Abstracts

Rationale: Perampanel (PER), a selective, noncompetitive AMPA receptor antagonist, is approved in >35 countries for adjunctive treatment of partial-onset seizures (POS) with or without secondarily generalized seizures in patients with epilepsy aged ≥12 yrs (Canada: ≥18 yrs). US Prescribing Information for PER includes a boxed warning for serious psychiatric and behavioral reactions, including hostility, aggression, irritability, anger, and homicidal ideation and threats. Aggression and irritability have been associated with other antiepileptic drugs (AEDs), including levetiracetam (LEV).¹ Here we present a post-hoc analysis of Phase III POS studies for hostility- and aggression-related adverse events based on concomitant administration of PER and LEV. Methods: Patients with refractory POS enrolled in the 3 Phase III studies were aged ≥12 yrs and receiving 1-3 concomitant AEDs. Following 6-wk baseline, patients were randomized to 19 wks of a once-daily double-blind treatment (6-wk titration, 13-wk maintenance) with placebo (PBO) or PER 8 or 12mg (Studies 304&305) or with PBO or PER 2, 4 or 8mg (Study 306). Study results were pooled for this post-hoc analysis and included 1480 patients. Treatment-emergent adverse events (TEAEs) grouped by concomitant medication of interest, LEV, were reported using narrow & broad Standardized MedDRA Query (SMQ) terms for hostility- and aggression-related events. Narrow & broad SMQs are groupings of MedDRA terms: narrow SMQ identifies cases highly likely to represent the condition of interest; broad SMQ identifies all possible cases, including those only "broadly" related. Results: Patients concomitantly taking LEV (+LEV) included PER=310, PBO=127; patients not taking LEV (−LEV) included PER=728, PBO=315. Hostility- and aggression-related TEAEs based on narrow SMQ terms occurred in 10(3.2%) PER+LEV compared to 21(2.9%) PER−LEV patients and 3(2.4%) PBO+LEV vs 0 PBO−LEV patients. Narrow & broad SMQs for hostility- and aggression-related TEAEs occurred in similar percentages for PER+LEV vs PER−LEV patients and PBO+LEV vs PBO−LEV patients (Table 1). For patients with and without concomitant LEV, a dose relationship for hostility- and aggression-related events (narrow and narrow & broad SMQ terms) was observed, as shown by the increase in incidence rate over PBO for the PER 8 and 12mg groups, driven mainly by irritability, aggression and anger. The majority of hostility- and aggression-related adverse events in patients concomitantly taking LEV were mild or moderate. These reactions occurred in patients with and without prior psychiatric history or prior aggressive behavior. Conclusions: Safety data from the Phase III POS studies appears to show no additional liability for hostility/aggression TEAEs with PER concomitant with LEV, although data reported here are limited. Patients, their caregivers and families should be aware of the potential hostility- and aggression-related adverse reactions associated with PER, as outlined in the boxed warning, especially when taking higher doses. Support: Eisai Inc. Ref:¹Piedad.CNS Drugs 2012;26:319-35