Abstracts

Rationale: The safety and tolerability of perampanel (PER) in patients (≥12yrs) with partial seizures has been well documented in 3 double-blind (DB) Phase 3 studies (Studies 304/305/306). The PER US Prescribing Information includes a Boxed Warning for serious psychiatric and behavioral reactions. In the Phase 3 partial seizure studies, using narrow and broad Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) terms for hostility/aggression, the incidence rate over placebo (PBO) in 8 and 12mg PER treatment groups was greater, driven mainly by irritability. Study 332, a randomized DB PBO-controlled study, was conducted to evaluate the efficacy and safety of adjunctive PER treatment in subjects aged ≥12yrs with uncontrolled primary generalized tonic-clonic seizures (PGTCS). This analysis reviews psychiatric and behavioral events from Study 332 using adverse event (AE) reporting to further understand PER and psychiatric and behavioral events.Methods: Subjects (≥12yrs) had a clinical diagnosis of PGTCS and were taking 1-3 concomitant AEDs. Following baseline period (4 or 8 wks), subjects were randomized into PER or PBO groups for DB Treatment Phase [Titration (4 wks); Maintenance (13 wks)], with a maximum dose of 8mg. Serious and non-serious treatment-emergent AEs (TEAEs) were evaluated using MedDRA search terms for psychiatric disorders and MedDRA SMQs for hostility/aggression-related events.Results: In the Safety Analysis Set (N=81, PER and N=82, PBO), the demographics and baseline disease characteristics were similar across the treatment groups, and previous medical histories (including psychiatric disorders) were reviewed for all patients. The median daily PER dose during the study was 8mg. Overall, psychiatric TEAEs occurred in 20 (24.7%) PER- and 16 (19.5%) PBO-treated subjects. The majority of these TEAEs in both groups were considered mild or moderate by the investigators. Using both narrow and broad SMQ terms, frequency of TEAEs-related to hostility/aggression was 18.5% for PER and 4.9% in the PBO group (Table 1). This difference was largely due to a higher rate of irritability in the PER (11.1%) vs PBO (2.4%) group. In PER-treated subjects, the incidences of serious AEs (SAEs) and discontinuations due to TEAEs related to hostility/aggression (narrow and broad SMQ terms) were 1.2%(n=1) and 3.7%(n=3), respectively; the incidences in PBO-treated patients were 0% and 1.2%(n=1). The first TEAEs related to hostility/aggression (narrow and broad SMQ terms) occurred by Week 1 in 3 PER-treated subjects and by Week 5 in 1 PBO-treated subject.Conclusions: The data presented here in subjects with uncontrolled PGTCS treated with PER are consistent with results seen in the Phase III clinical studies in partial seizures in which hostility/aggression-related TEAEs occurred at a higher rate in PER-treated patients than in those treated with PBO and were driven mainly by irritability. Patients and caregivers should be informed of potential psychiatric/behavioral risks associated with PER. Support: Eisai Inc.