Abstracts

Rationale: Perampanel is a once-daily oral anti-seizure drug for focal epilepsy and primary generalized tonic-clonic seizures. Psychiatric and behavioral adverse reactions have been reported with perampanel treatment in a dose-dependent manner, and dose reduction is advised if these symptoms occur. Here, we present a post hoc analysis of psychiatric safety data from four randomized controlled studies of perampanel (Studies 304 [NCT00699972], 305 [NCT00699582], 306 [NCT00700310], and 335 [NCT01618695]: the 'RCT analysis') and their open-label extension (OLEx) studies (Study 307 [NCT00735397] and Study 335 OLEx: the 'OLEx analysis') in patients with focal epilepsy, with and without a medical history of psychiatric illness. Methods: Treatment-emergent adverse events (TEAEs) were analyzed for patients with and without a history of psychiatric events (a 'psychiatric history', defined as selected relevant events recorded in the medical history case report form) in the RCT and OLEx populations. In the RCT analysis, patients who were randomized to receive 2 mg/day, 4 mg/day, 8 mg/day, or 12 mg/day perampanel in Studies 304, 305, 306, and 335 were pooled by dose group (actual treatment received) and compared with the pooled placebo group. During the OLEx studies, all patients received perampanel. For this analysis, data from Studies 307 and Study 335 OLEx were pooled by the treatment (perampanel or placebo) received during the double-blind studies. Results: In the RCT analysis, 352 (16.1%) patients had a psychiatric history (perampanel n=244; placebo n=108) and 1835 (83.9%) patients had no psychiatric history (perampanel n=1325; placebo n=510). The frequency of TEAEs and psychiatric TEAEs was dependent on perampanel dose in patients with/without a psychiatric history (Table 1). Overall, psychiatric TEAEs were observed in 73 (29.9%) and 21 (19.4%) patients with a psychiatric history in the pooled perampanel and placebo groups, respectively. In the 2 mg/day and 4 mg/day perampanel groups, psychiatric TEAEs were less frequent vs placebo (11.1% and 15.4% vs 19.4%, respectively). Most common psychiatric TEAEs were anxiety and insomnia. In patients without a psychiatric history, psychiatric TEAEs were observed in 157 (11.8%) and 47 (9.2%) patients in the pooled perampanel and placebo groups, respectively. Most common psychiatric TEAEs were insomnia, aggression, and anxiety. In the OLEx analysis, 283 (14.9%) patients had a psychiatric history and 1612 (85.1%) patients had no psychiatric history. Psychiatric TEAEs were observed in 151 (53.4%) and 521 (32.3%) patients with/without a psychiatric history, respectively. In those with a psychiatric history, more patients treated with perampanel than placebo in the double-blind studies had a psychiatric TEAE during treatment. The most common psychiatric TEAE was irritability (Table 2). Conclusions: Data collected from four randomized controlled studies of perampanel and their OLEx studies show that psychiatric TEAEs are reported by more patients with a psychiatric history than without. In the randomized controlled studies, psychiatric TEAEs were dependent on perampanel dose irrespective of previous psychiatric illness; at the 4 mg/day perampanel dose, patients with or without a history of psychiatric illness did not have an increased incidence of psychiatric TEAEs compared with placebo. Funding: Eisai Inc.