Clinical experience with perampanel: Focus on psychiatric adverse effects

Highlights

• Retrospective postmarketing survey of perampanel in a regional epilepsy clinic

• Retention rate of 55% and responder rate of 28%

• 6.5% of patients experienced suicidal ideation.

• The most common reasons for drug withdrawal were behavioral and mood-related adverse effects.

Abstract

Background

Perampanel (PER) is a novel antiepileptic drug that inhibits the AMPA class of glutamate receptors. It has been available in the UK since September 2012. We undertook a retrospective analysis of efficacy and tolerability of PER in 47 patients with drug-refractory epilepsy attending a regional epilepsy service in the UK.

Methods

Demographic and clinical data of patients with refractory epilepsy prescribed PER were collected by review of records. Efficacy, as measured by responder rates (> 50% reduction in seizure frequency), retention rates, and adverse effects, was analyzed.

Results

Of the 47 patients prescribed PER, 39 (87%) had focal epilepsy, four (9%) had idiopathic generalized epilepsy, 3 (6%) had symptomatic generalized epilepsy, and 1 had unclassified epilepsy. Patients were taking a median of 2 AEDs (range: 1–5) when starting on PER. The median dose of PER was 8 mg (range: 2–12 mg).

Thirteen (28%) patients were classed as responders, but no patients experienced sustained seizure freedom.

Twenty-one (45%) patients had withdrawn from PER during the study period, with 16 (76%) of them withdrawing due to intolerable adverse effects, 4 due to inadequate seizure control, and 1 due to the combination of both. The most frequent adverse effects requiring withdrawal from PER were behavioral reactions including suicidal ideation (n = 2), aggressive behavior (n = 2), and both (n = 1).

Conclusion

In our experience, PER had a retention rate of 55% and a responder rate of 28%. Psychiatric adverse effects, including suicidal ideation, were the most common reasons for withdrawal.

Introduction

Perampanel (PER) is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist licensed for the treatment of partial-onset seizures. Efficacy in partial-onset seizures was demonstrated in 3 randomized controlled trials [1], [2], [3]. In total, 1480 patients were randomized in the 3 pivotal studies. Overall, 50% responder rates were 28.5% (PER 4 mg); 35.3% (PER 8 mg) and 35.0% (PER 12 mg); all of which were statistically superior to the responder rate to placebo (19.3%) [4]. The proportions of patients in each randomized dose group who discontinued the trials prematurely were as follows: 11.3% (placebo), 14.4% (PER: 2 mg), 8.1% (PER: 4 mg), 14.8% (PER: 8 mg), and 24.3% (PER: 12 mg) [5].

The most frequently reported treatment emergent adverse effects from the 3 RCTs were dizziness, somnolence, fatigue, irritability, nausea, and falls, which were mild in severity in the majority of patients [6]. In the psychiatric domain, irritability, aggression, and depression were more frequently reported by patients on PER compared with those taking placebo. Depression was seen in 2.4% of patients taking PER 12 mg/day and in 1.6% of patients taking placebo. Aggression was reported in 3.1% of patients on PER 12 mg/day and in 0.5% of patients taking placebo [4]. However, rates of depression and aggression in patients taking PER 4 mg/day were lower than those seen in the placebo group. A larger pooled analysis of adverse effects occurring in all patients treated with PER during its development, including phase 2 studies in epilepsy, as well as in Parkinson's disease, also identified dizziness, ataxia, somnolence, irritability, and weight gain as the most frequent adverse effects [7]. Although rates of depression appeared low in the subjects in the RCTs since licensing, concern has been raised regarding the potential of PER to cause suicidality, including a recent report of 3 patients experiencing suicidal ideation after the initiation of PER [8].

Perampanel has been available to be prescribed in the UK since September 2012. Data from regulatory RCTs of AEDs may not be matched by ‘real life’ clinical experience, as RCTs employ rigid dosing schedules and rarely permit significant alterations in concomitant AEDs. Data from open-label postmarketing studies of AEDs can complement those from regulatory trials and help inform the use of newer drugs. In addition, important safety information can emerge from such studies. We, therefore, examined the outcomes from our use of PER in patients attending the Regional Epilepsy Clinic at the Greater Manchester Neurosciences Centre, which serves a population of 3.2 million in the north west of England.