Rx Only

DESCRIPTION

Topiramate is a sulfamate-substituted monosaccharide. TOPAMAX® (topiramate)Tablets are available as 25 mg, 50 mg, 100 mg, and 200 mg round tablets fororal administration. TOPAMAX® (topiramate capsules) SprinkleCapsules are available as 15 mg and 25mg sprinkle capsules for oraladministration as whole capsules or opened and sprinkled onto soft food.

Topiramateis a white crystalline powder with a bitter taste. Topiramate is most solublein alkaline solutions containing sodium hydroxide or sodium phosphate andhaving a pH of 9 to 10. It is freely soluble in acetone, chloroform, dimethylsulfoxide,and ethanol. The solubility in water is 9.8mg/mL. Its saturated solutionhas a pH of 6.3. Topiramate has the molecular formula C12H21NO8Sand a molecular weight of 339.36. Topiramate is designated chemically as 2,3:4,5-Di-O-isopropylidene-β-D-fructopyranose sulfamateand has the following structural formula:

TOPAMAX® (topiramate)Tablets contain the following inactive ingredients: lactose monohydrate, pregelatinizedstarch, microcrystalline cellulose, sodium starch glycolate, magnesium stearate,purified water, carnauba wax, hypromellose, titanium dioxide, polyethyleneglycol, synthetic iron oxide (50, 100, and 200 mg tablets) and polysorbate80.

TOPAMAX® (topiramate capsules) SprinkleCapsules contain topiramate coated beads in a hard gelatin capsule. The inactiveingredients are: sugar spheres (sucrose and starch), povidone, cellulose acetate,gelatin, sorbitan monolaurate, sodium lauryl sulfate, titanium dioxide, andblack pharmaceutical ink.

CLINICAL PHARMACOLOGY

Mechanism of Action:

The precise mechanisms by which topiramate exerts its anticonvulsantand migraine prophylaxis effects are unknown; however, preclinical studieshave revealed four properties that may contribute to topiramate's efficacyfor epilepsy and migraine prophylaxis. Electrophysiological and biochemicalevidence suggests that topiramate, at pharmacologically relevant concentrations,blocks voltage-dependent sodium channels, augments the activity of the neurotransmittergamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes theAMPA/kainate subtype of the glutamate receptor, and inhibits the carbonicanhydrase enzyme, particularly isozymes II and IV.

Pharmacodynamics:

Topiramate has anticonvulsant activity in rat and mouse maximalelectroshock seizure (MES) tests. Topiramate is only weakly effective in blockingclonic seizures induced by the GABAA receptor antagonist, pentylenetetrazole.Topiramate is also effective in rodent models of epilepsy, which include tonicand absence-like seizures in the spontaneous epileptic rat (SER) and tonicand clonic seizures induced in rats by kindling of the amygdala or by globalischemia.

Pharmacokinetics:

The sprinkle formulation is bioequivalent to the immediaterelease tablet formulation and, therefore, may be substituted as a therapeuticequivalent.

Absorption of topiramate is rapid, withpeak plasma concentrations occurring at approximately 2 hours following a400 mg oral dose. The relative bioavailability of topiramate from the tabletformulation is about 80% compared to a solution. The bioavailability of topiramateis not affected by food.

The pharmacokinetics of topiramateare linear with dose proportional increases in plasma concentration over thedose range studied (200 to 800mg/day). The mean plasma elimination half-lifeis 21 hours after single or multiple doses. Steady state is thus reached inabout 4 days in patients with normal renal function. Topiramate is 15-41%bound to human plasma proteins over the blood concentration range of 0.5-250μg/mL.The fraction bound decreased as blood concentration increased.

Carbamazepineand phenytoin do not alter the binding of topiramate. Sodium valproate, at500 μg/mL (a concentration 5-10 times higher than considered therapeuticfor valproate) decreased the protein binding of topiramate from 23% to 13%.Topiramate does not influence the binding of sodium valproate.

Metabolism and Excretion:

Topiramate is not extensively metabolized and is primarilyeliminated unchanged in the urine (approximately 70% of an administered dose).Six metabolites have been identified in humans, none of which constitutesmore than 5% of an administered dose. The metabolites are formed via hydroxylation,hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorptionof topiramate. In rats, given probenecid to inhibit tubular reabsorption,along with topiramate, a significant increase in renal clearance of topiramatewas observed. This interaction has not been eva luated in humans. Overall,oral plasma clearance (CL/F) is approximately 20 to 30mL/min in humansfollowing oral administration.

Pharmacokinetic Interactions

(see also Drug Interactions):

Antiepileptic Drugs

Potential interactions between topiramate and standard AEDswere assessed in controlled clinical pharmacokinetic studies in patients withepilepsy. The effect of these interactions on mean plasma AUCs are summarizedunder PRECAUTIONS (Table 3).

Special Populations:

Renal Impairment:

The clearance of topiramate was reduced by 42% in moderatelyrenally impaired (creatinine clearance 30-69mL/min/1.73m2)and by 54% in severely renally impaired subjects (creatinine clearance <30mL/min/1.73m2)compared to normal renal function subjects (creatinine clearance >70mL/min/1.73m2).Since topiramate is presumed to undergo significant tubular reabsorption,it is uncertain whether this experience can be generalized to all situationsof renal impairment. It is conceivable that some forms of renal disease coulddifferentially affect glomerular filtration rate and tubular reabsorptionresulting in a clearance of topiramate not predicted by creatinine clearance.In general, however, use of one-half the usual starting and maintenance doseis recommended in patients with moderate or severe renal impairment (see PRECAUTIONS: Adjustment of Dose inRenal Failure and DOSAGE AND ADMINISTRATION).

Hemodialysis:

Topiramate is cleared by hemodialysis. Using a high efficiency,counterflow, single pass-dialysate hemodialysis procedure, topiramate dialysisclearance was 120mL/min with blood flow through the dialyzer at 400mL/min. This high clearance (compared to 20-30 mL/min total oral clearancein healthy adults) will remove a clinically significant amount of topiramatefrom the patient over the hemodialysis treatment period. Therefore, a supplementaldose may be required (see DOSAGEAND ADMINISTRATION).

Hepatic Impairment:

In hepatically impaired subjects, the clearance of topiramatemay be decreased; the mechanism underlying the decrease is not well understood.

Age, Gender, and Race:

The pharmacokinetics of topiramate in elderly subjects (65-85years of age, N=16) were eva luated in a controlled clinical study. The elderlysubject population had reduced renal function [creatinine clearance (-20%)]compared to young adults. Following a single oral 100 mg dose, maximum plasmaconcentration for elderly and young adults was achieved at approximately 1-2hours.Reflecting the primary renal elimination of topiramate, topiramate plasmaand renal clearance were reduced 21%and 19%, respectively, in elderlysubjects, compared to young adults. Similarly, topiramate half-life was longer(13%) in the elderly. Reduced topiramate clearance resulted in slightly highermaximum plasma concentration (23%) and AUC (25%) in elderly subjects thanobserved in young adults. Topiramate clearance is decreased in the elderlyonly to the extent that renal function is reduced. As recommended for allpatients, dosage adjustment may be indicated in the elderly patient when impairedrenal function (creatinine clearance rate ≤70mL/min/1.73 m2)is evident. It may be useful to monitor renal function in the elderly patient(see Special Populations:Renal Impairment, PRECAUTIONS: Adjustment of Dose in Renal Failure and DOSAGE AND ADMINISTRATION).

Clearance of topiramate in adults was notaffected by gender or race.

Pediatric Pharmacokinetics:

Pharmacokinetics of topiramate were eva luated in patientsages 4 to 17 years receiving one or two other antiepileptic drugs. Pharmacokineticprofiles were obtained after one week at doses of 1, 3, and 9mg/kg/day.Clearance was independent of dose.

Pediatric patientshave a 50% higher clearance and consequently shorter elimination half-lifethan adults. Consequently, the plasma concentration for the same mg/kg dosemay be lower in pediatric patients compared to adults. As in adults, hepaticenzyme-inducing antiepileptic drugs decrease the steady state plasma concentrationsof topiramate.

CLINICAL STUDIES

The studies described in the following sections were conductedusing TOPAMAX® (topiramate) Tablets.

Epilepsy

Monotherapy Controlled Trial

The effectiveness of topiramate as initial monotherapy inadults and children 10 years of age and older with partial onset or primarygeneralized seizures was established in a multicenter, randomized, double-blind,parallel-group trial.

The trial was conducted in 487patients diagnosed with epilepsy (6 to 83 years of age) who had 1 or 2 well-documentedseizures during the 3-month retrospective baseline phase who then enteredthe study and received topiramate 25 mg/day for 7 days in an open-label fashion.Forty-nine percent of subjects had no prior AED treatment and 17% had a diagnosisof epilepsy for greater than 24 months. Any AED therapy used for temporaryor emergency purposes was discontinued prior to randomization. In the double-blindphase, 470 patients were randomized to titrate up to 50 mg/day or 400 mg/day.If the target dose could not be achieved, patients were maintained on themaximum tolerated dose. Fifty eight percent of patients achieved the maximaldose of 400 mg/day for≥ 2 weeks, and patients who did not tolerate150 mg/day were discontinued. The primary efficacy assessment was a betweengroup comparison of time to first seizure during the double-blind phase. Comparisonof the Kaplan-Meier survival curves of time to first seizure favored the topiramate400 mg/day group over the topiramate 50 mg/day group (p=0.0002, log rank test; Figure 1). Thetreatment effects with respect to time to first seizure were consistent acrossvarious patient subgroups defined by age, sex, geographic region, baselinebody weight, baseline seizure type, time since diagnosis, and baseline AEDuse.

Figure1: Kaplan-Meier Estimates of Cumulative Rates for Time to First Seizure

Adjunctive Therapy Controlled Trialsin Patients With Partial Onset Seizures

The effectiveness of topiramate as an adjunctive treatmentfor adults with partial onset seizures was established in six multicenter,randomized, double-blind, placebo-controlled trials, two comparing severaldosages of topiramate and placebo and four comparing a single dosage withplacebo, in patients with a history of partial onset seizures, with or withoutsecondarily generalized seizures.

Patients in thesestudies were permitted a maximum of two antiepileptic drugs (AEDs) in additionto TOPAMAX® Tablets or placebo. In each study, patients werestabilized on optimum dosages of their concomitant AEDs during baseline phaselasting between 4 and 12 weeks. Patients who experienced a prespecified minimumnumber of partial onset seizures, with or without secondary generalization,during the baseline phase (12 seizures for 12-week baseline, 8 for 8-weekbaseline, or 3 for 4-week baseline) were randomly assigned to placebo or aspecified dose of TOPAMAX® Tablets in addition to their otherAEDs.

Following randomization, patients began the double-blindphase of treatment. In five of the six studies, patients received active drugbeginning at 100mg per day; the dose was then increased by 100mgor 200mg/day increments weekly or every other week until the assigneddose was reached, unless intolerance prevented increases. In the sixth study(119), the 25 or 50 mg/day initial doses of topiramate were followed by respectiveweekly increments of 25 or 50 mg/day until the target dose of 200 mg/day wasreached. After titration, patients entered a 4, 8, or 12-week stabilizationperiod. The numbers of patients randomized to each dose, and the actual meanand median doses in the stabilization period are shown in Table 1.

Adjunctive Therapy Controlled Trialin Pediatric Patients Ages 2 - 16 Years With Partial Onset Seizures

The effectiveness of topiramate as an adjunctive treatmentfor pediatric patients ages 2 - 16 years with partial onset seizures was establishedin a multicenter, randomized, double-blind, placebo-controlled trial, comparingtopiramate and placebo in patients with a history of partial onset seizures,with or without secondarily generalized seizures.

Patientsin this study were permitted a maximum of two antiepileptic drugs (AEDs) inaddition to TOPAMAX® Tablets or placebo. In this study, patientswere stabilized on optimum dosages of their concomitant AEDs during an 8-weekbaseline phase. Patients who experienced at least six partial onset seizures,with or without secondarily generalized seizures, during the baseline phasewere randomly assigned to placebo or TOPAMAX® Tablets in additionto their other AEDs.

Following randomization, patientsbegan the double-blind phase of treatment. Patients received active drug beginningat 25 or 50mg per day; the dose was then increased by 25mg to150mg/day increments every other week until the assigned dosage of 125,175, 225, or 400mg/day based on patients' weight to approximate a dosageof 6mg/kg per day was reached, unless intolerance prevented increases.After titration, patients entered an 8-week stabilization period.

Adjunctive Therapy Controlled Trialin Patients With Primary Generalized Tonic-Clonic Seizures

The effectiveness of topiramate as an adjunctive treatmentfor primary generalized tonic-clonic seizures in patients 2 years old andolder was established in a multicenter, randomized, double-blind, placebo-controlledtrial, comparing a single dosage of topiramate and placebo.

Patientsin this study were permitted a maximum of two antiepileptic drugs (AEDs) inaddition to TOPAMAX® or placebo. Patients were stabilizedon optimum dosages of their concomitant AEDs during an 8-week baseline phase.Patients who experienced at least three primary generalized tonic-clonic seizuresduring the baseline phase were randomly assigned to placebo or TOPAMAX® inaddition to their other AEDs.

Following randomization,patients began the double-blind phase of treatment. Patients received activedrug beginning at 50mg per day for four weeks; the dose was then increasedby 50mg to 150mg/day increments every other week until the assigneddose of 175, 225, or 400mg/day based on patients' body weight to approximatea dosage of 6mg/kg per day was reached, unless intolerance preventedincreases. After titration, patients entered a 12-week stabilization period.

Adjunctive Therapy Controlled Trialin Patients With Lennox-Gastaut Syndrome

The effectiveness of topiramate as an adjunctive treatmentfor seizures associated with Lennox-Gastaut syndrome was established in amulticenter, randomized, double-blind, placebo-controlled trial comparinga single dosage of topiramate with placebo in patients 2 years of age andolder.

Patients in this study were permitted a maximumof two antiepileptic drugs (AEDs) in addition to TOPAMAX® orplacebo. Patients who were experiencing at least 60seizures per monthbefore study entry were stabilized on optimum dosages of their concomitantAEDs during a 4-week baseline phase. Following baseline, patients were randomlyassigned to placebo or TOPAMAX® in addition to their otherAEDs. Active drug was titrated beginning at 1 mg/kg per day for a week; thedose was then increased to 3 mg/kg per day for one week then to 6 mg/kg perday. After titration, patients entered an 8-week stabilization period. Theprimary measures of effectiveness were the percent reduction in drop attacksand a parental global rating of seizure severity.

In all add-on trials, the reduction in seizure rate frombaseline during the entire double-blind phase was measured. The median percentreductions in seizure rates and the responder rates (fraction of patientswith at least a 50% reduction) by treatment group for each study are shownbelow in Table 2. As described above, a global improvement in seizure severity wasalso assessed in the Lennox-Gastaut trial.