The results of controlled clinical trials established the efficacy of felbamate as monotherapy and adjunctive therapy in adults with partial-onset seizures with or without secondary generalization and in partial and generalized seizures associated with Lennox-Gastaut syndrome in children.

Felbamate Monotherapy Trials in Adults 

Felbamate (3600 mg/day given QID) and low-dose valproate (15 mg/kg/day) were compared as monotherapy during a 112-day treatment period in a multicenter and a single-center double-blind efficacy trial. Both trials were conducted according to an identical study design. During a 56-day baseline period, all patients had at least four partial-onset seizures per 28 days and were receiving one antiepileptic drug at a therapeutic level, the most common being carbamazepine. In the multicenter trial, baseline seizure frequencies were 12.4 per 28 days in the felbamate group and 21.3 per 28 days in the low-dose valproate group. In the single-center trial, baseline seizure frequencies were 18.1 per 28 days in the felbamate group and 15.9 per 28 days in the low-dose valproate group. Patients were converted to monotherapy with felbamate or low-dose valproic acid during the first 28 days of the 112-day treatment period. Study endpoints were completion of 112 study days or fulfilling an escape criterion. Criteria for escape relative to baseline were: (1) twofold increase in monthly seizure frequency, (2) twofold increase in highest 2-day seizure frequency, (3) single generalized tonic-clonic seizure (GTC) if none occurred during baseline, or (4) significant prolongation of GTCs. The primary efficacy variable was the number of patients in each treatment group who met escape criteria.

In the multicenter trial, the percentage of patients who met escape criteria was 40% (18/45) in the felbamate group and 78% (39/50) in the low-dose valproate group. In the single-center trial, the percentage of patients who met escape criteria was 14% (3/21) in the felbamate group and 90% (19/21) in the low-dose valproate group. In both trials, the difference in the percentage of patients meeting escape criteria was statistically significant (P<.001) in favor of felbamate. These two studies by design were intended to demonstrate the effectiveness of Felbamate monotherapy. The studies were not designed or intended to demonstrate comparative efficacy of the two drugs. For example, valproate was not used at the maximally effective dose.

Felbamate Adjunctive Therapy Trials in Adults

A double-blind, placebo-controlled crossover trial consisted of two 10-week outpatient treatment periods. Patients with refractory partial-onset seizures who were receiving phenytoin and carbamazepine at therapeutic levels were administered felbamate as add-on therapy at a starting dosage of 1400 mg/day in three divided doses, which was increased to 2600 mg/day in three divided doses. Among the 56 patients who completed the study, the baseline seizure frequency was 20 per month. Patients treated with felbamate had fewer seizures than patients treated with placebo for each treatment sequence. There was a 23% (P=.018) difference in percentage seizure frequency reduction in favor of felbamate.

Felbamate 3600 mg/day given QID and placebo were compared in a 28-day double-blind add-on trial in patients who had their standard antiepileptic drugs reduced while undergoing evaluations for surgery of intractable epilepsy. All patients had confirmed partial-onset seizures with or without generalization, seizure frequency during surgical evaluation not exceeding an average of four partial seizures per day or more than one generalized seizure per day, and a minimum average of one partial or generalized tonic­clonic seizure per day for the last 3 days of the surgical evaluation. The primary efficacy variable was time to fourth seizure after randomization to treatment with felbamate or placebo. Thirteen (46%) of 28 patients in the felbamate group versus 29 (88%) of 33 patients in the placebo group experienced a fourth seizure. The median times to fourth seizure were greater than 28 days in the felbamate group and 5 days in the placebo group. The difference between felbamate and placebo in time to fourth seizure was statistically significant (P=.002) in favor of felbamate.

Felbamate Adjunctive Therapy Trial in Children with Lennox-Gastaut Syndrome

In a 70-day double-blind, placebo-controlled add-on trial in the Lennox-Gastaut syndrome, felbamate 45 mg/kg/day given QID was superior to placebo in controlling the multiple seizure types associated with this condition. Patients had at least 90 atonic and/or atypical absence seizures per month while receiving therapeutic dosages of one or two other antiepileptic drugs. Patients had a past history of using an average of eight antiepileptic drugs. The most commonly used antiepileptic drug during the baseline period was valproic acid. The frequency of all types of seizures during the baseline period was 1617 per month in the felbamate group and 716 per month in the placebo group. Statistically significant differences in the effect on seizure frequency favored felbamate over placebo for total seizures (26% reduction vs 5% increase, P<.001), atonic seizures (44% reduction vs 7% reduction, P=.002), and generalized tonic-clonic seizures (40% reduction vs 12% increase, P=.017). Parent/guardian global evaluations based on impressions of quality of life with respect to alertness, verbal responsiveness, general well-being, and seizure control significantly (P<.001) favored felbamate over placebo.

When efficacy was analyzed by gender in four well-controlled trials of felbamate as adjunctive and monotherapy for partial-onset seizures and Lennox-Gastaut syndrome, a similar response was seen in 122 males and 142 females.