Topamax

[Topiramate]

Patients who experienced a prespecified minimum number of partial onset seizures, with or without secondary generalization, during the base-line phase (12 seizures for 12-week baseline, 8 for 8-week baseline, or 3 for 4-week baseline) were randomly assigned to placebo or a specified dose of TOPAMAX ® Tablets in addition to their other AEDs.

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

Pediatric Patients Ages 2 -16 Years With Partial Onset Seizures

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

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

Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 25 or 50 mg per day; the dose was then increased by 25 mg to 150 mg/ day increments every other week until the assigned dosage of 125, 175, 225, or 400 mg/ day based on patients' weight to approximate a dosage of 6 mg/ kg per day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period.

Controlled Trials in Patients With Primary Generalized Tonic-Clonic Seizures

The effectiveness of topiramate as an adjunctive treatment for primary generalized tonic-clonic seizures in patients 2 years old and older was
established in a multicenter, randomized, double-blind, placebo-controlled trial, comparing a single dosage of topiramate and placebo. Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to TOPAMAX ® or placebo. Patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least three primary generalized tonic-clonic seizures during the baseline phase were randomly assigned to placebo or TOPAMAX ® in addition to their other AEDs.

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

Controlled Trial in Patients With Lennox-Gastaut Syndrome

The effectiveness of topiramate as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome was established in a multicenter, randomized, double-blind, placebo-controlled trial comparing a single dosage of topiramate with placebo in patients 2 years of age and older.

Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to TOPAMAX ® or placebo. Patients who were experiencing at least 60 seizures per month before study entry were stabilized on optimum dosages of their concomitant AEDs during a four week baseline phase. Following baseline, patients were randomly assigned to placebo or TOPAMAX ® in addition to their other AEDs. Active drug was titrated beginning at 1 mg/ kg per day for a week; the dose was then increased to 3 mg/ kg per day for one week then to 6 mg/ kg per day. After titration, patients entered an 8-week stabilization period. The primary measures of effectiveness were the percent reduction in drop attacks and a parental global rating of seizure severity.

Table 1: Topiramate Dose Summary During the Stabilization Periods of Each of Five Double-Blind, Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizures b Target Topiramate Dosage (mg/ day)
Protocol Stabilization Dose Placebo a 200 400 600 800 1,000
YD N 42 42 40 41 ÐÐ Mean Dose 5.9 200 390 556 ÐÐ

Median Dose 6.0 200 400 600 ÐÐ
YE N 44 ÐÐ 40 45 40 Mean Dose 9.7 ÐÐ 544 739 796

Median Dose 10.0 ÐÐ 600 800 1,000
Y1 N 23 Ð 19 ÐÐÐ Mean Dose 3.8 Ð 395 ÐÐÐ

Median Dose 4.0 Ð 400 ÐÐÐ
Y2 N 30 ÐÐ 28 ÐÐ Mean Dose 5.7 ÐÐ 522 ÐÐ

Median Dose 6.0 ÐÐ 600 ÐÐ
Y3 N 28 ÐÐÐ 25 Ð Mean Dose 7.9 ÐÐÐ 568 Ð

Median Dose 8.0 ÐÐÐ 600 Ð 119 N 90 157 ÐÐÐÐ
Mean Dose 8 200 ÐÐÐÐ Median Dose 8 200 ÐÐÐÐ

a Placebo dosages are given as the number of tablets. Placebo target dosages were as follows: Protocol Y1, 4 tablets/ day; Protocols YD and Y2,
6 tablets/ day; Protocol Y3 and 119, 8 tablets/ day; Protocol YE, 10 tablets/ day.
b Dose-response studies were not conducted for other indications or pediatric partial onset seizures. In all add-on trials, the reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) by treatment group for each study are

shown below in Table 2. As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial.
Table 2: Efficacy Results in Double-Blind, Placebo-Controlled, Add-On Trials

Target Topiramate Dosage (mg/ day)
Protocol Efficacy Results Placebo 200 400 600 800 1,000 6
mg/ kg/ day*
Partial Onset Seizures Studies in Adults

YD N 45 45 45 46 ÐÐÐ Median % Reduction 11.6 27.2 a 47.5 b 44.7 c ÐÐÐ
% Responders 18 24 44 d 46 d ÐÐÐ
YE N 47 ÐÐ 48 48 47 Ð Median % Reduction 1.7 ÐÐ 40.8 c 41.0 c 36.0 c Ð

% Responders 9 ÐÐ 40 c 41 c 36 d Ð
Y1 N 24 Ð 23 ÐÐÐÐ Median % Reduction 1.1 Ð 40.7 e ÐÐÐÐ

% Responders 8 Ð 35 d ÐÐÐÐ
Y2 N 30 ÐÐ 30 ÐÐÐ Median % Reduction -12.2 ÐÐ 46.4 f ÐÐÐ

% Responders 10 ÐÐ 47 c ÐÐÐ
Y3 N 28 ÐÐÐ 28 ÐÐ Median % Reduction -20.6 ÐÐÐ 24.3 c ÐÐ

% Responders 0 ÐÐÐ 43 c ÐÐ 119 N 91 168 ÐÐÐÐÐ
Median % Reduction 20.0 44.2 c ÐÐÐÐÐ % Responders 24 45 c ÐÐÐÐÐ

Studies in Pediatric Patients
YP N 45 ÐÐÐÐÐ 41 Median % Reduction 10.5 ÐÐÐÐÐ 33.1 d

% Responders 20 ÐÐÐÐÐ 39
Primary Generalized Tonic-Clonic h
YTC N 40 ÐÐÐÐÐ 39 Median % Reduction 9.0 ÐÐÐÐÐ 56.7 d

% Responders 20 ÐÐÐÐÐ 56 c
Lennox-Gastaut Syndrome i
YL N 49 ÐÐÐÐÐ 46 Median % Reduction -5.1 ÐÐÐÐÐ 14.8 d

% Responders 14 ÐÐÐÐÐ 28 g Improvement in 28 ÐÐÐÐÐ 52 d
Seizure Severity j

Comparisons with placebo: a p= 0.080; b p 0.010; c p 0.001; d p 0.050; e p= 0.065; f p 0.005; g p= 0.071; h Median % reduction and % responders are reported for PGTC Seizures; i Median % reduction and % responders for drop attacks, i. e., tonic or atonic seizures; j Percent of subjects who were minimally, much, or very much improved from baseline

* For Protocols YP and YTC, protocol-specified target dosages (< 9.3 mg/ kg/ day) were assigned based on subject's weight to approximate a dosage of 6 mg/ kg per day; these dosages corresponded to mg/ day dosages of 125, 175, 225, and 400 mg/ day.

Subset analyses of the antiepileptic efficacy of TOPAMAX ® Tablets in these studies showed no differences as a function of gender, race, age, baseline seizure rate, or concomitant AED.

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