Topamax Clinical Pharmacology

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Topamax - Clinical Pharmacology [Topiramate]

Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to TOPAMAX Ў 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 Ў 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 аа Mean Dose 5.9 200 390 556 аа

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

Median Dose 10.0 аа 600 800 1,000
Y1 N 23 а 19 ааа Mean Dose 3.8 а 395 ааа

Median Dose 4.0 а 400 ааа
Y2 N 30 аа 28 аа Mean Dose 5.7 аа 522 аа

Median Dose 6.0 аа 600 аа
Y3 N 28 ааа 25 а Mean Dose 7.9 ааа 568 а

Median Dose 8.0 ааа 600 а 119 N 90 157 аааа
Mean Dose 8 200 аааа Median Dose 8 200 аааа

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 ааа Median % Reduction 11.6 27.2 a 47.5 b 44.7 c ааа
% Responders 18 24 44 d 46 d ааа
YE N 47 аа 48 48 47 а Median % Reduction 1.7 аа 40.8 c 41.0 c 36.0 c а

% Responders 9 аа 40 c 41 c 36 d а
Y1 N 24 а 23 аааа Median % Reduction 1.1 а 40.7 e аааа

% Responders 8 а 35 d аааа
Y2 N 30 аа 30 ааа Median % Reduction -12.2 аа 46.4 f ааа

% Responders 10 аа 47 c ааа
Y3 N 28 ааа 28 аа Median % Reduction -20.6 ааа 24.3 c аа

% Responders 0 ааа 43 c аа 119 N 91 168 ааааа
Median % Reduction 20.0 44.2 c ааааа % Responders 24 45 c ааааа

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

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

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

% Responders 14 ааааа 28 g Improvement in 28 ааааа 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 Ў Tablets in these studies showed no differences as a function of gender, race, age, baseline seizure rate, or concomitant AED.