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Red Blood Cell Disorders Frequent: anemia. Rare: marrow depression, pancytopenia. Reproductive Disorders, Male Text Continues Below
Infrequent: ejaculation disorder, breast discharge. Skin and Appendages Disorders Frequent: acne. Infrequent: urticaria, photosensitivity reaction, abnormal hair texture. Rare: chloasma. Special Senses Other, Disorders: Infrequent: taste loss, parosmia. Urinary System Disorders Frequent: dysuria, renal calculus. Infrequent: urinary retention, face edema, renal pain, albuminuria, polyuria, oliguria. Vascular (Extracardiac) Disorders Infrequent: flushing, deep vein thrombosis, phlebitis. Rare: vasospasm. Vision Disorders: Frequent: conjunctivitis. Infrequent: abnormal accommodation, photophobia, strabismus. Rare: mydriasis, iritis. White Cell and Reticuloendothelial System Disorders Infrequent: lymphadenopathy, eosinophilia, lymphopenia, granulocytopenia. Rare: lymphocytosis. Postmarketing and Other Experience In addition to the adverse experiences reported during clinical testing of TOPAMAX ® , the following adverse experiences have been reported worldwide in patients receiving topiramate post-approval. These adverse experiences have not been listed above and data are insuf-ficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), hepatic failure (including fatalities), hepatitis, pancreatitis, pemphigus, and renal tubular acidosis. Drug Interactions: Antiepileptic Drugs Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in the following table: In Table 3, the second column (AED concentration) describes what happens to the concentration of the AED listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the coadministration of a drug listed in the first column modifies the concentration of topiramate in experimental settings when TOPAMAX ® was given alone.
Table 3: Summary of AED Interactions with TOPAMAX ®
AED AED Topiramate Co-administered Concentration Concentration Phenytoin NC or 25% increase a 48% decrease Carbamazepine (CBZ) NC 40% decrease CBZ epoxide b NC NE Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE Primidone NC NE
a = Plasma concentration increased 25% in some patients, generally those on a b. i. d. dosing regimen of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. AED = Antiepileptic drug. NE = Not Evaluated.
Other Drug Interactions Digoxin In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant TOPAMAX ® administration. The clinical relevance of this observation has not been established. CNS Depressants Concomitant administration of TOPAMAX ® and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. Because of the potential of topiramate to cause CNS depression, as well as other cognitive and/ or neuropsychiatric adverse events, topiramate should be used with extreme caution if used in combination with alcohol and other CNS depressants. Oral Contraceptives In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contra-ceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), TOPAMAX ® given in the absence of other medications at doses of 50 to 200 mg/ day was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg/ day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, TOPAMAX ® (50 mg/ day to 800 mg/ day) did not significantly affect exposure to NET. Although there was a dose dependent decrease in EE exposure for doses between 200-800 mg/ day, there was no significant dose dependent change in EE exposure for doses of 50-200 mg/ day. The clinical significance of the changes observed is not known. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with TOPAMAX ® . Patients taking estrogen containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding. Metformin A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin and topiramate in plasma when metformin was given alone and when metformin and topiramate were given simultaneously. The results of this study indicated that metformin mean Cmax and mean AUC0-12h increased by 18% and 25%, respectively, while mean CL/ F decreased 20% when metformin was co-administered with topiramate. Topiramate did not affect metformin tmax . The clinical significance of the effect of topiramate on metformin pharmacokinetics is unclear. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The extent of change in the clearance is unknown. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unclear. When TOPAMAX ® is added or withdrawn in patients on metformin therapy, careful attention should be given to the routine monitoring for adequate control of their diabetic disease state. Others Concomitant use of TOPAMAX ® , a weak carbonic anhydrase inhibitor, with other carbonic anhydrase inhibitors, e. g., acetazolamide or dichlorphenamide, may create a physiological environment that increases the risk of renal stone formation, and should therefore be avoided. Drug/ Laboratory Test Interactions: There are no known interactions of topiramate with commonly used laboratory tests. Carcinogenesis, Mutagenesis, Impairment of Fertility An increase in urinary bladder tumors was observed in mice given topiramate (20, 75, and 300 mg/ kg) in the diet for 21 months. The elevated bladder tumor incidence, which was statistically significant in males and females receiving 300 mg/ kg, was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. Plasma exposures in mice receiving 300 mg/ kg were approximately 0.5 to 1 times steady-state exposures measured in patients receiving topiramate monotherapy at the recommended human dose (RHD) of 400 mg, and 1.5 to 2 times steady-state topiramate exposures in patients receiving 400 mg of topiramate plus phenytoin. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/ kg (approximately 3 times the RHD on a mg/ m 2 basis). Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo.
No adverse effects on male or female fertility were observed in rats at doses up to 100 mg/ kg (2.5 times the RHD on a mg/ m 2 basis). Pregnancy: Pregnancy Category C. Topiramate has demonstrated selective developmental toxicity, including teratogenicity, in experimental animal studies. When oral doses of 20, 100, or 500 mg/ kg were administered to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily cran-iofacial defects) was increased at all doses. The low dose is approximately 0.2 times the recommended human dose (RHD= 400 mg/ day) on a mg/ m 2 basis. Fetal body weights and skeletal ossification were reduced at 500 mg/ kg in conjunction with decreased maternal body weight gain. In rat studies (oral doses of 20, 100, and 500 mg/ kg or 0.2, 2.5, 30, and 400 mg/ kg), the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased among the offspring of dams treated with 400 mg/ kg (10 times the RHD on a mg/ m 2 basis) or greater during the organogenesis period of pregnancy. Embryotoxicity (reduced fetal body weights, increased incidence of structural variations) was observed at doses as low as 20 mg/ kg (0.5 times the RHD on a mg/ m 2 basis). Clinical signs of maternal toxicity were seen at 400 mg/ kg and above, and maternal body weight gain was reduced during treatment with 100 mg/ kg or greater. In rabbit studies (20, 60, and 180 mg/ kg or 10, 35, and 120 mg/ kg orally during organogenesis), embryo/ fetal mortality was increased at 35 mg/ kg (2 times the RHD on a mg/ m 2 basis) or greater, and teratogenic effects (primarily rib and vertebral malformations) were observed at 120 mg/ kg (6 times the RHD on a mg/ m 2 basis). Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/ or mortality) was seen at 35 mg/ kg and above. When female rats were treated during the latter part of gestation and throughout lactation (0.2, 4, 20, and 100 mg/ kg or 2, 20, and 200 mg/ kg), offspring exhibited decreased viability and delayed physical development at 200 mg/ kg (5 times the RHD on a mg/ m 2 basis) and reductions in pre-and/ or postweaning body weight gain at 2 mg/ kg (0.05 times the RHD on a mg/ m 2 basis) and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/ kg or greater. In a rat embryo/ fetal development study with a postnatal component (0.2, 2.5, 30, or 400 mg/ kg during organogenesis; noted above), pups exhibited delayed physical development at 400 mg/ kg (10 times the RHD on a mg/ m 2 basis) and persistent reductions in body weight gain at 30 mg/ kg (1 times the RHD on a mg/ m 2 basis) and higher. There are no studies using TOPAMAX ® in pregnant women. TOPAMAX ® should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. In post-marketing experience, cases of hypospadias have been reported in male infants exposed in utero to topiramate, with or without other anticonvulsants; however, a causal relationship with topiramate has not been established. Labor and Delivery: In studies of rats where dams were allowed to deliver pups naturally, no drug-related effects on gestation length or parturition were observed at dosage levels up to 200 mg/ kg/ day. The effect of TOPAMAX ® on labor and delivery in humans is unknown.
Nursing Mothers: Topiramate is excreted in the milk of lactating rats. The excretion of topiramate in human milk has not been evaluated in controlled studies. Limited observations in patients suggest an extensive secretion of topiramate into breast milk. Since many drugs are excreted in human milk, and because the potential for serious adverse reactions in nursing infants to TOPAMAX ® is unknown, the potential benefit to the mother should be weighed against the potential risk to the infant when considering recommendations regarding nursing. Pediatric Use: Safety and effectiveness in patients below the age of 2 years have not been established. Topiramate is associated with metabolic acidosis. Chronic untreated metabolic acidosis in pediatric patients may cause osteomalacia (rickets) and may reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of topiramate on growth and bone-related sequelae has not been sys-tematically investigated (see WARNINGS). Geriatric Use In clinical trials, 3% of patients were over 60. No age related difference in effectiveness or adverse effects were evident. However, clinical stud-ies of topiramate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with impaired renal function (creatinine clearance rate 70 mL/ min/ 1.73 m 2 ) due to reduced clearance of topiramate (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Race and Gender Effects Evaluation of effectiveness and safety in clinical trials has shown no race or gender related effects. Page: << Prev | 1 | 2 | 3 | 4 | 5
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