Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/dailymed/precaution
| Subject | Object |
|---|---|
| dailymed-drugs:1 |
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.
|
| dailymed-drugs:2 |
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.
|
| dailymed-drugs:3 |
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.
|
| dailymed-drugs:4 |
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.
|
| dailymed-drugs:5 |
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.
|
| dailymed-drugs:6 |
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.
|
| dailymed-drugs:7 |
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.
|
| dailymed-drugs:8 |
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.
|
| dailymed-drugs:10 |
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.
|
| dailymed-drugs:11 |
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.
|
| dailymed-drugs:12 |
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).
|
| dailymed-drugs:14 |
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.
|
| dailymed-drugs:15 |
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.
|
| dailymed-drugs:16 |
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.
|
| dailymed-drugs:17 |
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 .
|
| dailymed-drugs:18 |
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.
|
| dailymed-drugs:19 |
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.
|
| dailymed-drugs:20 |
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.
|
| dailymed-drugs:21 |
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.
|
| dailymed-drugs:22 |
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.
|
| dailymed-drugs:23 |
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.
|
| dailymed-drugs:24 |
Should a reaction of hypersensitivity occur the drug should be immediately withdrawn and appropriate measures taken. This preparation is not for ophthalmic use.
|
| dailymed-drugs:2598 |
Should a reaction of hypersensitivity occur the drug should be immediately withdrawn and appropriate measures taken. This preparation is not for ophthalmic use.
|
| dailymed-drugs:25 |
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 .
|
| dailymed-drugs:27 |
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 .
|
| dailymed-drugs:28 |
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.
|
| dailymed-drugs:29 |
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.
|
| dailymed-drugs:2140 |
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.
|
| dailymed-drugs:30 |
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 .
|
| dailymed-drugs:31 |
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.
|
| dailymed-drugs:32 |
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.
|
| dailymed-drugs:33 |
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.
|
| dailymed-drugs:3629 |
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.
|
| dailymed-drugs:34 |
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:
|
| dailymed-drugs:35 |
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).
|
| dailymed-drugs:36 |
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.
|
| dailymed-drugs:37 |
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 .
|
| dailymed-drugs:38 |
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.
|
| dailymed-drugs:39 |
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.
|
| dailymed-drugs:41 |
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.
|
| dailymed-drugs:42 |
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.
|
| dailymed-drugs:43 |
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.)
|
| dailymed-drugs:46 |
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.
|
| dailymed-drugs:47 |
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.
|
| dailymed-drugs:48 |
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).
|
| dailymed-drugs:49 |
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.
|
| dailymed-drugs:52 |
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.
|
| dailymed-drugs:54 |
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. .
|
| dailymed-drugs:55 |
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 .
|
| dailymed-drugs:58 |
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).
|
| dailymed-drugs:59 |
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.
|
| dailymed-drugs:60 |
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.
|
| dailymed-drugs:61 |
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).
|
| dailymed-drugs:63 |
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).
|
| dailymed-drugs:64 |
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).
|
| dailymed-drugs:65 |
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.
|
| dailymed-drugs:66 |
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.
|
| dailymed-drugs:67 |
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.
|
| dailymed-drugs:70 |
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.
|
| dailymed-drugs:71 |
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 .
|
| dailymed-drugs:72 |
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.
|
| dailymed-drugs:73 |
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.
|
| dailymed-drugs:75 |
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.
|
| dailymed-drugs:76 |
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.
|
| dailymed-drugs:77 |
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.
|
| dailymed-drugs:78 |
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.
|
| dailymed-drugs:79 |
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 .
|
| dailymed-drugs:80 |
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.
|
| dailymed-drugs:81 |
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.
|
| dailymed-drugs:83 |
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.
|
| dailymed-drugs:87 |
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.
|
| dailymed-drugs:88 |
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.
|
| dailymed-drugs:89 |
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.
|
| dailymed-drugs:91 |
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 .
|
| dailymed-drugs:92 |
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.
|
| dailymed-drugs:93 |
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.
|
| dailymed-drugs:94 |
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).
|
| dailymed-drugs:95 |
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.
|
| dailymed-drugs:96 |
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.
|
| dailymed-drugs:97 |
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.
|
| dailymed-drugs:100 |
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).
|
| dailymed-drugs:101 |
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.
|
| dailymed-drugs:102 |
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.
|
| dailymed-drugs:104 |
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 .
|
| dailymed-drugs:105 |
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.
|
| dailymed-drugs:106 |
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.
|
| dailymed-drugs:108 |
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.
|
| dailymed-drugs:109 |
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.
|
| dailymed-drugs:110 |
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).
|
| dailymed-drugs:111 |
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.
|
| dailymed-drugs:112 |
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.
|
| dailymed-drugs:113 |
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).
|
| dailymed-drugs:115 |
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.
|
| dailymed-drugs:116 |
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.
|
| dailymed-drugs:118 |
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).
|
| dailymed-drugs:120 |
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).
|
| dailymed-drugs:122 |
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.
|
| dailymed-drugs:123 |
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 .
|
| dailymed-drugs:125 |
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 .
|
| dailymed-drugs:126 |
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.
|
| dailymed-drugs:128 |
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 .
|
| dailymed-drugs:129 |
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.
|
| dailymed-drugs:131 |
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.
|
| dailymed-drugs:132 |
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.
|
| dailymed-drugs:134 |
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).
|
| dailymed-drugs:135 |
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.
|
| dailymed-drugs:136 |
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 .
|
| dailymed-drugs:137 |
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).
|
| dailymed-drugs:139 |
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.
|
| dailymed-drugs:141 |
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.
|
| dailymed-drugs:142 |
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.
|
| dailymed-drugs:144 |
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.
|
| dailymed-drugs:145 |
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.
|
| dailymed-drugs:148 |
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).
|
| dailymed-drugs:150 |
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.
|
| dailymed-drugs:153 |
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.
|
| dailymed-drugs:154 |
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.
|
| dailymed-drugs:155 |
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).
|
| dailymed-drugs:158 |
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.
|
| dailymed-drugs:159 |
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.
|
| dailymed-drugs:161 |
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 .
|
| dailymed-drugs:162 |
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.
|
| dailymed-drugs:163 |
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.
|
| dailymed-drugs:164 |
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.
|
| dailymed-drugs:165 |
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 .
|
| dailymed-drugs:166 |
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.
|
| dailymed-drugs:168 |
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.
|
| dailymed-drugs:171 |
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 .
|
| dailymed-drugs:172 |
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.
|
| dailymed-drugs:174 |
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.
|
| dailymed-drugs:177 |
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 .
|
| dailymed-drugs:179 |
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.
|
| dailymed-drugs:180 |
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.
|
| dailymed-drugs:182 |
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.
|
| dailymed-drugs:186 |
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.
|
| dailymed-drugs:187 |
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.
|
| dailymed-drugs:188 |
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.
|
| dailymed-drugs:189 |
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.
|
| dailymed-drugs:190 |
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.
|
| dailymed-drugs:191 |
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.
|
| dailymed-drugs:192 |
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.
|
| dailymed-drugs:193 |
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.
|
| dailymed-drugs:194 |
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.
|
| dailymed-drugs:196 |
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.
|
| dailymed-drugs:197 |
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.
|
| dailymed-drugs:198 |
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.
|
| dailymed-drugs:200 |
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.
|
| dailymed-drugs:201 |
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.
|
| dailymed-drugs:202 |
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).
|
| dailymed-drugs:203 |
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.
|
| dailymed-drugs:204 |
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.
|
| dailymed-drugs:205 |
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:
|
| dailymed-drugs:206 |
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.
|
| dailymed-drugs:207 |
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.
|
| dailymed-drugs:209 |
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.
|
| dailymed-drugs:210 |
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.
|
| dailymed-drugs:211 |
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.)
|
| dailymed-drugs:212 |
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.
|
| dailymed-drugs:213 |
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.
|
| dailymed-drugs:214 |
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.
|
| dailymed-drugs:216 |
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.
|
| dailymed-drugs:217 |
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���.
|
| dailymed-drugs:219 |
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.
|
| dailymed-drugs:220 |
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).
|
| dailymed-drugs:221 |
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.
|
| dailymed-drugs:222 |
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.
|
| dailymed-drugs:225 |
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.
|
| dailymed-drugs:227 |
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.
|
| dailymed-drugs:228 |
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.
|
| dailymed-drugs:229 |
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.
|
| dailymed-drugs:230 |
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.
|
| dailymed-drugs:232 |
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.
|
| dailymed-drugs:1940 |
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.
|
| dailymed-drugs:233 |
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.
|
| dailymed-drugs:234 |
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.
|
| dailymed-drugs:235 |
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.
|
| dailymed-drugs:237 |
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.
|
| dailymed-drugs:238 |
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.
|
| dailymed-drugs:239 |
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.
|
| dailymed-drugs:240 |
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.
|
| dailymed-drugs:242 |
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:
|
| dailymed-drugs:243 |
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.
|
| dailymed-drugs:244 |
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.
|
| dailymed-drugs:245 |
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.
|
| dailymed-drugs:246 |
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.
|
| dailymed-drugs:248 |
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.
|
| dailymed-drugs:249 |
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 .
|
| dailymed-drugs:250 |
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).
|
| dailymed-drugs:251 |
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.
|
| dailymed-drugs:252 |
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.
|
| dailymed-drugs:253 |
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.
|
| dailymed-drugs:254 |
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
|
| dailymed-drugs:257 |
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.
|
| dailymed-drugs:258 |
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 .
|
| dailymed-drugs:259 |
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.)
|
| dailymed-drugs:260 |
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.
|
| dailymed-drugs:262 |
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 .
|
| dailymed-drugs:263 |
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.
|
| dailymed-drugs:265 |
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).
|
| dailymed-drugs:267 |
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.
|