DESCRIPTION

CLINICAL PHARMACOLOGY

CLINICAL STUDIES

INDICATIONS & USAGE

Monotherapy Epilepsy

Topiramate tablets are indicated as initial monotherapy in patients 10 years of age and older with partial onset or primary generalized tonic-clonic seizures.

Effectiveness was demonstrated in a controlled trial in patients with epilepsy who had no more than 2 seizures in the 3 months prior to enrollment. Safety and effectiveness in patients who were converted to monotherapy from a previous regimen of other anticonvulsant drugs have not been established in controlled trials.

Adjunctive Therapy Epilepsy

Topiramate tablets are indicated as adjunctive therapy for adults and pediatric patients ages 2 to 16 years with partial onset seizures, or primary generalized tonic-clonic seizures, and in patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome.

CONTRAINDICATIONS

Topiramate tablets are contraindicated in patients with a history of hypersensitivity to any component of this product.

WARNINGS

PRECAUTIONS

INFORMATION FOR PATIENTS

LABORATORY TESTS

DRUG INTERACTIONS

DRUG & OR 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/m2 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/m2 basis).

PREGNANCY

LABOR & DELIVERY

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 topiramate 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

GERIATRIC USE

ADVERSE REACTIONS

DRUG ABUSE AND DEPENDENCE

OVERDOSAGE

DOSAGE & ADMINISTRATION

Epilepsy

In the controlled add-on trials, no correlation has been demonstrated between trough plasma concentrations of topiramate and clinical efficacy. No evidence of tolerance has been demonstrated in humans. Doses above 400 mg/day (600, 800, or 1000 mg/day) have not been shown to improve responses in dose-response studies in adults with partial onset seizures.

It is not necessary to monitor topiramate plasma concentrations to optimize topiramate therapy. On occasion, the addition of topiramate to phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy with topiramate may require adjustment of the dose of topiramate. Because of the bitter taste, tablets should not be broken.

Topiramate tablets can be taken without regard to meals.

Monotherapy Use

Morning DoseEvening DoseWeek 125 mg25 mgWeek 250 mg50 mgWeek 375 mg75 mgWeek 4100 mg100 mgWeek 5150 mg150 mgWeek 6200 mg200 mg

Adjunctive Therapy Use

Adults (17 Years of Age and Over) - Partial Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome

The recommended total daily dose of topiramate as adjunctive therapy in adults with partial seizures is 200 to 400 mg/day in two divided doses, and 400 mg/day in two divided doses as adjunctive treatment in adults with primary generalized tonic-clonic seizures. It is recommended that therapy be initiated at 25 to 50 mg/day followed by titration to an effective dose in increments of 25 to 50 mg/week. Titrating in increments of 25 mg/week may delay the time to reach an effective dose. Daily doses above 1,600 mg have not been studied.

In the study of primary generalized tonic-clonic seizures the initial titration rate was slower than in previous studies; the assigned dose was reached at the end of 8 weeks (see

CLINICAL STUDIES, Adjunctive Therapy Controlled Trials in Patients With Primary Generalized Tonic-Clonic Seizures

Pediatric Patients (Ages 2 to 16 Years)Partial Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome

The recommended total daily dose of topiramate as adjunctive therapy for patients with partial seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 to 9 mg/kg/day in two divided doses. Titration should begin at 25 mg (or less, based on a range of 1 to 3 mg/kg/day) nightly for the first week. The dosage should then be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day (administered in two divided doses), to achieve optimal clinical response. Dose titration should be guided by clinical outcome.

In the study of primary generalized tonic-clonic seizures the initial titration rate was slower than in previous studies; the assigned dose of 6 mg/kg/day was reached at the end of 8 weeks (see

CLINICAL STUDIES, Adjunctive Therapy Controlled Trials in Patients With Primary Generalized Tonic-Clonic Seizures

Patients with Renal Impairment:

In renally impaired subjects (creatinine clearance less than 70 mL/min/1.73 m2), one half of the usual adult dose is recommended. Such patients will require a longer time to reach steady-state at each dose.

Geriatric Patients (Ages 65 Years and Over):

Dosage adjustment may be indicated in the elderly patient when impaired renal function (creatinine clearance ratemL/min/1.73 m2) is evident (see

DOSAGE AND ADMINISTRATION: Patients with Renal Impairment

and

CLINICAL PHARMACOLOGY: Special Populations: Age, Gender, and Race

Patients Undergoing Hemodialysis:

Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than a normal individual. Accordingly, a prolonged period of dialysis may cause topiramate concentration to fall below that required to maintain an anti-seizure effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed.

Patients with Hepatic Disease:

In hepatically impaired patients topiramate plasma concentrations may be increased. The mechanism is not well understood.

HOW SUPPLIED

Topiramate tablets are available as debossed, film-coated, circular tablets in the following strengths and colors:

25 mg white (coded "S" on one side; "707" on the other)

They are supplied as follows:

25 mg tablets Bottles of 30's with Child Resistant Cap62756-707-83

Bottles of 60's with Child Resistant Cap62756-707-86

Bottles of 100's with Child Resistant Cap62756-707-88

Bottles of 100's with Non Child Resistant Cap62756-707-08

Bottles of 500's with Non Child Resistant Cap62756-707-13

Bottles of 1000's with Non Child Resistant Cap62756-707-18

50 mg tablets Bottles of 30's with Child Resistant Cap62756-710-83

Bottles of 60's with Child Resistant Cap62756-710-86

Bottles of 100's with Child Resistant Cap62756-710-88

Bottles of 100's with Non Child Resistant Cap62756-710-08

Bottles of 500's with Non Child Resistant Cap62756-710-13

Bottles of 1000's with Non Child Resistant Cap62756-710-18

100 mg tablets Bottles of 30's with Child Resistant Cap62756-711-83

Bottles of 60's with Child Resistant Cap62756-711-86

Bottles of 100's with Child Resistant Cap62756-711-88

Bottles of 100's with Non Child Resistant Cap62756-711-08

Bottles of 500's with Non Child Resistant Cap62756-711-13

Bottles of 1000's with Non Child Resistant Cap62756-711-18

200 mg tablets Bottles of 30's with Child Resistant Cap62756-712-83

Bottles of 60's with Child Resistant Cap62756-712-86

Bottles of 100's with Child Resistant Cap62756-712-88

Bottles of 100's with Non Child Resistant Cap62756-712-08

Bottles of 500's with Non Child Resistant Cap62756-712-13

Bottles of 1000's with Non Child Resistant Cap62756-712-18

SPL MEDGUIDE

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION

DRUG: Topiramate

GENERIC: Topiramate

DOSAGE: TABLET

ADMINSTRATION: ORAL

NDC: 49349-942-02

STRENGTH:200 mg

COLOR: brown

SHAPE: ROUND

SCORE: No score

SIZE: 12 mm

IMPRINT: 30

QTY: 30