Abstracts

Rationale: Carisbamate, a novel neurotherapeutic compound, has previously demonstrated efficacy and safety across a broad dose range from 300 to 1,600 mg/day in the adjunctive treatment of partial onset seizures (POS). An analysis was conducted to evaluate the safety and tolerability of carisbamate across 3 large multicenter, double-blind, randomized, placebo-controlled studies of adults with POS. Methods: Patients received fixed dosages of carisbamate 100, 300, 800, or 1,600 mg/day in a 16-week double-blind dose-ranging study or fixed dosages of 200 or 400 mg/day in two 12-week double-blind studies. A pooled safely analysis was conducted on these 3 trials. Results: In the pooled safety analysis a total of 1,179 patients with POS received at least 1 dose of carisbamate: 107 received 100 mg/day, 375 received 200 mg/day, 107 received 300 mg/day, 377 received 400 mg/day, 108 received 800 mg/day, and 105 received 1,600 mg/day; 484 were in the placebo group. The majority of patients took 2 concomitant antiepileptic drugs (~50% took carbamazepine). Comparable percentages of the patients in the total placebo group and the total carisbamate group experienced overall treatment-emergent adverse events (TEAEs; 59% vs 64%), TEAEs leading to discontinuation (4% vs 5%), and treatment-emergent serious adverse events (4% vs 3%); no deaths were reported. The only TEAEs reported with a frequency of >5% were headache, dizziness, somnolence, and nausea (Table 1). Within the therapeutically relevant dosage range of 400 to 800 mg/day, the differences from placebo did not exceed 10% except for headache, where the difference was 13%. Cognition-related TEAEs and psychosis-related TEAEs both occurred with low frequency, with no more than 2% of patients reporting these events in any carisbamate dosage group (Table 1). Behavioral TEAEs were reported for 6% of patients in the total carisbamate group; breakdown by dose is presented in Table 1. Mostly asymptomatic and reversible liver function test abnormalities (ALT elevations) were observed in about 1% of patients. Asymptomatic QTc shortening has also been observed. Conclusions: This combined tolerability analysis showed that carisbamate given adjunctively was well tolerated across an efficacious dose range (300-1,600 mg/day) in patients with POS. Adverse event-related discontinuation rates were found to be low. The 2 unspecific CNS adverse events, dizziness and somnolence, were the most prominent dose-related adverse events reported, whereas cognitive adverse events occurred infrequently, with an incidence rate comparable to placebo. Support for this work was provided by Johnson & Johnson Pharmaceutical Research & Development, L.L.C.