Safety Of Perampanel Research Articles

Perampanel in children with refractory epilepsy

Introduction: Approximately 30% of children with epilepsy, will develop drug-resistance and will fail to achieve satisfactory control of their seizures. New antiepileptic drugs may benefit patients with uncontrolled epilepsy. Perampanel is a selective antagonist of AMPA-type glutamate receptor, approved as adjunctive therapy for the treatment of partial-onset seizures with or without secondary generalized seizures and in idiopathic generalized epilepsy, in patients aged ≥12 years. Data on perampanel efficacy and tolerability in children are sparse. Objective: To assess the effectiveness and safety of perampanel as an adjunctive therapy in children and adolescents with drug-resistant epilepsy. Methods: We collected retrospective data on 5 children treated with add-on PER, monitored in the department of pediatric neurology in Children's Hospital ‘P. & A. Kyriakou', Athens, Greece. As PER is not licensed for children younger than 12 years, it was used as a rescue therapy in patients with particularly aggressive disease. Results: Two patients experienced significant improvement of their seizures (one became seizure free), one experienced mild deterioration and three patients did not experience any change. PER was well-tolerated by all subjects and no side effects were reported. Conclusion: PER may be useful in the treatment of selected children with difficult epilepsy. As it is well tolerated and has minimal propensity to cause pharmacokinetic interactions, it could be safely tried especially in multi-drug treatment settings.

Perampanel as add-on treatment in refractory focal epilepsy. The Dianalund experience.

Perampanel (PER) is an antagonist of AMPA receptors that has been approved for adjunctive treatment of partial-onset seizures. To evaluate effectiveness and safety of PER as add-on treatment in patients with severely refractory focal epilepsy. PER was introduced as add-on treatment in 22 consecutive patients with drug-resistant focal epilepsy. PER was started with 2 mg/day at bedtime and was up-titrated by 2 mg/day every 2-4 weeks. All patients suffered from severely refractory focal epilepsy (86% took 2 or more AEDs prior PER initiation; 40% had been submitted to surgery or were surgery candidates; 7 had VNS). After 12 months since PER initiation, the retention rate was 54.5% and the responder rate was 27.2%, including 9.1% seizure-free patients. Mean PER dose in the responders was 8 mg/day (range 4-10). Most common side effects were tiredness, behavioral changes (primarily aggressivity), dizziness and were reported in 59.1% of patients, leading to PER discontinuation in 31.8% of subjects. PER as add-on treatment can achieve clinically meaningful improvement in patients suffering from severely refractory focal epilepses. Further studies are warranted to explore the tolerability profile, with particular focus on psychiatric adverse events.

Efficacy and safety of perampanel in patients with drug-resistant partial seizures after conversion from double-blind placebo to open-label perampanel

To evaluate the efficacy and safety of perampanel in patients with drug-resistant partial seizures after the conversion from double-blind placebo in three phase III studies to open-label perampanel, and to assess the impact of perampanel titration rates through a comparison of weekly vs biweekly dose increases. Patients who completed the three multinational, double-blind, placebo-controlled, phase III core studies (studies 304, 305, or 306) were eligible to enroll in the extension study (study 307). Patients completing the double-blind treatment (6-week titration, 13-week maintenance) with placebo (DB-PBO) or perampanel (DB-PER) began the extension study with a 16-week blinded conversion period, during which DB-PBO patients were switched to perampanel. Doses were titrated in 2-mg increments (biweekly) to an individualized maximum tolerated dose of perampanel (up to 12 mg/day). Patients then entered a planned, open-label treatment period. Perampanel treatment during the extension study reduced total seizure frequency/28 days relative to the double-blind prerandomization baseline regardless of prior perampanel or placebo treatment in the core studies. In the DB-PBO patients, median percent reductions in seizure frequency at the end of the double-blind period, at the end of the conversion period, and at Weeks 40-52 in the open-label maintenance period were 18.6%, 44.3%, and 55.0%, respectively. Seizure control was also improved in the DB-PER patients during the extension period compared to the end of the double-blind period. Responder rates were similar between the 2 patient groups at the end of the conversion period. Perampanel was well tolerated, with the most common treatment-emergent adverse events being dizziness, somnolence, weight increase, irritability, fatigue, and headache. For those patients randomized to the 12 mg group (DB-PER 12 mg), 78.4% reached the daily dose of 10 or 12 mg by the end of the 6-week titration period of the double-blind phase. By the end of the 16-week conversion period of the extension study, 64.0% of DB-PBO patients reached the daily dose of 10 or 12 mg. Seizure frequency reduction was greater after the first 13-week maintenance period of the extension study in the DB-PBO group compared to patients assigned to DB-PER 12mg during the 13-week maintenance period of the double-blind study. Patients who received placebo in the phase III core DB studies and transitioned to perampanel in the open-label extension study (DB-PBO) achieved seizure control at the end of the conversion period similar to that of patients who had been previously exposed to perampanel (DB-PER) as well as comparable safety outcomes. Patients who received perampanel during the core studies and continued with treatment during the extension study (DB-PER) also showed sustained improvements in seizure control with long-term exposure to perampanel.

P41 – 2776: Efficacy and safety of perampanel as add-on treatment for focal refractory epilepsy in children with autism spectrum disorder

Objective The purpose of the study was to evaluate the efficacy and safety of perampanel (PRP) as add-on antiepileptic therapy in children with autism spectrum disorder and refractory focal epilepsy. Methods This was a retrospective review of 5 consecutive autistic patients with refractory focal epilepsy who were exposed to PRP for at least six months. All patients were analyzed for changes in seizure frequency per month, seizure freedom and adverse events (AEs). We also evaluated retention rate of PRP at six months. Results Five patients were included. All of them were male. Mean age was 10.8 years (range 6–14 years). The mean initial dose of PRP was 1.8 mg per day (range: 1–2 mg). The dosage was increased at 2 to 3 weeks intervals by increments of 1 to 2 mg. The mean maintenance dose of PRP was 8.4 mg per day (range 6–12 mg). Mean follow-up duration was 10 months (range 8–12 months). All 5 patients had focal frontal lobe epilepsy. Four of the 5 patients (80%) showed a seizure reduction of >or=50%, including 3 patients (60%) who became seizure-free for at least 3 months. Four patients (80%) reported AEs. The leading AEs were irritability (80%), somnolence (60%), dizziness (40%) and aggression (20%). There was no withdrawal from PRP because of AEs. Improvement in attention and reactivity was observed in 80% of patients. PRP had a retention rate of 80% at 6 months. Conclusion PRP adjunctive therapy is effective and safe for autistic patients with refractory focal epilepsy and has a good retention rate. Tolerability was worse in patients with two or more base-line antiepileptic drugs. All patients with psychiatric AEs had a previous history of behavioural disorders and similar previous reactions to other drugs like levetiracetam, vigabatrin and zonisamide. These AEs improved when we slowed dose titration.

Efficacy and safety of perampanel in the subgroup of elderly patients included in the phase III epilepsy clinical trials

Clinical data regarding use of antiepileptic drugs in the elderly are generally scarce. Therefore, a subanalysis of subjects aged ≥ 65 years who participated in the 3 phase III perampanel studies was undertaken to determine efficacy and safety in these patients. Efficacy (change in seizure frequency/28 days and 50% responder rate) in the elderly subgroup was found to be consistent with the adult population. Adverse event rates were also largely similar, with some exceptions. Because risks of falls, dizziness, and fatigue were greater in the elderly, careful titration of perampanel in patients aged ≥ 65 years is suggested, especially at higher doses, where balancing tolerability and clinical response is necessary.

Perampanel add-on for drug-resistant partial epilepsy

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To investigate the efficacy and safety of perampanel as an add‐on therapy for drug‐resistant partial epilepsy.

Erratum to: Systematic Review and Meta-Analysis of the Efficacy and Safety of Perampanel in the Treatment of Partial-Onset Epilepsy

Erratum to: Systematic Review and Meta-Analysis of the Efficacy and Safety of Perampanel in the Treatment of Partial-Onset Epilepsy

Systematic Review and Meta-Analysis of the Efficacy and Safety of Perampanel in the Treatment of Partial-Onset Epilepsy

IntroductionPerampanel is a first-in-class antiepileptic drug approved for adjunctive treatment of partial-onset seizure in patients aged 12 years or older. Published randomised controlled trials (RCTs) had small sample sizes, and meta-analyses have included too few studies to draw conclusive results for the assessment of tolerability, efficacy and safety of perampanel. There is a need to conduct a meta-analysis with a larger dataset and an appropriate study design.ObjectiveThe aim of this study was to systematically review the efficacy and safety of perampanel in the treatment of partial-onset epilepsy.MethodsElectronic and clinical trials databases were searched for RCTs of perampanel published up to March 2013. Outcomes of interest were 50 % responder rates, seizure freedom, treatment-emergent adverse events (TEAEs) and incidence of withdrawal. Meta-analysis was performed to investigate the outcomes of interest.ResultsFive RCTs with a total of 1,678 subjects were included. The 50 % responder rates were significantly greater in patients receiving 4, 8 and 12 mg perampanel versus placebo, with risk ratios of 1.54 (95 % CI 1.11–2.13), 1.80 (95 % CI 1.38–2.35) and 1.72 (95 % CI 1.17–2.52), respectively. There was no statistical evidence of a difference in seizure freedom between 8 or 12 mg perampanel and placebo. Of the five commonly reported TEAEs included, both dizziness and somnolence were statistically associated with 8 mg perampanel, whilst dizziness was statistically associated with 12 mg perampanel. Incidences of withdrawal due to adverse events were significantly higher in the 8 mg and 12 mg perampanel groups versus placebo.ConclusionThe use of perampanel resulted in a statistically significant reduction of seizure frequency with respect to the 50 % responder rate in patients with partial-onset epilepsy. Perampanel is well tolerated at 4 mg and reasonably tolerated at 8 and 12 mg. Further clinical and pharmacovigilance studies are required to investigate the long-term efficacy and safety of perampanel in the management of other types of epilepsy.Electronic supplementary materialThe online version of this article (doi:10.1007/s40263-013-0091-9) contains supplementary material, which is available to authorized users.

Concentration–effect relationships with perampanel in patients with pharmacoresistant partial‐onset seizures

Although there is a general paucity of published pharmacokinetic (PK) data for new antiepileptic drugs (AEDs), PK analyses of pooled data from clinical studies of perampanel have recently been presented. We present PK/pharmacodynamic (PD) analyses of pooled data from phase III studies of perampanel describing efficacy and safety as a function of exposure, in order to determine whether a predictable concentration-effect relationship exists for perampanel efficacy and/or adverse events (AEs). The effects of concomitant enzyme-inducing AEDs (EIAEDs) and non-enzyme-inducing AEDs on the exposure, efficacy, and safety of perampanel are also considered. Three multicenter, randomized, double-blind, placebo-controlled phase III studies investigated the efficacy and safety of perampanel 2-12 mg in patients with uncontrolled partial-onset seizures despite prior therapy with two or more AEDs. From baseline onward, patients also received ongoing treatment with stable doses of one to three approved concomitant AEDs. AEs were monitored throughout the studies. Changes from baseline in seizure frequency and 50% responder rates were evaluated. Exposure to perampanel was predicted based on the actual (last) dose using a previously established PK model. A population PK/PD model for the relationship between perampanel exposure and seizure frequency was estimated using nonlinear mixed-effect modeling with first-order conditional estimation, whereas logistic analyses for responder rate and AEs were performed using SAS analysis software. The PK/PD population included 1,109 patients. Seizure frequency decreased linearly as predicted perampanel average steady-state plasma concentrations increased. Concomitant EIAEDs (carbamazepine, oxcarbazepine, and phenytoin) reduced exposure to perampanel but had no effect on the slope of the PD model-predicted relationship between exposure and reduction in seizure frequency. The probability of patients achieving a response was predicted to increase as perampanel average plasma concentration at steady state increased. No demographic, AED, region, or study covariate had any effect on the probability of achieving a positive treatment response to perampanel or on the slope of the exposure-response curve. Across the phase III studies, there were reports of dizziness (32.9%), somnolence (21.7%), fatigue (13.9%), irritability (12.3%), gait disturbance (9.1%), weight increase (6.1%), dysarthria (4.5%), and euphoric mood (0.5%); the model-predicted probability of these AEs increased significantly at higher exposure to perampanel (all p < 0.001). There was no effect of demographic variables or region on the probability of experiencing any of the AEs analyzed. PK and PD analyses have played a pivotal role in the clinical development of perampanel as an adjunctive treatment for pharmacoresistant partial-onset seizures. Phase III data suggest that a significant relationship exists between increases in perampanel plasma concentration (i.e., systemic exposure) and reductions in seizure frequency. In addition, increases in perampanel plasma concentration may potentially be associated with increases in AE rates. The model-predicted concentration-safety profile of perampanel does not appear to be affected by patient age, gender, or ethnicity. Although concomitant EIAEDs may influence perampanel PK, they do not appear to alter the relationship between perampanel plasma concentration and seizure frequency. Understanding these relationships between perampanel plasma concentration and clinical response will be valuable in utilizing this novel AED.

Randomized phase III study 306

To evaluate the efficacy and safety of perampanel 2, 4, and 8 mg/day added to 1-3 concomitant antiepileptic drugs (AEDs) in patients with uncontrolled partial-onset seizures. During this double-blind, placebo-controlled trial, patients with persisting seizures on 1-3 AEDs were randomized to perampanel 2, 4, and 8 mg/day or placebo following a 6-week baseline phase. Perampanel was titrated weekly by 2 mg/day and maintained at the dose achieved for 13 weeks. Primary endpoints were median percent change in seizure frequency and 50% responder rate. Analysis of covariance was performed on all treated patients with any seizure data (recorded in daily diaries) in the double-blind phase. A total of 706 patients were randomized and received trial medication; 623 completed the trial. Median percent change in seizure frequency-the primary efficacy endpoint-was -10.7%, -13.6%, -23.3%, and -30.8% for placebo, perampanel 2, 4, and 8 mg/day, respectively. The difference from placebo was statistically significant for perampanel 4 mg/day (p = 0.0026) and 8 mg/day (p < 0.0001). The corresponding 50% responder rates were 17.9%, 20.6%, 28.5%, and 34.9%. The difference from placebo was statistically significant for perampanel 4 mg/day (p = 0.0132) and 8 mg/day (p = 0.0003). An apparent dose response was suggested for dizziness, which was the most frequent treatment-emergent adverse event. This trial demonstrated that adjunctive perampanel effectively reduced seizure frequency and possessed a favorable tolerability profile in patients ≥12 years with partial-onset seizures (with or without secondary generalization), with a minimum effective dose of 4 mg/day. This study provides Class I evidence that 4 and 8 mg/day doses of adjunctive perampanel are effective and tolerated in reducing partial-onset seizures.

Tolerability and safety of perampanel: two randomized dose-escalation studies

To evaluate, for the first time in patients with epilepsy, the tolerability and safety of escalating doses of oral perampanel, a novel, selective, non-competitive AMPA antagonist, as adjunctive therapy for refractory partial-onset seizures. Two consecutive, randomized, double-blind, dose-escalation studies recruited adults (18-70 years) with uncontrolled partial-onset seizures receiving one to three concomitant antiepileptic drugs. In study 206, patients were treated for 12 weeks (8-week dose-titration, 4-week dose-maintenance) with placebo or perampanel (up to 4 mg/day, dosed once- or twice-daily). In study 208, patients received placebo or perampanel once-daily (up to 12 mg) for 16 weeks (12-week titration, 4-week maintenance). Overall, 153 patients were randomized into study 206 (perampanel twice-daily, n = 51; perampanel once-daily, n = 51; placebo, n = 51). Study 208 included 48 patients (perampanel once-daily, n = 38; placebo, n = 10). The highest dose in study 206 - 4 mg/day - was well tolerated, with similar proportions of patients tolerating once-daily (82.4%) and twice-daily (82.4%) perampanel and placebo (82.4%) treatments. In study 208 most patients tolerated doses of ≥ 6 mg perampanel once-daily in a Kaplan-Meier analysis. In both studies, the most common adverse events were CNS-related; most were of mild/moderate severity. Perampanel was well tolerated across doses of 4-12 mg/day. The studies showed preliminary evidence of efficacy and identified doses to be evaluated in larger clinical studies.