Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/dailymed/precaution
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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.
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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.
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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.
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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.
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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.
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| 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.
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| 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.
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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.
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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.
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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.
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| 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.
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| 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.
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| 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.
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| 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.
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| 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 .
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| 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 .
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| 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.
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| 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.
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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.
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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.
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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:
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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).
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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.
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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 .
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| 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.
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| 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.
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| 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.
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| 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.
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| 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.)
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| 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.
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| 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).
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| 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.
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| 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.
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| 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. .
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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 .
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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).
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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.
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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.
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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).
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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).
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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).
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| 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.
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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.
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| 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.
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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.
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| 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 .
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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.
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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.
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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.
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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.
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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.
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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.
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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 .
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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.
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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.
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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.
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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.
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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.
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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.
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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 .
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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.
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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.
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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).
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| 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.
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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.
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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.
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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).
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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.
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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.
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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 .
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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.
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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.
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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.
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| 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.
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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).
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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.
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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.
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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).
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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.
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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.
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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).
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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).
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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.
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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 .
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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 .
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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.
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