Abstracts

Rationale: Perampanel (PER), a selective, noncompetitive AMPA-antagonist, has been approved as adjunctive treatment for partial-onset seizures (POS). The safety and tolerability of PER, which has a long half-life of 25-105hr with and without metabolism inducing AEDs, respectively, has been well documented in 3 double-blind (DB), randomized, placebo (PBO)-controlled phase III trials. Here we report severity, time to first onset, frequency, and duration for the 3 most common adverse events (AEs) from post-hoc analysis of pooled data from the phase III trials.Methods: Patients with refractory POS aged 12 yr receiving 1-3 concomitant AEDs were enrolled in 3 phase III trials. Following 6-wk baseline, patients were randomized to once-daily, DB treatment (6-wk titration, 13-wk maintenance) with PBO or PER 8 or 12mg (studies 304 & 305); or with PBO or PER 2, 4, or 8mg (study 306). Starting dose was 2mg for all patients, with a weekly increase by 2mg to the target dose. The weekly titration was standardized without regard to baseline AEDs, as the half-life of PER is 25-105hr with and without PER metabolism inducing AEDs, respectively. These study results were pooled and included 1480 patients in the safety population. Post-hoc analyses were performed on the 3 most-common treatment-emergent adverse events (TEAEs) in which incidence was higher for the total PER group than PBO.Results: Most-common TEAEs from the pooled phase III trials included dizziness (28.1% in total PER vs 9.0% in PBO), somnolence (14.5 % vs 7.2%), and fatigue (8.5% vs 4.8%). Occurrences of these TEAEs by highest severity are shown in Table 1. For PER-treated patients, the majority of dizziness, somnolence, and fatigue events were mild or moderate during treatment and did not progress to severe. These TEAEs led to discontinuation in 39 (3.8%) total PER vs 5 (1.1%) PBO and drug interruption/dose reduction in 127 (12.2%) total PER vs 7 (1.6%) PBO. Time to first onset of these TEAEs occurred during the titration period (within the first 4-6 wk). In total PER, the highest percentage of patients experiencing first onset occurred in week 1 for somnolence (4.0%) and fatigue (2.8%) and in week 3 for dizziness (5.1%). The duration of each dizziness, somnolence, or fatigue event was variable, ranging from 1 day to >3 months (Table 2). Median duration was shorter in total PER vs PBO for fatigue (52 vs 77 days) but longer in total PER vs PBO for dizziness (28 vs 13 days) and somnolence (55 vs 34 days).Conclusions: Analyses from the pooled phase III trials provide greater insight into patients reporting dizziness, somnolence, and fatigue while taking PER. The majority of these TEAEs were mild or moderate in severity and typically occurred during the titration period, with duration variable across dose groups. Considering the long half-life of PER, the weekly dose uptitration used in the phase III trials may in part explain the TEAE rates. The slower titration used in the open-label extension study 307 (2mg increments every 2 wk) may be an option for management of these events.