Abstracts

Rationale: Perampanel (PER), a selective, noncompetitive AMPA receptor antagonist, has been approved as adjunctive treatment for partial-onset seizures (POS) in patients 12 yrs old with epilepsy. PER US prescribing information (PI) includes a boxed warning for serious psychiatric and behavioral reactions. To provide context for this warning, more detail on psychiatric and behavioral safety from PER clinical studies are reviewed. Methods: The total safety database consisted of data from epilepsy (POS), non-epilepsy, and healthy volunteer populations. Serious and non-serious treatment-emergent adverse events (TEAEs) were evaluated using MedDRA dictionary search terms and standard MedDRA queries (SMQs). Narrow and broad SMQs are groupings of MedDRA terms; narrow SMQ identifies cases that are highly likely to represent the condition of interest, and broad SMQ identifies all possible cases, including broadly related cases.Results: Details for each population are included in Table 1. When all hostility- and aggression-related TEAEs from phase III double-blind (DB) POS trials were grouped (using narrow and broad SMQ terms), there was a dose-related increase (2mg: 5%, 4mg: 5%, 8mg: 12%, 12mg: 20%, total PER: 12% vs placebo [PBO]: 6%); the most common TEAE was irritability (total PER 7.0% vs PBO 2.9%). Serious TEAEs from phase III DB POS (narrow and broad SMQ) occurred in 7 (0.7%) of PER patients vs 1 (0.2%) of PBO patients. These reactions have occurred in patients with and without prior psychiatric history, prior aggressive behavior, or concomitant use of medications associated with hostility and aggression. Psychiatric/behavioral events in other populations provide additional safety data. In the all-treated population (POS and non-epilepsy patients), events associated with homicidal ideation and/or threat were exhibited in 6 (0.1%) PER patients (1 in phase III DB POS, 4 in phase III open-label extension [OLE] POS, 1 in non-epilepsy) and 0 PBO. In the non-epilepsy DB population, psychiatric TEAEs occurring in PER more often than PBO included disorientation (0.3% vs 0.1%), delusion (0.3% vs 0.1%), and paranoia (0.2% vs 0.0%); 2 of these events were SAEs in PER patients and discontinuation of treatment due to these events occurred in 9 patients in total PER group and 1 in placebo group. In healthy subjects, all TEAEs related to psychiatric disorders were mild or moderate; none were serious adverse events (SAEs), and none led to treatment discontinuation.Conclusions: The PER US PI includes a warning on serious psychiatric and behavioral reactions. Patients and caregivers should be counseled regarding potential for risk of psychiatric events with PER, and patients should be monitored for these events during treatment, especially during titration and at higher doses.