Abstracts

Rationale: A 2008 US FDA alert warned of increased risk of suicidal ideation and behavior in people treated with antiepileptic drugs (AEDs) based on a meta-analysis of 199 placebo (PBO)-controlled trials of 11 AEDs. Perampanel (PER) is a first-in-class, selective, orally active noncompetitive AMPA receptor antagonist approved in >35 countries, including the US and in the EU, for adjunctive treatment of partial-onset seizures (POS) with/without secondarily generalized seizures in patients with epilepsy aged ≥12yrs (Canada: ≥18yrs). PER was not included in the 11-AED meta-analysis, but the US Prescribing Information does include the class warning for increased risk of suicidal ideation and behavior. Here we review suicidal behaviors/ideation reported in PER clinical studies (Table 1). Methods: Total safety database included data from epilepsy (POS) and nonepilepsy populations and healthy volunteers from Phase I studies (Table 1). Nonserious and serious treatment-emergent adverse events (TEAEs and SAEs) were evaluated using Medical Dictionary for Regulatory Activities (MedDRA) preferred terms. Suicidal behaviors/ideation were determined retrospectively based on adverse event reporting. Results: TEAEs related to suicidality in the Phase III double-blind (DB) POS population included suicidal ideation (PBO: n=2, 0.5%; PER: n=2, 0.2%) and intentional multiple drug overdose (PER: n=1, 0.1%); 2 of these events were SAEs: suicidal ideation (PER 8mg) and multiple drug overdose-intentional (PER 12mg). In PER patients, all suicidality-related TEAEs led to study discontinuation; in PBO patients, none of these events led to study discontinuation. Among 1651 PER patients in the all-treated POS population, 18 (1.0%) had TEAEs related to suicidality [DB: n=3; open-label extension (OLE): n=15] vs 2 (0.4%) of 510 PBO patients. In addition to suicidal ideation, suicidal attempt was reported in 4 PER patients (0.2%). Of the 18 PER patients with suicidality-related TEAEs, 13 reported SAEs and 11 discontinued. No deaths due to TEAEs were related to suicidality. The exposure-adjusted rate was 0.001 subjects/subject-month for PER patients in the all-treated POS population and for PBO patients in the Phase III DB studies. In the nonepilepsy population treated with PER, suicidality-related TEAEs were observed in 2 (0.5%) patients with neuropathic pain and 3 (0.2%) with Parkinson's disease: 4 events were SAEs; 1 led to discontinuation. Volunteers from Phase I studies did not report suicidality-related TEAEs. Conclusions: The data reported here reflect the clinical trial experience for suicidal ideation/behavior events. The PER US Prescribing Information contains a class warning for suicidal behavior/ideation. It should be emphasized that patients on AEDs including PER should be monitored for emergence or worsening of depression, suicidal thoughts/behavior or unusual mood/behavior changes. Support: Eisai Inc.