodarone is a substrate for CYP3A4 and CYP2C8, drugs/substances that inhibit CYP3A4 may decrease the metabolism and increase serum concentrations of amiodarone. Reported examples include the following:<br/>Protease Inhibitors: Protease inhibitors are known to inhibit CYP3A4 to varying degrees. A case report of one patient taking amiodarone 200 mg and indinavir 800 mg three times a day resulted in increases in amiodarone concentrations from 0.9 mg/L to 1.3 mg/L. DEA concentrations were not affected. There was no evidence of toxicity. Monitoring for amiodarone toxicity and serial measurement of amiodarone serum concentration during concomitant protease inhibitor therapy should be considered.<br/>Histamine HAntagonists: Loratadine, a non-sedating antihistaminic, is metabolized primarily by CYP3A4. QT interval prolongation and torsade de pointes have been reported with the coadministration of loratadine and amiodarone.<br/>Histamine HAntagonists: Cimetidine inhibits CYP3A4 and can increase serum amiodarone levels.<br/>Antidepressants: Trazodone, an antidepressant, is metabolized primarily by CYP3A4. QT interval prolongation and torsade de pointes have been reported with the coadministration of trazodone and amiodarone.<br/>Other Substances: Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and Cby 84%, and decreased DEA to unquantifiable concentrations. Grapefruit juice inhibits CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone; therefore, grapefruit juice should not be taken during treatment with oral amiodarone. This information should be considered when changing from intravenous amiodarone to oral amiodarone (see DOSAGE AND ADMINISTRATION). Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A4. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates of p-glycoprotein. Reported examples of this interaction include the following:<br/>Immunosuppressives: Cyclosporine (CYP3A4 substrate) administered in combination with oral amiodarone has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine, despite reduction in dose of cyclosporine.<br/>HMG-CoA Reductase Inhibitors: Simvastatin (CYP3A4 substrate) in combination with amiodarone has been associated with reports of myopathy/rhabdomyolysis.<br/>Cardiovasculars: Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A4 (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in efficacy. Reported examples of this interaction include the following:<br/>Electrolyte Disturbances: Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when coadministering amiodarone with drugs which may induce hypokalemia and/or hypomagnesemia.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Amiodarone hydrochloride was associated with a statistically significant, dose-related increase in the incidence of thyroid tumors (follicular adenoma and/or carcinoma) in rats. The incidence of thyroid tumors was greater than control even at the lowest dose level tested, i.e., 5 mg/kg/day (approximately 0.08 times the maximum recommended human maintenance dose). Mutagenicity studies (Ames, micronucleus, and lysogenic tests) with amiodarone were negative. In a study in which amiodarone hydrochloride was administered to male and female rats, beginning 9 weeks prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately 1.4 times the maximum recommended human maintenance dose).<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Labor and Delivery: It is not known whether the use of amiodarone during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect of amiodarone on the duration of gestation or on parturition.<br/>Nursing Mothers: Amiodarone and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk, suggesting that breastfeeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered amiodarone have been shown to be less viable and have reduced body-weight gains. Therefore, when amiodarone therapy is indicated, the mother should be advised to discontinue nursing.<br/>Pediatric Use: The safety and effectiveness of amiodarone hydrochloride tablets in pediatric patients have not been established.<br/>Geriatric Use: Clinical studies of amiodarone hydrochloride tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:209 | dailymed-instance:precautio... | General: During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude and depression, despite maintenance or even improvement of respiratory function. In responsive patients, flunisolide may permit control of asthmatic symptoms with less suppression of HPA axis function than therapeutically equivalent oral doses of prednisone. Since flunisolide is absorbed into the circulation and can be systemically active, the beneficial effects of AEROSPAN Inhalation Aerosol in minimizing or preventing HPA axis dysfunction may be expected only whenrecommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing AEROSPAN Inhalation Aerosol. Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with AEROSPAN Inhalation Aerosol should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients post-operatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism, reduced bone mineral density, and adrenal suppression may appear in a small number of patients, particularly at higher doses. If such changes occur, the AEROSPAN Inhalation Aerosol dose should be reduced slowly, consistent with accepted procedures for management of asthma symptomsand for tapering of systemic corticosteroids. The long-term local and systemic effects of AEROSPAN Inhalation Aerosol in human subjects are not fully known. In particular, the effects resulting from chronic use of AEROSPAN Inhalation Aerosol on developmental or immunologic processes in the mouth, pharynx, trachea, and lung are unknown. Orally inhaled corticosteroids, including flunisolide, may cause a reduction in growth velocity when administered to pediatric patients. A reduction in growth velocity may occur as a result of inadequate control of asthma or from use of corticosteroids for treatment. The potential effects of prolonged treatment on growth velocity should be weighed against clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including AEROSPAN Inhalation Aerosol, each patient should be titrated to his/her lowest effective dose. Inhaled corticosteroids should be used with caution, if at all, in patients with untreated active or quiescent tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, parasitic or viral infections; or ocular herpes simplex. Rare instances of glaucoma, increased intraocular pressure, and cataracts have been reported in patients following the long- term administration of inhaled corticosteroids. In clinical studies with flunisolide, localized infections with Candida albicans or Aspergillus niger have occurred in the mouth and pharynx and occasionally in the larynx. These infections may require treatment with appropriate antifungal therapy and/or discontinuance of treatment with AEROSPAN Inhalation Aerosol.<br/>Information for Patients:: Patients being treated with AEROSPAN Inhalation Aerosol should receive the following information and instructions. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or beneficial effects. See Patient Information and illustrated Instructions for Using Your AEROSPAN Inhalation Aerosol for supplemental information. Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 22 month study in Swiss mice, flunisolide hemihydrate at oral doses up to 500 mcg/kg/day (approximately 3 and 4 times the maximum recommended daily inhalation dose in adults and children on a mg/mbasis) did not demonstrate any carcinogenic effects. In a two year study in Sprague Dawley rats, administration of flunisolide hemihydrate in the diet at a dose of 2.5 mcg/kg/day (less than the maximum recommended daily inhalation dose in adults or children on a mg/mbasis) resulted in an increased incidence of mammary gland adenomas and islet cell adenomas of the pancreas in females. The significance of these findings for humans is unknown. There were no significant increases in the incidence of any tumor type in female rats at a dose of 1.0 mcg/kg/day (less than the maximum recommended daily inhalation dose in adults or children on a mg/mbasis), or in male rats at a dose of 2.5 mcg/kg/day (less than the maximum recommended daily inhalation dose in adults or children on a mg/mbasis). Flunisolide hemihydrate showed no mutagenic activity when tested in in vitro bacterial assay systems (Ames Assay and the Rec-assay) and no clastogenic activity when tested in the in vitro chromosomal aberration assay using Chinese Hamster CHL cells and in the in vivo mouse bone marrow chromosomal aberration assay. Studies on the effects of flunisolide hemihydrate on fertility in female rats showed that flunisolide hemihydrate, at an oral dose of 200 mcg/kg/day (approximately 3 times the maximum recommended daily inhalation dose on a mg/mbasis) impaired fertility, but was devoid of such effects at doses up to 40 mcg/kg/day (less than the maximum recommended daily inhalation dose on a mg/mbasis).<br/>Pregnancy: Teratogenic Effects: Pregnancy Category C. As with other corticosteroids, flunisolide hemihydrate has been shown to be teratogenic and fetotoxic in rabbits and rats at doses of 40 and 200 mcg/kg/day, respectively, (approximately 1 and 3 times the maximum recommended daily inhalation dose on a mg/mbasis, respectively). There are no adequate and well-controlled studies of flunisolide hemihydrate in pregnant women. AEROSPAN Inhalation Aerosol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiological, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored. Nursing Mothers: It is not known whether flunisolide is excreted in human milk. Because other corticosteroids are excreted in human milk, caution should be exercised when AEROSPAN Inhalation Aerosol is administered to nursing women. Pediatric Use: The safety and effectiveness of AEROSPAN Inhalation Aerosol has been studied in patients ages 4-17 years of age. The safety and effectiveness of AEROSPAN Inhalation Aerosol has not been studied in patients less than 4 years of age. In clinical studies, the adverse event profile observed in patients exposed to AEROSPAN Inhalation Aerosol was similar between the 4-5 year age group (n=21), the 6-11 year age group (n=210), the 12-17 year age group (n=30), and those patients 18 years of age and older (n=258). Controlled clinical studies have shown that orally inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. In these studies, the mean reduction in growth velocity was approximately one cm per year (range 0.3 to 1.8 cm per year) and appears to depend upon the dose and duration of exposure. This effect was observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for���catch up���growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The growth of pediatric patients receiving orally inhaled corticosteroids, including AEROSPAN Inhalation Aerosol, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks/benefits of treatment alternatives.To minimize the systemic effects of orally inhaled corticosteroids, including AEROSPAN Inhalation Aerosol, each patient should be titrated to the lowest dose that effectively controls his/her symptoms. Geriatric Use: Clinical studies of AEROSPAN Inhalation Aerosol included 21 patients 65 to 78 years of age exposed to AEROSPAN Inhalation Aerosol. These studies did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drugtherapy. | lld:dailymed |
| dailymed-drugs:210 | dailymed-instance:precautio... | General: Patients with chronic occlusive arterial disease of the limbs frequently show other manifestations of arteriosclerotic disease. Pentoxifylline has been used safely for treatment of peripheral arterial disease in patients with concurrent coronary artery and cerebrovascular diseases, but there have been occasional reports of angina, hypotension, and arrhythmia. Controlled trials do not show that pentoxifylline causes such adverse effects more often than placebo, but, as it is a methylxanthine derivative, it is possible some individuals will experience such responses. Patients on warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration, cerebral and/or retinal bleeding) should have periodic examinations for bleeding including hematocrit and/orhemoglobin.<br/>Drug Interactions: Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with pentoxifylline with and without anticoagulants or platelet aggregation inhibitors. Patients on warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of pentoxifylline and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity insome individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. Pentoxifylline has been used concurrently with antihypertensive drugs, beta blockers, digitalis, diuretics, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies of the carcinogenic potential of pentoxifylline were conducted in mice and rats by dietary administration of the drug at doses up to 450 mg/kg (approximately 19 times the maximum recommended human daily dose [MRHD] in both species when based on body-weight; 1.5 times the MRHD in the mouse and 3.3 times the MRHD in the rat when based on body-surface area). In mice, the drug was administered for 18 months, whereas in rats, the drug was administered for 18 months followedby an additional 6 months without drug exposure. In the rat study, there was a statistically significant increase in benign mammary fibroadenomas in females of the 450 mg/kg group. The relevance of this finding to human use is uncertain. Pentoxifylline was devoid of mutagenic activity in various strains of Salmonella (Ames test) and in cultured mammalian cells (unscheduled DNA synthesis test) when tested in the presence and absence of metabolic activation. It was also negative in the in vivo mouse micronucleus test.<br/>Pregnancy:<br/>Teratogenic Effects. Category C: Teratogenicity studies have been performed in rats and rabbits, using oral doses up to 576 and 264 mg/kg, respectively. On a weight basis, these doses are 24 and 11 times the maximum recommended human dose (MRHD); on a body-surface-area basis, they are 4.2 and 3.5 times the MRHD. No evidence of fetal malformation was observed. Increased resorption was seen inrats of the 576 mg/kg group. There are no adequate and well controlled studies in pregnant women. Pentoxifylline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: Pentoxifylline and its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for pentoxifylline in rats, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric Use: Clinical studies of pentoxifylline did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. The active metabolite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. | lld:dailymed |
| dailymed-drugs:211 | dailymed-instance:precautio... | General:: TENORETIC may aggravate peripheral arterial circulatory disorders.<br/>Electrolyte and Fluid Balance Status: Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. Patients should be observed for clinical signs of fluid or electrolyte imbalance; i.e., hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Measurement of potassium levels is appropriate especially in elderly patients, those receiving digitalis preparations for cardiac failure, patients whose dietary intake of potassium is abnormally low, or those suffering from gastrointestinal complaints. Hypokalemia may develop especially with brisk diuresis, when severe cirrhosis is present, or during concomitant use of corticosteroids or ACTH. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (eg, increased ventricular irritability). Hypokalemia may be avoided or treated by use of potassium supplements or foods with a high potassium content. Any chloride deficit during thiazide therapy is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of salt except in rareinstances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.<br/>Drug Interactions:: TENORETIC may potentiate the action of other antihypertensive agents used concomitantly. Patients treated with TENORETIC plus a catecholamine depletor (eg, reserpine) should be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope or postural hypotension. Calcium channel blockers may also have an additive effect when given with TENORETIC. (See WARNINGS.) Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude the therapeutic effectiveness of norepinephrine. Thiazides may increase the responsiveness to tubocurarine. Concomitant use of prostaglandin synthase inhibiting drugs, eg, indomethacin, may decrease the hypotensive effects of beta blockers. Lithium generally should not be given with diuretics because they reduce its renal clearance and add a high risk of lithium toxicity. Read prescribing information for lithium preparations before use of such preparations with TENORETIC. Beta blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are coadministered, the beta blocker should be withdrawn several days before the gradual withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, the introduction of beta blockers should be delayed for several days after clonidine administration has stopped. While taking beta blockers, patients with a history of anaphylactic reaction to a variety of allergens may have a more severe reaction on repeated challenge, either accidental, diagnostic or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat the allergic reaction.<br/>Other Precautions: In patients receiving thiazides, sensitivity reactions may occur with or without a history of allergy or bronchial asthma. The possible exacerbation or activation of systemic lupus erythematosus has been reported. The antihypertensive effects of thiazides may be enhanced in the postsympathectomy patient.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:: Two long-term (maximum dosing duration of 18 or 24 months) rat studies and one long-term (maximum dosing duration of 18 months) mouse study, each employing dose levels as high as 300 mg/kg/day or 150 times the maximum recommended human antihypertensive dose1, did not indicate a carcinogenic potential of atenolol. A third (24 month) rat study, employing doses of 500 and 1,500 mg/kg/day (250 and 750 times the maximum recommended human antihypertensive dose1) resulted in increased incidences of benign adrenal medullary tumors in males and females, mammary fibroadenomas in females, and anterior pituitary adenomas and thyroid parafollicular cell carcinomas in males. No evidence of a mutagenic potential of atenolol was uncovered in the dominant lethal test (mouse), in vivo cytogenetics test (Chinese hamster) or Ames test (S typhimurium). Fertility of male or female rats (evaluated at dose levels as high as 200 mg/kg/day or 100 times the maximum recommended human dose1) was unaffected by atenolol administration.<br/>Animal Toxicology: Six month oral administration studies were conducted in rats and dogs using TENORETIC doses up to 12.5 mg/kg/day (atenolol/chlorthalidone 10/2.5 mg/kg/day -- approximately five times the maximum recommended human antihypertensive dose1). There were no functional or morphological abnormalities resulting from dosing either compound alone or together other than minor changes in heart rate, blood pressure and urine chemistry which were attributed to the known pharmacologic properties of atenolol and/or chlorthalidone. Chronic studies of atenolol performed in animals have revealed the occurrence of vacuolation of epithelial cells of Brunner's glands in the duodenum of both male and female dogs at all tested dose levels (starting at 15 mg/kg/day or 7.5 times the maximum recommended human antihypertensive dose1) and increased incidence of atrial degeneration of hearts of male rats at 300 but not 150 mg atenolol/kg/day (150 and 75 times the maximum recommended human antihypertensive dose,1 respectively).<br/>Use in Pregnancy: Pregnancy Category D: See WARNINGS - Pregnancy and Fetal Injury<br/>Nursing Mothers: Atenolol is excreted in human breast milk at a ratio of 1.5 to 6.8 when compared to the concentration in plasma. Caution should be exercised when atenolol is administered to a nursing woman. Clinically significant bradycardia has been reported in breast-fed infants. Premature infants, or infants with impaired renal function, may be more likely to develop adverse effects. Neonates born to mothers who are receiving atenolol at parturition or breast-feeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when TENORETIC is administered during pregnancy or to a woman who is breast-feeding. (See WARNINGS, Pregnancy and Fetal Injury.) | lld:dailymed |
| dailymed-drugs:212 | dailymed-instance:precautio... | As many other antihistamines, carbinoxamine maleate has an atropine-like action and, therefore, should be used with caution in patients with: increased intraocular pressure, hyperthyroidism, cardiovascular disease, hypertension. Antihistamines such as carbinoxamine maleate should not be used to treat lower respiratory tract symptoms, including asthma. Carbinoxamine maleate may diminish mental alertness in children. In the young child, particularly, they may produce excitation. Carbinoxamine maleate is more likely to cause dizziness, sedation, and hypotension in elderly patients (approximately 60 years or older).<br/>Information for Patients: Carbinoxamine maleate may cause drowsiness; alcohol, sedatives, and tranquilizers may increase the drowsiness effect. Avoid alcoholic beverages while taking this product. Do not take this product if you are taking sedatives or tranquilizers, without first consulting your doctor. Use caution when driving a motor vehicle or operating machinery.<br/>Drug Interactions: Monoamine oxidase inhibitors prolong and intensify the anticholinergic (drying) effects of antihistamines. Carbinoxamine maleate has additive effects with alcohol and other CNS depressants (hypnotics sedatives, tranquilizers, etc.).<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term studies in animals have been performed to determine the possible effects of carbinoxamine maleate on carcinogenesis, mutagenesis, and fertility.<br/>Pregnancy:<br/>Pregnancy Category C: Animal reproductive studies have not been conducted with carbinoxamine maleate. It is also not known whether carbinoxamine maleate can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Carbinoxamine maleate should be given to a pregnant woman only if clearly needed.<br/>Nursing Mothers: Because of the higher risk of antihistamines for infants generally and for newborns and prematures in particular, use of carbinoxamine maleate is contraindicated in nursing mothers .<br/>Pediatric Use: Carbinoxamine maleate is contraindicated in children younger than 2 years of age .<br/>Geriatric Use: Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on lower doses of carbinoxamine maleate and observed closely. | lld:dailymed |
| dailymed-drugs:213 | dailymed-instance:precautio... | General: As with other antibacterial preparations, use of this product may result in overgrowth of nonsusceptible organisms, including yeast and fungi. If the infection is not improved after one week of treatment, cultures should be obtained to guide further treatment. If otorrhea persists after a full course of therapy, or if two or more episodes of otorrhea occur within six months, further evaluation is recommended to exclude an underlying condition such as cholesteatoma, foreign body, or a tumor. The systemic administration of quinolones, including ciprofloxacin at doses much higher than given or absorbed by the otic route, has led to lesions or erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species. Guinea pigs dosed in the middle ear with CIPRODEX' Otic for one month exhibited no drug-related structural or functional changes of the cochlear hair cells and no lesions in the ossicles. CIPRODEX' Otic was also shown to lack dermal sensitizing potential in the guinea pig when tested according to the method of Buehler. No signs of local irritation were found when CIPRODEX' Otic was applied topically in the rabbit eye.<br/>Information for Patients: For otic use only. (This product is not approved for use in the eye.) Warm the bottle in your hand for one to two minutes prior to use and shake well immediately before using.Avoid contaminating the tip with material from the ear, fingers, or other sources.Protect from light.If rash or allergic reaction occurs, discontinue use immediately and contact your physician.It is very important to use the ear drops for as long as the doctor has instructed, even if the symptoms improve.Discard unused portion after therapy is completed. Acute Otitis Media in pediatric patients with tympanostomy tubes Prior to administration of CIPRODEX' Otic in patients (6 months and older) with acute otitis media through tympanostomy tubes, the suspension should be warmed by holding the bottle in the hand for one or two minutes to avoid dizziness which may result from the instillation of a cold suspension. The patient should lie with the affected ear upward, and then the drops should be instilled. The tragus should then be pumped 5 times by pushing inward to facilitate penetration of the drops into the middle ear. This position should be maintained for 60 seconds. Repeat, if necessary, for the opposite ear . Acute Otitis ExternaPrior to administration of CIPRODEX' Otic in patients with acute otitis externa, the suspension should be warmed by holding the bottle in the hand for one or two minutes to avoid dizziness which may result from the instillation of a cold suspension. The patient should lie with the affected ear upward, and then the drops should be instilled. This position should be maintained for 60 seconds to facilitate penetration of the drops into the ear canal. Repeat, if necessary, for the opposite ear .<br/>Drug Interactions: Specific drug interaction studies have not been conducted with CIPRODEX' Otic.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term carcinogenicity studies in mice and rats have been completed for ciprofloxacin. After daily oral doses of 750 mg/kg (mice) and 250 mg/kg (rats) were administered for up to 2 years, there was no evidence that ciprofloxacin had any carcinogenic or tumorigenic effects in these species. No long term studies of CIPRODEX' Otic have been performed to evaluate carcinogenic potential. Eight in vitro mutagenicity tests have been conducted with ciprofloxacin, and the test results are listed below: Salmonella/Microsome Test (Negative)E. coli DNA Repair Assay (Negative)Mouse Lymphoma Cell Forward Mutation Assay (Positive)Chinese Hamster VCell HGPRT Test (Negative)Syrian Hamster Embryo Cell Transformation Assay (Negative)Saccharomyces cerevisiae Point Mutation Assay (Negative)Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)Rat Hepatocyte DNA Repair Assay (Positive)Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems gave negative results:Rat Hepatocyte DNA Repair AssayMicronucleus Test (Mice)Dominant Lethal Test (Mice) Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg/day revealed no evidence of impairment. This would be over 100 times the maximum recommended clinical dose of ototopical ciprofloxacin based upon body surface area, assuming total absorption of ciprofloxacin from the ear of a patient treated with CIPRODEX' Otic twice per day according to label directions. Long term studies have not been performed to evaluate the carcinogenic potential of topical otic dexamethasone. Dexamethasone has been tested for in vitro and in vivo genotoxic potential and shown to be positive in the following assays; chromosomal aberrations, sister-chromatid exchange in human lymphocytes and micronuclei and sister-chromatid exchanges in mouse bone marrow. However, the Ames/Salmonella assay, both with and without S9 mix, did not show any increase in His+ revertants. The effect of dexamethasone on fertility has not been investigated following topical otic application. However, the lowest toxic dose of dexamethasone identified following topical dermal application was 1.802 mg/kg in a 26-week study in male rats and resulted in changes to the testes, epididymis, sperm duct, prostate, seminal vessicle, Cowper's gland and accessory glands. The relevance of this study for short term topical otic use is unknown.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C: Reproduction studies have been performed in rats and mice using oral doses of up to 100 mg/kg and IV doses up to 30 mg/kg and have revealed no evidence of harm to the fetus as a result of ciprofloxacin. In rabbits, ciprofloxacin (30 and 100 mg/kg orally) produced gastrointestinal disturbances resulting in maternal weight loss and an increased incidence of abortion, but no teratogenicity was observed at either dose. After intravenous administration of doses up to 20 mg/kg, no maternal toxicity was produced in the rabbit, and no embryotoxicity or teratogenicity was observed. Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. Animal reproduction studies have not been conducted with CIPRODEX' Otic. No adequate and well controlled studies have been performed in pregnant women. Caution should be exercised when CIPRODEX' Otic is used by a pregnant woman.<br/>Nursing Mothers: Ciprofloxacin and corticosteroids, as a class, appear in milk following oral administration. Dexamethasone in breast milk could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical otic administration of ciprofloxacin or dexamethasonecould result in sufficient systemic absorption to produce detectable quantities in human milk. Because of the potential for unwanted effects in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: The safety and efficacy of CIPRODEX' Otic have been established in pediatric patients 6 months and older (937 patients) in adequate and well-controlled clinical trials. Although no data are available on patients less than age 6 months, there are no known safety concerns or differences in the disease process in this population that would preclude use of this product. No clinically relevant changes in hearing function were observed in 69 pediatric patients (age 4 to 12 years) treated with CIPRODEX' Otic and tested for audiometric parameters. | lld:dailymed |
| dailymed-drugs:214 | dailymed-instance:precautio... | General: There are no reports of hypersensitivity in patients who have been administered trientine hydrochloride for Wilson's disease. However, there have been reports of asthma, bronchitis and dermatitis occurring after prolonged environmental exposure in workers who use trientine hydrochloride as a hardener of epoxy resins. Patients should be observed closely for signs of possible hypersensitivity.<br/>Information for Patients: Patients should be directed to take SYPRINE on an empty stomach, at least one hour before meals or two hours after meals and at least one hour apart from any other drug, food, or milk. The capsules should be swallowed whole with water and should not be opened or chewed. Because of the potential for contact dermatitis, any site of exposure to the capsule contents should be washed with water promptly. For the first month of treatment, the patient should have his temperature taken nightly, and he should be asked to report any symptom such as fever or skin eruption.<br/>Laboratory Tests: The most reliable index for monitoring treatment is the determination of free copper in the serum, which equals the difference between quantitatively determined total copper and ceruloplasmin-copper. Adequately treated patients will usually have less than 10 mcg free copper/dL of serum. Therapy may be monitored with a 24-hour urinary copper analysis periodically (i.e., every 6-12 months). Urine must be collected in copper-free glassware. Since a low copper diet should keep copper absorption down to less than one milligram a day, the patient probably will be in the desired state of negative copper balance if 0.5 to 1.0 milligram of copper is present in a 24-hour collection of urine.<br/>Drug Interactions: In general, mineral supplements should not be given since they may block the absorption of SYPRINE. However, iron deficiency may develop, especially in children and menstruating or pregnant women, or as a result of the low copper diet recommended for Wilson's disease. If necessary, iron may be given in short courses, but since iron and SYPRINE each inhibit absorption of the other, two hours should elapse between administration of SYPRINE and iron. It is important that SYPRINE be taken on an empty stomach, at least one hour before meals or two hours after meals and at least one hour apart from any other drug, food, or milk. This permits maximum absorption and reduces the likelihood of inactivation of the drug by metal binding in the gastrointestinal tract.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Data on carcinogenesis, mutagenesis, and impairment of fertility are not available.<br/>Pregnancy:<br/>Pregnancy Category C: Trientine hydrochloride was teratogenic in rats at doses similar to the human dose. The frequencies of both resorptions and fetal abnormalities, including hemorrhage and edema, increased while fetal copper levels decreased when trientine hydrochloride was given in the maternal diets of rats. There are no adequate and well-controlled studies in pregnant women. SYPRINE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SYPRINE is administered to a nursing mother.<br/>Pediatric Use: Controlled studies of the safety and effectiveness of SYPRINE in pediatric patients have not been conducted. It has been used clinically in pediatric patients as young as 6 years with no reported adverse experiences.<br/>Geriatric Use: Clinical studies of SYPRINE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience is insufficient to determine differences in responses between the elderly and younger patients. In general, dose selection should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:216 | dailymed-instance:precautio... | General: Since lactulose solution contains galactose (less than 1.6 g/15 mL) and lactose (less than 1.2 g/15 mL), it should be used with caution in diabetics.<br/>Information for Patients: In the event that an unusual diarrheal condition occurs, contact your physician.<br/>Laboratory Tests: Elderly, debilitated patients who receive lactulose solution for more than six months should have serum electrolytes (potassium, chloride, carbon dioxide) measured periodically.<br/>Drug Interactions: Results of preliminary studies in humans and rats suggest that nonabsorbable antacids given concurrently with lactulose may inhibit the desired lactulose-induced drop in colonic pH. Therefore, a possible lack of desired effect of treatment should be taken into consideration before such drugs are given concomitantly with lactulose solution.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: There are no known human data on long-term potential for carcinogenicity, mutagenicity, or impairment of fertility. There are no known animal data on long-term potential for mutagenicity. Administration of lactulose solution in the diet of mice for 18 months in concentrations of 3 and 10 percent (V/W) did not produce any evidence of carcinogenicity. In studies in mice, rats, and rabbits, doses of lactulose solution up to 6 or 12 mL/kg/day produced no deleterious effects in breeding, conception, or parturition.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category B: Reproduction studies have been performed in mice, rats, and rabbits at doses up to 3 or 6 times the usual human oral dose and have revealed no evidence of impaired fertility or harm to the fetus due to lactulose. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when lactulose solution is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established. | lld:dailymed |
| dailymed-drugs:217 | dailymed-instance:precautio... | General: Use with caution in the presence of hypertension, cardiovascular abnormalities, hyperglycemia (diabetes), hyperthyroidism, ocular infection or injury and when other medications are being used.<br/>Patient Information: Patients should be advised to discontinue the drug and consult a physician if relief is not obtained within 48 hours of therapy, if irritation, blurring, or redness persists or increases, or if symptoms of systemic absorption occur, i.e., dizziness, headache, nausea, decrease in body temperature, or drowsiness. To prevent contaminating the dropper tip and solution, do not touch the eyelids or the surrounding area with the dropper tip of the bottle. If solution changes color or becomes cloudy, do not use.<br/>Drug Interactions: Concurrent use of maprotiline or tricyclic antidepressants and naphazoline may potentiate the pressor effect of naphazoline. Patients under therapy with MAO inhibitors may experience a severe hypertensive crisis if given a sympathomimetic drug. (See WARNINGS).<br/>Pregnancy Category C: Animal reproduction studies have not been conducted with naphazoline. It is also not known whether naphazoline can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Naphazoline should be given to a pregnant woman only if clearly needed.<br/>Nursing Mothers: If is not known whether naphazoline is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when naphazoline is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in children have not been established. See���WARNINGS���and���CONTRAINDICATIONS���. | lld:dailymed |
| dailymed-drugs:219 | dailymed-instance:precautio... | The safety and efficacy of RIBASPHERE (ribavirin, USP) and peginterferon alfa-2a therapy for the treatment of adenovirus, RSV, parainfluenza or influenza infections have not been established. RIBASPHERE (ribavirin, USP) should not be used for these indications. Ribavirin for inhalation has a separate package insert, which should be consulted if ribavirin inhalation therapy is being considered. The safety and efficacy of RIBASPHERE (ribavirin, USP) and peginterferon alfa-2a therapy have not been established in liver or other organ transplant patients, patients with decompensated liver disease due to hepatitis C virus infection, patients who are non-responders to interferon therapy or patients coinfected with HBV or HIV and a CD4+ cell count<100 cells/��L.<br/>Information for Patients: Patients must be informed that ribavirin may cause birth defects and/or death of the exposed fetus. RIBASPHERE (ribavirin, USP) therapy must not be used by women who are pregnant or by men whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking RIBASPHERE (ribavirin, USP) therapy and for 6 months posttherapy. RIBASPHERE (ribavirin, USP) therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Patients must perform a pregnancy test monthly during therapy and for 6 months posttherapy. Female patients of childbearing potential and male patients with female partners of childbearing potential must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during RIBASPHERE (ribavirin, USP) therapy and for 6 months posttherapy. Patients should be advised to notify the healthcare provider immediately in the event of a pregnancy . The most common adverse event associated with ribavirin is anemia, which may be severe . Patients should be advised that laboratory evaluations are required prior to starting RIBASPHERE (ribavirin, USP) therapy and periodically thereafter (see Laboratory Tests). It is advised that patients be well hydrated, especially during the initial stages of treatment. Patients who develop dizziness, confusion, somnolence, and fatigue should be cautioned to avoid driving or operating machinery. Patients should be informed regarding the potential benefits and risks attendant to the use of RIBASPHERE (ribavirin, USP). Instructions on appropriate use should be given, including review of the contents of the enclosed MEDICATION GUIDE, which is not a disclosure of all or possible adverse effects. Patients should be advised to take RIBASPHERE (ribavirin, USP) with food.<br/>Laboratory Tests: Before beginning RIBASPHERE (ribavirin, USP) therapy, standard hematological and biochemical laboratory tests must be conducted for all patients. Pregnancy screening for women of childbearing potential must be done. After initiation of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy. Monthly pregnancy testing should be done during combination therapy and for 6 months after discontinuing therapy. The entrance criteria used for the clinical studies of ribavirin and peginterferon alfa-2a combination therapy may be considered as a guideline to acceptable baseline values for initiation of treatment: The maximum drop in hemoglobin usually occurred during the first 8 weeks of initiation of ribavirin therapy. Because of this initial acute drop in hemoglobin, it is advised that a complete blood count should be obtained pretreatment and at week 2 and week 4 of therapy or more frequently if clinically indicated. Additional testing should be performed periodically during therapy. Patients should then be followed as clinically appropriate.<br/>Drug Interactions: Results from a pharmacokinetic sub-study demonstrated no pharmacokinetic interaction between peginterferon alfa-2a and ribavirin.<br/>Nucleoside Analogues:<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis: In a p53 (+/-) mouse carcinogenicity study and a rat 2-year carcinogenicity study at doses up to the maximum tolerated doses of 100 mg/kg/day and 60 mg/kg/day, respectively, ribavirin was not oncogenic. On a body surface area basis, these doses are approximately 0.5 and 0.6 times the maximum recommended human 24-hour dose of ribavirin.<br/>Mutagenesis: Ribavirin demonstrated mutagenic activity in the in vitro mouse lymphoma assay. No clastogenic activity was observed in an in vivo mouse micronucleus assay at doses up to 2000 mg/kg. However, results from studies published in the literature show clastogenic activity in the in vivo mouse micronucleus assay at oral doses up to 2000 mg/kg. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes. However, potential carcinogenic risk to humans cannot be excluded.<br/>Impairment of Fertility: In a fertility study in rats, ribavirin showed a marginal reduction in sperm counts at the dose of 100 mg/kg/day with no effect on fertility. Upon cessation of treatment, total recovery occurred after 1 spermatogenesis cycle. Abnormalities in sperm were observed in studies in mice designed to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of 15 to150 mg/kg/day (approximately 0.1 to 0.8 times the maximum recommended human 24-hour dose ofribavirin) administered for 3 to 6 months. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenic cycles. Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive RIBASPHERE (ribavirin, USP) unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half-life (t) of ribavirin of 12 days,effective contraception must be utilized for 6 months posttherapy (i.e., 15 half-lives of clearance for ribavirin). No reproductive toxicology studies have been performed using peginterferon alfa-2a in combination with RIBASPHERE (ribavirin, USP). However, peginterferon alfa-2a and ribavirin when administered separately, each has adverse effects on reproduction. It should be assumed that the effects produced by either agent alone would also be caused by the combination of the two agents.<br/>Pregnancy: Pregnancy: Category X Ribavirin produced significant embryocidal and/or teratogenic effects in all animal species in which adequate studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of fetuses and offspring was reduced. In conventional embryotoxicity/teratogenicity studies in rats and rabbits, observed no-effect dose levels were well below those for proposed clinical use (0.3 mg/kg/day for both the rat and rabbit; approximately 0.06 times the recommended human 24-hour dose of ribavirin). No maternal toxicity or effects on offspring were observed in a peri/postnatal toxicity study in rats dosed orally at up to 1 mg/kg/day (approximately 0.01 times the maximum recommended human 24-hour dose of ribavirin).<br/>Treatment and Posttreatment: Potential Risk to the Fetus: Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether ribavirin is contained in sperm, and if so, will exert a potential teratogenic effect upon fertilization of the ova. In a study in rats, it was concluded that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg for 5 days (up to 1.7times the maximum recommended human dose of ribavirin). However, because of the potential human teratogenic effects of ribavirin, male patients should be advised to take every precaution to avoid risk of pregnancy for their female partners. RIBASPHERE (ribavirin, USP) should not be used by pregnant women or by men whose female partners are pregnant. Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive RIBASPHERE (ribavirin, USP) unless the patient and his/her partner are using effective contraception (two reliable forms) during therapy and for 6 months posttherapy.<br/>Ribavirin Pregnancy Registry: A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies of female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling 1-800-593-2214.<br/>Animal Toxicology: Long-term study in the mouse and rat (18 to 24 months; dose 20 to 75, and 10 to 40 mg/kg/day, respectively, approximately 0.1 to 0.4 times the maximum human daily dose of ribavirin) have demonstrated a relationship between chronic ribavirin exposure and an increased incidence of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence was increased in ribavirin-treated rats.<br/>Nursing Mothers: It is not known whether ribavirin is excreted in human milk. Because many drugs are excreted in human milk and to avoid any potential for serious adverse reactions in nursing infants from ribavirin, a decision should be made either to discontinue nursing or therapy with RIBASPHERE (ribavirin, USP), based on the importance of the therapy to the mother.<br/>Pediatric Use: Safety and effectiveness of RIBASPHERE (ribavirin, USP) have not been established in patients below the age of 18.<br/>Geriatric Use: Clinical studies of ribavirin and peginterferon alfa-2a did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Specific pharmacokinetic evaluations for ribavirin in the elderly have not been performed. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. RIBASPHERE (ribavirin, USP) should not be administered to patients with creatinine clearance<50 mL/min. .<br/>Effect of Gender: No clinically significant differences in the pharmacokinetics of ribavirin were observed between male and female subjects. | lld:dailymed |
| dailymed-drugs:220 | dailymed-instance:precautio... | General: Oxaprozin cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of oxaprozin in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.<br/>Hepatic effects: Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including oxaprozin. These laboratory abnormalities may progress, remain unchanged, or may be transient with continued therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminate hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with oxaprozin. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), oxaprozin should be discontinued.<br/>Photosensitivity: Oxaprozin has been associated with rash and/or mild photosensitivity in dermatologic testing. An increased incidence of rash on sun-exposed skin was seen in some patients in the clinical trials.<br/>Hematological effects: Anemia is sometimes seen in patients receiving NSAIDs, including oxaprozin. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythrogenesis. Patients on long-term treatment with oxaprozin, should have their hemoglobin or hematocrit values determined if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving oxaprozin who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.<br/>Preexisting asthma: Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with the severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, oxaprozin should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.<br/>Information for patients: Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. 1. Oxaprozin, like other NSAIDS, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects). 2. Oxaprozin, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation). 3. Oxaprozin, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. 4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. 5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and���flu-like���symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. 6. Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). 7. In late pregnancy, as with other NSAIDs, oxaprozin should be avoided because it may cause premature closure of the ductus arteriosus.<br/>Laboratory tests: Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g. eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, oxaprozin should be discontinued.<br/>Drug Interactions: ASPIRIN Concomitant administration of oxaprozin and aspirin is not recommended because oxaprozin displaces salicylates from plasma protein binding sites. Coadministration would be expected to increase the risk of salicylate toxicity. As with other NSAIDs concomitant administration of oxaprozin and aspirin is not generally recommended because of the potential for increased adverse effects. METHOTREXATE NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Coadministration of oxaprozin with methotrexate results in approximately a 36% reduction in apparent oral clearance of methotrexate. A reduction in methotrexate dosage may be considered due to the potential for increased methotrexate toxicity associated with increased exposure. ACE-INHIBITORS Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. Oxaprozin has been shown to alter the pharmacokinetincs of enalapril (significant decrease in dose-adjusted AUC0-24 and Cmax) and its active metabolite enalaprilat (significant increase in dose-adjusted AUC0-24). This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors. DIURETICS Clinical studies, as well as post marketing observations, have shown that oxaprozin can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS: Renal effects), as well as to assure diuretic efficacy. LITHIUM Oxaprozin, like other NSAIDs, has produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. GLYBURIDE While oxaprozin does alter the pharmacokinetics of glyburide, coadministration of oxaprozin to type II non-insulin dependent diabetic patients did not affect the area under the glucose concentration curve nor the magnitude or duration of control. However, it is advisable to monitor patients' blood glucose in the beginning phase of glyburide and oxaprozin cotherapy. WARFARIN The effects of warfarin and NSAIDs on gastrointestinal (GI) bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than that of users of either drug alone. H2-RECEPTOR ANTAGONISTS The total body clearance of oxaprozin was reduced by 20% in subjects who concurrently received therapeutic doses of cimetidine or ranitidine; no other pharmacokinetic parameter was affected. A change of clearance of this magnitude lies within the range of normal variation and is unlikely to produce a clinically detectable difference in the outcome of therapy. BETA-BLOCKERS Subjects receiving 1200 mg oxaprozin qd with 100 mg metoprolol bid exhibited statistically significant but transient increases in sitting and standing blood pressures after 14 days. Therefore, as with all NSAIDs, routine blood pressure monitoring should be considered in these patients when starting oxaprozin therapy. OTHER DRUGS The coadministration of oxaprozin and antacids, acetaminophen, or conjugated estrogens resulted in no statistically significant changes in pharmacokinetic parameters in single- and/or multiple-dose studies. The interaction of oxaprozin with cardiac glycosides has not been studied.<br/>LABORATORY TEST INTERACTIONS: False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking oxaprozin. This is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of oxaprozin therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish oxaprozin from benzodiazepines.<br/>Carcinogenesis, mutagenesis, impairment of fertility: In oncogenicity studies, oxaprozin administration for 2 years was associated with the exacerbation of liver neoplasms (hepatic adenomas and carcinomas) in male CD mice, but not in female CD mice or rats. The significance of this species-specific finding to man is unknown. Oxaprozin did not display mutagenic potential. Results from the Ames test, forward mutation in yeast and Chinese hamster ovary (CHO) cells, DNA repair testing in CHO cells, micronucleus testing in mouse bone marrow, chromosomal aberration testing in human lymphocytes, and cell transformation testing in mouse fibroblast all showed no evidence of genetic toxicity or cell-transforming ability. Oxaprozin administration was not associated with impairment of fertility in male and female rats at oral doses up to 200 mg/kg/day (1180 mg/m); the usual human dose is 17 mg/kg/day (629 mg/m). However, testicular degeneration was observed in beagle dogs treated with 37.5 to 150 mg/kg/day (750 to 3000 mg/m) of oxaprozin for 6 months, or 37.5 mg/kg/day for 42 days, a finding not confirmed in other species. The clinical relevance of this finding is not known.<br/>Pregnancy:<br/>Teratogenic effects. Pregnancy Category C.: Teratology studies with oxaprozin were performed in mice, rats and rabbits. In mice and rats, no drug-related developmental abnormalities were observed at 50 to 200 mg/kg/day of oxaprozin (225 to 900 mg/m). However in rabbits, infrequent malformed fetuses were observed in dams treated with 7.5 to 30 mg/kg/day of oxaprozin (the usual human dosage range). Animal reproductive studies are not always predictive of human response. There are no adequate or well-controlled studies in pregnant women. Oxaprozin should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.<br/>Nonteratogenic effects: Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.<br/>Labor and delivery: In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of oxaprozin on labor and delivery in pregnant women are unknown.<br/>Nursing mothers: It is not known whether this drug is excreted in human milk; however, oxaprozin was found in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from oxaprozin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric use: Safety and effectiveness in pediatric patients less than 6 years of age have not been established. The effectiveness of oxaprozin for the treatment of the signs and symptoms of juvenile rheumatoid arthritis (JRA) in pediatric patients aged 6-16 years is supported by evidence from adequate and well controlled studies in adult rheumatoid arthritis patients, and is based on an extrapolation of the demonstrated efficacy of oxaprozin in adults with rheumatoid arthritis and the similarity in the course of the disease and the drug's mechanism of effect between these two patient populations. Use of oxaprozin in JRA patients 6-16 years of age is also supported by the following pediatric studies. The pharmacokinetic profile and tolerability of oxaprozin were assessed in JRA patients relative to adult rheumatoid arthritis patients in a 14 day multiple dose pharmacokinetic study. Apparent clearance of unbound oxaprozin in JRA patients was reduced compared to adult rheumatoid arthritis patients, but this reduction could be accounted for by differences in body weight (see Pharmacokinetics: Pediatric patients). No pharmacokinetic data are available for pediatric patients under 6 years. Adverse events were reported by approximately 45% of JRA patients versus an approximate 30% incidence of adverse events in the adult rheumatoid arthritis patient cohort. Most of the adverse events were related to the gastrointestinal tract and were mild to moderate. In a 3 month open label study, 10-20 mg/kg/day of oxaprozin were administered to 59 JRA patients. Adverse events were reported by 58% of JRA patients. Most of those reported were generally mild to moderate, tolerated by the patients, and did not interfere with continuing treatment. Gastrointestinal symptoms were the most frequently reported adverse effects and occurred at a higher incidence than those historically seen in controlled studies in adults. Fifty-two patients completed 3 months of treatment with a mean daily dose of 20 mg/kg. Of 30 patients who continued treatment (19-48 week range total treatment duration), nine (30%) experienced rash on sun-exposed areas of the skin and 5 of those discontinued treatment. Controlled clinical trials with oxaprozin in pediatric patients have not been conducted.<br/>Geriatric use: No adjustment of the dose of oxaprozin is necessary in the elderly for pharmacokinetic reasons, although many elderly may need to receive a reduced dose because of low body weight or disorders associated with aging. No significant differences in the phar-macokinetic profile for oxaprozin were seen in studies in the healthy elderly (see CLINICAL PHARMACOLOGY: Special populations). Of the total number of subjects evaluated in four placebo controlled clinical studies of oxaprozin, 39% were 65 and over, and 11% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Although selected elderly patients in controlled clinical trials tolerated oxaprozin as well as younger patients, caution should be exercised in treating the elderly, and extra care should be taken when choosing a dose. As with any NSAID, the elderly are likely to tolerate adverse reactions less well than younger patients. Oxaprozin is substantially excreted by the kidney, and the risk of toxic reactions to oxaprozin may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see WARNINGS: Renal effects). | lld:dailymed |
| dailymed-drugs:221 | dailymed-instance:precautio... | A. General:<br/>1. Addition of a progestin when a woman has not had a hysterectomy: Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone treatment. These include a possible increased risk of breast cancer.<br/>2. Elevated blood pressure: In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use.<br/>3. Hypertriglyceridemia: In patients with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.<br/>4. Impaired liver function and past history of cholestatic jaundice: Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued.<br/>5. Hypothyroidism: Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free Tand Tserum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogen may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored to maintain their free thyroid hormone levels in an acceptable range.<br/>6. Fluid retention: Estrogens may cause some degree of fluid retention. Because of this, patients who have conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.<br/>7. Hypocalcemia: Estrogens should be used with caution in individuals with severe hypocalcemia.<br/>8. Ovarian cancer: The estrogen-plus-progestin substudy of WHI reported that after an average follow-up of 5.6 years, the relative risk for ovarian cancer for estrogen plus progestin vs. placebo was 1.58 (95% CI 0.77 - 3.24), but was not statistically significant. The absolute risk for estrogen plus progestin vs. placebo was 4.2 vs. 2.7 cases per 10,000 women-years. In some epidemiologicstudies, the use of estrogen-only products, in particular for 10 or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.<br/>9. Exacerbation of endometriosis: Endometriosis may be exacerbated with administration of estrogens. Malignant transformation of residual endometrial implants has been reported in women treated post-hysterectomy with estrogen-alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.<br/>10. Exacerbation of other conditions: Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.<br/>B. Patient Information: Physicians are advised to discuss the contents of the Patient Information leaflet with patients for whom they prescribe Activella 1.0 mg/0.5 mg or Activella 0.5 mg/0.1 mg.<br/>C. Laboratory Tests: Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response, rather than by serum hormone levels (e.g., estradiol, FSH).<br/>D. Drug/Laboratory Test Interactions: 1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity, increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. 2. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), Tlevels (by column or by radioimmunoassay), or Tlevels by radioimmunoassay. Tresin uptake is decreased, reflecting the elevated TBG. Free Tand free Tconcentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone. 3. Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin (CBG), SHBG) leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/rennin substrate, alpha-1 antitrypsin, ceruloplasmin). 4. Increased plasma HDL and HDLcholesterol subfraction concentration, reduced LDL cholesterol concentration, increased triglyceride levels. 5. Impaired glucose tolerance. 6. Reduced response to metyrapone test.<br/>E. Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term continuous administration of estrogen, with or without progestin, in women with or without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.<br/>F. Pregnancy: Activella should not be used during pregnancy.<br/>G. Nursing Mothers: Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of breast milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when Activella is administered to a nursing mother.<br/>H. Pediatric Use: Activella is not indicated in children.<br/>I. Geriatric Use: Clinical studies of Activella did not include sufficient number of subjects aged 65 and over to determine if they responded differently from younger subjects. Of the total number of subjects in the estrogen-plus-progestin substudy of the Women's Health Initiative (WHI) study, 44% (n=7,320) were 65-74 years of age, while 6.6% (n=1,095) were 75 years and over. There was a higher relative risk (CE/MPA vs. placebo) of non-fatal stroke and invasive breast cancer in women 75 and over compared to women less than 75 years of age. In women greater than 75, the increased risk of non-fatal stroke and invasive breast cancer observed in the estrogen-plus-progestin combination group compared to the placebo group was 75 vs. 24 per 10,000 women-years and 52 vs. 12 per 10,000 women-years, respectively. In the estrogen-plus-progestin Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 4,532 hysterectomized women, aged 65 to 79 years, was randomized to CE/MPA (0.625 mg/2.5 mg daily) or placebo. In the estrogen-plus-progestin group, after an average follow-up of four years, the relative risk (CE/MPA vs. placebo)of probable dementia was 2.05 (95% CI 1.21-3.48). The absolute risk of developing probable dementia with CE/MPA was 45 vs. 22 cases per 10,000 women-years with placebo. Of the total number of subjects in the estrogen-alone substudy of WHI, 46% (n=4,943) were 65 years and over, while 7.1% (n=767) were 75 years and over. There was a higher relative risk (CE vs. placebo) of stroke in women less than 75 years of age compared to women 75 years and over. In the estrogen-alone WHIMS substudy, a population of 2,947 hysterectomized women, aged 65 to 79 years, was randomized to CE (0.625 mg daily) or placebo. After an average follow-up of 5.2 years, the relative risk (CE vs. placebo) of probable dementia was 1.49 (95% CI 0.83-2.66). The absolute risk of developing probable dementia with estrogen alone was 37 vs. 25 cases per 10,000 women-years with placebo. Seventy-nine percent of the cases of probable dementia occurred in women that were older than 70 for the CE-alone group, and 82 percent of the cases of probable dementia occurred in women who were older than 70 in the CE/MPA group. The most common classification of probable dementia in both the treatment groups and placebo groups was Alzheimer's disease. When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI 1.19-2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women. | lld:dailymed |
| dailymed-drugs:222 | dailymed-instance:precautio... | Carcinogenesis, Mutagenesis, Impairment of Fertility:: Long-term studies in animals have not been performed to evaluate carcinogenic potential, mutagenicity, or possible impairment of fertility in males or females.<br/>Pregnancy: Pregnancy Category C:: Animal reproduction studies have not been conducted with OPHTHETIC (proparacaine hydrochloride ophthalmic solution) 0.5%. It is also not known whether proparacaine hydrochloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Proparacaine hydrochloride should be administered to a pregnant woman only if clearly needed.<br/>Nursing Mothers:: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when proparacaine hydrochloride is administered to a nursing mother.<br/>Pediatric Use:: Safety and effectiveness of proparacaine HCl ophthalmic solution in pediatric patients have been established. Use of proparacaine HCl is supported by evidence from adequate and well-controlled studies in adults and children over the age of twelve, and safety information in neonates and other pediatric patients.<br/>Geriatric Use:: No overall clinical differences in safety or effectiveness have been observed between the elderly and other adult patients. | lld:dailymed |
| dailymed-drugs:225 | dailymed-instance:precautio... | Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including ALTACE, may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another angiotensin converting enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of ALTACE and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when ALTACE has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of ALTACE and/or discontinuation of the diuretic may be required. Evaluation of the hypertensive patient should always include assessment of renal function. Hyperkalemia: In clinical trials, hyperkalemia (serum potassium greater than 5.7 mEq/L) occurred in approximately 1% of hypertensive patients receiving ALTACE (ramipril). In most cases, these were isolated values, which resolved despite continued therapy. None of these patients was discontinued from the trials because of hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with ALTACE. (See Drug Interactions .) Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. Impaired Liver Function: Since ramipril is primarily metabolized by hepatic esterases to its active moiety, ramiprilat, patients with impaired liver function could develop markedly elevated plasma levels of ramipril. No formal pharmacokinetic studies have been carried out in hypertensive patients with impaired liver function. However, since the renin-angiotensin system may be activated in patients with severe liver cirrhosis and/or ascites, particular caution should be exercised in treating these patients. Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce hypotension, ramipril may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.<br/>Information for Patients: Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to ACE inhibitors during pregnancy. These patients should be asked to report pregnancies to their physicians as soon as possible. Angioedema: Angioedema, including laryngeal edema, can occur with treatment with ACE inhibitors, especially following the first dose. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician. Symptomatic Hypotension: Patients should be cautioned that lightheadedness can occur, especially during the first days of therapy, and it should be reported. Patients should be told that if syncope occurs, ALTACE should be discontinued until the physician has been consulted. All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope. Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician. Neutropenia: Patients should be told to promptly report any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia.<br/>Drug Interactions: Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including ALTACE. With nonsteroidal anti-inflammatory agents: Rarely, concomitant treatment with ACE inhibitors and nonsteroidal anti-inflammatory agents have been associated with worsening of renal failure and an increase in serum potassium. With diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with ALTACE. The possibility of hypotensive effects with ALTACE can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with ALTACE. If this is not possible, the starting dose should be reduced. With potassium supplements and potassium-sparing diuretics: ALTACE can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution, and the patient's serum potassium should be monitored frequently. With lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other: Neither ALTACE nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin. The combination of ALTACE and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart rate). The co-administration of ALTACE and warfarin did not adversely affect the anticoagulant effects of the latter drug. Additionally, co-administration of ALTACE with phenprocoumon did not affect minimum phenprocoumon levels or interfere with the subjects' state of anti-coagulation.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites and degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as 500 mg/kg/day did not produce adverse effects on fertility.<br/>Pregnancy: Pregnancy Categories C (first trimester) and D (second and third trimesters). See WARNINGS : Fetal/Neonatal Morbidity and Mortality .<br/>Nursing Mothers: Ingestion of single 10 mg oral dose of ALTACE resulted in undetectable amounts of ramipril and its metabolites in breast milk. However, because multiple doses may produce low milk concentrations that are not predictable from single doses, women receiving ALTACE should not breast feed.<br/>Geriatric Use: Of the total number of patients who received ramipril in US clinical studies of ALTACE 11.0% were 65 and over while 0.2% were 75 and over. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. One pharmacokinetic study conducted in hospitalized elderly patients indicated that peak ramiprilat levels and area under the plasma concentration time curve (AUC) for ramiprilat are higher in older patients.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Irreversible kidney damage has been observed in very young rats given a single dose of ramipril. | lld:dailymed |
| dailymed-drugs:227 | dailymed-instance:precautio... | General: Prescribing Ampicillin and Sulbactam for Injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. A high percentage of patients with mononucleosis who receive ampicillin develop a skin rash. Thus, ampicillin class antibiotics should not be administered to patients with mononucleosis. In patients treated with ampicillin and sulbactam the possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur (usually involving PseudomonasorCandida), the drug should be discontinued and/or appropriate therapy instituted.<br/>Information for Patients: Patients should be counseled that antibacterial drugs including Ampicillin and Sulbactam for Injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Ampicillin and Sulbactam for Injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Ampicillin and Sulbactam for Injection or other antibacterial drugs in the future.<br/>Drug Interactions: Probenecid decreases the renal tubular secretion of ampicillin and sulbactam. Concurrent use of probenecid with ampicillin and sulbactam may result in increased and prolonged blood levels of ampicillin and sulbactam. The concurrent administration of allopurinol and ampicillin increases substantially the incidence of rashes in patients receiving both drugs as compared to patients receiving ampicillin alone. It is not known whether this potentiation of ampicillin rashes is due to allopurinol or the hyperuricemia present in these patients. There are no data with ampicillin and sulbactam and allopurinol administered concurrently. Ampicillin and sulbactam and aminoglycosides should not be reconstituted together due to the in vitro inactivation of aminoglycosides by the ampicillin component of Ampicillin and Sulbactam for Injection.<br/>Drug/Laboratory Test Interactions: Administration of ampicillin and sulbactam will result in high urine concentration of ampicillin. High urine concentrations of ampicillin may result in false positive reactions when testing for the presence of glucose in urine using Clinitest���, Benedict's Solution or Fehling's Solution. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix���) be used. Following administration of ampicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone and estradiol has been noted. This effect may also occur with ampicillin and sulbactam.<br/>Carcinogenesis and Mutagenesis and Impairment of Fertility: Long-term studies in animals have not been performed to evaluate carcinogenic or mutagenic potential.<br/>Pregnancy:<br/>Pregnancy Category B: Reproduction studies have been performed in mice, rats, and rabbits at doses up to ten (10) times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Ampicillin and Sulbactam for Injection. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. (See Drug/Laboratory Test Interactions.)<br/>Labor and Delivery: Studies in guinea pigs have shown that intravenous administration of ampicillin decreased the uterine tone, frequency of contractions, height of contractions, and duration of contractions. However, it is not known whether the use of Ampicillin and Sulbactam for Injection in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary.<br/>Nursing Mothers: Low concentrations of ampicillin and sulbactam are excreted in the milk; therefore, caution should be exercised when Ampicillin and Sulbactam for Injection is administered to a nursing woman.<br/>Pediatric Use: The safety and effectiveness of Ampicillin and Sulbactam for Injection have been established for pediatric patients one year of age and older for skin and skin structure infections as approved in adults. Use of Ampicillin and Sulbactam for Injection in pediatric patients is supported by evidence from adequate and well-controlled studies in adults with additional data from pediatric pharmacokinetic studies, a controlled clinical trial conducted in pediatric patients and post-marketing adverse events surveillance. (See CLINICAL PHARMACOLOGY,INDICATIONS AND USAGE, ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION, and CLINICAL STUDIES sections.) The safety and effectiveness of Ampicillin and Sulbactam for Injection have not been established for pediatric patients for intra-abdominal infections. | lld:dailymed |
| dailymed-drugs:228 | dailymed-instance:precautio... | General: Opioid analgesics should be used with caution when combined with CNS depressant drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh the known risks of respiratory depression, altered mental state, and postural hypotension.<br/>Acute Abdominal Conditions:: The administration of oxycodone and acetaminophen tablets or other opioids may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Oxycodone and acetaminophen tablets should be given with caution to patients with CNS depression, elderly or debilitated patients, patients with severe impairment of hepatic, pulmonary, or renal function, hypothyroidism, Addison's disease, prostatic hypertrophy, urethral stricture, acute alcoholism, delirium tremens, kyphoscoliosis with respiratory depression, myxedema, and toxic psychosis. Oxycodone and acetaminophen tablets may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Oxycodone may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings. Following administration of oxycodone and acetaminophen tablets, anaphylactic reactions have been reported in patients with a known hypersensitivity to codeine, a compound with a structure similar to morphine and oxycodone. The frequency of this possible cross-sensitivity is unknown.<br/>Interactions with Other CNS Depressants:: Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, centrally-acting anti-emetics, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with oxycodone and acetaminophen tablets may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced.<br/>Interactions with Mixed Agonist/Antagonist Opioid Analgesics:: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as oxycodone. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of oxycodone and/or may precipitate withdrawal symptoms in these patients.<br/>Ambulatory Surgery and Postoperative Use:: Oxycodone and other morphine-like opioids have been shown to decrease bowel motility. Ileus is a common postoperative complication, especially after intra-abdominal surgery with use of opioid analgesia. Caution should be taken to monitor for decreased bowel motility in postoperative patients receiving opioids. Standard supportive therapy should be implemented.<br/>Use in Pancreatic/Biliary Tract Disease:: Oxycodone may cause spasm of the Sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like oxycodone may cause increases in the serum amylase level.<br/>Tolerance and Physical Dependence:: Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued .<br/>Information for Patients/Caregivers: The following information should be provided to patients receiving oxycodone and acetaminophen tablets by their physician, nurse, pharmacist, or caregiver:<br/>Laboratory Tests: Although oxycodone may cross-react with some drug urine tests, no available studies were found which determined the duration of detectability of oxycodone in urine drug screens. However, based on pharmacokinetic data, the approximate duration of detectability for a single dose of oxycodone is roughly estimated to be one to two days following drug exposure. Urine testing for opiates may be performed to determine illicit drug use and for medical reasons such as evaluation of patients with altered states of consciousness or monitoring efficacy of drug rehabilitation efforts. The preliminary identification of opiates in urine involves the use of an immunoassay screening and thin-layer chromatography (TLC). Gas chromatography/mass spectrometry (GC/MS) may be utilized as a third-stage identification step in the medical investigational sequence for opiate testing after immunoassay and TLC. The identities of 6-keto opiates (e.g., oxycodone) can further be differentiated by the analysis of their methoximetrimethylsilyl (MO-TMS) derivative.<br/>Drug/Drug Interactions with Oxycodone: Opioid analgesics may enhance the neuromuscular-blocking action of skeletal muscle relaxants and produce an increase in the degree of respiratory depression. Patients receiving CNS depressants such as other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, centrally-acting anti-emetics, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with oxycodone and acetaminophen tablets may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced. The concurrent use of anticholinergics with opioids may produce paralytic ileus. Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, naltrexone, and butorphanol) should be administered with caution to a patient who has received or is receiving a pure opioid agonist such as oxycodone. These agonist/antagonist analgesics may reduce the analgesic effect of oxycodone or may precipitate withdrawal symptoms.<br/>Drug/Drug Interactions with Acetaminophen: Alcohol, Ethyl: Hepatotoxicity has occurred in chronic alcoholics following various dose levels (moderate to excessive) of acetaminophen. Anticholinergics: The onset of acetaminophen effect may be delayed or decreased slightly, but the ultimate pharmacological effect is not significantly affected by anticholinergics. Oral Contraceptives: Increase in glucuronidation resulting in increased plasma clearance and a decreased half-life of acetaminophen. Charcoal (Activated): Reduces acetaminophen absorption when administered as soon as possible after overdose. Beta Blockers (Propanolol): Propranolol appears to inhibit the enzyme systems responsible for the glucuronidation and oxidation of acetaminophen. Therefore, the pharmacologic effects of acetaminophen may be increased. Loop Diuretics: The effects of the loop diuretic may be decreased because acetaminophen may decrease renal prostaglandin excretion and decrease plasma renin activity. Lamotrigine: Serum lamotrigine concentrations may be reduced, producing a decrease in therapeutic effects. Probenecid: Probenecid may increase the therapeutic effectiveness of acetaminophen slightly. Zidovudine: The pharmacologic effects of zidovudine may be decreased because of enhanced non-hepatic or renal clearance of zidovudine.<br/>Drug/Laboratory Test Interactions: Depending on the sensitivity/specificity and the test methodology, the individual components of oxycodone and acetaminophen tablets may cross-react with assays used in the preliminary detection of cocaine (primary urinary metabolite, benzoylecgonine) or marijuana (cannabinoids) in human urine. A more specific alternate chemical method must be used in order to obtain a confirmed analytical result. The preferred confirmatory method is gas chromatography/mass spectrometry (GC/MS). Moreover, clinical considerations and professional judgment shouldbe applied to any drug-of-abuse test result, particularly when preliminary positive results are used. Acetaminophen may interfere with home blood glucose measurement systems; decreases of>20% in mean glucose values may be noted. This effect appears to be drug, concentration and system dependent.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis:: Animal studies to evaluate the carcinogenic potential of oxycodone and acetaminophen have not been performed.<br/>Mutagenesis:: The combination of oxycodone and acetaminophen has not been evaluated for mutagenicity. Oxycodone alone was negative in a bacterial reverse mutation assay (Ames), an in vitro chromosome aberration assay with human lymphocytes without metabolic activation and an in vivo mouse micronucleus assay. Oxycodone was clastogenic in the human lymphocyte chromosomal assay in the presence of metabolic activation and in the mouse lymphoma assay with or without metabolic activation.<br/>Fertility:: Animal studies to evaluate the effects of oxycodone on fertility have not been performed.<br/>Pregnancy:<br/>Teratogenic Effects::<br/>Pregnancy Category C:: Animal reproductive studies have not been conducted with oxycodone and acetaminophen tablets. It is also not known whether oxycodone and acetaminophen tablets can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Oxycodone and acetaminophen tablets should not be given to a pregnant woman unless in the judgment of the physician, the potential benefits outweigh the possible hazards.<br/>Nonteratogenic Effects:: Opioids can cross the placental barrier and have the potential to cause neonatal respiratory depression. Opioid use during pregnancy may result in a physically drug-dependent fetus. After birth, the neonate may suffer severe withdrawal symptoms.<br/>Labor and Delivery: Oxycodone and acetaminophen tablets are not recommended for use in women during and immediately prior to labor and delivery due to its potential effects on respiratory function in the newborn.<br/>Nursing Mothers: Ordinarily, nursing should not be undertaken while a patient is receiving oxycodone and acetaminophen tablets because of the possibility of sedation and/or respiratory depression in the infant. Oxycodone is excreted in breast milk in low concentrations, and there have been rare reports of somnolence and lethargy in babies of nursing mothers taking an oxycodone/acetaminophen product. Acetaminophen is also excreted in breast milk in low concentrations.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric Use: Special precaution should be given when determining the dosing amount and frequency of oxycodone and acetaminophen tablets for geriatric patients, since clearance of oxycodone may be slightly reduced in this patient population when compared to younger patients.<br/>Hepatic Impairment: In a pharmacokinetic study of oxycodone in patients with end-stage liver disease, oxycodone plasma clearance decreased and the elimination half-life increased. Care should be exercised when oxycodone is used in patients with hepatic impairment.<br/>Renal Impairment: In a study of patients with end-stage renal impairment, mean elimination half-life was prolonged in uremic patients due to increased volume of distribution and reduced clearance. Oxycodone should be used with caution in patients with renal impairment. | lld:dailymed |
| dailymed-drugs:229 | dailymed-instance:precautio... | General: Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid-base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Significant deviations from normal concentrations may require the use of additional electrolyte supplements, or the use of electrolyte-free dextrose solutions to which individualized electrolyte supplements may be added. Extraordinary electrolytes losses such as may occur during protracted nasogastric suction, vomiting, diarrhea or gastrointestinal fistula drainage may necessitate additional electrolyte supplementation. Sodium-containing solutions should be administered with caution to patients receiving corticosteroids or corticotropin, or to other salt-retaining patients. Potassium therapy should be guided primarily by serial electrocardiograms, especially in patients receiving digitalis. Serum potassium levels are not necessarily indicative of tissue potassium levels. Care should be exercised in administering solutions containing sodium or potassium to patients with renal or cardiovascular insufficiency, with or without congestive heart failure, particularly if they are postoperative or elderly. Solutions containing potassium or calcium should be used with caution in the presence of cardiac disease, particularly in the presence of renal disease. Parenteral calcium should be administered with extreme caution to patients receiving digitalis preparations. Solutions containing dextrose should be used with caution in patients with overt or known subclinical diabetes mellitus, or carbohydrate intolerance for any reason. To minimize the risk of possible incompatibilities arising from mixing this solution with other additives that may be prescribed, the final infusate should be inspected for cloudiness or precipitation immediately after mixing, prior to administration, and periodically during administration. Do not use plastic container in series connection. If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result. This solution is intended for intravenous administration using sterile equipment. It is recommended that intravenous administration apparatus be replaced at least once every 24 hours. Use only if solution is clear and container and seals are intact.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with 5% Dextrose in Ringer's Injection have not been performed to evaluate the carcinogenic potential, mutagenic potential, or effects on fertility.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when 5% Dextrose in Ringer's Injection is administered to a nursing mother.<br/>Pediatric Use: Safety and effectiveness of 5% Dextrose in Ringer's Injection in pediatric patients have not been established by adequate and well controlled trials, however, the use of dextrose and ringer's solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible hemorrhage. See DOSAGE AND ADMINISTRATION.<br/>Geriatric Use: Clinical studies of 5% Dextrose in Ringer's Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:230 | dailymed-instance:precautio... | General: Sulfonamides should be given with caution to patients with impaired renal or hepatic function and to those with severe allergy or bronchial asthma. Hemolysis may occur in individuals deficient in glucose-6-phosphate dehydrogenase. This reaction is dose related. Adequate fluid intake must be maintained in order to prevent crystalluria and stone formation.<br/>Information for Patients: Patients should be instructed to drink an eight ounce glass of water with each dose of medication and at frequent intervals throughout the day. Caution patients to report promptly the onset of sore throat, fever, pallor, purpura, or jaundice when taking this drug, since these may be early indications of serious blood disorders.<br/>Laboratory Tests: Complete blood counts and urinalyses with careful microscopic examinations should be done frequently in patients receiving sulfonamides.<br/>Drug Interactions: Administration of a sulfonamide may increase the effect of oral anticoagulants and methotrexate, probably by displacement of these drugs from binding sites on plasma albumin. Potentiation of the action of sulfonylurea hypoglycemic agents, thiazide diuretics, and uricosuric agents may also be noted. This may also be due to displacement of the drugs from albumin, or a pharmacodynamic mechanism may play a role. Conversely, agents such as indomethacin, probenecid, and salicylates may displace sulfonamides from plasma albumin and increase the concentrations of free drug in plasma.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: The sulfonamides bear certain chemical similarities to some goitrogens. Rats appear to be especially susceptible to the goitrogenic effects of sulfonamides, and long-term administration has produced thyroid malignancies in rats.<br/>Pregnancy:<br/>Teratogenic effects:<br/>Nursing Mothers: Sulfadiazine is contraindicated for use in nursing mothers because the sulfonamides cross the placenta, are excreted in breast milk and may cause kernicterus. Because of the potential for serious adverse reactions in nursing infants from sulfadiazine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. See CONTRAINDICATIONS.<br/>Pediatric Use: Sulfadiazine is contraindicated in infants less than 2 months of age (except as adjunctive therapy with pyrimethamine in the treatment of congenital toxoplasmosis). See CONTRAINDICATIONSand DOSAGE AND ADMINISTRATION. | lld:dailymed |
| dailymed-drugs:232 | dailymed-instance:precautio... | Do not use for intravenous injection unless the osmolar concentration of additives totals at least 112 mOsmol/liter (two-fifths of the normal osmolarity of the extracellular fluid���280 mOsmol/liter). Do not administer unless solution is clear and container is undamaged. Discard unused portion.<br/>Pregnancy Category C.: Animal reproduction studies have not been conducted with sterile water for injection. It is also not known whether sterile water containing additives can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sterile water for injection with additives should be given to a pregnant woman only if clearly needed.<br/>Pediatric Use:: The safety and effectiveness in the pediatric population are based on the similarity of the clinical conditions of the pediatric and adult populations. In neonates or very small infants the volume of fluid may affect fluid and electrolyte balance. This product contains no more than 25 mcg/L of aluminum. | lld:dailymed |
| dailymed-drugs:1940 | dailymed-instance:precautio... | Do not use for intravenous injection unless the osmolar concentration of additives totals at least 112 mOsmol/liter (two-fifths of the normal osmolarity of the extracellular fluid���280 mOsmol/liter). Do not administer unless solution is clear and container is undamaged. Discard unused portion.<br/>Pregnancy Category C.: Animal reproduction studies have not been conducted with sterile water for injection. It is also not known whether sterile water containing additives can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sterile water for injection with additives should be given to a pregnant woman only if clearly needed.<br/>Pediatric Use:: The safety and effectiveness in the pediatric population are based on the similarity of the clinical conditions of the pediatric and adult populations. In neonates or very small infants the volume of fluid may affect fluid and electrolyte balance. This product contains no more than 25 mcg/L of aluminum. | lld:dailymed |
| dailymed-drugs:233 | dailymed-instance:precautio... | General: Periodic assessment of organ system functions, including hematopoietic and hepatic, is advisable during prolonged therapy.<br/>Information for Patients: Patients should be informed of the potential risk to the fetus in women taking mebendazole during pregnancy, especially during the first trimester (See Pregnancy). Patients should also be informed that cleanliness is important to prevent reinfection and transmission of the infection.<br/>Drug Interactions: Preliminary evidence suggests that cimetidine inhibits mebendazole metabolism and may result in an increase in plasma concentrations of mebendazole.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In carcinogenicity tests of mebendazole in mice and rats, no carcinogenic effects were seen at doses as high as 40 mg/kg (one to two times the human dose, based on mg/m2) given daily over two years. Dominant lethal mutation tests in mice showed no mutagenicity at single doses as high as 640 mg/kg (18 times the human dose, based on mg/m2). Neither the spermatocyte test, the F1 translocation test, nor the Ames test indicated mutagenic properties. Doses up to 40 mg/kg in mice (equal to the human dose, based on mg/m2), given to males for 60 days and to females for 14 days prior to gestation, had no effect upon fetuses and offspring, though there was slight maternal toxicity.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: It is not known whether mebendazole is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when mebendazole is administered to a nursing woman.<br/>Pediatric Use: The drug has not been extensively studied in children under two years; therefore, in the treatment of children under two years the relative benefit/risk should be considered. | lld:dailymed |
| dailymed-drugs:234 | dailymed-instance:precautio... | Impairment of Vision:<br/>Optic Neuropathy and/or Neuritis: Cases of optic neuropathy and optic neuritis have been reported .<br/>Corneal Microdeposits: Corneal microdeposits appear in the majority of adults treated with amiodarone. They are usually discernible only by slit-lamp examination, but give rise to symptoms such as visual halos or blurred vision in as many as 10% of patients. Corneal microdeposits are reversible upon reduction of dose or termination of treatment. Asymptomatic microdeposits alone are not a reason to reduce dose or discontinue treatment .<br/>Neurologic: Chronic administration of oral amiodarone in rare instances may lead to the development of peripheral neuropathy that may resolve when amiodarone is discontinued, but this resolution has been slow and incomplete.<br/>Photosensitivity: Amiodarone has induced photosensitization in about 10% of patients; some protection may be afforded by the use of sun-barrier creams or protective clothing. During long-term treatment, a blue-gray discoloration of the exposed skin may occur. The risk may be increased in patients of fair complexion or thosewith excessive sun exposure, and may be related to cumulative dose and duration of therapy.<br/>Thyroid Abnormalities: Amiodarone inhibits peripheral conversion of thyroxine (T) to triiodothyronine (T) and may cause increased thyroxine levels, decreased Tlevels, and increased levels of inactive reverse T(rT) in clinically euthyroid patients. It is also a potential source of large amounts of inorganic iodine. Because of its release of inorganic iodine, or perhaps for other reasons, amiodarone can cause either hypothyroidism or hyperthyroidism. Thyroid function should be monitored prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of amiodarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid-function tests may persist for several weeks or even months following amiodarone withdrawal. Hypothyroidism has been reported in 2% to 4% of patients in most series, but in 8% to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Hypothyroidism is best managed by amiodarone hydrochloride dose reduction and/or thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue amiodarone hydrochloride tablets in some patients. Hyperthyroidism occurs in about 2% of patients receiving amiodarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and/or arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED. Hyperthyroidism is best identified by relevant clinical symptoms and signs, accompanied usually by abnormally elevated levels of serum TRIA, and further elevations of serum T, and a subnormal serum TSH level (using a sufficiently sensitive TSH assay). The finding of a flat TSH response to TRH is confirmatory of hyperthyroidism and may be sought in equivocal cases. Since arrhythmia breakthroughs may accompany amiodarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of amiodarone. The institution of antithyroid drugs,��-adrenergic blockers and/or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. Amiodarone-induced hyperthyroidism may be followed by a transient period of hypothyroidism . When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited and this form of therapy could inducethyroid storm. Therefore, surgical and anesthetic management require careful planning. There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with amiodarone. In some instances hyperthyroidism was also present .<br/>Surgery:<br/>Volatile Anesthetic Agents: Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalational anesthetics.<br/>Hypotension Postbypass: Rare occurrences of hypotension upon discontinuation of cardiopulmonary bypass during open-heart surgery in patients receiving amiodarone have been reported. The relationship of this event to amiodarone therapy is unknown.<br/>Adult Respiratory Distress Syndrome (ARDS): Postoperatively, occurrences of ARDS have been reported in patients receiving amiodarone therapy who have undergone either cardiac or noncardiac surgery. Although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. Until further studies have been performed, it is recommended that FiOand the determinants of oxygen delivery to the tissues (e.g., SaO, PaO) be closely monitored in patients on amiodarone.<br/>Corneal Refractive Laser Surgery: Patients should be advised that most manufacturers of corneal refractive laser surgery devices contraindicate that procedure in patients taking amiodarone.<br/>Information for Patients: Patients should be instructed to read the accompanying Medication Guide each time they refill their prescription. The complete text of the Medication Guide is reprinted at the end of this document.<br/>Laboratory Tests: Elevations in liver enzymes (SGOT and SGPT) can occur. Liver enzymes in patients on relatively high maintenance doses should be monitored on a regular basis. Persistent significant elevations in the liver enzymes or hepatomegaly should alert the physician to consider reducing the maintenance dose of amiodarone hydrochloride or discontinuing therapy. Amiodarone hydrochloride alters the results of thyroid-function tests, causing an increase in serum Tand serum reverse Tand a decline in serum Tlevels. Despite these biochemical changes, most patients remain clinically euthyroid.<br/>Drug Interactions: Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines . Amiodarone is an inhibitor of CYP3A4 and p-glycoprotein. Therefore, amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors or inducers of CYP3A4 and substrates of p-glycoprotein. While only a limited number of in vivo drug-drug interactions with amiodarone have been reported, the potential for other interactions should be anticipated. This is especially important for drugs associated with serious toxicity, such as other antiarrhythmics. If such drugs are needed, their dose should be reassessed and, where appropriate, plasma concentration measured. In view of the long and variable half-life of amiodarone, potential for drug interactions exists, not only with concomitant medication, but also with drugs administered after discontinuation of amiodarone. Since amiodarone is a substrate for CYP3A4 and CYP2C8, drugs/substances that inhibit CYP3A4 may decrease the metabolism and increase serum concentrations of amiodarone. Reported examples include the following:<br/>Protease Inhibitors: Protease inhibitors are known to inhibit CYP3A4 to varying degrees. A case report of one patient taking amiodarone 200 mg and indinavir 800 mg three times a day resulted in increases in amiodarone concentrations from 0.9 mg/L to 1.3 mg/L. DEA concentrations were not affected. There was no evidence of toxicity. Monitoring for amiodarone toxicity and serial measurement of amiodarone serum concentration during concomitant protease inhibitor therapy should be considered.<br/>Histamine HAntagonists: Loratadine, a non-sedating antihistaminic, is metabolized primarily by CYP3A4. QT interval prolongation and torsade de pointes have been reported with the co-administration of loratadine and amiodarone.<br/>Histamine HAntagonists: Cimetidine inhibits CYP3A4 and can increase serum amiodarone levels.<br/>Antidepressants: Trazodone, an antidepressant, is metabolized primarily by CYP3A4. QT interval prolongation and torsade de pointes have been reported with the co-administration of trazodone and amiodarone.<br/>Other substances: Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and Cby 84%, and decreased DEA to unquantifiable concentrations. Grapefruit juice inhibits CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone; therefore, grapefruit juice should not be taken during treatment with oral amiodarone. This information should be considered when changing from intravenous amiodarone to oral amiodarone . Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6 and CYP3A4. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates of p-glycoprotein. Reported examples of this interaction include the following:<br/>Immunosuppressives: Cyclosporine (CYP3A4 substrate) administered in combination with oral amiodarone has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine, despite reduction in dose of cyclosporine.<br/>HMG-CoA Reductase Inhibitors: HMG-CoA reductase inhibitors that are CYP3A4 substrates (including simvastatin and atorvastatin) in combination with amiodarone have been associated with reports of myopathy/rhabdomyolysis.<br/>Cardiovasculars:<br/>Antibiotics: Rifampin is a potent inducer of CYP3A4. Administration of rifampin concomitantly with oral amiodarone has been shown to result in decreases in serum concentrations of amiodarone and desethylamiodarone.<br/>Other substances, including herbal preparations: St. John's Wort (Hypericum perforatum) induces CYP3A4. Since amiodarone is a substrate for CYP3A4, there is the potential that the use of St. John's Wort in patients receiving amiodarone could result in reduced amiodarone levels.<br/>Other reported interactions with amiodarone: Fentanyl (CYP3A4 substrate) in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output. Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine (CYP3A4 substrate) given for local anesthesia. Seizure, associated with increased lidocaine concentrations, has been reported with concomitant administration of intravenous amiodarone. Dextromethorphan is a substrate for both CYP2D6 and CYP3A4. Amiodarone inhibits CYP2D6. Cholestyramine increases enterohepatic elimination of amiodarone and may reduce its serum levels and t. Disopyramide increases QT prolongation which could cause arrhythmia. Fluoroquinolones, macrolide antibiotics and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics or azoles were administered concomitantly. . Hemodynamic and electrophysiologic interactions have also been observed after concomitant administration with propranolol, diltiazem and verapamil. Volatile Anesthetic Agents In addition to the interactions noted above, chronic (>2 weeks) oral amiodarone administration impairs metabolism of phenytoin, dextromethorphan and methotrexate.<br/>Electrolyte Disturbances: Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before instituting and during amiodarone therapy. Use caution when co-administering amiodarone with drugs which may induce hypokalemia and/or hypomagnesemia.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Amiodarone hydrochloride was associated with a statistically significant, dose-related increase in the incidence of thyroid tumors (follicular adenoma and/or carcinoma) in rats. The incidence of thyroid tumors was greater than control even at the lowest dose level tested, i.e., 5 mg/kg/day (approximately 0.08 times the maximum recommended human maintenance dose*). Mutagenicity studies (Ames, micronucleus and lysogenic tests) with amiodarone were negative. In a study in which amiodarone hydrochloride was administered to male and female rats, beginning 9 weeks prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately 1.4 times the maximum recommended human maintenance dose*). *600 mg in a 50 kg patient (dose compared on a body surface area basis)<br/>Pregnancy:<br/>Pregnancy Category D: See WARNINGS, Neonatal Hypo- or Hyperthyroidism.<br/>Labor and Delivery: It is not known whether the use of amiodarone during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect of amiodarone on the duration of gestation or on parturition.<br/>Nursing Mothers: Amiodarone and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk, suggesting that breastfeeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered amiodarone have been shown to be less viable and have reduced body-weight gains. Therefore, when amiodarone therapy is indicated, the mother should be advised to discontinue nursing.<br/>Pediatric Use: The safety and effectiveness of amiodarone hydrochloride tablets in pediatric patients have not been established.<br/>Geriatric Use: Clinical studies of amiodarone hydrochloride tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:235 | dailymed-instance:precautio... | General: For ophthalmic use only.<br/>Information for Patients: The emulsion from one individual single-use vial is to be used immediately after opening for administration to one or both eyes and the remaining contents should be discarded immediately after administration. Do not allow the tip of the vial to touch the eye or any surface, as this may contaminate the emulsion. RESTASIS should not be administered while wearing contact lenses. Patients with decreased tear production typically should not wear contact lenses. If contact lenses are worn, they should be removed prior to the administration of the emulsion. Lenses may be reinserted 15 minutes following administration of RESTASIS ophthalmic emulsion.<br/>Carcinogenesis, Mutagenesis, and Impairment of Fertility: Systemic carcinogenicity studies were carried out in male and female mice and rats. In the 78-week oral (diet) mouse study, at doses of 1, 4, and 16 mg/kg/day, evidence of a statistically significant trend was found for lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose males significantly exceededthe control value. In the 24-month oral (diet) rat study, conducted at 0.5, 2, and 8 mg/kg/day, pancreatic islet cell adenomas significantly exceeded the control rate in the low dose level. The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose related. The low doses in mice and rats are approximately 1000 and 500 times greater, respectively, than the daily human dose of one drop (28��L) of 0.05% RESTASIS BID into each eye of a 60 kg person (0.001 mg/kg/day), assuming that the entire dose is absorbed. Cyclosporine has not been found mutagenic/genotoxic in the Ames Test, the V79-HGPRT Test, the micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese hamster bone-marrow, the mouse dominant lethal assay, and the DNA-repair test in sperm from treated mice. A study analyzing sister chromatid exchange (SCE) induction by cyclosporine using human lymphocytes in vitro gave indication of a positive effect (i.e., induction of SCE). No impairment in fertility was demonstrated in studies in male and female rats receiving oral doses of cyclosporine up to 15 mg/kg/day (approximately 15,000 times the human daily dose of 0.001 mg/kg/day) for 9 weeks (male) and 2 weeks (female) prior to mating.<br/>Pregnancy-Teratogenic effects: Pregnancy category C.<br/>Nursing Mothers: Cyclosporine is known to be excreted in human milk following systemic administration but excretion in human milk after topical treatment has not been investigated. Although blood concentrations are undetectable after topical administration of RESTASIS ophthalmic emulsion, caution should be exercised when RESTASIS is administered to a nursing woman.<br/>Pediatric Use: The safety and efficacy of RESTASIS ophthalmic emulsion have not been established in pediatric patients below the age of 16.<br/>Geriatric Use: No overall difference in safety or effectiveness has been observed between elderly and younger patients. | lld:dailymed |
| dailymed-drugs:237 | dailymed-instance:precautio... | A. General: 1. Addition of a Progestin. Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration have reported a lowered incidence of endometrial hyperplasia which would otherwise be induced by estrogen treatment. Morphological and biochemical studies of endometrium suggest that 10-14 days of progestin are needed to provide maximal maturation of the endometrium and to eliminate any hyperplastic changes. There are, however, possible additional risks which may be associated with the inclusion of progestins in estrogen replacement regimens. These include: (1) adverse effects or lipoprotein metabolism (lowering HDL and raising LDL) which may diminish the possible cardioprotective effect of estrogen therapy ; (2) impairment of glucose tolerance; and (3) possible enhancement of mitotic activity in breast epithelial tissue although few epidemiological data are available to address this point . The choice of progestin, its dose, and its regimen may be important in minimizing these adverse effects, but these issues remain to be clarified. 2. Cardiovascular Risk. A causal relationship between estrogen replacement therapy and reduction of cardiovascular disease in postmenopausal women has not been proven. Furthermore, the effect of added progestins on this putative benefit is not yet known. In recent years many published studies have suggested that there may be a cause-effect relationship between postmenopausal oral estrogen replacement therapy without added progestins and a decrease in cardiovascular disease in women. Although most of the observational studies which assessed this statistical association have reported a 20% to 50% reduction in coronary heart disease risk and associated mortality in estrogen takers, the following should be consideredwhen interpreting these reports: (1) Because only one of these studies was randomized and it was too small to yield statistically significant results, all relevant studies were subject to selection bias. Thus, the apparently reduced risk of coronary artery disease cannot be attributed with certainty to estrogen replacement therapy. It may instead have been caused by life-style and medical characteristics of the women studied with the result that healthier women were selected for estrogen therapy. In general, treated women were of higher socioeconomic and educational status, more slender, more physically active, more likely to have undergone surgical menopause, and less likely to have diabetes than the untreated women. Although some studies attempted to control for these selection factors, it is common for properly designed randomized trials to fail to confirm benefits suggested by less rigorous study designs. Thus, ongoing and future large-scale randomized trials may fail to confirm thisapparent benefit. (2) Current medical practice often includes the use of concomitant progestin therapy in women with intact uteri . While the effects of added progestins on the risk of ischemic heart disease are not known, all available progestins reverse at least some of the favorable effects of estrogens on HDL and LDL levels. (3) While the effects of added progestins on the risk of breast cancer are also unknown, available epidemiological evidence suggests that progestins do not reduce, and may enhance, the moderately increased breast cancer incidence that has been reported with prolonged estrogen replacement therapy . Because relatively long-term use of estrogens by a woman with a uterus has been shown to induce endometrial cancer, physicians often recommend that women who are deemed candidates for hormone replacement should take progestins as well as estrogens. When considering prescribing concomitant estrogens and progestins for hormonereplacement therapy, physicians and patients are advised to carefully weigh the potential benefits and risks of the added progestin, Large-scale randomized, placebo-controlled, prospective clinical trials are required to clarify these issues. 3. Physical Examination. A complete medical and family history should be taken prior to the initiation of any estrogen therapy. The pretreatment and periodic physical examinations should include special reference to blood pressure, breasts, abdomen, and pelvic organs, and should include a Papanicolaou smear. As a general rule, estrogen should not be prescribed for longer than one year without reexamining the patient. 4. Hypercoagulability. Some studies have shown that women taking estrogen replacement therapy have hypercoagulability, primarily related to decreased antithrombin activity. This effect appears dose- and duration-dependent and is less pronounced than that associated with oral contraceptive use. Also, postmenopausalwomen tend to have increased coagulation parameters at baseline compared to premenopausal women. There is some suggestion that low dose postmenopausal mestranol may increase the risk of thromboembolism, although the majority of studies (of primarily conjugated estrogen users) report no such increase. There is insufficient information on hypercoagulability in women who have had previous thromboembolic disease. 5. Familial Hyperlipoproteinemia. Estrogen therapy may be associated with massive elevations of plasma triglycerides leading to pancreatitis and other complications in patients with familial defects of lipoprotein metabolism. 6. Fluid Retention. Because estrogens may cause some degree of fluid retention, conditions which might be exacerbated by this factor, such as asthma, epilepsy, migraine, and cardiac or renal dysfunction, require careful observation. 7. Uterine Bleeding and Mastodynia. Certain patients may develop undesirable manifestations of estrogenic stimulation, such as abnormal uterine bleeding and mastodynia. 8. Impaired Liver Function. Estrogens may be poorly metabolized in patients with impaired liver function and should be administered with caution.<br/>B. Information For Patients: See text of Patient Package Insert below.<br/>C. Laboratory Tests: Estrogen administration should generally be guided by clinical response at the smallest dose, rather than laboratory monitoring, for relief of symptoms for those indications in which symptoms are observable. For prevention and treatment of osteoporosis, however, see DOSAGE AND ADMINISTRATION section.<br/>D. Drug/Laboratory Test Interactions:<br/>E. Carcinogenesis, Mutagenesis, Impairment Of Fertility: Long term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. See CONTRAINDICATIONS and WARNINGS.<br/>F. Pregnancy Category X: Estrogens should not be used during pregnancy. See CONTRAINDICATIONS and BOXED WARNINGS.<br/>G. Nursing Mothers: As a general principle, the administration of any drug to nursing mothers should be done only when clearly necessary since many drugs are excreted in human milk. In addition, estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk.<br/>H. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Large and repeated doses of estrogen over an extended period of time have been shown to accelerate epiphyseal closure, resulting in short adult stature if treatment is initiated before the completion of physiologic puberty in normally developing children. In patients in whom bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended. Estrogen treatment of prepubertal children also induces premature breast development and vaginal cornification, and may potentially induce vaginal bleeding in girls. In boys, estrogen treatment may modify the normal pubertal process. All other physiological and adverse reactions shown to be associated with estrogen treatment of adults could potentially occur in the pediatric population, including thromboembolic disorders and growth stimulation of certain tumors. Therefore, estrogens should only be administered to pediatric patients when clearly indicated and the lowest effective dose should always be utilized. | lld:dailymed |
| dailymed-drugs:238 | dailymed-instance:precautio... | Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations and acid-base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Solutions containing dextrose should be used with caution in patients with known subclinical or overt diabetes mellitus. Do not administer unless solution is clear and container is undamaged. Discard unused portion.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:: Studies with solutions from ADD-Vantage flexible plastic containers have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.<br/>Pregnancy Category C.: Animal reproduction studies have not been conducted with dextrose. It is also not known whether dextrose can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose should only be given to a pregnant woman if clearly needed.<br/>Nursing Mothers:: Caution should be exercised when solutions from ADD-Vantage flexible containers are administered to a nursing woman.<br/>Pediatric Use:: The safety and effectiveness in the pediatric population are based on the similarity of the clinical conditions of the pediatric and adult populations. In neonates or very small infants the volume of fluid may affect fluid and electrolyte balance. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolarity and possible intracerebral hemorrhage. Only additives in the ADD-Vantage vial should be delivered via this solution. | lld:dailymed |
| dailymed-drugs:239 | dailymed-instance:precautio... | General: Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. There is an enhanced effect of corticosteroids in patients with hypothyroidism and in those with cirrhosis. Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible corneal perforation. The lowest possible dose of corticosteroid should be used to control the condition under treatment, and when reduction in dosage is possible, the reduction should be gradual. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression, to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids. Steroids should be used with caution in nonspecific ulcerative colitis, if there is a probability of impending perforation, abscess or other pyogenic infection; diverticulitis; fresh intestinal anastomoses; active or latent peptic ulcer; renal insufficiency; hypertension; osteoporosis; and myasthenia gravis. Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed. Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that corticosteroids affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect. Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used. Convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Since concurrent use of these agents results in a mutual inhibition of metabolism, it is possible that adverse events associated with the individual use of either drug may be more apt to occur.<br/>Information for Patients: Persons who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay. | lld:dailymed |
| dailymed-drugs:240 | dailymed-instance:precautio... | General:<br/>Impaired Hepatic Function: Labetalol should be used with caution in patients with impaired hepatic function since metabolism of the drug may be diminished.<br/>Jaundice or Hepatic Dysfunction: (see WARNINGS).<br/>Information for Patients: As with all drugs with beta-blocking activity, certain advice to patients being treated with labetalol is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. While no incident of the abrupt withdrawal phenomenon (exacerbation of angina pectoris) has been reported with labetalol, dosing with labetalol HCl tablets should not beinterrupted or discontinued without a physician's advice. Patients being treated with labetalol HCl tablets should consult a physician at any signs or symptoms of impending cardiac failure or hepatic dysfunction . Also, transient scalp tingling may occur, usually when treatment with labetalol HCl tablets is initiated .<br/>Laboratory Tests: As with any new drug given over prolonged periods, laboratory parameters should be observed over regular intervals. In patients with concomitant illnesses, such as impaired renal function, appropriate tests should be done to monitor these conditions.<br/>Drug Interactions: In one survey, 2.3% of patients taking labetalol in combination with tricyclic antidepressants experienced tremor as compared to 0.7% reported to occur with labetalol alone. The contribution of each of the treatments to this adverse reaction is unknown but the possibility of a drug interaction cannot be excluded. Drugs possessing beta-blocking properties can blunt the bronchodilator effect of beta-receptor agonist drugs in patients with bronchospasm; therefore, doses greater than the normal anti-asthmatic dose of beta-agonist bronchodilator drugs may be required. Cimetidine has been shown to increase the bioavailability of labetalol. Since this could be explained either by enhanced absorption or by an alteration of hepatic metabolism of labetalol, special care should be used in establishing the dose required for blood pressure control in such patients. Synergism has been shown between halothane anesthesia and intravenously administered labetalol. During controlled hypotensive anesthesia using labetalol in association with halothane, high concentrations (3% or above) of halothane should not be used because the degree of hypotension will be increased and because of the possibility of a large reduction in cardiac output and an increase in central venous pressure. The anesthesiologist should be informed when a patient is receiving labetalol. Labetalol blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effect. If labetalol HCl is used with nitroglycerin in patients with angina pectoris, additional antihypertensive effects may occur. Care should be taken if labetalol is used concomitantly with calcium antagonists of the verapamil type.<br/>Risk of Anaphylactic Reaction: While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.<br/>Drug/Laboratory Test Interactions: The presence of labetalol metabolites in the urine may result in falsely elevated levels of urinary catecholamines, metanephrine, normetanephrine, and vanillylmandelic acid (VMA) when measured by fluorimetric or photometric methods. In screening patients suspected of having a pheochromocytoma and being treated with labetalol, a specific method, such as a high performance liquid chromatographic assay with solid phaseextraction (e.g., J. Chromatogr 385:241, 1987) should be employed in determining levels of catecholamines. Labetalol has also been reported to produce a false-positive test for amphetamine when screening urine for the presence of drugs using the commercially available assay methods Toxi-Lab A (thin-layer chromatographic assay) and Emit-d.a.u. (radioenzymatic assay). When patients being treated with labetalol have a positive urine test for amphetamine using these techniques, confirmation should be made by using more specific methods, such as a gas chromatographic-mass spectrometer technique.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term oral dosing studies with labetalol for 18 months in mice and for 2 years in rats showed no evidence of carcinogenesis. Studies with labetalol, using dominant lethal assays in rats and mice, and exposing microorganisms according to modified Ames tests, showed no evidence of mutagenesis.<br/>Pregnancy Category C: Teratogenic studies have been performed with labetalol in rats and rabbits at oral doses up to approximately 6 and 4 times the maximum recommended human dose (MRHD), respectively. No reproducible evidence of fetal malformations was observed. Increased fetal resorptions were seen in both species at doses approximating the MRHD. A teratology study performed with labetalol in rabbits at intravenous doses up to 1.7 times the MRHD revealed no evidence of drug-related harm to the fetus. There are no adequate and well-controlled studies in pregnant women. Labetalol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nonteratogenic Effects: Hypotension, bradycardia, hypoglycemia, and respiratory depression have been reported in infants of mothers who were treated with labetalol for hypertension during pregnancy. Oral administration of labetalol to rats during late gestation through weaning at doses of 2 to 4 times the MRHD caused a decrease in neonatal survival.<br/>Labor and Delivery: Labetalol given to pregnant women with hypertension did not appear to affect the usual course of labor and delivery.<br/>Nursing Mothers: Small amounts of labetalol (approximately 0.004% of the maternal dose) are excreted in human milk. Caution should be exercised when labetalol HCl tablets are administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established. | lld:dailymed |
| dailymed-drugs:242 | dailymed-instance:precautio... | General:<br/>Impaired Hepatic Function:<br/>Information for Patients:<br/>Drug Interactions:<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Pregnancy:<br/>Nursing Mothers:<br/>Pediatric Use:<br/>Geriatric Use:<br/>Use in the Elderly: | lld:dailymed |
| dailymed-drugs:243 | dailymed-instance:precautio... | General: ARIMIDEX is not recommended for use in premenopausal women as safety and efficacy has not been established (see CLINICAL PHARMACOLOGY, Pharmacodynamics, Effect on Estradiol section). Before starting treatment with ARIMIDEX, pregnancy must be excluded (see WARNINGS). ARIMIDEX should be administered under the supervision of a qualified physician experienced in the use of anticancer agents.<br/>Laboratory Tests: Results from the ATAC trial bone substudy at 12 and 24 months demonstrated that patients receiving ARIMIDEX had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline. Because ARIMIDEX lowers circulating estrogen levels it may cause a reduction in bone mineral density. During the ATAC trial, more patients receiving ARIMIDEX were reported to have an elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively).<br/>Drug Interactions: (See CLINICAL PHARMACOLOGY) Anastrozole inhibited in vitro metabolic reactions catalyzed by cytochromes P450 1A2, 2C8/9, and 3A4 but only at relatively high concentrations. Anastrozole did not inhibit P450 2A6 or the polymorphic P450 2D6 in human liver microsomes. Anastrozole did not alter the pharmacokinetics of antipyrine. Although there have been no formal interaction studies other than with antipyrine, based on these in vivo and in vitro studies, it is unlikely that co-administration of a 1 mg dose of ARIMIDEX with other drugs will result in clinically significant druginhibition of cytochrome P450-mediated metabolism of the other drugs. An interaction study with warfarin showed no clinically significant effect of anastrozole on warfarin pharmacokinetics or anticoagulant activity. At a median follow-up of 33 months, the combination of ARIMIDEX and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen in all patients as well as in the hormone receptor-positive subpopulation. This treatment arm was discontinued from the trial. Based on clinical and pharmacokinetic results from the ATAC trial, tamoxifen should not be administered with anastrozole (see CLINICAL PHARMACOLOGY���Drug Interactions and CLINICAL PHARMACOLOGY - Clinical Studies - Adjuvant Treatment of Breast Cancer in Postmenopausal Women subsections). Co-administration of anastrozole and tamoxifen resulted in a reduction of anastrozole plasma levels by 27% compared with those achieved with anastrozole alone. Estrogen-containing therapies should not be used with ARIMIDEX as they may diminish its pharmacologic action.<br/>Drug/Laboratory Test Interactions: No clinically significant changes in the results of clinical laboratory tests have been observed.<br/>Carcinogenesis: A conventional carcinogenesis study in rats at doses of 1.0 to 25 mg/kg/day (about 10 to 243 times the daily maximum recommended human dose on a mg/mbasis) administered by oral gavage for up to 2 years revealed an increase in the incidence of hepatocellular adenoma and carcinoma and uterine stromal polyps in females and thyroid adenoma in males at the high dose. A dose related increase was observed in the incidence of ovarian and uterine hyperplasia in females. At 25 mg/kg/day, plasma AUClevels in rats were 110 to 125 times higher than the level exhibited in postmenopausal volunteers at the recommended dose. A separate carcinogenicity study in mice at oral doses of 5 to 50 mg/kg/day (about 24 to 243 times the daily maximum recommended human dose on a mg/mbasis) for up to 2 years produced an increase in the incidence of benign ovarian stromal, epithelial and granulosa cell tumors at all dose levels. A dose related increase in the incidence of ovarian hyperplasia was also observed in female mice. These ovarian changes are considered to be rodent-specific effectsof aromatase inhibition and are of questionable significance to humans. The incidence of lymphosarcoma was increased in males and females at the high dose. At 50 mg/kg/day, plasma AUC levels in mice were 35 to 40 times higher than the level exhibited in postmenopausal volunteers at the recommended dose.<br/>Mutagenesis: ARIMIDEX has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests, CHO-K1 gene mutation assay) or clastogenic either in vitro (chromosome aberrations in human lymphocytes) or in vivo (micronucleus test in rats).<br/>Impairment of Fertility: Oral administration of anastrozole to female rats (from 2 weeks before mating to pregnancy day 7) produced significant incidence of infertility and reduced numbers of viable pregnancies at 1 mg/kg/day (about 10 times the recommended human dose on a mg/mbasis and 9 times higher than the AUCfound in postmenopausal volunteers at the recommended dose). Pre-implantation loss of ova or fetus was increased at doses equal to or greater than 0.02 mg/kg/day (about one-fifth the recommended human dose on a mg/mbasis). Recovery of fertility was observed following a 5-week non-dosing period which followed 3 weeks of dosing. It is not known whether these effects observed in female rats are indicative of impaired fertility in humans. Multiple-dose studies in rats administered anastrozole for 6 months at doses equal to or greater than 1 mg/kg/day (which produced plasma anastrozole Cand AUCthat were 19 and 9 times higher than the respective values found in postmenopausal volunteers at the recommended dose) resulted in hypertrophy of the ovaries and the presence of follicular cysts. In addition, hyperplastic uteri were observed in 6-month studies in female dogs administered doses equal to or greater than 1 mg/kg/day (which produced plasma anastrozole Cand AUCthat were 22 times and 16 times higher than the respective values found in postmenopausal women at the recommended dose). It is not known whether these effects on the reproductive organs of animals are associated with impaired fertility in premenopausal women.<br/>Pregnancy:<br/>Pregnancy Category D: (See WARNINGS)<br/>Nursing Mothers: It is not known if anastrozole is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ARIMIDEX is administered to a nursing woman (See WARNINGS and PRECAUTIONS).<br/>Pediatric Use: The safety and efficacy of ARIMIDEX in pediatric patients have not been established.<br/>Geriatric Use: In studies 0030 and 0027 about 50% of patients were 65 or older. Patients���65 years of age had moderately better tumor response and time to tumor progression than patients<65 years of age regardless of randomized treatment. In studies 0004 and 0005 50% of patients were 65 or older. Response rates and time to progression were similar for the over 65 and younger patients. In the ATAC study, patients who were 65 years of age or older (N=1413 for ARIMIDEX and N=1410 for tamoxifen), the hazard ratio for disease-free survival was 0.93 (95% CI: 0.80, 1.08) for Arimidex compared to tamoxifen. | lld:dailymed |
| dailymed-drugs:244 | dailymed-instance:precautio... | Cilostazol is contraindicated in patients with congestive heart failure. In patients without congestive heart failure, the long-term effects of PDE III inhibitors (including cilostazol) are unknown. Patients in the 3-6 month placebo-controlled trials of cilostazol were relatively stable (no recent myocardial infarction or strokes, no rest pain or other signs of rapidly progressing disease) and only 19 patients died (0.7% in the placebo group and 0.8% in the group on cilostazol). The calculated relative risk of death of 1.2 has a wide 95% confidence limit (0.5-3.1). There are no data as to longer-term risk or risk in patients with more severe underlying heart disease. Hematologic adverse reactions:Rare cases have been reported of thrombocytopenia or leucopenia to agranulocytosis when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of Cilostazol. Use with Clopidogrel:There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and clopidogrel, a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and clopidogrel, caution is advised for checking bleeding times during coadministration. Information for Patients:Please refer to the patient package insert.Patients should be advised: Hepatic Impairment:Patients with moderate or severe hepatic impairment have not been studied in clinical trials. Special caution is advised when cilostazol is used in such patients. Renal Impairment:Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95-98%). Special caution is advised when cilostazol is used in patients with severe renal impairment; estimated creatinine clearence,<25 ml/min. Drug Interactions :Since cilostazol is extensively metabolized by cytochrome P-450 isoenzymes, caution should be exercised when cilostazol is coadministered with inhibitors of CYP3A4 such as ketoconazole and erythromycin or inhibitors of CYP2C19 such as omeprazole. Pharmacokinetic studies have demonstrated that omeprazole and erythromycin significantly increased the systemic exposure of cilostazol and/or its major metabolites. Population pharmacokinetic studies showed higher concentrations of cilostazol among patients concurrently treated with diltiazem, an inhibitor of CYP3A4 . Cilostazol does not, however, appear to cause increased blood levels of drugs metabolized by CYP3A4, as it had no effect on lovastatin, a drug with metabolism very sensitive to CYP3A4 inhibition. Use with other anitplatelet agents:Cilostazol inhibits platelet aggregation but in a reversible manner. Caution is advised in patients at risk of bleeding from surgery or pathologic processes. Platelet aggregability returns to normal within 96 hours of stopping cilostazol. Caution is advised in patients receiving both cilostazol and any other antiplatelet agent, or in patients with thrombocytopenia. Cardiovascular Toxicity:Repeated oral administration of cilostazol to dogs (30 or more mg/kg/day for 52 weeks, 150 or more mg/kg/day for 13 weeks, and 450 mg/kg/day for 2 weeks), produced cardiovascular lesions that included endocardial hemorrhage, hemosiderin deposition and fibrosis in the left ventricle, hemorrhage in the right atrial wall, hemorrhage and necrosis of the smooth muscle in the wall of the coronary artery, intimal thickening of the coronary artery, and coronary arteritis and periarteritis. At the lowest dose associated with cardiovascular lesions in the 52-week study, systemic exposure (AUC) to unbound cilostazol was less than that seen in humans at the maximum recommended human dose (MRHD) of 100 mg b.i.d. Similar lesions have been reported in dogs following the administration of other positive inotropic agents (including PDE III inhibitors) and/or vasodilating agents. No cardiovascular lesions were seen in rats following 5 or 13 weeks of administration of cilostazol at doses up to 1500 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were only about 1.5 and 5 times (male and female rats, respectively) the exposure seen in humans atthe MRHD. Cardiovascular lesions were also not seen in rats following 52 weeks of administration of cilostazol at doses up to 150 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were about 0.5 and 5 times (male and female rats, respectively) the exposure in humans at the MRHD. In female rats, cilostazol AUCs were similar at 150 and 1500 mg/kg/day. Cardiovascular lesions were also not observed in monkeys after oral administration of cilostazol for 13 weeks at doses up to 1800 mg/kg/day. While this dose of cilostazol produced pharmacologic effects in monkeys, plasma cilostazol levels were less than those seen in humans given the MRHD, and those seen in dogs given doses associated with cardiovascular lesions. Carcinogenesis, Mutagenesis, Impairment of Fertility:Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation, and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay. Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males, and about 5 times in females, the exposure in humans at the MRHD. Pregnancy:Pregnancy Category C: In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights, and increased incidences of cardiovascular, renal, and skeletal anomalies (ventricular septal, aortic arch, and subclavian artery abnormalities, renal pelvic dilation, 14rib, and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD, and exposure to 3,4-dehydro-cilostazol was barely detectable. When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). There are no adequate and well-controlled studies in pregnant women. Nursing Mothers:Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol. Pediatric Use:The safety and effectiveness of cilostazol in pediatric patients have not been established. Geriatric Use:Of the total number of subjects (n = 2274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism, and elimination of cilostazol and its metabolites. | lld:dailymed |
| dailymed-drugs:245 | dailymed-instance:precautio... | CLINICAL EVALUATIONS AND LABORATORY DETERMINATIONS, AT THE DISCRETION OF THE ATTENDING PHYSICIAN, ARE NECESSARY FOR PROPER MONITORING DURING ADMINISTRATION. Blood studies should include glucose, urea nitrogen, serum electrolytes, acid-base balance, blood ammonia levels, serum proteins, kidney and liver function tests, serum osmolality and hemogram. Circulating blood volume should be determined if indicated. If sepsis is suspected, blood cultures should be taken. Clinically significant hypocalcemia, hypophosphatemia or hypomagnesemia may occur as a result of therapy with Aminosyn-RF 5.2%, Sulfite-Free, (an amino acid injection���renal formula) and hypertonic dextrose; electrolyte replacement may become necessary. In order to promote urea nitrogen reutilization in patients with renal failure, it is essential to provide adequate calories with minimal amounts of the essential amino acids and to restrict the intake of nonessential nitrogen. Hypertonic dextrose solutions are a convenient and metabolically effective source of concentrated calories. Special care must be taken when giving hypertonic glucose to provide calories in diabetic or prediabetic patients. Hypertonic solutions should be administered through an indwelling catheter with the tip located in the superior vena cava. When abrupt cessation of hypertonic dextrose is required, monitoring for rebound hypoglycemia should be instituted. Essential fatty acid deficiency (EFAD) is becoming increasingly recognized in patients on long term TPN (more than 5 days). The use of fat emulsion toprovide 4���10% of total caloric intake as linoleic acid may prevent EFAD. Fluid balance should be carefully monitored in patients with renal failure to avoid excessive fluid overload, especially in relation to cardiac insufficiency. SPECIAL PRECAUTIONS FOR CENTRAL INFUSIONS ADMINISTRATION BY CENTRAL VENOUS CATHETER SHOULD BE USED ONLY BY THOSE FAMILIAR WITH THIS TECHNIQUE AND ITS COMPLICATIONS. Central vein infusion (with added carbohydrate solutions) of amino acid solutions requires a knowledge of nutrition as well as clinical expertise in recognition and treatment of complications. Attention must be given to solution preparation, administration and patient monitoring. IT IS ESSENTIAL THAT A CAREFULLY PREPARED PROTOCOL, BASED ON CURRENT MEDICAL PRACTICES, BE FOLLOWED, PREFERABLY BY AN EXPERIENCED TEAM. SUMMARY HIGHLIGHTS OF COMPLICATIONS (Also see Current Medical Literature)<br/>Pregnancy Category C: Animal reproduction studies have not been conducted with Aminosyn-RF 5.2%. It is also not known whether Aminosyn-RF 5.2% can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Aminosyn-RF 5.2% should be given to a pregnant woman only if clearly needed.<br/>Geriatric Use: Clinical studies of Aminosyn-RF have not been performed to determine whether patients over 65 years respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal functions. Aminosyn 5.2% contains no more than 25 mcg/L of aluminum. SPECIAL PRECAUTIONS IN PATIENTS WITH RENAL INSUFFICIENCY Frequent laboratory studies are necessary in patients with renal insufficiency. In renal failure hyperglycemia may not be reflected by glycosuria. Blood glucose must be determined frequently, often every six hours to guide dosage of dextrose, and insulin should be given, if required.<br/>SPECIAL PRECAUTIONS IN PEDIATRIC PATIENTS: Aminosyn-RF 5.2%, Sulfite-Free, (an amino acid injection���renal formula) should be used with special caution in pediatric patients with acute renal failure, especially low birth weight infants. Laboratory and clinical monitoring of pediatric patients, especially those who are nutritionally depleted, must be extensive and frequent. See Children section under DOSAGE AND ADMINISTRATION for additional information. Frequent monitoring of blood glucose is required in low birth weight or septic infants as hypertonic dextrose infusion involves a greater risk of hyperglycemia in such patients. | lld:dailymed |
| dailymed-drugs:246 | dailymed-instance:precautio... | THE POTENTIATING ACTION OF HYDROXYZINE MUST BE CONSIDERED WHEN THE DRUG IS USED IN CONJUNCTION WITH CENTRAL NERVOUS SYSTEM DEPRESSANTS SUCH AS NARCOTICS, NON-NARCOTIC ANALGESICS AND BARBITURATES. Therefore, when central nervous system depressants are administered concomitantly with hydroxyzine, their dosage should be reduced. Since drowsiness may occur with use of this drug, patients should be warned of this possibility and cautioned against driving a car or operating dangerous machinery while taking hydroxyzine. Patients should be advised against the simultaneous use of other CNS depressant drugs, and cautioned that the effect of alcohol may be increased.<br/>Geriatric Use: A determination has not been made whether controlled clinical studies of hydroxyzine included sufficient numbers of subjects aged 65 and over to define a difference in response from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or otherdrug therapy. The extent of renal excretion of hydroxyzine has not been determined. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selections. Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally should be started on low doses of hydroxyzine and observed closely. | lld:dailymed |
| dailymed-drugs:248 | dailymed-instance:precautio... | Return of Sedation: Flumazenil may be expected to improve the alertness of patients recovering from a procedure involving sedation or anesthesia with benzodiazepines, but should not be substituted for an adequate period of postprocedure monitoring. The availability of flumazenil does not reduce the risks associated with the use of large doses of benzodiazepines for sedation. Patients should be monitored for resedation, respiratory depression or other persistent or recurrent agonist effects for an adequate period of time after administration of flumazenil. Resedation is least likely in cases where flumazenil is administered to reverse a low dose of a short-acting benzodiazepine (<10 mg midazolam). It is most likely in cases where a large single or cumulative dose of a benzodiazepine has been given in the course of a long procedure along with neuromuscular blocking agents and multiple anesthetic agents. Profound resedation was observed in 1% to 3% of adult patients in the clinical studies. In clinical situations where resedation must be prevented in adult patients, physicians may wish to repeat the initial dose (up to 1 mg of flumazenil given at 0.2 mg/min) at 30 minutes and possibly again at 60 minutes. This dosage schedule, although not studied in clinical trials, was effective in preventing resedation in a pharmacologic study in normal volunteers. The use of flumazenil to reverse the effects of benzodiazepines used for conscious sedation has been evaluated in one open-label clinical trial involving 107 pediatric patients between the ages of 1 and 17 years. This study suggested that pediatric patients who have become fully awake following treatment with flumazenil may experience a recurrence of sedation, especially younger patients (ages 1 to 5). Resedation was experienced in 7 of 60 patients who were fully alert 10 minutes after the start of flumazenil administration. No patient experienced a return to the baseline level of sedation. Mean time to resedation was 25 minutes (range: 19 to 50 minutes) . The safety and effectiveness of repeated flumazenil administration in pediatric patients experiencing resedation have not been established.<br/>Use in the ICU: Flumazenil should be used with caution in the ICU because of the increased risk of unrecognized benzodiazepine dependence in such settings. Flumazenil may produce convulsions in patients physically dependent on benzodiazepines . Administration of flumazenil to diagnose benzodiazepine-induced sedation in the ICU is not recommended due to the risk of adverse events as described above. In addition, the prognostic significance of a patient's failure to respond to flumazenil in cases confounded by metabolic disorder, traumatic injury, drugs other than benzodiazepines, or any other reasons not associated with benzodiazepine receptor occupancy is unknown.<br/>Use in Benzodiazepine Overdosage: Flumazenil is intended as an adjunct to, not as a substitute for, proper management of airway, assisted breathing, circulatory access and support, internal decontamination by lavage and charcoal, and adequate clinical evaluation. Necessary measures should be instituted to secure airway, ventilation and intravenous access prior to administering flumazenil. Upon arousal, patients may attempt to withdraw endotracheal tubes and/or intravenous lines as the result of confusion and agitation following awakening.<br/>Head Injury: Flumazenil should be used with caution in patients with head injury as it may be capable of precipitating convulsions or altering cerebral blood flow in patients receiving benzodiazepines. It should be used only by practitioners prepared to manage such complications should they occur.<br/>Use With Neuromuscular Blocking Agents: Flumazenil should not be used until the effects of neuromuscular blockade have been fully reversed.<br/>Use in Psychiatric Patients: Flumazenil has been reported to provoke panic attacks in patients with a history of panic disorder.<br/>Pain on Injection: To minimize the likelihood of pain or inflammation at the injection site, flumazenil should be administered through a freely flowing intravenous infusion into a large vein. Local irritation may occur following extravasation into perivascular tissues.<br/>Use in Respiratory Disease: The primary treatment of patients with serious lung disease who experience serious respiratory depression due to benzodiazepines should be appropriate ventilatory support rather than the administration of flumazenil. Flumazenil is capable of partially reversing benzodiazepine-induced alterations in ventilatory drive in healthy volunteers, but has not been shown to be clinically effective.<br/>Use in Cardiovascular Disease: Flumazenil did not increase the work of the heart when used to reverse benzodiazepines in cardiac patients when given at a rate of 0.1 mg/min in total doses of less than 0.5 mg in studies reported in the clinical literature. Flumazenil alone had no significant effects on cardiovascular parameters when administered to patients with stable ischemic heart disease.<br/>Use in Liver Disease: The clearance of flumazenil is reduced to 40% to 60% of normal in patients with mild to moderate hepatic disease and to 25% of normal in patients with severe hepatic dysfunction . While the dose of flumazenil used for initial reversal of benzodiazepine effects is not affected, repeat doses of the drug in liver disease should be reduced in size or frequency.<br/>Use in Drug- and Alcohol-Dependent Patients: Flumazenil should be used with caution in patients with alcoholism and other drug dependencies due to the increased frequency of benzodiazepine tolerance and dependence observed in these patient populations. Flumazenil is not recommended either as a treatment for benzodiazepine dependence or for the management of protracted benzodiazepine abstinence syndromes, as such use has not been studied. The administration of flumazenil can precipitate benzodiazepine withdrawal in animals and man. This has been seen in healthy volunteers treated with therapeutic doses of oral lorazepam for up to 2 weeks who exhibited effects such as hot flushes, agitation and tremor when treated with cumulative doses of up to 3 mg doses of flumazenil. Similar adverse experiences suggestive of flumazenil precipitation of benzodiazepine withdrawal have occurred in some adult patients in clinical trials. Such patients had a short-lived syndrome characterized by dizziness, mild confusion, emotional lability, agitation (with signs and symptoms of anxiety), and mild sensory distortions. This response was dose-related, most common at doses above 1 mg, rarely required treatment other than reassurance and was usually short lived. When required, these patients (5 to 10 cases) were successfully treated with usual doses of a barbiturate, a benzodiazepine, or other sedative drug. Practitioners should assume that flumazenil administration may trigger dose-dependent withdrawal syndromes in patients with established physical dependence on benzodiazepines and may complicate the management of withdrawal syndromes for alcohol, barbiturates and cross- tolerant sedatives.<br/>Drug Interactions: Interaction with central nervous system depressants other than benzodiazepines has not been specifically studied; however, no deleterious interactions were seen when flumazenil was administered after narcotics, inhalational anesthetics, muscle relaxants and muscle relaxant antagonists administered in conjunction with sedation or anesthesia. Particular caution is necessary when using flumazenil in cases of mixed drug overdosage since the toxic effects (such as convulsions and cardiac dysrhythmias) of other drugs taken in overdose (especially cyclic antidepressants) may emerge with the reversal of the benzodiazepine effect by flumazenil . The use of flumazenil is not recommended in epileptic patients who have been receiving benzodiazepine treatment for a prolonged period. Although flumazenil exerts a slight intrinsic anticonvulsant effect, its abrupt suppression of the protective effect of a benzodiazepine agonist can give rise to convulsions in epileptic patients. Flumazenil blocks the central effects of benzodiazepines by competitive interaction at the receptor level. The effects of nonbenzodiazepine agonists at benzodiazepine receptors, such as zopiclone, triazolopyridazines and others, are also blocked by flumazenil. The pharmacokinetics of benzodiazepines are unaltered in the presence of flumazenil and vice versa. There is no pharmacokinetic interaction between ethanol and flumazenil.<br/>Use in Ambulatory Patients: The effects of flumazenil may wear off before a long-acting benzodiazepine is completely cleared from the body. In general, if a patient shows no signs of sedation within 2 hours after a 1 mg dose of flumazenil, serious resedation at a later time is unlikely. An adequate period of observation must be provided for any patient in whom either long-acting benzodiazepines (such as diazepam) or large doses of short-acting benzodiazepines (such as>10 mg of midazolam) have been used . Because of the increased risk of adverse reactions in patients who have been taking benzodiazepines on a regular basis, it is particularly important that physicians query patients or their guardians carefully about benzodiazepine, alcohol and sedative use as part of the history prior to any procedure in which the use of flumazenil is planned .<br/>Information for Patients: Flumazenil does not consistently reverse amnesia. Patients cannot be expected to remember information told to them in the postprocedure period and instructions given to patients should be reinforced in writing or given to a responsible family member. Physicians are advised to discuss with patients or their guardians, both before surgery and at discharge, that although the patient may feel alert at the time of discharge, the effects of the benzodiazepine (e.g., sedation) may recur. As a result, the patient should be instructed, preferably in writing, that their memory and judgment may be impaired and specifically advised:<br/>Laboratory Tests: No specific laboratory tests are recommended to follow the patient's response or to identify possible adverse reactions.<br/>Drug/Laboratory Test Interactions: The possible interaction of flumazenil with commonly used laboratory tests has not been evaluated.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis: No studies in animals to evaluate the carcinogenic potential of flumazenil have been conducted.<br/>Mutagenesis: No evidence for mutagenicity was noted in the Ames test using five different tester strains. Assays for mutagenic potential in S. cerevisiae D7 and in Chinese hamster cells were considered to be negative as were blastogenesis assays in vitro in peripheral human lymphocytes and in vivo in a mouse micronucleus assay. Flumazenil caused a slight increase in unscheduled DNA synthesis in rat hepatocyte culture at concentrations which were also cytotoxic; no increase in DNA repair was observed in male mouse germ cells in an in vivo DNA repair assay.<br/>Impairment of Fertility: A reproduction study in male and female rats did not show any impairment of fertility at oral dosages of 125 mg/kg/day. From the available data on the area under the curve (AUC) in animals and man the dose represented 120 times the human exposure from a maximum recommended intravenous dose of 5 mg.<br/>Pregnancy:<br/>Pregnancy Category C: There are no adequate and well-controlled studies of the use of flumazenil in pregnant women. Flumazenil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Teratogenic Effects: Flumazenil has been studied for teratogenicity in rats and rabbits following oral treatments of up to 150 mg/kg/day. The treatments during the major organogenesis were on days 6 to 15 of gestation in the rat and days 6 to 18 of gestation in the rabbit. No teratogenic effects were observed in rats or rabbits at 150 mg/kg; the dose, based on the available data on the area under the plasma concentration-time curve (AUC) represented 120 times to 600 times the human exposure from a maximum recommended intravenous dose of 5 mg in humans. In rabbits, embryocidal effects (as evidenced by increased preimplantation and postimplantation losses) were observed at 50 mg/kg or 200 times the human exposure from a maximum recommended intravenous dose of 5mg. The no-effect dose of 15 mg/kg in rabbits represents 60 times the human exposure.<br/>Nonteratogenic Effects: An animal reproduction study was conducted in rats at oral dosages of 5, 25, and 125 mg/kg/day of flumazenil. Pup survival was decreased during the lactating period, pup liver weight at weaning was increased for the high-dose group (125 mg/kg/day) and incisor eruption and ear opening in the offspring were delayed; the delay in ear opening was associated with a delay in the appearance of the auditory startle response. No treatment-related adverse effects were noted for the other dose groups. Based on the available data from AUC, the effect level (125 mg/kg) represents 120 times the human exposure from 5 mg, the maximum recommended intravenous dose in humans. The no-effect level represents 24 times the human exposure from an intravenous dose of 5 mg.<br/>Labor and Delivery: The use of flumazenil to reverse the effects of benzodiazepines used during labor and delivery is not recommended because the effects of the drug in the newborn are unknown.<br/>Nursing Mothers: Caution should be exercised when deciding to administer flumazenil to a nursing woman because it is not known whether flumazenil is excreted in human milk.<br/>Pediatric Use: The safety and effectiveness of flumazenil have been established in pediatric patients 1 year of age and older. Use of flumazenil in this age group is supported by evidence from adequate and well-controlled studies of flumazenil in adults with additional data from uncontrolled pediatric studies including one open-label trial. The use of flumazenil to reverse the effects of benzodiazepines used for conscious sedation was evaluated in one uncontrolled clinical trial involving 107 pediatric patients between the ages of 1 and 17 years. At the doses used, flumazenil's safety was established in this population. Patients received up to 5 injections of 0.01 mg/kg flumazenil up to a maximum total dose of 1.0 mg at a rate not exceeding 0.2 mg/min. Of 60 patients who were fully alert at 10 minutes, 7 experienced resedation. Resedation occurred between 19 and 50 minutes after the start of flumazenil administration. None of the patients experienced a return to the baseline level of sedation. All 7 patients were between the ages of 1 and 5 years. The types and frequency ofadverse events noted in these pediatric patients were similar to those previously documented in clinical trials with flumazenil to reverse conscious sedation in adults. No patient experienced a serious adverse event attributable to flumazenil. The safety and efficacy of flumazenil in the reversal of conscious sedation in pediatric patients below the age of 1 year have not been established . The safety and efficacy of flumazenil have not been established in pediatric patients for reversal of the sedative effects of benzodiazepines used for induction of general anesthesia, for the management of overdose, or for the resuscitation of the newborn, as no well-controlled clinical studies have been performed to determine the risks, benefits and dosages to be used. However, published anecdotal reports discussing the use of flumazenil in pediatric patients for these indications have reported similar safety profiles and dosing guidelines to those described for the reversal of conscious sedation. The risks identified in the adult population with flumazenil use also apply to pediatric patients. Therefore, consult the CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS sections when using flumazenil in pediatric patients.<br/>Geriatric Use: Of the total number of subjects in clinical studies of flumazenil, 248 were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The pharmacokinetics of flumazenil have been studied in the elderly and are not significantly different from younger patients. Several studies of flumazenil in subjects over the age of 65 and one study in subjects over the age of 80 suggest that while the doses of benzodiazepine used to induce sedation should be reduced, ordinary doses of flumazenil may be used for reversal. | lld:dailymed |
| dailymed-drugs:249 | dailymed-instance:precautio... | General: The lowest possible dose of corticosteroid should be used to control the condition under treatment, and when reduction in dosage is possible, the reduction should be gradual. Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used. There is an enhanced effect of corticosteroids in patients with hypothyroidism and in those with cirrhosis. Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement.<br/>Cardio-renal: As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with hypertension, congestive heart failure, or renal insufficiency.<br/>Endocrine: Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently.<br/>Gastrointestinal: Steroids should be used with caution in nonspecific ulcerative colitis, if there is a probability of impending perforation, abscess or other pyogenic infection; diverticulitis; fresh intestinal anastomoses; active or latent peptic ulcer. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent.<br/>Musculoskeletal: Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in children and adolescents and thedevelopment of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (i.e., postmenopausal women) before initiating corticosteroid therapy.<br/>Neuro-psychiatric: Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that they affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect. . An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatinine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression, to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.<br/>Ophthalmic: Intraocular pressure may become elevated in some individuals. If steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored.<br/>Information for Patients: Patients should be warned not to discontinue the use of prednisolone sodium phosphate oral solution abruptly or without medical supervision, to advise any medical attendants that they are taking it and to seek medical advice at once should they develop fever or other signs of infection. Persons who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.<br/>Drug Interactions: Drugs such as barbiturates, phenytoin, ephedrine, and rifampin, which induce hepatic microsomal drug metabolizing enzyme activity may enhance metabolism of prednisolone and require that the dosage of prednisolone sodium phosphate oral solution be increased. Increased activity of both cyclosporin and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. Estrogens may decrease the hepatic metabolism of certain corticosteroids thereby increasing their effect. Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60% leading to an increased risk of corticosteroid side effects. Coadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect. Concomitant use of aspirin (or other non-steroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids. When corticosteroids are administered concomitantly with potassium-depleting agents (i.e., diuretics, amphotericin-B), patients should be observed closely for development of hypokalemia. Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy. Due to inhibition of antibody response, patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. If possible, routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued. Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. Corticosteroids may suppress reactions to skin tests.<br/>Pregnancy:<br/>Teratogenic effects:<br/>Nursing Mothers: Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when prednisolone sodium phosphate oral solution is administered to a nursing woman.<br/>Pediatric Use: The efficacy and safety of prednisolone in the pediatric population are based on the well-established course of effect of corticosteroids which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome (>2 years of age), and aggressive lymphomas and leukemias (>1 month of age). However, some of these conclusions and other indications for pediatric use of corticosteroid, e.g., severe asthma and wheezing, are based on adequate and well-controlled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations. The adverse effects of prednisolone in pediatric patients are similar to those in adults . Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Children who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (i.e., cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The linear growth of children treated with corticosteroids by any route should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of other treatment alternatives. In order to minimize the potential growth effects of corticosteroids, children should be titrated to the lowest effective dose.<br/>Geriatric Use: Clinical studies of prednisolone sodium phosphate oral solution did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience with prednisolone sodium phosphate has not identified differences in responses between the elderly and younger patients. However, the incidence of corticosteroid-induced side effects may be increased in geriatric patients and appear to be dose-related. Osteoporosis is the most frequently encountered complication, which occurs at a higher incidence rate in corticosteroid-treated geriatric patients as compared to younger populations and in age-matched controls. Losses of bone mineral density appear to be greatest early on in the course of treatment and may recover over time after steroid withdrawal or use of lower doses (i.e.,���5 mg/day). Prednisolone doses of 7.5 mg/day or higher have been associated with an increased relative risk of both vertebral and nonvertebral fractures, even in the presence of higher bone density compared to patients with involutional osteoporosis. Routine screening of geriatric patients, including regular assessments of bone mineral density and institution of fracture prevention strategies, along with regular review of prednisolone indication should be undertaken to minimize complications and keep the prednisolone dose at the lowest acceptable level. Coadministration of bisphosphonates has been shown to retard the rate of bone loss in corticosteroid-treated males and postmenopausal females, and these agents are recommended in the prevention and treatment ofcorticosteroid-induced osteoporosis. It has been reported that equivalent weight-based doses yield higher total and unbound prednisolone plasma concentrations and reduced renal and non-renal clearance in elderly patients compared to younger populations. However, it is not clear whether dosing reductions would be necessary in elderly patients, since these pharmacokinetic alterations may be offset by age-related differences in responsiveness of target organs and/or less pronounced suppression of adrenal release of cortisol. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function . | lld:dailymed |
| dailymed-drugs:250 | dailymed-instance:precautio... | General:<br/>Atrial Tachyarrhythmias: Patients with atrial flutter or fibrillation should be digitalized prior to Disopyramide Phosphate administration to ensure that drug-induced enhancement of AV conduction does not result in an increase of ventricular rate beyond physiologically acceptable limits.<br/>Conduction Abnormalities: Care should be taken when prescribing Disopyramide Phosphate for patients with sick sinus syndrome (bradycardia-tachycardia syndrome), Wolff-Parkinson-White syndrome (WPW), or bundle branch block. The effect of disopyramide phosphate in these conditions is uncertain at present.<br/>Cardiomyopathy: Patients with myocarditis or other cardiomyopathy may develop significant hypotension in response to the usual dosage of disopyramide phosphate, probably due to cardiodepressant mechanisms. Therefore, a loading dose of Disopyramide Phosphate should not be given to such patients, and initial dosage and subsequent dosage adjustments should be made under close supervision (see DOSAGE AND ADMINISTRATION).<br/>Renal Impairment: More than 50% of disopyramide is excreted in the urine unchanged. Therefore Disopyramide Phosphate dosage should be reduced in patients with impaired renal function (see DOSAGE AND ADMINISTRATION). The electrocardiogram should be carefully monitored for prolongation of PR interval, evidence of QRS widening, or other signs of overdosage (see OVERDOSAGE).<br/>Hepatic Impairment: Hepatic impairment also causes an increase in the plasma half-life of disopyramide. Dosage should be reduced for patients with such impairment. The electrocardiogram should be carefully monitored for signs of overdosage (see OVERDOSAGE). Patients with cardiac dysfunction have a higher potential for hepatic impairment; this should be considered when administering Disopyramide Phosphate.<br/>Potassium Imbalance: Antiarrhythmic drugs may be ineffective in patients with hypokalemia, and their toxic effects may be enhanced in patients with hyperkalemia. Therefore, potassium abnormalities should be corrected before starting Disopyramide Phosphate therapy.<br/>Drug Interactions: If phenytoin or other hepatic enzyme inducers are taken concurrently with Disopyramide Phosphate, lower plasma levels of disopyramide may occur. Monitoring of disopyramide plasma levels is recommended in such concurrent use to avoid ineffective therapy. Other antiarrhythmic drugs (e.g., quinidine, procainamide, lidocaine, propranolol) have occasionally been used concurrently with Disopyramide Phosphate. Excessive widening of the QRS complex and/or prolongation of the Q-T interval may occur in these situations (see WARNINGS). In healthy subjects, no significant drug-drug interaction was observed when Disopyramide Phosphate was coadministered with either propranolol or diazepam. Concomitant administration of Disopyramide Phosphate and quinidine resulted in slight increases in plasma disopyramide levels and slight decreases in plasma quinidine levels. Disopyramide Phosphate does not increase serum digoxin levels. Until data on possible interactions between verapamil and disopyramide phosphate are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration. Although potent inhibitors of cytochrome P450 3A4 (e.g., ketoconazole) have not been studied clinically, in vitro studies have shown that erythromycin and oleandomycin inhibit the metabolism of disopyramide. Cases of life-threatening interactions have been reported for disopyramide when given with clarithromycin and erythromycin indicating that coadministration of disopyramide with inhibitors of cytochrome P450 3A4 could result in potentially fatal interaction.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Eighteen months of Disopyramide Phosphate administration to rats, at oral doses up to 400 mg/kg/day (about 30 times the usual daily human dose of 600 mg/day, assuming a patient weight of at least 50 kg), revealed no evidence of carcinogenic potential. An evaluation of mutagenic potential by Ames test was negative. Disopyramide Phosphate, at doses up to 250 mg/kg/day, did not adversely affect fertility of rats.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nonteratogenic Effects: Disopyramide Phosphate has been reported to stimulate contractions of the pregnant uterus. Disopyramide has been found in human fetal blood.<br/>Labor and Delivery: It is not known whether the use of Disopyramide Phosphate during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention.<br/>Nursing Mothers: Studies in rats have shown that the concentration of disopyramide and its metabolites is between one and three times greater in milk than it is in plasma. Following oral administration, disopyramide has been detected in human milk at a concentration not exceeding that in plasma. Because of the potential for serious adverse reactions in nursing infants from Disopyramide Phosphate, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established (see DOSAGE AND ADMINISTRATION).<br/>Geriatric Use: Clinical studies of disopyramide phosphate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Because of its anticholinergic activity, disopyramide phosphate should not be used in patients with glaucoma, urinary retention, or benign prostatic hypertrophy (medical conditions commonly associated with the elderly) unless adequate overriding measures are taken (see WARNINGS: Anticholinergic Activity).In the event of increased anticholinergic side effects, plasma levels of disopyramide should be monitored and the dose of the drug adjusted accordingly. A reduction of the dose by one third, from the recommended 600 mg/day to 400 mg/day, wouldbe reasonable, without changing the dosing interval. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see PRECAUTIONS: Renal Impairment and DOSAGE AND ADMINISTRATION). | lld:dailymed |
| dailymed-drugs:251 | dailymed-instance:precautio... | General: It is recommended that Diclofenac Sodium Ophthalmic Solution, 0.1%, like other NSAIDs, be used with caution in surgical patients with known bleeding tendencies or who are receiving other medications that may prolong bleeding time. Diclofenac Sodium Ophthalmic Solution, 0.1% may slow or delay healing. Results from clinical studies indicate that Diclofenac Sodium Ophthalmic Solution, 0.1% has no significant effect upon intraocular pressure, however, elevations in intraocular pressure may occur following cataract surgery.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long term carcinogenicity studies in rats given oral diclofenac sodium up to 2 mg/kg/day (approximately the human oral dose) have revealed no significant increases in tumor incidence. There was a slight increase in benign rat mammary fibroadenomas in mid-dose females (high dose females had excessive mortality) but the increase was not significant for this common rat tumor. A 2-year carcinogenicity study conducted in mice employing oral diclofenac sodium up to 2 mg/kg/day did not reveal any oncogenic potential. Diclofenac sodium did not show mutagenic potential in various mutagenicity studies including the Ames test. Diclofenac sodium administered to male and female rats at 4 mg/kg/day did not affect fertility.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C. Reproduction studies performed in mice at oral doses up to 5000 times (20 mg/kg/day) and in rats and rabbits at oral doses up to 2500 times (10 mg/kg/day) the human topical dose have revealed no evidence of teratogenicity due to diclofenac sodium, despite the induction of maternal toxicity and fetal toxicity. In rats, maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac sodium has been shown to cross the placental barrier in mice and rats. There are however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.<br/>Nonteratogenic effects: Because of the known effects of prostaglandin biosynthesis-inhibiting drugs on the fetal cardiovascular system (closure of the ductus arteriosus), the use of Diclofenac Sodium Ophthalmic Solution, 0.1% during late pregnancy should be avoided.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established. | lld:dailymed |
| dailymed-drugs:252 | dailymed-instance:precautio... | Heart block: In patients without implanted pacemakers who are at high risk of complete atrioventricular block (eg, those with digitalis intoxication, second���degree atrioventricular block, or severe intraventricular conduction defects), quinidine should be used only with caution.<br/>Drug interactions: Altered pharmacokinetics of quinidine: Drugs that alkalinize the urine (carbonic���anhydrase inhibitors, sodium bicarbonate, thiazide diuretics) reduce renal elimination of quinidine. By pharmacokinetic mechanisms that are not well understood, quinidine levels are increased by coadministration of amiodarone or cimetidine. Very rarely, and again by mechanisms not understood, quinidine levels are decreased by coadministration of nifedipine. Hepatic elimination of quinidine may be accelerated by coadministration of drugs (phenobarbital, phenytoin, rifampin) that induce production of cytochrome P450IIIA4. Perhaps because of competition of the P450IIIA4 metabolic pathway, quinidine levels rise when ketaconazole is coadministered. Coadministration of propranolol usually does not affect quinidine pharmacokinetics, but in some studies, the�����blocker appeared to cause increases in the peak serum levels of quinidine, decreases in quinidine's volume of distribution and decreases in total quinidine clearance. The effects (if any) of coadministration of other�����blockers on quinidine pharmacokinetics have not been adequately studied. Hepatic clearance of quinidine is significantly reduced during coadministration of verapamil, with corresponding increases in serum levels and half���life. Altered pharmacokinetics of other drugs: Quinidine slows the elimination of digoxin and simultaneously reduces digoxin's apparent volume of distribution. As a result, serum digoxin levels may be as much as doubled. When quinidine and digoxin are coadministered, digoxin doses usually need to be reduced. Serum levels of digitoxin are also raised when quinidine is coadministered, although the effect appears to be smaller. By a mechanism that is not understood, quinidine potentiates the anticoagulatory action of warfarin, and the anticoagulant dosage may need to be reduced. Cytochrome P450IID6 is an enzyme critical to the metabolism of many drugs, notably including mexiletine, some phenothiazines, and most polycyclic antidepressants. Constitutional deficiency of cytochrome P450IID6 is found in less than 1% of Orientals, in about 2% of American blacks, and in about 8% of American whites. Testing with debrisoquine is sometimes used to distinguish the P450IID6���deficient "poor metabolizers" from the majority���phenotype "extensive metabolizers." When drugs whose metabolism is P450IID6���dependent are given to poor metabolizers, the serum levels achieved are higher, sometimes much higher, than the serum levels achieved when identical doses are given to extensive metabolizers. To obtain similar clinical benefit without toxicity, doses given to poor metabolizers may need to be greatly reduced. In the cases of prodrugs whose actions are actually mediated by P450IID6���produced metabolites (for example, codeine and hydrocodone, whose analgesic and antitussive effects appear to be mediated by morphine and hydromorphone, respectively), it may not be possible to achieve the desired clinical benefits in poor metabolizers. Quinidine is not metabolized by cytochrome P450IID6, but therapeutic serum levels of quinidine inhibit the action of cytochrome P450IID6, effectively converting extensive metabolizers into poor metabolizers. Caution must be exercised whenever quinidine is prescribed together with drugs metabolized by cytochrome P450IID6. Perhaps by competing for pathways of renal clearance, coadministration of quinidine causes an increase in serum levels of procainamide. Serum levels of haloperidol are increased when quinidine is coadministered. Presumably because both drugs are metabolized by cyctochrome P450IIIA4, coadministration of quinidine causes variable slowing of the metabolism of nifedipine. Interactions with other dihydropyridine calcium���channel blockers have not been reported, but these agents (including felodipine, nicardipine, and nimodipine) are all dependent upon P450IIIA4 for metabolism, so similar interactions with quinidine should be anticipated. Altered pharmacodynamics of other drugs: Quinidine's anticholinergic, vasodilating, and negative inotropic actions may be additive to those of other drugs with these effects, and antagonistic to those of drugs with cholinergic, vasoconstricting, and positive inotropic effects. For example, when quinidine and verapamil are coadministered in doses that are each well tolerated as monotherapy, hypotension attributable to additive peripheral�����blockade is sometimes reported. Quinidine potentiates the actions of depolarizing (succinylcholine, decamethonium) and nondepolarizing (d���tubocurarine, pancuronium) neuromuscular blocking agents. These phenomena are not well understood, but they are observed in animal models as well as in humans. In addition, in vitro addition of quinidine to the serum of pregnant women reduces the activity of pseudocholinesterase, an enzyme that is essential to the metabolism of succinylcholine. Diltiazem significantly decreases the clearance and increases the t��of quinidine, but quinidine does not alter the kinetics of diltiazem. Non���interactions of quinidine with other drugs: Quinidine has no clinically significant effect on the pharmacokinetics of diltiazem, flecainide, mephenytoin, metoprolol, propafenone, propranolol, quinine, timolol, or tocainide. Conversely, the pharmacokinetics of quinidine are not significantly affected by caffeine, ciprofloxacin, digoxin, felodipine, omeprazole, or quinine. Quinidine's pharmacokinetics are also unaffected by cigarette smoking.<br/>Carcinogenesis, mutagenesis, impairment of fertility: Animal studies to evaluate quinidine's carcinogenic or mutagenic potential have not been performed. Similarly, there are no animal data as to quinidine's potential to impair fertility.<br/>Pregnancy: Pregnancy Category C���Animal reproductive studies have not been conducted with quinidine. There are no adequate and well���controlled studies in pregnant women. Quinidine should be given to a pregnant woman only if clearly needed. In one neonate whose mother had received quinidine throughout her pregnancy, the serum level of quinidine was equal to that of the mother, with no apparent ill effect. The level of quinidine in amniotic fluid was about three times higher than that found in serum.<br/>Labor and Delivery: Quinine is said to be oxytocic in humans, but there are no adequate data as to quinidine's effect (if any) on human labor and delivery.<br/>Nursing mothers: Quinidine is present in human milk at levels slightly lower than those in maternal serum; a human infant ingesting such milk should (scaling directly by weight) be expected to develop serum quinidine levels at least an order of magnitude lower than those of the mother. On the other hand, the pharmacokinetics and pharmacodynamics of quinidine in human infants have not been adequately studied, and neonates' reduced protein binding of quinidine may increase their risk of toxicity at low total serum levels. Administration of quinidine should (if possible) be avoided in lactating women who continue to nurse.<br/>Pediatric use: In antimalarial trials, quinidine was as safe and effective in pediatric patients as in adults. Notwithstanding the known pharmacokinetic differences between pediatric patients and adults (see Pharmacokinetics and Metabolism), pediatric patients in these trials received the same doses (on a mg/kg basis) as adults. Safety and effectiveness of antiarrhythmic use in pediatric patients have not been established.<br/>Geriatric use: Safety and efficacy of quinidine in elderly patients has not been systematically studied. Clinical studies of quinidine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. The reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:253 | dailymed-instance:precautio... | General: Tachycardia and cardiac arrhythmias may occur with the use of phentolamine or other alpha-adrenergic blocking agents. When possible, administration of cardiac glycosides should be deferred until cardiac rhythm returns to normal.<br/>Drug Interactions: See DOSAGE AND ADMINISTRATION. Diagnosis of pheochromocytoma, Preparation.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term carcinogenicity studies, mutagenicity studies, and fertility studies have not been conducted with phentolamine.<br/>Pregnancy:<br/>Teratogenic Effects-Pregnancy Category C: Administration of phentolamine to pregnant rats and mice at oral doses 24 to 30 times the usual daily human dose (based on a 60 kg human) resulted in slightly decreased growth and slight skeletal immaturity of the fetuses. Immaturity was manifested by increased incidence of incomplete or unossified calcanei and phalangeal nuclei of the hind limb and of incompletely ossified sternebrae. At oral doses 60 times the usual daily human dose (based on a 60 kg human), a slightly lower rate of implantation was found in the rat. Phentolamine did not affect embryonic or fetal development in the rabbit at oral doses 20 times the usual daily human dose (based on a 60 kg human). No teratogenic or embryotoxic effects were observed in the rat, mouse, or rabbit studies. There are no adequate and well-controlled studies in pregnant women. Phentolamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from phentolamine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: See DOSAGE AND ADMINISTRATION. | lld:dailymed |
| dailymed-drugs:254 | dailymed-instance:precautio... | General: Wound healing may be delayed with the use of flurbiprofen sodium ophthalmic solution. It is recommended that flurbiprofen sodium ophthalmic solution be used with caution in surgical patients with known bleeding tendencies or who are receiving other medications which may prolong bleeding time.<br/>Drug Interactions: Interaction of flurbiprofen sodium ophthalmic solution with other topical ophthalmic medications has not been fully investigated. Although clinical studies with acetylcholine chloride and animal studies with acetylcholine chloride or carbachol revealed no interference, and there is no known pharmacological basis for an interaction, there have been reports that acetylcholine chloride and carbachol have been ineffective when used in patients treated with flurbiprofen sodium ophthalmic solution.<br/>Carcinogenesis, mutagenesis, impairment of fertility: Long-term studies in mice and/or rats have shown no evidence of carcinogenicity or impairment of fertility with flurbiprofen. Long-term mutagenicity studies in animals have not been performed.<br/>Pregnancy: Pregnancy Category C. Flurbiprofen has been shown to be embryocidal, delay parturition, prolong gestation, reduce weight, and/or slightly retard growth of fetuses when given to rats in daily oral doses of 0.4 mg/kg (approximately 67 times the human daily topical dose) and above. There are no adequate and well-controlled studies in pregnant women. Flurbiprofen sodium ophthalmic solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from flurbiprofen sodium, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric use: Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric use: No overall differences in safety or effectiveness have been observed between elderly and younger patients | lld:dailymed |
| dailymed-drugs:257 | dailymed-instance:precautio... | General: Severe hypotension, particularly with upright posture, may occur with even small doses of isosorbide dinitrate. This drug should therefore be used with caution in patients who may be volume depleted or who, for whatever reason, are already hypotensive. Hypotension induced by isosorbide dinitrate may be accompanied by paradoxical bradycardia and increased angina pectoris. Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy. As tolerance to isosorbide dinitrate develops, the effect of sublingual nitroglycerin on exercise tolerance, although still observable, is somewhat blunted. Some clinical trials in angina patients have provided nitroglycerin for about 12 continuous hours of every 24-hour day. During the daily dose-free intervals in some of these trials, anginal attacks have been more easily provoked than before treatment, and patients have demonstrated hemodynamic rebound and decreased exercise tolerance. The importance of these observations to the routine, clinical use of controlled-release oral isosorbide dinitrate is not known. In industrial workers who have had long-term exposure to unknown (presumable high) doses of organic nitrates, tolerance clearly occurs. Chest pain, acute myocardial infarction, and even sudden death have occurred during temporary withdrawal of nitrates from these workers, demonstrating the existence of true physical dependence. Information for Patients: Patients should be told that the anti-anginal efficacy of isosorbide dinitrate is strongly related to its dosing regimen, so the prescribed schedule of dosing should be followed carefully. In particular, daily headaches sometimes accompany treatment with isosorbide dinitrate. In patients who get these headaches, the headaches are a marker of the activity of the drug. Patients should resist the temptation to avoid headaches by altering the schedule of their treatment with isosorbide dinitrate, since loss of headache may be associated with simultaneous loss of anti-anginal efficacy. Aspirin and/or acetaminophen, on the other hand, often successfully relieve isosorbide dinitrate-induced headaches with no deleterious effect on isosorbide dinitrate's antianginal efficacy. Treatment with isosorbide dinitrate may be associated with lightheadedness on standing, especially just after rising from a recumbent or seated position. This effect may be more frequent in patients who have also consumed alcohol. Drug Interactions: The vasodilating effects of isosorbide dinitrate may be additive with those of other vasodilators. Alcohol, in particular, has been found to exhibit additive effects of this variety. Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term studies in animals have been performed to evaluate the carcinogenic potential of isosorbide dinitrate. In a modified two���litter reproduction study, there was no remarkable gross pathology and no altered fertility or gestation among rats fed isosorbide dinitrate at 25 or 100 mg/kg/day. Pregnancy Category C: At oral doses 35 and 150 times the maximum recommended human daily dose, isosorbide dinitrate has been shown to cause a dose-related increase in embryotoxicity (increase in mummified pups) in rabbits. There are no adequate, well-controlled studies in pregnant women. Isosorbide dinitrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known whether isosorbide dinitrate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when isosorbide dinitrate is administered to a nursing woman. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Geriatric Use: Clinical studies of isosorbide dinitrate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:258 | dailymed-instance:precautio... | General:<br/>Activation of Mania/Hypomania-: During premarketing testing, hypomania or mania occurred in approximately 0.4% of sertraline hydrochloride tablets treated patients.<br/>Weight Loss-: Significant weight loss may be an undesirable result of treatment with sertraline for some patients, but on average, patients in controlled trials had minimal, 1 to 2 pound weight loss, versus smaller changes on placebo. Only rarely have sertraline patients been discontinued for weight loss.<br/>Seizure-: Sertraline hydrochloride tablets have not been evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product's premarket testing. No seizures were observed among approximately 3000 patients treated with sertraline hydrochloride tablets in the development program for major depressive disorder. However, 4 patients out of approximately 1800 (220<18 years of age) exposed during the development program for another disorder, experienced seizures representing a crude incidence of 0.2%. Three of these patients were adolescents, two with a seizure disorder and one with a family history of seizure disorder, none of whom were receiving anticonvulsant medication. Accordingly, sertraline hydrochloride tablets should be introduced with care in patientswith a seizure disorder.<br/>Discontinuation of Treatment with Sertraline Hydrochloride Tablets: During marketing of sertraline hydrochloride tablets and other SSRIs and SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with sertraline hydrochloride tablets. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate .<br/>Abnormal Bleeding: SSRIs and SNRIs, including sertraline hydrochloride tablets, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of sertraline hydrochloride tablets and NSAIDs, aspirin, or other drugs that affect coagulation.<br/>Weak Uricosuric Effect-: Sertraline hydrochloride tablets are associated with a mean decrease in serum uric acid of approximately 7%. The clinical significance of this weak uricosuric effect is unknown.<br/>Use in Patients with Concomitant Illness-: Clinical experience with sertraline hydrochloride tablets in patients with certain concomitant systemic illness is limited. Caution is advisable in using sertraline hydrochloride tablets in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Patients with a recent history of myocardial infarction or unstable heart disease were excluded from clinical studies during the product's premarket testing. However, the electrocardiograms of 774 patients who received sertraline hydrochloride tablets in double-blind trials were evaluated and the data indicate that sertraline hydrochloride tablet is not associated with the development of significant ECG abnormalities. Sertraline hydrochloride tablets administered in a flexible dose range of 50 to 200 mg/day (mean dose of 89 mg/day) were evaluated in a post-marketing, placebo-controlled trial of 372 randomized subjects with a DSM-IV diagnosis of major depressive disorder and recent history of myocardial infarction or unstable angina requiring hospitalization. Exclusions from this trial included, among others, patients with uncontrolled hypertension, need for cardiac surgery, history of CABG within 3 months of index event, severe or symptomatic bradycardia, non-atherosclerotic cause of angina, clinically significant renal impairment (creatinine>2.5 mg/dl), and clinically significant hepatic dysfunction. Sertraline hydrochloride tablet treatment initiated during the acute phase of recovery (within 30 days post-MI or post-hospitalization for unstable angina) was indistinguishable from placebo in this study on the following week 16 treatment endpoints: left ventricular ejection fraction, total cardiovascular events (angina, chest pain, edema, palpitations, syncope, postural dizziness, CHF, MI, tachycardia, bradycardia, and changes in BP), and major cardiovascular events involving death or requiring hospitalization (for MI, CHF, stroke, or angina). Sertraline hydrochloride tablets are extensively metabolized by the liver. In patients with chronic mild liver impairment, sertraline clearance was reduced, resulting in increased AUC, Cand elimination half-life. The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied. The use of sertraline in patients with liver disease must be approached with caution. If sertraline is administered to patients with liver impairment, a lower or less frequent dose should be used . Since sertraline hydrochloride tablets are extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. A clinical study comparing sertraline pharmacokinetics in healthy volunteers to that in patients with renal impairment ranging from mild to severe (requiring dialysis) indicated that the pharmacokinetics and protein binding are unaffected by renal disease. Based on the pharmacokinetic results, there is no need for dosage adjustment in patients with renal impairment .<br/>Interference with Cognitive and Motor Performance-: In controlled studies, sertraline hydrochloride tablet did not cause sedation and did not interfere with psychomotor performance (see Information for Patients ).<br/>Hyponatremia���: Several cases of hyponatremia have been reported and appeared to be reversible when sertraline hydrochloride tablet was discontinued. Some cases were possibly due to the syndrome of inappropriate antidiuretic hormone secretion. The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume depleted.<br/>Platelet Function-: There has been rare reports of altered platelet function and/or abnormal results from laboratory studies in patients taking sertraline hydrochloride tablets. While there have been reports of abnormal bleeding or purpura in several patients taking sertraline hydrochloride tablets, it is unclear whether sertraline hydrochloride tablets had a causative role.<br/>Information for Patients: Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with sertraline hydrochloride tablets and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions" is available for sertraline hydrochloride tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking sertraline hydrochloride tablets.<br/>Clinical Worsening and Suicide Risk:: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Patients should be told that although sertraline hydrochloride tablets have not been shown to impair the ability of normal subjects to perform tasks requiring complex motor and mental skills in laboratory experiments, drugs that act upon the central nervous system may affect some individuals adversely. Therefore, patients should be told that until they learn how they respond to sertraline hydrochloride tablets they should be careful doing activities when they need to be alert, such as driving a car or operating machinery. Patients should be cautioned about the concomitant use of sertraline hydrochloride tablets and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding. Patients should be told that although sertraline hydrochloride tablets have not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of sertraline hydrochloride tablets and alcohol is not advised. Patients should be told that while no adverse interaction of sertraline hydrochloride tablets with over-the-counter (OTC) drug products is known to occur, the potential for interaction exists. Thus, the use of any OTC product should be initiated cautiously according to the directions of use given for the OTC product. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physician if they are breast feeding an infant.<br/>Laboratory Tests: None.<br/>Drug Interactions:<br/>Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins-: Because sertraline is tightly bound to plasma protein, the administration of sertraline hydrochloride tablets to a patient taking another drug which is tightly bound to protein (e.g., warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein bound sertraline hydrochloride tablets by other tightly bound drugs. In a study comparing prothrombin time AUC (0-120 hr) following dosing with warfarin (0.75 mg/kg) before and after 21 days of dosing with either sertraline hydrochloride tablets (50-200 mg/day) or placebo, there was a mean increase in prothrombin time of 8% relative to baseline for sertraline hydrochloride tablets compared to a 1% decrease for placebo (p<0.02). The normalization of prothrombin time for the sertraline hydrochloride tablets group was delayed compared to the placebo group. The clinical significance of this change is unknown. Accordingly, prothrombin time should be carefully monitored when sertraline hydrochloride tablets therapy is initiated or stopped.<br/>Cimetidine-: In a study assessing disposition of sertraline hydrochloride tablets (100 mg) on the second of 8 days of cimetidine administration (800 mg daily), there were significant increases in sertraline hydrochloride tablets mean AUC (50%), C(24%) and half-life (26%) compared to the placebo group. The clinical significance of these changes is unknown.<br/>CNS Active Drugs-: In a study comparing the disposition of intravenously administered diazepam before and after 21 days of dosing with either sertraline hydrochloride tablets (50 to 200 mg/day escalating dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the sertraline hydrochloride tablets group compared to a 19% decrease relative to baseline for the placebo group (p<0.03). There was a 23% increase in Tfor desmethyldiazepam in the sertraline hydrochloride tablets group compared to a 20% decrease in the placebo group (p<0.03). The clinical significance of these changes is unknown. In a placebo-controlled trial in normal volunteers, the administration of two doses of sertraline hydrochloride tablets did not significantly alter steady-state lithium levels or the renal clearance of lithium. Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following initiation of sertraline hydrochloride tablets therapy with appropriate adjustments to the lithium dose. In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.) co-administration to steady state was associated with a mean increase in pimozide AUC and Cof about 40%, but was not associated with any changes in EKG. Since the highest recommended pimozide dose (10 mg) has not been evaluated in combination with sertraline, the effect on QT interval and PK parameters at doses higher than 2 mg at this time are not known. While the mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide and due to the interaction noted at a low dose of pimozide, concomitant administration of sertraline hydrochloride tablets and pimozide should be contraindicated . Results of a placebo-controlled trial in normal volunteers suggest that chronic administration of sertraline 200 mg/day does not produce clinically important inhibition of phenytoin metabolism. Nonetheless, at this time, it is recommended that plasma phenytoin concentrations be monitored following initiation of sertraline hydrochloride tablets therapy with appropriate adjustments to the phenytoin dose, particularly in patients with multiple underlying medical conditions and/or those receiving multiple concomitant medications. The effect of sertraline on valproate levels has not been evaluated in clinical trials. In the absence of such data, it is recommended that plasma valproate levels be monitered following initiation of sertraline hydrochloride tablets therapy with appropriate adjustments to the valproate dose. The risk of using sertraline hydrochloride tablets in combination with other CNS active drugs has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of sertraline hydrochloride tablets and such drugs is required. There is limited controlled experience regarding the optimal timing of switching from other drugs effective in the treatment of major depressive disorder to sertraline. Care and prudent medical judgment should be exercised when switching, particularly from long-acting agents. The duration of an appropriate washout period which should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to another has not been established.<br/>Monoamine Oxidase Inhibitors-: See CONTRAINDICATIONS and WARNINGS.<br/>Drugs Metabolized by P450 3A4-: In three separate in vivo interaction studies, sertraline was co-administered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride under steady-state conditions. The results of these studies indicated that sertraline did not increase plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate that sertraline's extent of inhibition of P450 3A4 activity is not likely to be of clinical significance. Results of the interaction study with cisapride indicate that sertraline 200 mg (q.d.) induces the metabolism of cisapride (cisapride AUC and Cwere reduced by about 35%).<br/>Drugs Metabolized by P450 2D6-: Many drugs effective in the treatment of major depressive disorder, e.g., the SSRIs, including sertraline, and most tricyclic antidepressant drugs effective in the treatment of major depressive disorder inhibit the biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase), and, thus, may increase the plasma concentrations of co-administered drugs that are metabolized by P450 2D6. The drugs for which this potential interaction is of greatest concern are those metabolized primarily by 2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressant drugs effective in the treatment of major depressive disorder and the Type 1C antiarrhythmics propafenone and flecainide. The extent to which this interaction is animportant clinical problem depends on the extent of the inhibition of P450 2D6 by the antidepressant and the therapeutic index of the co-administered drug. There is variability among the drugs effective in the treatment of major depressive disorder in the extent of clinically important 2D6 inhibition, and in fact sertraline at lower doses has a less prominent inhibitory effect on 2D6 than some others in the class. Nevertheless, even sertraline has the potential for clinically important 2D6 inhibition. Consequently, concomitant use of a drug metabolized by P450 2D6 with sertraline hydrochloride tablets may require lower doses than usually prescribed for the other drug. Furthermore, whenever sertraline hydrochloride tablet is withdrawn from co-therapy, an increased dose of the co-administered drug may be required (see Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder under PRECAUTIONS ).<br/>Serotonergic Drugs-: Based on the mechanism of actions of SNRIs and SSRIs, including sertraline hydrochloride, and the potential for serotonin syndrome, caution is advised when SNRIs and SSRIs, including sertraline hydrochloride, are coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John's Wort . The concomitant use of sertraline hydrochloride with other SSRIs and SNRIs or tryptophan is not recommended .<br/>Triptans-: There have been rare postmarketing reports of serotonin syndrome with use of an SNRI or an SSRI and a triptan. If concomitant treatment of SNRIs and SSRIs, including sertraline hydrochloride, with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases .<br/>Sumatriptan-: There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised.<br/>Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder (TCAs)-: The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with sertraline hydrochloride tablets, because sertraline may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is co-administered with sertraline hydrochloride tablets (see Drugs Metabolized by P450 2D6 under PRECAUTIONS ).<br/>Hypoglycemic Drugs-: In a placebo-controlled trial in normal volunteers, administration of sertraline hydrochloride tablets for 22 days (including 200 mg/day for the final 13 days) caused a statistically significant 16% decrease from baseline in the clearance of tolbutamide following an intravenous 1000 mg dose. Sertraline hydrochloride tablets administration did not noticeably change either the plasma protein binding or the apparent volume of distribution of tolbutamide, suggesting that the decreased clearance was due to a change in the metabolism of the drug. The clinical significance of this decrease in tolbutamide clearance is unknown.<br/>Atenolol-: Sertraline hydrochloride tablets (100 mg) when administered to 10 healthy male subjects had no effect on the beta-adrenergic blocking ability of atenolol.<br/>Digoxin-: In a placebo-controlled trial in normal volunteers, administration of sertraline hydrochloride tablets for 17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or digoxin renal clearance.<br/>Microsomal Enzyme Induction-: Preclinical studies have shown sertraline hydrochloride tablets to induce hepatic microsomal enzymes. In clinical studies, sertraline hydrochloride tablet was shown to induce hepatic enzymes minimally as determined by a small (5%) but statistically significant decrease in antipyrine half-life following administration of 200 mg/day for 21 days. This small change in antipyrine half-life reflects a clinically insignificant change in hepatic metabolism.<br/>Drugs That Interfere With Hemostasis (Non-selective NSAIDs, Aspirin, Warfarin, etc.): Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent useof an NSAID or aspirin may potentiate this risk of bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when sertraline hydrochloride tablets is initiated or discontinued.<br/>Electroconvulsive Therapy-: There are no clinical studies establishing the risks or benefits of the combined use of electroconvulsive therapy (ECT) and sertraline hydrochloride tablets.<br/>Alcohol-: Although sertraline hydrochloride tablets did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of sertraline hydrochloride tablets and alcohol is not recommended.<br/>Carcinogenesis-: Lifetime carcinogenicity studies were carried out in CD-1 mice and Long-Evans rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and 2 times (rats) the maximum recommended human dose (MRHD) on a mg/mbasis. There was a dose-related increase of liver adenomas in male mice receiving sertraline at 10-40 mg/kg (0.25-1.0 times the MRHD on a mg/mbasis). No increase was seen in female mice or in rats of either sex receiving the same treatments, nor was there an increase in hepatocellular carcinomas. Liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse and are of unknown significance to humans. There was an increase in follicular adenomas of the thyroid in female rats receiving sertraline at 40 mg/kg (2 times the MRHD on a mg/mbasis); this was not accompanied by thyroid hyperplasia. While there was an increase in uterine adenocarcinomas in rats receiving sertraline at 10-40 mg/kg (0.5-2.0 times the MRHD on a mg/mbasis) compared to placebo controls, this effect was not clearly drug related.<br/>Mutagenesis-: Sertraline had no genotoxic effects, with or without metabolic activation, based on the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.<br/>Impairment of Fertility-: A decrease in fertility was seen in one of two rat studies at a dose of 80 mg/ kg (4 times the maximum recommended human dose on a mg/mbasis).<br/>Pregnancy-Pregnancy Category C-: Reproduction studies have been performed in rats and rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to approximately 4 times the maximum recommended human dose (MRHD) on a mg/mbasis. There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were given sertraline during the period of organogenesis, delayed ossification was observed in fetuses at doses of 10 mg/kg (0.5 times the MRHD on a mg/mbasis) in rats and 40 mg/kg (4 times the MRHD on a mg/mbasis) in rabbits. When female rats received sertraline during the last third of gestation and throughout lactation, there was an increase in the number of stillborn pups and in the number of pups dying during the first 4 days after birth. Pup body weights were also decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg (1 times the MRHD on a mg/mbasis). The no effect dose for rat pup mortality was 10 mg/kg (0.5 times the MRHD on a mg/mbasis). The decrease in pup survival was shown to be due to in utero exposure to sertraline. The clinical significance of these effects is unknown. There are no adequate and well-controlled studies in pregnant women. Sertraline hydrochloride tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Pregnancy-Nonteratogenic Effects-: Neonates exposed to sertraline hydrochloride tablets and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. These findings are based on postmarketing reports. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuationsyndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome . Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately sixfold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posedsimilar levels of PPHN risk. When treating a pregnant woman with sertraline hydrochloride tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment . Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic in the context of antidepressant therapy at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.<br/>Labor and Delivery-: The effect of sertraline hydrochloride tablets on labor and delivery in humans is unknown.<br/>Nursing Mothers-: It is not known whether, and if so in what amount, sertraline or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sertraline hydrochloride tablet is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in pediatric patients with major depressive disorder have not been established . Two placebo controlled trials (n=373) in pediatric patients with MDD have been conducted with sertraline, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of sertraline hydrochloride tablets in a child or adolescent must balance the potential risks with the clinical need. Sertraline pharmacokinetics were evaluated in a group of 61 pediatric patients between 6 and 17 years of age and revealed similar drug exposures to those of adults when plasma concentration was adjusted for weight . Approximately 600 pediatric patients between 6 and 17 years of age have received sertraline in clinical trials, both controlled and uncontrolled. The adverse event profile observed in these patients was generally similar to that observed in adult studies with sertraline hydrochloride tablets . As with other SSRIs, decreased appetite and weight loss have been observed in association with the use of sertraline hydrochloride tablets. In a pooled analysis of two 10-week, double-blind, placebo-controlled, flexible dose (50-200 mg) outpatient trials for major depressive disorder (n=373), there was a difference in weight change between sertraline and placebo of roughly 1 kilogram, for both children (ages 6-11) and adolescents (ages 12-17), in both cases representing a slight weight loss for sertraline compared to a slight gain for placebo. At baseline the mean weight for children was 39.0 kg for sertraline and 38.5 kg for placebo. At baseline the mean weight for adolescents was 61.4 kg for sertraline and 62.5 kg for placebo. There was a bigger difference between sertraline and placebo in the proportion of outliers for clinically important weight loss in children than in adolescents. For children, about 7% had a weight loss>7% of body weight compared to none of the placebo patients; for adolescents, about 2% had a weight loss>7% of body weight compared to about 1% of the placebo patients. A subset of these patients who completed the randomized controlled trials (sertraline n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label, extension study. A mean weight loss of approximately 0.5 kg was seen during the first eight weeks of treatment for subjects with first exposure to sertraline during the open-label extension study, similar to mean weight loss observed among sertraline treated subjects during the first eight weeks of the randomized controlled trials. The subjects continuing in the open label study began gaining weightcompared to baseline by week 12 of sertraline treatment. Those subjects who completed 34 weeks of sertraline treatment (10 weeks in a placebo controlled trial + 24 weeks open label, n=68), had weight gain that was similar to that expected using data from age-adjusted peers. Regular monitoring of weight and growth is recommended if treatment of a pediatric patient with an SSRI is to be continued long term. Safety and effectiveness in pediatric patients with major depressive disorder have not been established. The risks, if any, that may be associated with sertraline's use beyond 1 year in children and adolescents have not been systematically assessed. The prescriber should be mindful that the evidence relied upon to conclude that sertraline is safe for use in children and adolescents derives from clinical studies that were 10 to 52 weeks in duration and from the extrapolation of experience gained with adult patients. In particular, there are no studies that directly evaluate the effectsof long-term sertraline use on the growth, development, and maturation of children and adolescents. Although there is no affirmative finding to suggest that sertraline possesses a capacity to adversely affect growth, development or maturation, the absence of such findings is not compelling evidence of the absence of the potential of sertraline to have adverse effects in chronic use (see WARNINGS - Clinical Worsening and Suicide Risk ).<br/>Geriatric Use-: U.S. geriatric clinical studies of sertraline hydrochloride tablets in major depressive disorder included 663 sertraline hydrochloride tablets-treated subjects (65 years of age, of those, 180 were (75 years of age. No overall differences in the pattern of adverse reactions were observed in the geriatric clinical trial subjects relative to those reported in younger subjects (see ADVERSE REACTIONS ), and other reported experience has not identified differences in safety patterns between the elderly and younger subjects. As with all medications, greater sensitivity of some older individuals cannot be ruled out. There were 947 subjects in placebo-controlled geriatric clinical studies of sertraline hydrochloride tablets in major depressive disorder. No overall differences inthe pattern of efficacy were observed in the geriatric clinical trial subjects relative to those reported in younger subjects. Other Adverse Events in Geriatric Patients. In 354 geriatric subjects treated with sertraline hydrochloride tablets in placebo-controlled trials, the overall profile of adverse events was generally similar to that shown in Tables 1 and 2. Urinary tract infection was the only adverse event not appearing in Tables 1 and 2 and reported at an incidence of at least2% and at a rate greater than placebo in placebo-controlled trials. As with other SSRIs, sertraline hydrochloride tablets have been associated with cases of clinically significant hyponatremia in elderly patients . | lld:dailymed |
| dailymed-drugs:259 | dailymed-instance:precautio... | General: Diagnostic procedures which involve the use of iodinated intra-vascular contrast agents should be carried out under the direction of personnel skilled and experienced in the particular procedure to be performed. All procedures utilizing contrast media carry a definite risk of producing adverse reactions. While most reactions may be minor, life threatening and fatal reactions may occur without warning. The risk-benefit factor should always be carefully evaluated before such a procedure is undertaken. A fully equipped emergency cart, or equivalent supplies and equipment, and personnel competent in recognizing and treating adverse reactions of all severity, or situations which may arise as a result of the procedure, should be immediately available at all times. If a serious reaction should occur, immediately discontinue administration. Since severe delayed reactions have been known to occur, emergency facilities and competent personnel should be available for at least 30 to 60 minutes after administration . Preparatory dehydration is dangerous and may contribute to acute renal failure in infants, young children, the elderly, patients with pre-existing renal insufficiency, patients with advanced vascular disease and diabetic patients. Severe reactions to contrast media often resemble allergic responses. This has prompted the use of several provocative pretesting methods, none of which can be relied on to predict severe reactions. No conclusive relationship between severe reactions and antigen-antibody reactions or other manifestations of allergy has been established. The possibility of an idiosyncratic reaction in patients who havepreviously received a contrast medium without ill effect should always be considered. Prior to the injection of any contrast medium, the patient should be questioned to obtain a medical history with emphasis on allergy and hypersensitivity. A positive history of bronchial asthma or allergy, including food, a family history of allergy, or a previous reaction or hypersensitivity to a contrast agent, may imply a greater than usual risk. Such a history, by suggesting histamine sensitivity and consequently proneness to reactions, may be more accurate than pre-testing in predicting the potential for reaction, although not necessarily the severity or type of reaction in the individual case. A positive history of this type does not arbitrarily contraindicate the use of a contrast agent, when a diagnostic procedure is thought essential, but does call for caution. . Prophylactic therapy including corticosteroids and antihistamines should be considered for patients who present with a strong allergic history, a previous reaction to a contrast medium, or a positive pretest, since the incidence of reaction in these patients is two to three times that of the general population. Adequate doses of corticosteroids should be started early enough prior to contrast medium injection to be effective and should continue through the time of injection and for 24 hours after injection. Antihistamines should be administered within 30 minutes of the contrast medium injection. Recent reports indicate that such pre-treatment does not prevent serious life-threatening reactions, but may reduce both their incidence and severity. A separate syringe should be used for these injections. General anesthesia may be indicated in the performance of some procedures in young or uncooperative children and in selected adult patients; however, a higher incidence of adverse reactions has been reported in these patients. This may be attributable to the inability of the patient to identify untoward symptoms, or to thehypotensive effect of anesthesia, which can prolong the circulation time and increase the duration of contact of the contrast agent. Angiography should be avoided whenever possible in patients with homocystinuria because of the risk of inducing thrombosis and embolism. Information for Patients: Patients receiving iodinated intravascular contrast agents should be instructed to: Carcinogenesis, Mutagenesis, Impairment of Fertility���No long-term animal studies have been performed to evaluate carcinogenic potential. However, animal studies suggest that this drug is not mutagenic and does not affect fertility in males or females. Pregnancy Category B���Reproduction studies have been performed in mice, rats, and rabbits at doses up to 6.6 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to CONRAY. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers���Iothalamate salts are excreted unchanged in human milk. Because of the potential for adverse effects in nursing infants, bottle feedings should be substituted for breast feedings for 24 hours following the administration of this drug. (Precautions for specific procedures receive comment under that procedure.) | lld:dailymed |
| dailymed-drugs:260 | dailymed-instance:precautio... | General:: As with other antibiotic preparations, use of this drug may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, the antibiotic should be discontinued and appropriate therapy instituted. Bulging fontanels in infants and benign intracranial hypertension in adults have been reported in individuals receiving tetracyclines. These conditions disappeared when the drug was discontinued. Incision and drainage or other surgical procedures should be performed in conjunction with antibiotic therapy, when indicated. Doxycycline offers substantial but not complete suppression of the asexual blood stages of Plasmodium strains. Doxycycline does not suppress P. falciparum's sexual blood stage gametocytes. Subjects completing this prophylactic regimen may still transmit the infection to mosquitoes outside endemic areas. Prescribing DORYX in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.<br/>Information for Patients:: Patients taking doxycycline for malaria prophylaxis should be advised: All patients taking doxycycline should be advised: Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Patients should be counseled that antibacterial drugs including DORYX should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When DORYX is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by DORYX or other antibacterial drugs in the future.<br/>Laboratory tests: In venereal disease when coexistent syphilis is suspected, dark-field examination should be done before treatment is started and the blood serology repeated monthly for at least 4 months. In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal and hepatic studies should be performed.<br/>Drug interactions: Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, and iron-containing preparations. Absorption of tetracyclines is impaired by bismuth subsalicylate. Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. The concurrent use of tetracycline and Penthrane (methoxyflurane) has been reported to result in fatal renal toxicity. Concurrent use of tetracycline may render oral contraceptives less effective.<br/>Drug/Laboratory Test Interaction: False elevations of urinary catecholamines may occur due to interference with the fluorescence test.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals to evaluate carcinogenic potential of doxycycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibiotics, oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors). Likewise, although mutagenicity studies of doxycycline have not been conducted, positive results in in vitro mammalian cell assays have been reported for related antibiotics (tetracycline, oxytetracycline). Doxycycline administered orally at dosage levels as high as 250 mg/kg/day had no apparent effect on the fertility of female rats. Effect on male fertility has not been studied.<br/>Pregnancy:<br/>Teratogenic Effects. Pregnancy Category D:: There are no adequate and well-controlled studies on the use of doxycycline in pregnant women. The vast majority of reported experience with doxycycline during human pregnancy is short-term, first trimester exposure. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women such as that proposed for the treatment of anthrax exposure. An expert review of published data on experiences with doxycycline use during pregnancy by TERIS - the Teratogen Information System - concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as limited to fair), but the data are insufficient to state that there is no risk. A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. Sixty-three (0.19%) of the controls and 56 (0.30%) of the cases were treated with doxycycline. This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (i.e., in the second and third months of gestation) with the exception of a marginal relationship with neural tube defect based on only two exposed cases. A small prospective study of 81 pregnancies describes 43 pregnant women treated for 10 days with doxycycline during early first trimester. All mothers reported their exposed infants were normal at 1 year of age.<br/>Nonteratogenic effects:: .<br/>Labor and Delivery: The effect of tetracyclines on labor and delivery is unknown.<br/>Nursing Mothers: Tetracyclines are excreted in human milk, however, the extent of absorption of tetracyclines including doxycycline, by the breastfed infant is not known. Short-term use by lactating women is not necessarily contraindicated; however, the effects of prolonged exposure to doxycycline in breast milk are unknown. Because of the potential for serious adverse reactions in nursing infants from doxycycline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric use: See WARNINGS and DOSAGE AND ADMINISTRATION.<br/>Geriatric use: Clinical studies with DORYX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of the decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:262 | dailymed-instance:precautio... | General: Prescribing sulfamethoxazole and trimethoprim tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Sulfamethoxazole and trimethoprim should be given with caution to patients with impaired renal or hepatic function, to those with possible folate deficiency (e.g., the elderly, chronic alcoholics, patients receiving anticonvulsant therapy, patients with malabsorption syndrome, and patients in malnutrition states) and to those with severe allergies or bronchial asthma. In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is frequently dose-related. . Cases of hypoglycemia in non-diabetic patients treated with sulfamethoxazole and trimethoprim are seen rarely, usually occurring after a few days of therapy. Patients with renal dysfunction, liver disease, malnutrition or those receiving high doses of sulfamethoxazole and trimethoprim are particularly at risk. Hematological changes indicative of folic acid deficiency may occur in elderly patients or in patients with preexisting folic acid deficiency or kidney failure. These effects are reversible by folinic acid therapy. Trimethoprim has been noted to impair phenylalanine metabolism but this is of no significance in phenylketonuric patients on appropriate dietary restriction. As with all drugs containing sulfonamides, caution is advisable in patients with porphyria or thyroid dysfunction.<br/>Use in the Treatment of and Prophylaxis for Pneumocystis Carinii Pneumonia in Patients with Acquired Immunodeficiency Syndrome (AIDS): AIDS patients may not tolerate or respond to sulfamethoxazole and trimethoprim in the same manner as non-AIDS patients. The incidence of side effects, particularly rash, fever, leukopenia and elevated aminotransferase (transaminase) values, with sulfamethoxazole and trimethoprim therapy in AIDS patients who are being treated for Pneumocystis carinii pneumonia has been reported to be greatly increased compared with the incidence normally associated with the use of sulfamethoxazole and trimethoprim in non-AIDS patients. The incidence of hyperkalemia appears to be increased in AIDS patients receiving sulfamethoxazole and trimethoprim. Adverse effects are generally less severe in patients receiving sulfamethoxazole and trimethoprim for prophylaxis. A history of mild intolerance to sulfamethoxazole and trimethoprim in AIDS patients does not appear to predict intolerance of subsequent secondary prophylaxis.However, if a patient develops skin rash or any sign of adverse reaction, therapy with sulfamethoxazole and trimethoprim should be reevaluated . High dosage of trimethoprim, as used in patients with Pneumocystis carinii pneumonia, induces a progressive but reversible increase of serum potassium concentrations in a substantial number of patients. Even treatment with recommended doses may cause hyperkalemia when trimethoprim is administered to patients with underlying disorders of potassium metabolism, with renal insufficiency, or if drugs known to induce hyperkalemia are given concomitantly. Close monitoring of serum potassium is warranted in these patients. During treatment, adequate fluid intake and urinary output should be ensured to prevent crystalluria. Patients who are���slow acetylators���may be more prone to idiosyncratic reactions to sulfonamides.<br/>Information for Patients: Patients should be counseled that antibacterial drugs including sulfamethoxazole and trimethoprim tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When sulfamethoxazole and trimethoprim tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by sulfamethoxazole and trimethoprim tablets or other antibacterial drugs in the future. Patients should be instructed to maintain an adequate fluid intake in order to prevent crystalluria and stone formation. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.<br/>Laboratory Tests: Complete blood counts should be done frequently in patients receiving sulfamethoxazole and trimethoprim; if a significant reduction in the count of any formed blood element is noted, sulfamethoxazole and trimethoprim should be discontinued. Urinalyses with careful microscopic examination and renal function tests should be performed during therapy, particularly for those patients with impaired renal function.<br/>Drug Interactions: In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. It has been reported that sulfamethoxazole and trimethoprim may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin. This interaction should be kept in mind when sulfamethoxazole and trimethoprim is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed. Sulfamethoxazole and trimethoprim may inhibit the hepatic metabolism of phenytoin. Sulfamethoxazole and trimethoprim, given at a common clinical dosage, increased the phenytoin half-life by 39% and decreased the phenytoin metabolic clearance rate by 27%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect. Sulfonamides can also displace methotrexate from plasma protein binding sites and can compete with the renal transport of methotrexate, thus increasing free methotrexate concentrations. There have been reports of marked but reversible nephrotoxicity with coadministration of sulfamethoxazole and trimethoprim and cyclosporine in renal transplant recipients. Increased digoxin blood levels can occur with concomitant sulfamethoxazole and trimethoprim therapy, especially in elderly patients. Serum digoxin levels should be monitored. Increased sulfamethoxazole blood levels may occur in patients who are receiving indomethacin. Occasional reports suggest that patients receiving pyrimethamine as malaria prophylaxis in doses exceeding 25 mg weekly may develop megaloblastic anemia if sulfamethoxazole and trimethoprim is prescribed. The efficacy of tricyclic antidepressants can decrease when co-administered with sulfamethoxazole and trimethoprim. Like other sulfonamide-containing drugs, sulfamethoxazole and trimethoprim potentiates the effect of oral hypoglycemics. In the literature, a single case of toxic delirium has been reported after concomitant intake of trimethoprim/sulfamethoxazole and amantadine. In the literature, three cases of hyperkalemia in elderly patients have been reported after concomitant intake of trimethoprim/sulfamethoxazole and an angiotensin converting enzyme inhibitor.<br/>Drug/Laboratory Test Interactions: Sulfamethoxazole and trimethoprim, specifically the trimethoprim component, can interfere with a serum methotrexate assay as determined by the competitive binding protein technique (CBPA) when a bacterial dihydrofolate reductase is used as the binding protein. No interference occurs, however, if methotrexate is measured by a radioimmunoassay (RIA). The presence of sulfamethoxazole and trimethoprim may also interfere with the Jaff��alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis: Long-term studies in animals to evaluate carcinogenic potential have not been conducted with sulfamethoxazole and trimethoprim.<br/>Mutagenesis: Bacterial mutagenic studies have not been performed with sulfamethoxazole and trimethoprim in combination. Trimethoprim was demonstrated to be nonmutagenic in the Ames assay. No chromosomal damage was observed in human leukocytes In vitro with sulfamethoxazole and trimethoprim alone or in combination; the concentrations used exceeded blood levels of these compounds following therapy with sulfamethoxazole and trimethoprim. Observations of leukocytes obtained from patients treated with sulfamethoxazole and trimethoprim revealed no chromosomal abnormalities.<br/>Impairment of Fertility: No adverse effects on fertility or general reproductive performance were observed in rats given oral dosages as high as 350 mg/kg/day sulfamethoxazole plus 70 mg/kg/day trimethoprim.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nonteratogenic Effects: See CONTRAINDICATIONSsection.<br/>Nursing Mothers: See CONTRAINDICATIONSsection.<br/>Pediatric Use: Sulfamethoxazole and trimethoprim is not recommended for infants younger than 2 months of age .<br/>Geriatric Use: Clinical studies of sulfamethoxazole and trimethoprim did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. There may be an increased risk of severe adverse reactions in elderly patients, particularly when complicating conditions exist, e.g., impaired kidney and/or liver function, possible folate deficiency, or concomitant use of other drugs. Severe skin reactions, generalized bone marrow suppression , a specific decrease in platelets (with or without purpura), and hyperkalemia are the most frequently reported severe adverse reactions in elderly patients. In those concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. Increased digoxin blood levels can occur with concomitant sulfamethoxazole and trimethoprim therapy, especially in elderly patients. Serum digoxin levels should be monitored. Hematological changes indicative of folic acid deficiency may occur in elderly patients. These effects are reversible by folinic acid therapy. Appropriate dosage adjustments should be made for patients with impaired kidney function and duration of use should be as short as possible to minimize risks of undesired reactions . The trimethoprim component of sulfamethoxazole and trimethoprim may cause hyperkalemia when administeredto patients with underlying disorders of potassium metabolism, with renal insufficiency or when given concomitantly with drugs known to induce hyperkalemia, such as angiotensin converting enzyme inhibitors. Close monitoring of serum potassium is warranted in these patients. Discontinuation of sulfamethoxazole and trimethoprim treatment is recommended to help lower potassium serum levels. Sulfamethoxazole and Trimethoprim DS Tablets contain 3.6 mg (0.16 mEq) of sodium per tablet. Pharmacokinetics parameters for sulfamethoxazole were similar for geriatric subjects and younger adult subjects. The mean maximum serum trimethoprim concentration was higher and mean renal clearance of trimethoprim was lower in geriatric subjects compared with younger subjects . | lld:dailymed |
| dailymed-drugs:263 | dailymed-instance:precautio... | General:<br/>Cardiovascular Effects: No effect on the cardiovascular system is usually seen after the administration of inhaled salmeterol at recommended doses, but the cardiovascular and central nervous system effects seen with all sympathomimetic drugs (e.g., increased blood pressure, heart rate, excitement) can occur after use of salmeterol and may require discontinuation of SEREVENT DISKUS. SEREVENT DISKUS, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders or thyrotoxicosis; and in patients who are unusually responsive to sympathomimetic amines. As has been described with other beta-adrenergic agonist bronchodilators, clinically significant changes in systolic and/or diastolic blood pressure, pulse rate, and ECGs have been seen infrequently in individual patients in controlled clinical studies with salmeterol.<br/>Metabolic Effects: Doses of the related beta-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. Beta-adrenergic agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant changes in blood glucose and/or serum potassium were seen rarely during clinical studies with long-term administration of SEREVENT DISKUS at recommended doses.<br/>Information for Patients: Patients should be instructed to read the accompanying Medication Guide with each new prescription and refill. The complete text of the Medication Guide is reprinted at the end of this document. Patients being treated with SEREVENT DISKUS should receive the following information and instructions. This information is intended to aid them in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. It is important that patients understand how to use the DISKUS appropriately and how to use SEREVENT DISKUS in relation to other asthma or COPD medications they are taking. Patients should be given the following information:<br/>Drug Interactions:<br/>Inhibitors of Cytochrome P450 3A4:: In a drug interaction study in 20 healthy subjects, coadministration of salmeterol (50 mcg twice daily) and ketoconazole (400 mg once daily) for 7 days resulted in greater systemic exposure to salmeterol (AUC increased 16-fold and Cincreased 1.4-fold). Three (3) subjects were withdrawn due to beta-agonist side effects (2 with prolonged QTc and 1 with palpitations and sinus tachycardia). Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration. Due to the potential increased risk of cardiovascular adverse events, theconcomitant use of salmeterol with strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) is not recommended.<br/>Short-Acting Beta-Agonists: In two 12-week, repetitive-dose adolescent and adult clinical trials in patients with asthma (N = 149), the mean daily need for additional beta-agonist in patients using SEREVENT DISKUS was approximately 1��inhalations/day. Twenty-six percent (26%) of the patients in these trials used between 8 and 24 inhalations of short-acting beta-agonist per day on 1 or more occasions. Nine percent (9%) of the patients in these trials averaged over 4 inhalations/day over the course of the 12-week trials. No increase in frequency of cardiovascular events was observedamong the 3 patients who averaged 8 to 11 inhalations/day; however, the safety of concomitant use of more than 8 inhalations/day of short-acting beta-agonist with SEREVENT DISKUS has not been established. In 29 patients who experienced worsening of asthma while receiving SEREVENT DISKUS during these trials, albuterol therapy administered via either nebulizer or inhalation aerosol (1 dose in most cases) led to improvement in FEVand no increase in occurrence of cardiovascular adverse events. In 2 clinical trials in patients with COPD, the mean daily need for additional beta-agonist for patients using SEREVENT DISKUS was approximately 4 inhalations/day. Twenty-four percent (24%) of the patients using SEREVENT DISKUS in these trials averaged 6 or more inhalations of albuterol per day over the course of the 24-week trials. No increase in frequency of cardiovascular events was observed among patients who averaged 6 or more inhalations per day.<br/>Monoamine Oxidase Inhibitors and Tricyclic Antidepressants: Salmeterol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol on the vascular system may be potentiated by these agents.<br/>Corticosteroids and Cromoglycate: In clinical trials, inhaled corticosteroids and/or inhaled cromolyn sodium did not alter the safety profile of salmeterol when administered concurrently.<br/>Methylxanthines: The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by patients receiving salmeterol has not been completely evaluated. In 1 clinical asthma trial, 87 patients receiving SEREVENT Inhalation Aerosol 42 mcg twice daily concurrently with a theophylline product had adverse event rates similar to those in 71 patients receiving SEREVENT Inhalation Aerosol without theophylline. Resting heart rates were slightly higher in the patients on theophylline but were little affected by therapy with SEREVENT Inhalation Aerosol. In 2 clinical trials in patients with COPD, 39 subjects receiving SEREVENT DISKUS concurrently with a theophylline product had adverse event rates similar to those in 302 patients receiving SEREVENT DISKUS without theophylline. Based on the available data, the concomitant administration of methylxanthines with SEREVENT DISKUS did not alter the observed adverse event profile.<br/>Beta-Adrenergic Receptor Blocking Agents: Beta-blockers not only block the pulmonary effect of beta-agonists, such as SEREVENT DISKUS, but may also produce severe bronchospasm in patients with asthma or COPD. Therefore, patients with asthma or COPD should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma or COPD. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.<br/>Diuretics: The ECG changes and/or hypokalemia that may result from the administration of nonpotassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with nonpotassium-sparing diuretics.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In an 18-month oral carcinogenicity study in CD-mice, salmeterol xinafoate caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and ovarian cysts at doses of 1.4 mg/kg and above (approximately 20 times the maximum recommended daily inhalation dose in adults and children based on comparison of the area under the plasma concentration versus time curves [AUCs]). The incidence of leiomyosarcomas was not statistically significant. No tumors were seen at 0.2 mg/kg (approximately 3 times the maximum recommended daily inhalation doses in adults and children based on comparison of the AUCs). In a 24-month oral and inhalation carcinogenicity study in Sprague Dawley rats, salmeterol caused a dose-related increase in the incidence of mesovarian leiomyomas and ovarian cysts at doses of 0.68 mg/kg and above (approximately 55 times the maximum recommended daily inhalation dose in adults and approximately 25 times the maximum recommended daily inhalation dose in children on a mg/mbasis). No tumors were seen at 0.21 mg/kg (approximately 15 times the maximum recommended daily inhalation dose in adults and approximately 8 times the maximum recommended daily inhalation dose in children on a mg/mbasis). These findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown. Salmeterol produced no detectable or reproducible increases in microbial and mammalian gene mutation in vitro. No clastogenic activity occurred in vitro in human lymphocytes or in vivo in a rat micronucleus test. No effects on fertility were identified in male and female rats treated with salmeterol at oral doses up to 2 mg/kg (approximately 160 times the maximum recommended daily inhalation dose in adults on a mg/mbasis).<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C. No teratogenic effects occurred in rats at oral doses up to 2 mg/kg (approximately 160 times the maximum recommended daily inhalation dose in adults on a mg/mbasis). In pregnant Dutch rabbits administered oral doses of 1 mg/kg and above (approximately 50 times the maximum recommended daily inhalation dose in adults based on comparison of the AUCs), salmeterol exhibited fetal toxic effects characteristically resulting from beta-adrenoceptor stimulation. These included precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones. No significant effects occurred at an oral dose of 0.6 mg/kg (approximately 20 times the maximum recommended daily inhalation dose in adults based on comparison of the AUCs). New Zealand White rabbits were less sensitive since only delayed ossification of the frontal bones was seen at an oral dose of 10 mg/kg (approximately 1,600 times the maximum recommended daily inhalation dose in adults on a mg/mbasis). Extensive use of other beta-agonists has provided no evidence that these class effects in animals are relevant to their use in humans. There are no adequate and well-controlled studies with SEREVENT DISKUS in pregnant women. SEREVENT DISKUS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Salmeterol xinafoate crossed the placenta following oral administration of 10 mg/kg to mice and rats (approximately 410 and 810 times, respectively, the maximum recommended daily inhalation dose in adults on a mg/mbasis).<br/>Use in Labor and Delivery: There are no well-controlled human studies that have investigated effects of salmeterol on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of SEREVENT DISKUS during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.<br/>Nursing Mothers: Plasma levels of salmeterol after inhaled therapeutic doses are very low. In rats, salmeterol xinafoate is excreted in the milk. However, since there are no data from controlled trials on the use of salmeterol by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue SEREVENT DISKUS, taking into account the importance of SEREVENT DISKUS to the mother. Caution should be exercised when SEREVENT DISKUS is administered to a nursing woman.<br/>Pediatric Use: The safety and efficacy of SEREVENT DISKUS has been evaluated in over 2,500 patients aged 4 to 11 years with asthma, 346 of whom were administered SEREVENT DISKUS for 1 year. Based on available data, no adjustment of dosage of SEREVENT DISKUS in pediatric patients is warranted for either asthma or EIB (see DOSAGE AND ADMINISTRATION). In 2 randomized, double-blind, controlled clinical trials of 12 weeks' duration, SEREVENT DISKUS 50 mcg was administered to 211 pediatric patients with asthma who did and who did not receive concurrent inhaled corticosteroids. The efficacy of SEREVENT DISKUS was demonstrated over the 12-week treatment period with respect to PEF and FEV. SEREVENT DISKUS was effective in demographic subgroups (gender and age) of the population. SEREVENT DISKUS was effective when coadministered with other inhaled asthma medications, such as short-acting bronchodilators and inhaled corticosteroids. SEREVENT DISKUS was well tolerated in the pediatric population, and there were no safety issues identified specific to the administration of SEREVENT DISKUS to pediatric patients. In 2 randomized studies in children 4 to 11 years old with asthma and EIB, a single 50-mcg dose of SEREVENT DISKUS prevented EIB when dosed 30 minutes prior to exercise, with protection lasting up to 11.5 hours in repeat testing following this single dose in many patients.<br/>Geriatric Use: Of the total number of adolescent and adult patients with asthma who received SEREVENT DISKUS in chronic dosing clinical trials, 209 were 65 years of age and older. Of the total number of patients with COPD who received SEREVENT DISKUS in chronic dosing clinical trials, 167 were 65 years of age or older and 45 were 75 years of age or older. No apparent differences in the safety of SEREVENT DISKUS were observed when geriatric patients were compared with younger patients in clinical trials. As with other beta-agonists, however, special caution should be observed when using SEREVENT DISKUS in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by this class of drug. Data from the trials in patients with COPD suggested a greater effect on FEVof SEREVENT DISKUS in the<65 years age-group, as compared with the���65 years age-group. However, based on available data, no adjustment of dosage of SEREVENT DISKUS in geriatric patients is warranted. | lld:dailymed |
| dailymed-drugs:265 | dailymed-instance:precautio... | Dosage adjustment is recommended when administering acyclovir to patients with renal impairment (see DOSAGE AND ADMINISTRATION). Caution should also be exercised when administering acyclovir to patients receiving potentially nephrotoxic agents since this may increase the risk of renal dysfunction and/or the risk of reversible central nervous system symptoms such as those that have been reported in patients treated with intravenous acyclovir. Adequate hydration should be maintained.<br/>Information for patients: Patients are instructed to consult with their physician if they experience severe or troublesome adverse reactions, they become pregnant or intend to become pregnant, they intend to breastfeed while taking orally administered acyclovir, or they have any other questions. Patients should be advised to maintain adequate hydration. HERPES ZOSTER There are no data on treatment initiated more than 72 hours after onset of the zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster. GENITAL HERPES INFECTIONS Patients should be informed that acyclovir is not a cure for genital herpes. There are no data evaluating whether acyclovir will prevent transmission of infection to others. Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes can also be transmitted in the absence of symptoms through asymptomatic viral shedding. If medical management of a genital herpes recurrence is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode. CHICKENPOX Chickenpox in otherwise healthy children is usually a self-limited disease of mild to moderate severity. Adolescents and adults tend to have more severe disease. Treatment was initiated within 24 hours of the typical chickenpox rash in the controlled studies, and there is no information regarding the effects of treatment begun later in the disease course.<br/>Drug Interactions: See CLINICAL PHARMACOLOGY, Pharmacokinetics.<br/>Carcinogenesis, mutagenesis, impairment of fertility: The data presented below include references to peak steady-state plasma acyclovir concentrations observed in humans treated with 800 mg given orally five times a day (dosing appropriate for treatment of herpes zoster) or 200 mg given orally five times a day (dosing appropriate for treatment of genital herpes). Plasma drug concentrations in animal studies are expressed as multiples of human exposure to acyclovir at the higher and lower dosing schedules (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Acyclovir was tested in lifetime bioassays in rats and mice at single daily doses of up to 450 mg/kg administered by gavage. There was no statistically significant difference in the incidence of tumors between treated and control animals, nor did acyclovir shorten the latency of tumors. Maximum plasma concentrations were three to six times human levels in the mouse bioassay and one to two times human levels in the rat bioassay. Acyclovir was tested in 16 in vivo and in vitro genetic toxicity assays. Acyclovir was positive in 5 of the assays. Acyclovir did not impair fertility or reproduction in mice (450 mg/kg/day, p.o.) or in rats (25 mg/kg/day, s.c.). In the mouse study, plasma levels were 9 to 18 times human levels, while in the rat study, they were 8 to 15 times human levels. At higher doses (50 mg/kg/day, s.c.) in rats and rabbits (11 to 22 and 16 to 31 times human levels, respectively) implantationefficacy, but not litter size, was decreased. In a rat peri- and postnatal study at 50 mg/kg/day, s.c., there was a statistically significant decrease in group mean numbers of corpora lutea, total implantation sites, and live fetuses. No testicular abnormalities were seen in dogs given 50 mg/kg/day, i.v. for 1 month (21 to 41 times human levels) or in dogs given 60 mg/kg/day orally for 1 year (six to 12 times human levels). Testicular atrophy and aspermatogenesis were observed in rats and dogs at higher dose levels.<br/>Pregnancy:<br/>Teratogenic effects: PREGNANCY CATEGORY B Acyclovir administered during organogenesis was not teratogenic in the mouse (450 mg/kg/day, p.o.), rabbit (50 mg/kg/day, s.c. and i.v.), or rat (50 mg/kg/day, s.c.). These exposures resulted in plasma levels 9 and 18 , 16 and 106, and 11 and 22 times, respectively, human levels. There are no adequate and well-controlled studies in pregnant women. A prospective, epidemiological registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses. Acyclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing mothers: Acyclovir concentrations have been documented in breast milk in two women following oral administration of acyclovir and ranged from 0.6 to 4.1 times corresponding plasma levels. These concentrations would potentially expose the nursing infant to a dose of acyclovir up to 0.3 mg/kg/day. Acyclovir should be administered to a nursing mother with caution and only when indicated.<br/>Pediatric use: Safety and effectiveness of oral formulations of acyclovir in pediatric patients younger than 2 years of age have not been established.<br/>Geriatric use: Of 376 subjects who received acyclovir in a clinical study of herpes zoster treatment in immunocompetent subjects greater than or equal to 50 years of age, 244 were 65 and over while 111 were 75 and over. No overall differences in effectiveness for time to cessation of new lesion formation or time to healing were reported between geriatric subjects and younger adults subjects. The duration of painafter healing was longer in patients 65 and over. Nausea, vomiting, and dizziness were reported more frequently in elderly ubjects. Elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have renal or CNS adverse events. With respect to CNS adverse events observed during clinical practice, somnolence, hallucinations, confusion, and coma were reported more frequently in elderly patients (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS,Observed During Clinical Practice, and DOSAGE AND ADMINISTRATION). | lld:dailymed |
| dailymed-drugs:267 | dailymed-instance:precautio... | Information for Patients: Patients should be advised to take nitrofurantoin monohydrate/macrocrystals capsules with food (ideally breakfast and dinner) to further enhance tolerance and improve drug absorption. Patients should be instructed to complete the full course of therapy; however, they should be advised to contact their physician if any unusual symptoms occur during therapy. Patients should be advised not to use antacid preparations containing magnesium trisilicate while taking nitrofurantoin monohydrate/macrocrystals capsules. Patients should be counseled that antibacterial drugs including nitrofurantoin monohydrate/macrocrystals capsules should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When nitrofurantoin monohydrate/macrocrystals capsule is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by nitrofurantoin monohydrate/macrocrystals capsules or other antibacterial drugs in the future.<br/>General: Prescribing nitrofurantoin monohydrate/macrocrystals capsules in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.<br/>Drug Interactions: Antacids containing magnesium trisilicate, when administered concomitantly with nitrofurantoin, reduce both the rate and extent of absorption. The mechanism for this interaction probably is adsorption of nitrofurantoin onto the surface of magnesium trisilicate. Uricosuric drugs, such as probenecid and sulfinpyrazone, can inhibit renal tubular secretion of nitrofurantoin. The resulting increase in nitrofurantoin serum levels may increase toxicity, and the decreased urinary levels could lessen its efficacy as a urinary tract antibacterial.<br/>Drug/Laboratory Test Interactions: As a result of the presence of nitrofurantoin, a false-positive reaction for glucose in the urine may occur. This has been observed with Benedict's and Fehling's solutions but not with the glucose enzymatic test.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Nitrofurantoin was not carcinogenic when fed to female Holtzman rats for 44.5 weeks or to female Sprague-Dawley rats for 75 weeks. Two chronic rodent bioassays utilizing male and female Sprague-Dawley rats and two chronic bioassays in Swiss mice and in BDFmice revealed no evidence of carcinogenicity. Nitrofurantoin presented evidence of carcinogenic activity in female B6C3Fmice as shown by increased incidences of tubular adenomas, benign mixed tumors, and granulosa cell tumors of the ovary. In male F344/N rats, there were increased incidences of uncommon kidney tubular cell neoplasms, osteosarcomas of the bone, and neoplasms of the subcutaneous tissue. In one study involving subcutaneous administration of 75 mg/kg nitrofurantoin to pregnant female mice, lung papillary adenomas of unknown significance were observed in the F1 generation. Nitrofurantoin has been shown to induce point mutations in certain strains of Salmonella typhimurium and forward mutations in L5178Y mouse lymphoma cells. Nitrofurantoin induced increased numbers of sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells but not in human cells in culture. Results of the sex-linked recessive lethal assay in Drosophila were negative after administration of nitrofurantoin by feeding or by injection. Nitrofurantoin did not induce heritable mutation in the rodent models examined. The significance of the carcinogenicity and mutagenicity findings relative to the therapeutic use of nitrofurantoin in humans is unknown. The administration of high doses of nitrofurantoin to rats causes temporary spermatogenic arrest; this is reversible on discontinuing the drug. Doses of 10 mg/kg/day or greater in healthy human males may, in certain unpredictable instances, produce a slight to moderate spermatogenic arrest with a decrease in sperm count.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Non-Teratogenic Effects: Nitrofurantoin has been shown in one published transplacental carcinogenicity study to induce lung papillary adenomas in the F1 generation mice at doses 19 times the human dose on a mg/kg basis. The relationship of this finding to potential human carcinogenesis is presently unknown. Because of the uncertainty regarding the human implications of these animal data, this drug should be used during pregnancy only if clearly needed.<br/>Labor and Delivery: See CONTRAINDICATIONS.<br/>Nursing Mothers: Nitrofurantoin has been detected in human breast milk in trace amounts. Because of the potential for serious adverse reactions from nitrofurantoin in nursing infants under one month of age, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Nitrofurantoin monohydrate/macrocrystals capsules are contraindicated in infants below the age of one month. Safety and effectiveness in pediatric patients below the age of twelve years have not been established.<br/>Geriatric Use: Clinical studies of nitrofurantoin monohydrate/macrocrystals capsules did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Spontaneous reports suggest a higher proportion ofpulmonary reactions, including fatalities, in elderly patients; these differences appear to be related to the higher proportion of elderly patients receiving long-term nitrofurantoin therapy. As in younger patients, chronic pulmonary reactions generally are observed in patients receiving therapy for six months or longer . Spontaneous reports also suggest an increased proportion of severe hepatic reactions, including fatalities, in elderly patients . In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing nitrofurantion monohydrate/macrocrystals. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Anuria, oliguria, or significant impairment of renal function (creatinine clearance under 60 mL per minute or clinically significant elevated serum creatinine) are contraindications . Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function. | lld:dailymed |
| dailymed-drugs:268 | dailymed-instance:precautio... | General: Milrinone should not be used in patients with severe obstructive aortic or pulmonic valvular disease in lieu of surgical relief of the obstruction. Like other inotropic agents, it may aggravate outflow tract obstruction in hypertrophic subaortic stenosis. Supraventricular and ventricular arrhythmias have been observed in the high-risk population treated. In some patients, injections of milrinone and oral milrinone have been shown to increase ventricular ectopy, including nonsustained ventricular tachycardia. The potential for arrhythmia, present in congestive heart failure itself, may be increased by many drugs or combinations of drugs. Patients receiving milrinone should be closely monitored during infusion. Milrinone produces a slight shortening of AV node conduction time, indicating a potential for an increased ventricular response rate in patients with atrial flutter/fibrillation which is not controlled with digitalis therapy. During therapy with milrinone, blood pressure and heart rate should be monitored and the rate of infusion slowed or stopped in patients showing excessive decreases in blood pressure. If prior vigorous diuretic therapy is suspected to have caused significant decreases in cardiac filling pressure, milrinone should be cautiously administered with monitoring of blood pressure, heart rate, and clinical symptomatology. There is no experience in controlled trials with infusions of milrinone for periods exceeding 48 hours. Cases of infusion site reaction have been reported with intravenous milrinone therapy (see ADVERSE REACTIONS). Consequently, careful monitoring of the infusion site should be maintained to avoid possible extravasation.<br/>Use in Acute Myocardial Infarction: No clinical studies have been conducted in patients in the acute phase of post myocardial infarction. Until further clinical experience with this class of drugs is gained, milrinone is not recommended in these patients.<br/>Laboratory Tests:<br/>Fluid And Electrolytes: Fluid and electrolyte changes and renal function should be carefully monitored during therapy with milrinone. Improvement in cardiac output with resultant diuresis may necessitate a reduction in the dose of diuretic. Potassium loss due to excessive diuresis may predispose digitalized patients to arrhythmias. Therefore, hypokalemia should be corrected by potassium supplementation in advance of or during use of milrinone.<br/>Drug Interactions: No untoward clinical manifestations have been observed in limited experience with patients in whom milrinone was used concurrently with the following drugs: digitalis glycosides; lidocaine, quinidine; hydralazine, prazosin; isosorbide dinitrate, nitroglycerin; chlorthalidone, furosemide, hydrochlorothiazide, spironolactone; captopril; heparin, warfarin, diazepam, insulin; and potassium supplements.<br/>Chemical Interactions: There is an immediate chemical interaction which is evidenced by the formation of a precipitate when furosemide is injected into an intravenous line of an infusion of milrinone. Therefore, furosemide should not be administered in intravenous lines containing milrinone.<br/>Carcinogenesis and Mutagenesis and Impairment of Fertility: Twenty-four months of oral administration of milrinone to mice at doses up to 40 mg/kg/day (about 50 times the human oral therapeutic dose in a 50 kg patient) was unassociated with evidence of carcinogenic potential. Neither was there evidence of carcinogenic potential when milrinone was orally administered to rats at doses up to 5 mg/kg/day (about 6 times the human oral therapeutic dose) for twenty-four months or at 25 mg/kg/day (about 30 times the human oral therapeutic dose) for up to 18 months in males and 20 months in females. Whereas the Chinese Hamster Ovary Chromosome Aberration Assay was positive in the presence of a metabolic activation system, results from the Ames Test, the Mouse Lymphoma Assay, the Micronucleus Test and the in vivo Rat Bone Marrow Metaphase Analysis indicated an absence of mutagenic potential. In reproductive performance studies in rats, milrinone had no effect on male or female fertility at oral doses up to 32 mg/kg/day.<br/>Animal Toxicity: Oral and intravenous administration of toxic dosages of milrinone to rats and dogs resulted in myocardial degeneration/fibrosis and endocardial hemorrhage, principally affecting the left ventricular papillary muscles. Coronary vascular lesions characterized by periarterial edema and inflammation have been observed in dogs only. The myocardial/endocardial changes are similar to those produced by beta-adrenergic receptor agonists such as isoproterenol, while the vascular changes are similar to those produced by minoxidil and hydralazine. Doses within the recommended clinical dose range (up to 1.13 mg/kg/day) for congestive heart failure patients have not produced significant adverse effects in animals.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C.: Oral administration of milrinone to pregnant rats and rabbits during organogenesis produced no evidence of teratogenicity at dose levels up to 40 mg/kg/day and 12 mg/kg/day, respectively. Milrinone did not appear to be teratogenic when administered intravenously to pregnant rats at doses up to 3 mg/kg/day (about 2.5 times the maximum recommended clinical intravenous dose) or pregnant rabbits at doses up to 12 mg/kg/day, although an increased resorption rate was apparent at both 8 mg/kg/day and 12 mg/kg/day (intravenous) in the latter species. There are no adequate and well-controlled studies in pregnant women. Milrinone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: Caution should be exercised when milrinone is administered to nursing women, since it is not known whether it is excreted in human milk.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric Use: There are no special dosage recommendations for the geriatric patient. Ninety percent of all patients administered milrinone in clinical studies were within the age range of 45 to 70 years, with a mean age of 61 years. Patients in all age groups demonstrated clinically and statistically significant responses. No age-related effects on the incidence of adverse reactions have been observed. Controlled pharmacokinetic studies have not disclosed any age-related effects on the distribution and elimination of milrinone. | lld:dailymed |
| dailymed-drugs:270 | dailymed-instance:precautio... | General: In urinary retention, if the sphincter fails to relax as bethanechol contracts the bladder, urine may be forced up the ureter into the kidney pelvis. If there is bacteriuria, this may cause reflux infection.<br/>Information for Patients: Bethanechol chloride tablets should preferably be taken one hour before or two hours after meals to avoid nausea or vomiting. Dizziness, lightheadedness or fainting may occur, especially when getting up from a lying or sitting position. The 50 mg strength of this product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.<br/>Drug Interactions: Special care is required if this drug is given to patients receiving ganglion blocking compounds because a critical fall in blood pressure may occur. Usually, severe abdominal symptoms appear before there is such a fall in the blood pressure.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been performed to evaluate the effects upon fertility, mutagenic or carcinogenic potential of bethanechol chloride.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C. Animal reproduction studies have not been conducted with bethanechol chloride. It is also not known whether bethanechol chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Bethanechol chloride should be given to a pregnant woman only if clearly needed.<br/>Nursing Mothers: It is not known whether this drug is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions from bethanechol chloride in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established. | lld:dailymed |
| dailymed-drugs:271 | dailymed-instance:precautio... | General: Use of Dovonex may cause irritation of lesions and surrounding uninvolved skin. If irritation develops, Dovonex should be discontinued. For external use only. Keep out of the reach of children. Always wash hands thoroughly after use. Transient, rapidly reversible elevation of serum calcium has occurred with use of Dovonex. If elevation in serum calcium outside the normal range should occur, discontinue treatment until normal calcium levels are restored.<br/>Information for Patients: Patients using Dovonex should receive the following information and instructions:<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: The potential of calcipotriene to induce carcinogenesis in standard long-term animal studies (in the absence of ultraviolet radiation [UVR]) has not been evaluated. In a study in which albino hairless mice were exposed to both UVR and topically applied calcipotriene, a reduction in the time required for UVR to induce the formation of skin tumors was observed (statistically significant in males only), suggesting that calcipotriene may enhance the effect of UVR to induce skin tumors. Patients that apply Dovonex to exposed portions of the body should avoid excessive exposure to either natural or artificial sunlight (including tanning booths, sun lamps, etc.). Physicians may wish to limit or avoid use of phototherapy in patients that use Dovonex. Calcipotriene did not elicit any mutagenic effects in an Ames mutagenicity assay, a mouse lymphoma TK locus assay, a human lymphocyte chromosome aberration assay, or in a micronucleus assay conducted in mice. Studies in rats at doses up to 54��g/kg/day (318��g/m/day) of calcipotriene indicated no impairment of fertility or general reproductive performance.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C: Studies of teratogenicity were done by the oral route where bioavailability is expected to be approximately 40-60% of the administered dose. In rabbits, increased maternal and fetal toxicity were noted at a dosage of 12��g/kg/day (132��g/m/day); a dosage of 36��g/kg/day (396��g/m/day) resulted in a significant increase in the incidence of incomplete ossification of the pubic bones and forelimb phalanges of fetuses. In a rat study, a dosage of 54��g/kg/day (318��g/m/day) resulted in a significantly increased incidence of skeletal abnormalities (enlarged fontanelles and extra ribs). The enlarged fontanelles are most likely due to calcipotriene's effect upon calcium metabolism. The estimated maternal and fetal no-effect exposure levels in the rat (43.2��g/m/day) and rabbit (17.6��g/m/day) studies are approximately equal to the expected human systemic exposure level (18.5��g/m/day) from dermal application. There are no adequate and well-controlled studies in pregnant women. Therefore, Dovonex ointment should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: It is not known whether calcipotriene is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Dovonex (calcipotriene ointment), 0.005% is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness of Dovonex in pediatric patients have not been established. Because of a higher ratio of skin surface area to body mass, pediatric patients are at greater risk than adults of systemic adverse effects when they are treated with topical medication.<br/>Geriatric Use: Of the total number of patients in clinical studies of calcipotriene ointment, approximately 12% were 65 or older, while approximately 4% were 75 and over. The results of an analysis of severity of skin-related adverse events showed a statistically significant difference for subjects over 65 years (more severe) compared to those under 65 years (less severe). | lld:dailymed |
| dailymed-drugs:273 | dailymed-instance:precautio... | General: Nutropin AQ should be prescribed by physicians experienced in the diagnosis and management of patients with GH deficiency, idiopathic short stature, Turner syndrome, or chronic renal insufficiency (CRI). No studies have been completed evaluating Nutropin AQ therapy in patients who have received renal transplants. Currently, treatment of patients with functioning renal allografts is not indicated. Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses in susceptible patients. As a result, previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked during somatropin treatment. Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, especially in those with risk factors for diabetes mellitus, such as obesity (including obese patients with Prader-Willi syndrome), Turner syndrome, or a family history of diabetes mellitus. Patients with preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely during somatropin therapy. The doses of antihyperglycemic drugs (i.e., insulin or oral agents) may require adjustment when somatropin therapy is instituted in these patients. In subjects treated in a long-term study of Nutropin for idiopathic short stature, mean fasting and postprandial insulin levels increased, while mean fasting and postprandial glucose levels remained unchanged. Mean hemoglobin Alevels rose slightly from baseline as expected during adolescence; sporadic values outside normal limits occurred transiently. Nutropin therapy in adults with GH deficiency of adult onset was associated with an increase of median fasting insulin level in the Nutropin 0.0125 mg/kg/day group from 9.0��U/mL at baseline to 13.0��U/mL at Month 12 with a return to the baseline median level after a 3���week post���washout period of GH therapy. In the placebo group there was no change from 8.0��U/mL at baseline to Month 12, and after the post���washout period, the median was 9.0��U/mL. The between���treatment groups difference on the change from baseline to Month 12 in the median fasting insulin level was significant, p<0.0001. In childhood���onset subjects, there was an increase of median fasting insulin level in the Nutropin 0.025 mg/kg/day group from 11.0��U/mL at baseline to 20.0��U/mL at Month 12, in the Nutropin 0.0125 mg/kg/day group from 8.5��U/mL to 11.0��U/mL, and in the placebo group from 7.0��U/mL to 8.0��U/mL. The between���treatment groups difference for these changes were significant, p = 0.0007. In subjects with adult onset GH deficiency, there were no between���treatment group difference on change from baseline to Month 12 in mean HbA, p = 0.08. In childhood���onset mean HbAincreased in the Nutropin 0.025 mg/kg/day group from 5.2% at baseline to 5.5% at Month 12, and did not change in the Nutropin 0.0125 mg/kg/day group from 5.1% at baseline or in the placebo group from 5.3% at baseline. The between���treatment groups differences were significant, p = 0.009. Patients with preexisting tumors or growth hormone deficiency secondary to an intracranial lesion should be examined routinely for progression or recurrence of the underlying disease process. In pediatric patients, clinical literature has revealed no relationship between somatropin replacement therapy and central nervous system (CNS) tumor recurrence or new extracranial tumors. However, in childhood cancer survivors, an increased risk of a second neoplasm has been reported in patients treated with somatropin after their first neoplasm. Intracranial tumors, in particular meningiomas, in patients treated with radiation to the head for their first neoplasm, were the most common of these second neoplasms. In adults, it is unknown whether there is any relationship between somatropin replacement therapy and CNS tumor recurrence. Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a small number of patients treated with somatropin products. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin therapy. In all reported cases, IH���associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose. Funduscopic examination should be performed routinely before initiating treatment with somatropin to exclude preexisting papilledema, and periodically during the course of somatropin therapy. If papilledema is observed by funduscopy during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with somatropin can be restarted at a lower dose after IH���associated signs and symptoms have resolved. Patients with Turner syndrome, CRI, and Prader���Willi syndrome may be at increased risk for the development of IH. In patients with hypopituitarism (multiple hormone deficiencies), standard hormonal replacement therapy should be monitored closely when somatropin therapy is administered. Undiagnosed/untreated hypothyroidism may prevent an optimal response to somatropin, in particular, the growth response in children. Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism. In patients with growth hormone deficiency, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment. Therefore, patients treated with somatropin should have periodic thyroid function tests and thyroid hormone replacement therapy should be initiated or appropriately adjusted when indicated. Patients should be monitored carefully for any malignant transformation of skin lesions. When somatropin is administered subcutaneously at the same site over a long period of time, tissue atrophy may result. This can be avoided by rotating the injection site. As with any protein, local or systemic allergic reactions may occur. Parents/Patients should be informed that such reactions are possible and that prompt medical attention should be sought if allergic reactions occur.<br/>Pediatric Patients: Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders (including GH deficiency and Turner syndrome) or in patients undergoing rapid growth. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during somatropin therapy should be carefully evaluated. Children with growth failure secondary to CRI should be examined periodically for evidence of progression of renal osteodystrophy. Slipped capital femoral epiphysis or avascular necrosis of the femoral head may be seen in children with advanced renal osteodystrophy, and it is uncertain whether these problems are affected by somatropin therapy. X���rays of the hip should be obtained prior to initiating somatropin therapy in CRI patients. Physicians and parents should be alert to the development of a limp or complaints of hip or knee pain in CRI patients treated with Nutropin AQ. Progression of scoliosis can occur in patients who experience rapid growth. Because somatropin increases growth rate, patients with a history of scoliosis who are treated with somatropin should be monitored for progression of scoliosis. However, somatropin has not been shown to increase the occurence of scoliosis. Skeletal abnormalities including scoliosis are commonly seen in untreated Turner syndrome patients. Scoliosis is also commonly seen in untreated patients with Prader���Willi syndrome. Physicians should be alert to these abnormalities, which may manifest during somatropin therapy. Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear and hearing disorders. In a randomized, controlled trial, there was a statistically significant increase, as compared to untreated controls, in otitis media (43% vs. 26%) and ear disorders (18% vs. 5%) in patients receiving somatropin. In addition, patients with Turner syndrome should be monitored closely for cardiovascular disorders (e.g., stroke, aortic aneurysm/dissection, hypertension) as these patients are also at risk for these conditions.<br/>Adult Patients: Patients with epiphyseal closure who were treated with somatropin replacement therapy in childhood should be reevaluated according to the criteria in INDICATIONS AND USAGE before continuation of somatropin therapy at the reduced dose level recommended for GH deficient adults. Fluid retention during somatropin replacement therapy in adults may occur. Clinical manifestations of fluid retention are usually transient and dose dependent . Experience with prolonged somatropin treatment in adults is limited.<br/>Information for Patients: Patients being treated with Nutropin AQ (and/or their parents) should be informed about the potential benefits and risks associated with Nutropin AQ treatment, including a review of the contents of the Patient Information Insert. This information is intended to better educate patients (and caregivers); it is not a disclosure of all possible adverse or intended effects. Patients and caregivers who will administer Nutropin AQ should receive appropriate training and instruction on the proper use of Nutropin AQ from the physician or other suitably qualified health care professional. A puncture���resistant container for the disposal of used syringes and needles should be strongly recommended. Patients and/or parents should be thoroughly instructed in the importance of proper disposal, and cautioned against any reuse of needles and syringes. This information is intended to aid in the safe and effective administration of the medication (see Patient Information Insert).<br/>Laboratory Tests: Serum levels of inorganic phosphorus, alkaline phosphatase, and parathyroid hormone (PTH) may increase during somatropin therapy.<br/>Drug Interactions: Somatropin inhibits 11�����hydroxysteroid dehydrogenase type 1 (11��HSD���1) in adipose/hepatic tissue and may significantly impact the metabolism of cortisol and cortisone. As a consequence, in patients treated with somatropin, previously undiagnosed central (secondary) hypoadrenalism may be unmasked requiring glucocorticoid replacement therapy. In addition, patients treated with glucocorticoid replacement therapy for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses; this may be especially true for patients treated with cortisone acetate and prednisone since conversion of these drugs to their biologically active metabolites is dependent on the activity of the 11��HSD���1 enzyme. Excessive glucocorticoid therapy may attenuate the growth-promoting effects of somatropin in children. Therefore, glucocorticoid replacement therapy should be carefully adjusted in children with concomitant GH and glucocorticoid deficiency to avoid both hypoadrenalism and an inhibitory effect on growth. The use of Nutropin AQ in patients with CRI requiring glucocorticoid therapy has not been evaluated. Concomitant glucocorticoid therapy may inhibit the growth promoting effect of Nutropin AQ. Therefore, if glucocorticoid replacement is required for CRI, the glucocorticoid dose should be carefully adjusted to avoid an inhibitory effect on growth. There was no evidence in the controlled studies of Nutropin's interaction with drugs commonly used in chronic renal insufficiency patients. Limited published data indicate that somatropin treatment increases cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that somatropin administration may alter the clearance of compounds known to be metabolized by CP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporin). Careful monitoring is advisable when somatropin is administered in combination with other drugs known to be metabolized by CP450 liver enzymes. However, formal drug interaction studies have not been conducted. In adult women on oral estrogen replacement, a larger dose of somatropin may be required to achieve the defined treatment goal . In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral agent may require adjustment when somatropin therapy is initiated .<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity, mutagenicity, and reproduction studies have not been conducted with Nutropin AQ.<br/>Pregnancy:<br/>Pregnancy: Pregnancy (Category C). Animal reproduction studies have not been conducted with Nutropin AQ. It is also not known whether Nutropin AQ can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Nutropin AQ should be given to a pregnant woman only if clearly needed.<br/>Nursing Mothers: It is not known whether Nutropin AQ is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Nutropin AQ is administered to a nursing mother.<br/>Geriatric Usage: Clinical studies of Nutropin AQ did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients may be more sensitive to the action of somatropin, and therefore may be more prone to develop adverse reactions. A lower starting dose and smaller dose increments should be considered for older patients . | lld:dailymed |
| dailymed-drugs:274 | dailymed-instance:precautio... | General:: Prolonged use of cefazolin may result in the overgrowth of non susceptible organisms. Careful clinical observation of the patient is essential. When cefazolin is administered to patients with low urinary output because of impaired renal function, lower daily dosage is required . As with other��-lactam antibiotics, seizures may occur if inappropriately high doses are administered to patients with impaired renal function . Cefazolin Injection, USP, as with all cephalosporins, should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated. Prescribing cefazolin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.<br/>Drug Interactions: Probenecid may decrease renal tubular secretion of cephalosporins when used concurrently, resulting in increased and more prolonged cephalosporin blood levels.<br/>Drug/Laboratory Test Interactions: A false positive reaction for glucose in the urine may occur with Benedict's solution, Fehling's solution or with CLINITEST tablets, but not with enzyme-based tests such as CLINISTIX. Positive direct and indirect antiglobulin (Coombs) tests have occurred; these may also occur in neonates whose mothers received cephalosporins before delivery.<br/>Information for Patients:: Patients should be counseled that antibacterial drugs including cefazolin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefazolin Injection, USP is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cefazolin or other antibacterial drugs in the future.<br/>Carcinogenesis/Mutagenesis: Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of cefazolin have not been performed.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Labor and Delivery: When cefazolin has been administered prior to caesarean section, drug levels in cord blood have been approximately one quarter to one third of maternal drug levels. The drug appears to have no adverse effect on the fetus.<br/>Nursing Mothers: Cefazolin is present in very low concentrations in the milk of nursing mothers. Caution should be exercised when cefazolin is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness for use in premature infants and neonates have not been established. See DOSAGE AND ADMINISTRATION for recommended dosage in pediatric patients older than 1 month.<br/>Geriatric Use: Of the 920 subjects who received cefazolin injection in clinical studies, 313 (34%) were 65 years and over, while 138 (15%) were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function . | lld:dailymed |
| dailymed-drugs:277 | dailymed-instance:precautio... | General:<br/>Discontinuation of Treatment with Lexapro: During marketing of Lexapro and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Lexapro. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate .<br/>Abnormal Bleeding: SSRIs and SNRIs, including Lexapro, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to the risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of Lexapro and NSAIDs, aspirin, or other drugs that affect coagulation.<br/>Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Lexapro. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and was reversible when Lexapro was discontinued. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see Geriatric Use). Discontinuation of Lexapro should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.<br/>Activation of Mania/Hypomania: In placebo-controlled trials of Lexapro in major depressive disorder, activation of mania/hypomania was reported in one (0.1%) of 715 patients treated with Lexapro and in none of the 592 patients treated with placebo. One additional case of hypomania has been reported in association with Lexapro treatment. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with racemic citalopram and other marketed drugs effective in the treatment of major depressive disorder. As with all drugs effectivein the treatment of major depressive disorder, Lexapro should be used cautiously in patients with a history of mania.<br/>Seizures: Although anticonvulsant effects of racemic citalopram have been observed in animal studies, Lexapro has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product's premarketing testing. In clinical trials of Lexapro, cases of convulsion have been reported in association with Lexapro treatment. Like other drugs effective in the treatment of major depressive disorder, Lexapro should be introduced with care in patients with a history of seizure disorder.<br/>Interference with Cognitive and Motor Performance: In a study in normal volunteers, Lexapro 10 mg/day did not produce impairment of intellectual function or psychomotor performance. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Lexapro therapy does not affect their ability to engage in such activities.<br/>Use in Patients with Concomitant Illness: Clinical experience with Lexapro in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using Lexapro in patients with diseases or conditions that produce altered metabolism or hemodynamic responses. Lexapro has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical studies during the product's premarketing testing. In subjects with hepatic impairment, clearance of racemic citalopram was decreased and plasma concentrations were increased. The recommended dose of Lexapro in hepatically impaired patients is 10 mg/day . Because escitalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with Lexapro, however, it should be used with caution in such patients .<br/>Information for Patients: Physicians are advised to discuss the following issues with patients for whom they prescribe Lexapro. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Lexapro and triptans, tramadol or other serotonergic agents. In a study in normal volunteers, Lexapro 10 mg/day did not impair psychomotor performance. The effect of Lexapro on psychomotor coordination, judgment, or thinking has not been systematically examined in controlled studies. Because psychoactive drugs may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Lexapro therapy does not affect their ability to engage in such activities. Patients should be told that, although Lexapro has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of Lexapro and alcohol in depressed patients is not advised. Patients should be made aware that escitalopram is the active isomer of Celexa (citalopram hydrobromide) and that the two medications should not be taken concomitantly. Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions. Patients should be cautioned about the concomitant use of Lexapro and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physician if they are breastfeeding an infant. While patients may notice improvement with Lexapro therapy in 1 to 4 weeks, they should be advised to continue therapy as directed. Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Lexapro and should counsel them in its appropriate use. A patient Medication Guide about���Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions���is available for Lexapro. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Lexapro. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.<br/>Laboratory Tests: There are no specific laboratory tests recommended.<br/>Concomitant Administration with Racemic Citalopram: Citalopram - Since escitalopram is the active isomer of racemic citalopram (Celexa), the two agents should not be coadministered.<br/>Drug Interactions: Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs including Lexapro, and the potential for serotonin syndrome, caution is advised when Lexapro is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John's Wort . The concomitant use of Lexapro with other SSRIs, SNRIs or tryptophan is not recommended . Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Lexapro with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases . CNS Drugs - Given the primary CNS effects of escitalopram, caution should be used when it is taken in combination with other centrally acting drugs. Alcohol - Although Lexapro did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by patients taking Lexapro is not recommended. Monoamine Oxidase Inhibitors (MAOIs) - See CONTRAINDICATIONS and WARNINGS.<br/>Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.): Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of anNSAID or aspirin may potentiate the risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Lexapro is initiated or discontinued. Cimetidine - In subjects who had received 21 days of 40 mg/day racemic citalopram, combined administration of 400 mg/day cimetidine for 8 days resulted in an increase in citalopram AUC and Cof 43% and 39%, respectively. The clinical significance of these findings is unknown. Digoxin - In subjects who had received 21 days of 40 mg/day racemic citalopram, combined administration of citalopram and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin. Lithium - Coadministration of racemic citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of escitalopram, caution should be exercised when Lexapro and lithium are coadministered. Pimozide and Celexa - In a controlled study, a single dose of pimozide 2 mg co-administered with racemic citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Racemic citalopram did not alter the mean AUC or Cof pimozide. The mechanism of this pharmacodynamic interaction is not known. Sumatriptan - There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of an SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram) is clinically warranted, appropriate observation of the patient is advised. Theophylline - Combined administration of racemic citalopram (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline. The effect of theophylline on the pharmacokinetics of citalopram was not evaluated. Warfarin - Administration of 40 mg/day racemic citalopram for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance of which is unknown. Carbamazepine - Combined administration of racemic citalopram (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of escitalopram should be considered if the two drugs are coadministered. Triazolam - Combined administration of racemic citalopram (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam. Ketoconazole - Combined administration of racemic citalopram (40 mg) and ketoconazole (200 mg), a potent CYP3A4 inhibitor, decreased the Cand AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram. Ritonavir - Combined administration of a single dose of ritonavir (600 mg), both a CYP3A4 substrate and a potent inhibitor of CYP3A4, and escitalopram (20 mg) did not affect the pharmacokinetics of either ritonavir or escitalopram. CYP3A4 and -2C19 Inhibitors - In vitro studies indicated that CYP3A4 and -2C19 are the primary enzymes involved in the metabolism of escitalopram. However, coadministration of escitalopram (20 mg) and ritonavir (600 mg), a potent inhibitor of CYP3A4, did not significantly affect the pharmacokinetics of escitalopram. Because escitalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease escitalopram clearance. Drugs Metabolized by Cytochrome P4502D6 - In vitro studies did not reveal an inhibitory effect of escitalopram on CYP2D6. In addition, steady state levels of racemic citalopram were not significantly different in poor metabolizers and extensive CYP2D6 metabolizers after multiple-dose administration of citalopram, suggesting that coadministration, with escitalopram, of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on escitalopram metabolism. However, there are limited in vivo data suggesting a modest CYP2D6 inhibitory effect for escitalopram, i.e., coadministration of escitalopram (20 mg/day for 21 days) with the tricyclic antidepressant desipramine (single dose of 50 mg), a substrate for CYP2D6, resulted in a 40% increase in Cand a 100% increase in AUC of desipramine. The clinical significance of this finding is unknown. Nevertheless, caution is indicated in the coadministration of escitalopram and drugs metabolized by CYP2D6. Metoprolol - Administration of 20 mg/day Lexapro for 21 days in healthy volunteers resulted in a 50% increase in Cand 82% increase in AUC of the beta-adrenergic blocker metoprolol (given in a single dose of 100 mg). Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Coadministration of Lexapro and metoprolol had no clinically significant effects on blood pressure or heart rate. Electroconvulsive Therapy (ECT) - There are no clinical studies of the combined use of ECT and escitalopram.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis: Racemic citalopram was administered in the diet to NMRI/BOM strain mice and COBS WI strain rats for 18 and 24 months, respectively. There was no evidence for carcinogenicity of racemic citalopram in mice receiving up to 240 mg/kg/day. There was an increased incidence of small intestine carcinoma in rats receiving 8 or 24 mg/kg/day racemic citalopram. A no-effect dose for this finding was not established. The relevance of these findings to humans is unknown.<br/>Mutagenesis: Racemic citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Racemic citalopram was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in a coupled in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. It was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays.<br/>Impairment of Fertility: When racemic citalopram was administered orally to 16 male and 24 female rats prior to and throughout mating and gestation at doses of 32, 48, and 72 mg/kg/day, mating was decreased at all doses, and fertility was decreased at doses���32 mg/kg/day. Gestation duration was increased at 48 mg/kg/day.<br/>Pregnancy:<br/>Pregnancy Category C: In a rat embryo/fetal development study, oral administration of escitalopram (56, 112, or 150 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased fetal body weight and associated delays in ossification at the two higher doses (approximately���56 times the maximum recommended human dose [MRHD] of 20 mg/day on a body surface area [mg/m] basis). Maternal toxicity (clinical signs and decreased body weight gain and food consumption), mild at 56 mg/kg/day, was present at all dose levels. The developmental no-effect dose of 56 mg/kg/day is approximately 28 times the MRHD on a mg/mbasis. No teratogenicity was observed at any of the doses tested (as high as 75 times the MRHD on a mg/mbasis). When female rats were treated with escitalopram (6, 12, 24, or 48 mg/kg/day) during pregnancy and through weaning, slightly increased offspring mortality and growth retardation were noted at 48 mg/kg/day which is approximately 24 times the MRHD on a mg/mbasis. Slight maternal toxicity (clinical signs and decreased body weight gain and food consumption) was seen at this dose. Slightly increased offspring mortality was seen at 24 mg/kg/day. The no-effect dose was 12 mg/kg/day which is approximately 6 times the MRHD on a mg/mbasis. In animal reproduction studies, racemic citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at doses greater than human therapeutic doses. In two rat embryo/fetal development studies, oral administration of racemic citalopram (32, 56, or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose. This dose was also associated with maternal toxicity (clinical signs, decreased body weight gain). The developmental no-effect dose was 56 mg/kg/day. In a rabbit study, no adverse effects onembryo/fetal development were observed at doses of racemic citalopram of up to 16 mg/kg/day. Thus, teratogenic effects of racemic citalopram were observed at a maternally toxic dose in the rat and were not observed in the rabbit. When female rats were treated with racemic citalopram (4.8, 12.8, or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at the highest dose. The no-effect dose was 12.8 mg/kg/day. Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses���24 mg/kg/day. A no-effect dose was not determined in that study. There are no adequate and well-controlled studies in pregnant women; therefore, escitalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Pregnancy-Nonteratogenic Effects: Neonates exposed to Lexapro and other SSRIs or SNRIs, late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome . Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1���2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective, case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. When treating a pregnant woman with Lexapro during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment . Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.<br/>Labor and Delivery: The effect of Lexapro on labor and delivery in humans is unknown.<br/>Nursing Mothers: Racemic citalopram, like many other drugs, is excreted in human breast milk. There have been two reports of infants experiencing excessive somnolence, decreased feeding, and weight loss in association with breastfeeding from a citalopram-treated mother; in one case, the infant was reported to recover completely upon discontinuation of citalopram by its mother and, in the second case, no follow-up information was available. The decision whether to continue or discontinue either nursing or Lexapro therapy should take into account the risks of citalopram exposure for the infant and the benefits of Lexapro treatment for the mother.<br/>Pediatric Use: Safety and effectiveness in the pediatric population have not been established . One placebo-controlled trial in 264 pediatric patients with MDD has been conducted with Lexapro, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Lexapro in a child or adolescent must balance the potential risks with the clinical need.<br/>Geriatric Use: Approximately 6% of the 1144 patients receiving escitalopram in controlled trials of Lexapro in major depressive disorder and GAD were 60 years of age or older; elderly patients in these trials received daily doses of Lexapro between 10 and 20 mg. The number of elderly patients in these trials was insufficient to adequately assess for possible differential efficacy and safety measures on the basis of age. Nevertheless, greater sensitivity of some elderly individuals to effects of Lexapro cannot be ruled out. SSRIs and SNRIs, including Lexapro, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see PRECAUTIONS, Hyponatremia). In two pharmacokinetic studies, escitalopram half-life was increased by approximately 50% in elderly subjects as compared to young subjects and Cwas unchanged . 10 mg/day is the recommended dose for elderly patients . Of 4422 patients in clinical studies of racemic citalopram, 1357 were 60 and over, 1034 were 65 and over, and 457 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but again, greater sensitivity of some elderly individuals cannot be ruled out. | lld:dailymed |
| dailymed-drugs:278 | dailymed-instance:precautio... | General: The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur, amoxicillin should be discontinued and appropriate therapy instituted. Prescribing amoxicillin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.<br/>Information for Patients: Amoxicillin may be taken every 8 hours or every 12 hours, depending on the strength of the product prescribed. Patients should be counseled that antibacterial drugs including amoxicillin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When amoxicillin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by amoxicillin or other antibacterial drugs in the future.<br/>Laboratory Tests: As with any potent drug, periodic assessment of renal, hepatic, and hematopoietic function should be made during prolonged therapy. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with amoxicillin should have a follow-up serologic test for syphilis after 3 months.<br/>Drug Interactions: Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use of amoxicillin and probenecid may result in increased and prolonged blood levels of amoxicillin. Chloramphenicol, macrolides, sulfonamides, and tetracyclines may interfere with the bactericidal effects of penicillin. This has been demonstrated in vitro; however, the clinical significance of this interaction is not well documented.<br/>Drug/Laboratory Test Interactions: High urine concentrations of ampicillin may result in false-positive reactions when testing for the presence of glucose in urine using Clinitest, Benedict's Solution, or Fehling's Solution. Since this effect may also occur with amoxicillin, it is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix) be used. Following administration of ampicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted. This effect may also occur with amoxicillin.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Longterm studies in animals have not been performed to evaluate carcinogenic potential. Studies to detect mutagenic potential of amoxicillin alone have not been conducted; however, the following information is available from tests on a 4:1 mixture of amoxicillin and potassium clavulanate. Amoxicillin and potassium clavulanate was non-mutagenic in the Ames bacterial mutation assay, and the yeast geneconversion assay. Amoxicillin and potassium clavulanate was weakly positive in the mouse lymphoma assay, but the trend toward increased mutation frequencies in this assay occurred at doses that were also associated with decreased cell survival. Amoxicillin and potassium clavulanate was negative in the mouse micronucleus test, and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test, and was negative in each of these assays. In a multi-generation reproduction study in rats, no impairment of fertility or other adverse reproductive effects were seen at doses up to 500 mg/kg (approximately 3 times the human dose in mg/m).<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Labor and Delivery: Oral ampicillin-class antibiotics are poorly absorbed during labor. Studies in guinea pigs showed that intravenous administration of ampicillin slightly decreased the uterine tone and frequency of contractions but moderately increased the height and duration of contractions. However, it is not known whether use of amoxicillin in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary.<br/>Nursing Mothers: Penicillins have been shown to be excreted in human milk. Amoxicillin use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin is administered to a nursing woman.<br/>Pediatric Use: Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed. Dosing of amoxicillin should be modified in pediatric patients 12 weeks or younger (���3 months).<br/>Geriatric Use: An analysis of clinical studies of amoxicillin was conducted to determine whether subjects aged 65 and over respond differently from younger subjects. Of the 1,811 subjects treated with capsules of amoxicillin, 85% were<60 years old, 15% were���61 years old and 7% were���71 years old. This analysis and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because eldery patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. | lld:dailymed |
| dailymed-drugs:279 | dailymed-instance:precautio... | General: Before treatment with Seromycin is initiated, cultures should be taken and the organism's susceptibility to the drug should be established. In tuberculous infections, the organism's susceptibility to the other antituberculosis agents in the regimen should also be demonstrated. Anticonvulsant drugs or sedatives may be effective in controlling symptoms of CNS toxicity, such as convulsions, anxiety, and tremor. Patients receiving more than 500 mg of Seromycin daily should be closely observed for such symptoms. The value of pyridoxine in preventing CNS toxicity from Seromycin has not been proved. Administration of Seromycin and other antituberculosis drugs has been associated in a few instances with vitamin Band/or folic���acid deficiency, megaloblastic anemia, and sideroblastic anemia. If evidence of anemia develops during treatment, appropriate studies and therapy should be instituted.<br/>Laboratory Tests: Blood levels should be determined at least weekly for patients with reduced renal function, for individuals receiving a daily dosage of more than 500 mg, and for those showing signs and symptoms suggestive of toxicity. The dosage should be adjusted to keep the blood level below 30��g/mL.<br/>Drug Interactions: Concurrent administration of ethionamide has been reported to potentiate neurotoxic side effects. Alcohol and Seromycin are incompatible, especially during a regimen calling for large doses of the latter. Alcohol increases the possibility and risk of epileptic episodes. Concurrent administration of isoniazid may result in increased incidence of CNS effects, such as dizziness or drowsiness. Dosage adjustments may be necessary and patients should be monitored closely for signs of CNS toxicity.<br/>Carcinogenesis, Mutagenicity, and Impairment of Fertility: Studies have not been performed to determine potential for carcinogenicity. The Ames test and unscheduled DNA repair test were negative. A study in 2 generations of rats showed no impairment of fertility relative to controls for the first mating but somewhat lower fertility in the second mating.<br/>Pregnancy Category C: A study in 2 generations of rats given doses up to 100 mg/kg/day demonstrated no teratogenic effect in offspring. It is not known whether Seromycin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Seromycin should be given to a pregnant woman only if clearly needed.<br/>Nursing Mothers: Because of the potential for serious adverse reactions in nursing infants from Seromycin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Usage in Pediatric Patients: Safety and effectiveness in pediatric patients have not been established. | lld:dailymed |
| dailymed-drugs:280 | dailymed-instance:precautio... | General: Ticlopidine hydrochloride should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or pathological conditions. If it is desired to eliminate the antiplatelet effects of ticlopidine hydrochloride prior to elective surgery, the drug should be discontinued 10 to 14 days prior to surgery. Several controlled clinical studies have found increased surgical blood loss in patients undergoing surgery during treatment with ticlopidine. In TASS and CATS it was recommended that patients have ticlopidine discontinued prior to elective surgery. Several hundred patients underwent surgery during the trials, and no excessive surgical bleeding was reported. Prolonged bleeding time is normalized within 2 hours after administration of 20 mg methylprednisolone IV. Platelet transfusions may also be used to reverse the effect of ticlopidine hydrochloride on bleeding. Because platelet transfusions may accelerate thrombosis in patients with TTP on ticlopidine, they should, if possible, be avoided.<br/>Gl Bleeding: Ticlopidine hydrochloride prolongs template bleeding time. The drug should be used with caution in patients who have lesions with a propensity to bleed (such as ulcers). Drugs that might induce such lesions should be used with caution in patients on ticlopidine hydrochloride (See CONTRAINDICATIONS).<br/>Use in Hepatically Impaired Patients: Since ticlopidine is metabolized by the liver, dosing of ticlopidine hydrochloride or other drugs metabolized in the liver may require adjustment upon starting or stopping concomitant therapy. Because of limited experience in patients with severe hepatic disease, who may have bleeding diatheses, the use of ticlopidine hydrochloride is not recommended in this population (See CLINICAL PHARMACOLOGY and CONTRAINDICATIONS).<br/>Use in Renally Impaired Patients: There is limited experience in patients with renal impairment. Decreased plasma clearance, increased AUC values, and prolonged bleeding times can occur in renally impaired patients. In controlled clinical trials, no unexpected problems have been encountered in patients having mild renal impairment, and there is no experience with dosage adjustment in patients with greater degrees ofrenal impairment. Nevertheless, for renally impaired patients, it may be necessary to reduce the dosage of ticlopidine or discontinue it altogether, if hemorrhagic or hematopoietic problems are encountered (See CLINICAL PHARMACOLOGY).<br/>Information for the Patient [see Patient Package Insert (P.P.I.)]: Patients should be told that a decrease in the number of white blood cells (neutropenia) or platelets (thrombocytopenia) can occur with ticlopidine hydrochloride, especially during the first 3 months of treatment and that neutropenia, if it is severe, can result in an increased risk of infection. They should be told it is critically important to obtain the scheduled blood tests todetect neutropenia or thrombocytopenia. Patients should also be reminded to contact their physicians if they experience any indication of infection such as fever, chills, or sore throat, any of which might be a consequence of neutropenia. Thrombocytopenia may be part of a syndrome called TTP. Symptoms and signs of TTP, such as fever, weakness, difficulty speaking, seizures, yellowing of skin or eyes, dark or bloody urine, pallor or petechiae (pinpoint hemorrhagic spots on the skin), should be reported immediately. All patients should be told that it may take them longer than usual to stop bleeding when they take ticlopidine hydrochloride and that they should report any unusual bleeding to their physician. Patients should tell physicians and dentists that they are taking ticlopidine hydrochloride before any surgery is scheduled and before any new drug is prescribed. Patients should be told to promptly report side effects of ticlopidine hydrochloride such as severe or persistent diarrhea, skin rashes, or subcutaneous bleeding or any signs of cholestasis, such as yellow skin or sclera, dark urine, or light-colored stools. Patients should be told to take ticlopidine hydrochloride with food or just after eating in order to minimize gastrointestinal discomfort.<br/>Laboratory tests:<br/>LIVER FUNCTION: Ticlopidine hydrochloride therapy has been associated with elevations of alkaline phosphatase, bilirubin and transaminases, which generally occurred within 1 to 4 months of therapy initiation. In controlled clinical trials, the incidence of elevated alkaline phosphatase (greater than two times upper limit of normal) was 7.6% in ticlopidine patients, 6% in placebo patients and 2.5% in aspirin patients. The incidence of elevated AST (SGOT) (greater than two times upper limit of normal) was 3.1% in ticlopidine patients, 4% in placebo patients and 2.1% in aspirinpatients. No progressive increases were observed in closely monitored clinical trials (e.g. no transaminase greater than 10 times the upper limit of normal was seen), but most patients with these abnormalities had therapy discontinued. Occasionally patients had developed minor elevations in bilirubin. Post-marketing experience includes rare individuals with elevations in their transaminases and bilirubin to>10x above the upper limits of normal. Based on postmarketing and clinical trial experience, liver function testing, including ALT, AST, and GGT, should be considered whenever liver dysfunction is suspected, particularly during the first 4 months of treatment.<br/>Drug Interactions: Therapeutic doses of ticlopidine hydrochloride caused a 30% increase in the plasma half-life of antipyrine and may cause analogous effects on similarly metabolized drugs. Therefore, the dose of drugs metabolized by hepatic microsomal enzymes with low therapeutic ratios or being given to patients with hepatic impairment may require adjustment to maintain optimal therapeutic blood levels when starting or stopping concomitant therapy with ticlopidine. Studies of specific drug interactions yielded the following results:<br/>ASPIRIN AND OTHER NSAIDs: Ticlopidine potentiates the effect of aspirin or other NSAIDs on platelet aggregation. The safety of concomitant use of ticlopidine with aspirin or other NSAIDs has not been established. The safety of concomitant use of ticlopidine and aspirin beyond 30 days has not been established (See CLINICAL TRIALS: Stent Patients). Aspirin did not modify the ticlopidine-mediated inhibition of ADP-induced platelet aggregation, but ticlopidine potentiated the effect of aspirin on collagen-induced platelet aggregation. Caution should be exercised in patients who have lesions with a propensity to bleed, such as ulcers. Long-termconcomitant use of aspirin and ticlopidine is not recommended (See PRECAUTIONS - GI Bleeding).<br/>ANTACIDS: Administration of ticlopidine hydrochloride after antacids resulted in an 18% decrease in plasma levels of ticlopidine.<br/>CIMETIDINE: Chronic administration of cimetidine reduced the clearance of a single dose of ticlopidine hydrochloride by 50%.<br/>DIGOXIN: Co-administration of ticlopidine hydrochloride with digoxin resulted in a slight decrease (approximately 15%) in digoxin plasma levels. Little or no change in therapeutic efficacy of digoxin would be expected.<br/>THEOPHYLLINE: In normal volunteers, concomitant administration of ticlopidine hydrochloride resulted in a significant increase in the theophylline elimination half-life from 8.6 to 12.2 hours and a comparable reduction in total plasma clearance of theophylline.<br/>PHENOBARBITAL: In 6 normal volunteers, the inhibitory effects of ticlopidine hydrochloride on platelet aggregation were not altered by chronic administration of phenobarbital.<br/>PHENYTOIN: In vitro studies demonstrated that ticlopidine does not alter the plasma protein binding of phenytoin. However, the protein binding interactions of ticlopidine and its metabolites have not been studied in vivo. Several cases of elevated phenytoin plasma levels with associated somnolence and lethargy have been reported following coadministration with ticlopidine hydrochloride. Caution should be exercised in coadministering this drug with ticlopidine hydrochloride, and it may be useful to remeasure phenytoin blood concentrations.<br/>PROPRANOLOL: In vitro studies demonstrated that ticlopidine does not alter the plasma protein binding of propranolol. However, the protein binding interactions of ticlopidine and its metabolites have not been studied in vivo. Caution should be exercised in coadministering this drug with ticlopidine hydrochloride.<br/>OTHER CONCOMITANT THERAPY: Although specific interaction studies were not performed, in clinical studies ticlopidine hydrochloride was used concomitantly with beta blockers, calcium channel blockers, and diuretics without evidence of clinically significant adverse interactions (See PRECAUTIONS).<br/>Food Interaction: The oral bioavailability of ticlopidine is increased by 20% when taken after a meal. Administration of ticlopidine hydrochloride with food is recommended to maximize gastrointestinal tolerance. In controlled trials in stroke patients, ticlopidine hydrochloride was taken with meals.<br/>Carcinogenesis, Mutagenesis and Impairment of Fertility: In a 2-year oral carcinogenicity study in rats, ticlopidine at daily doses of up to 100 mg/kg (610 mg/m) was not tumorigenic. For a 70 kg person (1.73 mbody surface area), the dose represents 14 times the recommended clinical dose on a mg/kg basis and two times the clinical dose on body surface area basis. In a 78-week oral carcinogenicity study in mice, ticlopidine at daily doses up to 275 mg/kg (1180 mg/m) was not tumorigenic. The dose represents 40 times the recommended clinical dose on a mg/kg basis and four times the clinical dose on body surface area basis. Ticlopidine was not mutagenic in vitro in the Ames test, the rat hepatocyte DNA-repair assay, or the Chinese-hamster fibroblast chromosomal aberration test; or in vivo in the mouse spermatozoid morphology test, the Chinese-hamster micronucleus test, or the Chinese-hamster bone-marrow-cell sister-chromatid exchange test. Ticlopidine was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg/day.<br/>Pregnancy: Teratogenic Effects:<br/>PREGNANCY CATEGORY B: Teratology studies have been conducted in mice (doses up to 200 mg/kg/day), rats (doses up to 400 mg/kg/day) and rabbits (doses up to 200 mg/kg/day). Doses of 400 mg/kg in rats, 200 mg/kg/day in mice, and 100 mg/kg in rabbits produced maternal toxicity as well as fetal toxicity, but there was no evidence of a teratogenic potential of ticlopidine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, this drug should be used during pregnancy only if clearly needed.<br/>Nursing mothers: Studies in rats have shown ticlopidine is excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ticlopidine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric use: Safety and efficacy in pediatric patients have not been established.<br/>Geriatric use: Clearance of ticlopidine is somewhat lower in elderly patients and trough levels are increased. The major clinical trials with ticlopidine in stroke patients were conducted in an elderly population with an average age of 64 years. Of the total number of patients in the therapeutic trials, 45% of patients were over 65 years old and 12% were over 75 years old. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. | lld:dailymed |
| dailymed-drugs:281 | dailymed-instance:precautio... | During the course of acute febrile illness, encephalitides, gastroenteritis, dehydration and electrolyte imbalance, especially in pediatrics and the elderly or debilitated, CNS reactions such as opisthotonos, convulsions, coma and extrapyramidal symptoms have been reported with and without use of trimethobenzamide hydrochloride or other antiemetic agents. In such disorders caution should be exercised in administering trimethobenzamide, particularly to patients who have recently received other CNS-acting agents (phenothiazines, barbiturates, belladonna derivatives). Primary emphasis shouldbe directed toward the restoration of body fluids and electrolyte balance, the relief of fever and relief of the causative disease process. Overhydration should be avoided since it may result in cerebral edema. The antiemetic effects of trimethobenzamide may render diagnosis more difficult in such conditions as appendicitis and obscure signs of toxicity due to overdosage of other drugs. | lld:dailymed |
| dailymed-drugs:284 | dailymed-instance:precautio... | General: Chest discomfort (including pain, pressure, heaviness, tightness) has been reported after administration of 5-HTagonists, including AMERGE Tablets. These events have not been associated with arrhythmias or ischemic ECG changes in clinical trials with AMERGE Tablets. Because naratriptan may cause coronary artery vasospasm, patients who experience signs or symptoms suggestive of angina following naratriptan should be evaluated for the presence of CAD or a predisposition to Prinzmetal variant angina before receiving additional doses of naratriptan, and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur. Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud syndrome following naratriptan administration should be evaluated for atherosclerosis or predisposition to vasospasm (see CONTRAINDICATIONS and WARNINGS). AMERGE Tablets should also be administered with caution to patients with diseases that may alter the absorption, metabolism, or excretion of drugs, such as impaired renal or hepatic function (see CLINICAL PHARMACOLOGY, CONTRAINDICATIONS, and DOSAGE AND ADMINISTRATION). Care should be taken to exclude other potentially serious neurological conditions before treating headache in patients not previously diagnosed with migraine or who experience a headache that is atypical for them. There have been rare reports where patients received 5-HTagonists for severe headaches that were subsequently shown to have been secondary to an evolving neurologic lesion (see WARNINGS). For a given attack, if a patient has no response to the first dose of AMERGE, the diagnosis of migraine should be reconsidered before administration of a second dose. Overuse of acute migraine treatments has been associated with the exacerbation of headache (medication overuse headache) in susceptible patients. Withdrawal of the treatment may be necessary.<br/>Binding to Melanin-Containing Tissues: In rats treated with a single oral dose (10 mg/kg) of radiolabeled naratriptan, the elimination half-life of radioactivity from the eye was 90 days, suggesting that naratriptan and/or its metabolites may bind to the melanin of the eye. Because there could be accumulation in melanin-rich tissues over time, this raises the possibility that naratriptan could cause toxicity in these tissues after extended use. Although no systematic monitoring of ophthalmologic function was undertaken in clinical trials, and no specific recommendations for ophthalmologic monitoring are offered, prescribers should be aware of the possibility of long-term ophthalmologic effects.<br/>Changes in the Precorneal Tear Film: Dogs receiving oral naratriptan showed transient changes in the precorneal tear film. Corneal stippling was seen at the lowest dose tested, 1 mg/kg/day, and occurred intermittently from day 1 throughout the first 2 to 3 weeks of treatment. Although a no-effect dose was not established, the exposure at the lowest dose tested was approximately 5 times the human exposure after a 5-mg oral dose.<br/>Information for Patients: See PATIENT INFORMATION at the end of this labeling for the text of the separate leaflet provided for patients. Patients should be cautioned about the risk of serotonin syndrome with the use of naratriptan or other triptans, especially during combined use with SSRIs or SNRIs.<br/>Laboratory Tests: No specific laboratory tests are recommended for monitoring patients prior to and/or after treatment with AMERGE Tablets.<br/>Drug Interactions:<br/>Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome: Cases of life-threatening serotonin syndrome have been reported during combined use of SSRIs or SNRIs and triptans (see WARNINGS).<br/>Ergot-Containing Drugs: Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and naratriptan within 24 hours is contraindicated (see CONTRAINDICATIONS).<br/>Other 5-HTAgonists: The administration of naratriptan with other 5-HTagonists has not been evaluated in migraine patients. Because their vasospastic effects may be additive, coadministration of naratriptan and other 5-HTagonists within 24 hours of each other is not recommended (see CONTRAINDICATIONS).<br/>Drug/Laboratory Test Interactions: AMERGE Tablets are not known to interfere with commonly employed clinical laboratory tests.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis: Lifetime carcinogenicity studies, 104 weeks in duration, were carried out in mice and rats by oral gavage. There was no evidence of an increase in tumors related to naratriptan administration in mice receiving up to 200 mg/kg/day. That dose was associated with a plasma area-under-the-curve (AUC) exposure that was 110 times the exposure in humans receiving the maximum recommended daily dose of 5 mg. Two rat studies were conducted, 1 using a standard diet and the other a nitrite-supplemented diet (naratriptan can be nitrosated in vitro to form a mutagenic product that has been detected in the stomachs of rats fed a high nitrite diet). Doses of 5, 20, and 90 mg/kg were associated with week 13 AUC exposures that in the standard diet study were 7, 40, and 236 times, respectively, and in the nitrite-supplemented diet study were 7, 29, and 180 times, respectively, the exposure attained in humans given the maximum recommended daily dose of 5 mg. In both studies, there was an increase in the incidence of thyroid follicular hyperplasia in high-dose males and females and in thyroid follicular adenomas in high-dose males. In the standard diet study only, there was also an increase in the incidence of benign c-cell adenomas in the thyroid of high-dose males and females. The exposures achieved at the no-effect dose for thyroid tumors were 40 (standard diet) and 29 (nitrite-supplemented diet) times the exposure achieved in humans receiving the maximum recommended daily dose of 5 mg. In the nitrite-supplemented diet study only, the incidence of benign lymphocytic thymoma was increased in all treated groups of females. It was not determined if the nitrosated product is systemically absorbed. However, no changes were seen in the stomachs of rats in that study.<br/>Mutagenesis: Naratriptan was not mutagenic when tested in 2 gene mutation assays, the Ames test and the in vitro thymidine locus mouse lymphoma assay. It was not clastogenic in 2 cytogenetics assays, the in vitro human lymphocyte assay and the in vivo mouse micronucleus assay. Naratriptan can be nitrosated in vitro to form a mutagenic product (WHO nitrosation assay) that has been detected in the stomachs of ratsfed a nitrite-supplemented diet.<br/>Impairment of Fertility: In a reproductive toxicity study in which male and female rats were dosed prior to and throughout the mating period with 10, 60, 170, or 340 mg/kg/day (plasma exposures [AUC] approximately 11, 70, 230, and 470 times, respectively, the human exposure at the maximum recommended daily dose [MRDD] of 5 mg), there was a treatment-related decrease in the number of females exhibiting normal estrous cycles at doses of 170 mg/kg/day or greater and an increase in preimplantation loss at 60 mg/kg/day or greater. In high-dose group males, testicular/epididymal atrophy accompanied by spermatozoa depletion reduced mating success and may have contributed to the observed preimplantation loss. The exposures achieved at the no-effect doses for preimplantation loss, anestrus, and testicular effects were approximately 11, 70, and 230 times, respectively, the exposures in humans receiving the MRDD. In a study in which rats were dosed orally with 10, 60, or 340 mg/kg/day for 6 months, changes in the female reproductive tract including atrophic or cystic ovaries and anestrus were seen at the high dose. The exposure at the no-effect dose of 60 mg/kg was approximately 85 times the exposure in humans receiving the MRDD.<br/>Pregnancy: Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women; therefore, naratriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To monitor fetal outcomes of pregnant women exposed to AMERGE, GlaxoSmithKline maintains a Naratriptan Pregnancy Registry. Healthcare providers are encouraged to register patients by calling (800) 336-2176. In reproductive toxicity studies in rats and rabbits, oral administration of naratriptan was associated with developmental toxicity (embryolethality, fetal abnormalities, pup mortality, offspring growth retardation) at doses producing maternal plasma drug exposures as low as 11 and 2.5 times, respectively, the exposure in humans receiving the MRDD of 5 mg. When pregnant rats were administered naratriptan during the period of organogenesis at doses of 10, 60, or 340 mg/kg/day, there was a dose-related increase in embryonic death, with a statistically significant difference at the highest dose, and incidences of fetal structural variations (incomplete/irregular ossification of skull bones, sternebrae, ribs) were increased at all doses. The maternal plasma exposures (AUC) at these doses were approximately 11, 70, and 470 times the exposure in humans at the MRDD. The high dose was maternally toxic, as evidenced by decreased maternal body weight gain during gestation. A no-effect dose for developmental toxicity in rats exposed during organogenesis was not established. When doses of 1, 5, or 30 mg/kg/day were given to pregnant Dutch rabbits throughout organogenesis, the incidence of a specific fetal skeletal malformation (fused sternebrae) was increased at the high dose, and increased incidences of embryonic death and fetal variations (major blood vessel variations, supernumerary ribs, incomplete skeletal ossification) were observed at all doses (4, 20, and 120 times, respectively, the MRDD on a body surface area basis). Maternal toxicity (decreased body weight gain) was evident at the high dose in this study. In a similar study in New Zealand White rabbits (1, 5, or 30 mg/kg/day throughout organogenesis), decreased fetal weights and increased incidences of fetal skeletal variations were observed at all doses (maternal exposures equivalent to 2.5, 19, and 140 times exposure in humans receiving the MRDD), while maternal body weight gain was reduced at 5 mg/kg or greater. A no-effect dose for developmental toxicity in rabbits exposed during organogenesis was notestablished. When female rats were treated with 10, 60, or 340 mg/kg/day during late gestation and lactation, offspring behavioral impairment (tremors) and decreased offspring viability and growth were observed at doses of 60 mg/kg or greater, while maternal toxicity occurred only at the highest dose. Maternal exposures at the no-effect dose for developmental effects in this study were approximately 11 times the exposure in humans receiving the MRDD.<br/>Nursing Mothers: Naratriptan-related material is excreted in the milk of rats. Therefore, caution should be exercised when considering the administration of AMERGE Tablets to a nursing woman.<br/>Pediatric Use: Safety and effectiveness of AMERGE Tablets in pediatric patients (younger than 18 years) have not been established. One randomized, placebo-controlled clinical trial evaluating oral naratriptan (0.25 to 2.5 mg) in pediatric patients aged 12 to 17 years evaluated a total of 300 adolescent migraineurs. This study did not establish the efficacy of oral naratriptan compared to placebo in the treatment of migraine in adolescents (see CLINICAL TRIALS). Adverse events observed in this clinical trial were similar in nature to those reported in clinical trials in adults.<br/>Geriatric Use: The use of AMERGE Tablets in elderly patients is not recommended. Naratriptan is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in elderly patients who have reduced renal function. In addition, elderly patients are more likely to have decreased hepatic function; they are at higher risk for CAD; and blood pressure increases may be more pronounced in the elderly. Clinical studies of AMERGE Tablets did not include patients over 65 years of age. | lld:dailymed |
| dailymed-drugs:286 | dailymed-instance:precautio... | General: The possibility exists that stimulation of gallbladder contraction in patients with small gallbladder stones could lead to the evacuation of the stones from the gallbladder, resulting in their lodging in the cystic duct or in the common bile duct. The risk of such an event is considered to be minimal because sincalide, when given as directed, does not ordinarily cause complete contraction of the gallbladder.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been performed to evaluate carcinogenic or mutagenic potential, or possible impairment of fertility in males or females.<br/>Teratogenic Effects:<br/>Pregnancy Category B: Reproduction studies in rats in which sincalide was administered subcutaneously at doses up to 12.5 times the maximum recommended human dose revealed no evidence of harm to the fetus due to sincalide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed .<br/>Labor and Delivery: Sincalide should not be administered to pregnant women near term because of its effect on smooth muscle; the possibility of inducing labor prematurely exists. The effects of sincalide on labor, delivery and lactation in animals has not been determined .<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sincalide is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in children have not been established. | lld:dailymed |
| dailymed-drugs:287 | dailymed-instance:precautio... | General: Although hypotension has occurred only rarely, oxazepam should be administered with caution to patients in whom a drop in blood pressure might lead to cardiac complications. This is particularly true in the elderly patient.<br/>Information for Patients: To assure the safe and effective use of oxazepam, patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is advisable that they consult with their physician before either increasing the dose or abruptly discontinuing this drug.<br/>Pediatric Use: Safety and effectiveness in pediatric patients under 6 years of age have not been established. Absolute dosage for pediatric patients 6 to 12 years of age is not established.<br/>Geriatric Use: Clinical studies of oxazepam were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects. Age (<80 years old) does not appear to have a clinically significant effect on oxazepam kinetics . Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered. Greater sensitivity of some older individuals to the effects of oxazepam (e.g., sedation, hypotension, paradoxical excitation) cannot be ruled out . In general, dose selection for oxazepam for elderly patients should be cautious, usually starting at the lower end of the dosing range . | lld:dailymed |
| dailymed-drugs:2467 | dailymed-instance:precautio... | General: Although hypotension has occurred only rarely, oxazepam should be administered with caution to patients in whom a drop in blood pressure might lead to cardiac complications. This is particularly true in the elderly patient.<br/>Information for Patients: To assure the safe and effective use of oxazepam, patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is advisable that they consult with their physician before either increasing the dose or abruptly discontinuing this drug.<br/>Pediatric Use: Safety and effectiveness in pediatric patients under 6 years of age have not been established. Absolute dosage for pediatric patients 6 to 12 years of age is not established.<br/>Geriatric Use: Clinical studies of oxazepam were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects. Age (<80 years old) does not appear to have a clinically significant effect on oxazepam kinetics . Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered. Greater sensitivity of some older individuals to the effects of oxazepam (e.g., sedation, hypotension, paradoxical excitation) cannot be ruled out . In general, dose selection for oxazepam for elderly patients should be cautious, usually starting at the lower end of the dosing range . | lld:dailymed |
| dailymed-drugs:288 | dailymed-instance:precautio... | General: The possibility of suicide in seriously depressed patients is inherent in the illness and may persist until significant remission occurs. Therefore, prescriptions should be written for the smallest number of tablets consistent with good patient management. Hypotension, including orthostatic hypotension and syncope, has been reported to occur in patients receiving DESYREL. Concomitant administration of antihypertensive therapy with DESYREL may require a reduction in the dose of the antihypertensive drug. Little is known about the interaction between DESYREL and general anesthetics; therefore, prior to elective surgery, DESYREL should be discontinued for as long as clinically feasible. As with all antidepressants, the use of DESYREL should be based on the consideration of the physician that the expected benefits of therapy outweigh potential risk factors.<br/>Information for Patients: Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with DESYREL and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Teenagers is available for DESYREL. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking DESYREL.<br/>Clinical Worsening and Suicide Risk:: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Because priapism has been reported to occur in patients receiving DESYREL, patients with prolonged or inappropriate penile erection should immediately discontinue the drug and consult with the physician . Antidepressants may impair the mental and/or physical ability required for the performance of potentially hazardous tasks, such as operating an automobile or machinery; the patient should be cautioned accordingly. DESYREL may enhance the response to alcohol, barbiturates, and other CNS depressants. DESYREL should be given shortly after a meal or light snack. Within any individual patient, total drug absorption may be up to 20% higher when the drug is taken with food rather than on an empty stomach. The risk of dizziness/lightheadedness may increase under fasting conditions.<br/>Laboratory Tests: Occasional low white blood cell and neutrophil counts have been noted in patients receiving DESYREL. These were not considered clinically significant and did not necessitate discontinuation of the drug; however, the drug should be discontinued in any patient whose white blood cell count or absolute neutrophil count falls below normal levels. White blood cell and differential counts are recommended for patients who develop fever and sore throat (or other signs of infection) during therapy.<br/>Drug Interactions: In vitro drug metabolism studies suggest that there is a potential for drug interactions when trazodone is given with CYP3A4 inhibitors. Ritonavir, a potent CYP3A4 inhibitor, increased the C, AUC, and elimination half-life, and decreased clearance of trazodone after administration of ritonavir twice daily for 2 days. Adverse effects including nausea, hypotension, and syncope were observed when ritonavir and trazodone were co-administered. It is likely that ketoconazole, indinavir, and other CYP3A4 inhibitors such as itraconazole or nefazodone may lead to substantial increases in trazodone plasma concentrations, with the potential for adverse effects. If trazodone is used with a potent CYP3A4 inhibitor, a lower dose of trazodone should be considered. Carbamazepine reduced plasma concentrations of trazodone when co-administered. Patients should be closely monitored to see if there is a need for an increased dose of trazodone when taking both drugs. Increased serum digoxin or phenytoin levels have been reported to occur in patients receiving DESYREL concurrently with either of those two drugs. It is not known whether interactions will occur between monoamine oxidase (MAO) inhibitors and DESYREL. Due to the absence of clinical experience, if MAO inhibitors are discontinued shortly before or are to be given concomitantly with DESYREL, therapy should be initiated cautiously with gradual increase in dosage until optimum response is achieved.<br/>Therapeutic Interactions: Concurrent administration with electroshock therapy should be avoided because of the absence of experience in this area. There have been reports of increased and decreased prothrombin time occurring in warfarinized patients who take DESYREL.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No drug- or dose-related occurrence of carcinogenesis was evident in rats receiving DESYREL in daily oral doses up to 300 mg/kg for 18 months.<br/>Pregnancy Category C: DESYREL has been shown to cause increased fetal resorption and other adverse effects on the fetus in two studies using the rat when given at dose levels approximately 30���50 times the proposed maximum human dose. There was also an increase in congenital anomalies in one of three rabbit studies at approximately 15���50 times the maximum human dose. There are no adequate and well-controlled studies in pregnant women. DESYREL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: DESYREL and/or its metabolites have been found in the milk of lactating rats, suggesting that the drug may be secreted in human milk. Caution should be exercised when DESYREL is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in the pediatric population have not been established . Anyone considering the use of DESYREL in a child or adolescent must balance the potential risks with the clinical need. | lld:dailymed |
| dailymed-drugs:289 | dailymed-instance:precautio... | General:<br/>Abnormal Bleeding: SSRIs and SNRIs, including fluoxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of fluoxetine and NSAIDs, aspirin, or other drugs that affect coagulation (see Drug Interactions).<br/>Anxiety and Insomnia: In U.S. placebo-controlled clinical trials for major depressive disorder, 12% to 16% of patients treated with fluoxetine and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia. In U.S. placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with fluoxetine and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with fluoxetine and in 7% of patients treated with placebo. In U.S. placebo-controlled clinical trials for bulimia nervosa, insomnia was reported in 33% of patients treated with fluoxetine 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with fluoxetine 60 mg, and in 9% and 5% of patients treated with placebo. Among the most common adverse events associated with discontinuation (incidence at least twice that for placebo and at least 1% for fluoxetine in clinical trials collecting only a primary event associated with discontinuation) in U.S. placebo-controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in major depressive disorder) (see Table 4).<br/>Altered Appetite and Weight: Significant weight loss, especially in underweight depressed or bulimic patients may be an undesirable result of treatment with fluoxetine. In U.S. placebo-controlled clinical trials for major depressive disorder, 11% of patients treated with fluoxetine and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with fluoxetine and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with fluoxetine because of anorexia or weight loss . In U.S. placebo-controlled clinical trials for OCD, 17% of patients treated with fluoxetine and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with fluoxetine because of anorexia . In U.S. placebo-controlled clinical trials for bulimia nervosa, 8% of patients treated with fluoxetine 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with fluoxetine 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16-week double-blind trial. Weight change should be monitored during therapy.<br/>Activation of Mania/Hypomania: In U.S. placebo-controlled clinical trials for major depressive disorder, mania/hypomania was reported in 0.1% of patients treated with fluoxetine and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of major depressive disorder . In U.S. placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with fluoxetine and no patients treated with placebo. No patients reported mania/hypomania in U.S. placebo-controlled clinical trials for bulimia. In all U.S. fluoxetine clinical trials as of May 8, 1995, 0.7% of 10,782 patients reported mania/hypomania .<br/>Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including fluoxetine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when fluoxetine was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see Geriatric Use). Discontinuation of fluoxetine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death.<br/>Seizures: In U.S. placebo-controlled clinical trials for major depressive disorder, convulsions (or events described as possibly having been seizures) were reported in 0.1% of patients treated with fluoxetine and 0.2% of patients treated with placebo. No patients reported convulsions in U.S. placebo-controlled clinical trials for either OCD or bulimia. In all U.S. fluoxetine clinical trials as of May 8, 1995, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of major depressive disorder. Fluoxetine should be introduced with care in patients with a history of seizures.<br/>The Long Elimination Half-Lives of Fluoxetine and its Metabolites: Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment .<br/>Use in Patients with Concomitant Illness: Clinical experience with fluoxetine in patients with concomitant systemic illness is limited. Caution is advisable in using fluoxetine in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product's premarket testing. However, the electrocardiograms of 312 patients who received fluoxetine in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min. In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose should be used in patients with cirrhosis. Studies in depressed patients on dialysis did not reveal excessive accumulation of fluoxetine or norfluoxetine in plasma . Use of a lower or less frequent dose for renally impaired patients is not routinely necessary . In patients with diabetes, fluoxetine may alter glycemic control. Hypoglycemia has occurred during therapy with fluoxetine, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic dosage may need to be adjusted when therapy with fluoxetine is instituted or discontinued.<br/>Interference with Cognitive and Motor Performance: Any psychoactive drug may impair judgment, thinking, or motor skills, and patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely.<br/>Discontinuation of Treatment with Fluoxetine: During marketing of fluoxetine and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with fluoxetine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming thepreviously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy, which may minimize the risk of discontinuation symptoms with this drug .<br/>Information for Patients: Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with fluoxetine and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and other Serious Mental Illnesses,and Suicidal Thoughts or Actions" is available for fluoxetine. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking fluoxetine.<br/>Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.<br/>Serotonin Syndrome: Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of fluoxetine and triptans, tramadol or other serotonergic agents. Because fluoxetine may impair judgment, thinking, or motor skills, patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected. Patients should be advised to inform their physician if they are taking or plan to take any prescription or over-the-counter drugs, or alcohol. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physician if they are breast-feeding an infant. Patients should be advised to notify their physician if they develop a rash or hives.<br/>Laboratory Tests: There are no specific laboratory tests recommended.<br/>Drug Interactions: As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility .<br/>Drugs metabolized by CYP2D6: Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below), should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued .<br/>Drugs metabolized by CYP3A4: In an in vivo interaction study involving coadministration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine's extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.<br/>CNS active drugs: The risk of using fluoxetine in combination with other CNS active drugs has not been systematically evaluated. Nonetheless, caution is advised if the concomitant administration of fluoxetine and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status .<br/>Anticonvulsants: Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment.<br/>Antipsychotics: Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QTprolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QTprolongation warrants restricting the concurrent use of pimozide and fluoxetine. Concomitant use of fluoxetine and pimozide is contraindicated . For thioridazine, see CONTRAINDICATIONS and WARNINGS.<br/>Benzodiazepines: The half-life of concurrently administered diazepam may be prolonged in some patients . Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels.<br/>Lithium: There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly.<br/>Tryptophan: Five patients receiving fluoxetine in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress.<br/>Monoamine oxidase inhibitors: See CONTRAINDICATIONS.<br/>Other drugs effective in the treatment of major depressive disorder: In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2-to 10-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCA may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued .<br/>Serotonergic drugs: Based on the mechanism of action of SNRIs and SSRIs, including fluoxetine, and the potential for serotonin syndrome, caution is advised when fluoxetine is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John's Wort (see Serotonin Syndrome under WARNINGS). The concomitant use of fluoxetine with other SSRIs, SNRIs or tryptophan is not recommended (see Tryptophan).<br/>Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of fluoxetine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see Serotonin Syndrome under WARNINGS).<br/>Potential effects of coadministration of drugs tightly bound to plasma proteins: Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein-bound fluoxetine by other tightly-bound drugs .<br/>Drugs that interfere with hemostasis (e.g., NSAIDs, Aspirin,Warfarin): Serotonin release by platelets plays and important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown thatconcurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued.<br/>Electroconvulsive Therapy (ECT): There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: There is no evidence of carcinogenicity or mutagenicity from in vitro or animal studies. Impairment of fertility in adult animals at doses up to 12.5 mg/kg/day (approximately 1.5 times the MRHD on a mg/mbasis) was not observed.<br/>Carcinogenicity: The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively [approximately 1.2 and 0.7 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/mbasis], produced no evidence of carcinogenicity.<br/>Mutagenicity: Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells.<br/>Impairment of fertility: Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/mbasis) indicated that fluoxetine had no adverse effects on fertility (see Pediatric Use).<br/>Pregnancy:<br/>Pregnancy Category C: In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg on a mg/mbasis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/mbasis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/mbasis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/mbasis). Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nonteratogenic Effects: Neonates exposed to fluoxetine and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome . Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1���2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who hadnot been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. When treating a pregnant woman with fluoxetine during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment . Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.<br/>Labor and Delivery: The effect of fluoxetine on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended. In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother's plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools. The infant's plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding.<br/>Pediatric Use: The efficacy of fluoxetine for the treatment of major depressive disorder was demonstrated in two 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to���18 . The efficacy of fluoxetine for the treatment of OCD was demonstrated in one 13-week placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to<18 . The safety and effectiveness in pediatric patients<8 years of age in major depressive disorder and<7 years of age in OCD have not been established. Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to���18) with major depressive disorder or OCD . The acute adverse event profiles observed in the 3 studies (N=418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine. The longer-term adverse event profile observed in the 19-week major depressive disorder study (N=219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine . Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the acute phases of the 3 studies combined. Consequently, regular monitoring for the occurrence of mania/hypomania is recommended. As with other SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height (p=0.004) and 1.1 kg less in weight (p=0.008) than subjects treated with placebo. In addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels. The safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. In particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development, and maturation of children and adolescent patients. Therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine. Significant toxicity, including myotoxicity, long-term neurobehavioral and reproductive toxicity, and impaired bone development, has been observed following exposure of juvenile animals to fluoxetine. Some of these effects occurred at clinically relevant exposures. In a study in which fluoxetine (3, 10, or 30 mg/kg) was orally administered to young rats from weaning (Postnatal Day 21) through adulthood (Day 90), male and female sexual development was delayed at all doses, and growth (body weight gain, femur length) was decreased during the dosing period in animals receiving the highest dose. At the end of the treatment period, serum levels of creatine kinase (marker of muscle damage) were increased at the intermediate and high doses, and abnormal muscle and reproductive organ histopathology (skeletal muscle degeneration and necrosis, testicular degeneration and necrosis, epididymal vacuolation and hypospermia) was observed at the high dose. When animals were evaluated after a recovery period (up to 11 weeks after cessation of dosing), neurobehavioral abnormalities (decreased reactivity at all doses and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose) were seen; in addition, testicular and epididymal microscopic lesions and decreased sperm concentrations were found in the high dose group, indicating that the reproductive organ effects seen at the end of treatment were irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. Adverse effects similar to those observed in rats treated with fluoxetine during the juvenile period have not been reported after administration of fluoxetine to adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving the low, intermediate, and high dose in this study were approximately 0.1���0.2, 1���2, and 5���10 times, respectively, the average exposure in pediatric patients receiving the maximum recommended dose (MRD) of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, were approximately 0.3���0.8, 1���8, and 3���20 times, respectively, pediatric exposure at the MRD. A specific effect of fluoxetine on bone development has been reported in mice treated with fluoxetine during the juvenile period. When mice were treated with fluoxetine (5 or 20 mg/kg, intraperitoneal) for 4 weeks starting at 4 weeks of age, bone formation was reduced resulting in decreased bone mineral content and density. These doses did not affect overall growth (body weight gain or femoral length). The doses administered to juvenile mice in this study are approximately 0.5 and 2 times the MRD for pediatric patients on a body surface area (mg/m) basis. In another mouse study, administration of fluoxetine (10 mg/kg intraperitoneal) during early postnatal development (Postnatal Days 4 to 21) produced abnormal emotional behaviors (decreased exploratory behavior in elevated plus-maze, increased shock avoidance latency) in adulthood (12 weeks of age). The dose used in this study is approximately equal to the pediatric MRD on a mg/mbasis. Because of the early dosing period in this study, the significance of these findings to the approved pediatric use in humans is uncertain. Fluoxetine is approved for use in pediatric patients with MDD and OCD . Anyone considering the use of fluoxetine in a child or adolescent must balance the potential risks with the clinical need.<br/>Geriatric Use: U.S. fluoxetine clinical trials included 687 patients���65 years of age and 93 patients���75 years of age. The efficacy in geriatric patients has been established . For pharmacokinetic information in geriatric patients, see Age under CLINICAL PHARMACOLOGY. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including fluoxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event . | lld:dailymed |
| dailymed-drugs:290 | dailymed-instance:precautio... | General: Review of experience to date suggests that a subgroup of older patients with associated severe illness may tolerate diarrhea less well. When clindamycin is indicated in these patients, they should be carefully monitored for change in bowel frequency. Clindamycin phosphate should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. Clindamycin phosphate should be prescribed with caution in atopic individuals. Certain infections may require incision and drainage or other indicated surgical procedures in addition to antibiotic therapy. The use of clindamycin phosphate may result in overgrowth of nonsusceptible organisms���particularly yeasts. Should superinfections occur, appropriate measures should be taken as indicated by the clinical situation. Clindamycin phosphate should not be injected intravenously undiluted as a bolus, but should be infused over at least 10 to 60 minutes as directed in the DOSAGE AND ADMINISTRATION section. Clindamycin dosage modification may not be necessary in patients with renal disease. In patients with moderate to severe liver disease, prolongation of clindamycin half-life has been found. However, it was postulated from studies that when given every eight hours, accumulation should rarely occur. Therefore, dosage modification in patients with liver disease may not be necessary. However, periodic liver enzyme determinations should be made when treating patients with severe liver disease. Prescribing clindamycin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.<br/>Information for Patients: Patients should be counseled that antibacterial drugs including clindamycin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When clindamycin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by clindamycin or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.<br/>Laboratory Tests: During prolonged therapy periodic liver and kidney function tests and blood counts should be performed.<br/>Drug Interactions: Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, it should be used with caution in patients receiving such agents. Antagonism has been demonstrated between clindamycin and erythromycin in vitro. Because of possible clinical significance, the two drugs should not be administered concurrently.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long term studies in animals have not been performed with clindamycin to evaluate carcinogenic potential. Genotoxicity tests performed included a rat micronucleus test and an Ames Salmonella reversion test. Both tests were negative. Fertility studies in rats treated orally with up to 300 mg/kg/day (approximately 1.1 times the highest recommended adult human dose based on mg/m) revealed no effects on fertility or mating ability.<br/>Pregnancy::<br/>Teratogenic Effects:: Pregnancy Category B Reproduction studies performed in rats and mice using oral doses of clindamycin up to 600 mg/kg/day (2.1 and 1.1 times the highest recommended adult human dose based on mg/m, respectively) or subcutaneous doses of clindamycin up to 250 mg/kg/day (0.9 and 0.5 times the highest recommended adult human dose based on mg/m, respectively) revealed no evidence of teratogenicity. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed.<br/>Nursing Mothers: Clindamycin has been reported to appear in breast milk in the range of 0.7 to 3.8 mcg/mL at dosages of 150 mg orally to 600 mg intravenously. Because of the potential for adverse reactions due to clindamycin in neonates (see Pediatric Use), the decision to discontinue the drug should be made, taking into account the importance of the drug to the mother.<br/>Pediatric Use: When clindamycin phosphate injection is administered to the pediatric population (birth to 16 years), appropriate monitoring of organ system functions is desirable. Usage in Newborns and Infants The product contains benzyl alcohol as a preservative. Benzyl alcohol has been associated with a fatal���Gasping Syndrome���in premature infants. The potential for the toxic effect in the pediatric population from chemicals that mayleach from the single dose premixed I.V. preparation in plastic has not been evaluated.<br/>Geriatric Use: Clinical studies of clindamycin did not include sufficient numbers of patients age 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experience indicates that antibiotic-associated colitis and diarrhea (due to Clostridium difficile) seen in association with most antibiotics occur more frequently in the elderly (>60 years) and may be more severe. These patients should be carefully monitored for the development of diarrhea. Pharmacokinetic studies with clindamycin have shown no clinically important differences between young and elderly subjects with normal hepatic function and normal (age-adjusted) renal function after oral or intravenous administration. | lld:dailymed |
| dailymed-drugs:291 | dailymed-instance:precautio... | General: Naproxen sodium extended-release tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of naproxen sodium extended-release tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.<br/>Hepatic Effects: Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including naproxen sodium extended-release tablets. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs.In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with naproxen sodium extended-release tablets. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), naproxen sodium extended-release tablets should be discontinued.<br/>Hematological Effects: Anemia is sometimes seen in patients receiving NSAIDs, including naproxen sodium extended-release tablets. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including naproxen sodium extended-release tablets, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving naproxen sodium extended-release tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.<br/>Preexisting Asthma: Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, naproxen sodium extended-release tablets should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.<br/>Information for Patients: Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.<br/>Laboratory Tests: Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, naproxen sodium extended-release tablets should be discontinued.<br/>Drug Interactions:<br/>ACE-inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.<br/>Aspirin: [When naproxen sodium extended-release tablets in administered with aspirin, its protein binding is reduced, although the clearance of free naproxen sodium extended-release tablets is not altered. The clinical significance of this interaction is not known; however,] as with other NSAIDs, concomitant administration of naproxen and aspirin is not generally recommended because of the potential of increased adverse effects.<br/>Diuretics: Clinical studies, as well as post marketing observations, have shown that naproxen sodium extended-release tablets can reduce the natriuretic effect-of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure , as well as to assure diuretic efficacy.<br/>Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.<br/>Methotrexate: NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.<br/>Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.<br/>Drug/Laboratory Test Interactions: Naproxen may decrease platelet aggregation and prolong bleeding time. This effect should be kept in mind when bleeding times are determined. The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-dinitrobenzene used in this assay. Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. Naproxen may interfere with some urinary assays of 5-hydroxyindoleacetic acid (5HIAA).<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: A two year study was performed in rats to evaluate the carcinogenic potential of naproxen at doses of 8 mg/kg/day, 16 mg/kg/day, and 24 mg/kg/day (50 mg/m, 100 mg/m, and 150 mg/m). The maximum dose used was 0.28 times the systemic exposure to humans at the recommended dose. No evidence of tumorigenicity was found.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C: Reproduction studies have been performed in rats at 20 mg/kg/day (125 mg/m/day, 0.23 times the human systemic exposure), rabbits at 20 mg/kg/day (220 mg/m/day, 0.27 times the human systemic exposure) and mice at 170 mg/kg/day (510 mg/m/day, 0.28 times the human systemic exposure) with no evidence of impaired fertility or harm to the fetus due to the drug. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, naproxen sodium extended-release tablets should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.<br/>Nonteratogenic Effects: There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus, and intracranial hemorrhage. Naproxen treatment given in the late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin E levels in preterm infants. Because of the known effect of drugs of this class on the human fetal cardiovascular system (closure of ductus arteriosus), use during third trimester should be avoided.<br/>Labor and Delivery: In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. Naproxen-containing products are not recommended in labor and delivery because, through its prostaglandin synthesis inhibitory effect, naproxen may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage. The effects of naproxen sodium extended-release tablets on labor and delivery in pregnant women are unknown.<br/>Nursing Mothers: The naproxen anion has been found in the milk of lactating women at a concentration of approximately 1% of that found in the plasma. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be avoided.<br/>Pediatric Use: No pediatric studies have been performed with naproxen sodium extended-release tablets, thus safety of naproxen sodium extended-release tablets in pediatric populations has not been established.<br/>Geriatric Use: Clinical studies of naproxen sodium extended-release tablets did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Aging may affect the pharmacokinetics of naproxen. Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. Elderly or debilitated seem to tolerate GI ulcerations and bleeding less well than other individuals taking NSAIDs . Additionally, elderly patients may be more sensitive to dose dependent reduction in renal prostaglandin formation while taking NSAIDs . | lld:dailymed |
| dailymed-drugs:293 | dailymed-instance:precautio... | General:: Prescribing cefprozil in the absence of proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug resistant bacteria. In patients with known or suspected renal impairment ,careful clinical observation and appropriate laboratory studies should be done prior to and during therapy. The total daily dose of cefprozil should be reduced in these patients because high and/or prolonged plasma antibiotic concentrations can occur in such individuals from usual doses. Cephalosporins, including cefprozil, should be given with caution to patients receiving concurrent treatment with potent diuretics since these agents are suspected of adversely affecting renal function. Prolonged use of cefprozil may result in the overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken. Cefprozil should be prescribed with caution in individuals with a history of gastrointestinal disease particularly colitis. Positive direct Coombs' tests have been reported during treatment with cephalosporin antibiotics.<br/>Information for Patients:: Patients should be counseled that antibacterial drugs including cefprozil should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefprozil are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cefprozil or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.<br/>Drug Interactions:: Nephrotoxicity has been reported following concomitant administration of aminoglycoside antibiotics and cephalosporin antibiotics. Concomitant administration of probenecid doubled the AUC for cefprozil. The bioavailability of the capsule formulation of cefprozil was not affected when administered 5 minutes following an antacid.<br/>Drug/Laboratory Test Interactions:: Cephalosporin antibiotics may produce a false positive reaction for glucose in the urine with copper reduction tests (Benedict's or Fehling's solution or with Clinitest tablets), but not with enzyme-based tests for glycosuria (e.g., Clinistix). A false negative reaction may occur in the ferricyanide test for blood glucose. The presence of cefprozil in the blood does not interfere with the assay of plasma or urine creatinine by the alkaline picrate method.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:: Long term in vivo studies have not been performed to evaluate the carcinogenic potential of cefprozil. Cefprozil was not found to be mutagenic in either the Ames Salmonella or E. coli WP2 urvA reversion assays or the Chinese hamster ovary cell HGPRT forward gene mutation assay and it did not induce chromosomal abnormalities in Chinese hamster ovary cells or unscheduled DNA synthesis in rat hepatocytes in vitro. Chromosomal aberrations were not observed in bone marrow cells from rats dosed orally with over 30 times the highest recommended human dose based upon mg/m. Impairment of fertility was not observed in male or female rats given oral doses of cefprozil up to 18.5 times the highest recommended human dose based upon mg/m.<br/>Pregnancy::<br/>Teratogenic Effects- Pregnancy Category B:: Reproduction studies have been performed in rabbits, mice, and rats using oral doses of cefprozil of 0.8, 8.5, and 18.5 times the maximum daily human dose (1000 mg) based upon mg/m, and have revealed no harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.<br/>Labor and Delivery:: Cefprozil has not been studied for use during labor and delivery. Treatment should only be given if clearly needed.<br/>Nursing Mothers:: Small amounts of cefprozil (<0.3% of dose) have been detected in human milk following administration of a single 1 gram dose to lactating women. The average levels over 24 hours ranged from 0.25 to 3.3 mcg/mL. Caution should be exercised when cefprozil tablets are administered to a nursing woman, since the effect of cefprozil on nursing infants is unknown.<br/>Pediatric Use:: The safety and effectiveness of cefprozil in the treatment of otitis media have been established in the age groups 6 months to 12 years. Use of cefprozil for the treatment of otitis media is supported by evidence from adequate and well-controlled studies of cefprozil in pediatric patients. The safety and effectiveness of cefprozil in the treatment of pharyngitis/tonsillitis or uncomplicated skin and skin-structure infections have been established in the age groups 2 to 12 years. Use of cefprozil for the treatment of these infections is supported by evidence from adequate and well-controlled studies of cefprozil in pediatric patients. The safety and effectiveness of cefprozil in the treatment of acute sinusitis have been established in the age groups 6 months to 12 years. Use of cefprozil in these age groups is supported by evidence from adequate and well-controlled studies of cefprozil in adults. Safety and effectiveness in pediatric patients below the age of 6 months have not been established for the treatment of otitis media or acute sinusitis, or below the age of 2 years for the treatment of pharyngitis/tonsillitis or uncomplicated skin and skin-structure infections. However, accumulation of other cephalosporin antibiotics in newborn infants (resulting from prolonged drug half-life in this age group) has been reported.<br/>Geriatric Use:: Of the more than 4500 adults treated with cefprozil in clinical studies, 14% were 65 years and older, while 5% were 75 years and older. When geriatric patients received the usual recommended adult doses, their clinical efficacy and safety were comparable to clinical efficacy and safety in nongeriatric adult patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals to the effects of cefprozil cannot be excluded . Cefprozil is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function. See DOSAGE AND ADMINISTRATION for dosing recommendations for patients with impaired renal function. | lld:dailymed |
| dailymed-drugs:294 | dailymed-instance:precautio... | General: Discontinue use and do not retreat with terconazole if sensitization, irritation, fever, chills or flu-like symptoms are reported during use. Laboratory Tests: If there is a lack of response to terconazole, appropriate microbiological studies (standard KOH smear and/or cultures) should be repeated to confirm the diagnosis and rule out other pathogens.<br/>Drug Interactions:: The therapeutic effect of this product is not affected by oral contraceptive usage.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:: Carcinogenesis: Studies to determine the carcinogenic potential of terconazole have not been performed. Mutagenicity: Terconazole was not mutagenic when tested in vitro for induction of microbial point mutations (Ames test), or for inducing cellular transformation, or in vivo for chromosome breaks (micronucleus test) or dominant lethal mutations in mouse germ cells. Impairment of Fertility: No impairment of fertility occurred when female rats were administered terconazole orally up to 40 mg/kg/day for a three month period. Pregnancy: Teratogenic Effects: Pregnancy Category C: There was no evidence of teratogenicity when terconazole was administered orally up to 40 mg/kg/day (100x the intravaginal human dose of the 0.4% vaginal cream formulation) in rats, or 20 mg/kg/day in rabbits, or subcutaneously up to 20 mg/kg/day in rats. Dosages at or below 10 mg/kg/day produced no embryotoxicity; however, there was a delay in fetal ossification at 10 mg/kg/day in rats. There was some evidence of embryotoxicity in rabbits and rats at 20-40 mg/kg. In rats, this was reflected as a decrease in litter size and number of viable young and reduced fetal weight. There was also delay in ossification and an increase incidence of skeletal variants. The no-effect dose of 10 mg/kg/day resulted in a mean peak plasma level of terconazole in pregnant rats of 0.176 mcg/mL which exceeds by 44 times the mean peak plasma level (0.004 mcg/mL) seen in normal subjects after intravaginal administration of terconazole vaginal cream 0.4%. This safety assessment does not account for possible exposure of the fetus through direct transfer to terconazole from the irritated vagina by diffusion across amniotic membranes. Since terconazole is absorbed from the human vagina, it should not be used in the first trimester of pregnancy unless the physician considers it essential to the welfare of the patient. Nursing Mothers: It is not known whether this drug is excreted in human milk. Animal studies have shown that rat offspring exposed via the milk of treated (40 mg/kg/orally) dams showed decreased survival during the first few post-partum days, but overall pup weight and weight gain were comparable to or greater than controls throughout lactation. Because many drugs are excreted in human milk, and because of the potential for adverse reaction in nursing infants from terconazole, a decision should be made whether to discontinue nursing or to discontinuethe drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and efficacy in children have not been established. Geriatric Use: Clinical studies of terconazole vaginal cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. | lld:dailymed |
| dailymed-drugs:295 | dailymed-instance:precautio... | General: Lopressor: Lopressor should be used with caution in patients with impaired hepatic function. Hydrochlorothiazide: All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance, namely hyponatremia, hypochloremic alkalosis, and hypokalemia (see Laboratory Tests and Drug/Drug Interactions). Warning signs are dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbance, such as nausea or vomiting. Hypokalemia may develop, especially in cases of brisk diuresis or severe cirrhosis. Interference with adequate oral intake of electrolytes will also contribute to hypokalemia. Hypokalemia may be avoided or treated by the use of potassium supplements or foods with a high potassium content. Any chloride deficit is generally mild and usually does not require specific treatment, except under extraordinary circumstances (as in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when the hyponatremia is life-threatening. In cases of actual salt depletion, appropriate replacement is the therapy of choice. Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy. Latent diabetes may become manifest during thiazide administration (see Drug/Drug Interactions). The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient. If progressive renal impairment becomes evident, withholding or discontinuing diuretic therapy should be considered. Calcium excretion is decreased by thiazides. Pathological changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. The common complications of hyperparathyroidism, such as renal lithiasis, bone resorption, and peptic ulceration, have not been seen. Thiazide diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.<br/>Information for Patients: Patients should be advised to take Lopressor HCT regularly and continuously, as directed, with or immediately following meals. If a dose should be missed, the patient should take only the next scheduled dose (without doubling it). Patients should not discontinue Lopressor HCT without consulting the physician. Patients should be advised (1) to avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient's response to therapy with Lopressor HCT has been determined; (2) to contact the physician if any difficulty in breathing occurs; (3) to inform the physician or dentist before any type of surgery that he or she is taking Lopressor HCT.<br/>Laboratory Tests: Lopressor: Clinical laboratory findings may include elevated levels of serum transaminase, alkaline phosphatase, and lactate dehydrogenase. Hydrochlorothiazide: Initial and periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids.<br/>Drug/Drug Interactions: Lopressor: Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients treated with Lopressor plus a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension. Both digitalis glycosides and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Risk of Anaphylactic Reaction: While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.<br/>General Anesthetics: Some inhalation anesthetics may enhance the cardiodepressant effect of beta blockers (see WARNINGS; Lopressor; Major Surgery).<br/>CYP2D6 Inhibitors: Potent inhibitors of the CYP2D6 enzyme may increase the plasma concentration of Lopressor. Strong inhibition of CYP2D6 would mimic the pharmacokinetics of CYP2D6 poor metabolizer. Caution should therefore be exercised when administering potent CYP2D6 inhibitors with Lopressor. Known clinically significant potent inhibitors of CYP2D6 are antidepressants such as fluoxetine, paroxetine or bupropion, antipsychotics such as thioridazine, antiarrhythmics such as quinidine or propafenone, antiretrovirals such as ritonavir, antihistamines such as diphenhydramine, antimalarials such as hydroxychloroquine or quinidine, antifungals such as terbinafine and medications for stomach ulcers such as cimetidine.<br/>Clonidine: If a patient is treated with clonidine and Lopressor concurrently, and clonidine treatment is to be discontinued, Lopressor should be stopped several days before clonidine is withdrawn. Rebound hypertension that can follow withdrawal of clonidine may be increased in patients receiving concurrent beta blocker treatment. Hydrochlorothiazide: Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalemia may develop during concomitant use of steroids or ACTH. Insulin requirements in diabetic patients may be increased, decreased, or unchanged. Thiazides may decrease arterial responsiveness to norepinephrine, but not enough to preclude effectiveness of the pressor agent for therapeutic use. Thiazides may increase the responsiveness to tubocurarine. Lithium renal clearance is reduced by thiazides, increasing the risk of lithium toxicity. There have been rare reports in the literature of hemolytic anemia occurring with the concomitant use of hydrochlorothiazide and methyldopa. Concurrent administration of some nonsteroidal anti-inflammatory agents may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics. Cholestyramine and colestipol resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.<br/>Drug/Laboratory Test Interactions: Hydrochlorothiazide: Thiazides may decrease serum levels of protein-bound iodine without signs of thyroid disturbance. Thiazides should be discontinued before tests for parathyroid function are made. (see General, Hydrochlorothiazide, Calcium excretion).<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Lopressor HCT: Carcinogenicity and mutagenicity studies have not been conducted with Lopressor HCT. Lopressor HCT produced no evidence of impaired fertility in male or female rats administered gavaged doses up to 200/50 mg/kg (100/50 times the maximum recommended daily human dose) prior to mating and throughout gestation and rearing of young. Lopressor: Long-term studies in animals have been conducted to evaluate carcinogenic potential. In a 2-year study in rats at three oral dosage levels of up to 800 mg/kg per day, there was no increase in the development of spontaneously occurring benign or malignant neoplasms of any type. The only histologic changes that appeared to be drug related were an increased incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg per day, benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (benign plus malignant) lung tumors, or in the overall incidence of tumors or malignant tumors. This 21-month study was repeated in CD-1 mice, and no statistically or biologically significant differences were observed between treated and control miceof either sex for any type of tumor. All mutagenicity tests performed (a dominant lethal study in mice, chromosome studies in somatic cells, a Salmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly test in somatic interphase nuclei) were negative. No evidence of impaired fertility due to Lopressor was observed in a study performed in rats at doses up to 55.5 times the maximum daily human dose of 450 mg. Hydrochlorothiazide: Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses up to approximately 600 mg/kg/day) or in male and female rats (at doses up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (Ames assay) and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300��g/mL, and in the Aspergillus nidulans nondisjunction assay at an unspecified concentration. Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg/day, respectively, prior to mating and throughout gestation.<br/>Pregnancy: Teratogenic Effects. Pregnancy Category C: Lopressor HCT: No evidence of adverse effects on pregnancy or the fetus were observed in rats when dams were administered gavaged doses up to 200/50 mg/kg of Lopressor HCT (100/50 times the maximum recommended daily human dose) during the period of organogenesis. Increased postimplantation loss and decreased postnatal survival were observed with these doses when administered later in pregnancy (gestation days 15-21). In rabbits, increased fetal loss was observed with oral doses of 25/6.25 mg/kg of Lopressor HCT (12/6 times the maximum recommended daily human dose), but not with lower doses. There are no adequate and well-controlled studies of Lopressor HCT in pregnant women. Lopressor HCT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Lopressor: Lopressor has been shown to increase postimplantation loss and decrease neonatal survival in rats at doses up to 55.5 times the maximum daily human dose of 450 mg. Distribution studies in mice confirm exposure of the fetus when Lopressor is administered to the pregnant animal. These studies have revealed no evidence of teratogenicity. Hydrochlorothiazide: Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus.<br/>Nonteratogenic Effects: Hydrochlorothiazide: Thiazides cross the placental barrier and appear in cord blood, and there is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.<br/>Nursing Mothers: Lopressor is excreted in breast milk in a very small quantity. An infant consuming 1 liter of breast milk daily would receive a dose of metoprolol of less than 1 mg. Thiazides are also excreted in breast milk. If the use of Lopressor HCT is deemed essential, the patient should stop nursing.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric Use: Clinical studies of Lopressor HCT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Hydrochlorothiazide is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see WARNINGS). In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:296 | dailymed-instance:precautio... | Dantrium should be used with caution in patients with impaired pulmonary function, particularly those with obstructive pulmonary disease, and in patients with severely impaired cardiac function due to myocardial disease. It should be used with caution in patients with a history of previous liver disease or dysfunction . Information for Patients: Patients should be cautioned against driving a motor vehicle or participating in hazardous occupations while taking Dantrium. Caution should be exercised in the concomitant administration of tranquilizing agents. Dantrium might possibly evoke a photosensitivity reaction; patients should be cautioned about exposure to sunlight while taking it. | lld:dailymed |
| dailymed-drugs:298 | dailymed-instance:precautio... | Concomitant Use With Oral Contraceptives: Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations of lamotrigine (see PRECAUTIONS, Drug Interactions). Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking lamotrigine (see DOSAGE AND ADMINISTRATION, Special Populations, Women and oral contraceptives, Adjustments to the maintenance dose of lamotrigine). During the week of inactive hormone preparation (���pill-free���week) of oral contraceptive therapy, plasma levels are expected to rise, as much as doubling by the end of the week. Adverse events consistent with elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur.<br/>Dermatological Events (see BOX WARNING, WARNINGS): Serious rashes associated with hospitalization and discontinuation of lamotrigine have been reported. Rare deaths have been reported, but their numbers are too few to permit a precise estimate of the rate. There are suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have been reported in the absence of these factors. In epilepsy clinical trials, approximately 10% of all patients exposed to lamotrigine developed a rash. In the Bipolar Disorder clinical trials, 14% of patients exposed to lamotrigine developed a rash. Rashes associated with lamotrigine do not appear to have unique identifying features. Typically, rash occurs in the first 2 to 8 weeks following treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the first appearance of arash. Although most rashes resolved even with continuation of treatment with lamotrigine, it is not possible to predict reliably which rashes will prove to be serious or life threatening. ACCORDINGLY, LAMOTRIGINE SHOULD ORDINARILY BE DISCONTINUED AT THE FIRST SIGN OF RASH, UNLESS THE RASH IS CLEARLY NOT DRUG RELATED. DISCONTINUATION OF TREATMENT MAY NOT PREVENT A RASH FROM BECOMING LIFE THREATENING OR PERMANENTLY DISABLING OR DISFIGURING. It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater considerationshould be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism, and DOSAGE AND ADMINISTRATION).<br/>Use in Patients With Epilepsy:<br/>Sudden Unexplained Death in Epilepsy (SUDEP): During the premarketing development of lamotrigine, 20 sudden and unexplained deaths were recorded among a cohort of 4,700 patients with epilepsy (5,747 patient-years of exposure). Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving lamotrigine (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004 for a recently studied clinical trial population similar to that in the clinical development program for lamotrigine, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or suggest concern depends on the comparability of the populations reported upon to the cohort receiving lamotrigine and the accuracy of the estimates provided. Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving lamotrigine and those receiving another antiepileptic drug that underwent clinical testing in a similar population at about the same time. Importantly, that drug is chemically unrelated to lamotrigine. This evidence suggests, although it certainly does not prove, that the high SUDEP rates reflect population rates, not a drug effect.<br/>Status Epilepticus: Valid estimates of the incidence of treatment emergent status epilepticus among patients treated with lamotrigine are difficult to obtain because reporters participating in clinical trials did not all employ identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status. In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure flurries, etc.) were made.<br/>Use in Patients With Bipolar Disorder:<br/>Acute Treatment of Mood Episodes: Safety and effectiveness of lamotrigine in the acute treatment of mood episodes has not been established.<br/>Children and Adolescents (Less Than 18 Years of Age): Treatment with antidepressants is associated with an increased risk of suicidal thinking and behavior in children and adolescents with major depressive disorder and other psychiatric disorders. It is not known whether lamotrigine is associated with a similar risk in this population (see PRECAUTIONS, Clinical Worsening and Suicide Risk Associated with Bipolar Disorder). Safety and effectiveness of lamotrigine in patients below the age of 18 years with mood disorders have not been established.<br/>Clinical Worsening and Suicide Risk Associated with Bipolar Disorder: Patients with bipolar disorder may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviors (suicidality) whether or not they are taking medications for bipolar disorder. Patients should be closely monitored for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes. In addition, patients with a history of suicidal behavior or thoughts, those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, and young adults, are at an increased risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition (including development of new symptoms) and /or the emergence of suicidal ideation/behavior or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening (including development of new symptoms) and/or the emergence of suicidal ideation/behavior especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Prescriptions for lamotrigine tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Overdoses have been reported for lamotrigine, some of which have been fatal (see OVERDOSAGE).<br/>Addition of Lamotrigine to a Multi drug Regimen That Includes Valproate (Dosage Reduction): Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the presence of valproate is less than half of that required in its absence (see DOSAGE AND ADMINISTRATION).<br/>Use in Patients With Concomitant Illness: Clinical experience with lamotrigine in patients with concomitant illness is limited. Caution is advised when using lamotrigine in patients with diseases or conditions that could affect metabolism or elimination of the drug, such as renal, hepatic, or cardiac functional impairment. Hepatic metabolism to the glucuronide followed by renal excretion is the principal route of elimination of lamotrigine (see CLINICAL PHARMACOLOGY). A study in individuals with severe chronic renal failure (mean creatinine clearance = 13 mL/min) not receiving other AEDs indicated that the elimination half-life of unchanged lamotrigine is prolonged relative to individuals with normal renal function. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine, it should be used with caution in these patients, generally using a reducedmaintenance dose for patients with significant impairment. Because there is limited experience with the use of lamotrigine in patients with impaired liver function, the use in such patients may be associated with as yet unrecognized risks (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).<br/>Binding in the Eye and Other Melanin-Containing Tissues: Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological testing was performed in one controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine's binding to melanin is unknown. Accordingly, although there are no specific recommendations for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.<br/>Information for Patients: Prior to initiation of treatment with lamotrigine, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately. In addition, the patient should notify his or her physician if worsening of seizure control occurs. Patients should be advised that lamotrigine may cause dizziness, somnolence, and other symptoms and signs of central nervous system (CNS) depression. Accordingly, they should be advised neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on lamotrigine to gauge whether or not it adversely affects their mental and/or motor performance. Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physicians if they intend to breast-feed or are breast-feeding an infant. Women should be advised to notify their physician if they plan to start or stop use of oral contraceptives or other female hormonal preparations. Starting estrogen-containing oral contraceptives may significantly decrease lamotrigine plasma levels and stopping estrogen-containing oral contraceptives (including the���pill-free���week) may significantly increase lamotrigine plasma levels (see PRECAUTIONS, Drug Interactions). Women should also be advised to promptly notify their physician if they experience adverse events or changes in menstrual pattern (e.g., break-through bleeding) while receiving lamotrigine in combination with these medications. Patients should be advised to notify their physician if they stop taking lamotrigine for any reason and not to resume lamotrigine without consulting their physician. Patients should be informed of the availability of a patient information leaflet, and they should be instructed to read the leaflet prior to taking lamotrigine. See PATIENT INFORMATION at the end of this labeling for the text of the leaflet provided for patients.<br/>Laboratory Tests: The value of monitoring plasma concentrations of lamotrigine has not been established. Because of the possible pharmacokinetic interactions between lamotrigine and other drugs including AEDs (see Table 3), monitoring of the plasma levels of lamotrigine and concomitant drugs may be indicated, particularly during dosage adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma levels of lamotrigine and other drugs and whether or not dosage adjustments are necessary.<br/>Drug Interactions: The net effects of drug interactions with lamotrigine are summarized in Table 3 (see also DOSAGE AND ADMINISTRATION).<br/>Oral Contraceptives: In 16 female volunteers, an oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel increased the apparent clearance of lamotrigine (300 mg/day) by approximately 2 fold with a mean decrease in AUC of 52% and in Cof 39%. In this study, trough serum lamotrigine concentrations gradually increased and were approximately 2 fold higher on average at the end of the week of the inactive preparation compared to trough lamotrigine concentrations at the end of the active hormone cycle. Gradual transient increases in lamotrigine plasma levels (approximate 2 fold increase) occurred during the week of inactive hormone preparation (���pill-free���week) for women not also taking a drug that increased the clearance of lamotrigine (carbamazepine, phenytoin, phenobarbital, primidone, or rifampin). The increase in lamotrigine plasma levels will be greater if the dose of lamotrigine is increased in the few days before or during the���pill-free���week. Increases in lamotrigine plasma levels could result in dose-dependent adverse effects (see PRECAUTIONS, Concomitant Use With Oral Contraceptives). In the same study, coadministration of lamotrigine (300 mg/day) in 16 female volunteers did not affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive preparation. There was a mean decrease in the AUC and Cof the levonorgestrel component of 19% and 12%, respectively. Measurement of serum progesterone indicated that there was no hormonal evidence of ovulation in any of the 16 volunteers, although measurement of serum FHS, LH, and estradiol indicated that there was some loss of suppression of the hypothalamic-pituitary-ovarian axis. The effects of doses of lamotrigine other than 300 mg/day have not been studied in clinical trials. The clinical significance of the observed hormonal changes on ovulatory activity is unknown. However, the possibility of decreased contraceptive efficacy in some patients cannot be excluded. Therefore, patients should be instructed to promptly report changes in their menstrual pattern (e.g., break-though bleeding). Dosage adjustments will be necessary for most women receiving estrogen-containing oral contraceptive preparations (see DOSAGE AND ADMINISTRATION, Special Populations, Women and oral contraceptives).<br/>Other Hormonal Contraceptives or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2 fold, and the progestin only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.<br/>Bupropion: The pharmacokinetics of a 100 mg single dose of lamotrigine in healthy volunteers (n = 12) were not changed by coadministration of bupropion sustained-release formulation (150 mg twice a day) starting 11 days before lamotrigine.<br/>Carbamazepine: Lamotrigine has no appreciable effect on steady-state carbamazepine plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness, diplopia, ataxia, and blurred vision in patients receiving carbamazepine with lamotrigine than in patients receiving other AEDs with lamotrigine (see ADVERSE REACTIONS). The mechanism of this interaction is unclear. The effect of lamotrigine on plasma concentrations of carbamazepine-epoxide is unclear. In a small subset of patients (n = 7) studied in a placebo-controlled trial, lamotrigine had no effect on carbamazepine-epoxide plasma concentrations, but in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels increased. The addition of carbamazepine decreases lamotrigine steady-state concentrations by approximately 40%.<br/>Felbamate: In a study of 21 healthy volunteers, coadministration of felbamate (1,200 mg twice daily) with lamotrigine (100 mg twice daily for 10 days) appeared to have no clinically relevant effects on the pharmacokinetics of lamotrigine.<br/>Folate Inhibitors: Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers should be aware of this action when prescribing other medications that inhibit folate metabolism.<br/>Gabapentin: Based on a retrospective analysis of plasma levels in 34 patients who received lamotrigine both with and without gabapentin, gabapentin does not appear to change the apparent clearance of lamotrigine.<br/>Levetiracetam: Potential drug interactions between levetiracetam and lamotrigine were assessed by evaluating serum concentrations of both agents during placebo-controlled clinical trials. These data indicate that lamotrigine does not influence the pharmacokinetics of levetiracetam and that levetiracetam does not influence the pharmacokinetics of lamotrigine.<br/>Lithium: The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by coadministration of lamotrigine (100 mg/day) for 6 days.<br/>Olanzapine: The AUC and Cof olanzapine were similar following the addition of olanzapine (15 mg once daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 16) compared to the AUC and Cin healthy male volunteers receiving olanzapine alone (n = 16). In the same study, the AUC and Cof lamotrigine was reduced on average by 24% and 20%, respectively, following the addition of olanzapine to lamotrigine in healthy male volunteers compared to those receiving lamotrigine alone. This reduction in lamotrigine plasma concentrations is not expected to be clinically relevant.<br/>Oxcarbazepine: The AUC and Cof oxcarbazepine and its active 10-monohydroxy oxcarbazepine metabolite were not significantly different following the addition of oxcarbazepine (600 mg twice daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 13) compared to healthy male volunteers receiving oxcarbazepine alone (n = 13). In the same study, the AUC and Cof lamotrigine were similar following the addition of oxcarbazepine (600 mg twice daily) to lamotrigine in healthy male volunteers compared to those receiving lamotrigine alone. Limited clinical data suggest a higher incidence of headache, dizziness, nausea, and somnolence with coadministration of lamotrigine and oxcarbazepine compared to lamotrigine alone or oxcarbazepine alone.<br/>Phenobarbital, Primidone: The addition of phenobarbital or primidone decreases lamotrigine steady-state concentrations by approximately 40%.<br/>Phenytoin: Lamotrigine has no appreciable effect on steady-state phenytoin plasma concentrations in patients with epilepsy. The addition of phenytoin decreases lamotrigine steady-state concentrations by approximately 40%.<br/>Pregabalin: Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic interactions between lamotrigine and pregabalin.<br/>Rifampin: In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased the apparent clearance of a single 25 mg dose of lamotrigine by approximately 2 fold (AUC decreased by approximately 40%).<br/>Topiramate: Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of lamotrigine resulted in a 15% increase in topiramate concentrations.<br/>Valproate: When lamotrigine was administered to healthy volunteers (n = 18) receiving valproate, the trough steady-state valproate plasma concentrations decreased by an average of 25% over a 3 week period, and then stabilized. However, adding lamotrigine to the existing therapy did not cause a change in valproate plasma concentrations in either adult or pediatric patients in controlled clinical trials. The addition of valproate increased lamotrigine steady-state concentrations in normal volunteers by slightly more than 2 fold. In one study, maximal inhibition of lamotrigine clearance was reached at valproate doses between 250 mg/day and 500 mg/day and did not increase as the valproate dose was further increased.<br/>Zonisamide: In a study of 18 patients with epilepsy, coadministration of zonisamide (200 to 400 mg/day) with lamotrigine (150 to 500 mg/day) for 35 days had no significant effect on the pharmacokinetics of lamotrigine.<br/>Known Inducers or Inhibitors of Glucuronidation: Drugs other than those listed above have not been systematically evaluated in combination with lamotrigine. Since lamotrigine is metabolized predominately by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine, and doses of lamotrigine may require adjustmentbased on clinical response.<br/>Other: Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine, haloperidol, lorazepam, phenelzine, risperidone, sertraline, or trazodone (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism). Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of drugs eliminated predominantly by CYP2D6 (see CLINICAL PHARMACOLOGY).<br/>Drug/Laboratory Test Interactions: None known.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of carcinogenicity was seen in 1 mouse study or 2 rat studies following oral administration of lamotrigine for up to 2 years at maximum tolerated doses (30 mg/kg per day for mice and 10 to 15 mg/kg per day for rats, doses that are equivalent to 90 mg/mand 60 to 90 mg/m, respectively). Steady-state plasma concentrations ranged from 1 to 4 mcg/mL in the mouse study and 1 to 10 mcg/mL in the rat study. Plasma concentrations associated with the recommended human doses of 300 to 500 mg/day are generally in the range of 2 to 5 mcg/mL, but concentrations as high as 19 mcg/mL have been recorded. Lamotrigine was not mutagenic in the presence or absence of metabolic activation when tested in 2 gene mutation assays (the Ames test and the in vitro mammalian mouse lymphoma assay). In 2 cytogenic assays (the in vitro human lymphocyte assay and the in vivo rat bone marrow assay), lamotrigine did not increase the incidence of structural or numerical chromosomal abnormalities. No evidence of impairment of fertility was detected in rats given oral doses of lamotrigine up to 2.4 times the highest usual human maintenance dose of 8.33 mg/kg per day or 0.4 times the human dose on a mg/mbasis. The effect of lamotrigine on human fertility is unknown.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nonteratogenic Effects: As with other antiepileptic drugs, physiological changes during pregnancy may affect lamotrigine concentrations and/or therapeutic effect. There have been reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-partum concentrations after delivery. Dosage adjustments may be necessary to maintain clinical response.<br/>Pregnancy Exposure Registry: To facilitate monitoring fetal outcomes of pregnant women exposed to lamotrigine, physicians should encourage patients, before fetal outcome (e.g., ultrasound, results of amniocentesis, birth, etc.) is known, to register in the North American Antiepileptic Drug Pregnancy Registry by calling (888) 233-2334 (toll free).<br/>Labor and Delivery: The effect of lamotrigine on labor and delivery in humans is unknown.<br/>Use in Nursing Mothers: Preliminary data indicate that lamotrigine passes into human milk. Because the effects on the infant exposed to lamotrigine by this route are unknown, breast-feeding while taking lamotrigine is not recommended.<br/>Pediatric Use: Lamotrigine tablets are indicated as adjunctive therapy for partial seizures and for the generalized seizures of Lennox-Gastaut syndrome in patients above 2 years of age. Safety and effectiveness in patients below the age of 18 years with Bipolar Disorder has not been established.<br/>Geriatric Use: Clinical studies of lamotrigine for epilepsy and in Bipolar Disorder did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:299 | dailymed-instance:precautio... | General: The initial dose of droperidol should be appropriately reduced in elderly, debilitated and other poor-risk patients. The effect of the initial dose should be considered in determining incremental doses. Certain forms of conduction anesthesia, such as spinal anesthesia and some peridural anesthetics, can alter respiration by blocking intercostal nerves and can cause peripheral vasodilation and hypotension because of sympathetic blockade. Through other mechanisms , droperidol can also alter circulation. Therefore, when droperidol is used to supplement these forms of anesthesia, the anesthetist should be familiar with the physiological alterations involved, and be prepared to manage them in the patients elected for these forms of anesthesia. If hypotension occurs, the possibility of hypovolemia should be considered and managed with appropriate parenteral fluid therapy. Repositioning the patient to improve venous return to the heart should be considered when operative conditions permit. It should be noted that in spinal and peridural anesthesia, tilting the patient into a head-down position may result in a higher level of anesthesia than is desirable, as well as impair venous return to the heart. Care should be exercised in moving and positioning of patients because of a possibility of orthostatic hypotension. If volume expansion with fluids plus these other countermeasures do not correct the hypotension, then the administration of pressor agents other than epinephrine should be considered. Epinephrine may paradoxically decrease the blood pressure in patients treated with droperidol due to the alpha-adrenergic blocking action of droperidol. Since droperidol may decrease pulmonary arterial pressure, this fact should be considered by those who conduct diagnostic or surgical procedures where interpretation of pulmonary arterial pressure measurements might determine final management of the patient. Vital signs and ECG should be monitored routinely. When the EEG is used for postoperative monitoring, it may be found that the EEG pattern returns to normal slowly. Impaired Hepatic or Renal Function: Droperidol should be administered with caution to patients with liver and kidney dysfunction because of the importance of these organs in the metabolism and excretion of drugs. Pheochromocytoma: In patients with diagnosed/suspected pheochromocytoma, severe hypertension and tachycardia have been observed after the administration of droperidol.<br/>Drug Interactions:: Potentially Arrhythmogenic Agents: Any drug known to have the potential to prolong the QT interval should not be used together with droperidol. Possible pharmacodynamic interactions can occur between droperidol and potentially arrhythmogenic agents such as class I or III antiarrhythmics, antihistamines that prolong the QT interval, antimalarials, calcium channel blockers, neuroleptics that prolong the QT interval, and antidepressants. Caution should be used when patients are taking concomitant drugs known to induce hypokalemia or hypomagnesemia as they may precipitate QT prolongation and interact with droperidol. These would include diuretics, laxatives and supraphysiological use of steroid hormones with mineralocorticoid potential. CNS Depressant Drugs: Other CNS depressant drugs (e.g. barbiturates, tranquilizers, opioids and general anesthetics) have additive or potentiating effects with droperidol. When patients have received such drugs, the dose of droperidol required will be less than usual. Following the administration of droperidol, the dose of other CNS depressant drugs should be reduced. Carcinogenesis, Mutagenesis, Impairment of Fertility: No carcinogenicity studies have been carried out with droperidol. The micronucleus test in female rats revealed no mutagenic effects in single oral doses as high as 160 mg/kg. An oral study in rats (Segment 1) revealed no impairment of fertility in either males or females at 0.63, 2.5 and 10 mg/kg doses (approximately 2, 9 and 36 times maximum recommended human iv/im dosage). Pregnancy: Category C. Droperidol administered intravenously has been shown to cause a slight increase in mortality of the newborn rat at 4.4 times the upper human dose. At 44 times the upper human dose, mortality rate was comparable to that for control animals. Following intramuscular administration, increased mortality of the offspring at 1.8 times the upper human dose is attributed to CNS depression in the dams who neglected to remove placentae from their offspring. Droperidol has not been shown to be teratogenic in animals. There are no adequate and well-controlled studies in pregnant women. Droperidol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery: There are insufficient data to support the use of droperidol in labor and delivery. Therefore, such use is not recommended. Nursing Mothers: It is not known whether droperidol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when droperidol is administered to a nursing mother. Pediatric Use: The safety of droperidol in children younger than two years of age has not been established. | lld:dailymed |
| dailymed-drugs:300 | dailymed-instance:precautio... | General: The lowest possible dose of corticosteroids should be used to control the condition under treatment. When reduction in dosage is possible, the reduction should be gradual. Since complications of treatment with corticosteroids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used. Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement.<br/>Cardio-renal: As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency.<br/>Endocrine: Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relativeinsufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently.<br/>Gastrointestinal: Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. There is an enhanced effect due to decreased metabolism of corticosteroids in patients with cirrhosis.<br/>Musculoskeletal: Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (e.g., postmenopausal women) before initiating corticosteroid therapy.<br/>Neuro-psychiatric: Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that they affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect. An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatinine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression, to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.<br/>Ophthalmic: Intraocular pressure may become elevated in some individuals. If steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored.<br/>Information for Patients: Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision. As prolonged use may cause adrenal insufficiency and make patients dependent on corticosteroids, they should advise any medical attendants that they are taking corticosteroids and they should seek medical advice at once should they develop an acute illness including fever or other signs of infection. Following prolonged therapy, withdrawal of corticosteroids may result in symptoms of the corticosteroid withdrawal syndrome including myalgia, arthralgia, and malaise. Persons who are on corticosteroids should be warned to avoid exposure to chickenpox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.<br/>Drug Interactions: Aminoglutethimide: Aminoglutethimide may diminish adrenal suppression by corticosteroids. Amphotericin B injection and potassium-depleting agents: When corticosteroids are administered concomitantly with potassium-depleting agents (e.g., amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. In addition, there have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance (see Drug Interactions, Hepatic Enzyme Inducers, Inhibitors and Substrates ). Anticholinesterases: Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy. Anticoagulants, oral: Co-administration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect. Antidiabetics: Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. Antitubercular drugs: Serum concentrations of isoniazid may be decreased. Cholestyramine: Cholestyramine may increase the clearance of corticosteroids. Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. Dexamethasone suppression test (DST): False-negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported. Thus, results of the DST should be interpreted with caution in these patients. Digitalis glycosides: Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Ephedrine: Ephedrine may enhance the metabolic clearance of corticosteroids, resulting in decreased blood levels and lessened physiologic activity, thus requiring an increase in corticosteroid dosage. Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Hepatic Enzyme Inducers, Inhibitors and Substrates: Drugs which induce cytochrome P450 3A4 (CYP 3A4) enzyme activity (e.g., barbiturates, phenytoin, carbamazepine, rifampin) may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. Drugs which inhibit CYP 3A4 (e.g., ketoconazole, macrolide antibiotics such as erythromycin) have the potential to result in increased plasma concentrations of corticosteroids. Dexamethasone is a moderate inducer of CYP 3A4. Co-administration with other drugs that are metabolized by CYP 3A4 (e.g., indinavir, erythromycin) may increase their clearance, resulting in decreased plasma concentration. Ketoconazole: Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects. In addition, ketoconazole alone can inhibit adrenal corticosteroid synthesis and may cause adrenal insufficiency during corticosteroid withdrawal. Nonsteroidal anti-inflammatory agents (NSAIDS): Concomitant use of aspirin (or other nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids. Phenytoin: In post-marketing experience, there have been reports of both increases and decreases in phenytoin levels with dexamethasone co-administration, leading to alterations in seizure control. Skin tests: Corticosteroids may suppress reactions to skin tests. Thalidomide: Co-administration with thalidomide should be employed cautiously, as toxic epidermal necrolysis has been reported with concomitant use. Vaccines: Patients on corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS, Infections, Vaccination).<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C.: Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and well-controlled studies in pregnant women. Corticosteroidsshould be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.<br/>Nursing Mothers: Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from corticosteroids, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: The efficacy and safety of corticosteroids in the pediatric population are based on the well-established course of effect of corticosteroids, which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome (patients>2 years of age), and aggressive lymphomas and leukemias (patients>1 month of age). Other indications for pediatric use of corticosteroids, e.g., severe asthma and wheezing, are based on adequate and well-controlled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations. The adverse effects of corticosteroids in pediatric patients are similar to those in adults (see ADVERSE REACTIONS). Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Pediatric patients who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression (i.e., cosyntropin stimulation and basalcortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids,pediatric patients should be titrated to the lowest effective dose.<br/>Geriatric Use: Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In particular, the increased risk of diabetes mellitus, fluid retention and hypertension in elderly patients treated with corticosteroids should be considered. | lld:dailymed |
| dailymed-drugs:301 | dailymed-instance:precautio... | General: Alcohol and Dextrose Injections USP should be administered slowly, and the patient observed for restlessness or narcosis. The half lives of phenytoin, warfarin and tolbutamide may be shortened 50% to 75% by concurrent administration of alcohol. Alcohol increases serum uric acid and can precipitate acute gout. The vasodilating effect of alcohol may potentiate postural hypotension, particularly in association with some antihypertensive drugs. If the administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result. To minimize the risk of possible incompatibilities arising from mixing this solution with other additives that may be prescribed, the final infusate should be inspected for cloudiness or precipitation immediately after mixing, prior to administration, and periodically during administration. Use only if solution is clear and vacuum is present.<br/>Usage in Pregnancy:<br/>Pregnancy Category C: Animal reproduction studies have not been conducted with Alcohol and Dextrose Injections USP. It is also not known whether Alcohol and Dextrose Injections USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Alcohol and Dextrose Injections USP should be given to a pregnant woman only if clearly needed.<br/>Pediatric Use: Safety and effectiveness in children have not been established. | lld:dailymed |
| dailymed-drugs:302 | dailymed-instance:precautio... | Clemastine fumarate should be used with caution in patients with: history of bronchial asthma, increased intraocular pressure, hyperthyroidism, cardiovascular disease, and hypertension.<br/>Drug Interactions: MAO inhibitors prolong and intensify the anticholinergic (drying) effects of antihistamines. | lld:dailymed |
| dailymed-drugs:303 | dailymed-instance:precautio... | Acute shortness of breath and severe bronchospasm have been reported following the administration of vinca alkaloids in patients who had previously or simultaneously received MUTAMYCIN. The onset of this acute respiratory distress occurred within minutes to hours after the vinca alkaloid injection. The total number of doses for each drug has varied considerably. Bronchodilators, steroids and/or oxygen have produced symptomaticrelief. A few cases of adult respiratory distress syndrome have been reported in patients receiving MUTAMYCIN in combination with other chemotherapy and maintained at FIOconcentrations greater than 50% perioperatively. Therefore, caution should be exercised using only enough oxygen to provide adequate arterial saturation since oxygen itself is toxic to the lungs. Careful attention should be paid to fluid balance and overhydration should be avoided. Bladder fibrosis/contraction has been reported with intravesical administration (not an approved route of administration), which in rare cases has required cystectomy.<br/>Nursing Mothers: It is not known if mitomycin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from mitomycin, it is recommended that nursing be discontinued when receiving mitomycin therapy.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established. | lld:dailymed |
| dailymed-drugs:304 | dailymed-instance:precautio... | Prescribing Program for LOTRONEX: To prescribe LOTRONEX, the physician must be enrolled in the Prescribing Program for LOTRONEX. To enroll, physicians must understand the benefits and risks of treatment with LOTRONEX for severe diarrhea-predominant IBS, including the information in the Prescribing Information, Medication Guide, and Patient-Physician Agreement for LOTRONEX. Physicians need to be able to: To enroll in the Prescribing Program for LOTRONEX call 1-888-423-5227 or visit www.lotronex.com to complete the Physician Enrollment Form.<br/>Information for Patients: Patients should be fully counseled on and understand the risks and benefits of LOTRONEX before an initial prescription is written. The patient may be educated by the enrolled physician or a healthcare provider under a physician's direction. PHYSICIANS MUST: Copies of the Patient-Physician Agreement for LOTRONEX and additional copies of the Medication Guide are available by contacting Prometheus at 1-888-423-5227 or visiting www.lotronex.com. PATIENTS WHO ARE PRESCRIBED LOTRONEX SHOULD BE INSTRUCTED TO:<br/>Drug Interactions: Because alosetron is metabolized by a variety of hepatic CYP drug-metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance of alosetron. Fluvoxamine is a known strong inhibitor of CYP1A2 and also inhibits CYP3A4, CYP2C9, and CYP2C19. In a pharmacokinetic study, 40 healthy female subjects received fluvoxamine in escalating doses from 50 to 200 mg per day for 16 days, with coadministration of alosetron 1 mg on the last day. Fluvoxamine increased mean alosetron plasma concentrations (AUC) approximately 6���fold and prolonged the half-life by approximately 3���fold. Concomitant administration of alosetron and fluvoxamine is contraindicated (see CONTRAINDICATIONS). Concomitant administration of alosetron and moderate CYP1A2 inhibitors, including quinolone antibiotics and cimetidine, has not been evaluated, but should be avoided unless clinically necessary because of similar potential drug interactions. Ketoconazole is a known strong inhibitor of CYP3A4. In a pharmacokinetic study, 38 healthy female subjects received ketoconazole 200 mg twice daily for 7 days, with coadministration of alosetron 1 mg on the last day. Ketoconazole increased mean alosetron plasma concentrations (AUC) by 29%. Caution should be used when alosetron and ketoconazole are administered concomitantly. Coadministration of alosetron and strong CYP3A4 inhibitors, such as clarithromycin, telithromycin, protease inhibitors, voriconazole, and itraconazole has not been evaluated but should be undertaken with caution because of similar potential drug interactions. The effect of induction or inhibition of other pathways on exposure to alosetron and its metabolites is not known. In vitro human liver microsome studies and an in vivo metabolic probe study demonstrated that alosetron did not inhibit CYP enzymes 2D6, 3A4, 2C9, or 2C19. In vitro, at total drug concentrations 27-fold higher than peak plasma concentrations observed with the 1-mg dose, alosetron inhibited CYP enzymes 1A2 (60%) and 2E1 (50%). In an in vivo metabolic probe study, alosetron did not inhibit CYP2E1but did produce 30% inhibition of both CYP1A2 and N-acetyltransferase. Although not studied with alosetron, inhibition of N-acetyltransferase may have clinically relevant consequences for drugs such as isoniazid, procainamide, and hydralazine. The effect on CYP1A2 was explored further in a clinical interaction study with theophylline and no effect on metabolism was observed. Another study showed that alosetron had no clinically significant effect on plasma concentrations of the oral contraceptive agents ethinyl estradiol and levonorgestrel (CYP3A4 substrates). A clinical interaction study was also conducted with alosetron and the CYP3A4 substrate cisapride. No significant effects on cisapride metabolism or QT interval were noted. The effects of alosetron on monoamine oxidases and on intestinal first pass secondary to high intraluminal concentrations have not been examined. Based on the above data from in vitro and in vivo studies, it is unlikely that alosetron will inhibit the hepatic metabolic clearance ofdrugs metabolized by the major CYP enzyme 3A4, as well as the CYP enzymes 2D6, 2C9, 2C19, 2E1, or 1A2. Alosetron does not appear to induce the major cytochrome P450 (CYP) drug metabolizing enzyme 3A. Alosetron also does not appear to induce CYP enzymes 2E1 or 2C19. It is not known whether alosetron might induce other enzymes.<br/>Hepatic Insufficiency: Due to the extensive hepatic metabolism of alosetron, increased exposure to alosetron and/or its metabolites is likely to occur in patients with hepatic insufficiency. Alosetron should not be used in patients with severe hepatic impairment and should be used with caution in patients with mild or moderatehepatic impairment (see CLINICAL PHARMACOLOGY: Population Subgroups: Reduced Hepatic Function).<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In 2-year oral studies, alosetron was not carcinogenic in mice at doses up to 30 mg/kg/day or in rats at doses up to 40 mg/kg/day. These doses are, respectively, about 60 to 160 times the recommended human dose of alosetron of 2 mg/day (1 mg twice daily) based on body surface area. Alosetron was not genotoxic in the Ames tests, the mouse lymphoma cell (L5178Y/TK) forward gene mutation test, the human lymphocyte chromosome aberration test, the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, or the in vivo rat micronucleus test for mutagenicity. Alosetron at oral doses up to 40 mg/kg/day (about 160 times the recommended daily human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male or female rats.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in rats at doses up to 40 mg/kg/day (about 160 times the recommended human dose based on body surface area) and rabbits at oral doses up to 30 mg/kg/day (about 240 times the recommended daily human dose based on body surface area). These studies have revealed no evidence of impaired fertility or harm to the fetus due to alosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, LOTRONEX should be used during pregnancy only if clearly needed.<br/>Nursing Mothers: Alosetron and/or metabolites of alosetron are excreted in the breast milk of lactating rats. It is not known whether alosetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when LOTRONEX is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric Use: Postmarketing experience suggests that elderly patients may be at greater risk for complications of constipation (see WARNINGS). | lld:dailymed |
| dailymed-drugs:306 | dailymed-instance:precautio... | General: Immediately after initiation of PA therapy, patients should be closely observed for possible hypersensitivity reactions, especially if procaine or local anesthetic sensitivity is suspected, and for muscular weakness if myasthenia gravis is a possibility. In conversion of atrial fibrillation to normal sinus rhythm by any means, dislodgement of mural thrombi may lead to embolization, which should be kept in mind. After a day or so, steady state plasma PA levels are produced following regular oral administration of a given dose of PRONESTYL (Procainamide Hydrochloride Tablets; Procainamide Hydrochloride Capsules) at set intervals, with peak plasma concentrations at about 90 to 120 minutes after each dose. After achieving and maintaining therapeutic plasma concentrations and satisfactory electrocardiographic and clinical responses, continued frequent periodic monitoring of vital signs and electrocardiograms is advised. If evidence of QRS widening of more than 25 percent or marked prolongation of the Q-T interval occurs, concern for overdosage is appropriate, and reduction in dosage is advisable if a 50 percent increase occurs. Elevated serum creatinine or urea nitrogen, reduced creatinine clearance, or history of renal insufficiency, as well as use in older patients (over age 50), provide grounds to anticipate that less than the usual dosage and longer time intervals between doses may suffice, since the urinary elimination of PA and NAPA may be reduced, leading to gradual accumulation beyond normally predicted amounts. If facilities are available for measurement of plasma PA and NAPA, or acetylation capability, individual dose adjustment for optimal therapeutic levels may be easier, but close observation of clinical effectiveness is the most important criterion. In the longer term, periodic complete blood counts are useful to detect possible idiosyncratic hematologic effects of PA on neutrophil, platelet or red cell homeostasis; agranulocytosis has been reported to occur occasionally in patients on long-term PA therapy. A rising titer of serum ANA may precede clinical symptoms of the lupoid syndrome . If the lupus erythematosus-like syndrome develops in apatient with recurrent life-threatening arrhythmias not controlled by other agents, corticosteroid suppressive therapy may be used concomitantly with PA. Since the PA-induced lupoid syndrome rarely includes the dangerous pathologic renal changes, PA therapy may not necessarily have to be stopped unless the symptoms of serositis and the possibility of further lupoid effects are of greater risk then the benefit of PA in controlling arrhythmias. Patients with rapid acetylation capability are less likely to develop the lupoid syndrome after prolonged PA therapy. PRONESTYL Tablets (Procainamide Hydrochloride Tablets) contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.<br/>Information for Patients: The physician is advised to explain to the patient that close cooperation in adhering to the prescribed dosage schedule is of great importance in controlling the cardiac arrhythmia safely. The patient should understand clearly that more medication is not necessarily better and may be dangerous, that skipping doses or increasing intervals between doses to suit personal convenience may lead to loss of control of the heart problem, and that���making up���missed doses by doubling up later may be hazardous. The patient should be encouraged to disclose any past history of drug sensitivity, especially to procaine or other local anesthetic agents, or aspirin, and to report any history of kidney disease, congestive heart failure, myasthenia gravis, liver disease, or lupus erythematosus. The patient should be counseled to report promptly any symptoms of arthralgia, myalgia, fever, chills, skin rash, easy bruising, sore throat or sore mouth, infections, dark urine or icterus, wheezing, muscular weakness, chest or abdominal pain, palpitations, nausea, vomiting, anorexia, diarrhea, hallucinations, dizziness, or depression.<br/>Laboratory Tests: Laboratory tests such as complete blood count (CBC), electrocardiogram, and serum creatinine or urea nitrogen may be indicated, depending on the clinical situation, and periodic rechecking of the CBC and ANA may be helpful in early detection of untoward reactions.<br/>Drug Interactions: If other antiarrhythmic drugs are being used, additive effects on the heart may occur with PA administration, and dosage reduction may be necessary . Anticholinergic drugs administered concurrently with PA may produce additive antivagal effects on A-V nodal conduction, although this is not as well documented for PA as for quinidine. Patients taking PA who require neuromuscular blocking agents such as succinylcholine may require less than usual doses of the latter, due to PA effects on reducing acetylcholine release.<br/>Drug/Laboratory Test Interactions: Suprapharmacologic concentrations of lidocaine and meprobamate may inhibit fluorescence of PA and NAPA, and propranolol shows a native fluorescence close to the PA/NAPA peak wavelengths, so that tests which depend on fluorescence measurement may be affected.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long term studies in animals have not been performed.<br/>Teratogenic Effects: Pregnancy Category C: Animal reproduction studies have not been conducted with PA. It also is not known whether PA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PA should be given to a pregnant woman only if clearly needed.<br/>Nursing Mothers: Both PA and NAPA are excreted in human milk, and absorbed by the nursing infant. Because of the potential for serious adverse reactions in nursing infants, a decision to discontinue nursing or the drug should be made, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in children have not been established. | lld:dailymed |
| dailymed-drugs:309 | dailymed-instance:precautio... | Information for Patients: Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with doxepin and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and other Serious Mental Illness and Suicidal Thoughts or Actions" is available for doxepin. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking doxepin.<br/>Clinical Worsening and Suicide Risk: Patients, their families and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day to day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.<br/>Pediatric Use: Safety and effectiveness in the pediatric population have not been established . Anyone considering the use of doxepin in a child or adolescent must balance the potential risks with the clinical need.<br/>Drug Interactions:<br/>Drugs Metabolized by P450 2D6: The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7 to 10% of Caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and otherpopulations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., citalopram, escitalopram, fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from cotherapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6. Doxepin is primarily metabolized by CYP2D6 (with CYP1A2&CYP3A4 as minor pathways). Inhibitors or substrates of CYP2D6 (i.e., quinidine, selective serotonin reuptake inhibitors [SSRIs]) may increase the plasma concentration of doxepin when administered concomitantly. The extent of interaction depends on the variability of effect on CYP2D6. The clinical significance of this interaction with doxepin has not been systematically evaluated.<br/>MAO Inhibitors: Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Therefore, MAO inhibitors should be discontinued at least two weeks prior to the cautious initiation of therapy with doxepin. The exact length of time may vary and is dependent upon the particular MAO inhibitor being used, the length of time it has been administered, and the dosage involved.<br/>Cimetidine: Cimetidine has been reported to produce clinically significant fluctuations in steady-state serum concentrations of various tricyclic antidepressants. Serious anticholinergic symptoms (i.e., severe dry mouth, urinary retention and blurred vision) have been associated with elevations in the serum levels of tricyclic antidepressant when cimetidine therapy is initiated. Additionally, higher than expected tricyclic antidepressant levels have been observed when they are begun in patients already taking cimetidine. In patients who have been reported to be well controlled on tricyclic antidepressants receiving concurrent cimetidine therapy, discontinuation of cimetidine has been reported to decrease established steady-state serum tricyclic antidepressant levels and compromise their therapeutic effects.<br/>Alcohol: It should be borne in mind that alcohol ingestion may increase the danger inherent in any intentional or unintentional doxepin overdosage. This is especially important in patients who may use alcohol excessively.<br/>Tolazamide: A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 gm/day) 11 days after the addition of doxepin (75 mg/day).<br/>Drowsiness: Since drowsiness may occur with the use of this drug, patients should be warned of the possibility and cautioned against driving a car or operating dangerous machinery while taking the drug. Patients should also be cautioned that their response to alcohol may be potentiated. Sedating drugs may cause confusion and over sedation in the elderly; elderly patients generally should be started on low doses of doxepin and observed closely .<br/>Suicide: Since suicide is an inherent risk in any depressed patient and may remain so until significant improvement has occurred, patients should be closely supervised during the early course of therapy. Prescriptions should be written for the smallest feasible amount.<br/>Psychosis: Should increased symptoms of psychosis or shift to manic symptomatology occur, it may be necessary to reduce dosage or add a major tranquilizer to the dosage regimen.<br/>Geriatric Use: A determination has not been made whether controlled clinical studies of doxepin included sufficient numbers of subjects aged 65 and over to define a difference in response from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. The extent of renal excretion of doxepin has not been determined. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selections. Sedating drugs may cause confusion and over sedation in the elderly; elderly patients generally should be started on low doses of doxepin and observed closely. | lld:dailymed |
| dailymed-drugs:310 | dailymed-instance:precautio... | General: All drugs should be stopped and an evaluation made at the first sign of a hypersensitivity reaction. If isoniazid therapy must be reinstituted, the drug should be given only after symptoms have cleared. The drug should be restarted in very small and gradually increasing doses and should be withdrawn immediatelyif there is any indication of recurrent hypersensitivity reaction. Use of isoniazid should be carefully monitored in the following:<br/>Laboratory Tests: Because there is a higher frequency of isoniazid associated hepatitis among certain patient groups, including Age>35, daily users of alcohol, chronic liver disease, injection drug use and women belonging to minority groups, particularly in the post-partum period, transaminase measurements should be obtained prior to starting and monthly during preventative therapy, or more frequently as needed. If any of the values exceed three to five times the upper limit of normal, isoniazid should be temporarily discontinued and consideration given to restarting therapy.<br/>Drug interactions:<br/>Food: Isoniazid should not be administered with food. Studies have shown that the bioavailability of isoniazid is reduced significantly when administered with food.<br/>Acetaminophen: a report of severe acetaminophen toxicity was reported in a patient receiving Isoniazid. It is believed that the toxicity may have resulted from a previously unrecognized interaction between isoniazid and acetaminophen and a molecular basis for this interaction has been proposed. However, current evidence suggests that isoniazid does induce P-450IIE1, a mixed-function oxidase enzyme that appears to generate the toxic metabolites, in the liver. Furthermore it has been proposed that isoniazid resulted in induction of P-450IIE1 in the patient's liver which, in turn, resulted in a greater proportion of the ingested acetaminophen being converted to the toxic metabolites. Studies have demonstrated that pretreatment with isoniazid potentiates acetaminophen hepatotoxicity in rats.<br/>Carbamazepine: Isoniazid is known to slow the metabolism of carbamazepine and increase its serum levels. Carbamazepine levels should be determined prior to concurrent administration with isoniazid, signs and symptoms of carbamazepine toxicity should be monitored closely, and appropriate dosage adjustment of the anticonvulsant should be made.<br/>Ketoconazole: Potential interaction of Ketoconazole and Isoniazid may exist. When Ketoconazole is given in combination with isoniazid and rifampin the AUC of ketoconazole is decreased by as much as 88% after 5 months of concurrent Isoniazid and Rifampin therapy.<br/>Phenytoin: Isoniazid may increase serum levels of phenytoin. To avoid phenytoin intoxication, appropriate adjustment of the anticonvulsant should be made.<br/>Theophylline: A recent study has shown that concomitant administration of isoniazid and theophylline may cause elevated plasma levels of theophylline, and in some instances a slight decrease in the elimination of isoniazid. Since the therapeutic range of theophylline is narrow, theophylline serum levels should be monitored closely, and appropriate dosage adjustments of theophylline should be made.<br/>Valproate: A recent case study has shown a possible increase in the plasma level of valproate when co-administered with isoniazid. Plasma valproate concentration should be monitored when isoniazid and valproate are co-administered, and appropriate dosage adjustments of valproate should be made.<br/>Carcinogenesis and Mutagenesis: Isoniazid has been shown to induce pulmonary tumors in a number of strains of mice. Isoniazid has not been shown to be carcinogenic in humans. (Note: a diagnosis of mesothelioma in a child with prenatal exposure to isoniazid and no other apparent risk factors has been reported). Isoniazid has been found to be weakly mutagenic in strains TA 100 and TA 1535 of Salmonella typhimurium (Ames assay) without metabolic activation.<br/>Pregnancy:<br/>Teratogenic effects:<br/>Nonteratogenic effects: Since isoniazid is known to cross the placental barrier, neonates of isoniazidtreated mothers should be carefully observed for any evidence of adverse effects.<br/>Nursing Mothers: The small concentrations of isoniazid in breast milk do not produce toxicity in the nursing newborn; therefore, breast feeding should not be discouraged. However, because levels of isoniazid are so low in breast milk, they can not be relied upon for prophylaxis or therapy of nursing infants. | lld:dailymed |
| dailymed-drugs:312 | dailymed-instance:precautio... | Electrolyte deficits, particularly in serum potassium and phosphate, may occur during prolonged use of concentrated dextrose solutions. Blood electrolyte monitoring is essential, and fluid and electrolyte imbalances should be corrected. Essential vitamins and minerals also should be provided as needed. To minimize hyperglycemia and consequent glycosuria, it is desirable to monitor blood and urine glucose and if necessary, add insulin. When concentrated dextrose infusion is abruptly withdrawn, it is advisable to follow with the administration of 5% or 10% dextrose to avoid rebound hypoglycemia. Solutions containing dextrose should be used with caution in patients with known subclinical or overt diabetes mellitus. Care should be exercised to insure that the needle (or catheter) is well within the lumen of the vein and that extravasation does not occur. Concentrated dextrose solutions should not be administered subcutaneously or intramuscularly. Do not administer unless solution is clear and container is undamaged. Discard unused portion.<br/>Pregnancy Category C.: Animal reproduction studies have not been conducted with dextrose. It is also not known whether dextrose can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose should be given to a pregnant woman only if clearly needed.<br/>Pediatric Use:: The safety and effectiveness in the pediatric population are based on the similarity of the clinical conditions of the pediatric and adult populations. In neonates or very small infants the volume of fluid may affect fluid and electrolyte balance. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. This product contains no more than 25 mcg/L of aluminum. | lld:dailymed |
| dailymed-drugs:313 | dailymed-instance:precautio... | General: Cataflam (diclofenac potassium immediate-release tablets) cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of Cataflam in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.<br/>Hepatic Effects: Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including Cataflam. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continued therapy. Based on this experience, in patients on chronic treatment with Cataflam, periodic monitoring of transaminases is recommended (see PRECAUTIONS, Laboratory Tests). Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 2%-4% of patients, including marked elevations (eight or more times the upper limit of normal) in about 1% of patients in clinical trials with diclofenac. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Cataflam. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Cataflam should be discontinued.<br/>Hematological Effects: Anemia is sometimes seen in patients receiving NSAIDs, including Cataflam. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Cataflam, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Cataflam who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.<br/>Preexisting Asthma: Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross-reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Cataflam should not be administered to patients with this form of aspirin sensitivity and should be used with caution in all patients with preexisting asthma.<br/>Information for Patients: Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.<br/>Laboratory Tests: Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. In patients on long-term treatment with NSAIDs, including Cataflam, CBC and a chemistry profile (including transaminase levels) should be checked periodically. If clinical signs and symptoms consistent with liver orrenal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Cataflam should be discontinued.<br/>Drug Interactions:<br/>Aspirin: When Cataflam is administered with aspirin, its protein binding is reduced. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diclofenac and aspirin is not generally recommended because of the potential of increased adverse effects.<br/>Methotrexate: NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.<br/>Cyclosporine: Cataflam, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs. Therefore, concomitant therapy with Cataflam may increase cyclosporine's nephrotoxicity. Caution should be used when Cataflam is administered concomitantly with cyclosporine.<br/>ACE Inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors.<br/>Furosemide: Clinical studies, as well as post-marketing observations, have shown that Cataflam can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy.<br/>Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.<br/>Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C: Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women.<br/>Nonteratogenic Effects: Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.<br/>Labor and Delivery: In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Cataflam on labor and delivery in pregnant women are unknown.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Cataflam, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric Use: As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older). | lld:dailymed |
| dailymed-drugs:315 | dailymed-instance:precautio... | General: The safe and effective use of mercaptopurine demands close monitoring of the CBC and patient clinical status. After selection of an initial dosage schedule, therapy will frequently need to be modified depending upon the patient's response and manifestations of toxicity. It is probably advisable to start with lower dosages in patients with impaired renal function, due to slower elimination of the drug and metabolites and a greater cumulative effect.<br/>Information for Patients: Patients should be informed that the major toxicities of mercaptopurine are related to myelosuppression, hepatotoxicity, and gastrointestinal toxicity. Patients should never be allowed to take the drug without medical supervision and should be advised to consult their physician if they experience fever, sore throat, jaundice, nausea, vomiting, signs of local infection, bleeding from any site, or symptoms suggestive of anemia. Women of childbearing potential should be advised to avoid becoming pregnant.<br/>Laboratory Tests: It is recommended that evaluation of the hemoglobin or hematocrit, total white blood cell count and differential count, and quantitative platelet count be obtained weekly while the patient is on therapy with mercaptopurine. Bone marrow examination may also be useful for the evaluation of marrow status. The decision to increase, decrease, continue, or discontinue a given dosage of mercaptopurine must be based upon the degree of severity and rapidity with which changes are occurring. In many instances, particularly during the induction phase of acute leukemia, complete blood counts will need to be done morefrequently than once weekly in order to evaluate the effect of the therapy. If a patient has clinical or laboratory evidence of severe bone marrow toxicity, particularly myelosuppression, TPMT testing should be considered.<br/>TPMT Testing: Genotypic and phenotypic testing of TPMT status are available. Genotypic testing can determine the allelic pattern of a patient. Currently, 3 alleles - TPMT*2, TPMT*3A and TPMT*3C - account for about 95% of individuals with reduced levels of TPMT activity. Individuals homozygous for these alleles are TPMT deficient and those heterozygous for these alleles have variable TPMT (low or intermediate) activity. Phenotypic testing determines the level of thiopurine nucleotides or TPMT activity in erythrocytesand can also be informative. Caution must be used with phenotyping since some coadministered drugs can influence measurement of TPMT activity in blood, and recent blood transfusions will misrepresent a patient's actual TPMT activity.<br/>Drug Interactions: When allopurinol and mercaptopurine are administered concomitantly, the dose of mercaptopurine must be reduced to one third to one quarter of the usual dose to avoid severe toxicity. There is usually complete cross-resistance between mercaptopurine and thioguanine. The dosage of mercaptopurine may need to be reduced when this agent is combined with other drugs whose primary or secondary toxicity is myelosuppression. Enhanced marrow suppression has been noted in some patients also receiving trimethoprimsulfamethoxazole. Inhibition of the anticoagulant effect of warfarin, when given with mercaptopurine, has been reported. As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, mesalazine, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent mercaptopurine therapy .<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Mercaptopurine causes chromosomal aberrations in animals and humans and induces dominant-lethal mutations in male mice. In mice, surviving female offspring of mothers who received chronic low doses of mercaptopurine during pregnancy were found sterile, or if they became pregnant, had smaller litters and more dead fetuses as compared to control animals. Carcinogenic potential exists in humans, but the extent of the risk is unknown. The effect of mercaptopurine on human fertility is unknown for either males or females.<br/>Pregnancy:<br/>Teratogenic Effects. Pregnancy Category D: See WARNINGS section.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from mercaptopurine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: See DOSAGE AND ADMINISTRATION section.<br/>Geriatric Use: Clinical studies of mercaptopurine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:316 | dailymed-instance:precautio... | General: Symptomatic response to therapy with famotidine does not preclude the presence of gastric malignancy.<br/>Patients with Moderate or Severe Renal Insufficiency: Since CNS adverse effects have been reported in patients with moderate or severe renal insufficiency, longer intervals between doses or lower doses may need to be used in patients with moderate (creatinine clearance<50 mL/min) or severe (creatinine clearance<10 mL/min) renal insufficiency to adjust for the longer elimination half-life of famotidine (see CLINICAL PHARMACOLOGY IN ADULTS and DOSAGE AND ADMINISTRATION).<br/>Drug Interactions: No drug interactions have been identified. Studies with famotidine in man, in animal models, and in vitro have shown no significant interference with the disposition of compounds metabolized by the hepatic microsomal enzymes, e.g., cytochrome P450 system. Compounds tested in man include warfarin, theophylline, phenytoin, diazepam, aminopyrine and antipyrine. Indocyanine green as an index of hepatic drug extraction has been tested and no significant effects have been found.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 106 week study in rats and a 92 week study in mice given oral doses of up to 2000 mg/kg/day (approximately 2500 times the recommended human dose for active duodenal ulcer), there was no evidence of carcinogenic potential for famotidine. Famotidine was negative in the microbial mutagen test (Ames test) using Salmonella typhimurium and Escherichia coli with or without rat liver enzyme activation at concentrations up to 10,000 mcg/plate. In in vivo studies in mice, with a micronucleus test and a chromosomal aberration test, no evidence of a mutagenic effect was observed. In studies with rats given oral doses of up to 2000 mg/kg/day or intravenous doses of up to 200 mg/kg/day, fertility and reproductive performance were not affected.<br/>Pregnancy:<br/>PREGNANCY CATEGORY B: Reproductive studies have been performed in rats and rabbits at oral doses of up to 2000 and 500 mg/kg/day, respectively, and in both species at I.V. doses of up to 200 mg/kg/day, and have revealed no significant evidence of impaired fertility or harm to the fetus due to famotidine.While no direct fetotoxic effects have been observed, sporadic abortions occurring only in mothers displaying marked decreased food intake were seen in some rabbits at oral doses of 200 mg/kg/day (250 times the usual human dose) or higher. There are, however, no adequate or well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.<br/>Nursing mothers: Studies performed in lactating rats have shown that famotidine is secreted into breast milk. Transient growth depression was observed in young rats suckling from mothers treated with maternotoxic doses of at least 600 times the usual human dose. Famotidine is detectable in human milk. Because of the potential for serious adverse reactions in nursing infants from famotidine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Patients<1 year of age: Use of famotidine in pediatric patients<1 year of age is supported by evidence from adequate and wellcontrolled studies of famotidine in adults, and by the following studies in pediatric patients<1 year of age. Two pharmacokinetic studies in pediatric patients<1 year of age (N=48) demonstrated that clearance of famotidine in patients>3 months to 1 year of age is similar to that seen in older pediatric patients (1 to 15 years of age) and adults. In contrast, pediatric patients 0 to 3 months of age had famotidine clearance values that were 2- to 4-fold less than those in older pediatric patients and adults. These studies also show that the mean bioavailability in pediatric patients<1 year of age after oral dosing is similar to older pediatric patients and adults. Pharmacodynamic data in pediatic patients 0 to 3 months of age suggest that the duration of acid suppression is longer compared with older pediatric patients, consistent with the longer famotidine half-life in pediatric patients 0 to 3 months of age. (see CLINICAL PHARMACOLOGY IN PEDIATRIC PATIENTS, Pharmacokinetics and Pharmacodynamics.) In a double-blinded, randomized, treatment-withdrawal study, 35 pediatric patients<1 year of age who were diagnosed as having gastroesophageal reflux disease were treated for up to 4 weeks with famotidine oral suspension (0.5 mg/kg/dose or 1 mg/kg/dose). Although an intravenous formulation was available, no patients were treated with intravenous famotidine in this study. Also, caregivers were instructed to provide conservative treatment including thickened feedings. Enrolled patients were diagnosed primarily by history of vomiting (spitting up) and irritability (fussiness). The famotidine dosing regimen was once daily for patients<3 months of age and twice daily for patients���3 months of age. After 4 weeks of treatment, patients were randomly withdrawn from the treatment and followed an additional 4 weeks for adverse events and symptomatology. Patients were evaluated for vomiting (spitting up), irritability (fussiness) and global assessments of improvement. The study patients ranged in age at entry from 1.3 to 10.5 months (mean 5.6��2.9 months), 57% were female, 91% were white and 6% were black. Most patients (27/35) continued into the treatment-withdrawal phase of the study. Two patients discontinued famotidine due to adverse events. Most patients improved during the initial treatment phase of the study. Results of the treatment-withdrawal phase were difficult to interpret because of small numbers of patients. Of the 35 patients enrolled in the study, agitation was observed in 5 patients on famotidine that resolved when the medication was discontinued; agitation was notobserved in patients on placebo (see ADVERSE REACTIONS, Pediatric Patients). These studies suggest that a starting dose of 0.5 mg/kg/dose of famotidine oral suspension may be of benefit for the treatment of GERD for up to 4 weeks once daily in patients<3 months of age and twice daily in patients 3 months to<1 year of age; the safety and benefit of famotidine treatment beyond 4 weeks have not been established. Famotidine should be considered for the treatment of GERD only if conservative measures (e.g., thickened feedings) are used concurrently and if the potential benefit outweighs the risk.<br/>Pediatric Patients 1 to 16 years of age: Use of famotidine in pediatric patients 1 to 16 years of age is supported by evidence from adequate and wellcontrolled studies of famotidine in adults, and by the following studies in pediatric patients: In published studies in small numbers of pediatric patients 1 to 15 years of age, clearance of famotidine was similar to that seen in adults. In pediatric patients 11 to 15 years of age, oral doses of 0.5 mg/kg were associated with a mean area under the curve (AUC) similar to that seen in adults treated orally with 40 mg. Similarly, in pediatric patients 1 to 15 years of age, intravenous doses of 0.5 mg/kg were associated with a mean AUC similar to that seen in adults treated intravenously with 40 mg. Limited published studies also suggest that the relationship between serum concentration and acid suppression is similar in pediatric patients 1 to 15 years of age as compared with adults. These studies suggest a starting dose for pediatric patients 1 to 16 years of age asfollows: PEPTIC ULCER 0.5 mg/kg/day p.o. at bedtime or divided b.i.d. up to 40 mg/day. GASTROESOPHAGEAL REFLUX DISEASE WITH OR WITHOUT ESOPHAGITIS INCLUDING EROSIONS AND ULCERATIONS 1.0 mg/kg/day p.o. divided b.i.d. up to 40 mg b.i.d. While published uncontrolled studies suggest effectiveness of famotidine in the treatment of gastroesophageal reflux disease and peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy. Therefore, treatment duration (initially based on adult duration recommendations) and dose should be individualized based on clinical response and/or pH determination (gastric or esophageal) and endoscopy. Published uncontrolled clinical studies in pediatric patients have employed doses up to 1 mg/kg/day for peptic ulcer and 2 mg/kg/day for GERD with or without esophagitis including erosions and ulcerations.<br/>Geriatric use: Of the 4,966 subjects in the clinical studies who were treated with famotidine, 488 subjects (9.8%) were 65 or older, and 88 (1.7%) were greater than 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. However, greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment is required based on age (see CLINICAL PHARMACOLOGY IN ADULTS, Pharmacokinetics). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Dosage adjustment in the case of moderate or severe renal impairment is necessary (see PRECAUTIONS, Patients with Moderate or Severe Renal Insufficiency and DOSAGE AND ADMINISTRATION, Dosage Adjustment for Patients with Moderate or Severe Renal Insufficiency). | lld:dailymed |
| dailymed-drugs:320 | dailymed-instance:precautio... | General: Prescribing doxycycline in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. As with other antibiotic preparations, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, the antibiotic should be discontinued and appropriate therapy instituted. In venereal diseases when coexistent syphilis is suspected, a dark field examination should be done before treatment is started and the blood serology repeated monthly for at least 4 months. Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal and hepatic studies should be performed. All infections due to group A beta-hemolytic streptococci should be treated for at least 10 days. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline in conjunction with penicillin.<br/>Information for Patients: Patients should be counseled that antibacterial drugs including doxycycline should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When doxycycline is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by doxycycline or other antibacterial drugs in the future. | lld:dailymed |
| dailymed-drugs:321 | dailymed-instance:precautio... | General:<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No long term animal studies have been performed to evaluate carcinogenic or mutagenic potential, or whether this drug affects fertility in males or females.<br/>Pregnancy:<br/>Pregnancy Category C.: Animal reproduction studies have not been conducted with technetium Tc 99m mertiatide. It is also not known whether this drug can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Technetium Tc 99m mertiatide should be given to a pregnant woman only if clearly needed.<br/>Nursing Mothers: Technetium Tc 99m is excreted in human milk during lactation, therefore, formula feedings should be substituted for breast feeding.<br/>Pediatric Use: Safety and effectiveness in pediatric patients under the age of 30 days have not been established. | lld:dailymed |
| dailymed-drugs:324 | dailymed-instance:precautio... | DO NOT INTERCHANGE :DO NOT INTERCHANGE ZAROXOLYN TABLETS AND OTHER FORMULATIONS OF METOLAZONE THAT SHARE ITS SLOW AND INCOMPLETE BIOAVAILABILITY AND ARE NOT THERAPEUTICALLY EQUIVALENT AT THE SAME DOSES TO MYKROX TABLETS, A MORE RAPIDLY AVAILABLE AND COMPLETELY BIOAVAILABLE METOLAZONE PRODUCT. FORMULATIONS BIOEQUIVALENT TO ZAROXOLYN AND FORMULATIONS BIOEQUIVALENT TO MYKROX SHOULD NOT BE INTERCHANGED FOR ONE ANOTHER.<br/>General:<br/>Fluid And Electrolytes: All patients receiving therapy with ZAROXOLYN Tablets should have serum electrolyte measurements done at appropriate intervals and be observed for clinical signs of fluid and/or electrolyte imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. In patients with severe edema accompanying cardiac failure or renal disease, a low-salt syndrome may be produced, especially with hot weather and a low-salt diet. Serum and urine electrolyte determinations are particularly important when the patient has protracted vomiting, severe diarrhea, or is receiving parenteral fluids. Warning signs of imbalance are: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hyponatremia may occur at any time during long term therapy and, on rare occasions, may be life threatening. The risk of hypokalemia is increased when larger doses are used, when diuresis is rapid, when severe liver disease is present, when corticosteroids are given concomitantly, when oral intake is inadequate or when excess potassium is being lost extrarenally, such as with vomiting or diarrhea. Thiazide-like diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.<br/>Glucose Tolerance: Metolazone may raise blood glucose concentrations possibly causing hyperglycemia and glycosuria in patients with diabetes or latent diabetes.<br/>Hyperuricemia: ZAROXOLYN regularly causes an increase in serum uric acid and can occasionally precipitate gouty attacks even in patients without a prior history of them.<br/>Azotemia: Azotemia, presumably prerenal azotemia, may be precipitated during the administration of ZAROXOLYN. If azotemia and oliguria worsen during treatment of patients with severe renal disease, ZAROXOLYN should be discontinued.<br/>Renal Impairment: Use caution when administering ZAROXOLYN Tablets to patients with severely impaired renal function. As most of the drug is excreted by the renal route, accumulation may occur.<br/>Orthostatic Hypotension: Orthostatic hypotension may occur; this may be potentiated by alcohol, barbiturates, narcotics, or concurrent therapy with other antihypertensive drugs.<br/>Hypercalcemia: Hypercalcemia may infrequently occur with metolazone, especially in patients taking high doses of vitamin D or with high bone turnover states, and may signify hidden hyperparathyroidism. Metolazone should be discontinued before tests for parathyroid function are performed.<br/>Systemic Lupus Erythematosus: Thiazide diuretics have exacerbated or activated systemic lupus erythematosus and this possibility should be considered with ZAROXOLYN Tablets.<br/>Information For Patients: Patients should be informed of possible adverse effects, advised to take the medication as directed, and promptly report any possible adverse reactions to the treating physician.<br/>Drug Interactions:<br/>Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes .<br/>Other Antihypertensives: When ZAROXOLYN Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary.<br/>Alcohol, Barbiturates, And Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy.<br/>Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result.<br/>Corticosteroids Or ACTH: May increase the risk of hypokalemia and increase salt and water retention.<br/>Lithium: Serum lithium levels may increase .<br/>Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine)���the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue ZAROXOLYN three days before elective surgery.<br/>Salicylates And Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of ZAROXOLYN Tablets.<br/>Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.<br/>Insulin And Oral Antidiabetic Agents: See Glucose Tolerance under PRECAUTIONS, General.<br/>Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone.<br/>Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary.<br/>Drug/Laboratory Test Interactions: None reported.<br/>Carcinogenesis, Mutagenesis, Impairment Of Fertility: Mice and rats administered metolazone 5 days/week for up to 18 and 24 months, respectively, at daily doses of 2, 10, and 50 mg/kg, exhibited no evidence of a tumorigenic effect of the drug. The small number of animals examined histologically and poor survival in the mice limit the conclusions that can be reached from these studies. Metolazone was not mutagenic in vitro in the Ames Test using Salmonella typhimurium strains TA-97, TA-98, TA-100, TA-102, and TA-1535. Reproductive performance has been evaluated in mice and rats. There is no evidence that metolazone possesses the potential for altering reproductive capacity in mice. In a rat study, in which males were treated orally with metolazone at doses of 2, 10, and 50 mg/kg for 127 days prior to mating with untreated females, an increased number of resorption sites was observed in dams mated with males from the 50 mg/kg group. In addition, the birth weight of offspring was decreased and the pregnancy rate was reduced in dams mated with males from the 10 and 50 mg/kg groups.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Non-Teratogenic Effects: The use of ZAROXOLYN Tablets in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult. It is not known what effect the use of the drug during pregnancy has on the later growth, development, and functional maturation of the child. No such effects have been reported with metolazone.<br/>Labor And Delivery: Based on clinical studies in which women received metolazone in late pregnancy until the time of delivery, there is no evidence that the drug has any adverse effects on the normal course of labor or delivery.<br/>Nursing Mothers: Metolazone appears in breast milk. Because of the potential for serious adverse reactions in nursing infants from metolazone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established in controlled clinical trials. There is limited experience with the use of ZAROXOLYN in pediatric patients with congestive heart failure, hypertension, bronchopulmonary dysplasia, nephrotic syndrome and nephrogenic diabetes insipidus. Doses used generally ranged from 0.05 to 0.1 mg/kg administered once daily and usually resulted in a 1 to 2.8 kg weight loss and 150 to 300 cc increase in urine output. Not all patients responded and some gained weight. Those patients who did respond did so in the first few daysof treatment. Prolonged use (beyond a few days) was generally associated with no further beneficial effect or a return to baseline status and is not recommended. There is limited experience with the combination of ZAROXOLYN and furosemide in pediatric patients with furosemide-resistant edema. Some benefited while others did not or had an exaggerated response with hypovolemia, tachycardia, and orthostatic hypotension requiring fluid replacement. Severe hypokalemia was reported and therewas a tendency for diuresis to persist for up to 24 hours after ZAROXOLYN was discontinued. Hyperbilirubinemia has been reported in 1 neonate. Close clinical and laboratory monitoring of all children treated with diuretics is indicated. See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS.<br/>Geriatric Use: Clinical studies of ZAROXOLYN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. | lld:dailymed |
| dailymed-drugs:325 | dailymed-instance:precautio... | General:: The initial prescription and renewal of the medication order beyond 20 milliliters of HMS suspension should be made by a physician only after examination of the patient with the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. If signs and symptoms fail to improve after two days, the patient should be re-evaluated. As fungal infections of the cornea are particularly prone to develop coincidentally with long-term local corticosteroid applications, fungal invasion should be suspected in any persistent corneal ulceration where a corticosteroid has been used or is in use. Fungal cultures should be taken when appropriate. If this product is used for 10 days or longer, intraocular pressure should be monitored .<br/>Information for Patients:: If inflammation or pain persists longer than 48 hours or becomes aggravated, the patient should be advised to discontinue use of the medication and consult a physician. This product is sterile when packaged. To prevent contamination, care should be taken to avoid touching the bottle tip to eyelids or to any other surface. The use of this bottle by more than one person may spread infection. Keep bottle tightly closed when not in use. Keep out of the reach of children.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:: No studies have been conducted in animals or in humans to evaluate the potential of these effects.<br/>Pregnancy:: Teratogenic effects. Pregnancy Category C. Medrysone has been shown to be embryocidal in rabbits when given in doses 10 and 30 times the human ocular dose. Two drops of medrysone were applied to both eyes of pregnant rabbits 4 times per day on day 6 through 18 of gestation. A significant increase in early resorptions was observed in the treated rabbits. There are no adequate and well-controlled studies of medrysone in pregnant women. Medrysone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers:: It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human breast milk. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from medrysone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use:: Safety and effectiveness in pediatric patients below the age of 3 years have not been established.<br/>Geriatric Use:: No overall differences in safety or effectiveness have been observed between elderly and younger patients. | lld:dailymed |
| dailymed-drugs:326 | dailymed-instance:precautio... | General:<br/>Worsening of Seizures: When used in patients in whom several different types of seizure disorders coexist, clonazepam may increase the incidence or precipitate the onset of generalized tonic-clonic seizures (grand mal). This may require the addition of appropriate anticonvulsants or an increase in their dosages. The concomitant use of valproic acid and clonazepam may produce absence status.<br/>Laboratory Testing During Long-Term Therapy: Periodic blood counts and liver function tests are advisable during long-term therapy with clonazepam.<br/>Risks of Abrupt Withdrawal: The abrupt withdrawal of clonazepam, particularly in those patients on long-term, high-dose therapy, may precipitate status epilepticus. Therefore, when discontinuing clonazepam, gradual withdrawal is essential. While clonazepam is being gradually withdrawn, the simultaneous substitution of another anticonvulsant may be indicated.<br/>Caution in Renally Impaired Patients: Metabolites of clonazepam are excreted by the kidneys; to avoid their excess accumulation, caution should be exercised in the administration of the drug to patients with impaired renal function.<br/>Hypersalivation: Clonazepam may produce an increase in salivation. This should be considered before giving the drug to patients who have difficulty handling secretions. Because of this and the possibility of respiratory depression, clonazepam should be used with caution in patients with chronic respiratory diseases.<br/>Information for Patients: Physicians are advised to discuss the following issues with patients for whom they prescribe clonazepam.<br/>Dose Changes: To assure the safe and effective use of benzodiazepines, patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is advisable that they consult with their physician before either increasing the dose or abruptly discontinuing this drug.<br/>Interference With Cognitive and Motor Performance: Because benzodiazepines have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that clonazepam therapy does not affect them adversely.<br/>Pregnancy: Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with clonazepam (see WARNINGS).<br/>Nursing: Patients should be advised not to breastfeed an infant if they are taking clonazepam.<br/>Concomitant Medication: Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.<br/>Alcohol: Patients should be advised to avoid alcohol while taking clonazepam.<br/>Drug Interactions:<br/>Effect of Clonazepam on the Pharmacokinetics of Other Drugs: Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine, or phenobarbital. The effect of clonazepam on the metabolism of other drugs has not been investigated.<br/>Effect of Other Drugs on the Pharmacokinetics of Clonazepam: Ranitidine and propantheline, agents that decrease stomach acidity, do not greatly alter clonazepam pharmacokinetics. Fluoxetine does not affect the pharmacokinetics of clonazepam. Cytochrome P-450 inducers, such as phenytoin, carbamazepine, and phenobarbital induce clonazepam metabolism, causing an approximately 30% decrease in plasma clonazepam levels. Although clinical studies have not been performed, based on the involvement of the cytochrome P-450 3A family in clonazepam metabolism, inhibitors of this enzyme system, notably oral antifungal agents, should be used cautiously in patients receiving clonazepam.<br/>Pharmacodynamic Interactions: The CNS-depressant action of the benzodiazepine class of drugs may be potentiated by alcohol, narcotics, barbiturates, nonbarbiturate hypnotics, antianxiety agents, the phenothiazines, thioxanthene and butyrophenone classes of antipsychotic agents, monoamine oxidase inhibitors and the tricyclic antidepressants, and by other anticonvulsant drugs.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies have not been conducted with clonazepam. The data currently available are not sufficient to determine the genotoxic potential of clonazepam. In a two-generation fertility study in which clonazepam was given orally to rats at 10 and 100 mg/kg/day (low dose approximately 5 times and 24 times the maximum recommended human dose of 20 mg/day for seizure disorder and 4 mg/day for panic disorder, respectively, on a mg/mbasis), there was a decrease in the number of pregnancies and in the number of offspring surviving until weaning.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category D (see WARNINGS).<br/>Labor and Delivery: The effect of clonazepam on labor and delivery in humans has not been specifically studied; however, perinatal complications have been reported in children born to mothers who have been receiving benzodiazepines late in pregnancy, including findings suggestive of either excess benzodiazepine exposure or of withdrawal phenomena (see Pregnancy Risks under WARNINGS).<br/>Nursing Mothers: Mothers receiving clonazepam should not breastfeed their infants.<br/>Pediatric Use: Because of the possibility that adverse effects on physical or mental development could become apparent only after many years, a benefit-risk consideration of the long-term use of clonazepam is important in pediatric patients being treated for seizure disorder (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION sections). Safety and effectiveness in pediatric patients with panic disorder below the age of 18 have not been established.<br/>Geriatric Use: Clinical studies of clonazepam did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will impair clonazepam elimination. Metabolites of clonazepam are excreted by kidneys; to avoid their excess accumulation, caution should be exercised in the administration of the drug to patients with impaired renal function. Because elderly patients are more likely to have decreased hepatic and/or renal function, care should be taken in dose selection, and it may be useful to assess hepatic and/or renal functions at the time of dose selection. Sedating drugs may cause confusion and over-sedation in the elderly; elderly patient generally should be started on low doses of clonazepam and observed closely. | lld:dailymed |
| dailymed-drugs:327 | dailymed-instance:precautio... | General: Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of ondansetron in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distension. Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported.<br/>Drug Interactions: Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver . Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of available data, no dosage adjustment is recommended for patients on these drugs.<br/>Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.<br/>Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.<br/>Chemotherapy: Tumor response to chemotherapy in the P-388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate.<br/>Use in Surgical Patients: The coadministration of ondansetron had no effect on the pharmacokinetics and pharmacodynamics of temazepam.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenic effects were not seen in 2-year studies in rats and mice with oral ondansetron doses up to 10 and 30 mg/kg/day, respectively. Ondansetron was not mutagenic in standard tests for mutagenicity. Oral administration of ondansetron up to 15 mg/kg/day did not affect fertility or general reproductive performance of male and female rats.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in pregnant rats and rabbits at daily oral doses up to 15 and 30 mg/kg/day, respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to ondansetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.<br/>Nursing Mothers: Ondansetron is excreted in the breast milk of rats. It is not known whether ondansetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ondansetron is administered to a nursing woman.<br/>Pediatric Use: Little information is available about dosage in pediatric patients 4 years of age or younger .<br/>Geriatric Use: Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting in US- and foreign-controlled clinical trials, for which there were subgroup analysis, 938 were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment is not needed in patients over the age of 65 . | lld:dailymed |
| dailymed-drugs:328 | dailymed-instance:precautio... | General:<br/>Hepatic Effects:: Ketorolac tromethamine should be used with caution in patients with impaired hepatic function or a history of liver disease. Treatment with ketorolac tromethamine may cause elevations of liver enzymes, and, in patients with pre-existing liver dysfunction, it may lead to the development of a more severe hepatic reaction. The administration of ketorolac tromethamine should be discontinued in patients in whom an abnormal liver test has occurred as a result of ketorolac tromethamine therapy.<br/>Hematologic Effects:: Ketorolac tromethamine inhibits platelet aggregation and may prolong bleeding time; therefore, it is contraindicated as a preoperative medication, and caution should be used when hemostasis is critical. Unlike aspirin, the inhibition of platelet function by ketorolac tromethamine disappears within 24 to 48 hours after the drug is discontinued. Ketorolac tromethamine does not appear to affect platelet count, prothrombin time (PT) or partial thromboplastin time (PTT). In controlled clinical studies, where ketorolac tromethamine was administered intramuscularly or intravenously postoperatively, the incidence of clinically significant postoperative bleeding was 0.4% for ketorolac tromethamine compared to 0.2% in the control groups receiving narcotic analgesics.<br/>Information for Patients: Ketorolac tromethamine is a potent NSAID and may cause serious side effects such as gastrointestinal bleeding or kidney failure, which may result in hospitalization and even fatal outcome. Physicians, when prescribing ketorolac tromethamine, should inform their patients of the potential risks of ketorolac tromethamine treatment (see Boxed WARNING, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS sections). Advise patients not to give ketorolac tromethamine tablets to other family members and to discard any unused drug. Remember that the total duration of ketorolac tromethamine therapy is not to exceed five (5) days.<br/>Drug Interactions: Ketorolac is highly bound to human plasma protein (mean 99.2%). Thein vitro binding ofwarfarin to plasma proteins is only slightly reduced by ketorolac tromethamine (99.5% control vs. 99.3%) when ketorolac plasma concentrations reach 5 to 10 mcg/mL. Ketorolac does not alterdigoxin protein binding. In vitro studies indicate that, at therapeutic concentrations of salicylate (300 mcg/mL), the binding of ketorolac was reduced from approximately 99.2% to 97.5%, representing a potential two-fold increase in unbound ketorolac plasma levels. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin and tolbutamide did not alter ketorolac tromethamine protein binding. In a study involving 12 volunteers, ketorolac tromethamine tablets were coadministered with a single dose of 25 mg warfarin, causing no significant changes in pharmacokinetics or pharmacodynamics of warfarin. In another study, Ketorolac Tromethamine Injection was given with two doses of 5000 U of heparin to 11 healthy volunteers, resulting in a mean template bleeding time of 6.4 minutes (3.2 to 11.4 min) compared to a mean of 6.0 minutes (3.4 to 7.5 min) forheparin alone and 5.1 minutes (3.5 to 8.5 min) for placebo. Although these results do not indicate a significant interaction between ketorolac tromethamine and warfarin or heparin, the administration of ketorolac tromethamine to patients taking anticoagulants should be done extremely cautiously, and patients should be closely monitored . Ketorolac Tromethamine Injection reduced the diuretic response to furosemide in normo-volemic healthy subjects by approximately 20% (mean sodium and urinary output decreased 17%). Concomitant administration of ketorolac tromethamine tablets and probenecid resulted in decreased clearance of ketorolac and significant increases in ketorolac plasma levels (total AUC increased approximately three-fold from 5.4 to 17.8 mcg/h/mL) and terminal half-life increased approximately two-fold from 6.6 to 15.1 hours. Therefore, concomitant use of ketorolactromethamine and probenecid is contraindicated. Inhibition of renal lithiumclearance, leading to an increase in plasma lithium concentration, has been reported with some prostaglandin synthesis-inhibiting drugs. The effect of ketorolac tromethamine on plasma lithium has not been studied, but cases of increased lithium plasma levels during ketorolac tromethamine therapy have been reported. Concomitant administration of methotrexateand some NSAIDs has been reported to reduce the clearance of methotrexate, enhancing the toxicity of methotrexate. The effect of ketorolac tromethamine on methotrexate clearance has not been studied. In postmarketing experience there have been reports of a possible interaction between Ketorolac Tromethamine Injection andnondepolarizing muscle relaxants that resulted in apnea. The concurrent use of ketorolac tromethamine with muscle relaxants has not been formally studied. Concomitant use of ACE inhibitorsmay increase the risk of renal impairment, particularly in volume-depleted patients. Sporadic cases of seizures have been reported during concomitant use of ketorolac tromethamine and antiepileptic drugs (phenytoin, carbamazepine). Hallucinations have been reported when ketorolac tromethamine was used in patients taking psychoactive drugs (fluoxetine, thiothixene, alprazolam). Ketorolac Tromethamine Injection has been administered concurrently withmorphine in several clinical trials of postoperative pain without evidence of adverse interactions. Do not mix ketorolac tromethamine and morphine in the same syringe. There is no evidence in animal or human studies that ketorolac tromethamine induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs.<br/>Carcinogenesis, Mutagenesis and Impairment of Fertility: An 18-month study in mice with oral doses of ketorolac tromethamine at 2 mg/kg/day (0.9 times the human systemic exposure at the recommended IM or IV dose of 30 mg qid, based on area-under-the-plasma-concentration curve (AUC), and a 24-month study in rats at 5 mg/kg/day (0.5 times the human AUC) showed no evidence of tumorigenicity. Ketorolac tromethamine was not mutagenic in the Ames test, unscheduled DNA synthesis and repair, and in forward mutation assays. Ketorolac tromethamine did not cause chromosome breakage in the in vivo mouse micronucleus assay. At 1590 mcg/mL and at higher concentrations, ketorolac tromethamine increased the incidence of chromosomal aberrations in Chinese hamster ovarian cells. Impairment of fertility did not occur in male or female rats at oral doses of 9 mg/kg (0.9 times the human AUC) and 16 mg/kg (1.6 times the human AUC) of ketorolac tromethamine, respectively.<br/>Pregnancy:<br/>Pregnancy Category C: Reproduction studies have been performed during organogenesis using daily oral doses of ketorolac tromethamine at 3.6 mg/kg (0.37 times the human AUC) in rabbits and at 10 mg/kg (1 times the human AUC) in rats. Results of these studies did not reveal evidence of teratogenicity to the fetus. Oral doses of ketorolac tromethamine at 1.5 mg/kg (0.14 times the human AUC), administered after gestation day 17, caused dystocia and higher pup mortality in rats. There are no adequate and well-controlled studies of ketorolac tromethamine in pregnant women. Ketorolac tromethamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Labor and Delivery: The use of ketorolac tromethamine is contraindicated in labor and delivery because, through its prostaglandin synthesis inhibitory effect, it may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage .<br/>Lactation and Nursing: After a single administration of 10 mg of ketorolac tromethamine tablets to humans, the maximum milk concentration observed was 7.3 ng/mL, and the maximum milk-to-plasma ratio was 0.037. After 1 day of dosing (qid), the maximum milk concentration was 7.9 ng/mL, and the maximum milk-to-plasma ratio was 0.025. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers is CONTRAINDICATED.<br/>Pediatric Use: Safety and efficacy in pediatric patients (less than 16 years of age) have not been established. Therefore, use of ketorolac tromethamine in pediatric patients is not recommended.<br/>Use In The Elderly (���65 Years Of Age): Because ketorolac tromethamine may be cleared more slowly by the elderly (see CLINICAL PHARMACOLOGY) who are also more sensitive to the adverse effects of NSAIDs (see WARNINGS - Renal Effects), extra caution and reduced dosages (see DOSAGE AND ADMINISTRATION) must be used when treating the elderly with Ketorolac Tromethamine Injection. The lower end of the Ketorolac Tromethamine Injection dosage range is recommended for patients over 65 years of age, and total daily dose is not to exceed 60 mg. The incidence and severity of gastrointestinal complications increases with increasing dose of,and duration of treatment with, ketorolac tromethamine. | lld:dailymed |
| dailymed-drugs:330 | dailymed-instance:precautio... | General:<br/>Dyskinesia: Ropinirole hydrochloride may potentiate the dopaminergic side effects of L-dopa and may cause and/or exacerbate preexisting dyskinesia in patients treated with L-dopa for Parkinson's disease. Decreasing the dose of L-dopa may ameliorate this side effect.<br/>Renal Impairment: No dosage adjustment is needed in patients with mild to moderate renal impairment (creatinine clearance of 30 to 50 mL/min). The use of ropinirole hydrochloride in patients with severe renal impairment has not been studied.<br/>Hepatic Impairment: The pharmacokinetics of ropinirole have not been studied in patients with hepatic impairment. Since patients with hepatic impairment may have higher plasma levels and lower clearance, ropinirole hydrochloride should be titrated with caution in these patients.<br/>Events Reported with Dopaminergic Therapy:<br/>Melanoma: Some epidemiologic studies have shown that patients with Parkinson's disease have a higher risk (perhaps 2 to 4 fold higher) of developing melanoma than the general population. Whether the observed increased risk was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, was unclear. Ropinirole hydrochloride is one of the dopamine agonists used to treat Parkinson's disease. Although ropinirole hydrochloride has not been associated with an increased risk of melanoma specifically, its potential role as a risk factor has not been systemically studied. Patients using ropinirole hydrochloride for any indication should be made aware of these results and should undergo periodic dermatologic screening.<br/>Augmentation and Rebound in RLS: Reports in the literature indicate treatment of RLS with dopaminergic medications can result in a worsening of symptoms in the early morning hours, referred to as rebound. Augmentation has also been described during therapy for RLS. Augmentation refers to the earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other extremities. The controlled trials of ropinirole hydrochloride in patients with RLS excluded patients with augmentation and rebound and were generally not of sufficient duration to capture these phenomena. The frequency of augmentation and/or rebound after longer use of ropinirole hydrochloride and the appropriate management of these events, have not been evaluated in controlled clinical trials.<br/>Retinal Pathology:<br/>Binding to Melanin: Ropinirole hydrochloride binds to melanin-containing tissues (i.e., eyes, skin) in pigmented rats. After a single dose, long-term retention of drug was demonstrated, with a half-life in the eye of 20 days. It is not known if ropinirole hydrochloride accumulates in these tissues over time.<br/>Information for Patients: Physicians should instruct their patients to read the Patient Information leaflet before starting therapy with ropinirole hydrochloride and to reread it upon prescription renewal for new information regarding the use of ropinirole hydrochloride. Patients should be instructed to take ropinirole hydrochloride only as prescribed. If a dose is missed, patients should be advised not to double their next dose. Ropinirole hydrochloride can be taken with or without food. Patients may be advised that taking ropinirole hydrochloride with food may reduce the occurrence of nausea. However, this has not been established in controlled clinical trials. Patients should be advised that they may develop postural (orthostatic) hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating. Hypotension and/or orthostatic symptoms may occur more frequently during initial therapy or with an increase in dose at any time (cases have been seen after weeks of treatment). Accordingly, patients should be cautioned against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods, and especially at the initiation of treatment with ropinirole hydrochloride. Patients should be alerted to the potential sedating effects associated with ropinirole hydrochloride, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Since somnolence is a frequent adverse event with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with ropinirole hydrochloride to gauge whether or not it affects their mental and/or motor performance adversely. Patients should be advised that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Because of possible additive effects, caution should be advised when patients are taking other sedating medications or alcohol in combination with ropinirole hydrochloride and when taking concomitant medications that increase plasma levels of ropinirole (e.g., ciprofloxacin). Because of the possible additive sedative effects, caution should also be used when patients are taking alcohol or other CNS depressants (e.g., benzodiazepines, antipsychotics, antidepressants, etc.) in combination with ropinirole hydrochloride. Patients should be informed they may experience hallucinations (unreal visions, sounds, or sensations) while taking ropinirole hydrochloride. These were uncommon in patients taking ropinirole hydrochloride for Restless Legs Syndrome. The risk is greater in patients with Parkinson's disease; the elderly are at greater risk than younger patients with Parkinson's disease; and the risk is greater in patients who are taking ropinirole hydrochloride with L-dopa, or taking higher doses of ropinirole hydrochloride. Because of the possibility that ropinirole may be excreted in breast milk, patients should be advised to notify their physicians if they intend to breastfeed or are breastfeeding an infant. Because ropinirole has been shown to have adverse effects on embryo-fetal development, including teratogenic effects, in animals, and because experience in humans is limited, patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy (see PRECAUTIONS, Pregnancy).<br/>Drug Interactions:<br/>PInteraction: In vitro metabolism studies showed that CYP1A2 was the major enzyme responsible for the metabolism of ropinirole. There is thus the potential for substrates or inhibitors of this enzyme when coadministered with ropinirole to alter its clearance. Therefore, if therapy with a drug known to be a potent inhibitor of CYP1A2 is stopped or started during treatment with ropinirole hydrochloride, adjustment of the dose of ropinirole hydrochloride may be required.<br/>L-dopa: Coadministration of carbidopa + L-dopa (10/100 mg twice daily) with ropinirole (2 mg 3 times daily) had no effect on the steady-state pharmacokinetics of ropinirole (n = 28 patients). Oral administration of ropinirole hydrochloride 2 mg 3 times daily increased mean steady state Cof L-dopa by 20%, but its AUC was unaffected (n = 23 patients).<br/>Digoxin: Coadministration of ropinirole hydrochloride (2 mg 3 times daily) with digoxin (0.125 to 0.25 mg once daily) did not alter the steady-state pharmacokinetics of digoxin in 10 patients.<br/>Theophylline: Administration of theophylline (300 mg twice daily, a substrate of CYP1A2) did not alter the steady-state pharmacokinetics of ropinirole (2 mg 3 times daily) in 12 patients with Parkinson's disease. Ropinirole (2 mg 3 times daily) did not alter the pharmacokinetics of theophylline (5 mg/kg IV) in 12 patients with Parkinson's disease.<br/>Ciprofloxacin: Coadministration of ciprofloxacin (500 mg twice daily), an inhibitor of CYP1A2, with ropinirole (2 mg 3 times daily) increased ropinirole AUC by 84% on average and Cby 60% (n = 12 patients).<br/>Estrogens: Population pharmacokinetic analysis revealed that estrogens (mainly ethinylestradiol: intake 0.6 to 3 mg over 4 month to 23 year period) reduced the oral clearance of ropinirole by 36% in 16 patients. Dosage adjustment may not be needed for ropinirole hydrochloride in patients on estrogen therapy becausepatients must be carefully titrated with ropinirole to tolerance or adequate effect. However, if estrogen therapy is stopped or started during treatment with ropinirole hydrochloride, then adjustment of the dose of ropinirole hydrochloride may be required.<br/>Dopamine Antagonists: Since ropinirole is a dopamine agonist, it is possible that dopamine antagonists, such as neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide may diminish the effectiveness of ropinirole hydrochloride. Patients with major psychotic disorders treated with neuroleptics should only be treated with dopamine agonists if the potential benefits outweigh the risks. Population analysis showed that commonly administered drugs, e.g., selegiline, amantadine, tricyclic antidepressants, benzodiazepines, ibuprofen, thiazides, antihistamines, and anticholinergics, did not affect the oral clearance of ropinirole.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Two-year carcinogenicity studies were conducted in Charles River CD-1 mice at doses of 5, 15, and 50 mg/kg/day and in Sprague-Dawley rats at doses of 1.5, 15, and 50 mg/kg/day (top doses equivalent to 10 and 20 times, respectively, the maximum recommended human dose of 24 mg/day on a mg/mbasis). In the male rat, there was a significant increase in testicular Leydig cell adenomas at all doses tested, i.e.,���1.5 mg/kg (0.6 times the maximum recommended human dose on a mg/mbasis). This finding is of questionable significance because the endocrine mechanisms believed to be involved in the production of Leydig cell hyperplasia and adenomas in rats are not relevant to humans. In the female mouse, there was an increase in benign uterine endometrial polyps at a dose of 50 mg/kg/day (10 times the maximum recommended human dose on a mg/mbasis). Ropinirole was not mutagenic or clastogenic in the in vitro Ames test, the in vitro chromosome aberration test in human lymphocytes, the in vitro mouse lymphoma (L1578Y cells) assay, and the in vivo mouse micronucleus test. When administered to female rats prior to and during mating and throughout pregnancy, ropinirole caused disruption of implantation at doses of 20 mg/kg/day (8 times the maximum recommended human dose on a mg/mbasis) or greater. This effect is thought to be due to the prolactin-lowering effect of ropinirole. In humans, chorionic gonadotropin, not prolactin, is essential for implantation. In rat studies using low doses (5 mg/kg) during the prolactin-dependent phase of early pregnancy (gestation days 0 to 8), ropinirole did not affect female fertility at dosages up to 100 mg/kg/day (40 times the maximum recommended human dose on a mg/mbasis). No effect on male fertility was observed in rats at dosages up to 125 mg/kg/day (50 times the maximum recommended human dose on a mg/mbasis).<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: Ropinirole hydrochloride inhibits prolactin secretion in humans and could potentially inhibit lactation. Studies in rats have shown that ropinirole hydrochloride and/or its metabolite(s) is excreted in breast milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ropinirole hydrochloride, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in the pediatric population have not been established. | lld:dailymed |
| dailymed-drugs:331 | dailymed-instance:precautio... | General: Prescribing clindamycin injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Review of experience to date suggests that a subgroup of older patients with associated severe illness may tolerate diarrhea less well. When clindamycin is indicated in these patients, they should be carefully monitored for change in bowel frequency. Clindamycin injection should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. Clindamycin injection should be prescribed with caution in atopic individuals. Certain infections may require incision and drainage or other indicated surgical procedures in addition to antibiotic therapy. The use of clindamycin injection may result in overgrowth of nonsusceptible organisms���particularly yeasts. Should superinfections occur, appropriate measures should be taken as indicated by the clinical situation. Clindamycin injection should not be injected intravenously undiluted as a bolus, but should be infused over at least 10 to 60 minutes as directed in the DOSAGE AND ADMINISTRATION section. Clindamycin dosage modification may not be necessary in patients with renal disease. In patients with moderate to severe liver disease, prolongation of clindamycin half-life has been found. However, it was postulated from studies that when given every eight hours, accumulation should rarely occur. Therefore, dosage modification in patients with liver disease may not be necessary. However, periodic liver enzyme determinations should be made when treating patients with severe liverdisease.<br/>Information for Patients: Patients should be counseled that antibacterial drugs including clindamycin injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When clindamycin injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by clindamycin injection or other antibacterial drugs in the future.<br/>Laboratory Tests: During prolonged therapy periodic liver and kidney function tests and blood counts should be performed.<br/>Drug Interactions: Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, it should be used with caution in patients receiving such agents. Antagonism has been demonstrated between clindamycin and erythromycin in vitro. Because of possible clinical significance, the two drugs should not be administered concurrently.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been performed with clindamycin to evaluate carcinogenic potential. Genotoxicity tests performed included a rat micronucleus test and an Ames Salmonella reversion test. Both tests were negative. Fertility studies in rats treated orally with up to 300 mg/kg/day (approximately 1.1 times the highest recommended adult human dose based on mg/m) revealed no effects on fertility or mating ability.<br/>Pregnancy:<br/>Teratogenic Effects; Pregnancy Category B: Reproduction studies performed in rats and mice using oral doses of clindamycin up to 600 mg/kg/day (2.1 and 1.1 times the highest recommended adult human dose based on mg/m, respectively) or subcutaneous doses of clindamycin up to 250 mg/kg/day (0.9 and 0.5 times the highest recommended adult human dose based on mg/m, respectively) revealed no evidence of teratogenicity. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed.<br/>Nursing Mothers: Clindamycin has been reported to appear in breast milk in the range of 0.7 to 3.8 mcg/mL at dosages of 150 mg orally to 600 mg intravenously. Because of the potential for adverse reactions due to clindamycin in neonates (see Pediatric Use), the decision to discontinue the drug should be made, taking into account the importance of the drug to the mother.<br/>Pediatric Use: When clindamycin injection is administered to the pediatric population (birth to 16 years) appropriate monitoring of organ system functions is desirable.<br/>Usage in Newborns and Infants: This product contains benzyl alcohol as a preservative. Benzyl alcohol has been associated with a fatal���Gasping Syndrome���in premature infants.<br/>Geriatric Use: Clinical studies of clindamycin did not include sufficient numbers of patients age 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experience indicates that antibiotic-associated colitis and diarrhea (due to Clostridium difficile) seen in association with most antibiotics occur more frequently in the elderly (>60 years) and may be more severe. These patients should be carefully monitored for the development of diarrhea. Pharmacokinetic studies with clindamycin have shown no clinically important differences between young and elderly subjects with normal hepatic function and normal (age-adjusted) renal function after oral or intravenous administration. | lld:dailymed |
| dailymed-drugs:332 | dailymed-instance:precautio... | General:<br/>Special Risk Patients: As with any narcotic analgesic agent, hydrocodone bitartrate and acetaminophen capsules should be used with caution in elderly or debilitated patients, and those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease, prostatic hypertrophy or urethral stricture. The usual precautions should be observed and the possibility of respiratory depression should be kept in mind.<br/>Cough Reflex: Hydrocodone suppresses the cough reflex; as with all narcotics, caution should be exercised when hydrocodone bitartrate and acetaminophen capsules are used postoperatively and in patients with pulmonary disease.<br/>Information for Patients: Hydrocodone, like all narcotics, may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery; patients should be cautioned accordingly. Alcohol and other CNS depressants may produce an additive CNS depression, when taken with this combination product, and should be avoided. Hydrocodone may be habit-forming. Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed.<br/>Laboratory Tests: In patients with severe hepatic or renal disease, effects of therapy should be monitored with serial liver and/or renal function tests.<br/>Drug Interactions: Patients receiving others narcotics, antihistamines, antipsychotics, antianxiety agents, or other CNS depressants (including alcohol) concomitantly with hydrocodone bitartrate and acetaminophen capsules may exhibit an additive CNS depression. When combined therapy is contemplated, the dose of one or both agents should be reduced. The use of MAO inhibitors or tricyclic antidepressants with hydrocodone preparations may increase the effect of either the antidepressant or hydrocodone.<br/>Drug/Laboratory Test Interactions: Acetaminophen may produce false-positive test results for urinary 5-hydroxyindoleacetic acid.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No adequate studies have been conducted in animals to determine whether hydrocodone or acetaminophen have a potential for carcinogenesis, mutagenesis, or impairment of fertility.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Hydrocodone bitartrate and acetaminophen capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nonteratogenic Effects: Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal.<br/>Labor and Delivery: As with all narcotics, administration of this product to the mother shortly before delivery may result in some degree of respiratory depression in the newborn, especially if higher doses are used.<br/>Nursing Mother: Acetaminophen is excreted in breast milk in small amounts, but the significance of its effects on nursing infants is not known. It is not known whether hydrocodone is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from hydrocodone and acetaminophen, a decision should be made whether to discontinue nursing or to discontinue thedrug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric Use: Clinical Studies of hydrocodone bitartrate and acetaminophen tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Hydrocodone and the major metabolites of acetaminophen are known to be substantially excreted by the kidney. Thus the risk of toxic reactions may be greater in patients with impaired renal function due to the accumulation of the parent compound and/or metabolites in the plasma. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Hydrocodone may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of hydrocodone bitartrate and acetaminophen tablets and observed closely. | lld:dailymed |
| dailymed-drugs:333 | dailymed-instance:precautio... | General: Mentax Cream, 1%, is for external use only. If irritation or sensitivity develops with the use of Mentax Cream, 1%, treatment should be discontinued and appropriate therapy instituted. Diagnosis of the disease should be confirmed either by culture on an appropriate medium, [except M. furfur (formerly P. orbiculare)] or by direct microscopic examination of infected superficial epidermal tissue in a solution of potassium hydroxide. Patients who are known to be sensitive to allylamine antifungals should use Mentax (butenafine HCl) Cream, 1%, with caution since cross-reactivity may occur. Use Mentax Cream, 1%, as directed by the physician, and avoid contact with the eyes, nose, mouth, and other mucous membranes.<br/>Information for Patients: The patient should be instructed to:<br/>Drug Interactions: Potential drug interactions between Mentax (butenafine HCl) Cream, 1%, and other drugs have not been systematically evaluated.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies to evaluate the carcinogenic potential of Mentax Cream, 1%, have not been conducted. Two in vitro assays (bacterial reverse mutation test and chromosome aberration test in Chinese hamster lymphocytes) and one in vivo study (rat micronucleus bioassay) revealed no mutagenic or clastogenic potential for butenafine. In subcutaneous fertility studies conducted in rats at dose levels up to 25 mg/kg/day (0.5 times the maximum recommended dose in humans for tinea versicolor based on body surface area comparisons), butenafine did not produce any adverse effects on male or female fertility.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C: Subcutaneous doses of butenafine (dose levels up to 25 mg/kg/day administered during organogenesis) (equivalent to 0.5 times the maximum recommended dose in humans for tinea versicolor based on body surface area comparisons) were not teratogenic in rats. In an oral embryofetal development study in rabbits (dose levels up to 400 mg butenafine HCl/kg/day administered during organogenesis) (equivalent to 16 times the maximum recommended dose in humans for tinea versicolor based on body surface area comparisons), no treatment-related external, visceral, skeletal malformations or variations were observed. In an oral peri- and post-natal developmental study in rats (dose levels up to 125 mg butenafine HCl/kg/day) (equivalent to 2.5 times the maximum recommended dose in humans for tinea versicolor based on body surface area comparisons), no treatment-related effects on postnatal survival, development of the F1 generation or their subsequent maturation and fertility were observed. There are, however, no adequate and well-controlled studies that have been conducted with topically applied butenafine in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.<br/>Nursing Mothers: It is not known if butenafine HCl is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised in prescribing Mentax Cream, 1%, to a nursing woman.<br/>Pediatric Use: Safety and efficacy in pediatric patients below the age of 12 years have not been studied since tinea versicolor is uncommon in patients below the age of 12 years. | lld:dailymed |
| dailymed-drugs:334 | dailymed-instance:precautio... | Animal reproduction studies have not been conducted with the drug combination���promethazine and codeine. It is not known whether this drug combination can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Promethazine hydrochloride and codeine phosphate syrup should be given to a pregnant woman only if clearly needed.<br/>General: Narcotic analgesics, including codeine, should be administered with caution and the initial dose reduced in patients with acute abdominal conditions, convulsive disorders, significant hepatic or renal impairment, fever, hypothyroidism, Addison's disease, ulcerative colitis, prostatic hypertrophy, in patients withrecent gastrointestinal or urinary tract surgery, and in the very young or elderly or debilitated patients. Drugs having anticholinergic properties should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, stenosing peptic ulcer, pyloroduodenal obstruction, and bladder-neck obstruction. Promethazine should be used cautiously in persons with cardiovascular disease or with impairment of liver function. Ultra-rapid Metabolizers of Codeine Some individuals may be ultra-rapid metabolizers due to a specific CYP2D6*2x2 genotype. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regiments, individuals who are ultra-rapid metabolizers may experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing. The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1-10% in Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups. When physicians prescribe codeine-containing drugs, they should choose the lowest effective dose for the shortest period of time and should inform their patients about these risks and the signs of morphine overdose. .<br/>Information for patients: Promethazine and codeine may cause marked drowsiness or may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. Ambulatory patients should be told to avoid engaging in such activities until it is known that they do not become drowsy or dizzy from promethazine and codeine therapy. The concomitant use of alcohol or other central nervous system depressants, including narcotic analgesics, sedatives, hypnotics, and tranquilizers, may have an additive effect and should be avoided or their dosage reduced. Patients should be advised to report any involuntary muscle movements. Avoid prolonged exposure to the sun. Codeine, like other narcotic analgesics, may produce orthostatic hypotension in some ambulatory patients. Patients should be cautioned accordingly. Caution patients that some people have a variation in a liver enzyme and change codeine into morphine more rapidly and completely than other people. These people are ultra-rapid metabolizers and are more likely to have higher-than-normal levels of morphine in their blood after taking codeine which can result in overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. In most cases, it is unknown if someone is an ultra-rapid codeine metabolizer. Nursing mothers taking codeine can also have higher morphine levels in their breast milk of they are ultra-rapid metabolizers. These higher levels of morphine in breast milk may lead to life-threatening or fatal side effects in nursing babies. Instruct nursing mothers to watch for signs of morphine toxicity in their infants including increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Instruct nursing mothers to talk to the baby's doctor immediately if they notice these signs and, if they cannot reach the doctor right away, to take the baby to an emergency room or call 911 (or local emergency services).<br/>Interactions:<br/>Drug interactions: Codeine: In patients receiving MAO inhibitors, an initial small test dose is advisable to allow observation of any excessive narcotic effects or MAOI interaction. Promethazine: CNS depressants���Promethazine may increase, prolong, or intensify the sedative action of other central-nervous-system depressants, such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore, such agents should be avoided or administered in reduced dosage to patients receiving promethazine HCl. When given concomitantly with promethazine, the dose of barbiturates should be reduced by at least one-half, and the dose of narcotics should be reduced by one-quarter to one-half. Dosage must be individualized. Excessive amounts of promethazine HCl relative to a narcotic may lead to restlessness and motor hyperactivity in the patient with pain; these symptoms usually disappear with adequate control of the pain. Epinephrine���Because of the potential for promethazine to reverse epinephrine's vasopressor effect, epinephrine should NOT be used to treat hypotension associated with promethazine overdose. Anticholinergics���Concomitant use of other agents with anticholinergic properties should be undertaken with caution. Monoamine oxidase inhibitors (MAOI)���Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAOI and phenothiazines are used concomitantly.<br/>Drug/laboratory test interactions: Because narcotic analgesics may increase biliary tract pressure, with resultant increase in plasma amylase or lipase levels, determination of these enzyme levels may be unreliable for 24 hours after a narcotic analgesic has been given. The following laboratory tests may be affected in patients who are receiving therapy with promethazine hydrochloride: Pregnancy Tests: Diagnostic pregnancy tests based on immunological reactions between HCG and anti-HCG may result in false-negative or false-positive interpretations. Glucose Tolerance Test: An increase in blood glucose has been reported in patients receiving promethazine.<br/>Carcinogenesis, mutagenesis, impairment of fertility: Long-term animal studies have not been performed to assess the carcinogenic potential of codeine or of promethazine, nor are there other animal or human data concerning carcinogenicity, mutagenicity, or impairment of fertility with these agents. Codeine has been reported to show no evidence of carcinogenicity or mutagenicity in a variety of test systems, including the micronucleus and sperm abnormality assays and the Salmonella assay. Promethazine was nonmutagenic in the Salmonella test system of Ames.<br/>Pregnancy:<br/>Teratogenic effects: Pregnancy Category C Codeine: A study in rats and rabbits reported no teratogenic effect of codeine administered during the period of organogenesis in doses ranging from 5 to 120 mg/kg. In the rat, doses at the 120-mg/kg level, in the toxic range for the adult animal were associated with an increase in embryo resorption at the time of implantation. In another study a single 100-mg/kg dose of codeine administered to pregnant mice reportedly resulted in delayed ossification in the offspring. There are no studies in humans, and the significance of these findings to humans, if any, is not known. Promethazine: Teratogenic effects have not been demonstrated in rat-feeding studies at doses of 6.25 and 12.5 mg/kg of promethazine HCl. These doses are from approximately 2.1 to 4.2 times the maximum recommended total daily dose of promethazine for a 50-kg subject depending upon the indication for which the drug is prescribed. Daily doses of 25 mg/kg intraperitoneally have been found to produce fetal mortality in rats. Specific studies to test the action of the drug on parturition lactation, and development of the animal neonate were not done, but a general preliminary study in rats indicated no effect on these parameters. Although antihistamines have been found to produce fetal mortality in rodents, the pharmacological effects of histamine in the rodent do not parallel those in man. There are no adequate and well-controlled studies of promethazine in pregnant women. Promethazine and codeine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nonteratogenic effects: Dependence has been reported in newborns whose mothers took opiates regularly during pregnancy. Withdrawal signs include irritability, excessive crying, tremors, hyperreflexia, fever, vomiting, and diarrhea. Signs usually appear during the first few days of life. Promethazine administered to a pregnant woman within two weeks of delivery may inhibit platelet aggregation in the newborn.<br/>Labor and delivery: Narcotic analgesics cross the placental barrier. The closer to delivery and the larger the dose used, the greater the possibility of respiratory depression in the newborn. Narcotic analgesics should be avoided during labor if delivery of a premature infant is anticipated. If the mother has received narcotic analgesics during labor, newborn infants should be observed closely for signs of respiratory depression. Resuscitation may be required (see Overdosage). Limited data suggests that use of promethazine hydrochloride during labor and delivery does not have an appreciable effect on the duration of labor or delivery and does not increase the risk for intervention in the newborn. The effect of promethazine and/or codeine on later growth and development of the newborn is unknown.<br/>Nursing mothers: Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. Despite the common use of codeine products to manage postpartum pain, reports of adverse events in infants are rare. However, some women are ultra-rapid metabolizers of codeine. These women achieve higher-than-expected serum levels of codeine's active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants. The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1-10% in Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups. The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and baby. Caution should be exercised when codeine is administered to a nursing woman. If a codeine containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Mothers using codeine should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding. . It is not known whether promethazine is excreted in human milk. Caution should be exercised when promethazine hydrochloride and codeine phosphate syrup is administered to a nursing woman.<br/>Pediatric use: THE COMBINATION OF PROMETHAZINE HYDROCHLORIDE AND CODEINE PHOSPHATE IS CONTRAINDICATED IN PEDIATRIC PATIENTS LESS THAN 6 YEARS OF AGE, BECAUSE THE COMBINATION MAY CAUSE FATAL RESPIRATORY DEPRESSION IN THIS AGE POPULATION (see WARNINGS���Black Box Warning and Use in Pediatric Patients).<br/>Geriatric use: Clinical studies of promethazine hydrochloride and codeine phosphate syrup did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of promethazine hydrochloride and codeine phosphate syrup and observed closely. | lld:dailymed |
| dailymed-drugs:336 | dailymed-instance:precautio... | General: Pilocarpine toxicity is characterized by an exaggeration of its parasympathomimetic effects. These may include: headache, visual disturbance, lacrimation, sweating, respiratory distress, gastrointestinal spasm, nausea, vomiting, diarrhea, atrioventricular block, tachycardia, bradycardia, hypotension, hypertension, shock, mental confusion, cardiac arrhythmia, and tremors. The dose-related cardiovascular pharmacologic effects of pilocarpine include hypotension, hypertension, bradycardia, and tachycardia. Pilocarpine should be administered with caution to patients with known or suspected cholelithiasis or biliary tract disease. Contractions of the gallbladder or biliary smooth muscle could precipitate complications including cholecystitis, cholangitis, and biliary obstruction. Pilocarpine may increase ureteral smooth muscle tone and could theoretically precipitate renal colic (or "ureteral reflux"), particularly in patients with nephrolithiasis. Cholinergic agonists may have dose-related central nervous system effects. This should be considered when treating patients with underlying cognitive or psychiatric disturbances.<br/>Hepatic Insufficiency: Based on decreased plasma clearance observed in patients with moderate hepatic impairment, the starting dose in these patients should be 5 mg twice daily, followed by adjustment based on therapeutic response and tolerability. Patients with mild hepatic insufficiency (Child-Pugh score of 5 to 6) do not require dosage reductions. To date, pharmacokinetic studies in subjects withsevere hepatic impairment (Child-Pugh score of 10 to 15) have not been carried out. The use of pilocarpine in these patients is not recommended. Reference: Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Brit. J. Surg. 1973; 60:646-9.<br/>Information for Patients: Patients should be informed that pilocarpine may cause visual disturbances, especially at night, that could impair their ability to drive safely. If a patient sweats excessively while taking pilocarpine hydrochloride and cannot drink enough liquid, the patient should consult a physician. Dehydration may develop.<br/>Drug Interactions: Pilocarpine should be administered with caution to patients taking beta-adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sjogren's efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Lifetime oral carcinogenicity studies were conducted in CD-1 mice and Sprague-Dawley rats. Pilocarpine did not induce tumors in mice at any dosage studied (up to 30 mg/kg/day, which yielded a systemic exposure approximately 50 times larger than the maximum systemic exposure observed clinically). In rats, a dosage of 18 mg/kg/day, which yielded a systemic exposure approximately 100 times larger than the maximum systemic exposure observed clinically, resulted in a statistically significant increase in the incidence of benign pheochromocytomas in both males and females, and a statistically significant increase in the incidence of hepatocellular adenomas in female rats. The tumorigenicity observed in rats was observed only at a large multiple of the maximum labeled clinical dose, and may not be relevant to clinical use. No evidence that pilocarpine has the potential to cause genetic toxicity was obtained in a series of studies that included: 1) bacterial assays (Salmonella and E. coli) for reverse gene mutations; 2) an in vitro chromosome aberration assay in a Chinese hamster ovary cell line; 3) an in vivo chromosome aberration assay (micronucleus test) in mice; and 4) a primary DNA damage assay (unscheduled DNA synthesis) in rat hepatocyte primary cultures. Oral administration of pilocarpine to male and female rats at a dosage of 18 mg/kg/day, which yielded a systemic exposure approximately 100 times larger than the maximum systemic exposure observed clinically, resulted in impaired reproductive function, including reduced fertility, decreased sperm motility, and morphologic evidence of abnormal sperm. It is unclear whether the reduction in fertilitywas due to effects on male animals, female animals, or both males and females. In dogs, exposure to pilocarpine at a dosage of 3 mg/kg/day (approximately 3 times the maximum recommended human dose when compared on the basis of body surface area (mg/m) estimates) for six months resulted in evidence of impaired spermatogenesis. The data obtained in these studies suggest that pilocarpine may impair the fertility of male and female humans. Pilocarpine Hydrochloride Tablets should be administered to individuals who are attempting to conceive a child only if the potential benefit justifies potential impairment of fertility.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from pilocarpine hydrochloride tablets, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric Use:<br/>Head and Neck Cancer Patients: In the placebo-controlled clinical trials (see Clinical Studies section) the mean age of patients was approximately 58 years (range 19 to 80). Of these patients, 97/369 (61/217 receiving pilocarpine) were over the age of 65 years. In the healthy volunteer studies, 15/150 subjects were over the age of 65 years. In both study populations, the adverse events reported by those over 65 years and those 65 years and younger were comparable. Of the 15 elderly volunteers (5 women, 10 men), the 5 women had higher Cand AUC's than the men. (See Pharmacokinetics section.)<br/>Sjogren's Syndrome Patients: In the placebo-controlled clinical trials (see Clinical Studies section), the mean age of patients was approximately 55 years (range 21 to 85). The adverse events reported by those over 65 years and those 65 years and younger were comparable except for notable trends for urinary frequency, diarrhea, and dizziness . | lld:dailymed |
| dailymed-drugs:337 | dailymed-instance:precautio... | General:<br/>Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, lisinopril should be given with caution to patients with obstruction in the outflow tract of the left ventricle.<br/>Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including lisinopril, may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another angiotensin-converting enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of lisinopril and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy. Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when lisinopril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or lisinopril may be required. Patients with acute myocardial infarction in the GISSI���3 trial treated with lisinopril had a higher (2.4% vs. 1.1%) incidence of renal dysfunction in-hospital and at six weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration). In acute myocardial infarction, treatment with lisinopril should be initiated with caution in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. If renal dysfunction develops during treatment with lisinopril (serum creatinine concentration exceeding 3 mg/dL or a doubling from the pre-treatment value) then the physicianshould consider withdrawal of lisinopril. Evaluation of patients with hypertension, heart failure, or myocardial infarction should alwaysinclude assessment of renal function (see DOSAGE AND ADMINISTRATION).<br/>Hyperkalemia: In clinical trials hyperkalemia (serum potassium greater than 5.7 mEq/L) occurred in approximately 2.2% of hypertensive patients and 4.8% of patients with heart failure. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in approximately 0.1% of hypertensive patients, 0.6% of patients with heart failure and 0.1% of patients with myocardial infarction. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes. Hyperkalemia can cause serious, sometimes fatal, arrhythmias. Lisinopril should be used cautiously, if at all, with these agents and with frequent monitoring of serum potassium (see Drug Interactions).<br/>Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, almost always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.<br/>Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, lisinopril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.<br/>Information for Patients:<br/>Angioedema: Angioedema, including laryngeal edema, may occur at any time during treatment with angiotensin-converting enzyme inhibitors, including lisinopril. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physician.<br/>Symptomatic Hypotension: Patients should be cautioned to report lightheadedness especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician. All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with their physician.<br/>Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician.<br/>Hypoglycemia: Diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor should be told to closely monitor for hypoglycemia, especially during the first month of combined use (see PRECAUTIONS, Drug Interactions).<br/>Leukopenia/Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a sign of leukopenia/neutropenia.<br/>Pregnancy: Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to ACE inhibitors, and they should also be told that these consequences do not appear to have resulted from intrauterine ACE inhibitor exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible. NOTE: As with many other drugs, certain advice to patients being treated with lisinopril is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.<br/>Drug Interactions:<br/>Hypotension���Patients on Diuretic Therapy: Patients on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with lisinopril. The possibility of hypotensive effects with lisinopril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with lisinopril. If it is necessary to continue the diuretic, initiate therapy with lisinopril at a dose of 5 mg daily, and provide close medical supervision after the initial dose until blood pressure has stabilized (see WARNINGS and DOSAGE AND ADMINISTRATION). When a diuretic is added to the therapy of a patient receiving lisinopril, an additional antihypertensive effect is usually observed. Studies with ACE inhibitors in combination with diuretics indicate that the dose of the ACE inhibitor can be reduced when it is given with a diuretic (see DOSAGE AND ADMINISTRATION).<br/>Antidiabetics: Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycemic agents) may cause an increased blood-glucose-lowering effect with risk of hypoglycemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment. In diabetic patients treated with oral antidiabetic agents or insulin, glycemic control should be closely monitored for hypoglycemia, especially during the first month of treatment with an ACE inhibitor.<br/>Non-steroidal Anti-inflammatory Agents: In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs, the coadministration of lisinopril may result in further deterioration of renal function. These effects are usually reversible. In a study in 36 patients with mild to moderate hypertension where the antihypertensive effects of lisinopril alone were compared to lisinopril given concomitantly with indomethacin, the use of indomethacin was associated witha reduced effect, although the difference between the two regimens was not significant.<br/>Other Agents: Lisinopril has been used concomitantly with nitrates and/or digoxin without evidence of clinically significant adverse interactions. This included post myocardial infarction patients who were receiving intravenous or transdermal nitroglycerin. No clinically important pharmacokinetic interactions occurred when lisinopril was used concomitantly with propranolol or hydrochlorothiazide. The presence of food in the stomach does not alter the bioavailability of lisinopril.<br/>Agents Increasing Serum Potassium: Lisinopril attenuates potassium loss caused by thiazide-type diuretics. Use of lisinopril with potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium. Potassium-sparing agents should generally not be used in patients with heart failure who are receiving lisinopril.<br/>Lithium: Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. Lithium toxicity was usually reversible upon discontinuation of lithium and the ACE inhibitor. It is recommended that serum lithium levels be monitored frequently if lisinopril is administered concomitantly with lithium.<br/>Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including lisinopril.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: There was no evidence of a tumorigenic effect when lisinopril was administered for 105 weeks to male and female rats at doses up to 90 mg/kg/day (about 56 or 9 timesthe maximum recommended daily human dose, based on body weight and body surface area, respectively). There was no evidence of carcinogenicity when lisinopril was administered for 92 weeks to (male and female) mice at doses up to 135 mg/kg/day (about 84 timesthe maximum recommended daily human dose). This dose was 6.8 times the maximum human dose based on body surface area in mice. Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic activation. It was also negative in a forward mutation assay using Chinese hamster lung cells. Lisinopril did not produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte assay. In addition, lisinopril did not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow. There were no adverse effects on reproductive performance in male and female rats treated with up to 300 mg/kg/day of lisinopril. This dose is 188 times and 30 times the maximum human dose when based on mg/kg and mg/m, respectively. Calculations assume a human weight of 50 kg and human body surface area of 1.62 m.<br/>Pregnancy:<br/>Pregnancy Categories C (first trimester) and D (second and third trimesters): See WARNINGS, Fetal/Neonatal Morbidity and Mortality.<br/>Nursing Mothers: Milk of lactating rats contains radioactivity following administration ofC lisinopril. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ACE inhibitors, a decision should be made whether to discontinue nursing or discontinue lisinopril, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Antihypertensive effects of lisinopril have been established in hypertensive pediatric patients aged 6 to 16 years. There are no data on the effect of lisinopril on blood pressure in pediatric patients under the age of 6 or in pediatric patients with glomerular filtration rate<30 mL/min/1.73 m(see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism and Pharmacodynamics and Clinical Effects, and DOSAGE AND ADMINISTRATION).<br/>Geriatric Use: Clinical studies of lisinopril in patients with hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience in this population has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In the ATLAS trial of lisinopril in patients with congestive heart failure, 1596 (50%) were 65 and over, while 437 (14%) were 75 and over. In a clinical study of lisinopril in patients with myocardial infarctions, 4413 (47%) were 65 and over, while 1656 (18%) were 75 and over. In these studies, no overall differences in safety or effectiveness were observed between elderly and younger patients, and other reported clinical experiences have not identified differences in responses between the elderly and younger patients (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Heart Failure and CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Acute Myocardial Infarction). Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies indicate that maximum blood levels and area under plasma concentration time curve (AUC) are doubled in older patients (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Evaluation of patients with hypertension, congestive heart failure, or myocardial infarctionshould always include assessment of renal function (see DOSAGE AND ADMINISTRATION). | lld:dailymed |
| dailymed-drugs:338 | dailymed-instance:precautio... | General: Prolonged use of Cefazolin for Injection USP and Dextrose Injection USP may result in the overgrowth of nonsusceptible organisms. Careful clinical observation of the patient is essential. When Cefazolin for Injection USP and Dextrose Injection USP is administered to patients with low urinary output because of impaired renal function, lower daily dosage is required . As with other beta-lactam antibiotics, seizures may occur if inappropriately high doses are administered to patients with impaired renal function . Cefazolin for Injection USP and Dextrose Injection USP, as with all cephalosporins, should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated. As with other dextrose-containing solutions, Cefazolin for Injection USP and Dextrose Injection USP should be prescribed with caution in patients with overt or known subclinical diabetes mellitus or carbohydrate intolerance for any reason. Prescribing Cefazolin for Injection USP and Dextrose Injection USP in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result. Use only if solution is clear and container and seals are intact.<br/>Drug Interactions: Probenecid may decrease renal tubular secretion of cephalosporins when used concurrently, resulting in increased and more prolonged cephalosporin blood levels.<br/>Drug/Laboratory Test Interactions: A false positive reaction for glucose in the urine may occur with Benedict's solution, Fehling's solution or with Clinitest tablets, but not with enzyme-based tests such as Clinistix. Positive direct and indirect antiglobulin (Coombs) tests have occurred; these may also occur in neonates whose mothers received cephalosporins before delivery.<br/>Information for Patients: Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Patients should be counseled that antibacterial drugs including Cefazolin for Injection USP and Dextrose Injection USP should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefazolin for Injection USP and Dextrose Injection USP is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Cefazolin for Injection USP and Dextrose Injection USP or other antibacterial drugs in the future.<br/>Carcinogenesis/Mutagenesis: Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of Cefazolin for Injection USP and Dextrose Injection USP have not been performed.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Labor and Delivery: When cefazolin has been administered prior to caesarean section, drug levels in cord blood have been approximately one quarter to one third of maternal drug levels. The drug appears to have no adverse effect on the fetus.<br/>Nursing Mothers: Cefazolin is present in very low concentrations in the milk of nursing mothers. Caution should be exercised when Cefazolin for Injection USP and Dextrose Injection USP is administered to a nursing woman.<br/>Pediatric Use: Cefazolin for Injection USP and Dextrose Injection USP is designed to deliver a 1 g dose of cefazolin. To prevent unintentional overdose, Cefazolin for Injection USP and Dextrose Injection USP should not be used in pediatric patients who require less than the full adult dose of cefazolin.<br/>Geriatric Use: Of the 920 subjects who received cefazolin in clinical studies, 313 (34%) were 65 years and over, while 138 (15%) were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function . | lld:dailymed |
| dailymed-drugs:339 | dailymed-instance:precautio... | General: Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria in some patients. Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids. Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity . If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted. In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled.<br/>Information for the Patient: Patients using topical corticosteroids should receive the following information and instructions:<br/>Laboratory Tests: The following tests may be helpful in evaluating the HPA axis suppression: Urinary free cortisol test ACTH stimulation test<br/>Carcinogenesis, Mutagenesis and Impairment of Fertility: Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of topical corticosteroids. Studies to determine mutagenicity with prednisolone and hydrocortisone have revealed negative results.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C:: Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids. Therefore, topical corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Drugs of this class should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time.<br/>Nursing Mothers: It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant. Nevertheless, caution should be exercised when topical corticosteroids are administered to a nursing woman.<br/>Pediatric Use: Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced HPA axis suppression and Cushing's syndrome than mature patients because of a larger skin surface area to body weight ratio. Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include linear growth retardation, delayed weight gain, low plasma cortisol levels,and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Administration of topical corticosteroids to pediatric patients should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of pediatric patients. | lld:dailymed |
| dailymed-drugs:340 | dailymed-instance:precautio... | General: ATROVENT HFA Inhalation Aerosol should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction.<br/>Information for Patients: Appropriate and safe use of ATROVENT HFA Inhalation Aerosol includes providing the patient with the information listed below and an understanding of the way it should be administered (see Patient's Instructions for Use). Patients should be advised that ATROVENT HFA Inhalation Aerosol is a bronchodilator for the maintenance treatment of bronchospasm associated with COPD and is not indicated for the initial treatment of acute episodes of bronchospasm where rescue therapy is required for rapid response. Patients should be cautioned to avoid spraying the aerosol into their eyes and be advised that this may result in precipitation or worsening of narrow-angle glaucoma, mydriasis, increased intraocular pressure, acute eye pain or discomfort, temporary blurring of vision, visual halos or colored images in association with red eyes from conjunctival and corneal congestion. Patients should also be advised that should any combination of these symptoms develop, they should consult their physician immediately. The action of Atrovent' HFA (ipratropium bromide HFA) Inhalation Aerosol should last 2-4 hours. Patients should be advised not to increase the dose or frequency of ATROVENT HFA Inhalation Aerosol without patients consulting their physician. Patients should also be advised to seek immediate medical attention if treatment with ATROVENT HFA Inhalation Aerosol becomes less effective for symptomatic relief, their symptoms become worse, and/or patients need to use the product more frequently than usual. Patients should be advised on the use of ATROVENT HFA Inhalation Aerosol in relation to other inhaled drugs. Patients should be reminded that ATROVENT HFA Inhalation Aerosol should be used consistently as prescribed throughout the course of therapy. Patients should be advised that although the taste and inhalation sensation of ATROVENT HFA Inhalation Aerosol may be slightly different from that of the CFC (chlorofluorocarbon) formulation of ATROVENT Inhalation Aerosol, they are comparable in terms of safety and efficacy.<br/>Drug Interactions: ATROVENT HFA Inhalation Aerosol has been used concomitantly with other drugs, including sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids, that may be used in the treatment of chronic obstructive pulmonary disease. With the exception of albuterol, there are no formal studies fully evaluating the interaction effects of ATROVENT and these drugs with respect to effectiveness. Anticholinergic agents: Although ipratropium bromide is minimally absorbed into the systemic circulation, there is some potential for an additive interaction with concomitantly used anticholinergic medications. Caution is therefore advised in the co-administration of ATROVENT HFA Inhalation Aerosol with other anticholinergic-containing drugs.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In two-year oral carcinogenicity studies in rats and mice, ipratropium bromide at oral doses up to 6 mg/kg (approximately 240 and 120 times the maximum recommended daily inhalation dose in adults on a mg/mbasis) showed no carcinogenic activity. Results of various mutagenicity studies (Ames test, mouse dominant lethal test, mouse micronucleus test and chromosome aberration of bone marrow in Chinese hamsters) were negative. Fertility of male or female rats at oral doses up to 50 mg/kg (approximately 2000 times the maximum recommended daily inhalation dose in adults on a mg/mbasis) was unaffected by ipratropium bromide administration. At an oral dose of 500 mg/kg (approximately 20,000 times the maximum recommended daily inhalation dose in adults on a mg/mbasis), ipratropium bromide produced a decrease in the conception rate.<br/>Pregnancy:<br/>Teratogenic Effects:Pregnancy Category B.: Oral reproduction studies were performed at doses of 10 mg/kg/day in mice, 1,000 mg/kg in rats and 125 mg/kg/day in rabbits. These doses correspond in each species, respectively, to approximately 200, 40000, and 10000 times the maximum recommended daily inhalation dose in adults on a mg/mbasis. Inhalation reproduction studies were conducted in rats and rabbits at doses of 1.5 and 1.8 mg/kg (approximately 60 and 140 times the maximum recommended daily inhalation dose in adults on a mg/mbasis). These studies demonstrated no evidence of teratogenic effects as a result of ipratropium bromide. At oral doses 90 mg/kg and above in rats (approximately 3600 times the maximum recommended daily inhalation dose in adults on a mg/mbasis) embryotoxicity was observed as increased resorption. This effect is not considered relevant to human use due to the large doses at which it was observed and the difference in route of administration. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Atrovent' HFA (ipratropium bromide HFA) Inhalation Aerosol should be used during pregnancy only if clearly needed.<br/>Nursing Mothers: It is not known whether the active component, ipratropium bromide, is excreted in human milk. Although lipid-insoluble quaternary cations pass into breast milk, it is unlikely that ipratropium bromide would reach the infant to an important extent, especially when taken by aerosol. However, because many drugs are excreted in human milk, caution should be exercised when ATROVENT HFA Inhalation Aerosol is administered to a nursing mother.<br/>Pediatric Use: Safety and effectiveness in the pediatric population have not been established.<br/>Geriatric Use: In the pivotal 12-week study, both ATROVENT HFA Inhalation Aerosol and Atrovent (ipratropium bromide) Inhalation Aerosol CFC formulations were equally effective in patients over 65 years of age and under 65 years of age. Of the total number of subjects in clinical studies of ATROVENT HFA Inhalation Aerosol, 57% were���65 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. | lld:dailymed |
| dailymed-drugs:343 | dailymed-instance:precautio... | General: Myocardial stimulation produced by hydralazine can cause anginal attacks and ECG changes of myocardial ischemia. The drug has been implicated in the production of myocardial infarction. It must, therefore, be used with caution in patients with suspected coronary artery disease. The ``hyperdynamic������circulation caused by hydralazine may accentuate specific cardiovascular inadequacies. For example, hydralazine may increase pulmonary artery pressure in patients with mitral valvular disease. The drug may reduce the pressor responses to epinephrine. Postural hypotension may result from hydralazine but is less common than with ganglionic blocking agents. It should be used with caution in patients with cerebral vascular accidents. In hypertensive patients with normal kidneys who are treated with hydralazine, there is evidence of increased renal blood flow and a maintenance of glomerular filtration rate. In some instances where control values were below normal, improved renal function has been noted after administration of hydralazine. However, as with any antihypertensive agent, hydralazine should be used with caution in patients with advanced renal damage. Peripheral neuritis, evidenced by paresthesia, numbness, and tingling, has been observed. Published evidence suggests an antipyridoxine effect, and that pyridoxine should be added to the regimen if symptoms develop. Laboratory Tests: Complete blood counts and antinuclear antibody titer determinations are indicated before and periodically during prolonged therapy with hydralazine even though the patient is asymptomatic. These studies are also indicated if the patient develops arthralgia, fever, chest pain, continued malaise, or other unexplained signs or symptoms. A positive antinuclear antibody titer requires that the physician carefully weigh the implications of the test results against the benefits to be derived from antihypertensive therapy with hydralazine hydrochloride. Blood dyscrasias, consisting of reduction in hemoglobin and red cell count, leukopenia, agranulocytosis, and purpura, have been reported. If such abnormalities develop, therapy should be discontinued. Drug Interactions: MAO inhibitors should be used with caution in patients receiving hydralazine. When other potent parenteral antihypertensive drugs, such as diazoxide, are used in combination with hydralazine, patients should be continuously observed for several hours for any excessive fall in blood pressure. Profound hypotensive episodes may occur when diazoxide injection and hydralazine injection are used concomitantly. Carcinogenesis, Mutagenesis, Impairment of Fertility: In a lifetime study in Swiss albino mice, there was a statistically significant increase in the incidence of lung tumors (adenomas and adenocarcinomas) of both male and female mice given hydralazine continuously in their drinking water at a dosage of about 250 mg/kg per day (about 80 times the maximum recommended human dose). In a 2-year carcinogenicity study of rats given hydralazine by gavage at dose levels of 15, 30, and 60 mg/kg/day (approximately 5 to 20 times the recommended human daily dosage), microscopic examination of the liver revealed a small, but statistically significant, increasein benign neoplastic nodules in male and female rats from the high-dose group and in female rats from the intermediate-dose group. Benign interstitial cell tumors of the testes were also significantly increased in male rats from the high-dose group. The tumors observed are common in aged rats and a significantly increased incidence was not observed until 18 months of treatment. Hydralazine was shown to be mutagenic in bacterial systems (Gene Mutation and DNA Repair) and in one of two rats and one rabbit hepatocyte in vitro DNA repair studies. Additional in vivo and in vitro studies using lymphoma cells, germinal cells, and fibroblasts from mice, bone marrow cells from chinese hamsters and fibroblasts from human cell lines did not demonstrate any mutagenic potential for hydralazine. The extent to which these findings indicate a risk to man is uncertain. While long-term clinical observation has not suggested that human cancer is associated with hydralazine use, epidemiologic studies have so far been insufficient to arrive at any conclusions. Pregnancy:Teratogenic effects. Pregnancy Category C: Animal studies indicate that hydralazine is teratogenic in mice at 20-30 times the maximum daily human dose of 200-300 mg and possibly in rabbits at 10-15 times the maximum daily human dose, but that it is nonteratogenic in rats. Teratogenic effects observed were cleft palate and malformations of facial and cranial bones. There are no adequate and well-controlled studies in pregnant women. Although clinical experience does not include any positive evidence of adverse effects on the human fetus, hydralazine should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when hydralazine injection is administered to a nursing woman. Pediatric Use: Safety and effectiveness in pediatric patients have not been established in controlled clinical trials, although there is experience with the use of hydralazine hydrochloride in children. The usual recommended parenteral dosage, administered intramuscularly or intravenously, is 1.7-3.5 mg/kg of body weight daily, divided into four to six doses. | lld:dailymed |
| dailymed-drugs:345 | dailymed-instance:precautio... | General: In all instances where the use of VePesid is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse reactions. Most such adverse reactions are reversible if detected early. If severe reactions occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician. Reinstitution of VePesid therapy should be carried out with caution, and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity. Patients with low serum albumin may be at an increased risk for etoposide associated toxicities.<br/>Drug Interactions: High-dose cyclosporin A resulting in concentrations above 2000 ng/mL administered with oral etoposide has led to an 80% increase in etoposide exposure with a 38% decrease in total body clearance of etoposide compared to etoposide alone.<br/>Laboratory Tests: Periodic complete blood counts should be done during the course of VePesid treatment. They should be performed prior to each cycle of therapy and at appropriate intervals during and after therapy. At least one determination should be done prior to each dose of VePesid.<br/>Renal Impairment: In patients with impaired renal function, the following initial dose modification should be considered based on measured creatinine clearance: Subsequent VePesid dosing should be based on patient tolerance and clinical effect. Data are not available in patients with creatinine clearances<15 mL/min and further dose reduction should be considered in these patients.<br/>Carcinogenesis (see WARNINGS), Mutagenesis, Impairment of Fertility: Etoposide has been shown to be mutagenic in Ames assay. Treatment of Swiss-Albino mice with 1.5 mg/kg I.P. of VePesid on day 7 of gestation increased the incidence of intrauterine death and fetal malformations as well as significantly decreased the average fetal body weight. Maternal weight gain was not affected. Irreversible testicular atrophy was present in rats treated with etoposide intravenously for 30 days at 0.5 mg/kg/day (about 1/16th of the human dose on a mg/mbasis).<br/>Pregnancy:<br/>Pregnancy Category D: See WARNINGS.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VePesid, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric Use: Of more than 600 patients in 4 clinical studies in the NDA databases who received VePesid or etoposide phosphate in combination with other chemotherapeutic agents for the treatment of small cell lung cancer (SCLC), about one-third were older than 65 years. When advanced age was determined to be a prognostic factor for responseor survival in these studies, comparisons between treatment groups were performed for the elderly subset. In the one study (etoposide in combination with cyclophosphamide and vincristine compared with cyclophosphamide and vincristine or cyclophosphamide, vincristine, and doxorubicin) where age was a significant prognostic factor for survival, a survival benefit for elderly patients was observed for the etoposide regimen compared with the control regimens. No differences in myelosuppression were seen betweenelderly and younger patients in these studies except for an increased frequency of WHO Grade III or IV leukopenia among elderly patients in a study of etoposide phosphate or etoposide in combination with cisplatin. Elderly patients in this study also had more anorexia, mucositis, dehydration, somnolence, and elevated BUN levels than younger patients. In 5 single-agent studies of etoposide phosphate in patients with a variety of tumor types, 34% of patients were age 65 years or more. WHO Grade III or IV leukopenia, granulocytopenia, and asthenia were more frequent among elderly patients. Postmarketing experience also suggests that elderly patients may be more sensitive to some of the known adverse effects of etoposide, including myelosuppression, gastrointestinal effects, infectious complications, and alopecia. Although some minor differences in pharmacokinetic parameters between elderly and nonelderly patients have been observed, these differences were not considered clinically significant. Etoposide and its metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see PRECAUTIONS: Renal Impairment for recommended dosing adjustments in patients with renal impairment). | lld:dailymed |
| dailymed-drugs:347 | dailymed-instance:precautio... | General: Alteration of the dosage regimen is recommended for patients with impairment of renal function (Cl<40 mL/min/1.73 m). (See Dosage and Administration.) Prescribing Maxaquin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.<br/>Information for patients: Patients should be advised<br/>Drug interactions:<br/>Theophylline: In three pharmacokinetic studies including 46 normal, healthy subjects, theophylline clearance and concentration were not significantly altered by the addition of lomefloxacin. In clinical studies where patients were on chronic theophylline therapy, lomefloxacin had no measurable effect on the mean distribution of theophylline concentrations or the mean estimates of theophylline clearance. Though individual theophylline levels fluctuated, there were no clinically significant symptoms of drug interaction.<br/>Antacids and sucralfate: Sucralfate and antacids containing magnesium or aluminum, as well as formulations containing divalent and trivalent cations such as Videx (didanosine), chewable/buffered tablets or the pediatric powder for oral solution can form chelation complexes with lomefloxacin and interfere with its bioavailability. Sucralfate administered 2 hours before lomefloxacin resulted in a slower absorption (mean Cdecreased by 30% and mean Tincreased by 1 hour) and a lesser extent of absorption (mean AUC decreased by approximately 25%). Magnesium- and aluminum-containing antacids, administered concomitantly with lomefloxacin, significantly decreased the bioavailability (48%) of lomefloxacin. Separating the doses of antacid and lomefloxacin minimizes this decrease in bioavailability; therefore, administration of these agents should precede lomefloxacin dosing by 4 hours or follow lomefloxacin dosing by at least 2 hours.<br/>Caffeine: Two hundred mg of caffeine (equivalent to 1 to 3 cups of American coffee) was administered to 16 normal, healthy volunteers who had achieved steady-state blood concentrations of lomefloxacin after being dosed at 400 mg qd. This did not result in any statistically or clinically relevant changes in the pharmacokinetic parameters of either caffeine or its major metabolite, paraxanthine. No data are available on potential interactions in individuals who consume greater than 200 mg of caffeine per day or in those, such as the geriatric population, who are generally believed to be more susceptible to the development of drug-induced CNS-related adverse effects. Other quinolones have demonstrated moderate to marked interference with the metabolism of caffeine, resulting in a reduced clearance, a prolongation of plasma half-life, and an increase in symptoms that accompany high levels of caffeine.<br/>Cimetidine: Cimetidine has been demonstrated to interfere with the elimination of other quinolones. This interference has resulted in significant increases in half-life and AUC. The interaction between lomefloxacin and cimetidine has not been studied.<br/>Cyclosporine: Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with other members of the quinolone class. Interaction between lomefloxacin and cyclosporine has not been studied.<br/>Omeprazole: No clinically significant changes in lomefloxacin pharmacokinetics (AUC, Cor T) were observed when a single dose of lomefloxacin 400 mg was given after multiple doses of omeprazole (20 mg qd) in 13 healthy volunteers. Changes in omeprazole pharmacokinetics were not studied.<br/>Phenytoin: No significant differences were observed in mean phenytoin AUC, C, Cor T(although Cincreased by 11%) when extended phenytoin sodium capsules (100 mg tid) were coadministered with lomefloxacin (400 mg qd) for five days in 15 healthy males. Lomefloxacin is unlikely to have a significant effect on phenytoin metabolism.<br/>Probenecid: Probenecid slows the renal elimination of lomefloxacin. An increase of 63% in the mean AUC and increases of 50% and 4%, respectively, in the mean Tand mean Cwere noted in 1 study of 6 individuals.<br/>Terfenadine: No clinically significant changes occurred in heart rate or corrected QT intervals, or in terfenadine metabolite or lomefloxacin pharmacokinetics, during concurrent administration of lomefloxacin and terfenadine at steady-state in 28 healthy males.<br/>Warfarin: Quinolones may enhance the effects of the oral anticoagulant, warfarin, or its derivatives. When these products are administered concomitantly, prothrombin or other suitable coagulation tests should be monitored closely. However, no clinically or statistically significant differences in prothrombin time ratio or warfarin enantiomer pharmacokinetics were observed in a small study of 7 healthy males who received both warfarin and lomefloxacin under steady-state conditions.<br/>Carcinogenesis, mutagenesis, impairment of fertility:<br/>Carcinogenesis: Hairless (Skh-1) mice were exposed to UVA light for 3.5 hours five times every two weeks for up to 52 weeks while concurrently being administered lomefloxacin. The lomefloxacin doses used in this study caused a phototoxic response. In mice treated with both UVA and lomefloxacin concomitantly, the time to development of skin tumors was 16 weeks. In mice treated concomitantly in this model with both UVA and other quinolones, the times to development of skin tumors ranged from 28 to 52 weeks. Ninety-two percent (92%) of the mice treated concomitantly with both UVA and lomefloxacin developed well-differentiated squamous cell carcinomas of the skin. These squamous cell carcinomas were nonmetastatic and were endophytic in character. Two-thirds of these squamous cell carcinomas contained large central keratinous inclusion masses and were thought to arise from the vestigial hair follicles in these hairless animals. In this model, mice treated with lomefloxacin alone did not develop skin or systemic tumors. There are no data from similar models using pigmented mice and/or fully haired mice The clinical significance of these findings to humans is unknown.<br/>Mutagenesis: One in vitro mutagenicity test (CHO/HGPRT assay) was weakly positive at lomefloxacin concentrations���226��g/mL and negative at concentrations<226��g/mL. Two other in vitro mutagenicity tests (chromosomal aberrations in Chinese hamster ovary cells, chromosomal aberrations in human lymphocytes) and two in vivo mouse micronucleus mutagenicity tests were all negative.<br/>Impairment of fertility: Lomefloxacin did not affect the fertility of male and female rats at oral doses up to 8 times the recommended human dose based on mg/m(34 times the recommended human dose based on mg/kg).<br/>Pregnancy:<br/>Teratogenic effects. Pregnancy Category C: Reproductive function studies have been performed in rats at doses up to 8 times the recommended human dose based on mg/m(34 times the recommended human dose based on mg/kg), and no impaired fertility or harm to the fetus was reported due to lomefloxacin. Increased incidence of fetal loss in monkeys has been observed at approximately 3 to 6 times the recommended human dose based on mg/m(6 to 12 times the recommended human dose based on mg/kg). No teratogenicity has been observed in rats and monkeys at up to 16 times the recommended human dose exposure. In the rabbit, maternal toxicity and associated fetotoxicity, decreased placental weight, and variations of the coccygeal vertebrae occurred at doses 2 times the recommended human exposure based on mg/m. There are, however, no adequate and well-controlled studies in pregnant women. Lomefloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing mothers: It is not known whether lomefloxacin is excreted in human milk. However, it is known that other drugs of this class are excreted in human milk and that lomefloxacin is excreted in the milk of lactating rats. Because of the potential for serious adverse reactions from lomefloxacin in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric use: The safety and effectiveness of lomefloxacin in pediatric patients and adolescents less than 18 years of age have not been established. Lomefloxacin causes arthropathy in juvenile animals of several species. (See Warnings and Animal Pharmacology.)<br/>Geriatric use: Of the total number of subjects in clinical studies of lomefloxacin, 25% were���65 years and 9% were���75 years. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See Clinical Pharmacology���Pharmacokinetics in the geriatric population.) | lld:dailymed |
| dailymed-drugs:348 | dailymed-instance:precautio... | Drug/Laboratory Test Interactions: In a study on five patients given from 12 to 24 mg of prazosin per day for 10 to 14 days, there was an average increase of 42% in the urinary metabolite of norepinephrine and an average increase in urinary VMA of 17%. Therefore, false positive results may occur in screening tests for pheochromocytoma in patients who are being treated with prazosin. If an elevated VMA is found, prazosin should be discontinued and the patient retested after a month.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No carcinogenic or mutagenic studies have been conducted with MINIZIDE. However, no carcinogenic potential was demonstrated in 18 month studies in rats with either MINIPRESS or RENESE at dose levels more than 100 times the usual maximum human doses. MINIPRESS was not mutagenic in in vivo genetic toxicology studies. MINIZIDE produced no impairment of fertility in male or female rats at 50 and 25 mg/kg/day of MINIPRESS and RENESE respectively. In chronic studies (one year or more) of MINIPRESS in rats and dogs, testicular changes consisting of atrophy and necrosis occurred at 25 mg/kg/day (60 times the usual maximum recommended human dose). No testicular changes were seen in rats or dogs at 10 mg/kg/day (24 times the usual maximum recommended human dose). In view of the testicular changes observed in animals, 105 patients on long termMINIPRESS therapy were monitored for 17-ketosteroid excretion and no changes indicating a drug effect were observed. In addition, 27 males on MINIPRESS alone for up to 51 months did not have changes in sperm morphology suggestive of drug effect.<br/>Use in Pregnancy: Pregnancy Category C. MINIZIDE was not teratogenic in either rats or rabbits when administered in oral doses more than 100 times the usual maximum human dose. Studies in rats indicated that the combination of RENESE (40 times the usual maximum recommended human dose) and MINIPRESS (8 times the usual maximum recommended human dose) caused a greater number of stillbirths, a more prolonged gestation, and a decreased survival of pups to weaning than that caused by MINIPRESS alone. There are no adequate and well controlled studies in pregnant women. Therefore, MINIZIDE should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: It is not known whether MINIPRESS or RENESE is excreted in human milk. Thiazides appear in breast milk. Thus, if use of the drug is deemed essential the patient should stop nursing.<br/>Pediatric Use: Safety and effectiveness in children has not been established. | lld:dailymed |
| dailymed-drugs:350 | dailymed-instance:precautio... | General: Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, magnesium, and potassium, should be carefully monitored following initiation of therapy with pamidronate disodium. Cases of asymptomatic hypophosphatemia (12%), hypokalemia (7%), hypomagnesemia (11%), and hypocalcemia (5% to 12%), were reported in pamidronate disodium-treated patients. Rare cases of symptomatic hypocalcemia (including tetany) have been reported in association with pamidronatetherapy. If hypocalcemia occurs, short-term calcium therapy may be necessary. In Paget's disease of bone, 17% of patients treated with 90 mg of pamidronate disodium showed serum calcium levels below 8 mg/dL. Patients with a history of thyroid surgery may have relative hypoparathyroidism that may predispose to hypocalcemia with pamidronate disodium.<br/>Renal Insufficiency: Pamidronate disodium is excreted intact primarily via the kidney, and the risk of renal adverse reactions may be greater in patients with impaired renal function. Patients who receive pamidronate disodium should have serum creatinine assessed prior to each treatment. In patients receiving pamidronate disodium for bone metastases, who show evidence of deterioration in renal function, pamidronate disodium treatment should be withheld until renal function returns to baseline . In clinical trials, patients with real impairment (serum creatinine>3.0 mg/dL) have not been studied. Limited pharmacokinetic data exist in patients with creatinine clearance<30 mL/min For the treatment of bone metastases, the use of pamidronate disodium in patients with severe renal impairment is not recommended. In other indications, clinical judgement should determine whether the potential benefit outweighs the potential risk in such patients.<br/>Osteonecrosis of the Jaw: Osteonecrosis of the jaw (ONJ) has been reported in patients with cancer receiving treatment regimens including bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures such as tooth extraction. Many had signs of local infection including osteomyelitis. A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g., cancer, chemotherapy, corticosteroids, poor oral hygiene). While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.<br/>Musculoskeletal Pain: In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking biphosphonates. However, such reports have been infrequent. This category of drugs includes pamidronate disodium injection. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallanged with the same drug or another biphosphonate.<br/>Laboratory Tests: Patients who receive pamidronate disodium should have serum creatinine assessed prior to each treatment. Serum calcium, electrolytes, phosphate, magnesium, and CBC, differential, and hematocrit/hemoglobin must be closely monitored in patients treated with pamidronate disodium. Patients who have preexisting anemia, leukopenia, or thrombocytopenia should be monitored carefully in the first 2 weeks following treatment.<br/>Drug Interactions: Concomitant administration of a loop diuretic had no effect on the calcium-lowering action of pamidronate disodium. Caution is indicated when pamidronate disodium is used with other potentially nephrotoxic drugs. In multiple myeloma patients, the risk of renal dysfunction may be increased when pamidronate disodium is used in combination with thalidomide.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 104 week carcinogenicity study (daily oral administration) in rats, there was a positive dose response relationship for benign adrenal pheochromocytoma in males (P<0.00001). Although this condition was also observed in females, the incidence was not statistically significant. When the dose calculations were adjusted to account for the limited oral bioavailability of pamidronate disodium in rats, the lowest daily dose associated with adrenal pheochromocytoma was similar to the intended clinical dose. Adrenal pheochromocytoma was also observed in low numbers in the control animals and is considered a relatively common spontaneous neoplasm in the rat. Pamidronate disodium (daily oral administration) was not carcinogenic in an 80 week study in mice. Pamidronate disodium was nonmutagenic in six mutagenicity assays: Ames test, Salmonella and Escherichia/liver-microsome test, nucleus-anomaly test, sister-chromatid-exchange study, point-mutation test, and micronucleus test in the rat. In rats, decreased fertility occurred in first-generation offspring of parents who had received 150 mg/kg of pamidronate disodium orally; however, this occurred only when animals were mated with members of the same dose group. Pamidronate disodium has not been administered intravenously in such a study.<br/>Animal Toxicology: In both rats and dogs, nephropathy has been associated with intravenous (bolus and infusion) administration of pamidronate disodium. Two 7 day intravenous infusion studies were conducted in the dog wherein pamidronate disodium was given for 1, 4, or 24 hours at doses of 1 to 20 mg/kg for up to 7 days. In the first study, the compound was well tolerated at 3 mg/kg (1.7 x highest recommended human dose [HRHD] for a single intravenous infusion) when administered for 4 or 24 hours, but renal findings such as elevated BUN and creatinine levels and renal tubular necrosis occurred when 3 mg/kg was infused for 1 hour and at doses of���10 mg/kg. In the second study, slight renal tubular necrosis was observed in 1 male at 1 mg/kg when infused for 4 hours. Additional findings included elevated BUN levels in several treated animals and renal tubular dilation and/or inflammation at���1 mg/kg after each infusion time. Pamidronate disodium was given to rats at doses of 2, 6, and 20 mg/kg and to dogs at doses of 2, 4, 6, and 20 mg/kg as a 1 hour infusion, once a week, for 3 months followed by a 1 month recovery period. In rats, nephrotoxicity was observed at���6 mg/kg and included increased BUN and creatinine levels and tubular degeneration and necrosis. These findings were still present at 20 mg/kg at the end of the recovery period. In dogs, moribundity/death and renal toxicity occurred at 20 mg/kg as did kidney findings of elevated BUN and creatinine levels at���6 mg/kg and renal tubular degeneration at���4 mg/kg. The kidney changes were partially reversible at 6 mg/kg. In both studies, the dose level that produced no adverse renal effects was considered to be 2 mg/kg (1.1 x HRHD for a single intravenous infusion).<br/>Pregnancy Category D (see WARNINGS): There are no adequate and well-controlled studies in pregnant women. Bolus intravenous studies conducted in rats and rabbits determined that pamidronate disodium produces maternal toxicity and embryo/fetal effects when given during organogenesis at doses of 0.6 to 8.3 times the highest recommended human dose for a single intravenous infusion. As it has been shown that pamidronate disodium can cross the placenta in rats and has produced marked maternal and nonteratogenic embryo/fetal effects in rats and rabbits, it should not be given to women during pregnancy. Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systematic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established.<br/>Nursing Mothers: It is not known whether pamidronate disodium is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when pamidronate disodium is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness of pamidronate disodium in pediatric patients have not been established.<br/>Geriatric Use: Of the total number of subjects in clinical studies of pamidronate disodium, approximately 20% were 65 and over, while approximately 15% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:352 | dailymed-instance:precautio... | General: Naproxen-containing products such as naproxen tablets, naproxen delayed-release tablets, naproxen sodium tablets, naproxen suspension, and other naproxen products should not be used concomitantly since they all circulate in the plasma as the naproxen anion. Naproxen tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids and the patient should be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation ofsymptoms of arthritis. Patients with initial hemoglobin values of 10 g or less who are to receive long-term therapy should have hemoglobin values determined periodically. The pharmacological activity of naproxen tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed non-infectious, non-inflammatory painful conditions. Because of adverse eye findings in animal studies with drugs of this class, it is recommended that ophthalmic studies be carried out if any change or disturbance in vision occurs.<br/>Hepatic Effects: Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including naproxen tablets. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. These laboratory abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with naproxen tablets. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), naproxen tablets should be discontinued. Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. Caution is advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to use the lowest effective dose.<br/>Hematological Effects: Anemia is sometimes seen in patients receiving NSAIDs, including naproxen tablets. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including naproxen tablets, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving naproxen tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.<br/>Preexisting Asthma: Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, naproxen tablets should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.<br/>Information for Patients: Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.<br/>Laboratory Tests: Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, naproxen tablets should be discontinued.<br/>Drug Interactions:<br/>ACE-Inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.<br/>Antacids and Sucralfate: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.<br/>Aspirin: When naproxen tablets are administered with aspirin, its protein binding is reduced, although the clearance of free naproxen is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of naproxen tablets and aspirin is not generally recommended because of the potential of increased adverse effects.<br/>Cholestyramine: As with other NSAIDs, concomitant administration of cholestyramine can delay the absorption of naproxen.<br/>Diuretics: Clinical studies, as well as postmarketing observations, have shown that naproxen tablets can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy.<br/>Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observedcarefully for signs of lithium toxicity.<br/>Methotrexate: NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. Naproxen, naproxen sodium, and other non-steroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.<br/>Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. No significant interactions have been observed in clinical studies with naproxen and coumarin-type anticoagulants. However, caution is advised since interactions have been seen with other non-steroidal agents of this class. The free fraction of warfarin may increase substantially in some subjects and naproxen interferes with platelet function.<br/>Selective Serotonin Reuptake Inhibitors (SSRIs): There is an increased risk of gastrointestinal bleeding when selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs. Caution should be used when NSAIDs are administered concomitantly with SSRIs.<br/>Other Information Concerning Drug Interactions: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. Naproxen and other non-steroidal anti-inflammatory drugs can reduce the antihypertensive effect of propranolol and other beta-blockers. Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.<br/>Drug/Laboratory Test Interactions: Naproxen may decrease platelet aggregation and prolong bleeding time. This effect should be kept in mind when bleeding times are determined. The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay. Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).<br/>Carcinogenesis: A 2 year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day (50, 100, and 150 mg/m). The maximum dose used was 0.28 times the systemic exposure to humans at the recommended dose. No evidence of tumorigenicity was found.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nonteratogenic Effects: There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension,renal dysfunction and abnormal prostaglandin E levels in preterm infants. Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.<br/>Labor and Delivery: In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. Naproxen-containing products are not recommended in labor and delivery because, through its prostaglandin synthesis inhibitory effect, naproxen may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage. The effects of naproxen tablets on labor and delivery in pregnant women are unknown.<br/>Nursing Mothers: The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be avoided.<br/>Pediatric Use: Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Pediatric dosing recommendations for juvenile arthritis are based on well-controlled studies (see DOSAGE AND ADMINISTRATION). There are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in juvenile arthritis and other use experience have established that single doses of 2.5 to 5 mg/kg (as naproxen suspension, see DOSAGE AND ADMINISTRATION), with totaldaily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age.<br/>Geriatric Use: Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose. Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of non-steroidal anti-inflammatory drugs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population (see WARNINGS). Naproxen is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of non-steroidal anti-inflammatory drugs (see WARNINGS, Renal Effects). | lld:dailymed |
| dailymed-drugs:353 | dailymed-instance:precautio... | General: In all instances where the use of CeeNU is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risks of toxic effects or adverse reactions. Most such adverse reactions are reversible if detected early. When such effects or reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician. Reinstitution of CeeNU therapy should be carried out with caution, and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity.<br/>Information for the Patient: Patients receiving CeeNU should be given the following information and instructions by the physician:<br/>Laboratory Tests: Due to delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose. Baseline pulmonary function studies should be conducted along with frequent pulmonary function tests during treatment. Patients with a baseline below 70% of the predicted Forced Vital Capacity (FVC) or Carbon Monoxide Diffusing Capacity (DL) are particularly at risk. Since CeeNU may cause liver dysfunction, it is recommended that liver function tests be monitored periodically. Renal function tests should also be monitored periodically.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: CeeNU is carcinogenic in rats and mice, producing a marked increase in tumor incidence in doses approximating those employed clinically. Nitrosourea therapy does have carcinogenic potential in humans . CeeNU also affects fertility in male rats at doses somewhat higher than the human dose.<br/>Pregnancy:<br/>Pregnancy���Category D.���(See WARNINGS.):<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from CeeNU, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug tothe mother.<br/>Pediatric Use: See ADVERSE REACTIONS: Pulmonary Toxicity, and DOSAGE AND ADMINISTRATION.<br/>Geriatric Use: No data from clinical studies of CeeNU are available for patients 65 years of age and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Lomustine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored. | lld:dailymed |
| dailymed-drugs:355 | dailymed-instance:precautio... | General: Terbinafine hydrochloride tablets are not recommended for patients with chronic or active liver disease. Before prescribing terbinafine hydrochloride tablets, preexisting liver disease should be assessed. Hepatotoxicity may occur in patients with and without preexisting liver disease. Pretreatment serum transaminase (ALT and AST) tests are advised for all patients before taking terbinafine hydrochloride tablets. Patients prescribed terbinafine hydrochloride tablets should be warned to report immediately to their physician any symptoms of persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain or jaundice, dark urine or pale stools (see WARNINGS). Patients with these symptoms should discontinue taking oral terbinafine, and the patient's liver function should be immediately evaluated. In patients with renal impairment (creatinine clearance���50 mL/min), the use of terbinafine hydrochloride has not been adequately studied, and therefore, is not recommended (see CLINICAL PHARMACOLOGY, Pharmacokinetics). During postmarketing experience, precipitation and exacerbation of cutaneous and systemic lupus erythematosus have been reported infrequently in patients taking terbinafine hydrochloride. Terbinafine hydrochloride therapy should be discontinued in patients with clinical signs and symptoms suggestive of lupus erythematosus. Changes in the ocular lens and retina have been reported following the use of terbinafine hydrochloride tablets in controlled trials. The clinical significance of these changes is unknown. Transient decreases in absolute lymphocyte counts (ALC) have been observed in controlled clinical trials. In placebo-controlled trials, 8/465 terbinafine hydrochloride-treated patients (1.7%) and 3/137 placebo-treated patients (2.2%) had decreases in ALC to below 1,000/mmon 2 or more occasions. The clinical significance of this observation is unknown. However, in patients with known or suspected immunodeficiency, physicians should consider monitoring complete blood counts in individuals using terbinafine hydrochloride therapy for greater than 6 weeks. Isolated cases of severe neutropenia have been reported. These were reversible upon discontinuation of terbinafine hydrochloride, with or without supportive therapy. If clinical signs and symptoms suggestive of secondary infection occur, a complete blood count should be obtained. If the neutrophil count is���1,000 cells/mm, terbinafine hydrochloride should be discontinued and supportive management started.<br/>Drug Interactions: In vivo studies have shown that terbinafine is an inhibitor of the CYP450 2D6 isozyme. Drugs predominantly metabolized by the CYP450 2D6 isozyme include the following drug classes: tricyclic antidepressants, selective serotonin reuptake inhibitors, beta-blockers, antiarrhythmics class 1C (e.g., flecainide andpropafenone) and monoamine oxidase inhibitors Type B. Coadministration of terbinafine hydrochloride should be done with careful monitoring and may require a reduction in dose of the 2D6-metabolized drug. In a study to assess the effects of terbinafine on desipramine in healthy volunteers characterized as normal metabolizers, the administration of terbinafine resulted in a 2 fold increase in Cand a 5 fold increase in AUC. In this study, these effects were shown to persist at the last observation at 4 weeks after discontinuation of terbinafine hydrochloride. In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vivo drug-drug interaction studies conducted in healthy volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between terbinafine hydrochloride tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CYP450 enzyme inducer, and decreased 33% by cimetidine, a CYP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, and calcium channel blockers.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 28 month oral carcinogenicity study in rats, an increase in the incidence of liver tumors was observed in males at the highest dose tested, 69 mg/kg/day [2 times the Maximum Recommended Human Dose (MRHD) based on AUC comparisons of the parent terbinafine]; however, even though dose-limiting toxicity was not achieved at the highest tested dose, higher doses were not tested. The results of a variety of in vitro (mutations in E. coli and S. typhimurium, DNA repair in rat hepatocytes, mutagenicity in Chinese hamster fibroblasts, chromosome aberration and sister chromatid exchanges in Chinese hamster lung cells), and in vivo (chromosome aberration in Chinese hamsters, micronucleus test in mice) genotoxicity tests gave no evidence of a mutagenic or clastogenic potential. Oral reproduction studies in rats at doses upto 300 mg/kg/day (approximately 12 times the MRHD based on body surface area comparisons, BSA) did not reveal any specific effects on fertility or other reproductive parameters. Intravaginal application of terbinafine hydrochloride at 150 mg/day in pregnant rabbits did not increase the incidence of abortions or premature deliveries nor affect fetal parameters.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: After oral administration, terbinafine is present in breast milk of nursing mothers. The ratio of terbinafine in milk to plasma is 7:1. Treatment with terbinafine hydrochloride is not recommended in nursing mothers.<br/>Pediatric Use: The safety and efficacy of terbinafine hydrochloride have not been established in pediatric patients. | lld:dailymed |
| dailymed-drugs:356 | dailymed-instance:precautio... | General: When treating pain, methadone given on a fixed-dose schedule may have a narrow therapeutic index in certain patient populations, especially when combined with other drugs, and should be reserved for cases where the benefits of opioid analgesia with methadone outweigh the known potential risks of cardiac conduction abnormalities, respiratory depression, altered mental states and postural hypotension. Methadone should be used with caution in elderly and debilitated patients; patients who are known to be sensitive to central nervous system depressants, such as those with cardiovascular, pulmonary, renal, or hepatic disease; and in patients with comorbid conditions or concomitant medications which may predispose to dysrhythmia. Selection of patients for treatment with methadone should be governed by the same principles that apply to the use of other opioids . Physicians should individualize treatment in every case , taking into account the high degree of interpatient variability in response to and metabolism of methadone<br/>Drug Interactions: In vitro results suggest that methadone undergoes hepatic N-demethylation by cytochrome P450 enzymes, principally CYP3A4, CYP2B6, CYP2C19 and to a lesser extent by CYP2C9 and CYP2D6. Coadministration of methadone with CYP inducers of these enzymes may result in a more rapid metabolism and potential for decreased effects of methadone, whereas administration with CYP inhibitors may reduce metabolism and potentiate methadone's effects. Although antiretroviral drugs such as efavirenz, nelfinavir, nevirapine, ritonavir, lopinavir+ritonavir combination are known to inhibit CYPs, they are shown to reduce the plasma levels of methadone, possibly due to their CYP induction activity. Therefore, drugs administered concomitantly with methadone should be evaluated for interaction potential; clinicians are advised to evaluate individual response to drug therapy.<br/>Opioid Antagonists, Mixed Agonist/Antagonists, and Partial Agonists: As with other mu-agonists, patients maintained on methadone may experience withdrawal symptoms when given opioid antagonists, mixed agonist/antagonists, and partial agonists. Examples of such agents are naloxone, naltrexone, pentazocine, nalbuphine, butorphanol, and buprenorphine.<br/>Anti-retroviral Agents:<br/>Abacavir, amprenavir, efavirenz, nelfinavir, nevirapine, ritonavir, lopinavir+ritonavir combination: Coadministration of these anti-retroviral agents resulted in increased clearance or decreased plasma levels of methadone. Methadone-maintained patients beginning treatment with these antiretroviral drugs should be monitored for evidence of withdrawal effects and methadone dose should be adjusted accordingly.<br/>Didanosine and Stavudine: Experimental evidence demonstrated that methadone decreased the AUC and peak levels for didanosine and stavudine, with a more significant decrease for didanosine. Methadone disposition was not substantially altered.<br/>Zidovudine: Experimental evidence demonstrated that methadone increased the area under the concentration-time curve (AUC) of zidovudine which could result in toxic effects.<br/>Cytochrome P450 Inducers: Methadone-maintained patients beginning treatment with CYP3A4 inducers should be monitored for evidence of withdrawal effects and methadone dose should be adjusted accordingly. The following drug interactions were reported following coadministration of methadone with inducers of cytochrome P450 enzymes:<br/>Rifampin: In patients well-stabilized on methadone, concomitant administration of rifampin resulted in a marked reduction in serum methadone levels and a concurrent appearance of withdrawal symptoms.<br/>Phenytoin: In a pharmacokinetic study with patients on methadone maintenance therapy, phenytoin administration (250 mg b.i.d. initially for 1 day followed by 300 mg QD for 3 to 4 days) resulted in an approximately 50% reduction in methadone exposure and withdrawal symptoms occurred concurrently. Upon discontinuation of phenytoin, the incidence of withdrawal symptoms decreased and methadone exposure increased to a level comparable to that prior to phenytoin administration.<br/>St. John's Wort, Phenobarbital, Carbamazepine: Administration of methadone along with other CYP3A4 inducers may result in withdrawal symptoms.<br/>Cytochrome P450 Inhibitors: Since the metabolism of methadone is mediated primarily by CYP3A4 isozyme, coadministration of drugs that inhibit CYP3A4 activity may cause decreased clearance of methadone. The expected clinical results would be increased or prolonged opioid effects. Thus, methadone-treated patients coadministered strong inhibitors of CYP3A4, such as azole antifungal agents (e.g., ketoconazole) and macrolide antibiotics (e.g., erythromycin), with methadone should be carefully monitored and dosageadjustment should be undertaken if warranted. Some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine) may increase methadone plasma levels upon coadministration with methadone and result in increased opiate effects and/or toxicity.<br/>Voriconazole: Repeat dose administration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 4 days) increased the Cand AUC of (R)-methadone by 31% and 47%, respectively, in subjects receiving a methadone maintenance dose (30 to 100 mg QD). The Cand AUC of (S)-methadone increased by 65% and 103%, respectively. Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed.<br/>Others:<br/>Monoamine Oxidase (MAO) Inhibitors: Therapeutic doses of meperidine have precipitated severe reactions in patients concurrently receiving monoamine oxidase inhibitors or those who have received such agents within 14 days. Similar reactions thus far have not been reported with methadone. However, if the use of methadone is necessary in such patients, a sensitivity test should be performed in which repeated small, incremental doses of methadone are administered over the course of several hours while the patient's condition and vital signs are undercareful observation.<br/>Desipramine: Blood levels of desipramine have increased with concurrent methadone administration.<br/>Potentially Arrhythmogenic Agents: Extreme caution is necessary when any drug known to have the potential to prolong the QT interval is prescribed in conjunction with methadone. Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents such as class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Caution should also be exercised when prescribing methadone concomitantly with drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia) that may prolong the QT interval. These drugs include diuretics, laxatives, and, in rare cases, mineralocorticoid hormones.<br/>Interactions with Alcohol and Drugs of Abuse: Methadone may be expected to have additive effects when used in conjunction with alcohol, other opioids or CNS depressants, or with illicit drugs that cause central nervous system depression. Deaths have been reported when methadone has been abused in conjunction with benzodiazepines.<br/>Anxiety: Since methadone as used by tolerant patients at a constant maintenance dosage does not act as a tranquilizer, patients who are maintained on this drug will react to life problems and stresses with the same symptoms of anxiety as do other individuals. The physician should not confuse such symptoms with those of narcotic abstinence and should not attempt to treat anxiety by increasing the dose of methadone. The action of methadone in maintenance treatment is limited to the control of narcotic withdrawal symptoms and is ineffective for relief of general anxiety.<br/>Acute Pain: Maintenance patients on a stable dose of methadone who experience physical trauma, postoperative pain or other acute pain cannot be expected to derive analgesia from their existing dose of methadone. Such patients should be administered analgesics, including opioids, in doses that would otherwise be indicated for non-methadone-treated patients with similar painful conditions. Due to the opioid tolerance induced by methadone, when opioids are required for management of acute pain in methadone patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant patients.<br/>Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction: Abrupt opioid discontinuation can lead to development of opioid withdrawal symptoms . Presentation of these symptoms have been associated with an increased risk of susceptible patients to relapse to illicit drug use and should be considered when assessing the risks and benefit of methadone use.<br/>Tolerance and Physical Dependence: Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and/or tolerance are not unusual during chronic opioid therapy. If methadone is abruptly discontinued in a physically dependent patient, an abstinence syndrome may occur. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, chronically administered methadone should not be abruptly discontinued.<br/>Special-Risk Patients: Methadone should be given with caution and the initial dose reduced in certain patients, such as the elderly and debilitated and those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease, prostatic hypertrophy, or urethral stricture. The usual precautions appropriate to the use of parenteral opioids should be observed and the possibility of respiratory depression should always be kept in mind.<br/>Information for Patients:<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis: The results of carcinogenicity assessment in B6C2F1 mice and Fischer 344 rats following dietary administration of two doses of methadone HCl have been published. Mice consumed 15 mg/kg/day or 60 mg/kg/day methadone for two years. These doses were approximately 0.6 and 2.5 times a human daily oral dose of 120 mg/day on a body surface area basis (mg/m). There was a significant increase in pituitary adenomas in female mice treated with 15 mg/kg/day but not with 60 mg/kg/day. Under the conditions of the assay, there was no clear evidence for a treatment-related increase in the incidence of neoplasms in male rats. Due to decreased food consumption in males at the high dose, male rats consumed 16 mg/kg/day and 28 mg/kg/day of methadone for two years. These doses were approximately 1.3 and 2.3 times a human daily oral dose of 120 mg/day, based on body surfacearea comparison. In contrast, female rats consumed 46 mg/kg/day or 88 mg/kg/day for two years. These doses were approximately 3.7 and 7.1 times a human daily oral dose of 120 mg/day, based on body surface area comparison. Under the conditions of the assay, there was no clear evidence for a treatment-related increase in the incidence of neoplasms in either male or female rats.<br/>Mutagenesis: There are several published reports on the potential genetic toxicity of methadone. Methadone tested negative in tests for chromosome breakage and disjunction and sex-linked recessive lethal gene mutations in germ cells of Drosophila using feeding and injection procedures. In contrast, methadone tested positive in the in vivo mouse dominant lethal assay and the in vivo mammalian spermatogonial chromosome aberration test. Additionally, methadone tested positive in the E. coli DNA repair system and Neurospora crassa and mouse lymphoma forward mutation assays.<br/>Fertility: Reproductive function in human males may be decreased by methadone treatment. Reductions in ejaculate volume and seminal vesicle and prostate secretions have been reported in methadone-treated individuals. In addition, reductions in serum testosterone levels and sperm motility, and abnormalities in sperm morphology have been reported. Published animal studies provide additional data indicating that methadone treatment of males can alter reproductive function. Methadone produces a significant regression of sex accessory organs and testes of male mice and rats. Additional data have been published indicating that methadone treatment of male rats (once a day for three consecutive days) increased embryolethality and neonatal mortality. Examination of uterine contents of methadone-naive female mice bred to methadone-treated mice indicated that methadone treatment produced an increase in the rate of preimplantation deaths in all post-meiotic states.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nonteratogenetic Effects: Babies born to mothers who have been taking opioids regularly prior to delivery may be physically dependent. Onset of withdrawal symptoms in infants is usually in the first days after birth. Withdrawal signs in the newborn include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the maternaldose or the duration of maternal exposure. The duration of the withdrawal signs may vary from a few days to weeks or even months. There is no consensus on the appropriate management of infant withdrawal. There are conflicting reports on whether SIDS occurs with an increased incidence in infants born to women treated with methadone during pregnancy. Abnormal fetal nonstress tests (NSTs) have been reported to occur more frequently when the test is performed 1 to 2 hours after a maintenance dose of methadone in late pregnancy compared to controls. Published animal data have reported increased neonatal mortality in the offspring of male rodents that were treated with methadone prior to mating. In these studies, the female rodents were not treated with methadone, indicating paternally-mediated developmental toxicity. Specifically, methadone administered to the male rat prior to mating with methadone-na��ve females resulted in decreased weight gain in progeny after weaning. The male progeny demonstrated reduced thymus weights, whereas the female progeny demonstrated increased adrenal weights. Further, behavioral testing of these male and female progeny revealed significant differences in behavioral tests compared to control animals, suggesting that paternal methadone exposure can produce physiological and behavioral changes in progeny in this model. Other animal studies have reported that perinatal exposure to opioids including methadone alters neuronal development and behavior in the offspring. Perinatal methadone exposure in rats has been linked to alterations in learning ability, motor activity, thermal regulation, nociceptive responses and sensitivity to drugs. Additional animal data demonstrates evidence for neurochemical changes in the brains of methadone-treated offspring, including changes to the cholinergic, dopaminergic, noradrenergic and serotonergic systems. Additional studies demonstrated that methadone treatment of male rats for 21 to32 days prior to mating with methadone-na��ve females did not produce any adverse effects, suggesting that prolonged methadone treatment of the male rat resulted in tolerance to the developmental toxicities noted in the progeny. Mechanistic studies in this rat model suggest that the developmental effects of���paternal���methadone on the progeny appear to be due to decreased testosterone production. These animal data mirror the reported clinical findings of decreased testosterone levels in human males on methadone maintenance therapy for opioid addiction and in males receiving chronic intraspinal opioids.<br/>Clinical Pharmacology for Pregnancy: Pregnant women appear to have significantly lower trough plasma methadone concentrations, increased plasma methadone clearance, and shorter methadone half-life than after delivery. Dosage adjustment using higher doses or administering the daily dose in divided doses may be necessary in pregnant women treated with methadone . Methadone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Labor and Delivery: As with all opioids, administration of this product to the mother shortly before delivery may result in some degree of respiratory depression in the newborn, especially if higher doses are used. Methadone is not recommended for obstetric analgesia because its long duration of action increases the probability of respiratory depression in the newborn. Narcotics with mixed agonist-antagonist properties should not be used for pain control during labor in patients chronically treated with methadone as they may precipitate acute withdrawal.<br/>Nursing Mothers: Methadone is secreted into human milk. The safety of breastfeeding while taking oral methadone is controversial. At maternal oral doses of 10 to 80 mg/day, methadone concentrations from 50 to 570 mcg/L in milk have been reported, which, in the majority of samples, were lower than maternal serum drug concentrations at steady state. Peak methadone levels in milk occur approximately 4 to 5 hours after an oral dose. Based on an average milk consumption of 150 mL/kg/day, an infant would consume approximately 17.4 mcg/kg/day which is approximately 2 to 3% of the oral maternal dose. Methadone has been detected in very low plasma concentrations in some infants whose mothers were taking methadone. Women on high dose methadone maintenance, who are already breast feeding, should be counseled to wean breast-feeding gradually in order to prevent neonatal abstinence syndrome. Methadone-treated mothers considering nursing an opioid-na��ve infant should be counseled regarding the presence of methadone in breast milk. Because of the potential for serious adverse reactions in nursing infants from methadone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. In patients being treated for opioid dependence, this should include weighing the risk of methadone against the risk of maternal illicit drug use.<br/>Pediatric Use: Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Accidental or deliberate ingestion by a child may cause respiratory depression that can result in death. Patients and caregivers should be instructed to keep methadone in a secure place out of the reach of children and to discard unused methadone in such a way that individuals other than the patient for whom it was originally prescribed will not come in contact with the drug.<br/>Geriatric Use: Clinical studies of methadone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently compared to younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for elderly patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreasedhepatic, renal, or cardiac function and of concomitant disease or other drug therapy.<br/>Renal Impairment: The use of methadone has not been extensively evaluated in patients with renal insufficiency.<br/>Hepatic Impairment: The use of methadone has not been extensively evaluated in patients with hepatic insufficiency. Methadone is metabolized in the liver and patients with liver impairment may be at risk of accumulating methadone after multiple dosing.<br/>Gender: The use of methadone has not been evaluated for gender specificity. | lld:dailymed |
| dailymed-drugs:358 | dailymed-instance:precautio... | Oxybutynin chloride should be used with caution in the elderly and in all patients with autonomic neuropathy, hepatic or renal disease. Oxybutynin chloride may aggravate the symptoms of hyperthyroidism, coronary heart disease, congestive heart failure, cardiac arrhythmias, hiatal hernia, tachycardia, hypertension, and prostatic hypertrophy. Administration of oxybutynin chloride to patients with ulcerative colitis may suppress intestinal motility to the point of producing a paralytic ileus and precipitate or aggravate toxic megacolon, a serious complication of the disease.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: A 24-month study in rats at dosages up to approximately 400 times the recommended human dosage showed no evidence of carcinogenicity. Oxybutynin chloride showed no increase of mutagenic activity when tested in Schizosaccharomyces pompholiciformis, Saccharomyces cerevisiae and Salmonella typhimurium test systems. Reproduction studies in the hamster, rabbit, rat, and mouse have shown no definite evidence of impaired fertility.<br/>Pregnancy:<br/>Teratogenic Effects-Pregnancy Category B: Reproduction studies in the hamster, rabbit, rat, and mouse have shown no definite evidence of impaired fertility or harm to the animal fetus. The safety of oxybutynin chloride administered to women who are or who may become pregnant has not been established. Therefore, oxybutynin chloride should not be given to pregnant women unless, in the judgment of the physician, the probable clinical benefits outweigh the possible hazards.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when oxybutynin chloride is administered to a nursing woman.<br/>Pediatric Use: The safety and efficacy of oxybutynin chloride administration have been demonstrated for pediatric patients 5 years of age and older . However, as there is insufficient clinical data for pediatric patients under age 5, oxybutynin chloride is not recommended for this age group. | lld:dailymed |
| dailymed-drugs:359 | dailymed-instance:precautio... | Blood-Pressure and ECG Monitoring Blood pressure should be monitored with the patient supine during parenteral, especially intravenous, administration of PA (see DOSAGE AND ADMINISTRATION). There is a possibility that relatively high although transient plasma levels of PA may be attained and cause hypotension before the PA can be distributed from the plasma volume to its full apparent volume of distribution which is approximately 50 times greater. Therefore, caution should be exercised to avoid overly rapid administration of PA.If the blood pressure falls 15 mm Hg or more, PA administration should be temporarily discontinued. Electrocardiographic (ECG) monitoring is advisable as well, both for observation of the progress and response of the arrhythmia under treatment, and for early detection of any tendency to excessive widening of the QRS complex, prolongation of the P-R interval, or any signs of heart block (see OVERDOSAGE). Parenteral therapy with PA should be limited to use in hospitals in which monitoring and intensive supportive care are available, or to emergency situations in which equivalent observation and treatment can be provided.<br/>General: Immediately after initiation of PA therapy, patients should be closely observed for possible hypersensitivity reactions. In conversion of atrial fibrillation to normal sinus rhythm by any means, dislodgement of mural thrombi may lead to embolization, which should be kept in mind. After achieving and maintaining therapeutic plasma concentrations and satisfactory electrocardiographic and clinical responses, continued frequent periodic monitoring of vital signs and electrocardiograms is advised. If evidence of QRS widening of more than 25 percent or marked prolongation of the Q-T interval occurs, concern for overdosage is appropriate, and interruption of the PA infusion is advisable if a 50 percent increase occurs. Elevated serum creatinine or urea nitrogen, reduced creatinine clearance or history of renal insufficiency, as well as use in older patients (over age 50), provide grounds to anticipate that less than the usual dosage or infusion rate may suffice, since the urinary elimination of PA and NAPA may be reduced, leading to gradual accumulation beyond normally-predicted amounts. If facilities are available for measurement of plasma PA and NAPA, or acetylation capability, individual dose adjustment for optimal therapeutic levels may be easier, but close observation of clinical effectiveness is the most important criterion.<br/>Information for Patients: The patient should be encouraged to disclose any past history of drug sensitivity, especially to procaine or other local anesthetic agents, or aspirin, and to report any history of kidney disease, congestive heart failure, myasthenia gravis, liver disease, or lupus erythematosus. The patient should be counseled to report any symptoms of arthralgia, myalgia, fever, chills, skin rash, easy bruising, sore throat or sore mouth, infections, dark urine or icterus, wheezing, muscular weakness, chest or abdominal pain, palpitations, nausea, vomiting, anorexia, diarrhea, hallucinations, dizziness, or depression.<br/>Laboratory Tests: Laboratory tests such as complete blood count (CBC), electrocardiogram and serum creatinine or urea nitrogen may be indicated depending on the clinical situation, and periodic rechecking of the CBC and ANA may be helpful in early detection of untoward reactions.<br/>Drug Interactions: If other antiarrhythmic drugs are being used, additive effects on the heart may occur with PA administration, and dosage reduction may be necessary (see WARNINGS). Anticholinergic drugs administered concurrently with PA may produce additive antivagal effects on A-V nodal conduction, although this is not as well documented for PA as for quinidine. Patients taking PA who require neuromuscular blocking agents such as succinylcholine may require less than usual doses of the latter, due to PA effects on reducing acetylcholine release.<br/>Drug/Laboratory Test Interactions: Suprapharmacologic concentrations of lidocaine and meprobamate may inhibit fluorescence of PA and NAPA, and propranolol shows a native fluorescence close to the PA/NAPA peak wavelengths, so that tests which depend on fluorescence measurement may be affected.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been performed.<br/>Teratogenic Effects: Pregnancy Category C: Animal reproduction studies have not been conducted with PA. It also is not known whether PA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PA should be given to a pregnant woman only if clearly needed.<br/>Nursing Mothers: Both PA and NAPA are excreted in human milk, absorbed by the nursing infant. Because of the potential for serious adverse reactions in nursing infants, a decision to discontinue nursing or the drug should be made, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established. | lld:dailymed |
| dailymed-drugs:360 | dailymed-instance:precautio... | General: Since the vasodilation induced by amlodipine besylate tablets is gradual in onset, acute hypotension has rarely been reported after oral administration. Nonetheless, caution, as with any other peripheral vasodilator, should be exercised when administering amlodipine besylate tablets, particularly in patientswith severe aortic stenosis.<br/>Use in Patients with Congestive Heart Failure: In general, calcium channel blockers should be used with caution in patients with heart failure. Amlodipine besylate tablets (5���10 mg per day) have been studied in a placebo-controlled trial of 1153 patients with NYHA Class III or IV heart failure on stable doses of ACE inhibitor, digoxin, and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure). Amlodipine besylate tablets have been compared to placebo in four8���12 week studies of patients with NYHA class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or LVEF.<br/>Beta-Blocker Withdrawal: Amlodipine is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of beta-blocker.<br/>Patients with Hepatic Failure: Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t 1/2) is 56 hours in patients with impaired hepatic function, caution should be exercised when administering amlodipine besylate tablets to patients with severe hepatic impairment.<br/>Drug Interactions: In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.<br/>Effect of other agents on amlodipine besylate tablets: CIMETIDINE: Co-administration of amlodipine besylate tablets with cimetidine did not alter the pharmacokinetics of amlodipine. GRAPEFRUIT JUICE: Co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine. MAALOX (antacid): Co-administration of the antacid Maalox with a single dose of amlodipine besylate tablets had no significant effect on the pharmacokinetics of amlodipine. SILDENAFIL: A single 100 mg dose of sildenafil (Viagra') in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine besylate tablets and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.<br/>Effect of amlodipine besylate tablets on other agents: ATORVASTATIN: Co-administration of multiple 10 mg doses of amlodipine besylate tablets with 80 mg of atorvastatin resulted in no significant change in the steady state pharmacokinetic parameters of atorvastatin. DIGOXIN: Co-administration of amlodipine besylate tablets with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers. ETHANOL (alcohol): Single and multiple 10 mg doses of amlodipine besylate tablets had no significant effect on the pharmacokinetics of ethanol. WARFARIN: Co-administration of amlodipine besylate tablets with warfarin did not change the warfarin prothrombin response time. In clinical trials, amlodipine besylate tablets have been safely administered with thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.<br/>Drug/Laboratory Test Interactions: None known.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 amlodipine mg/kg/day showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a mg/mbasis, similar to the maximum recommended human dose of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/mbasis, about twice the maximum recommended human dose. Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or chromosome level. There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses up to 10 mg amlodipine/kg/day (8 timesthe maximum recommended human dose of 10 mg/day on a mg/mbasis).<br/>Pregnancy Category C: No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day (respectively 8 timesand 23 timesthe maximum recommended human dose of 10 mg on a mg/mbasis) during their respective periods of major organogenesis. However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose. There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while amlodipine is administered.<br/>Pediatric Use: The effect of amlodipine on blood pressure in patients less than 6 years of age is not known.<br/>Geriatric Use: Clinical studies of amlodipine besylate tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40���60%, and a lower initial dose may be required . | lld:dailymed |
| dailymed-drugs:361 | dailymed-instance:precautio... | Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Caution must be exercised in the administration of 3% and 5% Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Pediatric Use: Safety and effectiveness of 3% and 5% Sodium Chloride Injection, USP in pediatric patients have not been established by adequate and well controlled trials, however, the use of sodium chloride solutions in the pediatric population is referenced in the medical literature. The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population.<br/>Geriatric Use: Clinical studies of 3% and 5% Sodium Chloride Injection, USP, did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Do not administer unless solution is clear and seal is intact. | lld:dailymed |
| dailymed-drugs:362 | dailymed-instance:precautio... | General: An ECG recording should be taken prior to the initiation of larger-than-usual doses of Tofranil and at appropriate intervals thereafter until steady state is achieved. (Patients with any evidence of cardiovascular disease require cardiac surveillance at all dosage levels of the drug. See WARNINGS.) Elderly patients and patients with cardiac disease or a prior history of cardiac disease are at special risk of developing the cardiac abnormalities associated with the use of Tofranil. It should be kept in mind that the possibility of suicide in seriously depressed patients is inherent in the illness and may persist until significant remission occurs. Such patients should be carefully supervised during the early phase of treatment with Tofranil, and may require hospitalization. Prescriptions should be written for the smallest amount feasible. Hypomanic or manic episodes may occur, particularly in patients with cyclic disorders. Such reactions may necessitate discontinuation of the drug. If needed, Tofranil may be resumed in lower dosage when these episodes are relieved. Administration of a tranquilizer may be useful in controlling such episodes. An activation of the psychosis may occasionally be observed in schizophrenic patients and may require reduction of dosage and the addition of a phenothiazine. Concurrent administration of Tofranil with electroshock therapy may increase the hazards; such treatment should be limited to those patients for whom it is essential, since there is limited clinical experience. Patients taking imipramine hydrochloride should avoid excessive exposure to sunlight since there have been reports of photosensitization. Both elevation and lowering of blood sugar levels have been reported with imipramine hydrochloride use. Imipramine hydrochloride should be used with caution in patients with significantly impaired renal or hepatic function. Patients who develop a fever and a sore throat during therapy with imipramine hydrochloride should have leukocyte and differential blood counts performed. Imipramine hydrochloride should be discontinued if there is evidence of pathological neutrophil depression. Prior to elective surgery, imipramine hydrochloride should be discontinued for as long as the clinical situation will allow.<br/>Information for Patients: Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with imipramine hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions" is available for imipramine hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking imipramine hydrochloride. Clinical Worsening and Suicide Risk���Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.<br/>Drug Interactions: Drugs Metabolized by P450 2D6���The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so-called���poor metabolizers���); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interaction may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. The plasma concentration of imipramine may increase when the drug is given concomitantly with hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and decrease by concomitant administration with hepatic enzyme inducers (e.g., barbiturates, phenytoin), and adjustment of the dosage of imipramine may therefore be necessary. In occasional susceptible patients or in those receiving anticholinergic drugs (including antiparkinsonism agents) in addition, the atropine-like effects may become more pronounced (e.g., paralytic ileus). Close supervision and careful adjustment of dosage is required when imipramine hydrochloride is administered concomitantly with anticholinergic drugs. Avoid the use of preparations, such as decongestants and local anesthetics, that contain any sympathomimetic amine (e.g., epinephrine, norepinephrine), since it has been reported that tricyclic antidepressants can potentiate the effects of catecholamines. Caution should be exercised when imipramine hydrochloride is used with agents that lower blood pressure. Imipramine hydrochloride may potentiate the effects of CNS depressant drugs. Patients should be warned that imipramine hydrochloride may enhance the CNS depressant effects of alcohol .<br/>Pregnancy: Animal reproduction studies have yielded inconclusive results . There have been no well-controlled studies conducted with pregnant women to determine the effect of Tofranil on the fetus. However, there have been clinical reports of congenital malformations associated with the use of the drug. Although a causal relationship between these effects and the drug could not be established, the possibility of fetal risk from the maternal ingestion of Tofranil cannot be excluded. Therefore, Tofranil should be used in women who are or might become pregnant only if the clinical condition clearly justifies potential risk to the fetus.<br/>Nursing Mothers: Limited data suggest that Tofranil is likely to be excreted in human breast milk. As a general rule, a woman taking a drug should not nurse since the possibility exists that the drug may be excreted in breast milk and be harmful to the child.<br/>Pediatric Use: Safety and effectiveness in the pediatric population other than pediatric patients with nocturnal enuresis have not been established . Anyone considering the use of imipramine hydrochloride in a child or adolescent must balance the potential risks with the clinical need. The safety and effectiveness of the drug as temporary adjunctive therapy for nocturnal enuresis in pediatric patients less than 6 years of age has not been established. The safety of the drug for long-term, chronic use as adjunctive therapy for nocturnal enuresis in pediatric patients 6 years of age or older has not been established; consideration should be given to instituting a drug-free period following an adequate therapeutic trial with a favorable response. A dose of 2.5 mg/kg/day should not be exceeded in childhood. ECG changes of unknown significance have been reported in pediatric patients with doses twice this amount.<br/>Geriatric Use: In the literature, there were four well-controlled, randomized, double-blind, parallel group comparison clinical studies done with Tofranil in the elderly population. There was a total number of 651 subjects included in these studies. These studies did not provide a comparison to younger subjects. There wereno additional adverse experiences identified in the elderly. Clinical studies of Tofranil in the original application did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Post-marketing clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for the elderly should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:363 | dailymed-instance:precautio... | General:<br/>Patient Information: Physicians are advised to discuss the Patient Information leaflet with patients for whom they prescribe Vivelle.<br/>Laboratory Tests: Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response, rather than by serum hormone levels (e.g., estradiol, FSH).<br/>Drug/Laboratory Test Interactions:<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS.) Long-term, continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.<br/>Pregnancy: Vivelle should not be used during pregnancy. (See CONTRAINDICATIONS.)<br/>Nursing Mothers: Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when Vivelle is administered to a nursing woman.<br/>Pediatric Use: Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established. Large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, which could result in short adult stature if treatment is initiated before the completion of physiologic puberty in normally developing children. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during estrogen administration. Estrogen treatment of prepubertal girls also induces premature breast development and vaginal cornification, and may induce vaginal bleeding. (See INDICATIONS and DOSAGE AND ADMINISTRATION.)<br/>Geriatric Use: The safety and effectiveness in geriatric patients have not been established. In the Women's Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of four years, 82% (n=3,729) were 65 to 74 while 18% (n=803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer's disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70. (See WARNINGS, Dementia.) It is unknown whether these findings apply to estrogen alone therapy. | lld:dailymed |
| dailymed-drugs:364 | dailymed-instance:precautio... | A. General:<br/>1. Addition of a progestin when a woman has not had a hysterectomy: Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer.<br/>2. Elevated blood pressure: In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use.<br/>3. Hypertriglyceridemia: In patients with pre-existing hypertriglyceridemia, oral estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.<br/>4. Impaired liver function and past history of cholestatic jaundice: Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.<br/>5. Hypothyroidism: Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free Tand Tserum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.<br/>6. Fluid retention: Estrogen and estrogen/progestin therapy may cause some degree of fluid retention. Because of this, patients with conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.<br/>7. Hypocalcemia: Estrogens should be used with caution in individuals with severe hypocalcemia.<br/>8. Ovarian cancer: The CE/MPA sub-study of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95% confidence interval 0.77- 3.24) but was not statistically significant. The absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiological studies, the use of estrogen alone, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.<br/>9. Exacerbation of endometriosis: Endometriosis may be exacerbated with administration of estrogens.<br/>10. Exacerbation of other conditions: Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.<br/>B. Information for Patients: Physicians are advised to discuss the Patient Information leaflet with patients for whom they prescribe Climara Pro.<br/>C. Laboratory Tests: Estrogen administration should be initiated at the lowest dose for the approved indication and then guided by clinical response, rather than by serum hormone levels (e.g., estradiol, FSH).<br/>D. Drug/laboratory Test Interactions:<br/>E. Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.<br/>F. Preganacy: Climara Pro should not be used during pregnancy.<br/>G. Nursing mothers: Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens and progestins have been identified in the milk of mothers receiving this drug. Caution should be exercised when Climara Pro is administered to a nursing woman.<br/>H. Pediatric use: Climara Pro is not indicated in children.<br/>I. Geriatric use: There have not been sufficient numbers of geriatric patients involved in studies utilizing Climara Pro to determine whether those over 65 years of age differ from younger subjects in their response to Climara Pro. Of the total number of subjects in the estrogen plus progestin substudy of the WHI study, 44 percent (n = 7,320) were 65 years and older, while 6.6 percent (n = 1,095) were 75 years and older. There was a higher relative risk (CE/MPA versus placebo) of stroke and invasive breast cancer in women 75 and older compared to women less than 75 years of age. In the estrogen plus progestin substudy of WHIMS, a population of 4,532 postmenopausal women, aged 65 to 70 years, was randomized to conjugated estrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg) or placebo. In the estrogen plus progestin group, after an average follow-up of 4 years, the relative risk(CE/MPA versus placebo) of probable dementia was 2.05 (95 percent CI, 1.21-3.48). Of the total number of subjects in the estrogen-alone substudy of the WHI study, 46 percent (n = 4,943) were 65 years and older, while 7.1 percent (n = 767) were 75 years and older. There was a higher relative risk (CE versus placebo) of stroke in women less than 75 years of age compared to women 75 years and older. In the estrogen-alone substudy of the WHIMS, a population of 2,947 hysterectomized women, aged 65 to 79 years, was randomized to estrogen alone (CE 0.625 mg) or placebo. In the estrogen-alone group, after an average follow-up of 5.2 years, the relative risk (CE versus placebo) of probable dementia was 1.49 (95 percent CI, 0.83-2.66). Pooling the events in women receiving CE or CE/MPA in comparison to those in women on placebo, the overall relative risk of probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women. | lld:dailymed |
| dailymed-drugs:365 | dailymed-instance:precautio... | General: Hypoglycemia and hypokalemia are among the potential clinical adverse effects associated with the use of all insulins. Because of differences in the action of NovoLog Mix 70/30 and other insulins, care should be taken in patients in whom such potential side effects might be clinically relevant (e.g., patients who are fasting, have autonomic neuropathy, or are using potassium-lowering drugs or patients taking drugs sensitive to serum potassium level). Fixed ratio insulins are typically dosed on a twice daily basis, i.e., before breakfast and supper, with each dose intended to cover two meals or a meal and snack . The dose of insulin required to provide adequate glycemic control for one of the meals may result in hyper- or hypoglycemia for the other meal. The pharmacodynamic profile may also be inadequate for patients (e.g. pregnant women) who require more frequent meals. Adjustments in insulin dose or insulin type may be needed during illness, emotional stress, and other physiologic stress in addition to changes in meals and exercise. The pharmacokinetic and pharmacodynamic profiles of all insulins may be altered by the site used for injection and the degree of vascularization of the site. Smoking, temperature, and exercise contribute to variations in blood flow and insulin absorption. These and other factors contribute to inter- and intra-patient variability. Lipodystrophy and hypersensitivity are among other potential clinical adverse effects associated with the use of all insulins.<br/>Hypoglycemia: As with all insulin preparations, hypoglycemic reactions may be associated with the administration of NovoLog Mix 70/30. Rapid changes in serum glucose concentrations may induce symptoms of hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, or intensified diabetes control.<br/>Renal Impairment: Clinical or pharmacology studies with NovoLog Mix 70/30 in diabetic patients with various degrees of renal impairment have not been conducted. As with other insulins, the requirements for NovoLog Mix 70/30 may be reduced in patients with renal impairment.<br/>Hepatic Impairment: Clinical or pharmacology studies with NovoLog Mix 70/30 in diabetic patients with various degrees of hepatic impairment have not been conducted. As with other insulins, the requirements for NovoLog Mix 70/30 may be reduced in patients with hepatic impairment.<br/>Allergy: Local Reactions- Erythema, swelling, and pruritus at the injection site have been observed with NovoLog Mix 70/30 as with other insulin therapy. Reactions may be related to the insulin molecule, other components in the insulin preparation including protamine and cresol, components in skin cleansing agents, or injection techniques. Systemic Reactions- Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash (including pruritus) over the whole body, shortness of breath, wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized allergy, including anaphylactic reaction, may be life threatening. Localized reactions and generalized myalgias have been reported with the use of cresol as an injectable excipient<br/>Antibody production: Specific anti-insulin antibodies as well as cross-reacting anti-insulin antibodies were monitored in the 3-month, open-label comparator trial as well as in a long-term extension trial. Changes in cross-reactive antibodies were more common after NovoLog Mix 70/30 than with Novolin 70/30 but these changes did not correlate with change in HbA1c or increase in insulin dose. The clinical significance of these antibodies has not been established. Antibodies did not increase further after long-term exposure (>6 months) to NovoLog Mix 70/30.<br/>Information for patients: Patients should be informed about potential risks and advantages of NovoLog Mix 70/30 therapy including the possible side effects. Patients should also be offered continued education and advice on insulin therapies, injection technique, life-style management, regular glucose monitoring, periodic glycosylated hemoglobin testing, recognition and management of hypo- and hyperglycemia, adherence to meal planning, complications of insulin therapy, timing of dose, instruction for use of injection devices, and proper storage of insulin. Female patients should be advised to discuss with their physician if they intend to, or if they become, pregnant because information is not available on the use of NovoLog Mix 70/30 during pregnancy or lactation .<br/>Laboratory tests: The therapeutic response to NovoLog Mix 70/30 should be assessed by measurement of serum or blood glucose and glycosylated hemoglobin.<br/>Drug interactions: A number of substances affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring. The following are examples of substances that may increase the blood-glucose-lowering effect and susceptibility to hypoglycemia: oral antidiabetic products, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, propoxyphene, salicylates, somatostatin analog (e.g. octreotide), sulfonamide antibiotics. The following are examples of substances that may reduce the blood-glucose-lowering effect: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives). Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the blood-glucose-lowering effect of insulin. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. In addition, under the influence of sympatholytic medical products such as beta-blockers, clonidine, guanethidine, and reserpine, the signs of hypoglycemia may be reduced or absent .<br/>Mixing of insulins: NovoLog Mix 70/30 should not be mixed with any other insulin product.<br/>Carcinogenesis, mutagenesis, impairment of fertility: Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of NovoLog Mix 70/30. In 52-week studies, Sprague-Dawley rats were dosed subcutaneously with NovoLog, the rapid-acting component of NovoLog Mix 70/30, at 10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area, respectively). At a dose of 200 U/kg/day, NovoLog increased the incidence of mammary gland tumors in females when compared to untreated controls. The incidence of mammary tumors for NovoLog was not significantly different than for regular human insulin. The relevance of these findings to humans is not known. NovoLog was not genotoxic in the following tests: Ames test, mouse lymphoma cell forward gene mutation test, human peripheral blood lymphocyte chromosome aberration test, in vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes. In fertility studies in male and female rats, NovoLog at subcutaneous doses up to 200 U/kg/day (approximately 32 times the human subcutaneous dose, based on U/body surface area) had no direct adverse effects on male and female fertility, or on general reproductive performance of animals.<br/>Pregnancy - Teratogenic Effects - Pregnancy Category C: Animal reproduction studies have not been conducted with NovoLog Mix 70/30. However, reproductive toxicology and teratology studies have been performed with NovoLog (the rapid-acting component of NovoLog Mix 70/30) and regular human insulin in rats and rabbits. In these studies, NovoLog was given to female rats before mating, during mating, and throughout pregnancy, and to rabbits during organogenesis. The effects of NovoLog did not differ from those observed with subcutaneous regular human insulin. NovoLog, like human insulin, caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at a dose of 200 U/kg/day (approximately 32 times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area), and in rabbits at a dose of 10 U/kg/day (approximately three times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area). The effects are probably secondary to maternal hypoglycemia at high doses. No significant effects were observed in rats at a dose of 50 U/kg/day and rabbits at a dose of 3 U/kg/day. These doses are approximately 8 times the human subcutaneous dose of 1.0 U/kg/day for rats and equal to the human subcutaneous dose of 1.0 U/kg/day for rabbits based on U/body surface area. It is not known whether NovoLog Mix 70/30 can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. There are no adequate and well-controlled studies of the use of NovoLog Mix 70/30 in pregnant women. NovoLog Mix 70/30 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing mothers: It is unknown whether NovoLog Mix 70/30 is excreted in human milk as is human insulin. There are no adequate and well-controlled studies of the use of NovoLog Mix 70/30 or NovoLog in lactating women.<br/>Pediatric use: Safety and effectiveness of NovoLog Mix 70/30 in children have not been established.<br/>Geriatric use: Clinical studies of NovoLog Mix 70/30 did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in this population. | lld:dailymed |
| dailymed-drugs:367 | dailymed-instance:precautio... | Although seizures may be brought under control promptly, a significant proportion of patients experience a return to seizure activity, presumably due to the short-lived effect of diazepam after IV administration. The physician should be prepared to readminister the drug. However, diazepam is not recommended for maintenance, and once seizures are brought under control, consideration should be given to the administration of agents useful in longer term control of seizures. If diazepam is to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed���particularly with known compounds which may potentiate the action of diazepam, such as phenothiazines, narcotics, barbiturates, MAO inhibitors and other antidepressants. In highly anxious patients with evidence of accompanying depression, particularly those who may have suicidal tendencies, protective measures may be necessary. The usual precautions in treating patients with impaired hepatic function should be observed. Metabolites of diazepam are excreted by the kidney; to avoid their excess accumulation, caution should be exercised in the administration to patients with compromised kidney function. Since an increase in cough reflex and laryngospasm may occur with peroral endoscopic procedures, the use of a topical anesthetic agent and the availability of necessary countermeasures are recommended. Diazepam Injection has produced hypotension or muscular weakness in some patients particularly when used with narcotics, barbiturates or alcohol. Lower doses (usually 2 mg to 5 mg) should be used for elderly and debilitated patients. The clearance of diazepam and certain other benzodiazepines can be delayed in association with Tagamet' (cimetidine) administration. The clinical significance of this is unclear.<br/>Labor and Delivery: In humans, measurable amounts of diazepam were found in maternal and cord blood, indicating placental transfer of the drug. Until additional information is available, Diazepam Injection is not recommended for obstetrical use. | lld:dailymed |
| dailymed-drugs:368 | dailymed-instance:precautio... | General: Excessive diuresis may cause dehydration and blood volume reduction with circulatory collapse and possible vascular thrombosis and embolism, particularly in elderly patients. As with any effective diuretic, electrolyte depletion may occur during furosemide therapy, especially in patients receiving higher doses and restricted salt intake. Hypokalemia may develop with furosemide, especially with brisk diuresis, inadequate oralelectrolyte intake, when cirrhosis is present, or during concomitant use of corticosteroids or ACTH. Digitalis therapy may exaggerate metabolic effects of hypokalemia, especially myocardial effects. All patients receiving furosemide therapy should be observed for these signs or symptoms of fluid or electrolyte imbalance (hyponatremia, hypochloremic alkalosis or hypokalemia): dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, arrhythmia, or gastrointestinal disturbances such as nausea and vomiting. Increases in blood glucose and alterations in glucose tolerance tests (with abnormalities of the fasting and 2-hour postprandial sugar) have been observed, and rarely, precipitation of diabetes mellitus has been reported. Asymptomatic hyperuricemia can occur and gout may rarely be precipitated. Patients allergic to sulfonamides may also be allergic to furosemide. The possibility exists of exacerbation or activation of systemic lupus erythematosus. As with many other drugs, patients should be observed regularly for the possible occurrence of blood dyscrasias, liver damage, or other idiosyncratic reactions.<br/>Information for Patients: Patients receiving furosemide should be advised that they may experience symptoms from excessive fluid and/or electrolyte losses. The postural hypotension that sometimes occurs can usually be managed by getting up slowly. Potassium supplements and/or dietary measures may be needed to control or avoid hypokalemia. Patients with diabetes mellitus should be told that furosemide may increase blood glucose levels and thereby affect urine glucose tests. The skin of some patients may be more sensitive to the effects of sunlight while taking furosemide. Hypertensive patients should avoid medications that may increase blood pressure, including over-the-counter products for appetite suppression and cold symptoms.<br/>Laboratory Tests: Serum electrolytes, COand BUN should be determined frequently during the first few months of furosemide therapy and periodically thereafter. Serum and urine electrolyte determinations are particularly important when the patient is vomiting profusely or receiving parenteral fluids. Abnormalities should be corrected or the drug temporarily withdrawn. Other medications may also influence serum electrolytes. Reversible elevations of BUN may occur and are associated with dehydration, which should be avoided, particularly in patients with renal insufficiency. Urine and blood glucose should be checked periodically in diabetics receiving furosemide, even in those suspected of latent diabetes. Furosemide may lower serum calcium levels and tetany has been reported rarely. Accordingly, serum calcium levels should be determined periodically.<br/>Drug Interactions: Furosemide may increase the ototoxic potential of aminoglycoside antibiotics, especially in the presence of impaired renal function. Except in life-threatening situations, avoid this combination. Furosemide should not be used concomitantly with ethacrynic acid because of the possibility of ototoxicity. Patients receiving high doses of salicylates concomitantly with furosemide, as in rheumatic disease, may experience salicylate toxicity at lower doses because of competitive renal excretory sites. Furosemide has a tendency to antagonize the skeletal muscle relaxing effect of tubocurarine and may potentiate the action of succinylcholine. Lithium generally should not be given with diuretics because they reduce lithium's renal clearance and add a high risk of lithium toxicity. Furosemide may add to or potentiate the therapeutic effect of other antihypertensive drugs. Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs. Furosemide may decrease arterial responsiveness to norepinephrine. However, norepinephrine may still be used effectively. One study in six subjects demonstrated that the combination of furosemide and acetylsalicylic acid temporarily reduced creatinine clearance in patients with chronic renal insufficiency. There are case reports of patients who developed increased BUN, serum creatinine and serum potassium levels, and weight gain when furosemide was used in conjunction with NSAIDs. Literature reports indicate that coadministration of indomethacin may reduce the natriuretic and antihypertensive effects of furosemide in some patients by inhibiting prostaglandin synthesis. Indomethacin may also affect plasma renin levels, aldosterone excretion, and renin profile evaluation. Patients receiving both indomethacin and furosemide should be observed closely to determine if the desired diuretic and/or antihypertensive effect of furosemide is achieved.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Furosemide was tested for carcinogenicity by oral administration in one strain of mice and one strain of rats. A small but significantly increased incidence of mammary gland carcinomas occurred in female mice at a dose 17.5 times the maximum human dose of 600 mg. There were marginal increases in uncommon tumors in male rats at a dose of 15 mg/kg (slightly greater than the maximum human dose) but not at 30 mg/kg. Furosemide was devoid of mutagenic activity in various strains of Salmonella typhimurium when tested in the presence or absence of an in vitro metabolic activation system, and questionably positive for gene mutation in mouse lymphoma cells in the presence of rat liver S9 at the highest dose tested. Furosemide did not induce sister chromatid exchange in human cells in vitro, but other studies on chromosomal aberrations in human cells in vitro gave conflicting results. In Chinese hamster cells it induced chromosomal damage but was questionably positive for sister chromatid exchange. Studies on the induction by furosemide of chromosomal aberrations in mice were inconclusive. The urine of rats treated with this drug did not induce gene conversion in Saccharomyces cerevisiae. Furosemide produced no impairment of fertility in male or female rats, at 100 mg/kg/day (the maximum effective diuretic dose in the rat and 8 times the maximal human dose of 600 mg/day).<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: Because it appears in breast milk, caution should be exercised when furosemide is administered to a nursing mother.<br/>Pediatric Use: Renal calcifications (from barely visible on x-ray to staghorn) have occurred in some severely premature infants treated with intravenous furosemide for edema due to patent ductus arteriosus and hyaline membrane disease. The concurrent use of chlorothiazide has been reported to decrease hypercalciuria and dissolve some calculi. | lld:dailymed |
| dailymed-drugs:369 | dailymed-instance:precautio... | Information for patients: To prevent contaminating the dropper tip and solution, do not touch the eyelids or surrounding areas with the dropper tip. Keep the bottle tightly closed when not in use. Patients should be advised not to wear contact lenses if their eye is red. ALAMAST should not be used to treat contact lens related irritation. The preservative in ALAMAST, lauralkonium chloride, may be absorbed by soft contact lenses. Patients who wear soft contact lenses and whose eyes are not red should be instructed to wait at least ten minutes after instilling ALAMAST before they insert their contact lenses.<br/>Carcinogenesis, mutagenesis, impairment of fertility: Pemirolast potassium was not mutagenic or clastogenic when tested in a series of bacterial and mammalian tests for gene mutation and chromosomal injury in vitro nor was it clastogenic when tested in vivo in rats. Pemirolast potassium had no effect on mating and fertility in rats at oral doses up to 250 mg/kg (approximately 20,000 fold the human dose at 2 drops/eye, 40��L/drop, QID for a 50 kg adult). A reduced fertility and pregnancy index occurred in the Fgeneration when Fdams were treated with 400 mg/kg pemirolast potassium during late pregnancy and lactation period (approximately 30,000 fold the human dose).<br/>Pregnancy:<br/>Teratogenic effects: Pregnancy Category C. Pemirolast potassium caused an increased incidence of thymic remnant in the neck, interventricular septal defect, fetuses with wavy rib, splitting of thoracic vertebral body, and reduced numbers of ossified sternebrae, sacral and caudal vertebrae, and metatarsi when rats were given oral doses���250 mg/kg (approximately 20,000 fold the human dose at 2 drops/eye, 40��L/drop, QID for a 50 kg adult) during organogenesis. Increased incidence of dilation of renal pelvis/ureter in the fetuses and neonates was also noted when rats were given an oral dose of 400 mg/kg pemirolast potassium (approximately 30,000 fold the human dose). Pemirolast potassium was not teratogenic in rabbits given oral doses up to 150 mg/kg (approximately 12,000 fold the human dose) during the same time period. There are no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, ALAMAST ophthalmic solution should be used during pregnancy only if the benefit outweighs the risk.<br/>Non-teratogenic effects: Pemirolast potassium produced increased pre- and post-implantation losses, reduced embryo/fetal and neonatal survival, decreased neonatal body weight, and delayed neonatal development in rats receiving an oral dose at 400 mg/kg (approximately 30,000 fold the human dose). Pemirolast potassium also caused a reduction in the number of corpus lutea, the number of implantations, and number of live fetuses in the Fgeneration in rats when Fdams were given oral dosages���250 mg/kg (approximately 20,000 fold the human dose) during late gestation and the lactation period.<br/>Nursing Mothers: Pemirolast potassium is excreted in the milk of lactating rats at concentrations higher than those in plasma. It is not known whether pemirolast potassium is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ALAMAST ophthalmic solution is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in pediatric patients below the age of 3 years have not been established. | lld:dailymed |
| dailymed-drugs:370 | dailymed-instance:precautio... | General: Meloxicam cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of meloxicam in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.<br/>Hepatic Effects: Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including meloxicam. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with meloxicam. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), meloxicam should be discontinued.<br/>Renal Effects: Caution should be used when initiating treatment with meloxicam in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with meloxicam. Caution is also recommended in patients with pre-existing kidney disease (see WARNINGS, Renal Effects and Advanced Renal Disease). The extent to which metabolites may accumulate in patients with renal failure has not been studied with meloxicam. Because some meloxicam metabolites are excreted by the kidney, patients with significantly impaired renal function should be more closely monitored.<br/>Hematological Effects: Anemia is sometimes seen in patients receiving NSAIDs, including meloxicam. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including meloxicam, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. Drugs which inhibit the biosynthesis of prostaglandins may interfere to some extent with platelet function and vascular responses to bleeding. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving meloxicam who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.<br/>Pre-existing Asthma: Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, meloxicam should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma.<br/>Information for Patients: Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.<br/>Laboratory Tests: Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, meloxicam shouldbe discontinued.<br/>Drug Interactions:<br/>ACE-Inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.<br/>Aspirin: When meloxicam is administered with aspirin (1000 mg TID) to healthy volunteers, it tended to increase the AUC (10%) and C(24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with meloxicam may result in an increased rate of GI ulceration or other complications, compared to use of meloxicam alone. Meloxicam is not a substitute for aspirin for cardiovascular prophylaxis.<br/>Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established.<br/>Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam.<br/>Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after��-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam.<br/>Furosemide: Clinical studies, as well as postmarketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with meloxicam, patients should be observed closely for signs of declining renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy.<br/>Lithium: In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by meloxicam. Patients on lithium treatment should be closely monitored for signs of lithium toxicity when meloxicam is introduced, adjusted, or withdrawn.<br/>Methotrexate: NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites.<br/>Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing meloxicam therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering meloxicam with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No carcinogenic effect of meloxicam was observed in rats given oral doses up to 0.8 mg/kg/day (approximately 0.4 fold the human dose at 15 mg/day for a 50 kg adult based on body surface area conversion) for 104 weeks or in mice given oral doses up to 8.0 mg/kg/day (approximately 2.2 fold the human dose, as noted above) for 99 weeks. Meloxicam was not mutagenic in an Ames assay, or clastogenic in a chromosome aberration assay with human lymphocytes and an in vivo micronucleus test in mouse bone marrow. Meloxicam did not impair male and female fertility in rats at oral doses up to 9 and 5 mg/ kg/day, respectively (4.9 fold and 2.5 fold the human dose, as noted above). However, an increased incidence of embryolethality at oral doses���1 mg/kg/day (0.5 fold the human dose, as noted above) was observed in rats when dams were given meloxicam 2 weeks prior to mating and during early embryonic development.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nonteratogenic Effects: Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Meloxicam caused a reduction in birth index, live births, and neonatal survival at oral doses���0.125 mg/kg/day (approximately 0.07 fold the human dose at 15 mg/day for a 50 kg adult based on body surface area conversion) when rats were treated during the late gestation and lactation period. No studies have been conducted to evaluate the effect of meloxicam on the closure of the ductus arteriosus in humans; use of meloxicam during the third trimester of pregnancy should be avoided.<br/>Labor and Delivery: Studies in rats with meloxicam, as with other drugs known to inhibit prostaglandin synthesis, showed an increased incidence of stillbirths, prolonged delivery, and delayed parturition at oral dosages���1 mg/kg/day (approximately 0.5 fold the human dose at 15 mg/day for a 50 kg adult based on body surface area conversion), and decreased pup survival at an oral dose of 4 mg/kg/day (approximately 2.1 fold the human dose, as noted above) throughout organogenesis. Similar findings were observed in rats receiving oral dosages���0.125 mg/kg/day (approximately 0.07 fold the human dose, as noted above) during late gestation and the lactation period. The effects of meloxicam on labor and delivery in pregnant women are unknown.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk however, meloxicam was excreted in the milk of lactating rats at concentrations higher than those in plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from meloxicam, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Use of this drug for a pediatric indication is protected by marketing exclusivity.<br/>Geriatric Use: As with any NSAID, caution should be exercised in treating the elderly (65 years and older). | lld:dailymed |
| dailymed-drugs:371 | dailymed-instance:precautio... | When Intralipid is administered, the patients capacity to eliminate the infused fat from the circulation must be monitored by use of an appropriate laboratory determination of serum triglycerides. Overdosage must be avoided. During long term intravenous nutrition with Intralipid, liver function tests should be performed. If these tests indicate that liver function is impaired, the therapy should be withdrawn. Frequent (some advise daily) platelet counts should be done in neonatal patients receiving parenteral nutrition with Intralipid. Drug product contains no more than 25 mcg/L of aluminum. Carcinogenesis, Mutagenesis, Impairment of Fertility. Studies with Intralipid have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy Category C: Animal reproduction studies have not been conducted with Intralipid. It is also not known whether Intralipid can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Intralipid should be given to a pregnant woman only if clearly needed. Nursing Mothers: Caution should be exercised when Intralipid is administered to a nursing woman. Pediatric Use: See DOSAGE AND ADMINISTRATION. AVOID OVERDOSAGE ABSOLUTELY. | lld:dailymed |
| dailymed-drugs:3480 | dailymed-instance:precautio... | When Intralipid is administered, the patients capacity to eliminate the infused fat from the circulation must be monitored by use of an appropriate laboratory determination of serum triglycerides. Overdosage must be avoided. During long term intravenous nutrition with Intralipid, liver function tests should be performed. If these tests indicate that liver function is impaired, the therapy should be withdrawn. Frequent (some advise daily) platelet counts should be done in neonatal patients receiving parenteral nutrition with Intralipid. Drug product contains no more than 25 mcg/L of aluminum. Carcinogenesis, Mutagenesis, Impairment of Fertility. Studies with Intralipid have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility. Pregnancy Category C: Animal reproduction studies have not been conducted with Intralipid. It is also not known whether Intralipid can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Intralipid should be given to a pregnant woman only if clearly needed. Nursing Mothers: Caution should be exercised when Intralipid is administered to a nursing woman. Pediatric Use: See DOSAGE AND ADMINISTRATION. AVOID OVERDOSAGE ABSOLUTELY. | lld:dailymed |
| dailymed-drugs:372 | dailymed-instance:precautio... | General:: The least amount feasible should be prescribed or dispensed at 1 time in order to minimize the possibility of overdosage. The tablets contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.<br/>Information for Patients:: Amphetamines may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or vehicles; the patient should therefore be cautioned accordingly. Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with dextroamphetamine and should counsel them in its appropriate use. A patient Medication Guide is available for DEXEDRINE. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.<br/>Drug Interactions::<br/>Acidifying agents:: Gastrointestinal acidifying agents (guanethidine, reserpine, glutamic acid HCl, ascorbic acid, fruit juices, etc.) lower absorption of amphetamines. Urinary acidifying agents (ammonium chloride, sodium acid phosphate, etc.) increase the concentration of the ionized species of the amphetamine molecule, thereby increasing urinary excretion. Both groups of agents lower blood levels and efficacy of amphetamines.<br/>Adrenergic blockers:: Adrenergic blockers are inhibited by amphetamines.<br/>Alkalinizing agents:: Gastrointestinal alkalinizing agents (sodium bicarbonate, etc.) increase absorption of amphetamines. Urinary alkalinizing agents (acetazolamide, some thiazides) increase the concentration of the non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion. Both groups of agents increase blood levels and therefore potentiate the actions of amphetamines.<br/>Antidepressants, tricyclic:: Amphetamines may enhance the activity of tricyclic or sympathomimetic agents; d-amphetamine with desipramine or protriptyline and possibly other tricyclics cause striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated.<br/>MAO inhibitors:: MAOI antidepressants, as well as a metabolite of furazolidone, slow amphetamine metabolism. This slowing potentiates amphetamines, increasing their effect on the release of norepinephrine and other monoamines from adrenergic nerve endings; this can cause headaches and other signs of hypertensive crisis. A variety of neurological toxic effects and malignant hyperpyrexia can occur, sometimes with fatal results.<br/>Antihistamines:: Amphetamines may counteract the sedative effect of antihistamines.<br/>Antihypertensives:: Amphetamines may antagonize the hypotensive effects of antihypertensives.<br/>Chlorpromazine:: Chlorpromazine blocks dopamine and norepinephrine reuptake, thus inhibiting the central stimulant effects of amphetamines, and can be used to treat amphetamine poisoning.<br/>Ethosuximide:: Amphetamines may delay intestinal absorption of ethosuximide.<br/>Haloperidol:: Haloperidol blocks dopamine and norepinephrine reuptake, thus inhibiting the central stimulant effects of amphetamines.<br/>Lithium carbonate:: The stimulatory effects of amphetamines may be inhibited by lithium carbonate.<br/>Meperidine:: Amphetamines potentiate the analgesic effect of meperidine.<br/>Methenamine therapy:: Urinary excretion of amphetamines is increased, and efficacy is reduced, by acidifying agents used in methenamine therapy.<br/>Norepinephrine:: Amphetamines enhance the adrenergic effect of norepinephrine.<br/>Phenobarbital:: Amphetamines may delay intestinal absorption of phenobarbital; co-administration of phenobarbital may produce a synergistic anticonvulsant action.<br/>Phenytoin:: Amphetamines may delay intestinal absorption of phenytoin; co-administration of phenytoin may produce a synergistic anticonvulsant action.<br/>Propoxyphene:: In cases of propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal convulsions can occur.<br/>Veratrum alkaloids:: Amphetamines inhibit the hypotensive effect of veratrum alkaloids.<br/>Drug/Laboratory Test Interactions:: Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinations.<br/>Carcinogenesis/Mutagenesis:: Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of DEXEDRINE have not been performed.<br/>Pregnancy::<br/>Teratogenic Effects:: Pregnancy Category C. DEXEDRINE has been shown to have embryotoxic and teratogenic effects when administered to A/Jax mice and C57BL mice in doses approximately 41 times the maximum human dose. Embryotoxic effects were not seen in New Zealand white rabbits given the drug in doses 7 times the human dose nor inrats given 12.5 times the maximum human dose. While there are no adequate and well-controlled studies in pregnant women, there has been 1 report of severe congenital bony deformity, tracheoesophageal fistula, and anal atresia (VATER association) in a baby born to a woman who took dextroamphetamine sulfate with lovastatin during the first trimester of pregnancy. DEXEDRINE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nonteratogenic Effects:: Infants born to mothers dependent on amphetamines have an increased risk of premature delivery and low birth weight. Also, these infants may experience symptoms of withdrawal as demonstrated by dysphoria, including agitation, and significant lassitude.<br/>Nursing Mothers:: Amphetamines are excreted in human milk. Mothers taking amphetamines should be advised to refrain from nursing.<br/>Pediatric Use:: Long-term effects of amphetamines in pediatric patients have not been well established. Amphetamines are not recommended for use in pediatric patients under 3 years of age with Attention Deficit Disorder with Hyperactivity described under INDICATIONS AND USAGE. Clinical experience suggests that in psychotic children, administration of amphetamines may exacerbate symptoms of behavior disturbance and thought disorder. Amphetamines have been reported to exacerbate motor and phonic tics and Tourette's syndrome. Therefore, clinical evaluation for tics and Tourette's syndrome in children and their families should precede use of stimulant medications. Data are inadequate to determine whether chronic administration of amphetamines may be associated with growth inhibition; therefore, growth should be monitored during treatment. Drug treatment is not indicated in all cases of Attention Deficit Disorder with Hyperactivity and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe amphetamines should depend on the physician's assessment of the chronicity and severity of the child's symptoms and their appropriateness for his or her age. Prescription should not depend solely on the presence of one or more of the behavioral characteristics. When these symptoms are associated with acute stress reactions, treatment with amphetamines is usually not indicated. | lld:dailymed |
| dailymed-drugs:374 | dailymed-instance:precautio... | General: Caution should be exercised when administering pergolide to patients prone to cardiac dysrhythmias. In a study comparing pergolide and placebo, patients taking pergolide were found to have significantly more episodes of atrial premature contractions (APCs) and sinus tachycardia. The use of pergolide in patients on l -dopa may cause and/or exacerbate preexisting states of confusion and hallucinations (see WARNINGS) and preexisting dyskinesia. Also, the abrupt discontinuation of pergolide in patients receiving it chronically as an adjunct to l -dopa may precipitate the onset of hallucinations and confusion; these may occur within a span of several days. Discontinuation of pergolide should be undertaken gradually whenever possible, even if the patient is to remain on l -dopa. A symptom complex resembling the neuroleptic malignant syndrome (NMS) (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy, including pergolide.<br/>Information for Patients: Because pergolide mesylate may cause somnolence and the possibility of falling asleep during activities of daily living, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that pergolide mesylate therapy does not affect them adversely. Patients should be advised that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Due to the possible additive sedative effects, cautionshould also be used when patients are taking other CNS depressants in combination with pergolide mesylate. Patients and their families should be informed of the common adverse consequences of the use of pergolide (see ADVERSE REACTIONS) and the risk of hypotension (see WARNINGS). Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physician if they are breast feeding an infant.<br/>Laboratory Tests: No specific laboratory tests are deemed essential for the management of patients on pergolide. Periodic routine evaluation of all patients, however, is appropriate.<br/>Drug Interactions: Dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthines) or metoclopramide, ordinarily should not be administered concurrently with pergolide (a dopamine agonist); these agents may diminish the effectiveness of pergolide. Because pergolide is approximately 90% bound to plasma proteins, caution should be exercised if pergolide is coadministered with other drugs known to affect protein binding.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: A 2-year carcinogenicity study was conducted in mice using dietary levels of pergolide equivalent to oral doses of 0.6, 3.7, and 36.4 mg/kg/day in males and 0.6, 4.4, and 40.8 mg/kg/day in females. A 2-year study in rats was conducted using dietary levels equivalent to oral doses of 0.04, 0.18, and 0.88 mg/kg/day in males and 0.05, 0.28, and 1.42 mg/kg/day in females. The highest doses tested in the mice and rats were approximately 340 and 12 times the maximum human oral dose administered in controlled clinical trials (6 mg/day equivalent to 0.12 mg/kg/day). A low incidence of uterine neoplasms occurred in both rats and mice. Endometrial adenomas and carcinomas were observed in rats. Endometrial sarcomas were observed in mice. The occurrence of these neoplasms is probably attributable to the high estrogen/progesterone ratio that would occur in rodents as a result of the prolactin-inhibiting action of pergolide. The endocrine mechanisms believed to be involved in the rodents are not present in humans. However, even though there is no known correlation between uterine malignancies occurring in pergolide-treated rodents and human risk, there are no human data to substantiate this conclusion. Pergolide was evaluated for mutagenic potential in a battery of tests that included an Ames bacterial mutation assay, a DNA repair assay in cultured rat hepatocytes, an in vitro mammalian cell-gene-mutation assay in cultured L5178Y cells, and a determination of chromosomealteration in bone marrow cells of Chinese hamsters. A weak mutagenic response was noted in the mammalian cell-gene-mutation assay only after metabolic activation with rat liver microsomes. No mutagenic effects were obtained in the 2 other in vitro assays and in the in vivo assay. The relevance of these findings in humans is unknown. A fertility study in male and female mice showed that fertility was maintained at 0.6 and 1.7 mg/kg/day but decreased at 5.6 mg/kg/day. Prolactin has been reported to be involved in stimulating and maintaining progesterone levels required for implantation in mice, and, therefore, the impaired fertility at the high dose may have occurred because of depressed prolactin levels.<br/>Usage in Pregnancy:<br/>Pregnancy Category B: Reproduction studies were conducted in mice at doses of 5, 16 and 45 mg/kg/day and in rabbits at doses of 2, 6 and 16 mg/kg/day. The highest doses tested in mice and rabbits were 375 and 133 times the 6 mg/day maximum human dose administered in controlled clinical trials. In these studies, there was no evidence of harm to the fetus due to pergolide. There are, however, no adequate and well-controlled studies in pregnant women. Among women who received pergolide for endocrine disorders in premarketing studies, there were 33 pregnancies that resulted in healthy babies and 6 pregnancies that resulted in congenital abnormalities (3 major, 3 minor); a causal relationship has not been established. Because human data are limited and because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. The pharmacologic action of pergolide suggests that it may interfere with lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions to pergolide in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric Use: Of the total number of subjects in clinical studies of pergolide mesylate, 78 were 65 and over. There were no apparent differences in efficacy between these subjects and younger subjects. There was an increased incidence of confusion, somnolence, and peripheral edema in patients 65 and over. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. | lld:dailymed |
| dailymed-drugs:375 | dailymed-instance:precautio... | General: Patients should be adequately hydrated prior to the ETHYOL infusion and blood pressure should be monitored . The safety of ETHYOL administration has not been established in elderly patients, or in patients with preexisting cardiovascular or cerebrovascular conditions such as ischemic heart disease, arrhythmias, congestive heart failure, or history of stroke or transient ischemic attacks. ETHYOL should be used with particular care in these and other patients in whom the common ETHYOL adverse effects of nausea/vomiting and hypotension may be more likely to have serious consequences. Prior to chemotherapy, ETHYOL should be administered as a 15-minute infusion . Blood pressure should be monitored every 5 minutes during the infusion, and thereafter as clinically indicated. Prior to radiation therapy, ETHYOL should be administered as a 3-minute infusion . Blood pressure should be monitored at least before and immediately after the infusion, and thereafter as clinically indicated.<br/>Cutaneous Reactions: Cutaneous reactions may require permanent discontinuation of ETHYOL or urgent dermatologic consultation and biopsy (see below). Cutaneous evaluation of the patient prior to each ETHYOL administration should be performed with particular attention paid to the development of the following: Cutaneous reactions must be clearly differentiated from radiation-induced dermatitis and from cutaneous reactions related to an alternate etiology. ETHYOL should be permanently discontinued for serious or severe cutaneous reactions or for cutaneous reactions associated with fever or other constitutional symptoms not known to be due to another etiology. ETHYOL should be withheld and dermatologic consultation and biopsy considered for cutaneous reactions or mucosal lesions of unknown etiology appearing outside of the injection site or radiation port and for erythematous, edematous or bullous lesions on the palms of the hand or soles of the feet. Reinitiation of ETHYOL should be at the physician's discretion based on medical judgment and appropriate dermatologic evaluation.<br/>Allergic Reactions: In case of severe acute allergic reactions ETHYOL should be immediately and permanently discontinued. Epinephrine and other appropriate measures should be available for treatment of serious allergic events such as anaphylaxis.<br/>Drug Interactions: Special consideration should be given to the administration of ETHYOL in patients receiving antihypertensive medications or other drugs that could cause or potentiate hypotension.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No long term animal studies have been performed to evaluate the carcinogenic potential of ETHYOL. ETHYOL was negative in the Ames test and in the mouse micronucleus test. The free thiol metabolite was positive in the Ames test with S9 microsomal fraction in the TA1535 Salmonella typhimurium strain and at the TK locus in the mouse L5178Y cell assay. The metabolite wasnegative in the mouse micronucleus test and negative for clastogenicity in human lymphocytes.<br/>Pregnancy: Pregnancy Category C. ETHYOL has been shown to be embryotoxic in rabbits at doses of 50 mg/kg, approximately sixty percent of the recommended dose in humans on a body surface area basis. There are no adequate and well-controlled studies in pregnant women. ETHYOL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: No information is available on the excretion of ETHYOL or its metabolites into human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, it is recommended that breast feeding be discontinued if the mother is treated with ETHYOL.<br/>Pediatric Use: The safety and effectiveness in pediatric patients have not been established.<br/>Geriatric Use: The clinical studies did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in elderly patients. | lld:dailymed |
| dailymed-drugs:379 | dailymed-instance:precautio... | General: Doses of vitamin Bexceeding 10 mcg daily may produce a hematologic response in patients who have a folate deficiency. Indiscriminate administration of vitamin Bmay mask the true diagnosis of pernicious anemia. Vitamin Bdeficiency that is allowed to progress for longer than three months may produce permanent degenerative lesions of the spinal cord. Doses of folic acid greater than 0.1 mg per day may result in hematologic remission in patients with vitamin Bdeficiency. Neurologic manifestations will not be prevented with folic acid, and if not treated with vitamin B, irreversible damage will result.<br/>Laboratory Tests: Patients with pernicious anemia have about three times the incidence of carcinoma of the stomach as the general population, so appropriate tests for this condition should be carried out when indicated.<br/>Drug Interactions: Neomycin, colchicine, para-aminosalicylic acid, or excessive alcohol intake longer than two weeks may cause malabsorption of vitamin B. Chloramphenicol and other drugs having bone marrow suppressant properties may cause a lack of therapeutic response to vitamin B; this effect may be due to interference with erythrocyte maturation.<br/>Drug/Laboratory Test Interactions: Most antibiotics, methotrexate, and pyrimethamine invalidate folic acid and vitamin Bdiagnostic microbiological blood assays.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals to evaluate carcinogenic potential have not been done. There is no evidence from long-term use in patients with pernicious anemia that cyanocobalamin is carcinogenic. Pernicious anemia is associated with an increased incidence of carcinoma of the stomach, but this is believed to be related to the underlying pathology and not to treatment with cyanocobalamin.<br/>Pregnancy: Pregnancy Category C. Adequate and well-controlled studies have not been done in pregnant women. However, vitamin Bis an essential vitamin and requirements are increased during pregnancy. Amounts of vitamin Bthat are recommended by the Food and Nutrition Board, National Academy of Science-National Research Council for pregnant women (4 mcg daily) should be consumed during pregnancy.<br/>Nursing Mothers: Vitamin Bis known to be excreted in human milk. Amounts of vitamin Bthat are recommended by the Food and Nutrition Board, National Academy of Science-National Research Council for lactating women (4 mcg daily) should be consumed during lactation. Vitamin Bappears in the milk of nursing mothers in concentrations that approximate the mother's vitamin Bblood level.<br/>Pediatric Use: Safety and effectiveness in pediatric patients has not been established. | lld:dailymed |
| dailymed-drugs:380 | dailymed-instance:precautio... | General: Prescribing cephalexin capsules, cephalexin for oral suspension, or cephalexin tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Patients should be followed carefully so that any side effects or unusual manifestations of drug idiosyncrasy may be detected. If an allergic reaction to cephalexin occurs, the drug should be discontinued and the patient treated with the usual agents (e.g., epinephrine or other pressor amines, antihistamines, or corticosteroids). Prolonged use of cephalexin may result in the overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken. Positive direct Coombs' tests have been reported during treatment with the cephalosporin antibiotics. In hematologic studies or in transfusion cross-matching procedures when antiglobulin tests are performed on the minor side or in Coombs' testing of newborns whose mothers have received cephalosporin antibiotics before parturition, it should be recognized that a positive Coombs' test may be due to the drug. Cephalexin should be administered with caution in the presence of markedly impaired renal function. Under such conditions, careful clinical observation and laboratory studies should be made because safe dosage may be lower than that usually recommended. Indicated surgical procedures should be performed in conjunction with antibiotic therapy. Broad-spectrum antibiotics should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated.<br/>Information for Patients: Patients should be counseled that antibacterial drugs including cephalexin capsules, cephalexin for oral suspension, and cephalexin tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cephalexin capsules, cephalexin for oral suspension, or cephalexin tablets are prescribed to treat a bacterial infection, patients should be told that although it is commonto feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cephalexin capsules, cephalexin for oral suspension, cephalexin tablets, or other antibacterial drugs in the future.<br/>Drug Interactions:<br/>Metformin: In healthy subjects given single 500 mg doses of cephalexin and metformin, plasma metformin mean Cand AUC increased by an average of 34% and 24%, respectively, and metformin mean renal clearance decreased by 14%. No information is available about the interaction of cephalexin and metformin following multiple doses of either drug. Although not observed in this study, adverse effects could potentially arise from coadministration of cephalexin and metformin by inhibition of tubular secretion via organic cationic transporter systems. Accordingly, careful patient monitoring and dose adjustment of metformin is recommended in patients concomitantly taking cephalexin and metformin.<br/>Probenecid: As with other��-lactams, the renal excretion of cephalexin is inhibited by probenecid.<br/>Drug/Laboratory Test Interactions: As a result of administration of cephalexin, a false-positive reaction for glucose in the urine may occur. This has been observed with Benedict's and Fehling's solutions and also with Clinitest' tablets.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Lifetime studies in animals have not been performed to evaluate the carcinogenic potential of cephalexin. Tests to determine the mutagenic potential of cephalexin have not been performed. In male and female rats, fertility and reproductive performance were not affected by cephalexin oral doses up to 1.5 times the highest recommended human dose based upon mg/m.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: The excretion of cephalexin in human milk increased up to 4 hours after a 500 mg dose; the drug reached a maximum level of 4 mcg/mL, then decreased gradually, and had disappeared 8 hours after administration. Caution should be exercised when cephalexin is administered to a nursing woman.<br/>Pediatric Use: The safety and effectiveness of cephalexin in pediatric patients was established in clinical trials for the dosages described in the DOSAGE AND ADMINISTRATION section. In these trials, pediatric patients may have received cephalexin capsules or cephalexin for oral suspension. Cephalexin capsules should only be used in children and adolescents capable of ingesting the capsule.<br/>Geriatric Use: Of the 701 subjects in 3 published clinical studies of cephalexin, 433 (62%) were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see PRECAUTIONS, General). | lld:dailymed |
| dailymed-drugs:381 | dailymed-instance:precautio... | General: Although signs and symptoms of ergotism rarely develop even after long term intermittent use of the rectally administered drug, care should be exercised to remain within the limits of recommended dosage. Ergotism is manifested by intense arterial vasoconstriction, producing signs and symptoms of peripheral vascular ischemia. Ergotamine induces vasoconstriction by a direct action on vascular smooth muscle. In chronic intoxication with ergot derivatives, headache, intermittent claudication, muscle pains, numbness, coldness and pallor of the digits may occur. If the condition is allowed to progress untreated, gangrene can result. While most cases of ergotism associated with ergotamine treatment result from frank overdosage, some cases have involved apparent hypersensitivity. There are few reports of ergotism among patients taking doses within the recommended limits or for brief periods of time. In rare instances, patients, particularly those who have used the medication indiscriminately over long periods of time, may display withdrawal symptoms consisting of rebound headache upon discontinuation of the drug. Rare cases of solitary rectal or anal ulcer have occurred from abuse of ergotamine suppositories usually in higher than recommended doses or with continual use at the recommended dose for many years. Spontaneous healing occurs within usually 4-8 weeks after drug withdrawal.<br/>Information for Patients: Patients should be advised that two tablets of ergotamine tartrate and caffeine should be taken at the first sign of a migraine headache. No more than 6 tablets should be taken for any single migraine attack. No more than 10 tablets should be taken during any 7-day period. Administration of ergotamine tartrate and caffeine tablets should not exceed the dosing guidelines and should be used for chronic daily administration . Ergotamine tartrate and caffeine should be used only for migraine headaches. It is not effective for other types of headaches and it lacks analgesic properties. Patients should be advised to report to the physician immediately any of the following: numbness or tingling in the fingers and toes, muscle pain in the arms and legs, weakness in the legs, pain in the chest or temporary speeding or slowing of the heart rate, swelling or itching.<br/>Drug Interactions:<br/>CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors): See CONTRAINDICATIONS and WARNINGS. Ergotamine tartrate and caffeine should not be administered with other vasoconstrictors. Use with sympathominetics (pressor agents) may cause extreme elevation of blood pressure. The beta-blocker Inderal (propranolol) has been reported to potentiate the vasoconstrictive action of ergotamine tartrate and caffeine by blocking the vasodilating property of epinephrine. Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy. The blood levels of ergotamine-containing drugs are reported to be elevated by the concomitant administration of macrolide antibiotics and vasospastic reactions have been reported with therapeutic doses of the ergotamine-containing drugs when coadministered with those antibiotics.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category X: There are no studies on the placental transfer or teratogenicity of the combined products of ergotamine tartrate and caffeine. Caffeine is known to cross the placenta and has been shown to be teratogenic in animals. Ergotamine crosses the placenta in small amounts, although it does not appear to be embryotoxic in this quantity. However, prolonged vasoconstriction of the uterine vessels and/or increased myometrial tone leading to reduced myometrial and placental blood flow may have contributed to fetal growth retardation observed in animals .<br/>Nonteratogenic Effects: Ergotamine tartrate and caffeine is contraindicated in pregnancy due to the oxytocic effects of ergotamine .<br/>Labor and Delivery: Ergotamine tartrate and caffeine is contraindicated in labor and delivery due to its oxytocic effect which is maximal in the third trimester .<br/>Nursing Mothers: Ergot drugs are known to inhibit prolactin but there are no reports of decreased lactation with ergotamine tartrate and caffeine. Ergotamine is excreted in breast milk and may cause symptoms of vomiting, diarrhea, weak pulse and unstable blood pressure in nursing infants. Because of the potential for serious adverse reactions in nursing infants from ergotamine tartrate and caffeine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established. | lld:dailymed |
| dailymed-drugs:382 | dailymed-instance:precautio... | Dexchlorpheniramine Maleate, USP has an atropine-like action and, therefore, should be used with caution in patients with:<br/>Drug Interaction: MAO inhibitors prolong and intensify the anticholinergic (drying) effects of antihistamines. | lld:dailymed |
| dailymed-drugs:383 | dailymed-instance:precautio... | General - Hypotension: Because nifedipine decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of nifedipine extended-release tablets is suggested. Close observation is especially recommended for patients already taking medications that areknown to lower blood pressure . Peripheral Edema: Mild to moderate peripheral edema occurs in a dose-dependent manner with nifedipine extended-release tablets. The placebo subtracted rate is approximately 8% at 30 mg, and 12% at 60 mg daily. This edema is a localized phenomenon, thought to be associated with vasodilation of dependent arterioles and small blood vessels and not due to left ventricular dysfunction or generalized fluid retention. With patients whose hypertension is complicated by congestive heart failure, care should be taken to differentiate this peripheral edema from the effects of increasing left ventricular dysfunction. Information for Patients: Nifedipine extended-release tablets is an extended release tablet and should be swallowed whole and taken on an empty stomach. It should not be administered with food. Do not chew, divide or crush tablets. Laboratory Tests: Rare, usually transient, but occasionally significant elevations of enzymes such as alkaline phosphatase, CPK, LDH, SGOT, and SGPT have been noted. The relationship to nifedipine therapy is uncertain in most cases, but probable in some. These laboratory abnormalities have rarely been associated with clinical symptoms;however, cholestasis with or without jaundice has been reported. A small increase (<5%) in mean alkaline phosphatase was noted in patients treated with nifedipine extended-release tablets. This was an isolated finding and it rarely resulted in values which fell outside the normal range. Rare instances of allergic hepatitis have been reported with nifedipine treatment. In controlled studies, nifedipine extended-release tablets did not adversely affect serum uric acid, glucose, cholesterol or potassium. Nifedipine, like other calcium channel blockers, decreases platelet aggregation in vitro. Limited clinical studies have demonstrated a moderate but statistically significant decrease in platelet aggregation and increase in bleeding time in some nifedipine patients. This is thought to be a function of inhibition of calcium transport across the platelet membrane. No clinical significance for these findings has been demonstrated. Positive direct Coombs' test with or without hemolytic anemia has been reported but a causal relationship between nifedipine administration and positivity of this laboratory test, including hemolysis, could not be determined. Although nifedipine has been used safely in patients with renal dysfunction and has been reported to exert a beneficial effect in certain cases, rare reversible elevations in BUN and serum creatinine have been reported in patients with pre-existing chronic renal insufficiency. The relationship to nifedipine therapy is uncertain in most cases but probable in some.<br/>Drug Interactions::<br/>Beta-adrenergic blocking agents: Nifedipine is mainly eliminated by metabolism and is a substrate of CYP3A. Inhibitors and inducers of CYP3A4 can impact the exposure to nifedipine and consequently its desirable and undesirable effects. In vitro and in vivo data indicate that nifedipine can inhibit the metabolism of drugs that are substrates of CYP3A, thereby increasing the exposure to other drugs. Nifedipine is a vasodilator, and co-administration of other drugs affecting blood pressure may result in pharmacodynamic interactions.<br/>Cardiovascular Drugs:<br/>Calcium Channel Blockers:<br/>ACE Inhibitors:<br/>Angiotensin-II Blockers:<br/>Beta-blockers: Nifedipine extended-release tablets was well tolerated when administered in combination with beta-blockers in 187 hypertensive patients in a placebo-controlled clinical trial. However, there have been occasional literature reports suggesting that the combination of nifedipine and beta-adrenergic blocking drugs may increase the likelihood of congestive heart failure, severe hypotension or exacerbation of angina in patients with cardiovascular disease.Clinical monitoring is recommended and a dose adjustment of nifedipine should be considered.<br/>Central Alpha1-Blockers:<br/>Digitalis:<br/>Antithrombotics:<br/>Platelet Aggregation Inhibitors:<br/>Non-Cardiovascular Drugs:<br/>Antibacterial Drugs:<br/>Antitubercular Drugs:<br/>Antiviral Drugs: Amprenavir, atanazavir, delavirine, fosamprinavir, indinavir, nelfinavir and ritonavir, as CYP3A inhibitors, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine. Caution is warranted and clinical monitoring of patients recommended.<br/>CNS Drugs: Nefazodone, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a reduction of the dose of nifedipine considered. Valproic acid may increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a dose reduction of nifedipine considered.<br/>Antiemetic Drugs:<br/>Immunosuppressive Drugs:<br/>Glucose Lowering Drugs:<br/>Drugs Interfering with Food Absorption:<br/>Dietary Supplements:<br/>Herbals:<br/>CYP2D6 Probe Drug: Carcinogenesis, Mutagenesis, Impairment of Fertility: Nifedipine was administered orally to rats for two years and was not shown to be carcinogenic. When given to rats prior to mating, nifedipine caused reduced fertility at a dose approximately 30 times the maximum recommended human dose. There is a literature report of reversible reduction in the ability of human sperm obtained from a limited number of infertile men taking recommended doses of nifedipine to bind to and fertilize an ovum in vitro.In vivo mutagenicity studies were negative. Pregnancy: Pregnancy Category C. In rodents, rabbits and monkeys, nifedipine has been shown to have a variety of embryotoxic, placentotoxic and fetotoxic effects, including stunted fetuses (rats, mice and rabbits), digital anomalies (rats and rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice and rabbits), prolonged pregnancy (rats; not evaluated in other species), and decreased neonatal survival (rats; not evaluated in other species). On a mg/kg or mg/mbasis, some of the doses associated with these various effects are higher than the maximum recommended human dose and some are lower, but all are within an order of magnitude of it. The digital anomalies seen in nifedipine-exposed rabbit pups are strikingly similar to those seen in pups exposed to phenytoin, and these are in turn similar to the phalangeal deformities that are the most common malformation seen in human children with in utero exposure to phenytoin. There are no adequate and well-controlled studies in pregnant women. Nifedipine extended-release tablets should generally be avoided during pregnancy and used only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: Nifedipine is excreted in human milk. Therefore, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Geriatric Use: Although small pharmacokinetic studies have identified an increased half-life and increased Cand AUC , clinical studies of nifedipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderlypatient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. | lld:dailymed |
| dailymed-drugs:384 | dailymed-instance:precautio... | Dermatologic reactions to PLAQUENIL may occur and, therefore, proper care should be exercised when it is administered to any patient receiving a drug with a significant tendency to produce dermatitis. The methods recommended for early diagnosis of "chloroquine retinopathy" consist of (1) funduscopic examination of the macula for fine pigmentary disturbances or loss of the foveal reflex and (2) examination of the central visual field with a small red test object for pericentral or paracentral scotoma or determination of retinal thresholds to red. Any unexplained visual symptoms, such as light flashes or streaks should also be regarded with suspicion as possible manifestations of retinopathy. If serious toxic symptoms occur from overdosage or sensitivity, it has been suggested that ammonium chloride (8 g daily in divided doses for adults) be administered orally three or four days a week for several months after therapy has been stopped, as acidification of the urine increases renal excretion of the 4-aminoquinoline compounds by 20 to 90 percent. However, caution must be exercised in patients with impaired renal function and/or metabolic acidosis. | lld:dailymed |
| dailymed-drugs:388 | dailymed-instance:precautio... | Heart Block: In patients without implanted pacemakers who are at high risk of complete atrioventricular block (e.g., those with digitalis intoxication, second-degree atrioventricular block, or severe intraventricular conduction defects), quinidine should be used only with caution.<br/>Drug Interactions:<br/>Altered pharmacokinetics of quinidine: Drugs that alkalinize the urine (carbonic-anhydrase inhibitors, sodium bicarbonate, thiazide diuretics) reduce renal elimination of quinidine. By pharmacokinetic mechanisms that are not well understood, quinidine levels are increased by coadministration of amiodarone or cimetidine. Very rarely, and again by mechanisms not understood, quinidine levels are decreased by coadministration of nifedipine. Hepatic elimination of quinidine may be accelerated by coadministration of drugs (phenobarbital, phenytoin, rifampin) that induce production of cytochrome P450. Perhaps because of competition for the P450metabolic pathway, quinidine levels rise when ketaconazole is coadministered. Coadministration of propranolol usually does not affect quinidine pharmacokinetics, but in some studies the��-blocker appeared to cause increases in the peak serum levels of quinidine, decreases in quinidine's volume of distribution, and decreases in total quinidine clearance. The effects (if any) of coadministration of other��-blockers on quinidine pharmacokinetics have not been adequately studied. Diltiazem significantly decreases the clearance and increases the tof quinidine, but quinidine does not alter the kinetics of diltiazem. Hepatic clearance of quinidine is significantly reduced during coadministration of verapamil, with corresponding increases in serum levels and half-life.<br/>Altered pharmacokinetics of other drugs: Quinidine slows the elimination of digoxin and simultaneously reduces digoxin's apparent volume of distribution. As a result, serum digoxin levels may be as much as doubled. When quinidine and digoxin are coadministered, digoxin doses usually need to be reduced. Serum levels of digitoxin are also raised when quinidineis coadministered, although the effect appears to be smaller. By a mechanism that is not understood, quinidine potentiates the anticoagulatory action of warfarin, and the anticoagulant dosage may need to be reduced. Cytochrome P450is an enzyme critical to the metabolism of many drugs, notably including mexiletine, some phenothiazines, and most polycyclic antidepressants. Constitutional deficiency of cytochrome P450is found in less than 1% of Orientals, in about 2% of American blacks, and in about 8% of American whites. Testing with debrisoquine is sometimes used to distinguish the P450-deficient "poor metabolizers" from the majority-phenotype "extensive metabolizers". When drugs whose metabolism is P450-dependent are given to poor metabolizers, the serum levels achieved are higher, sometimes much higher, than the serum levels achieved when identical doses are given to extensive metabolizers. To obtain similar clinical benefit without toxicity, doses given to poor metabolizers may need to be greatly reduced. In the cases of prodrugs whose actions are actually mediated by P450-produced metabolites (for example, codeine and hydrocodone, whose analgesic and antitussive effects appear to be mediated by morphine and hydromorphone, respectively), it may not be possible to achieve the desired clinical benefits in poor metabolizers. Quinidine is not metabolized by cytochrome P450, but therapeutic serum levels of quinidine inhibit the action of cytochrome P450, effectively converting extensive metabolizers into poor metabolizers. Caution must be exercised whenever quinidine is prescribed together with drugs metabolized by cytochrome P450. Perhaps by competing for pathways of renal clearance, coadministration of quinidine causes an increase in serum levels of procainamide. Serum levels of haloperidol are increased when quinidine is coadministered. Presumably because both drugs are metabolized by cytochrome P450, coadministration of quinidine causes variable slowing of the metabolism of nifedipine. Interactions with other dihydropyridine calcium-channel blockers have not been reported, but these agents (including felodipine, nicardipine, and nimodipine) are all dependent upon P450for metabolism, so similar interactions with quinidine should be anticipated.<br/>Altered pharmacodynamics of other drugs: Quinidine's anticholinergic, vasodilating, and negative inotropic actions may be additive to those of other drugs with these effects, and antagonistic to those of drugs with cholinergic, vasoconstricting, and positive inotropic effects. For example, when quinidine and verapamil are coadministered in doses that are each well tolerated as monotherapy, hypotension attributable to additive peripheral��-blockade is sometimes reported. Quinidine potentiates the actions of depolarizing (succinylcholine, decamethonium) and nondepolarizing (d-tubocurarine, pancuronium) neuromuscular blocking agents. These phenomena are not well understood, but they are observed in animal models as well as in humans. In addition, in vitro addition of quinidine to the serum of pregnant women reduces the activity of pseudocholinesterase, an enzyme that is essential to the metabolism of succinylcholine.<br/>Non-interactions of quinidine with other drugs: Quinidine has no clinically significant effect on the pharmacokinetics of diltiazem, flecainide, mephenytoin, metoprolol, propafenone, propranolol, quinine, timolol, or tocainide. Conversely, the pharmacokinetics of quinidine are not significantly affected by caffeine, ciprofloxacin, digoxin, diltiazem, felodipine, omeprazole, or quinine. Quinidine's pharmacokinetics are also unaffected by cigarette smoking.<br/>Information for patients: Before prescribing quinidine sulfate as prophylaxis against recurrence of atrial fibrillation, the physician should inform the patient of the risks and benefits to be expected . Discussion should include the facts:<br/>Carcinogenesis, Mutagenesis, Impairment Of Fertility: Animal studies to evaluate quinidine's carcinogenic or mutagenic potential have not been performed. Similarly, there are no animal data as to quinidine's potential to impair fertility.<br/>Pregnancy:<br/>Pregnancy Category C: Animal reproductive studies have not been conducted with quinidine. There are no adequate and well-controlled studies in pregnant women. Quinidine should be given to a pregnant woman only if clearly needed. Human placental transport of quinidine has not been systematically studied. In one neonate whose mother had received quinidine throughout her pregnancy, the serum level of quinidine was equal to that of the mother, with no apparent ill effect. The level of quinidine in amniotic fluid was about three times higher than that found in serum. In another case, the levels of quinidine and 3-hydroxyquinidine in cord blood were about 30% of simultaneous maternal levels.<br/>Labor and Delivery: Quinine is said to be oxytocic in humans, but there are no adequate data as to quinidine's effects (if any) on human labor and delivery.<br/>Nursing Mothers: Quinidine is present in human milk at levels slightly lower than those in maternal serum; a human infant ingesting such milk should (scaling directly by weight) be expected to develop serum quinidine levels at least an order of magnitude lower than those of the mother. On the other hand, the pharmacokinetics and pharmacodynamics of quinidine in human infants have not been adequately studied, and neonates' reduced protein binding of quinidine may increase theirrisk of toxicity at low total serum levels. Administration of quinidine should (if possible) be avoided in lactating women who continue to nurse.<br/>Geriatric Use: Safety and efficacy of quinidine in elderly patients has not been systematically studied.<br/>Pediatric Use: In antimalarial trials, quinidine was as safe and effective in pediatric patients as in adults. Notwithstanding the known pharmacokinetic differences between children and adults , children in these trials received the same doses (on a mg/kg basis) as adults. Safety and effectiveness of antiarrhythmic use in pediatric patients have not been established. | lld:dailymed |
| dailymed-drugs:389 | dailymed-instance:precautio... | Caution is to be exercised in prescribing IONAMIN for patients with even mild hypertension. Insulin requirements in diabetes mellitus may be altered in association with the use of IONAMIN and the concomitant dietary regimen. IONAMIN may decrease the hypotensive effect of adrenergic neuron blocking drugs. The least amount feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage.<br/>Geriatric Use: Clinical studies of IONAMIN did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. | lld:dailymed |
| dailymed-drugs:390 | dailymed-instance:precautio... | Periodic determination of PT/INR is essential. Numerous factors, alone or in combination, including changes in diet and medications, botanicals, and genetic variations in the CYP2C9 and VKORC1 enzymes may influence the response of the patient to warfarin.<br/>Drug/Drug and Drug/Disease Interactions: It is generally good practice to monitor the patient's response with additional PT/INR determinations in the period immediately after discharge from the hospital, and whenever other medications, including botanicals, are initiated, discontinued or taken irregularly. The following factors are listed for reference; however, other factors may also affect the anticoagulant response. Drugs may interact with Jantoven' Tablets (Warfarin Sodium Tablets, USP) through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with Jantoven' Tablets are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and altered physiologic control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions with Jantoven' Tablets are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding. It is important to note that some drugs may interact by more than one mechanism. The following factors, alone or in combination, may be responsible for INCREASED PT/INR response: ENDOGENOUS FACTORS: EXOGENOUS FACTORS: Potential drug interactions with Jantoven' Tablets are listed below by drug class and by specific drugs. The following factors, alone or in combination, may be responsible for DECREASED PT/INR response: ENDOGENOUS FACTORS: EXOGENOUS FACTORS: Potential drug interactions with Jantoven' Tablets (Warfarin Sodium Tablets, USP) are listed below by drug class and by specific drugs. Because a patient may be exposed to a combination of the above factors, the net effect of Jantoven' Tablets on PT/INR response may be unpredictable. More frequent PT/INR monitoring is therefore advisable. Medications of unknown interaction with coumarins are best regarded with caution. When these medications are started or stopped, more frequent PT/INR monitoring is advisable. It has been reported that concomitant administration of warfarin and ticlopidine may be associated with cholestatic hepatitis.<br/>Botanical (Herbal) Medicines: Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with Jantoven' Tablets. Few adequate, well-controlled studies exist evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and Jantoven' Tablets. Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulation. It is good practice to monitor the patient's response with additional PT/INR determinations when initiating or discontinuing botanicals. Specific botanicals reported to affect Jantoven' Tablets therapy include the following: Some botanicals may cause bleeding events when taken alone (e.g., garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet, and/or fibrinolytic properties. These effects would be expected to be additive to the anticoagulant effects of Jantoven' Tablets. Conversely, other botanicals may have coagulent properties when taken alone or may decrease the effects of Jantoven' Tablets. Some botanicals that may affect coagulation are listed below for reference; however, this list should not be considered all-inclusive. Many botanicals have several common names and scientific names. The most widely recognized common botanical names are listed.<br/>Effect on Other Drugs: Coumarins may also affect the action of other drugs. Hypoglycemic agents (chlorpropamide and tolbutamide) and anticonvulsants (phenytoin and phenobarbital) may accumulate in the body as a result of interference with either their metabolism or excretion.<br/>Considerations for Increased Bleeding Risk: Jantoven' Tablets is a narrow therapeutic range (index) drug, and additional caution should be observed when warfarin sodium is administered to certain patients. Reported risk factors for bleeding include high intensity of anticoagulation (INR>4.0), age���65, highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, concomitant drugs and long duration of warfarin therapy. Identification of risk fators for bleeding and certain genetic variations in CYP2CP and VKORC1 in a patient may increase the need for more frequent INR monitoring and the use of lower warfarin doses Bleeding is more likely to occur during the starting period and with a higher dose of Jantoven' Tablets (resulting in a higher INR). Intramuscular (I.M.) injections of concomitant medications should be confined to the upper extremities which permits easy access for manual compression, inspections for bleeding and use of pressure bandages. Caution should be observed when Jantoven' Tablets (or warfarin) is administered concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, to be certain that no change in anticoagulation dosage is required. In addition to specific drug interactions that might affect PT/INR, NSAIDs, including aspirin, can inhibit platelet aggregation, and can cause gastrointestinal bleeding, peptic ulceration and/or perforation.<br/>Information for Patients: The objective of anticoagulant therapy is to decrease the clotting ability of the blood so that thrombosis is prevented, while avoiding spontaneous bleeding. Effective therapeutic levels with minimal complications are in part dependent upon cooperative and well-instructed patients who communicate effectively with their physician. Patients should be advised: Strict adherence to prescribed dosage schedule is necessary. Do not take or discontinue any other medication, including salicylates (e.g., aspirin and topical analgesics), other over-the-counter medications, and botanical (herbal) products - except on advice of the physician. Avoid alcohol consumption. Do not takeJantoven' Tablets during pregnancy and do not become pregnant while taking it . Avoid any activity or sport that may result in traumatic injury. Prothombin time tests and regular visits to physician or clinic are needed to monitor therapy. Carry identification stating that Jantoven' Tablets are being taken. If the prescribed dose of Jantoven' Tablets is forgotten, notify the physician immediately. Take the dose as soon as possible on the same day but do not take a double dose of Jantoven' Tablets the next day to make up for missed doses. The amount of vitamin K in food may affect therapy with Jantoven' Tablets. Eat a normal, balanced diet maintaining a consistent amount of vitamin K. Avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables. You should also avoid intake of cranberry juice or any other cranberry products. Notify your healthcare provider if any of these products are part of your normal diet. Contact physician to report any illness, such as diarrhea, infection or fever. Notify physician immediately if any unusual bleeding or symptoms occur. Signs and symptoms of bleeding include: pain, swelling or discomfort, prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or dark brown urine, red or tar black stools, headache, dizziness, or weakness. If therapy with Jantoven' Tablets is discontinued, patients should be cautioned that the anticoagulant effectsof Jantoven' Tablets may persist for about 2 to 5 days. Patients should be informed that all warfarin sodium, USP, products represent the same medication, and should not be taken concomitantly, as overdosage may result. A Medication Guideshould be available to patients when their prescriptions for warfarin sodium are issued.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity and mutagenicity studies have not been performed with Jantoven' Tablets. The reproductive effects of Jantoven' Tablets have not been evaluated. The use of warfarin during pregnancy has been associated with the development of fetal malformations in humans .<br/>Use in Pregnancy: Pregnancy Category X - See CONTRAINDICATIONS.<br/>Pediatric Use: Safety and effectiveness in pediatric patients below the age of 18 have not been established, in randomized, controlled clinical trials. However, the use of Jantoven' Tablets in pediatric patients is well-documented for the prevention and treatment of thromboembolic events. Difficulty achieving and maintaining therapeutic PT/INR ranges in the pediatric patient has been reported. More frequent PT/INR determinations are recommended because of possible changing warfarin requirements.<br/>Geriatric Use: Patients 60 years or older appear to exhibit greater than expected PT/INR response to the anticoagulant effects of warfarin . Jantoven' Tablets are contraindicated in any unsupervised patient with senility. Caution should be observed with administration of warfarin sodium to elderly patients in any situation or physical condition where added risk of hemorrhage is present. Lower initiation and maintenance doses of Jantoven' Tablets are recommended for elderly patients . | lld:dailymed |
| dailymed-drugs:391 | dailymed-instance:precautio... | General: The contents of the kit before preparation are not radioactive. However, after the sodium pertechnetate Tc99m injection is added, adequate shielding of the final preparation must be maintained. Contents of the vial are intended only for use in the preparation of technetium Tc99m medronate injection and are NOT to be administered directly to the patient. Technetium Tc99m medronate injection, as well as other radioactive drugs, must be handled with care. Once sodium pertechnetate Tc99m injection is added to the vial, appropriate safety measures should be used to minimize external radiation to clinical occupational personnel. Care should also be taken to minimize radiation exposure to patients in a manner consistent with proper patient management. To minimize radiation dose to the bladder, the patient should be encouraged to drink fluids and to void immediately before the examination and as often thereafter as possible for the next 4-6 hours. Technetium Tc99m medronate injection contains no bacteriostatic preservative. The preparation should be formulated within 6 hours prior to clinical use. Optimal imaging results are obtained 1 to 4 hours after administration. Technetium Tc99m medronate injection should be discarded 6 hours after reconstitution. The solution should not be used if cloudy. Image quality may be adversely affected by patient obesity, old age, and impaired renal function. The finding of an abnormal concentration of radioactivity implies the existence of underlying pathology, but further study is required to distinguish benign from malignant lesions. The components of the kit are sterile and pyrogen-free. It is essential to follow directions carefully and to adhere to strict aseptic procedures during preparation. Technetium Tc99m labeling reactions involved depend on maintaining the stannous ion in the reduced state. Hence, sodium pertechnetate Tc99m containing oxidants should not be used. Radiopharmaceuticals should be used only by physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate government agency authorized to license the use of radionuclides.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term animal studies have been performed to evaluate carcinogenic potential, mutagenic potential, or whether technetium Tc99m medronate injection affects fertility in males or females.<br/>Pregnancy Category C: Animal reproduction studies have not been conducted with technetium Tc99m medronate injection. It is also not known whether technetium Tc99m medronate injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Technetium Tc99m medronate injection should be given to a pregnant woman only if clearly needed. Ideally, examinations using radiopharmaceuticals, especially those elective in nature, of a woman of childbearing capability, should be performed during the first few (approximately 10) days following the onset of menses.<br/>Nursing Mothers: Technetium Tc99m is excreted in human milk during lactation. Therefore, formula feedings should be substituted for breast feedings.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established. | lld:dailymed |
| dailymed-drugs:799 | dailymed-instance:precautio... | General: The contents of the kit before preparation are not radioactive. However, after the sodium pertechnetate Tc99m injection is added, adequate shielding of the final preparation must be maintained. Contents of the vial are intended only for use in the preparation of technetium Tc99m medronate injection and are NOT to be administered directly to the patient. Technetium Tc99m medronate injection, as well as other radioactive drugs, must be handled with care. Once sodium pertechnetate Tc99m injection is added to the vial, appropriate safety measures should be used to minimize external radiation to clinical occupational personnel. Care should also be taken to minimize radiation exposure to patients in a manner consistent with proper patient management. To minimize radiation dose to the bladder, the patient should be encouraged to drink fluids and to void immediately before the examination and as often thereafter as possible for the next 4-6 hours. Technetium Tc99m medronate injection contains no bacteriostatic preservative. The preparation should be formulated within 6 hours prior to clinical use. Optimal imaging results are obtained 1 to 4 hours after administration. Technetium Tc99m medronate injection should be discarded 6 hours after reconstitution. The solution should not be used if cloudy. Image quality may be adversely affected by patient obesity, old age, and impaired renal function. The finding of an abnormal concentration of radioactivity implies the existence of underlying pathology, but further study is required to distinguish benign from malignant lesions. The components of the kit are sterile and pyrogen-free. It is essential to follow directions carefully and to adhere to strict aseptic procedures during preparation. Technetium Tc99m labeling reactions involved depend on maintaining the stannous ion in the reduced state. Hence, sodium pertechnetate Tc99m containing oxidants should not be used. Radiopharmaceuticals should be used only by physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate government agency authorized to license the use of radionuclides.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term animal studies have been performed to evaluate carcinogenic potential, mutagenic potential, or whether technetium Tc99m medronate injection affects fertility in males or females.<br/>Pregnancy Category C: Animal reproduction studies have not been conducted with technetium Tc99m medronate injection. It is also not known whether technetium Tc99m medronate injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Technetium Tc99m medronate injection should be given to a pregnant woman only if clearly needed. Ideally, examinations using radiopharmaceuticals, especially those elective in nature, of a woman of childbearing capability, should be performed during the first few (approximately 10) days following the onset of menses.<br/>Nursing Mothers: Technetium Tc99m is excreted in human milk during lactation. Therefore, formula feedings should be substituted for breast feedings.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established. | lld:dailymed |
| dailymed-drugs:393 | dailymed-instance:precautio... | Diabetes: Caution should be exercised when administering triamterene/hydrochlorothiazide capsules to patients with diabetes, since thiazides may cause hyperglycemia, glycosuria and alter insulin requirements in diabetes. Also, diabetes mellitus may become manifest during thiazide administration.<br/>Impaired Hepatic Function: Thiazides should be used with caution in patients with impaired hepatic function. They can precipitate hepatic coma in patients with severe liver disease. Potassium depletion induced by the thiazide may be important in this connection. Administer triamterene/hydrochlorothiazide capsules cautiously and be alert for such early signs of impending coma as confusion, drowsiness and tremor; if mental confusion increases discontinue triamterene/hydrochlorothiazide capsules for a few days. Attention must be given to other factors that may precipitate hepatic coma, such as blood in the gastrointestinal tract or preexisting potassium depletion.<br/>Hypokalemia: Hypokalemia is uncommon with triamterene/hydrochlorothiazide capsules,but, should it develop, corrective measures should be taken such as potassium supplementation or increased intake of potassium-rich foods. Institute such measures cautiously with frequent determinations of serum potassium levels, especially in patients receiving digitalis or with a history of cardiac arrhythmias. If serious hypokalemia (serum potassium less than 3.0 mEq/L) is demonstrated by repeat serum potassium determinations, triamterene/hydrochlorothiazide capsules should be discontinued and potassium chloride supplementation initiated. Less serious hypokalemia should be evaluated with regard to other coexisting conditions and treated accordingly.<br/>Electrolyte Imbalance: Electrolyte imbalance, often encountered in such conditions as heart failure, renal disease or cirrhosis of the liver, may also be aggravated by diuretics and should be considered during triamterene/hydrochlorothiazide capsule therapy when using high doses for prolonged periods or in patients on a salt-restricted diet. Serum determinations of electrolytes should be performed, and are particularly important if the patient is vomiting excessively or receiving fluids parenterally. Possible fluid and electrolyte imbalance may be indicated by such warning signs as: dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia and gastrointestinal symptoms.<br/>Hypochloremia: Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis. Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.<br/>Renal Stones: Triamterene has been found in renal stones in association with the other usual calculus components. Triamterene/hydrochlorothiazide capsules should be used with caution in patients with a history of renal stones.<br/>Laboratory Tests:<br/>Serum Potassium:: The normal adult range of serum potassium is 3.5 to 5.0 mEq per liter with 4.5 mEq often being used for a reference point. If hypokalemia should develop, corrective measures should be taken such as potassium supplementation or increased dietary intake of potassium-rich foods. Institute such measures cautiously with frequent determinations of serum potassium levels. Potassium levels persistently above 6 mEq per liter require careful observation and treatment. Serum potassium levels do not necessarily indicate true body potassium concentration. A rise in plasma pH may cause a decrease in plasma potassium concentration and an increase in the intracellular potassium concentration. Discontinue corrective measures for hypokalemia immediately if laboratory determinations reveal an abnormal elevation of serum potassium. Discontinue triamterene/hydrochlorothiazide capsules and substitute a thiazide diuretic alone until potassium levels return to normal.<br/>Serum Creatinine and BUN:: Triamterene/hydrochlorothiazide capsules may produce an elevated blood urea nitrogen level, creatinine level or both. This apparently is secondary to a reversible reduction of glomerular filtration rate or a depletion of intravascular fluid volume (prerenal azotemia) rather than renal toxicity; levels usually return to normal when triamterene/hydrochlorothiazide capsules are discontinued. If azotemia increases, discontinue triamterene/hydrochlorothiazide capsules. Periodic BUN or serum creatinine determinations should be made, especially in elderly patients and in patients with suspected or confirmed renal insufficiency.<br/>Serum PBI:: Thiazide may decrease serum PBI levels without sign of thyroid disturbance.<br/>Parathyroid Function:: Thiazides should be discontinued before carrying out tests for parathyroid function. Calcium excretion is decreased by thiazides. Pathologic changes in the parathyroid glands with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. The common complications of hyperparathyroidism such as bone resorption and peptic ulceration have not been seen.<br/>Drug Interactions:<br/>Angiotensin-converting enzyme inhibitors:: Potassium-sparing agents should be used with caution in conjunction with angiotensin-converting enzyme (ACE) inhibitors due to an increased risk of hyperkalemia.<br/>Oral hypoglycemic drugs:: Concurrent use with chlorpropamide may increase the risk of severe hyponatremia.<br/>Nonsteroidal anti-inflammatory drugs:: A possible interaction resulting in acute renal failure has been reported in a few patients on triamterene/hydrochlorothiazide capsules when treated with indomethacin, a nonsteroidal anti-inflammatory agent. Caution is advised in administering nonsteroidal anti-inflammatory agents with triamterene/hydrochlorothiazide capsules.<br/>Lithium:: Lithium generally should not be given with diuretics because they reduce its renal clearance and increase the risk of lithium toxicity. Read circulars for lithium preparations before use of such concomitant therapy with triamterene/ hydrochlorothiazide capsules.<br/>Surgical considerations:: Thiazides have been shown to decrease arterial responsiveness to norepinephrine (an effect attributed to loss of sodium). This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Thiazides have also been shown to increase the paralyzing effect of nondepolarizing muscle relaxants such as tubocurarine (an effect attributed to potassium loss); consequently caution should be observed in patients undergoing surgery.<br/>Other Considerations:: Concurrent use of hydrochlorothiazide with amphotericin B or corticosteroids or corticotropin (ACTH) may intensify electrolyte imbalance, particularly hypokalemia, although the presence of triamterene minimizes the hypokalemic effect. Thiazides may add to or potentiate the action of other antihypertensive drugs. See INDICATIONS AND USAGE for concomitant use with other antihypertensive drugs. The effect of oral anticoagulants may be decreased when used concurrently with hydrochlorothiazide; dosage adjustment may be necessary. Triamterene/hydrochlorothiazide capsules may raise the level of blood uric acid; dosage adjustments of antigout medication may be necessary to control hyperuricemia and gout. The following agents given together with triamterene may promote serum potassium accumulation and possibly result in hyperkalemia because of the potassiumsparing nature of triamterene, especially in patients with renal insufficiency: blood from blood bank (may contain up to 30 mEq of potassium per liter of plasma or up to 65 mEq per liter of whole blood when stored for more than 10 days); lowsalt milk (may contain up to 60 mEq of potassium per liter); potassium-containing medications (such as parenteral penicillin G potassium); salt substitutes (most contain substantial amounts of potassium). Exchange resins, such as sodium polystyrene sulfonate, whether administered orally or rectally, reduce serum potassium levels by sodium replacement of the potassium; fluid retention may occur in some patients because of the increased sodium intake. Chronic or overuse of laxatives may reduce serum potassium levels by promoting excessive potassium loss from the intestinal tract; laxatives may interfere with the potassium-retaining effects of triamterene. The effectiveness of methenamine may be decreased when used concurrently with hydrochlorothiazide because of alkalinization of the urine.<br/>Drug/Laboratory Test Interactions: Triamterene and quinidine have similar fluorescence spectra; thus, triamterene/ hydrochlorothiazide capsules will interfere with the fluorescent measurement of quinidine.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis: Long-term studies have not been conducted with the triamterene/hydrochlorothiazide combination, or with triamterene alone.<br/>Mutagenesis: Studies of the mutagenic potential of the triamterene/hydrochlorothiazide combination, or of triamterene alone have not been performed.<br/>Impairment of Fertility: Studies of the effects of the triamterene/hydrochlorothiazide combination, or of triamterene alone on animal reproductive function have not been conducted.<br/>Pregnancy: Category C<br/>Teratogenic Effects:<br/>Nonteratogenic Effects: Thiazides and triamterene have been shown to cross the placental barrier and appear in cord blood. The use of thiazides and triamterene in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, pancreatitis, thrombocytopenia and possible other adverse reactions which have occurred in the adult.<br/>Nursing Mothers: Thiazides and triamterene in combination have not been studied in nursing mothers. Triamterene appears in animal milk; this may occur in humans. Thiazides are excreted in human breast milk. If use of the combination drug product is deemed essential, the patient should stop nursing.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established. | lld:dailymed |
| dailymed-drugs:394 | dailymed-instance:precautio... | General: Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of ondansetron in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distension. Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported.<br/>Drug Interactions: Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver . Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of available data, no dosage adjustment is recommended for patients on these drugs.<br/>Phenytoin, Carbamazepine, and Rifampicin:: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3<br/>Tramadol:: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5<br/>Chemotherapy:: Tumor response to chemotherapy in the P-388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate.<br/>Use in Surgical Patients: The coadministration of ondansetron had no effect on the pharmacokinetics and pharmacodynamics of temazepam.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenic effects were not seen in 2-year studies in rats and mice with oral ondansetron doses up to 10 and 30 mg/kg/day, respectively. Ondansetron was not mutagenic in standard tests for mutagenicity. Oral administration of ondansetron up to 15 mg/kg/day did not affect fertility or general reproductive performance of male and female rats.<br/>Pregnancy:<br/>Teratogenic Effects::<br/>Nursing Mothers: Ondansetron is excreted in the breast milk of rats. It is not known whether ondansetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ondansetron is administered to a nursing woman.<br/>Pediatric Use: Little information is available about dosage in pediatric patients 4 years of age or younger .<br/>Geriatric Use: Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting in US- and foreign-controlled clinical trials, for which there were subgroup analyses, 938 were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individualscannot be ruled out. Dosage adjustment is not needed in patients over the age of 65 . | lld:dailymed |
| dailymed-drugs:396 | dailymed-instance:precautio... | Hematologic Monitoring: Periodic CBC, differential, and platelet counts are advised during prolonged therapy.<br/>Information for Patients: Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with dexmethylphenidate and should counsel them in its appropriate use. A patient Medication Guide is available for Focalin XR. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.<br/>Drug Interactions: Focalin XR should not be used in patients being treated (currently or within the preceding two weeks) with MAO Inhibitors (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors). Because of possible effects on blood pressure, Focalin XR should be used cautiously with pressor agents. Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. Dexmethylphenidate is metabolized primarily to d-ritalinic acid by de-esterification and not through oxidative pathways. The effects of gastrointestinal pH alterations on the absorption of dexmethylphenidate from Focalin XR have not been studied. Since the modified release characteristics of Focalin XR are pH dependent, the coadministration of antacids or acid suppressants could alter the release of dexmethylphenidate. Human pharmacologic studies have shown that racemic methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g., imipramine, clomipramine, desipramine). Downward dose adjustments of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentration (or, in the case of coumarin, coagulation times), when initiating or discontinuing methylphenidate. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally-acting alpha-2-agonists has not been systematically evaluated.<br/>Carcinogenesis, Mutagenesis, and Impairment of Fertility: Lifetime carcinogenicity studies have not been carried out with dexmethylphenidate. In a lifetime carcinogenicity study carried out in B6C3F1 mice, racemic methylphenidate caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Racemic methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day. In a 24-week study of racemic methylphenidate in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Mice were fed diets containing the same concentrations as in the lifetime carcinogenicity study; the high-dose group was exposed to 60-74 mg/kg/day of racemic methylphenidate. Dexmethylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, the in vitro mouse lymphoma cell forward mutation assay, or the in vivo mouse bone marrow micronucleus test. Racemic methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or the in vitro mouse lymphoma cell forward mutation assay, and was negative in vivo in the mouse bone marrow micronucleus assay. However, sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay of racemic methylphenidate in cultured Chinese Hamster Ovary (CHO) cells. Racemic methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses of up to 160 mg/kg/day.<br/>Pregnancy:<br/>Pregnancy Category C: In studies conducted in rats and rabbits, dexmethylphenidate was administered orally at doses of up to 20 and 100 mg/kg/day, respectively, during the period of organogenesis. No evidence of teratogenic activity was found in either the rat or rabbit study; however, delayed fetal skeletal ossification was observed at the highest dose level in rats. When dexmethylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 20 mg/kg/day, postweaning body weight gain was decreased in male offspring atthe highest dose, but no other effects on postnatal development were observed. At the highest doses tested, plasma levels (AUCs) of dexmethylphenidate in pregnant rats and rabbits were approximately 5 and 1 times, respectively, those in adults dosed with 20 mg/day. Racemic methylphenidate has been shown to have teratogenic effects in rabbits when given in doses of 200 mg/kg/day throughout organogenesis. Adequate and well-controlled studies in pregnant women have not been conducted. Focalin XR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: It is not known whether dexmethylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Focalin XR is administered to a nursing woman.<br/>Pediatric Use: The safety and efficacy of Focalin XR in children under 6 years old have not been established. Long-term effects of Focalin in children have not been well established (see WARNINGS). In a study conducted in young rats, racemic methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] of racemic methylphenidate on a mg/mbasis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (12 times the racemic MRHD on a mg/mbasis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the racemic MRHD on a mg/mbasis). The clinical significance of the long-term behavioral effects observed in rats is unknown. | lld:dailymed |
| dailymed-drugs:397 | dailymed-instance:precautio... | General:<br/>Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Patients with impaired renal function may be more sensitive to the glucose-lowering effect of glimepiride. A starting dose of 1 mg once daily followed by appropriate dose titration is recommended in those patients. Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs.Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used. Combined use of glimepiride with insulin or metformin may increase the potential for hypoglycemia.<br/>Loss of Control of Blood Glucose: When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of control may occur. At such times, it may be necessary to add insulin in combination with glimepiride or even use insulin monotherapy. The effectiveness of any oral hypoglycemic drug, including glimepiride, in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when first given. Should secondary failure occur with glimepiride or metformin monotherapy, combined therapy with glimepiride and metformin or glimepiride and insulin may result in a response. Should secondary failure occur with combined glimepiride/metformin therapy, it may be necessary to initiate insulin therapy.<br/>Information for Patients: Patients should be informed of the potential risks and advantages of glimepiride and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose. The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. The potential for primary and secondary failure should also be explained.<br/>Laboratory Tests: Fasting blood glucose should be monitored periodically to determine therapeutic response. Glycosylated hemoglobin should also be monitored, usually every 3 to 6 months, to more precisely assess long-term glycemic control.<br/>Drug Interactions: (See CLINICAL PHARMACOLOGY, Drug Interactions.)<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies in rats at doses of up to 5000 ppm in complete feed (approximately 340 times the maximum recommended human dose, based on surface area) for 30 months showed no evidence of carcinogenesis. In mice, administration of glimepiride for 24 months resulted in an increase in benign pancreatic adenoma formation which was dose related and is thought to be the result of chronic pancreatic stimulation. The no-effect dose for adenoma formation in mice in this study was 320 ppm in complete feed, or 46 to 54 mg/kg body weight/day. This is about 35 times the maximum human recommended dose of 8 mg once daily based on surface area. Glimepiride was non-mutagenic in a battery of in vitro and in vivo mutagenicity studies (Ames test, somatic cell mutation, chromosomal aberration, unscheduled DNA synthesis, mouse micronucleus test). There was no effect of glimepiride on male mouse fertility in animals exposed up to 2500 mg/kg body weight (>1,700 times the maximum recommended human dose based on surface area). Glimepiride had no effect on the fertility of male and female rats administered up to 4000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area).<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nonteratogenic Effects: In some studies in rats, offspring of dams exposed to high levels of glimepiride during pregnancy and lactation developed skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. Significant concentrations of glimepiride were observed in the serum and breast milk of the dams as well as in the serum of the pups. These skeletal deformations were determined to be the result of nursing from mothers exposed to glimepiride. Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. Patients who are planning a pregnancy should consult their physician, and it is recommended that they change over to insulin for the entire course ofpregnancy and lactation.<br/>Nursing Mothers: In rat reproduction studies, significant concentrations of glimepiride were observed in the serum and breast milk of the dams, as well as in the serum of the pups. Although it is not known whether glimepiride is excreted in human milk, other sulfonylureas are excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, and because of the effects on nursing animals, glimepiride should be discontinued in nursing mothers. If glimepiride is discontinued, and if diet and exercise alone are inadequate for controlling blood glucose, insulin therapy should be considered. (See above Pregnancy, Nonteratogenic Effects.)<br/>Pediatric Use: The safety and efficacy of glimepiride were evaluated in an active-controlled, single-blind (patients only), 24 week trial involving 272 pediatric patients, ranging from 8 to 17 years of age, with Type 2 diabetes. Glimepiride (n = 135) was administered at 1 mg initially, and then titrated up to 2, 4 or 8 mg (mean last dose 4 mg) until the therapeutic goal of self-monitored fasting blood glucose<7.0 mmol/L (<126 mg/dL) was achieved. The active comparator metformin (n = 137) was administered at 500 mg twice daily initially and titrated up to 1000 mg twice daily (mean last dose 1469 mg). The profile of adverse reactions in pediatric patients treated with glimepiride was similar to that observed in adults. Hypoglycemic events, as documented by blood glucose values<36 mg/dL, were observed in 4% of patients treated with glimepiride and in 1% of patients treated with metformin.<br/>Geriatric Use: In U.S. clinical studies of glimepiride, 608 of 1986 patients were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. Comparison of glimepiride pharmacokinetics in Type 2 diabetic patients���65 years (n = 49) and those>65 years (n = 42) was performed in a study using a dosing regimen of 6 mg daily. There were no significant differences in glimepiride pharmacokinetics between the two age groups (see CLINICAL PHARMACOLOGY, Special Populations, Geriatric). The drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Elderly patients are particularly susceptible to hypoglycemic action of glucose-lowering drugs. In elderly, debilitated, or malnourished patients, or in patients with renal and hepatic insufficiency, the initial dosing, dose increments, and maintenance dosage should be conservative based upon blood glucose levels prior to and after initiation of treatment to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents (see CLINICAL PHARMACOLOGY, Special Populations, Renal Insufficiency; PRECAUTIONS, General; and DOSAGE AND ADMINISTRATION, Special Patient Population). | lld:dailymed |
| dailymed-drugs:401 | dailymed-instance:precautio... | General:: BETAGAN (levobunolol hydrochloride ophthalmic solution, USP) sterile should be used with caution in patients with known hypersensitivity to other beta-adrenoceptor blocking agents. Use with caution in patients with known diminished pulmonary function. BETAGAN should be used with caution in patients who are receiving a beta-adrenergic blocking agent orally, because of the potential for additive effects on systemic beta-blockade or on intraocular pressure. Patients should not typically use two or more topical ophthalmic beta-adrenergic blocking agents simultaneously. Because of the potential effects of beta-adrenergic blocking agents on blood pressure and pulse rates, these medications must be used cautiously in patients with cerebrovascular insufficiency. Should signs or symptoms develop that suggest reduced cerebral blood flow while using BETAGAN ophthalmic solution, alternative therapy should be considered. In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires, in most cases, constricting the pupil with a miotic. BETAGAN ophthalmic solution has little or no effect on the pupil. When BETAGAN is used to reduce elevated intraocular pressure in angle-closure glaucoma, it should be followed with a miotic and not alone.<br/>Muscle Weakness:: Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis and generalized weakness).<br/>Drug Interactions:: Although BETAGAN ophthalmic solution used alone has little or no effect on pupil size, mydriasis resulting from concomitant therapy with BETAGAN and epinephrine may occur. Close observation of the patient is recommended when a beta-blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may produce vertigo, syncope, or postural hypotension. Patients receiving beta-adrenergic blocking agents along with either oral or intravenous calcium antagonists should be monitored for possible atrioventricular conduction disturbances, left ventricular failure and hypotension. In patients with impaired cardiac function, simultaneous use should be avoided altogether. The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects on prolonging atrioventricular conduction time. Phenothiazine-related compounds and beta-adrenergic blocking agents may have additive hypotensive effects due to the inhibition of each other's metabolism.<br/>Risk of anaphylactic reaction:: While taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.<br/>Animal Studies:: No adverse ocular effects were observed in rabbits administered BETAGAN ophthalmic solution topically in studies lasting one year in concentrations up to 10 times the human dose concentration.<br/>Carcinogenesis, mutagenesis, impairment of fertility:: In a lifetime oral study in mice, there were statistically significant (p0.05) increases in the incidence of benign leiomyomas in female mice at 200 mg/kg/day (14,000 times the recommended human dose for glaucoma), but not at 12 or 50 mg /kg/day (850 and 3,500 times the human dose). In a two year oral study of levobunolol HCl in rats, there was a statistically significant (p0.05) increase in the incidence of benign hepatomas in male rats administered 12,800 times the recommended human dose for glaucoma. Similar differences were not observed in rats administered oral doses equivalent to 350 times to 2,000 times the recommended human dose for glaucoma. Levobunolol did not show evidence of mutagenic activity in a battery of microbiological and mammalian in vitro and in vivo assays. Reproduction and fertility studies in rats showed no adverse effect on male or female fertility at doses up to 1,800 times the recommended human dose for glaucoma.<br/>Pregnancy:: Pregnancy Category C: Fetotoxicity (as evidenced by a greater number of resorption sites) has been observed in rabbits when doses of levobunolol HCl equivalent to 200 and 700 times the recommended dose for the treatment of glaucoma were given. No fetotoxic effects have been observed in similar studies with rats at up to 1,800 times the human dose for glaucoma. Teratogenic studies with levobunolol in rats at doses up to 25 mg/kg/day (1,800 times the recommended human dose for glaucoma) showed no evidence of fetal malformations. There were no adverse effects on postnatal development of offspring. It appears when results from studies using rats and studies with other beta-adrenergic blockers are examined, that the rabbit may be a particularly sensitive species. There are no adequate and well-controlled studies in pregnant women. BETAGAN ophthalmic solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers:: It is not known whether this drug is excreted in human milk. Systemic beta-blockers and topical timolol maleate are known to be excreted in human milk. Caution should be exercised when BETAGAN is administered to a nursing woman.<br/>Pediatric Use:: Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric Use:: No overall differences in safety or effectiveness have been observed between elderly and younger patients. | lld:dailymed |
| dailymed-drugs:402 | dailymed-instance:precautio... | General: Tretinoin Cream, USP (Emollient) should only be used as an adjunct to a comprehensive skin care and sunlight avoidance program. If a drug sensitivity, chemical irritation, or a systemic adverse reaction develops, use of Tretinoin Cream, USP (Emollient) should be discontinued. Weather extremes, such as wind or cold, may be more irritating to patients using tretinoin-containing products.<br/>Information for Patients: Tretinoin Cream, USP (Emollient) 0.05% is to be used as described below unless otherwise directed by your physician: Please refer to the Patient Package Insert for additional patient information.<br/>Drug Interactions: Concomitant topical medications, medicated or abrasive soaps, shampoos, cleansers, cosmetics with a strong drying effect, products with high concentrations of alcohol, astringents, spices or lime, permanent wave solutions, electrolysis, hair depilatories or waxes, and products that may irritate the skin should be used with caution in patients being treated with Tretinoin Cream, USP (Emollient) because they may increase irritation with Tretinoin Cream, USP (Emollient). Tretinoin Cream, USP (Emollient) should not be administered if the patient is also taking drugs known to be photosensitizers (e.g., thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) because of the possibility of augmented phototoxicity.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas were observed in some female mice. These concentrations are lower than the concentration of tretinoin in this clinical formulation (0.05%). A dose-related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the 0.017% and 0.035% formulations are 0.5 and 1.0 mg/kg/day. These doses are 4 and 8 times the maximum human systemic dose, when adjusted for total body surface area. The biological significance of the neoplastic findings is not clear because they occurred at doses that exceeded the maximally tolerated dermal dose of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (1/5th of times the maximum human systemic dose, adjusted for total body surface area). For purposes of comparisons of the systemic animal exposure to the systemic human exposure, the maximum human systemic dose is 1 gram of Tretinoin Cream, USP (Emollient) 0.05% applied daily to a 50 kg person (0.01 mg tretinoin/kg body weight,or 0.37 mg/mtotal body surface area). Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies in humans is not clear, patients should minimizeexposure to sunlight or artificial ultraviolet irradiation sources. The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative. In dermal Segment I fertility studies in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (8 times the maximum human systemic dose adjusted for total body surface area), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day (4 times the maximum human systemic dose adjusted for total body surface area) and above were observed. A dermal Segment III study with Tretinoin Cream, USP (Emollient) has not been performed in any species. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (>33 times the maximum human systemic dose adjusted for total body surface area).<br/>Pregnancy:<br/>Teratogenic effects: Pregnancy Category C.: ORAL tretinoin has been shown to be teratogenic in rats, mice, rabbits, hamsters, and subhuman primates. It was teratogenic and fetotoxic in Wistar rats when given orally or topically in doses greater than 1 mg/kg/day (17 times the maximum human systemic dose normalized for total body surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which, metabolically, is closer to humans for tretinoin than the other species examined, fetal malformations were reported at doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (167 times the maximum human systemic dose adjusted for total body surface area), although increased skeletal variations were observed at all doses. A dose-related increase in embryolethality and abortion was reported. Similar results have also been reported in pigtail macaques. TOPICAL tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (17 times the maximum human systemic dose adjusted for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when10 mg/kg/day was dermally applied. There are other reports in New Zealand White rabbits administered doses of greater than 0.2 mg/kg/day (7 times the maximum human systemic dose adjusted for total body surface area) of an increased incidence of domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species. In contrast, several well-controlled animal studies have shown that dermally applied tretinoin may be fetotoxic, but not overtly teratogenic, in rats and rabbits at doses of 1.0 and 0.5 mg/kg/day, respectively (17 times the maximum human systemic dose adjusted for total body surface area in both species). With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty human cases of temporally-associated congenital malformations have been reported during twenty-five years of clinical use of another formulation of topical tretinoin (Retin-A). Although no definite pattern of teratogenicity and no causal association has been established from these cases, 5 of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known.<br/>Non-teratogenic effects: Dermal tretinoin has been shown to be fetotoxic in rabbits when administered 0.5 mg/kg/day (17 times the human topical dose normalized for total body surface area). Oral tretinoin has been shown to be fetotoxic, resulting in skeletal variations and increased intrauterine death, in rats when administered 2.5 mg/kg/day (42 times the maximum human systemic dose adjusted for total body surface area). There are, however, no adequate and well-controlled studies in pregnant women. Tretinoin Cream, USP (Emollient) should not be used during pregnancy.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Since many drugs are excreted in human milk, mitigation of fine wrinkles, mottled hyperpigmentation, and tactile roughness on the face with Tretinoin Cream, USP (Emollient) may be postponed in nursing mothers until after completion of the nursing period.<br/>Pediatric Use: Safety and effectiveness in patients less than 18 years of age have not been established.<br/>Geriatric Use: Clinical studies of Tretinoin Cream, USP (Emollient) 0.05% did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. | lld:dailymed |
| dailymed-drugs:403 | dailymed-instance:precautio... | General: Pseudotumor cerebri (benign intracranial hypertension) in adults has been associated with the use of tetracyclines. The usual clinical manifestations are headache and blurred vision. Bulging fontanels have been associated with the use of tetracyclines in infants. While both of these conditions and related symptoms usually resolve soon after discontinuation of the tetracycline, the possibility for permanent sequelae exists. As with other antibiotic preparations, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, the antibiotic should be discontinued and appropriate therapy should be instituted. Incision and drainage or other surgical procedures should be performed in conjunction with antibiotic therapy, when indicated. Prescribing demeclocycline hydrochloride tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.<br/>Information for Patients: Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. (See Drug Interactions.) Patients should be informed that demeclocycline hydrochloride tablets should be taken at least 1 hour before meals or 2 hours after meals. Unused supplies of tetracycline antibiotics should be discarded by the expiration date. Patients who are experiencing headache, dizziness, light-headedness, vertigo, or blurred vision while on demeclocycline therapy, should be cautioned about driving vehicles or using hazardous machinery while receiving demeclocycline therapy. Patients should be counseled that antibacterial drugs including demeclocycline hydrochloride tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When demeclocycline hydrochloride tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by demeclocycline hydrochloride tablets or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.<br/>Laboratory Tests: In venereal diseases when coexistent syphilis is suspected, darkfield examination should be done before treatment is started and the blood serology repeated monthly for at least 4 months. In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal and hepatic, should be performed. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with demeclocycline hydrochloride should have a follow-up serologic test for syphilis after 3 months.<br/>Drug Interactions: Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillins, it is advisable to avoid giving tetracycline-class drugs in conjunction with penicillin. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. The concurrent use of tetracyclines and methoxyflurane has been reported to result in fatal renal toxicity. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium, and by iron-containing preparations.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals to evaluate carcinogenic potential of demeclocycline hydrochloride have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibiotics oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors). Although mutagenicity studies of demeclocycline hydrochloride have not been conducted, positive results in in vitro mammalian cell assays (i.e., mouse lymphoma and Chinese hamster lung cells) have been reported for related antibiotics (tetracycline hydrochloride and oxytetracycline). Demeclocycline hydrochloride had no effect on fertility when administered in the diet to male and female rats at a daily intake of 45 times the human dose.<br/>Pregnancy: Teratogenic effects. Pregnancy Category D. Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity has been noted in animals treated early in pregnancy. Nonteratogenic effects.<br/>Labor and Delivery: The effect of tetracyclines on labor and delivery is unknown.<br/>Nursing Mothers: Tetracyclines are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from the tetracyclines, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.<br/>Pediatric Use: Not for use in patients younger than eight years of age. See WARNINGS, PRECAUTIONS (General subsection) and DOSAGE AND ADMINISTRATION. | lld:dailymed |
| dailymed-drugs:404 | dailymed-instance:precautio... | Renal Impairment: Sotalol hydrochloride is eliminated principally via the kidneys through glomerular filtration and to a small degree by tubular secretion. There is a direct relationship between renal function, as measured by serum creatinine or creatinine clearance, and the elimination rate of sotalol hydrochloride. Guidance for dosing in conditions of renal impairment can be found under "DOSAGE ANDADMINISTRATION."<br/>Information for Patients: Please refer to the patient package insert. Prior to initiation of sotalol hydrochloride tablets (AF) therapy, the patient should be advised to read the patient package insert and reread it each time therapy is renewed. The patient should be fully instructed on the need for compliance with the recommended dosing of sotalol hydrochloride tablets (AF), the potential interactions with drugs that prolong the QT interval and other antiarrhythmics, and the need for periodic monitoring of QT and renal function to minimize the risk of serious abnormal rhythms.<br/>Medications and Supplements:: Assessment of patients' medication history should include all over-counter, prescription and herbal/natural preparations with emphasis on preparations that may affect the pharmacodynamics of sotalol such as other cardiac antiarrhythmic drugs, some phenothiazines, bepridil, tricyclic antidepressants and oral macrolides (see WARNINGS and Use with Drugs that Prolong QT Interval and Antiarrhythmic Agents ). Patients should be instructed to notify their health care providers of any change in over-the-counter, prescription or supplement use. If a patient is hospitalized or is prescribed a new medication for any condition, the patient must inform thehealth care provider of ongoing sotalol hydrochloride tablets (AF) therapy. Patients should also check with their health care provider and/or pharmacist prior to taking a new over-the-counter medicine.<br/>Electrolyte Imbalance:: If patients experience symptoms that may be associated with altered electrolyte balance, such as excessive or prolonged diarrhea, sweating, or vomiting, or loss of appetite or thirst, these conditions should be immediately reported to their health care provider.<br/>Dosing Schedule:: Patients should be instructed NOT to double the next dose if a dose is missed. The next dose should be taken at the usual time. | lld:dailymed |
| dailymed-drugs:406 | dailymed-instance:precautio... | General:<br/>Hepatic Effects: Ketorolac tromethamine should be used with caution in patients with impaired hepatic function or a history of liver disease. Treatment with ketorolac tromethamine may cause elevations of liver enzymes, and, in patients with pre-existing liver dysfunction, it may lead to the development of a more severe hepatic reaction. The administration of ketorolac tromethamine should be discontinued in patients in whom an abnormal liver test has occurred as a result of ketorolac tromethamine therapy.<br/>Hematologic Effects: Ketorolac tromethamine inhibits platelet aggregation and may prolong bleeding time; therefore, it is contraindicated as a preoperative medication, and caution should be used when hemostasis is critical. Unlike aspirin, the inhibition of platelet function by ketorolac tromethamine disappears within 24 to 48 hours after the drug is discontinued. Ketorolac tromethamine does not appear to affect platelet count, prothrombin time (PT) or partial thromboplastin time (PTT). In controlled clinical studies, where ketorolac tromethamine was administered intramuscularly or intravenously postoperatively, the incidence of clinically significant postoperative bleeding was 0.4% for ketorolac tromethamine compared to 0.2% in the control groups receiving narcotic analgesics.<br/>Information for Patients: Ketorolac tromethamine is a potent NSAID and may cause serious side effects such as gastrointestinal bleeding or kidney failure, which may result in hospitalization and even fatal outcome. Physicians, when prescribing ketorolac tromethamine, should inform their patients or their guardians of the potential risks of ketorolac tromethamine treatment (see Boxed WARNING, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS sections). Advise patients not to give ketorolac tromethamine tablets to other family members and to discard any unused drug. Remember that the total duration of ketorolac tromethamine therapy is not to exceed five (5) days in adults or a single dose in pediatric patients ages 2 to 16 years.<br/>Drug Interactions: Ketorolac is highly bound to human plasma protein (mean 99.2%).<br/>Warfarin, Digoxin, Salicylate, and Heparin: Thein vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac tromethamine (99.5% control vs. 99.3%) when ketorolac plasma concentrations reach 5 to 10 mcg/mL. Ketorolac does not alter digoxin protein binding. In vitrostudies indicate that, at therapeutic concentrations of salicylate (300 mcg/mL), the binding of ketorolac was reduced from approximately 99.2% to 97.5%, representing a potential two-fold increase in unbound ketorolac plasma levels. Therapeutic concentrations ofdigoxin,warfarin, ibuprofen, naproxen,piroxicam, acetaminophen, phenytoin andtolbutamide did not alter ketorolac tromethamine protein binding. In a study involving 12 adult volunteers, ketorolac tromethamine tablets were coadministered with a single dose of 25 mg warfarin, causing no significant changes in pharmacokinetics or pharmacodynamics of warfarin. In another study, Ketorolac Tromethamine Injection was given with two doses of 5000 U of heparin to 11 healthy volunteers, resulting in a mean template bleeding time of 6.4 minutes (3.2 to 11.4 min) compared to a mean of 6.0 minutes (3.4 to 7.5 min) for heparin alone and 5.1 minutes (3.5 to 8.5 min) for placebo. Although these results do not indicate a significant interaction between ketorolac tromethamine and warfarin or heparin, the administration of ketorolac tromethamine to patients taking anticoagulants should be done extremely cautiously, and patients should be closely monitored .<br/>Furosemide: Ketorolac Tromethamine Injection reduced the diuretic response to furosemide in normovolemic healthy subjects by approximately 20% (mean sodium and urinary output decreased 17%).<br/>Probenecid: Concomitant administration of ketorolac tromethamine tablets and probenecid resulted in decreased clearance of ketorolac and significant increases in ketorolac plasma levels (total AUC increased approximately three-fold from 5.4 to 17.8 mcg/h/mL) and terminal half-life increased approximately two-fold from 6.6 to 15.1 hours. Therefore, concomitant use of ketorolac tromethamine and probenecid is contraindicated.<br/>Lithium: Inhibition of renal lithium clearance, leading to an increase in plasma lithium concentration, has been reported with some prostaglandin synthesis-inhibiting drugs. The effect of ketorolac tromethamine on plasma lithium has not been studied, but cases of increased lithium plasma levels during ketorolac tromethamine therapy have been reported.<br/>Methotrexate: Concomitant administration of methotrexate and some NSAIDs has been reported to reduce the clearance of methotrexate, enhancing the toxicity of methotrexate. The effect of ketorolac tromethamine on methotrexate clearance has not been studied.<br/>Nondepolarizing Muscle Relaxants: In postmarketing experience there have been reports of a possible interaction between Ketorolac Tromethamine Injection and nondepolarizing muscle relaxants that resulted in apnea. The concurrent use of ketorolac tromethamine with muscle relaxants has not been formally studied.<br/>ACE Inhibitors: Concomitant use of ACE inhibitors may increase the risk of renal impairment, particularly in volume-depleted patients.<br/>Antiepileptic Drugs: Sporadic cases of seizures have been reported during concomitant use of ketorolac tromethamine and antiepileptic drugs (phenytoin, carbamazepine).<br/>Psychoactive Drugs: Hallucinations have been reported when ketorolac tromethamine was used in patients taking psychoactive drugs (fluoxetine, thiothixene, alprazolam).<br/>Morphine: Ketorolac Tromethamine Injection has been administered concurrently with morphine in several clinical trials of postoperative pain without evidence of adverse interactions. Do not mix ketorolac tromethamine and morphine in the same syringe. There is no evidence in animal or human studies that ketorolac tromethamine induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs.<br/>Carcinogenesis and Mutagenesis and Impairment of Fertility: An 18-month study in mice with oral doses of ketorolac tromethamine at 2 mg/kg/day (0.9 times the human systemic exposure at the recommended IM or IV dose of 30 mg qid, based on area-under-the-plasma-concentration curve [AUC]), and a 24-month study in rats at 5 mg/kg/day (0.5 times the human AUC) showed no evidence of tumorigenicity. Ketorolac tromethamine was not mutagenic in the Ames test, unscheduled DNA synthesis and repair, and in forward mutation assays. Ketorolac tromethamine did not cause chromosome breakage in the in vivo mouse micronucleus assay. At 1590 mcg/mL and at higher concentrations, ketorolac tromethamine increased the incidence of chromosomal aberrations in Chinese hamster ovarian cells. Impairment of fertility did not occur in male or female rats at oral doses of 9 mg/kg (0.9 times the human AUC) and 16 mg/kg (1.6 times the human AUC) of ketorolac tromethamine, respectively.<br/>Pregnancy:<br/>Pregnancy Category C: Reproduction studies have been performed during organogenesis using daily oral doses of ketorolac tromethamine at 3.6 mg/kg (0.37 times the human AUC) in rabbits and at 10 mg/kg (1.0 times the human AUC) in rats. Results of these studies did not reveal evidence of teratogenicity to the fetus. Oral doses of ketorolac tromethamine at 1.5 mg/kg (0.14 times the human AUC), administered after gestation day 17, caused dystocia and higher pup mortality in rats. There are no adequate and well-controlled studies of ketorolac tromethamine in pregnant women. Ketorolac tromethamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Labor and Delivery: The use of ketorolac tromethamine is contraindicated in labor and delivery because, through its prostaglandin synthesis inhibitory effect, it may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage .<br/>Lactation and Nursing: After a single administration of 10 mg of ketorolac tromethamine tablets to humans, the maximum milk concentration observed was 7.3 ng/mL, and the maximum milk-to-plasma ratio was 0.037. After 1 day of dosing (qid), the maximum milk concentration was 7.9 ng/mL, and the maximum milk-to-plasma ratio was 0.025. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers is CONTRAINDICATED.<br/>Pediatric Use: The safety and effectiveness of single doses of Ketorolac Tromethamine Injection have been established in pediatric patients between the ages of 2 and 16 years. Ketorolac Tromethamine Injection has been shown to be effective in the management of moderately severe acute pain that requires analgesia at the opioid level, usually in a postoperative setting. Safety and efficacy in pediatric patients below the age of 2 have not been established. Therefore, Ketorolac Tromethamine Injection is not recommended in pediatric patients below the age of 2. The risk of bleeding was greater in those patients administered Ketorolac Tromethamine Injection following tonsillectomy. Physicians should consider the increased risk of bleeding before deciding to administer Ketorolac Tromethamine Injection in patients following tonsillectomy (see WARNINGS, Hemorrhage and Pediatrics and Tonsillectomy). The risks identified in the adult population with Ketorolac Tromethamine Injection use also apply to pediatric patients. Therefore, consult the CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS sections when prescribing Ketorolac Tromethamine Injection to pediatric patients.<br/>Geriatric Use (���65 Years Of Age): Because ketorolac tromethamine may be cleared more slowly by the elderly (see CLINICAL PHARMACOLOGY) who are also more sensitive to the adverse effects of NSAIDs (see WARNINGS, Renal Effects), extra caution and reduced dosages (see DOSAGE AND ADMINISTRATION) must be used when treating the elderly with Ketorolac Tromethamine Injection. The lower end of the Ketorolac Tromethamine Injection dosage range is recommended for patients over 65 years of age, and total daily dose is not to exceed 60 mg. The incidence and severity of gastrointestinal complications increases with increasing dose of, and duration of treatment with, ketorolac tromethamine. | lld:dailymed |
| dailymed-drugs:408 | dailymed-instance:precautio... | If a reaction suggesting sensitivity or chemical irritation should occur with the use of ciclopirox olamine cream, USP, treatment should be discontinued and appropriate therapy instituted.<br/>Information for Patients: The patient should be told to:<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: A carcinogenicity study in female mice dosed cutaneously twice per week for 50 weeks followed by a 6-month drug-free observation period prior to necropsy revealed no evidence of tumors at the application site. The following in vitro and in vivo genotoxicity tests have been conducted with ciclopirox olamine: studies to evaluate gene mutation in the Ames Salmonella/Mammalian Microsome Assay (negative) and Yeast Saccharomyces Cerevisiae Assay (negative) and studies to evaluate chromosome aberrations in vivo in the Mouse Dominant Lethal Assay and in the Mouse Micronucleus Assay at 500 mg/kg (negative). The following battery of in vitro genotoxicity tests were conducted with ciclopirox: a chromosome aberration assay in V79 Chinese Hamster Cells, with and without metabolic activation (positive); a gene mutation assay in the HGPRT - test with V79 Chinese Hamster Cells (negative); and a primary DNA damage assay (i.e., unscheduled DNA Synthesis Assay in A549 Human Cells (negative)). An in vitro Cell Transformation Assay in BALB/C3T3 Cells was negative for cell transformation. In an in vivo Chinese Hamster Bone Marrow Cyctogenetic Assay, ciclopirox was negative for chromosome aberrations at 5000 mg/kg.<br/>Pregnancy Category B: Reproduction studies have been performed in the mouse, rat, rabbit, and monkey (via various routes of administration) at doses 10 times or more the topical human dose and have revealed no significant evidence of impaired fertility or harm to the fetus due to ciclopirox. There are, however, no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy onlyif clearly needed.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ciclopirox olamine cream, USP is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in pediatric patients below the age of 10 years have not been established. | lld:dailymed |