perampanel and Seizures

N-methyl-d-aspartate receptors (NMDARs) are ligand-gated ion channels that mediate excitatory synaptic transmission and brain development in the central nervous system. Mutations in GRIN2D encoding the NMDAR subunit GluN2D are associated with a wide spectrum of neurodevelopmental disorders.. We report a novel de novo GRIN2D variant (NM_000836.2: c.2024C > T, p.Ala675Val) in an infant with severe developmental and epileptic encephalopathy. Clinical characteristics and treatment outcomes of patients with GRIN2D-related developmental and epileptic encephalopathy were summarized by reviewing the literature.. In silico analysis suggested this p.Ala675Val variant residing in the highly conserved M3 helix of GluN2D would interfere with channel gating. Therapeutic options including multiple anticonvulsants, oral corticosteroid therapy, and ketogenic diet failed to achieve seizure control. Eventually, adjunctive therapy with perampanel led to marked electroclinical improvement.. Perampanel can be beneficial adjuvant therapy for patients with GRIN2D-related intractable epilepsy. Mechanistic understanding and case-per-se analysis are required to enable more individualized treatment for the patients.

Topics: Epilepsy, Generalized; Humans; Infant; Nitriles; Pyridones; Receptors, N-Methyl-D-Aspartate; Seizures

This study was undertaken to estimate the cost-effectiveness of add-on cenobamate in the UK when used to treat drug-resistant focal seizures in adults who are not adequately controlled with at least two prior antiseizure medications, including at least one used adjunctively.. We estimated the cost per quality-adjusted life-year (QALY) for cenobamate compared to brivaracetam, eslicarbazepine, lacosamide, and perampanel in the UK National Health Service over a lifetime time horizon. We used a Markov cohort structure to determine response to treatment, using pooled data from three long-term studies of cenobamate. A network meta-analysis informed the likelihood of response to therapy with brivaracetam, eslicarbazepine, lacosamide, and perampanel relative to cenobamate. Once individuals discontinued treatment, they transitioned to subsequent treatment health states, including other antiseizure medicines, surgery, and vagus nerve stimulation. Costs included treatment, administration, routine monitoring, event management, and adverse events. Published evidence and expert opinion informed the likelihood of response to subsequent treatments, associated adverse events, and costs. Utility data were based on Short-Form six-dimension form utility. Discounting was applied at 3.5% per annum as per National Institute for Health and Care Excellence guidance. Uncertainty was explored through deterministic and probabilistic sensitivity analyses.. In the base case, cenobamate led to cost savings of £51 967 (compared to brivaracetam), £21 080 (compared to eslicarbazepine), £33 619 (compared to lacosamide), and £28 296 (compared to perampanel) and increased QALYs of 1.047 (compared to brivaracetam), 0.598 (compared to eslicarbazepine), 0.776 (compared to lacosamide), and 0.703 (compared to perampanel) per individual over a lifetime time horizon. Cenobamate also dominated the four drugs across most sensitivity analyses. Differences were due to reduced seizure frequency with cenobamate relative to comparators.. Cenobamate improved QALYs and was less costly than brivaracetam, eslicarbazepine, lacosamide, and perampanel. Therefore, cenobamate may be considered as a cost-effective adjunctive antiseizure medication for people with drug-resistant focal seizures.

Topics: Adult; Anticonvulsants; Cost-Benefit Analysis; Drug Resistant Epilepsy; Humans; Lacosamide; Seizures; State Medicine

Perampanel (PER) is a novel antiepileptic drug. The efficacy, tolerability and safety of PER in children and adolescents with epilepsy are still unclear. We aimed to study the efficacy and safety of PER in children and adolescents with epilepsy.. We searched PubMed, Embase and Cochrane Library for relevant literature up to November 2022. Then we extracted the relevant data from eligible literature for systematic review and meta-analysis.. Twenty-one studies involving 1968 children and adolescent patients were included. A reduction in seizure frequency of at least 50 percent occurred in 51.5% (95% confidence interval [CI] [47.1%, 55.9%]) of patients. Complete seizure cessation occurred in 20.6% (95%CI [16.7%, 25.4%]). The incidence of adverse events was 40.8% (95%CI [33.8%, 48.2%]). The most common adverse events were drowsiness 15.3% (95% CI [13.7%, 16.9%]), irritability 9.3% (95%CI [8.0%, 10.6%]), dizziness 8.4% (95% CI [7.2%, 9.7%]). The incidence of drug discontinuation due to adverse events was 9.2% (95% CI [7.0%, 11.5%]).. PER is generally well tolerated and effective in the treatment of epilepsy in children and adolescents. Larger studies are still needed to explore the application of PER in children and adolescents.. The funnel plot suggests that there may be publication bias in our meta-analysis, and most of the included studies were Asian, so there may be some racial differences.

Topics: Adolescent; Anticonvulsants; Child; Drug Therapy, Combination; Epilepsy; Humans; Seizures; Treatment Outcome

Epilepsy is one of the most common neurological disorders. Approximately 30% of people with epilepsy are considered to be drug-resistant, and usually need treatment with a combination of other antiepileptic drugs. Perampanel is a newer antiepileptic drug that has been investigated as add-on therapy for drug-resistant focal epilepsy.. To evaluate the benefits and harms of perampanel as add-on therapy for people with drug-resistant focal epilepsy.. We used standard, extensive Cochrane search methods. The latest search date was 20 October 2022.. We included randomised controlled trials comparing add-on perampanel with placebo.. We used standard Cochrane methods. Our primary outcome was 1. 50% or greater reduction in seizure frequency. Our secondary outcomes were 2. seizure freedom, 3. treatment withdrawal due to any reason, 4. treatment withdrawal due to adverse effects, and 5.. We used an intention-to-treat population for all primary analyses. We presented the results as risk ratios (RR) with 95% confidence intervals (CIs), except for individual adverse effects, which we reported with 99% CIs to compensate for multiple testing. We used GRADE to assess certainty of evidence for each outcome.. We included seven trials involving 2524 participants, all aged over 12 years. The trials were double-blind, randomised, placebo-controlled trials with treatment duration of 12 to 19 weeks. We assessed four trials at overall low risk of bias, and three trials at overall unclear risk of bias, due to risk of detection, reporting, and other biases. Compared with placebo, participants receiving perampanel were more likely to achieve a 50% or greater reduction in seizure frequency (RR 1.67, 95% CI 1.43 to 1.95; 7 trials, 2524 participants; high-certainty evidence). Compared to placebo, perampanel increased seizure freedom (RR 2.50, 95% CI 1.38 to 4.54; 5 trials, 2323 participants; low-certainty evidence) and treatment withdrawal (RR 1.30, 95% CI 1.03 to 1.63; 7 trials, 2524 participants; low-certainty evidence). Participants treated with perampanel were more likely to withdraw from treatment due to adverse effects compared to those receiving placebo (RR 2.36, 95% CI 1.59 to 3.51; 7 trials, 2524 participants; low-certainty evidence). A higher proportion of participants receiving perampanel reported one or more adverse effects when compared to participants who received placebo (RR 1.17, 95% CI 1.10 to 1.24; 7 trials, 2524 participants; high-certainty evidence). Compared with placebo, participants receiving perampanel were more likely to experience ataxia (RR 14.32, 99% CI 1.09 to 188.31; 2 trials, 1098 participants; low-certainty evidence), dizziness (RR 2.87, 99% CI 1.45 to 5.70; 7 trials, 2524 participants; low-certainty evidence), and somnolence (RR 1.76, 99% CI 1.02 to 3.04; 7 trials, 2524 participants). Subgroup analysis indicated that a larger proportion of participants who received perampanel at a dose of 4 mg/day (RR 1.38, 95% CI 1.05 to 1.83; 2 trials, 710 participants), 8 mg/day (RR 1.83, 95% CI 1.51 to 2.22; 4 trials, 1227 participants), or 12 mg/day (RR 2.38, 95% CI 1.86 to 3.04; 3 trials, 869 participants) achieved a 50% or greater reduction in seizure frequency compared to placebo; however, treatment with perampanel 12 mg/day also increased treatment withdrawal (RR 1.77, 95% CI 1.31 to 2.40; 3 trials, 869 participants).. Add-on perampanel is effective at reducing seizure frequency and may be effective at maintaining seizure freedom for people with drug-resistant focal epilepsy. Although perampanel was well-tolerated, there was a higher proportion of treatment withdrawals with perampanel compared with placebo. Subgroup analysis suggested that 8 mg/day and 12 mg/day are the most efficacious perampanel doses; however, the use of 12 mg/day would likely increase the number of treatment withdrawals. Future research should focus on investigating the efficacy and tolerability of perampanel with longer-term follow-up, as well as exploring an optimal dose.

Topics: Aged; Anticonvulsants; Drug Resistant Epilepsy; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Epilepsies, Partial; Humans; Randomized Controlled Trials as Topic; Seizures

To compare the efficacy and safety of antiseizure medications (ASMs), both as monotherapies and adjunctive therapies, for idiopathic generalized epilepsies (IGEs) and related entities.. Two reviewers independently searched PubMed, Embase, and the Cochrane Library for relevant randomized controlled trials from December 2022 to February 2023. Studies on the efficacy and safety of ASM monotherapies or adjunctive therapies for IGEs and related entities-including juvenile myoclonic epilepsy, childhood absence epilepsy (CAE), juvenile absence epilepsy, or generalized tonic-clonic seizures alone (GTCA)-were included. Efficacy outcomes were the proportions of patients remaining seizure free for 1, 3, 6, and 12 months; safety outcomes were the proportions of any treatment-emergent adverse event (TEAE) and TEAEs leading to discontinuation. Network meta-analyses were performed in a random-effects model to obtain odds ratios and 95% confidence intervals. Rankings of ASMs were based on the surface under the cumulative ranking curve (SUCRA). This study is registered with PROSPERO (No. CRD42022372358).. Twenty-eight randomized controlled trials containing 4282 patients were included. As monotherapies, all ASMs were more effective than placebo, and valproate and ethosuximide were significantly better than lamotrigine. According to the SUCRA for efficacy, ethosuximide ranked first for CAE, whereas valproate ranked first for other types of IGEs. As adjunctive therapies, topiramate ranked best for GTCA as well as overall for IGEs, while levetiracetam ranked best for myoclonic seizures. For safety, perampanel ranked best (measured by any TEAE).. All of the studied ASMs were more effective than placebo. Valproate monotherapy ranked best overall for IGEs, whereas ethosuximide ranked best for CAE. Adjunctive topiramate and levetiracetam were most effective for GTCA and myoclonic seizures, respectively. Furthermore, perampanel had the best tolerability.

Topics: Anticonvulsants; Child; Epilepsy, Generalized; Ethosuximide; Humans; Levetiracetam; Network Meta-Analysis; Randomized Controlled Trials as Topic; Seizures; Topiramate; Valproic Acid

The last decade has seen an increase in the use of anti-seizure medications (ASMs); however, the burden of treating drug-resistant epilepsy has not fallen. We performed this meta-analysis to evaluate the optimal dose of Perampanel (PER) as a new adjunctive treatment for drug-resistant seizures.. We searched for studies published from inception to February 1, 2021 from PubMed, Central Register of Controlled Trials (CENTRAL), and ScienceDirect. Research characteristics, patients' characteristics, and treatment regimen, concomitant ASMs, clinical outcomes were extracted. The practical outcome included a reduction in seizures frequency ≥50%, ≥75%, and ≥100% from baseline convulsive seizure frequency, and the safety outcome included the proportion of drug withdrawal and adverse reactions. Odds ratios (OR) for 95% confidence intervals (95% CI) were estimated by the inverse variance method.. Four trials which enrolled 2187 participants (1569 in the PER group and 618 in the placebo group) were included. Results showed that 8 or 12 mg per day had the best effect on all three outcomes, with no significant difference between 8 and 12 mg per day (≥50% reduction, 35.5% vs 36.1%, P = .84; ≥75% reduction, 17.8% vs 19.1%, P = .64; seizure-free, 3.5% vs 3.7%, P = .85). In addition, 12-mg PER compared to 8 mg had a higher proportion of trial withdrawal (8.7% vs 17.0%; P < .00001) and treatment-emergent adverse event (TEAE) resulting in dose reduction/discontinuation (18.5% vs 32.0%; P < .00001). The adverse events (AEs) significantly associated with adjunctive PER were dizziness, somnolence, fatigue, and irritability.. Adjunctive treatment of PER was associated with a more significant reduction in the frequency of seizures in patients with refractory epilepsy than placebo, but with a higher frequency of AEs. PER at a daily dose of 8 mg appears to have the best ratio between efficacy and tolerance in most study participants.

Topics: Anticonvulsants; Drug Resistant Epilepsy; Epilepsy; Humans; Nitriles; Pyridones; Seizures; Treatment Outcome

Brivaracetam (BRV), cenobamate (CNB), eslicarbazepine acetate (ESL), lacosamide (LCM) and perampanel (PER) are antiseizure medications (ASMs) approved for adjunctive treatment of focal-onset seizures. So far, no randomised controlled trial directly compared the efficacy and safety of these drugs.. We estimated the comparative efficacy and safety of these ASMs for the treatment of focal-onset seizures in adults with epilepsy using a network meta-analysis (NMA).. We systematically searched (June week 4, 2021) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institutes of Health Clinical Trials Registry ( http://www.clinicaltrials.gov ). There were no date limitations or language restrictions. Randomised, double-blinded, controlled, parallel-group, add-on studies that compared oral BRV, CNB, ESL, LCM, and PER versus any comparator over maintenance periods of at least 12 weeks and included adult patients with focal seizures uncontrolled by concomitant ASMs were identified. The efficacy outcomes were the proportions of patients with ≥ 50% and 100% reduction in baseline seizure frequency during the maintenance period. The tolerability outcomes were the proportions of participants who experienced at least one treatment-emergent adverse event (TEAE) and experienced at least one TEAE leading to discontinuation. Effect sizes were estimated by network meta-analyses within a frequentist framework. The hierarchy of competing interventions was established using the surface under the cumulative ranking curve (SUCRA).. Sixteen trials (BRV: n = 3, CNB: n = 1, ESL: n = 4, LCM: n = 4, PER: n = 4) were included, overall enrolling 4507 patients randomised to add-on active treatments (BRV = 803, CNB = 221, ESL =9 90, LCM = 1104, and PER = 1389) and 2246 to add-on placebo. Cenobamate was associated with a higher rate of ≥ 50% seizure frequency reduction than BRV [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.11-3.66], ESL (OR 1.93, 95% CI 1.07-3.48), LCM (OR 1.86, 95% CI 1.04-3.32), and PER (OR 2.07, 95% CI 1.16-3.70). There was a not statistically significant trend favouring CNB over ESL, LCM and PER for the seizure freedom outcome. Brivaracetam (OR 0.61, 95% CI 0.44-0.86) and LCM (OR 0.60, 95% CI 0.40-0.88) were associated with a lower proportion of participants experiencing TEAEs compared to ESL, and patients treated with PER were associated with a higher risk to experience at least one TEAE (OR 1.42, 95% CI 1.02-1.96) than BRV. According to SUCRA, CNB had the greatest likelihood of being the best option for the ≥ 50% and 100% seizure frequency reduction, and BRV and LCM had the highest probabilities of being the best-tolerated treatments.. Cenobamate ranked best for efficacy, and BRV and LCM were best tolerated over the other comparators. Although NMAs cannot replace direct comparisons, they may support physicians in clinical decision making.

Topics: Adult; Anticonvulsants; Carbamates; Chlorophenols; Dibenzazepines; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Lacosamide; Male; Middle Aged; Network Meta-Analysis; Nitriles; Pyridones; Pyrrolidinones; Randomized Controlled Trials as Topic; Seizures; Tetrazoles

Focal seizures are associated with various co-morbidities. Seizure disorders also affect the quality of life of the patients. A huge proportion of patients continue to have uncontrolled seizures despite the availability of numerous antiepileptic drugs. Novel therapeutic targets too, have failed to overcome this problem. Therefore, drugs acting on conventional targets are being explored. Perampanel is one such drug. The present study aimed to assess its efficacy, safety, and effect on quality of life and cognition in patients aged 12 years and above.. Database search was conducted using keywords perampanel, partial seizures and randomized controlled trials (RCTs). Single and double blinded RCTs were included in the analysis. The primary outcomes assessed were 50% responder rate and seizure freedom rates. Secondary outcomes assessed were Improvement in Clinical Global Improvement for Change (CGI-C), number of patients who experienced adverse events, number of patients who withdrew from trials, adverse drug reaction (ADR) profile from Vigibase, long term safety, quality of Life (QoL) assessment and cognitive assessment, especially in adolescents. The Risk ratios (RR) were calculated for these parameters.. 24 full text articles were obtained out of a total 421 studies. From these seven double blind randomized controlled trials were included in the meta-analysis. Perampanel treated patients showed higher 50% responder rates than those treated with placebo. The Risk Ratios (RRs) were 1.39 [95% confidence interval (CI) 1.08-1.79], 1.83 [95% CI 1.51 - 2.22] and 1.81 [95% CI 1.45-2.27] for the 4 mg per day, 8 mg once daily and 12 mg once daily subgroups of perampanel respectively. The RRs for the seizure freedom rates were 4.52 [95% CI 1.30-15.73], 3.65 [95% CI 1.40-9.52] and 2.14 [95% CI 1.11-4.11] for 4 mg per day, 8 mg once daily and 12 mg once daily subgroups of perampanel respectively. There was a significantly higher risk of TEAEs with the 8 mg and 12 mg doses of perampanel as compared to that with placebo. Number of patients who withdrew from the trials due to adverse events was statistically significant in only the 12 mg subgroup of perampanel in comparison to that with placebo group.. Perampanel was observed to be an effective add on drug for treating pharmacoresistant focal seizures. The patients achieved higher 50% response rates and freedom from seizures with its use. Tolerability of perampanel was more at lower doses.

Topics: Adolescent; Epilepsies, Partial; Humans; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Seizures; Treatment Outcome

Epileptic myoclonus or myoclonic seizures can occur in idiopathic generalized epilepsy (IGE) and progressive myoclonus epilepsy (PME). However, symptomatic myoclonus which is stimulus-sensitive and provoked by movement is typically seen in PME and Lance-Adams syndrome. Symptomatic myoclonus is not always associated with epileptiform discharges on the electroencephalogram. Therapeutic interventions such as anti-seizure medications (ASMs), the ketogenic diet and vagus nerve stimulation are not always effective. There is emerging evidence that perampanel (PER), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, may be effective for the treatment of myoclonic seizures and symptomatic myoclonus. We performed a systematic review of the literature to assess the efficacy of PER as treatment for myoclonic seizures and symptomatic myoclonus. Twenty-seven studies with a total sample size of 260 patients were included. The efficacy of PER was analysed separately for myoclonic seizures and symptomatic myoclonus. In the group with myoclonic seizures, 50% responder, 75% responder and seizure freedom rates were reported as 74.3% (101/ 136), 60.3% (82/136) and 57.4% (78/136), respectively, with a follow-up duration of 6-12 months. However, in one post-hoc analysis of data from patients with IGE, the efficacy of PER as treatment for myoclonic seizures during the double-blind phase showed no significant difference compared to placebo. The efficacy of PER for symptomatic myoclonus was reported in a total of 119 patients. Four studies (n=88 patients) reported the efficacy of PER as a decrease in myoclonus score/scale. In the remaining 31 patients, symptomatic myoclonus resolved in three patients, decreased in 21 patients and seven patients showed no improvement. We also analysed the number of patients who were already on levetiracetam (LEV) or valproic acid (VPA) at the time of PER initiation; these data were available for 153 patients. Of these, 56.8% were on LEV and 75.1% were on VPA when PER was initiated. This systematic review suggests that PER maybe effective as treatment for drug-resistant myoclonic seizures and symptomatic myoclonus. It may also be effective in patients who have already failed to respond to LEV and VPA. These findings are preliminary yet encouraging. This study has several limitations, particularly given the scarcity of high-quality randomized controlled trials and marked heterogeneity regarding the type and results of

Topics: Anticonvulsants; Epilepsies, Myoclonic; Epilepsy, Generalized; Humans; Immunoglobulin E; Levetiracetam; Myoclonic Epilepsies, Progressive; Myoclonus; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Seizures; Treatment Outcome; Valproic Acid

In order to characterize the real-world effectiveness and safety of perampanel during clinical use in Europe, we conducted a structured literature search and scoping review of real-world studies conducted in Europe in adolescents (aged ≥ 12 years) or adults who were prescribed perampanel for focal epilepsy or primary generalized tonic-clonic seizures in the context of idiopathic generalized epilepsy, published between January 2016 and July 2021. We identified 29 relevant studies (20 retrospective and 9 prospective) in 3608 patients; median study duration was 12 months. Most patients (76.1%) were receiving two or more antiseizure drugs (ASDs) when perampanel was initiated. The maintenance perampanel dose ranged from 2 to 16 mg/day (most commonly 6 mg/day). Retention rate at 12 months ranged from 46% to 90.5% (median 71.1%). The proportion of patients who were free of seizures during perampanel ranged from 1.8% to 84.6%, but were consistently below 20% in studies where patients had received an average of ≥5 prior ASDs and above 20% where patients had received an average of <5 prior ASDs. The proportion of patients who achieved ≥50% reduction in seizures during perampanel ranged from 20.0% to 85.7%. Across all studies, the incidence of adverse events (AEs) ranged from 18.2% to 67.4% (median 37.1%) and discontinuation due to AEs from 6.2% to 56% (median 12.5%). Discontinuation rates tended to be higher in UK studies than in studies from Italy or Spain. The most commonly reported individual AEs were dizziness/vertigo (median incidence 13.7%), somnolence (median 11.9%), aggression (median 9.8%), irritability (median 9.1%), and cognitive deficits (median 7.0%). There was no relationship between the overall rate of AEs and perampanel dose, perampanel plasma levels, or number of concomitant medications. Our global overview of European observational studies with perampanel provides evidence that this agent is effective and safe in clinical practice in a range of countries, patients, and settings.

Topics: Adolescent; Adult; Anticonvulsants; Drug Therapy, Combination; Europe; Humans; Nitriles; Prospective Studies; Pyridones; Retrospective Studies; Seizures; Treatment Outcome

Perampanel (PER) has been used clinically as monotherapy and adjunctive therapy for focal seizures and as adjunctive therapy for generalized tonic-clonic seizures in epilepsy patients in Japan. In recent years in Japan and worldwide, clinical studies have been conducted on patients with various seizure types of epilepsy. The results have shown that PER has broad spectrum properties. The pooled analysis of controlled trials (PERMIT study) showed PER efficacy in patients with status epilepticus, myoclonic seizures, and absence seizures. In addition, PER has been shown to be safe and effective in patients with juvenile myoclonic epilepsy, Lennox-Gastaut syndrome, and elderly-onset epilepsy that are often difficult to treat with narrow-spectrum ASM. In this review article, we summarize the latest findings on PER, and overview the broad spectrum characteristics of PER. In addition, we discuss the optimal use of PER for patients with epilepsy, focusing on low-dose initiation and on slow titration of PER to minimize adverse events. (Received December 7, 2021; Accepted March 29, 2022; Published July 1, 2022).

Topics: Aged; Anticonvulsants; Epilepsy; Epilepsy, Generalized; Humans; Nitriles; Pyridones; Seizures; Treatment Outcome

Perampanel a third-generation antiseizure medication, belongs to a new promising class of drugs called AMPA receptor antagonists, approved to treat focal-onset seizures with or without focal to bilateral tonic clonic seizures and primary generalized tonic-clonic seizures.. This review included RCTs on patients with epilepsy exposed to perampanel compared with placebo, or one or more pre-existing antiseizure medications. Four databases and two clinical trial registries were searched from inception to July 2021. Included outcomes were 50% responder rate, seizure-free rate, discontinuation due to treatment-emergent adverse events (TEAE)s, having any TEAEs, and most reported TEAEs. Cochrane risk of bias tool was used to assess the internal validity of the included RCTs.. From 2211 retrieved citations, eight RCTs were included in the meta-analysis. Fifty-percent responder and seizure freedom rates were significantly higher in patients receiving perampanel when compared to placebo (RR 1.57, 95 % CI 1.35 to 1.82, I. This systematic review reports significant reduction in seizures and a potential dose-based increase in discontinuations due to TEAE. The most-reported TEAEs were non-threatening, with the possibility of rare but serious adverse psychological outcomes. Further independent RCTs studying the most efficient dose for efficacy and safety are needed.

Topics: Anticonvulsants; Drug Therapy, Combination; Epilepsy; Humans; Pyridones; Randomized Controlled Trials as Topic; Seizures; Treatment Outcome

Information on the effects of perampanel in Chinese children ≤12 years of age with refractory epilepsy is limited; thus, we conducted an observational study to assess the effectiveness, safety, and tolerability of adjunctive perampanel in this pediatric population. In this study, we reviewed the medical records of pediatric patients aged 4 to 12 years with refractory epilepsy who were admitted to Children's Hospital of Soochow University and prescribed perampanel between January 2020 and January 2021. Effectiveness of perampanel was measured by 50% responder rates, seizure-freedom rates, and retention rates for up to 48 weeks. Adverse events were monitored and recorded throughout the study. A total of 34 patients (male, n = 15) who exhibited refractory epilepsy were included in this study, and 64.71% of patients had focal-onset seizures combined with generalized epilepsy. The mean (± standard deviation) age of patients was 7.21 (± 2.12) years, with a mean (± standard deviation) age at seizure onset of 4.57 (± 2.59) years. After the addition of perampanel, the 50% responder rates at 4, 8, 12, 24, 36, and 48 weeks were 37.50% (12/32), 43.75% (14/32), 53.13% (17/32), 59.38% (19/32), 59.38% (19/32), and 62.07% (18/29). Two patients withdrew from perampanel treatment due to adverse events in the first 2 weeks. Adverse events were reported by 44.12% (15/34) of patients, and the retention rates at 36 and 48 weeks were 94.12% (32/34) and 85.29% (29/34), respectively. Overall, perampanel exhibited good effectiveness, safety, and tolerability in the treatment of pediatric patients (aged 4-12 years) with refractory epilepsy. These findings suggest that personalized treatment and better baseline seizure control may increase the responder rate and retention rate of perampanel.

Topics: Anticonvulsants; Child; Drug Resistant Epilepsy; Humans; Male; Observational Studies as Topic; Pyridones; Seizures; Treatment Outcome

To date, there has not been a single randomized controlled trial (RCT) conducted to directly compare the efficacy and safety of perampanel to brivaracetam in the adjunctive treatment of focal-onset seizures. This study makes these comparisons through the use of indirect treatment comparison (ITC) methods.. A systematic review was conducted to identify RCTs that evaluated either one of perampanel or brivaracetam in the treatment of patients with focal-onset seizures. The Bucher ITC method was then used to compare efficacy and safety outcomes between perampanel and brivaracetam. Additional subgroup analyses, by levetiracetam usage (prior or concomitant), were conducted.. Eight RCTs (four comparing perampanel to placebo, four comparing brivaracetam to placebo) were included in the ITC. For patients taking concomitant levetiracetam, perampanel showed a significantly better responder rate compared to brivaracetam [relative risk (RR) and 95 % confidence interval (CI): 2.62 (1.15, 5.99)]. For patients who had previously, or never, taken levetiracetam, there was no difference in the responder rate. In the overall population, both perampanel and brivaracetam were more effective than placebo in terms of responder rate, seizure freedom, and secondarily generalized tonic-clonic seizure responder rate; however, for these outcomes, no evidence of a difference between perampanel and brivaracetam was found. Patients taking brivaracetam showed significantly less dizziness compared to patients taking perampanel. No differences for any other safety outcome were found.. Perampanel and brivaracetam are effective for the adjunctive treatment of focal-onset seizures and display similar adverse event profiles. Perampanel demonstrated an improved focal-onset seizure responder rate compared to brivaracetam in patients taking concomitant levetiracetam. This may be due to the similarity in the mechanism of action between brivaracetam and levetiracetam.

Topics: Anticonvulsants; Drug Therapy, Combination; Humans; Levetiracetam; Nitriles; Pyridones; Pyrrolidinones; Randomized Controlled Trials as Topic; Seizures; Treatment Outcome

Topics: Animals; Anticonvulsants; Drug Therapy, Combination; Epilepsies, Partial; Epilepsy, Generalized; Humans; Nitriles; Pyridones; Seizures

Medical therapy is the mainstay of management of epilepsy. Despite the increasing number of available antiepileptic drugs (AEDs), approximately one-third of epileptic patients do not have adequate control of seizures. There is still a need for the development of new AEDs with enhanced effectiveness and tolerability. Areas covered: The present manuscript is based on an Internet and PubMed search (January 2005 to August 2018). It is focused on pharmacokinetic and clinical data of perampanel (PER) for the treatment of epilepsy. Expert opinion: PER has a novel mechanism of action, which opens up new options for a rational combination therapy. Phase III trials have demonstrated the efficacy and safety of PER as adjunctive therapy for the treatment of partial-onset seizures (POS) and primary generalized tonic-clonic seizures in patients aged ≥12 years. PER is also approved by FDA as monotherapy for the treatment of POS. A clinical trial is ongoing to verify the efficacy and safety of PER monotherapy in untreated patients with POS. In the future, head-to-head comparisons are needed to determine the exact position of PER relative to other AEDs. Moreover, further studies are needed to evaluate the efficacy and safety of PER in patients aged <12 years.. 4βOHC: 4β-hydroxycholesterol; AUC: area under the curve; CBZ: Carbamazepine; CLCr: creatinine clearance; Cmax: maximum plasma concentration; CYP: cytochrome P; EIAED: enzyme-inducing antiepileptic drug; EMA: European Medicines Agency; FDA: Food and Drug Administration; GI: gastrointestinal; OXC: oxcarbazepine; PER: perampanel; PGTC: primary generalized tonic-clonic; PHT: phenytoin; POS: partial-onset seizures; QD: once-daily; TEAE: treatment-emergent adverse event; Tmax: median time to reach peak concentration; UGT: uridine diphosphoglucose-glucuronosyltransferase; VPA: valproic acid.

Topics: Animals; Anticonvulsants; Child; Epilepsy; Humans; Nitriles; Pyridones; Seizures; Treatment Outcome

In previous works, alterations of neurotransmitters and neuropeptides in the brain areas involved in generalized epilepsy have been reported.. We reviewed the alterations of these neurotransmitters and neuropeptides in the following brain areas involved in generalized epilepsy: hippocampus, hypothalamus, thalamus and cerebral cortex. In these brain areas, the neural networks are also actualized. The mechanisms of action of newer antiepileptic drugs in the treatment of generalized epilepsy are also discussed.. Up-dating the neurotransmitter and neuropeptide alterations, we found that hippocampal GABAergic neurons presynaptically inhibit epileptogenic neurons via GABAB receptors. Epilepsy modulating neuropeptides (galanin, neuropeptide Y, dynorphin) are also involved. GABA deficiency, serotonin hyperactivity, dopamine hyperactivity and glutamate excitotoxicity can enhance ictogenesis: neurons containing these neurotransmitters form the main neural circuit. An increased excitability occurs when the alteration of these neurotransmitters is permanent.. In preclinical studies, the GABAB receptor agonist GS 39,783 exerted a good antiepileptic effect. Perampanel, an AMPA receptor antagonist, showed good clinical effects in the treatment of partial-onset seizures and primary generalized tonic-clonic seizures. In this treatment, perampanel can be combined with other antiepileptic drugs. Brivaracetam, which shows a high affinity for the synaptic vesicle 2A, exerted a good efficacy in the treatment of adult focal seizures and secondarily generalized tonic-clonic seizures.

Topics: Anticonvulsants; Cyclopentanes; Epilepsy, Generalized; GABA Antagonists; Humans; Nerve Net; Neurotransmitter Agents; Nitriles; Pyridones; Pyrimidines; Pyrrolidinones; Receptors, AMPA; Seizures

Epileptic seizures are refractory to treatment in approximately one-third of patients despite the recent introduction of many newer antiepileptic drugs (AEDs). Development of novel AEDs therefore remains a high priority. Perampanel is a first-in-class non-competitive selective AMPA receptor antagonist with a unique mechanism of action. Clinical efficacy and safety of perampanel as adjunctive treatment for focal seizures with/without secondary generalization (±SG) and primary generalized tonic-clonic (PGTC) seizures have been established in five phase 3 randomized controlled trials (RCTs), and a long-term extension study, and perampanel is approved as monotherapy for focal seizures ±SG in the USA. In patients with focal seizures ±SG, add-on perampanel resulted in median percent reduction in seizure frequency 23.3%-34.5% and ≥50% responder rate 28.5%-37.6%; in PGTC seizures, these results were 76.5% and 64.2%, respectively. Efficacy among adolescents (reduction in seizure frequency 34.8%-35.6%; ≥50% responder rate 40.9%-45.0%) and elderly people (reduction in seizure frequency 12.5%-16.9%; ≥50% responder rate 22.2%-42.9%) is similar to those in adults, and results remain comparable between Asian (reduction in seizure frequency 17.3%-38.0%) and global populations. Perampanel has been extensively studied in real-world clinical practice, with similar efficacy and safety results to the RCTs (≥50% responder rate 12.8%-75.0%; adverse events of somnolence/sedation, dizziness, ataxia, and behavioral changes). Real-world observational studies suggest that perampanel tolerability can be improved by slow titration (2 mg every 2-4 weeks), and bedtime administration can mitigate somnolence and dizziness. Counseling about the potential for behavioral changes and close monitoring are recommended.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Female; Humans; Male; Nitriles; Pyridones; Receptors, AMPA; Seizures; Treatment Outcome

A generalized tonic-clonic seizure (GTCS) is the most severe form of common epileptic seizure and carries the greatest risk of harm. The aim of this review is to provide an evidence-based guide for the selection of antiepileptic drugs (AEDs) for patients with GTCSs. Eight AEDs are approved in Europe and the USA for the treatment of both primarily GTCSs (PGTCSs) and secondarily GTCSs (SGTCSs) and are considered in this paper.. Each AED is evaluated using five criteria: (1) efficacy, by seizure type (a: PGTCSs and b: SGTCSs); (2) adverse effects; (3) interactions; (4) adherence and dosing; and (5) mechanism of action (MOA). To ensure the inclusions of robust data, only efficacy data accepted by regulatory authorities were considered, and data related to adverse effects, interactions, adherence, and MOA were all extracted from UK Summaries of Product Characteristics (SPCs).. (1a) There is class 1 evidence of the efficacy of only four AEDs in controlling PGTCSs (lamotrigine, levetiracetam, perampanel, and topiramate). (1b) There is no class 1 evidence of the efficacy of any AED in SGTCSs although some evidence from pooled/subgroup analyses or meta-analyses supports the use of the four AEDs (levetiracetam, perampanel, topiramate, and with less robust data for lamotrigine). (2) AEDs are associated with different, but to some extent overlapping, common adverse effect profiles but have differing idiosyncratic adverse effects. (3) Pharmacokinetic interactions are seen with most, but not all, AEDs and are most common with carbamazepine and phenytoin. (4) Good adherence is important for seizure control and is influenced by frequency of dosing, among other factors. (5) Mechanism of action is also a consideration in rationalising AED selection when switching or combining AEDs.. Ultimately, the choice of AED depends on all these factors but particularly on efficacy and adverse effects. Different patients will weigh the various factors differently, and the role of the treating physician is to provide accurate information to allow patients to make informed choices.

Topics: Anticonvulsants; Benzodiazepines; Carbamazepine; Drug and Narcotic Control; Drug-Related Side Effects and Adverse Reactions; Humans; Lamotrigine; Levetiracetam; Nitriles; Phenytoin; Pyridones; Seizures; Topiramate; Treatment Outcome

Perampanel is a first-in-class antiepileptic medication approved for the treatment of partial (focal) seizures, and as adjunctive treatment for primarily generalized tonic-clonic seizures. The pharmacology, efficacy data, adverse-effect profile, pharmacokinetics and place in therapy are reviewed.. Perampanel is indicated for use in patients with epilepsy who are 12 years of age or older. It is the first medication designed specifically to be a non-competitive antagonist at post-synaptic α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors. Efficacy in refractory seizures has been established, and ongoing efficacy demonstrated by post-marketing data. The drug is completely absorbed, and exhibits a half-life that allows for once-daily administration in doses up to 12 mg/day. Drug interactions are minimal, but increased doses may be necessary when given with strong inducers of cytochrome P450 enzymes, including when perampanel is co-administered with other antiepileptics that exhibit this property. The most common adverse effects noted in both clinical trials and post-marketing are dizziness and somnolence. Psychiatric and behavioral adverse events have been documented in both adult and pediatric patients, including those with no corresponding diagnostic history.. Perampanel is a novel adjunctive antiepileptic medication that is an effective option for adolescents and adults with partial seizures, and primarily generalized tonic-clonic seizures uncontrolled with other medications.

Topics: Adolescent; Adult; Anticonvulsants; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Epilepsy; Humans; Nitriles; Pyridones; Seizures

Four "third-generation" antiepileptic drugs (AEDs) were approved for adjunctive treatment of refractory focal onset seizures during the past 10 years. Long-term efficacy and safety of the drugs were demonstrated in large extension studies and in reports of subgroups of patients not studied in pivotal trials. Reviewing extension study and post-marketing outcome series for the four newer AEDs-lacosamide, perampanel, eslicarbazepine acetate and brivaracetam-can guide clinicians in treating and monitoring patients. AED extension studies evaluate treatment retention, drug tolerability, and drug safety during individualized treatment with flexible dosing and thus provide information not available in rigid pivotal trials. Patient retention in the studies ranged from 75 to 80% at 1 year and from 36 to 68% at 2-year treatment intervals. Safety findings were generally similar to those of pivotal trials, with no major safety risks identified and with several specific adverse drug effects, such as hyponatremia, reported. The third-generation AEDs, some through new mechanisms and others with improved tolerability compared to related AEDs, provide new options in efficacy and tolerability.

Topics: Acetamides; Anticonvulsants; Dibenzazepines; Drug-Related Side Effects and Adverse Reactions; Follow-Up Studies; Humans; Lacosamide; Longitudinal Studies; Medication Adherence; Nitriles; Product Surveillance, Postmarketing; Pyridones; Pyrrolidinones; Seizures

The non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) - receptor antagonist perampanel (PER) was approved in 2015 for treatment of primary generalized tonic-clonic seizures (pGTCS). The aim of this narrative review is to summarize available data on pharmacological properties, efficacy and tolerability of PER in pGTCs.. Data sources included MEDLINE, EMBASE, Google Scholar and ClinicalTrials.gov, conference proceedings of the ILAE congresses and the most recent conference proceedings of the American Epilepsy Society (2013 to 2015).. A placebo-controlled clinical phase III study including 164 patients (≥ 12 years) with pGTCS in idiopathic generalized epilepsies (IGE) demonstrated efficacy of PER in reducing pGTCS with good tolerability profile, and without aggravating absence seizures or myoclonic seizures. Dizziness, the main adverse event (AE), can be avoided by bedtime administration. Psychiatric AEs ranging from mild depression to aggression and suicidal attempts should be especially monitored in patients with a history of psychiatric disorders. Co-administration of enzyme inducing antiepileptic drugs (AEDs) might decrease PER plasma levels and make dose adjustment necessary. A reduced efficacy of progesterone-containing oral contraceptives should be considered when administering PER to young women. There is lack of evidence on PER treatment in pregnancy. Although no teratogenic effects were observed in animal models, PER is not recommended for women of childbearing age without contraception.

Topics: Anticonvulsants; Drug Therapy, Combination; Epilepsy, Generalized; Epilepsy, Tonic-Clonic; Humans; Mental Disorders; Nitriles; Pyridones; Receptors, AMPA; Seizures; Treatment Outcome

Perampanel (Fycompa®), an orally-active, selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, is a first-in-class antiepileptic drug (AED) offering the convenience of once-daily administration. In the EU and US, perampanel is approved in patients with epilepsy aged ≥12 years for the adjunctive treatment of primary generalized tonic-clonic seizures (GTCS) and partial-onset seizures (POS; with or without secondary generalization). In phase III trials of 17 or 19 weeks' duration, add-on perampanel ≤12 mg/day significantly improved seizure control in patients aged ≥12 years who were experiencing either primary GTCS or POS (with or without secondary generalization), despite ongoing treatment with stable dosages of one to three AEDs. Improvements in seizure control were maintained for up to 2 years in extensions of these core studies. Perampanel also provided sustained seizure control for up to ≈4 years in an extension of two phase II studies in patients aged ≥18 years with drug-resistant POS. Adjunctive perampanel therapy was generally well tolerated. Treatment-emergent adverse events were most commonly CNS-related (e.g. dizziness, somnolence, fatigue and irritability) and dose-related; however, most were of mild to moderate intensity. Clinical experience with perampanel is accumulating, although comparative studies and pharmacoeconomic data that could assist in positioning it relative to other AEDS that are approved and/or recommended as adjunctive therapy are lacking. Nonetheless, on the basis of its overall clinical profile and unique mechanism of action, perampanel is a useful additional adjunctive treatment option for patients with drug-resistant POS, with or without secondary generalization, and primary GTCS.

Topics: Anticonvulsants; Drug Resistant Epilepsy; Humans; Nitriles; Pyridones; Seizures

Quality of life is directly related to the number and severity of adverse effects, and a successful antiepileptic medication must demonstrate a good balance between efficacy and tolerability. Perampanel is a newly licensed antiepileptic medication for the adjunctive treatment of patients (age 12 and older) with partial epilepsy with or without secondary generalization. Safety endpoints in the three phase III trials (304, 305, and 306) included treatment-emergent adverse events (TEAEs), vital signs, clinical laboratory parameters, and electrocardiography studies (ECGs). The most common adverse drug reactions in patients receiving perampanel were dizziness, somnolence, fatigue, irritability, nausea, and falls. Of particular concern to patients are cognitive and psychiatric side effects. Overall, depression and aggression were reported more frequently in patients taking perampanel, particularly at higher doses, than in patients taking placebo. TEAEs necessitated the withdrawal of perampanel in 99 patients (9.5%) and placebo in 21 patients (4.8%). Typically this was due to dizziness, convulsion, and somnolence. There were no clinically important changes or treatment group differences in vital signs, ECG measures, or biochemical or hematologic parameters. Weight increase of greater than 7% was seen in 14.6% of perampanel-treated patients versus 7.1% of placebo-treated patients. Overall, perampanel appears to be associated with a relatively low incidence of serious adverse effects, particularly at low doses, and the majority of TEAEs were mild or moderate in intensity. The incidence of predictable side effects, such as somnolence and dizziness, is seen more frequently at higher doses. Of importance is the greater rate of psychiatric side effects in patients treated with perampanel, principally, irritability and aggression, than with placebo. However, the rate of serious psychiatric TEAEs was low.

Topics: Anticonvulsants; Dizziness; Epilepsy; Female; Humans; Male; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Seizures; Treatment Outcome

Several antiepileptic drugs are available for the treatment of epileptic patients. However, the treatment of some seizure types and novel drug formulations deserve further advances in epilepsy research.. The authors analyze the published evidence on the efficacy of perampanel against secondarily generalized seizures (SGS) and report the currently available development of intravenous (IV) formulations of carbamazepine (CBZ), commenting on their potential in the clinical setting.. Perampanel is the first noncompetitive AMPA receptor antagonist to be approved as adjunctive treatment in patients with partial-onset (focal) seizures (POS) with or without secondary generalization. Apart from its efficacy and safety on POS, a consistent body of evidence supports its efficacy in SGS at a minimum dose of 8 mg/day; however, such dose appears close to the best-tolerated dose. CBZ is a poorly water-soluble compound; many efforts to develop a parenteral formulation have not been successful so far. Novel IV CBZ formulations seem to exhibit favorable pharmacokinetics along with good tolerability in animal models and in patients taking oral CBZ. Further studies are needed to assess whether larger doses will be as well tolerated, allowing IV CBZ to be used as bridge therapy when the oral route is not feasible or in patients naïve to CBZ.

Topics: Animals; Anticonvulsants; Carbamazepine; Clinical Trials, Phase III as Topic; Epilepsy, Generalized; Humans; Infusions, Intravenous; Injections, Intravenous; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Seizures; Treatment Outcome

Secondary generalized tonic-clonic seizures (SGTCS) are among the most severe forms of seizures, and the main risk factor for sudden unexpected death in epilepsy (SUDEP). Whether some antiepileptic drugs (AEDs) might be more efficacious than others on SGTCS in patients with drug-resistant focal epilepsy thus represents an important clinical issue for which no data are currently available.. We performed a meta-analysis of randomized controlled trials of adjunctive AED in which information on efficacy outcomes (i.e., responder rate and/or frequency per 28 days relative to baseline) were available both for all seizure types and for SGTCS. The primary analysis evaluated the efficacy of AEDs on all types of seizure and on SGTCS by comparing the responder rates for AED and for placebo.. Responder rate was available both for all seizure types and for SGTCS in 13 of the 72 eligible trials, evaluating 7 AEDs. Only three AEDs--lacosamide, perampanel and topiramate--showed greater efficacy than placebo. However, confidence intervals of relative risks overlapped for all AEDs but pregabalin, which demonstrated significantly lower efficacy than lacosamide, perampanel, and topiramate. Moreover, there was a nonsignificant trend toward a lower relative risk of responder rate for SGTCS than for all seizure types, which appeared related to a greater response to placebo for this outcome.. Indirect comparison of AEDs using randomized placebo-controlled add-on trials does not support robust differences between AEDs to prevent SGTCS. Alternative designs for evaluation of therapeutic interventions in patients at risk for SGTCS-related complications are required.

Topics: Acetamides; Anticonvulsants; Chronic Disease; Death, Sudden; Early Medical Intervention; Epilepsies, Partial; Fructose; Humans; Lacosamide; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Recurrence; Risk Factors; Seizures; Topiramate; Treatment Outcome

To identify adverse events (AEs) significantly associated with perampanel treatment in double-blind clinical studies (RCTs). Serious AEs, study withdrawals due to AEs and dose-effect responses of individual AEs were also investigated.. All placebo controlled, double-blind RCTs investigating therapeutic effects of oral perampanel were searched. AEs were assessed for their association with perampanel after exclusion of synonyms, rare AEs and non-assessable AEs. Risk difference (RD) was used to evaluate the association of any AE (99% confidence intervals) and withdrawals or serious AEs (95% confidence intervals) with perampanel.. Nine RCTs (five in pharmacoresistant epilepsy and four in Parkinson's disease) were included in our study. Almost 4000 patients had been recruited, 2627 of whom were randomized to perampanel and treated with drug doses of 0.5 mg/day (n = 68), 1 mg/day (n = 65), 2 mg/day (n = 753), 4 mg/day (n = 1017), 8 mg/day (n = 431) or 12 mg/day (n = 293). Serious AEs were not significantly associated with perampanel treatment. The experimental drug was significantly associated with an increased risk of AE-related study withdrawals at 4 mg/day [RD (95% confidence interval) 0.03 (0.00, 0.06)] and 12 mg/day [RD (95% confidence interval) 0.13 (0.07, 0.18)]. Of 15 identified AEs, five (dizziness, ataxia, somnolence, irritability and weight increase) were found to be significantly associated with perampanel and one (seizure worsening) was significantly associated with placebo.. Vestibulocerebellar AEs (dizziness, ataxia), sedative effects (somnolence), irritability and weight increase were significantly associated with perampanel treatment.

Topics: Anticonvulsants; Confidence Intervals; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance; Epilepsies, Partial; Epilepsy; Humans; Nitriles; Parkinson Disease; Pyridones; Randomized Controlled Trials as Topic; Risk Assessment; Seizures

This paper compares the efficacy and tolerability of perampanel (PER) relative to other recently approved anti-epileptic drug (AEDs) - lacosamide (LCS), retigabine (RTG), and eslicarbazepine (ESL) for the adjunctive treatment of partial onset seizures with or without secondary generalization and specifically in the secondary generalization subgroup.. A systematic literature review of all RCTs of PER and selected AEDs in EMBASE, Medline, and the Cochrane Central from 1998 to January 2011 with an update in PubMed in March 2013 was performed. A network meta-analysis was conducted for 50% responder rate for overall seizures; withdrawal due to adverse events; seizure freedom; and 50% responder rate for secondary generalized seizures.. Twelve RCTs (three PER, three LCS, three RTG and three ESL) were included. PER performed significantly better than placebo for 'responder rate' (OR 2.151, 95% CrI 1.348-3.472) and 'seizure freedom' (OR 2.507, 95% CrI 1.067-7.429). When compared to other agents, PER was found to be equally effective. For 'withdrawal due to adverse events', PER had the lowest odds ratio vs. placebo compared with other AEDs. In the analysis for the subgroup of patients with secondary generalization, only four RCTs (three PER and one LCS) met the inclusion criteria for one outcome (responder rate) for LCS. In this subgroup, PER was statistically significantly better than placebo (OR 2.448, 95% CrI 1.088-5.828).. PER was statistically significantly superior to placebo in responder rate, seizure freedom, and responder rate in the secondary generalization population. Though PER had statistically significant greater withdrawal compared to placebo, it had the lowest ORs vs. placebo, suggesting a superior safety profile among the comparators included in this analysis. In patients with partial onset seizure with secondary generalization, PER had a statistically significant effect on responder rate compared to placebo.

Topics: Anticonvulsants; Bayes Theorem; Humans; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Seizures

This study was undertaken to evaluate perampanel (PER) when used under real-world conditions to treat people with idiopathic generalized epilepsy (IGE) included in the PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) study.. The multinational, retrospective, pooled analysis PERMIT explored the use of PER in people with focal and generalized epilepsy treated in clinical practice across 17 countries. This subgroup analysis included PERMIT participants with IGE. Time points for retention and effectiveness measurements were 3, 6, and 12 months (last observation carried forward, defined as "last visit," was also applied to effectiveness). Effectiveness was evaluated by seizure type (total seizures, generalized tonic-clonic seizures [GTCS], myoclonic seizures, absence seizures) and included ≥50% responder rate and seizure freedom rate (defined as no seizures since at least the previous visit). Safety/tolerability was monitored throughout PER treatment and evaluated by documenting the incidence of adverse events (AEs), including psychiatric AEs and those leading to treatment discontinuation.. The Full Analysis Set included 544 people with IGE (51.9% women, mean age = 33.3 years, mean epilepsy duration = 18.1 years). At 3, 6, and 12 months, 92.4%, 85.5%, and 77.3% of participants were retained on PER treatment, respectively (Retention Population, n = 497). At the last visit, responder and seizure freedom rates were, respectively, 74.2% and 54.6% (total seizures), 81.2% and 61.5% (GTCS), 85.7% and 66.0% (myoclonic seizures), and 90.5% and 81.0% (absence seizures) (Effectiveness Population, n = 467). AEs occurred in 42.9% of patients and included irritability (9.6%), dizziness/vertigo (9.2%), and somnolence (6.3%) (Tolerability Population, n = 520). Treatment discontinuation due to AEs was 12.4% over 12 months.. This subgroup analysis of the PERMIT study demonstrated the effectiveness and good tolerability of PER in people with IGE when administered under everyday clinical practice conditions. These findings are in line with clinical trial evidence, supporting PER's use as broad-spectrum antiseizure medication for the treatment of IGE.

Topics: Adult; Anticonvulsants; Drug Therapy, Combination; Epilepsies, Myoclonic; Epilepsy, Absence; Epilepsy, Generalized; Female; Humans; Immunoglobulin E; Male; Pyridones; Retrospective Studies; Seizures; Treatment Outcome

This post hoc analysis evaluated whether continued treatment with perampanel monotherapy beyond initial titration may be appropriate for patients with focal-onset seizures (FOS) with currently untreated epilepsy to achieve seizure freedom with an effective dose.. Study 342 (NCT03201900; FREEDOM) is a single-arm, open-label, Phase III study of perampanel monotherapy. Patients aged ≥12 years with untreated FOS received perampanel 4 mg/d in a 32-week Treatment Phase (6-week Titration and 26-week Maintenance Periods); in case of seizure(s) during Maintenance Period, patients could enter a 30-week Treatment Phase (4-week Titration and 26-week Maintenance Periods) to be up-titrated to perampanel 8 mg/d. The primary endpoint was seizure-freedom rate during Maintenance Period in the modified Intent-to-Treat (mITT) Analysis Set (patients who had ≥1 post-dose efficacy measurement during Maintenance Period); safety was monitored. This analysis of 4-mg/d efficacy data assessed the proportion of patients achieving seizure freedom during the Maintenance Period (responders) relative to patients with an early/later response (depending on seizure status during the Titration Period).. In the mITT population (n = 73), 46 patients were 4-mg/d responders; of whom, 37 (80.4%) were early responders and nine (19.6%) were later responders. The mean (standard deviation) percent reductions in FOS frequency from baseline at the end of the 4-mg/d Titration Period were 100.0% (0.0%; early responders) and 46.3% (97.3%; later responders). Among the 27 4-mg/d nonresponders, nine (33.3%) patients who had an early response experienced seizure(s) during the subsequent 4-mg/d Maintenance Period. Safety outcomes were similar, regardless of responder status, without new safety concerns.. Some patients with untreated FOS may benefit from continued treatment beyond initial titration of perampanel monotherapy to achieve seizure freedom, suggesting that it may not be appropriate to make treatment decisions to discontinue or switch from perampanel monotherapy solely based on seizure response before an effective dose has been reached.

Topics: Anticonvulsants; Child; Double-Blind Method; Epilepsy; Freedom; Humans; Nitriles; Pyridones; Seizures; Treatment Outcome

To assess retention, dosing, efficacy, and safety of perampanel in a large cohort of patients with epilepsy during routine clinical care.. PROVE was a retrospective, non-interventional Phase IV study (NCT03208660). Data were obtained retrospectively from the medical records of patients in the United States initiating perampanel after January 1, 2014, according to treating clinicians' recommendation. Retention rate was the primary efficacy endpoint. Secondary efficacy endpoints included median percent changes in seizure frequency per 28 days from baseline, seizure-freedom rate, and overall investigator impression of seizure effect. Safety endpoints included incidence of treatment-emergent adverse events (TEAEs). Efficacy and safety were also assessed according to baseline use of enzyme-inducing antiseizure medications (EIASMs).. Overall, 1703 patients were enrolled and included in the Safety Analysis Set (SAS; ≥1 baseline EIASMs, n = 358 [21.0%]; no baseline EIASMs, n = 1345 [79.0%]). Mean (standard deviation [SD]) cumulative duration of exposure to perampanel was 17.4 (15.7) months; mean (SD) daily perampanel dose was 5.6 (2.7) mg. The most frequent perampanel titration intervals were weekly (23.4%) and every 2 weeks (24.7%). Across the SAS, 24-month retention rate was 48.1% (n = 501/1042). Based on overall investigator impression at the end of treatment, 51.9%, 35.8%, and 12.3% of patients in the SAS experienced improvement, no change, or worsening of seizures, respectively. TEAEs occurred in 704 (41.3%) patients; 79 (4.6%) had serious TEAEs. The most common TEAE was dizziness (7.3%). There was some variation in efficacy according to EIASM use, while retention rates and safety were generally consistent.. In this final analysis of >1700 patients with epilepsy receiving perampanel in routine clinical care, favorable retention and sustained efficacy were demonstrated for ≥12 months.

Topics: Anticonvulsants; Double-Blind Method; Drug Therapy, Combination; Epilepsy; Humans; Nitriles; Pyridones; Retrospective Studies; Seizures; Treatment Outcome

Since increased mortality rates have been associated with convulsive seizures, it is important to achieve seizure control in these patients. Here, we report post hoc analyses to assess long-term seizure-freedom rates with adjunctive perampanel in patients (aged ≥ 12 years) with refractory focal to bilateral tonic-clonic seizures (FBTCS) or generalized tonic-clonic seizures (GTCS) who participated in open-label extension (OLEx) studies.. Patients with focal-onset seizures, with/without FBTCS, who completed double-blind, Phase III Studies 304, 305, or 306 could enter OLEx Study 307 (16-week blinded Conversion; 256-week Maintenance). Patients with GTCS who completed the double-blind phase of Study 332 could enter the OLEx Phase (6-week blinded Conversion; 136-week Maintenance). Maximum perampanel dose: 12 mg/day. Seizure-freedom rates for up to 24 months were assessed in perampanel-treated patients who achieved seizure freedom during the double-blind studies to determine if their seizure-free status was maintained during the OLEx. In addition, to ensure any patients who only achieved seizure freedom during the OLEx were captured, seizure-freedom rates were also assessed in all patients who achieved and maintained a seizure-free status for a period of at least six consecutive months at any time during the double-blind and/or OLEx studies; some of these patients may have received placebo during the double-blind study but only their time on perampanel is included in the seizure-free analysis. Univariate and multivariate analyses were used to identify predictive factors for achieving seizure freedom for at least 6 months. Treatment-emergent adverse events (TEAEs) were assessed.. Overall, 53.8% (n = 42/78) of patients who received perampanel and were FBTCS free during the double-blind studies remained seizure free for up to 24 months during Study 307, and 31.6% (n = 6/19) of patients who were GTCS free during the double-blind phase of Study 332 remained seizure free for up to 24 months during the OLEx Phase. Over 40% (FBTCS, 41.5% [n = 197/475]; GTCS, 52.9% [n = 73/138]) of patients were seizure free for a period of at least six consecutive months. Multivariate analysis showed that the best predictors of achieving seizure freedom from FBTCS for at least 6 months were lower baseline seizure frequency (p = 0.0014) and absence of enzyme-inducing anti-seizure medications at baseline (p = 0.0056); multivariate analysis was not conducted for GTCS since only one variable was identified as a significant predictor of seizure freedom in the univariate analysis (lower baseline seizure frequency). Perampanel was generally well tolerated with no new safety signals identified. The most common TEAE was dizziness. For both seizure types, 10% or fewer seizure-free patients discontinued perampanel due to TEAEs.. These results suggest that adjunctive perampanel may be a suitable long-term treatment option for patients (aged ≥ 12 years) with convulsive seizures to achieve and maintain seizure freedom.

Topics: Anticonvulsants; Child; Double-Blind Method; Drug Therapy, Combination; Freedom; Humans; Nitriles; Pyridones; Seizures; Treatment Outcome

Assess the longer-term efficacy and safety of adjunctive perampanel (up to 12 mg/day) in patients aged ≥12 years with generalized tonic-clonic (GTC) seizures from the Open-label Extension (OLEx) Phase of Study 332 to determine whether responses obtained during the Core Study are maintained during long-term treatment.. Patients with GTC seizures previously enrolled in a randomized placebo-controlled trial of perampanel could enter an OLEx Phase comprising 6-week blinded conversion (during which patients previously randomized to placebo-switched to perampanel) and up to 136-week maintenance periods (maximum perampanel dose of 12 mg/day). A 4-week follow-up period was completed by all patients after the last on-treatment visit during the OLEx. We assessed seizure frequency outcomes from preperampanel baseline and the Core Study Pre-randomization Phase, retention rates, doses selected, and treatment-emergent adverse events (TEAEs).. Overall, 138 patients entered the OLEx. Median percent reductions in GTC seizures per 28 days from preperampanel were 77% (Weeks 1-13) and 90% (Weeks 40-52). Retention rates were 88% (6 months) and 75% (12 months). Seizure-freedom rates were maintained for at least 2 years regardless of prior treatment received during the Core Study. Most common modal daily dose was >4-8 mg/day (n = 93). Across the Core and OLEx Phases, 120 (87%) patients experienced TEAEs; the most common was dizziness.. Perampanel was generally well-tolerated, and the TEAEs reported here are consistent with the known safety profile of perampanel. Perampanel offers a long-term treatment option for patients (aged ≥12 years) with GTC seizures.

Topics: Anticonvulsants; Double-Blind Method; Epilepsy, Generalized; Humans; Nitriles; Pyridones; Seizures; Treatment Outcome

Report final data from adolescent (12-<18 years) and adult (≥18 years) patients from PROVE (NCT03208660), a multicenter, retrospective, non-interventional, Phase IV study to assess retention, efficacy, safety, and dosing of perampanel in patients with epilepsy during routine clinical care.. Data were retrospectively collected from medical/pharmacy records of patients in the US initiating perampanel after January 1, 2014, according to treating clinicians' recommendation. Retention rate was the primary efficacy endpoint. Secondary endpoints included median percent changes in seizure frequency, seizure-freedom rates, investigator's impression of seizure effect, and treatment-emergent adverse events (TEAEs).. The Safety Analysis Set (SAS) included 294 adolescents and 1157 adults (median maximum perampanel dose, 6.0 mg/day). In patients eligible for inclusion in the retention rate analysis, 24-month retention rates were 53.5% (n=91/170) in adolescents and 47.8% (n=354/741) in adults. In patients with available efficacy data during Months 10-12, median percent seizure frequency reductions were 79.3% (n=20) in adolescents and 70.8% (n=92) in adults. Most patients in the SAS with seizure-effect data experienced an improvement in seizures at the last follow-up time point (adolescents, 51.4% [n=128/249]; adults, 52.3% [n=506/967]). TEAEs occurred in 113 adolescents (38.4%; most common, aggression [6.5%]) and 512 adults (44.3%; most common, dizziness [9.2%]).. Perampanel demonstrated favorable retention rates and sustained efficacy (up to 2 years) in adolescent and adult patients during routine clinical care; no new safety signals were observed.. NCT03208660 (https://clinicaltrials.gov/ct2/show/NCT03208660).

Topics: Adolescent; Adult; Anticonvulsants; Double-Blind Method; Drug Therapy, Combination; Epilepsy; Humans; Nitriles; Pyridones; Retrospective Studies; Seizures; Treatment Outcome

To evaluate the exploratory time to exceed pre-randomization seizure count (T-PSC) in the determination of efficacy of adjunctive perampanel in participants with primary generalized tonic-clonic (PGTC) seizures in generalized-onset epilepsy.. In this multicenter, double-blind study (ClinicalTrials.gov identifier: NCT01393743), participants ≥12 years of age with treatment-resistant idiopathic generalized epilepsy were randomized to receive placebo or adjunctive perampanel (≤8 mg/day) across a 17-week double-blind treatment phase (4-week titration; 13-week maintenance). We evaluated the pre-planned exploratory end point of the T-PSC using a Kaplan-Meier analysis. We also re-evaluated the correspondence of the primary end points of median percent seizure frequency change (MPC) and 50% responder rate (50RR) calculated at T-PSC and at the end of the trial.. The exploratory end point of median T-PSC on placebo was 43 days and >120 days on perampanel (log-rank p < .001). The primary end points calculated at T-PSC did not differ significantly from the end points at the end of the trial (MPC -31% vs -42% at T-PSC; 50RR 32% vs 51% at T-PSC). After T-PSC was reached, participants had a median (interquartile range) of 5 (3-13) additional seizures on placebo and 5 (2-10) on perampanel.. The exploratory end point of T-PSC demonstrated the effectiveness of perampanel despite a shorter duration of monitoring. The seizures that occurred after T-PSC did not influence the conclusions of the trial; therefore, T-PSC may be a viable alternative to traditional trial end points that reduces the risk to participants.

Topics: Anticonvulsants; Double-Blind Method; Drug Therapy, Combination; Humans; Infant, Newborn; Pyridones; Random Allocation; Seizures; Treatment Outcome

This post hoc analysis of four open-label extension (OLEx) studies evaluated the long-term efficacy and safety of adjunctive perampanel in adolescent patients (aged 12 to ≤17 years) with focal-onset seizures (FOS), with/without focal to bilateral tonic-clonic seizures (FBTCS), or generalized tonic-clonic seizures (GTCS).. Patients who completed one of six double-blind, placebo-controlled studies could enter one of four OLEx studies comprising a blinded Conversion Period (6-16 weeks) followed by a Maintenance Phase (27 to ≤256 weeks; perampanel dose: ≤12 mg/day). Exposure, retention, seizure outcomes, and treatment-emergent adverse events (TEAEs) were analyzed. Efficacy outcomes were analyzed using observed case and last observation carried forward (LOCF) approaches; the latter was used to account for early dropouts.. The Full Analysis Set comprised 309 adolescents with FOS (FBTCS, n = 109) and 19 with GTCS, and the Safety Analysis Set comprised 311 with FOS (FBTCS, n = 110) and 19 with GTCS. Mean (standard deviation) cumulative duration of perampanel exposure (weeks) was: FOS, 77.7 (58.7); FBTCS, 88.7 (63.8); and GTCS, 97.0 (35.5). Retention rates were maintained for ≤2 years (FOS, 50.0 %; FBTCS, 57.1 %; GTCS, 41.7 %). Seizure control (median percent reduction in seizure frequency/28 days) was sustained for up to 2 years; FOS (59.4 %, n = 113), FBTCS (64.6 %, n = 53), and GTCS (86.5 %, n = 17). At Year 2, 50 % responder rates were: FOS, 58.4 % (n = 66); FBTCS, 54.7 % (n = 29); and GTCS, 82.4 % (n = 14); seizure-freedom rates were: FOS, 5.3 % (n = 6); FBTCS, 24.5 % (n = 13); and GTCS, 35.3 % (n = 6). Long-term seizure control was observed even in LOCF analyses. The incidence of TEAEs was highest during Year 1 (FOS, n = 269 [86.5 %]; FBTCS, n = 95 [86.4 %]; GTCS, n = 15 [78.9 %]), compared with Years 2-4; the most common (≥10 % of patients) were dizziness, somnolence, and nasopharyngitis. No new safety signals emerged with long-term treatment.. This post hoc analysis suggests that long-term (≤2 years) adjunctive perampanel (≤12 mg/day) is efficacious and generally well tolerated in adolescent patients with FOS, with or without FBTCS, or GTCS.

Topics: Adolescent; Anticonvulsants; Double-Blind Method; Drug Therapy, Combination; Epilepsy; Humans; Nitriles; Pyridones; Seizures; Treatment Outcome

This post hoc analysis assessed the efficacy and safety/tolerability of adjunctive perampanel in patients from China (aged ≥12 years) with focal seizures (FS), with/without focal to bilateral tonic-clonic seizures (FBTCS), or generalized tonic-clonic seizures (GTCS).. Study centers in China were identified using data from five double-blind, randomized, phase III studies of adjunctive perampanel (2-12 mg/day) and their open-label extensions (OLEx). Efficacy assessments included median percent reduction in seizure frequency per 28 days, and 50% and 75% responder and seizure-freedom rates. Safety/tolerability assessments included monitoring of treatment-emergent adverse events (TEAEs).. Overall, 277 patients (placebo, n = 79; perampanel, n = 198) were included in the double-blind safety analysis set. The full analysis set comprised 274 patients (FS, n = 238 [placebo, n = 60; perampanel, n = 178]; FBTCS, n = 120 [placebo, n = 31; perampanel, n = 89]; GTCS, n = 36 [placebo, n = 18; perampanel, n = 18]). Median percent reductions in seizure frequency for placebo vs perampanel were as follows: 16.6% vs 32.4% (FS; P < 0.05) and 39.1% vs 48.2% (FBTCS; not significant [NS]) at 4-12 mg/day, and 37.9% vs 82.6% (GTCS; NS) at 8 mg/day; 50% responder rates were 31.7% vs 37.4% (FS; NS), 48.4% vs 51.9% (FBTCS; NS), and 33.3% vs 61.1% (GTCS; NS), respectively. Seizure-freedom rates were 1.7% vs 9.2%, 16.1% vs 25.3%, and 16.7% vs 44.4%, respectively (all NS). Overall, 262 patients entered the OLEx (FS, n = 228; GTCS, n = 34). Perampanel was efficacious for up to four years for FS and FBTCS and up to two years for GTCS. Across the double-blind and OLEx studies, TEAEs were reported in 65.7% and 81.3% of perampanel-treated patients, respectively; the most common was dizziness. Efficacy and safety/tolerability outcomes were generally similar between Chinese and non-Chinese patients.. Adjunctive perampanel (up to 12 mg/day) may be a suitable treatment for Chinese patients with FS, with/without FBTCS, or GTCS, with similar efficacy and safety/tolerability compared to non-Chinese patients.

Topics: Adolescent; Adult; Anticonvulsants; China; Double-Blind Method; Drug Therapy, Combination; Female; Gastrointestinal Diseases; Humans; Male; Nitriles; Pyridones; Seizures; Treatment Outcome; Young Adult

To assess the retention rate, efficacy, safety, and dosing of perampanel administered to patients with epilepsy during routine clinical care in the retrospective phase IV, PROVE Study (NCT03208660).. Exposure, efficacy, and safety data were obtained from the medical records of patients initiating perampanel after January 1, 2014, across 29 US study sites. The cutoff date for this interim analysis was October 10, 2018. The primary efficacy endpoint was retention rate. Secondary efficacy endpoints included median percent changes in seizure frequency, seizure-freedom rate, and overall investigator impression of seizure effect.. All enrolled patients (N = 1121) received perampanel. Mean (standard deviation [SD]) cumulative duration of exposure to perampanel was 16.6 (14.7) months; overall mean (SD) daily perampanel dose was 5.7 (2.7) mg. Perampanel uptitration occurred weekly (21.1%), biweekly (23.8%), every 3 weeks (1.5%), other (43.3%), and unknown (10.3%). Across the Safety Analysis Set (N = 1121), retention rate on perampanel at 24 months was 49.5% (n = 319/645).At 12 months, the median reduction in seizure frequency per 28 days from baseline in the small number of patients for whom data were available was 75.0% (n = 85), and 30/85 (35.3%) patients were seizure free. Based on investigator impression at the end of treatment, improvement, no change (ie, stable), or worsening of seizures was reported in 54.3%, 33.7%, and 12.0% of patients, respectively.Treatment-emergent adverse events occurred in 500 (44.6%) patients; the most common were dizziness (9.2%), aggression (5.4%), and irritability (4.5%). Serious treatment-emergent adverse events occurred in 32 (2.9%) patients.. Favorable retention and sustained efficacy were demonstrated for ≥12 months following initiation of perampanel during routine clinical care in patients with epilepsy.

Topics: Adult; Anticonvulsants; Dizziness; Double-Blind Method; Epilepsy, Generalized; Female; Humans; Male; Nitriles; Pyridones; Receptors, AMPA; Retrospective Studies; Seizures; Treatment Outcome

This post hoc analysis assessed the efficacy and safety of adjunctive perampanel in patients (aged ≥ 12 years) with focal seizures (FS), with/without focal to bilateral tonic-clonic seizures (FBTCS), or generalized tonic-clonic seizures (GTCS) in India.. Centers in India were identified from six double-blind, randomized, Phase II and Phase III studies of adjunctive perampanel (2-12 mg/day) and their open-label extensions (OLEx). Efficacy assessments included median percent change in seizure frequency per 28 days, 50% and 75% responder and seizure-freedom rates. Treatment-emergent adverse events (TEAEs) were monitored.. Overall, 128 patients (placebo, n = 39; perampanel, n = 89) were included in the double-blind Safety Analysis Set and 126 (FS, n = 113 [placebo, n = 32; perampanel, n = 81]; FBTCS, n = 35 [placebo, n = 14; perampanel, n = 21]; GTCS, n = 13 [placebo, n = 6; perampanel, n = 7]) comprised the Full Analysis Set. Median percent reductions in seizure frequency per 28 days for placebo vs perampanel for Indian patients were as follows: 34.8% vs 49.8% (FS; not significant [NS]) and 43.1% vs 60.5% (FBTCS; NS) at 4-12 mg/day, respectively, and -22.4% vs 8.2% (GTCS; NS) at 8 mg/day, respectively. Fifty-percent responder rates were 37.5% vs 55.1% (FS; NS), 42.9% vs 60.0% (FBTCS; NS), and 16.7% vs 42.9% (GTCS; NS), respectively; seizure-freedom rates were 0.0% vs 5.8%, 7.1% vs 10.0%, and 0.0% vs 14.3%, respectively (all NS). Overall, 110 patients entered OLEx studies (FS, n = 99; GTCS, n = 11). Perampanel was efficacious for up to four years for FS and FBTCS and two years for GTCS. Across double-blind and OLEx studies, TEAEs occurred in 58.4% and 83.6% of Indian perampanel-treated patients, respectively; dizziness was most common. Efficacy and safety outcomes were generally similar overall between Indian and non-Indian patients.. These data suggest adjunctive perampanel (up to 12 mg/day) may be a suitable anti-seizure medication for patients (aged ≥ 12 years) with FS, with/without FBTCS, or GTCS in India.

Topics: Adult; Anticonvulsants; Asian People; Dizziness; Double-Blind Method; Drug Therapy, Combination; Female; Humans; India; Male; Nitriles; Pyridones; Seizures; Treatment Outcome; Young Adult

Study 311 (E2007-G000-311; NCT02849626) was a Phase 3, multicenter, open-label single-arm study of adjunctive perampanel oral suspension in pediatric patients (aged 4 to <12 years) with partial-onset seizures (POS) (with/without secondarily generalized tonic-clonic seizures [SGTCS]) or primary generalized tonic-clonic seizures (PGTCS). Health-related quality of life (HRQoL) was an exploratory endpoint initially analyzed through simple descriptive summaries. The aim of this post hoc analysis was to provide a more thorough assessment of HRQoL.. This analysis focused on EQ-5D-Y data collected at Baseline, Week 23, and Week 52. Individual dimensions, visual analog scale (VAS) and summed misery index (MI) were evaluated at all visits and compared by seizure type (POS versus SGTCS versus PGTCS), age (4 to <7 versus 7 to <12), and use of concomitant enzyme-inducing antiepileptic drugs (EIAEDs) (yes versus no). Paretian Classification of Health Change (PCHC) analysis summarized the proportion of patients who showed improvement or deterioration in HRQoL. Waterfall plots assessed changes in EQ-5D-Y scores by treatment-emergent adverse events (TEAEs) and by reduction in seizure frequency. Health state utility values associated with differing seizure frequency states were estimated using a linear mixed model.. One hundred and fifteen patients completed EQ-5D-Y at relevant study visits (Seizure type: POS n = 84 [of which 21 had SGTCS], PGTCS n = 31; Age: 4 to <7 years n = 30, 7 to <12 years n = 85; Concomitant EIAEDs: Yes n = 35, No n = 80). Completion rates out of those expected to complete EQ-5D-Y were high at both timepoints (84.4% at Week 23 and 97.2% at Week 52). Overall, VAS/MI remained stable over time (did not exceed minimal important difference); this was similar according to seizure type, age, and EIAED usage. In patients with 'no problems' on any EQ-5D-Y dimension at Baseline, nearly all retained their full health at Week 23 (94.7%), and all retained it at Week 52 (100.0%). PCHC analysis showed fewer patients with POS experienced deterioration in EQ-5D-Y than patients with PGTCS at Week 23 (24.1% versus 42.1%). Not experiencing a TEAE, or remaining seizure-free, was associated with improvements in VAS score at Week 23 compared to those experiencing TEAEs or seizures, respectively. Health state utility values (HSUVs) were estimated as follows: seizure free (LS Mean 0.914 [95% CIs 0.587, 1.240]), ≥1 seizure per year (0.620 [0.506, 0.734]), ≥1 seizure per month (0.596 [0.338, 0.855]), ≥1 seizure per week (0.284 [-0.014, 0.582]).. An in-depth analysis of EQ-5D-Y data allowed for a more nuanced exploration of HRQoL than previous descriptive summaries. Our findings provide evidence that perampanel as adjunctive therapy did not result in deterioration of patient HRQoL. The association between TEAEs or remaining seizure-free and HRQoL warrants further exploration. Increasing seizure frequency was associated with decreasing HSUVs; these can inform cost-effectiveness modeling of perampanel and other therapies aiming to reduce seizure frequency in pediatric patients.

Topics: Anticonvulsants; Child; Child, Preschool; Drug Therapy, Combination; Humans; Nitriles; Pyridones; Quality of Life; Seizures; Treatment Outcome

Study 311 (NCT02849626) was a global, multicenter, open-label, single-arm study that assessed safety, tolerability, pharmacokinetics, and pharmacokinetics/pharmacodynamics of once-daily adjunctive perampanel oral suspension in pediatric patients (aged 4 to <12 years) with focal seizures (FS) (with/without focal to bilateral tonic-clonic seizures [FBTCS]) or generalized tonic-clonic seizures (GTCS).. In the 311 Core Study, a 4-week Pre-treatment Period (Screening/Baseline) preceded a 23-week Treatment Period (11-week Titration; 12-week Maintenance) and 4-week Follow-up. Endpoints included safety/tolerability (primary endpoint), median percent change in seizure frequency per 28 days from Baseline (Treatment Period), and 50% responder and seizure-freedom rates (Maintenance Period). Patients were stratified by age (4 to <7; 7 to <12 years) and concomitant enzyme-inducing anti-seizure drug (EIASD) use.. One hundred eighty patients were enrolled (FS, n = 149; FBTCS, n = 54; GTCS, n = 31). The Core Study was completed by 146 patients (81%); the most common primary reason for discontinuation was adverse event (AE) (n = 14 [8%]). Mean (standard deviation) daily perampanel dose was 7.0 (2.6) mg/day and median (interquartile range) duration of exposure was 22.9 (2.0) weeks. The overall incidence of treatment-emergent AEs (TEAEs; 89%) was similar between patients with FS (with/without FBTCS) and GTCS. The most common TEAEs were somnolence (26%) and nasopharyngitis (19%). There were no clinically important changes observed for cognitive function, laboratory, or electrocardiogram (ECG) parameters or vital signs. Median percent reductions in seizure frequency per 28 days from Baseline were as follows: 40% (FS), 59% (FBTCS), and 69% (GTCS). Corresponding 50% responder and seizure-freedom rates were as follows: FS, 47% and 12%; FBTCS, 65% and 19%; and GTCS, 64% and 55%, respectively. Improvements in response/seizure frequency from Baseline were seen regardless of age or concomitant EIASD use.. Results from the 311 Core Study suggest that daily oral doses of adjunctive perampanel are generally safe, well tolerated, and efficacious in children age 4 to <12 years with FS (with/without FBTCS) or GTCS.

Topics: Anticonvulsants; Chemotherapy, Adjuvant; Child; Child, Preschool; Female; Humans; Male; Nitriles; Pyridones; Seizures; Treatment Outcome

This post hoc analysis evaluated the efficacy and safety of adjunctive perampanel 4 mg/d received as modal dose, which may have differed from randomized dose, for treatment of focal seizures.. Data were pooled from four randomized, double-blind, placebo-controlled, phase III studies of adjunctive perampanel in patients (aged ≥12 years) with focal seizures, with/without focal to bilateral tonic-clonic (FBTC) seizures: studies 304 (NCT00699972), 305 (NCT00699582), 306 (NCT00700310), and 335 (NCT01618695). Efficacy assessments included median percentage reductions in seizure frequency per 28 days and seizure-freedom rates for patients receiving placebo and perampanel 4 mg/d (modal dose). Treatment-emergent adverse events (TEAEs) were assessed in patients receiving perampanel 4 mg/d at their TEAE onset. Outcomes were also assessed with/without enzyme-inducing antiseizure medications (EIASMs).. The full analysis set included 979 patients with focal seizures (placebo: n = 616 [235 with FBTC seizures]; perampanel 4 mg/d: n = 363 [134 with FBTC seizures]). Compared with placebo, perampanel 4 mg/d conferred significantly greater median percentage reductions in seizure frequency per 28 days for focal (12.6% vs 21.1%; P = .0004) and FBTC seizures (17.4% vs 49.8%; P < .0001), and seizure-freedom rates for focal (0.8% vs 3.6%; P = .0018) and FBTC seizures (11.1% vs 18.7%; P = .0424). Seizure improvements with perampanel 4 mg/d were greater without EIASMs than with EIASMs. For assessment of TEAEs, overall 1376 patients with focal seizures received perampanel 4 mg/d at any time (FBTC seizures, n = 499). TEAEs with perampanel 4 mg/d occurred in 419 of 1376 (30.5%) and 148 of 499 (29.7%) patients with focal and FBTC seizures, respectively; most common was dizziness. The proportion of TEAEs was similar with or without EIASMs.. This post hoc analysis showed adjunctive perampanel 4 mg/d was efficacious and well tolerated in patients with focal seizures, with or without FBTC seizures. This dose may be a valuable treatment option in patients unable to tolerate higher perampanel doses up to 12 mg/d.

Topics: Adult; Anticonvulsants; Double-Blind Method; Drug Resistant Epilepsy; Epilepsies, Partial; Epilepsy, Tonic-Clonic; Female; Humans; Male; Middle Aged; Nitriles; Pyridones; Seizures; Treatment Outcome

This post hoc analysis evaluated long-term efficacy and safety in patients with focal to bilateral tonic-clonic seizures (FBTCS) or generalized tonic-clonic seizures (GTCS) who entered open-label extension (OLEx) studies to receive long-term adjunctive perampanel.. Patients aged 12 years and older who completed phase II or III randomized, double-blind, placebo-controlled studies could enter an OLEx study, each comprising a blinded conversion period followed by an open-label maintenance period (32-424 weeks; maximum perampanel dose = 12 mg/d). Exposure, seizure outcomes, and treatment-emergent adverse events (TEAEs) were analyzed.. Baseline characteristics were generally balanced between patients with FBTCS (n = 720) and GTCS (n = 138). Mean (standard deviation) cumulative duration of perampanel exposure was 102.3 (70.3) weeks (FBTCS) and 83.9 (38.4) weeks (GTCS). Retention rates were 50.0% for up to 4 years (FBTCS) and 49.2% for up to 2 years (GTCS). Across OLEx treatment durations, median reductions in seizure frequency per 28 days were 66.7% (FBTCS) and 80.6% (GTCS). Fifty percent and 75% responder and seizure-freedom rates were 59.5%, 45.3%, and 18.4%, respectively (FBTCS), and 72.5%, 51.5%, and 16.7%, respectively (GTCS). Efficacy was sustained for up to 4 years (FBTCS) and up to 3 years (GTCS), even when accounting for early dropouts. TEAE incidence was highest during Year 1 (FBTCS, 85.3%; GTCS, 86.2%); most common were dizziness and somnolence. During Year 1, serious TEAEs were reported in 81 (11.3%; FBTCS) and 10 (7.2%; GTCS) patients. TEAEs were consistent with the known safety profile of perampanel; no new safety signals were identified with long-term treatment.. This post hoc analysis suggests long-term (up to 4 years) adjunctive perampanel (up to 12 mg/d) is efficacious and well tolerated in patients (aged 12 years and older) with FBTCS or GTCS.

Topics: Adolescent; Adult; Anticonvulsants; Dizziness; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nitriles; Pyridones; Seizures; Sleepiness; Time Factors; Treatment Outcome; Young Adult

Study 232, an open-label pilot study with an extension phase, evaluated the pharmacokinetics and preliminary safety/tolerability and efficacy of adjunctive perampanel oral suspension (≤0.18 mg/kg/d) in epilepsy patients aged ≥2 to <12 years. Patients were grouped into cohorts 1 (aged ≥7 to <12 years) and 2 (aged ≥2 to <7 years). The Core Study included pretreatment (≤2 weeks) and treatment phases (7-week titration; 4-week maintenance; 4-week follow-up [for those not entering the extension]). The extension phase consisted of 41-week maintenance and 4-week follow-up periods. Pharmacokinetic data were pooled with adolescent pharmacokinetic data from phase II/III studies. Population pharmacokinetic analysis showed that perampanel pharmacokinetics was independent of age, weight, or liver function, suggesting age- or weight-based dosing is not required and that the same dose can be given to adults and children to achieve exposures shown to be efficacious. Perampanel was well tolerated and efficacious for ≤52 weeks.

Topics: Administration, Oral; Adolescent; Anticonvulsants; Child; Child, Preschool; Drug Therapy, Combination; Epilepsy; Humans; Nitriles; Pilot Projects; Pyridones; Seizures; Treatment Outcome

People of different ethnic or racial backgrounds may experience variations in pharmacokinetic and pharmacodynamic responses to drug therapies. Our post hoc analysis evaluated the efficacy, safety, and tolerability of perampanel in Asian and non-Asian populations with refractory focal seizures with or without focal to bilateral tonic-clonic (FBTC) seizures. This analysis pooled data from 4 randomized, placebo-controlled, phase-3 studies involving patients aged ≥12 years who have focal seizures with or without FBTC seizures. Patients were receiving 2, 4, 8, or 12 mg perampanel (or placebo) by the end of a 6-week titration period and for a further 13 weeks during the maintenance phase. Efficacy endpoints included median percent change in seizure frequency per 28 days, and 50% and seizure-freedom responder rates relative to baseline. The median percent change in seizure frequency per 28 days from baseline was significantly greater than placebo for perampanel 8 and 12 mg (-31.1% and -38.1% change, respectively; each P < 0.0001) in the Asian population, and for perampanel 4, 8, and 12 mg (-21.1% [P = 0.0001], -26.3% [P < 0.0001], and -27.7% [P = 0.0001] change, respectively) in the non-Asian population. The 50% responder rate relative to baseline was significantly greater than placebo for perampanel 8 and 12 mg (40.1% and 43.8%, respectively; each P < 0.0001) in the Asian population, and for perampanel 4, 8, and 12 mg (29.4% [P = 0.0002], 32.8% [P < 0.0001] and 34.5% [P = 0.0001]), respectively, in the non-Asian population. Seizure-freedom rate among all patients was 4.9%-11.7% for perampanel 2, 4, 8, and 12 mg. The most frequently reported treatment-emergent adverse events (TEAEs) across both populations were dizziness, somnolence, irritability, headache, and fatigue. The most common psychiatric TEAEs were aggression and irritability. Perampanel demonstrated a favorable and similar risk-benefit profile in both Asian and non-Asian populations with refractory focal seizures.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Asian People; Child; Double-Blind Method; Drug Resistant Epilepsy; Epilepsy, Tonic-Clonic; Female; Humans; Male; Middle Aged; Nitriles; Pyridones; Receptors, AMPA; Risk Assessment; Seizures; Treatment Outcome; Young Adult

This post hoc analysis assessed the long-term safety, tolerability, and efficacy of perampanel in Asian patients with refractory focal seizures; an additional analysis assessed the effect of perampanel on focal impaired awareness seizures (FIAS) with focal to bilateral tonic-clonic (FBTC) seizures. In this subanalysis, data from Asian patients ≥12 years of age who had focal seizures with FBTC seizures despite taking one to 3 concomitant antiepileptic drugs at baseline, and who had entered either the long-term extension phase of 3 phase-3 perampanel trials (study 307) or the 10-week extension phase of study 335, were analyzed for the effect of perampanel on duration of exposure, safety, and seizure outcomes. Of 874 Asian patients included in the analysis, 205 had previously received placebo during the double-blind phase-3 trials and 669 had previously received perampanel 2-12 mg/day; 313 had FIAS with FBTC seizures at core study baseline. The median duration of exposure to perampanel was 385.0 days, and the retention rate at one year was 62.6%. Overall, during the first 52 weeks of perampanel treatment, 777 patients (88.9%) had treatment-emergent adverse events (TEAEs), most of which were mild to moderate in severity. The most frequent TEAEs were dizziness (47.1%), somnolence (22.3%), and nasopharyngitis (17.4%). During the first 52 weeks of perampanel treatment, median percent change in seizure frequency per 28 days from pre-perampanel baseline for all focal seizures was -28.1%, and -51.7% for FIAS with FBTC seizures. The 50% responder rate relative to pre-perampanel baseline for all focal seizures was 33.8%, and 51.1% for FIAS with FBTC seizures. Long-term treatment with perampanel in Asian patients had safety, tolerability, and efficacy similar to that of the global population in the phase-3 trials and extension study 307. The safety profile and response rate suggest benefit for an Asian population of patients with refractory epilepsy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Asian People; Child; Double-Blind Method; Drug Resistant Epilepsy; Epilepsy, Tonic-Clonic; Female; Humans; Long-Term Care; Male; Middle Aged; Nitriles; Patient Safety; Pyridones; Seizures; Treatment Outcome; Young Adult

Perampanel is an approved adjunctive treatment for focal seizures with or without focal to bilateral tonic-clonic (FBTC) seizures and generalized tonic-clonic (GTC) seizures. We compared efficacy and safety of perampanel vs placebo in Asian and non-Asian populations in a post hoc analysis of pooled data from 5 randomized phase 3 studies. Patients (≥12 years old) with focal + FBTC seizures received perampanel 2, 4, 8, or 12 mg or placebo; patients with GTC seizures received perampanel 8 mg or placebo (titration: 4-6 weeks; maintenance: 13 weeks). Efficacy endpoints included median percentage change in FBTC or GTC seizure frequency per 28 days and 50% responder rate relative to baseline. Median percentage change in FBTC seizure frequency was significantly greater for perampanel 8 and 12 mg than placebo in the Asian population (median difference from placebo: -30.32%, P = 0.0017; -30.06%, P = 0.0008, respectively) and perampanel 4, 8, and 12 mg in the non-Asian population (-35.07%, P = 0.0001; -37.78%, P < 0.0001; -34.53%, P < 0.0001, respectively). In both populations, median percentage change in GTC seizure frequency was significantly greater for perampanel 8 mg than placebo (median difference from placebo: Asian, -37.37%, P = 0.0139; non-Asian, -27.04%, P = 0.0006). The 50% responder rates were significantly greater than placebo for perampanel 8 and 12 mg for FBTC seizures (Asian: 58.0%, P = 0.0017 and 58.6%, P = 0.0013, respectively; non-Asian: 59.3%, P < 0.0001 and 54.3%, P = 0.0050, respectively) and perampanel 8 mg for GTC seizures (Asian: 57.6%, P = 0.0209; non-Asian: 68.8%, P = 0.0329). Pooled FBTC/GTC seizure data showed generally similar patterns of response to perampanel in both populations. The most frequent treatment-related adverse events were fatigue, irritability, dizziness, somnolence, and headache. Perampanel was effective, well tolerated, and can be considered a therapeutic option for FBTC/GTC seizures in Asian populations.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Asian People; Child; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsy, Generalized; Epilepsy, Partial, Motor; Epilepsy, Tonic-Clonic; Female; Humans; Male; Middle Aged; Nitriles; Pyridones; Seizures; Treatment Outcome; Young Adult

Explore perampanel pharmacokinetics (PK) in all subjects (aged ≥12 years) vs adolescents (aged ≥12 to ≤17 years) with partial-onset seizures (POS) and identify factors explaining between-subject variability in efficacy using a population PK/pharmacodynamic (PD) analysis.. Population PK analysis was performed using nonlinear mixed-effect modeling with data from phase II/III randomized, double-blind, placebo-controlled studies of adjunctive perampanel in POS. Perampanel exposure was predicted for all subjects and adolescents. Population PK/PD analyses were performed using data from phase III studies to explore the relationship between perampanel exposure and 28-day average seizure frequency and responder probability.. Pooled perampanel PK data from 1318 subjects were described by a one-compartment disposition model. In the absence of antiepileptic drugs (AEDs) affecting perampanel PK, estimated perampanel apparent clearance (CL/F) was 0.668 L/h (all subjects) and 0.682 L/h (adolescent subjects). Co-administration of carbamazepine and oxcarbazepine/phenytoin reduced perampanel exposure. Gender, Asian race (excluding Japanese or Chinese), and increasing alanine aminotransferase lowered perampanel CL/F, but differences were small and not considered clinically relevant. Adolescent outcomes were similar to the total population. Based on PK/PD data from 1748 subjects, percent reduction in 28-day average seizure frequency from baseline and responder probability increased with increasing perampanel exposure; concomitant CYP3A-inducing AEDs lowered perampanel exposure but did not impact the slope for responder probability.. These results are consistent with previous analyses but expand on these through inclusion of a larger number of patients from different ethnic groups, and demonstrate that outcomes were similar between adults and adolescents.

Topics: Adolescent; Adult; Anticonvulsants; Child; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistant Epilepsy; Drug Therapy, Combination; Female; Humans; Male; Nitriles; Pyridones; Seizures

To evaluate the efficacy, safety, and tolerability of perampanel, a selective, non-competitive, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, as an adjunctive treatment for patients with refractory partial-onset seizures (POS) from Asia-Pacific.. This multicenter, randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT01618695) involved patients aged ≥12 years with refractory POS (receiving 1-3 antiepileptic drugs). Patients were randomized (1:1:1:1) to receive once-daily placebo or perampanel 4, 8, or 12 mg over a 6-week titration and 13-week maintenance double-blind period. Enzyme-inducing antiepileptic drugs were equally stratified between groups. The primary efficacy endpoint was percent change in POS frequency per 28 days (double-blind phase vs baseline). Other efficacy endpoints included ≥50% responder rate and seizure freedom. Treatment-emergent adverse events (TEAEs) were also monitored.. Of 710 randomized patients, seizure frequency data were available for 704 patients. Median percent changes in POS frequency per 28 days indicated dose-proportional reductions in seizure frequency: -10.8% with placebo and -17.3% (P = .2330), -29.0% (P = .0003), and -38.0% (P < .0001) with perampanel 4, 8, and 12 mg, respectively. In total, 108 (15.3%) patients discontinued treatment; 44 (6.2%) due to TEAEs. TEAEs occurring in ≥5% of patients, and reported at least twice as frequently with perampanel vs placebo, included dizziness and irritability.. Adjunctive perampanel (8 and 12 mg/d) significantly improved seizure control in patients with refractory POS. Safety and tolerability were acceptable at daily doses of perampanel 4-12 mg.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Asia; Double-Blind Method; Drug Resistant Epilepsy; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Nitriles; Pyridones; Seizures; Treatment Outcome; Young Adult

To evaluate long-term safety/tolerability and seizure outcomes in patients with focal seizures treated with adjunctive perampanel in the open-label extension (OLEx) Study 307 (ClinicalTrials.gov identifier: NCT00735397).. Patients could enter the OLEx after completing one of the double-blind, phase III studies. Safety/tolerability and seizure outcomes (median percent reduction in seizure frequency per 28 days, and 50% responder and seizure freedom rates) were analyzed during the OLEx in cohorts with the same minimum perampanel exposure for all focal seizures and secondarily generalized seizures (SGS). An additional sensitivity analysis accounted for early dropouts from the OLEx.. Of 1480 patients randomized across the double-blind studies, 1218 enrolled in the OLEx. The majority of patients (65.4%-80.9%) received a last daily dose of perampanel 12 mg and completed long-term assessment on the same, or one fewer, concomitant antiepileptic drug compared with baseline. The long-term safety/tolerability profile was consistent with the double-blind studies. Treatment-emergent adverse events (TEAEs) leading to discontinuation in >1% of patients were dizziness, irritability, and fatigue; TEAEs of clinical interest were stable for 4 years. In all cohorts, seizure outcome improvements were sustained over time. Median percent seizure reductions per 28 days reached 62.0% and 70.6% for patients with ≥3 (n = 436) or ≥4 (n = 78) years of exposure, respectively; corresponding 50% responder rates were 59.6% and 67.9%. The largest median percent seizure reduction per 28 days occurred in SGS for patients with SGS at baseline: 88.0% and 100.0% for patients with ≥3 (n = 190) or ≥4 (n = 28) years of exposure, respectively; in these cohorts 40.0% and 53.6% of patients, respectively, attained freedom from SGS. Median percent seizure reductions per 28 days were similar when early dropouts were accounted for.. Long-term (≤4 years) adjunctive perampanel treatment did not raise new safety/tolerability signals and was associated with markedly improved seizure control, particularly in patients with SGS at baseline.

Topics: Anticonvulsants; Dizziness; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Epilepsies, Partial; Female; Follow-Up Studies; Headache; Humans; Nitriles; Pyridones; Seizures; Time Factors; Treatment Outcome

The aim of this study was to evaluate long-term effects of adjunctive perampanel on cognition, efficacy, growth, safety, and tolerability in adolescents with inadequately controlled partial seizures.. Study 235, a multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase II study with an open-label extension phase (NCT01161524), was primarily designed to assess the effects of adjunctive perampanel on cognition. Patients (aged ≥12 to <18years) had a diagnosis of epilepsy with inadequately controlled partial seizures, with or without secondary generalization, despite receiving 1-3 antiepileptic drugs. During the double-blind phase, adjunctive perampanel or placebo was administered over a 6-week titration period and a 13-week maintenance period up to 12mg/day. During the extension phase, all patients received perampanel. Data from the extension phase are presented here. Study endpoints included change from baseline in Cognitive Drug Research (CDR) measures of cognition, seizure frequency, growth, development, the occurrence of treatment-emergent adverse events (TEAEs), and laboratory values.. A total of 114 patients entered the extension phase (prior double-blind treatment: placebo, n=41; perampanel, n=73). Perampanel had no effect on the CDR system global cognition score, continuity of attention, quality of episodic memory, quality of working memory, or speed of memory but was associated with a significant decline in power of attention at end of treatment compared with baseline (p=0.03). There were no effects on language skills or manual dexterity from baseline to end of treatment. At Weeks 40-52, median reduction in seizure frequency was 74.1%, and 50% responder rate was 66.0%. There were no clinically relevant effects of perampanel on growth or development at end of treatment compared with baseline. Overall, 84.2% of patients experienced at least one TEAE and 70.2% experienced at least one treatment-related TEAE. The most common TEAEs were dizziness (29.8%) and somnolence (19.3%). The TEAEs resulted in the discontinuation of treatment in 6.1% of patients.. In keeping with the 19-week double-blind phase, long-term adjunctive treatment with perampanel did not have any significant overall effects on the CDR system global cognition score in adolescent patients with inadequately controlled partial seizures. Similar trends were observed across the individual CDR system domains. Adjunctive perampanel showed sustained long-term seizure control and had a safety and tolerability profile similar to that observed in prior clinical studies.

Topics: Adolescent; Anticonvulsants; Attention; Child; Cognition; Cross-Over Studies; Dizziness; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Memory, Short-Term; Nitriles; Pyridones; Seizures; Time Factors; Treatment Outcome

Perampanel is a selective, noncompetitive AMPA receptor antagonist with demonstrated efficacy and tolerability in partial seizures in patients aged ≥ 12 years in Phase III studies. Post-hoc analysis of these studies was conducted to determine the efficacy and tolerability of perampanel based on the number of concomitant antiepileptic drugs (AEDs) at baseline, as well as to examine which baseline characteristics, if any, were predictors of efficacy. Efficacy parameters were based on the number of baseline AEDs, and logistic regression analyses were used to evaluate the association of demographic and baseline clinical factors with probability of ≥ 50% reduction in seizure frequency. Patients on 1 AED at baseline were significantly more likely to have reduced seizure frequency (P<0.02) and improved 50% responder rate (P<0.02) than patients on 3 AEDs at baseline. Secondarily generalized seizures at baseline, unknown etiology, and use of concomitant non-inducer AEDs were also established as positive predictors of efficacy (50% responder rate; P<0.01). Patients with more AEDs at baseline were associated with greater use of inducers (P<0.01), which may result in decreased exposure of perampanel in these patients and lower efficacy. Patients with 1 AED at baseline had a significantly shorter time since diagnosis compared with patients in the 3 (P<0.01) AEDs group, as well as a lower median seizure frequency at baseline compared to patients on 3 AEDs (P<0.05), suggesting that the reduced efficacy of perampanel with 3 AEDs may also be associated with the greater severity of seizures in the patient groups. The incidence of adverse events in perampanel-treated patients was similar regardless of the number of AEDs at baseline. Greater efficacy is predicted for patients receiving fewer concomitant AEDs when starting perampanel, as well as for those receiving concomitant treatment with AEDs that are not CYP3A4 enzyme-inducers, compared to patients treated with multiple concomitant AEDs. The results of this study provide additional information for clinicians considering adding perampanel to their patients' treatment regimen earlier rather than later, and offer evidence regarding the potential for increased efficacy with a decreased medication burden.

Topics: Adult; Anticonvulsants; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Epilepsy; Female; Follow-Up Studies; Humans; Logistic Models; Male; Nitriles; Precision Medicine; Pyridones; Seizures; Severity of Illness Index; Treatment Outcome

To characterize, in adolescents aged 12-17, the pharmacokinetic (PK) profile of perampanel, the impact of intrinsic and extrinsic factors on PK, and the relationships between perampanel exposure and cognitive function, seizure frequency, and responder status.. Population PK analysis used plasma concentration data from Phase II study 235 (NCT01161524), in which adolescents with inadequately controlled POS despite treatment with 1-3 antiepileptic drugs (AEDs) were randomized to receive once daily oral placebo or perampanel (8-12mg/day) for 19 weeks, pooled with data from adolescent patients in perampanel Phase III studies 304, 305, 306. Exposure-cognition and exposure-efficacy relationships were modelled using data from study 235.. Population PK results from 152 adolescent patients revealed a perampanel apparent clearance of 0.729L/h, consistent with previous analyses in adolescents and adults. Clearance was increased with coadministration of inducing AEDs (carbamazepine, oxcarbazepine and phenytoin), and was slightly higher in females. The PK/pharmacodynamics (PD) analysis for cognition (n=110) showed that increasing perampanel exposure had no significant effect on overall cognition, measured by the Cognitive Drug Research global cognition score. The PK/PD analysis for efficacy (n=123) showed a significant decrease in seizure frequency and significant increased probability of being a responder, as perampanel concentration increased - both in the presence and absence of inducing AEDs. Carbamazepine, oxcarbazepine and phenytoin reduced perampanel exposure in adolescents, but reduced the magnitude of seizure frequency reduction and responder probability to a lesser extent.. Pharmacokinetics of perampanel are similar in adolescents to adults. Increasing perampanel exposure reduces seizure frequency and increases probability of being a responder regardless of concomitant inducers. The lack of relationship between perampanel exposure and cognitive function suggests a benign cognitive profile for this AED in adolescents. We await results from long-term exposure.

Topics: Administration, Oral; Adolescent; Anticonvulsants; Attention; Cognition; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Memory; Nitriles; Pyridones; Seizures; Treatment Outcome

Assess perampanel's efficacy and safety as adjunctive therapy in adolescents (ages 12-17) with drug-resistant partial seizures.. Adolescent patients enrolled in multinational, double-blind, placebo-controlled, phase III core studies (studies 304, 305, or 306) completed 19-week, double-blind phase (6-week titration/13-week maintenance) with once-daily perampanel or placebo. Upon completion, patients were eligible for the extension (study 307), beginning with 16-week, blinded conversion, during which placebo patients switched to perampanel. Patients then entered the open-label treatment.. Of 1480 patients from the core studies, 143 were adolescents. Pooled adolescent data from these core studies demonstrated median percent decreases in seizure frequency for perampanel 8 mg (34.8%) and 12 mg (35.6%) were approximately twice that of placebo (18.0%). Responder rates increased with perampanel 8 mg (40.9%) and 12 mg (45.0%) versus placebo (22.2%). Adolescents receiving concomitant enzyme-inducing antiepileptic drugs (AEDs) had smaller reductions in seizure frequency (8 mg:31.6%; 12 mg:26.8%) than those taking non-inducing AEDs (8 mg:54.6%; 12 mg:52.7%). Relative to pre-perampanel baseline, seizure frequency and responder rates during the extension (Weeks 1-52) improved with perampanel. Most commonly reported adverse events in adolescents during the core studies were dizziness (20.4%), somnolence (15.3%), aggression (8.2%), decreased appetite (6.1%), and rhinitis (5.1%). Dizziness (13.2%), somnolence (11.6%), and aggression (6.6%) most often led to perampanel interruption/dose adjustment during the extension.. Data demonstrated adjunctive perampanel treatment in adolescents with drug-resistant partial seizures produced better seizure control versus placebo, sustained seizure frequency improvements, and a generally favorable safety profile. Results were comparable to the overall study population.. clinicaltrials.gov Identifiers: Study 304: NCT00699972; 305: NCT00699582; 306: NCT00700310; Study 307: NCT00735397.

Topics: Adolescent; Anticonvulsants; Double-Blind Method; Drug Resistant Epilepsy; Drug Therapy, Combination; Epilepsies, Partial; Female; Humans; Male; Nitriles; Pyridones; Seizures; Treatment Outcome

To determine whether a novel endpoint of time to prerandomization monthly seizure count could be used to differentiate efficacious and nonefficacious therapies in clinical trials of new add-on antiepileptic drugs (AEDs).. This analysis used data from 3 randomized, double-blind, placebo-controlled phase III trials of perampanel as an add-on therapy in patients with epilepsy who were experiencing refractory partial seizures: studies 304 (ClinicalTrials.gov identifier NCT00699972), 305 (NCT00699582), and 306 (NCT00700310). Time to prerandomization monthly seizure count was evaluated post hoc for each trial, and findings were compared with the original primary outcomes (median percent change in seizure frequency and 50% responder rate). Outcomes were assessed for all partial-onset seizures, secondarily generalized (SG) tonic-clonic seizures only, and complex partial plus SG (CP + SG) seizures.. Perampanel 4-12 mg significantly prolonged median time to prerandomization monthly seizure count, generally by more than 1 week, compared with placebo, across all 3 studies, consistent with the original primary outcomes. Analysis of SG seizures only, and CP + SG seizures, also indicated a significantly prolonged median time to prerandomization monthly seizure count with perampanel 8 mg and 12 mg compared with placebo.. Time to prerandomization monthly seizure count is a promising novel alternative to the standard endpoints of median percent change in seizure frequency and 50% responder rates used in trials of add-on AEDs. Use of this endpoint could reduce exposure to placebo or ineffective treatments, thereby facilitating trial recruitment and improving safety.

Topics: Anticonvulsants; Double-Blind Method; Drug Therapy, Combination; Endpoint Determination; Epilepsies, Partial; Humans; Kaplan-Meier Estimate; Nitriles; Pyridones; Seizures; Treatment Outcome

Perampanel (PER) is a novel noncompetitive AMPA-receptor antagonist approved in over 40 countries for treatment of partial seizures. The safety and tolerability of PER have been well-documented in three double-blind, randomized, placebo (PBO)-controlled Phase III studies and an open-label extension (OLE). This post hoc analysis evaluated the occurrence and characteristics of the most common treatment-emergent adverse events (TEAEs) associated with PER. Results from the Phase III studies were pooled; post hoc analyses on the double-blind phase and up to 1 year of the OLE were performed on the four most common TEAEs for which incidence was higher for PER than PBO. The four most common TEAEs were dizziness, somnolence, fatigue, and irritability. For most subjects in the Phase III double-blind studies, these TEAEs were observed during 6-week titration and were mild or moderate in severity. For severe AEs, no dose-response relationship was observed. Patients in the PBO group during Phase III (who therefore received their first PER treatment during OLE) experienced these TEAEs with incidence and timing similar to that of PER-treated patients in Phase III. The first onset of these TEAEs occurred during the early weeks of PER conversion in the OLE. After 6months and up to 1 year of PER treatment, low to no incidence of the first onset of the four TEAEs was observed. Post hoc analyses of data from pooled Phase III studies provide greater insight into occurrence/duration of TEAEs. Phase III double-blind and OLE data showed that dizziness, somnolence, fatigue, and irritability were the most common TEAEs reported by patients taking PER. Additionally, these results suggest consistency between studies in patient responses to onset of these TEAEs. Although concomitant antiepileptic drugs (AEDs) might be predicted to affect development of TEAEs in patients taking PER, an effect was not observed in this analysis. The low incidence of TEAEs in these studies provides additional support for long-term PER treatment.

Topics: Adult; Aged; Anticonvulsants; Double-Blind Method; Drug Therapy, Combination; Epilepsies, Partial; Female; Humans; Male; Middle Aged; Nitriles; Pyridones; Seizures; Time Factors; Treatment Outcome

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.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Child; Double-Blind Method; Drug Resistant Epilepsy; Endpoint Determination; Epilepsies, Partial; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Nitriles; Pyridones; Seizures; Treatment Outcome; Young Adult

To assess efficacy and safety of adjunctive perampanel in patients with drug-resistant, primary generalized tonic-clonic (PGTC) seizures in idiopathic generalized epilepsy (IGE).. In this multicenter, double-blind study (ClinicalTrials.gov identifier: NCT01393743; funded by Eisai Inc.), patients 12 years or older with PGTC seizures and IGE were randomized to placebo or perampanel during a 4-week titration period (perampanel up titrated from 2 to 8 mg/d, or highest tolerated dose) and 13-week maintenance period. The primary endpoint was percent change in PGTC seizure frequency per 28 days (titration plus maintenance vs baseline). The key secondary endpoint (primary endpoint for European Union registration) was 50% PGTC seizure responder rate (patients achieving $50% reduction in PGTC seizure frequency; maintenance vs baseline). Treatment-emergent adverse events were monitored.. Of 164 randomized patients, 162 comprised the full analysis set (placebo, 81; perampanel, 81). Compared with placebo, perampanel conferred a greater median percent change in PGTC seizure frequency per 28 days (238.4%vs 276.5%; p , 0.0001) and greater 50%PGTC seizure responder rate (39.5% vs 64.2%; p 5 0.0019). During maintenance, 12.3% of placebo treated patients and 30.9%of perampanel-treated patients achieved PGTC seizure freedom. For the safety analysis (placebo, 82; perampanel, 81), the most frequent treatment-emergent adverse events with perampanel were dizziness (32.1%) and fatigue (14.8%).. Adjunctive perampanel was well tolerated and improved control of drug-resistant PGTC seizures in patients with IGE.. This study provides Class I evidence that adjunctive perampanel reduces PGTC seizure frequency, compared with placebo, in patients with drug-resistant PGTC seizures in IGE.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Child; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Epilepsy, Generalized; Female; Humans; Male; Middle Aged; Nitriles; Pyridones; Seizures; Treatment Outcome; Young Adult

Topics: Adolescent; Adult; Anticonvulsants; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; International Cooperation; Longitudinal Studies; Male; Nitriles; Pyridones; Seizures; Young Adult

To assess efficacy and safety of once-daily 8 or 12 mg perampanel, a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, when added to concomitant antiepileptic drugs (AEDs) in the treatment of drug-resistant partial-onset seizures.. This was a multicenter, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT00699972). Patients (≥12 years, with ongoing seizures despite 1-3 AEDs) were randomized (1:1:1) to once-daily perampanel 8 mg, 12 mg, or placebo. Following baseline (6 weeks), patients entered a 19-week double-blind phase: 6-week titration (2 mg/week increments to target dose) followed by a 13-week maintenance period. Percent change in seizure frequency was the primary endpoint; 50% responder rate was the primary endpoint for EU registration.. Of 388 patients randomized and treated, 387 provided seizure frequency data. Using this intent-to-treat population over the double-blind phase, the median percent change in seizure frequency was -21.0%, -26.3%, and -34.5% for placebo and perampanel 8 and 12 mg, respectively (p = 0.0261 and p = 0.0158 for 8 and 12 mg vs placebo, respectively). Fifty percent responder rates during the maintenance period were 26.4%, 37.6%, and 36.1%, respectively, for placebo, perampanel 8 mg, and perampanel 12 mg; these differences were not statistically significant for 8 mg (p = 0.0760) or 12 mg (p = 0.0914). Sixty-eight (17.5%) patients discontinued, including 40 (10.3%) for adverse events. Most frequent treatment-emergent adverse events were dizziness, somnolence, irritability, headache, fall, and ataxia.. This trial demonstrated that once-daily, adjunctive perampanel at doses of 8 or 12 mg improved seizure control in patients with uncontrolled partial-onset seizures. Doses of perampanel 8 and 12 mg were safe, and tolerability was acceptable.. This study provides Class I evidence that once-daily 8 and 12 mg doses of adjunctive perampanel are effective in patients with uncontrolled partial-onset seizures.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Child; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Epilepsies, Partial; Female; Humans; Male; Middle Aged; Nitriles; Pyridones; Seizures; Young Adult

Neuroelectric disruptions such as seizures and cortical spreading depolarization may contribute to the development of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH). However, effects of antiepileptic drug prophylaxis on outcomes remain controversial in SAH. The authors investigated if prophylactic administration of new-generation antiepileptic drugs levetiracetam and perampanel was beneficial against delayed neurovascular events after SAH. This was a retrospective single-center cohort study of 121 consecutive SAH patients including 56 patients of admission World Federation of Neurological Surgeons grades IV - V who underwent aneurysmal obliteration within 72 h post-SAH from 2013 to 2021. Prophylactic antiepileptic drugs differed depending on the study terms: none (2013 - 2015), levetiracetam for patients at high risks of seizures (2016 - 2019), and perampanel for all patients (2020 - 2021). The 3rd term had the lowest occurrence of delayed cerebral microinfarction on diffusion-weighted magnetic resonance imaging, which was related to less development of DCI. Other outcome measures were similar among the 3 terms including incidences of angiographic vasospasm, computed tomography-detectable delayed cerebral infarction, seizures, and 3-month good outcomes (modified Rankin Scale 0 - 2). The present study suggests that prophylactic administration of levetiracetam and perampanel was not associated with worse outcomes and that perampanel may have the potential to reduce DCI by preventing microcirculatory disturbances after SAH. Further studies are warranted to investigate anti-DCI effects of a selective α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonist perampanel in SAH patients in a large-scale prospective study.

Topics: Anticonvulsants; Brain Ischemia; Cerebral Infarction; Cohort Studies; Humans; Levetiracetam; Microcirculation; Prospective Studies; Retrospective Studies; Seizures; Subarachnoid Hemorrhage

Antiseizure medications (ASMs) may affect nocturnal sleep and daytime vigilance. Perampanel (PER), a third-generation ASM, showed to improve nocturnal sleep in patients with epilepsy (PWE). Although ASMs can have beneficial effects on nocturnal sleep and daytime sleepiness, no study investigated the effect of PER on both sleep-wake cycle and daytime sleepiness. Therefore, this study aimed to objectively evaluate the sleep-wake cycle and daytime sleepiness in PWE treated with PER as adjunctive therapy.. This prospective study included adult PWE who received PER as add-on treatment. Sleep-wake cycle was assessed through actigraphic monitoring and daytime sleepiness by the multiple sleep latency test (MSLT) performed at the end of the actigraphic recording. All patients performed both tests at baseline and at 6-month follow-up.. Ten patients (mean age: 44.50 ± 22.71 years, 50.0% female) were included. The mean monthly seizure frequency was 3.20 ± 5.94. Six of ten patients started PER as a first add-on treatment. The final PER dose was 5.11 ± 2.02 mg/day, and nine of ten patients achieved seizure freedom at follow-up. There was a significant decrease in mean monthly seizure frequency from baseline to follow-up (p = 0.004). No significant changes were found in the sleep-wake cycle parameters. An increase in sleep latency mean was observed at MSLT at 6-month follow-up (p = 0.005).. This study confirms that adjunctive PER is effective on seizures without pathologically change of the sleep-wake cycle in PWE and can even improve daytime sleepiness. This effect can be mediated by the achievement of seizure control. Therefore, PER may be promising in PWE with sleep disturbances and daytime sleepiness.

Topics: Adult; Aged; Disorders of Excessive Somnolence; Epilepsy; Female; Humans; Male; Middle Aged; Prospective Studies; Seizures; Sleep; Young Adult

Perampanel, a noncompetitive antagonist of the postsynaptic a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor, is effective for controlling focal to bilateral tonic-clonic seizures but is also known to increase feelings of anger. Using statistical parametric mapping-derived measures of activation and task-modulated functional connectivity (psychophysiologic interaction), we investigated 14 people with focal epilepsy who had verbal fluency functional magnetic resonance imaging (fMRI) twice, before and after the add-on treatment of perampanel. For comparison, we included 28 people with epilepsy, propensity-matched for clinical characteristics, who had two scans but no change in anti-seizure medication (ASM) regimen in-between. After commencing perampanel, individuals had higher task-related activations in left orbitofrontal cortex (OFC), fewer task-related activations in the subcortical regions including the left thalamus and left caudate, and lower task-related thalamocaudate and caudate-subtantial nigra connectivity. Decreased task-related connectivity is observed between the left OFC and precuneus and left medial frontal lobe. Our results highlight the brain regions associated with the beneficiary therapeutic effects on focal to bilateral tonic-clonic seizures (thalamus and caudate) but also the undesired affective side effects of perampanel with increased anger and aggression (OFC).

Topics: Anticonvulsants; Drug-Related Side Effects and Adverse Reactions; Epilepsies, Partial; Humans; Magnetic Resonance Imaging; Pyridones; Seizures; Treatment Outcome

Perampanel, an antiseizure drug with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist properties, may have a targeted effect in genetic epilepsies with overwhelming glutamate receptor activation. Epilepsies with loss of γ-aminobutyric acid inhibition (e.g., SCN1A), overactive excitatory neurons (e.g., SCN2A, SCN8A), and variants in glutamate receptors (e.g., GRIN2A) hold special interest. We aimed to collect data from a large rare genetic epilepsy cohort treated with perampanel, to detect possible subgroups with high efficacy.. This multicenter project was based on the framework of NETRE (Network for Therapy in Rare Epilepsies), a web of pediatric neurologists treating rare epilepsies. Retrospective data from patients with genetic epilepsies treated with perampanel were collected. Outcome measures were responder rate (50% seizure reduction), and percentage of seizure reduction after 3 months of treatment. Subgroups of etiologies with high efficacy were identified.. A total of 137 patients with 79 different etiologies, aged 2 months to 61 years (mean = 15.48 ± 9.9 years), were enrolled. The mean dosage was 6.45 ± 2.47 mg, and treatment period was 2.0 ± 1.78 years (1.5 months-8 years). Sixty-two patients (44.9%) were treated for >2 years. Ninety-eight patients (71%) were responders, and 93 (67.4%) chose to continue therapy. The mean reduction in seizure frequency was 56.61% ± 34.36%. Sixty patients (43.5%) sustained >75% reduction in seizure frequency, including 38 (27.5%) with >90% reduction in seizure frequency. The following genes showed high treatment efficacy: SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, POLG1, POLG2, and NEU1. Eleven of 17 (64.7%) patients with Dravet syndrome due to an SCN1A pathogenic variant were responders to perampanel treatment; 35.3% of them had >90% seizure reduction. Other etiologies remarkable for >90% reduction in seizures were GNAO1 and PIGA. Fourteen patients had a continuous spike and wave during sleep electroencephalographic pattern, and in six subjects perampanel reduced epileptiform activity.. Perampanel demonstrated high safety and efficacy in patients with rare genetic epilepsies, especially in SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, CDKL5, NEU1, and POLG, suggesting a targeted effect related to glutamate transmission.

Topics: Anticonvulsants; Child; Epilepsies, Partial; Epilepsy; Glutamic Acid; GTP-Binding Protein alpha Subunits, Gi-Go; Humans; Protocadherins; Pyridones; Retrospective Studies; Seizures; Treatment Outcome

Patients in Japan often have difficulty in screening and selecting chronic-care and rehabilitation hospitals for transfer because of the high cost and unavailability of new antiseizure medications, such as perampanel and lacosamide. To investigate whether the requirement for perampanel and lacosamide interfered with patients' hospital transfer by comparing the number of days required for hospital transfer. Data were obtained from patients 1) who were diagnosed with intracerebral hemorrhage or cerebral infarction, 2) who were treated with antiseizure medications for epilepsy, and 3) who were transferred to another hospital. The main outcome measures were the length of hospital stay and days from the last seizure to hospital transfer.Ninety-four eligible patients were divided into those treated with perampanel or lacosamide (n = 18) and those treated with other agents (n = 76). The mean length of hospital stay and days from the last seizure to hospital transfer were 52.9 and 45.4 d in the perampanel and lacosamide group, and 32.7 and 28.6 d in the other medication group (p < 0.001). The mean antiseizure medication costs and total drug costs were U.S. $4.88 and $6.85 in the perampanel/lacosamide group and U.S. $1.94 and $4.41 in the other medication group (p < 0.001, p = 0.007), respectively. Considering antiseizure medication availability and cost in the transfer destination hospital is important when choosing medications for patients requiring hospital transfer from an acute-care hospital.

Topics: Hospitals; Humans; Japan; Lacosamide; Retrospective Studies; Seizures; Stroke

Topics: Animals; Anticonvulsants; Astrocytes; Epilepsy; Nitriles; Pyridones; Rats; Receptors, AMPA; Seizures; Treatment Outcome

This retrospective study assessed long-term effectiveness of add-on perampanel (PER) in patients with Lennox-Gastaut syndrome (LGS). Outcomes included time to PER failure and time to seizure relapse in responders. PER failure was defined as either discontinuation of PER or initiation of another treatment. Seizure relapse in responders was defined as occurrence of a seizure in seizure-free patients and increase of at least 50% in average monthly seizure frequency for those who were responders. Eighty-seven patients were included. Treatment failure occurred in 52 (59.8%) subjects at a median time of 12 months. Treatment failure was due to lack of efficacy in 27 (52.0%) patients, lack of tolerability in 14 (27.0%), and both reasons in 11 (21.0%). A slower titration was associated with a lower risk of PER failure compared to faster titration schedules, and the occurrence of adverse events increased the risk of treatment failure. Thirty-six patients (41.4%) were responders during a median follow-up of 11 months. Seizure relapse occurred in 13 of 36 (36.1%) patients after a median time of 21 months. The overall rate of seizure responders was 23 of 87 (26.4%) at the end of follow-up. This study provides real-world evidence on the effectiveness of PER as adjunctive treatment in LGS patients.

Topics: Anticonvulsants; Humans; Lennox Gastaut Syndrome; Retrospective Studies; Seizures; Treatment Outcome

The efficacy of perampanel (PER) in pediatric epilepsy with specific etiologies has not been well established. Here, we investigated outcome and predictors of PER treatment in a pediatric cohort with known and presumed genetic etiology.. We included pediatric patients with potential genetic epilepsy who received PER treatment and underwent whole-exome sequencing (WES) from January 2020 to September 2021. All patients were followed up for >12 months.. A total of 124 patients were included. Overall response rates were 51.6% and 49.6% at 6 months and 12 months, respectively. Pathogenic or likely pathogenic variants in 27 multiple genes were detected among 58 patients (46.8%) by WES. On performing multivariate logistic regression analysis, only developmental delay (OR = 0.406, P = 0.042) was a negative predictor of treatment response. However, the seizure onset age, positive WES results, and number of ASMs before PER administration were not significantly. Thirteen carriers with variants in the SCN1A gene showed a better response compared to eight patients with other sodium channels (P = 0.007), and to the other 45 patients with positive WES results (OR = 7.124, 95% CI = 1.306-38.860, P = 0.023). Adverse events were only reported in 23 patients, the most common being emotional problems.. PER is safe and efficacious in pediatric patients with known and presumed genetic etiology. The response rate is comparable to that reported in other pediatric populations, and lower among those with developmental delay. A gene-specific response to PER is found along with better efficacy links to pathogenic variants in the SCN1A gene.

Topics: Causality; Child; Epilepsy; Humans; Pyridones; Seizures

Perampanel (PER) is a potent third-generation antiepileptic drug only available for oral administration. Additionally, PER has shown potential in managing epilepsy comorbidities such as anxiety. Previously, we demonstrated that the intranasal (IN) administration of PER, loaded in a self-microemulsifying drug delivery system (SMEDDS), improved brain-targeting and exposure in mice. Herein, we investigated PER brain biodistribution, its anticonvulsant and anxiolytic effects, and its potential olfactory and neuromotor toxicity after IN administration to mice (1 mg/kg). PER showed a rostral-caudal brain biodistribution pattern when administered intranasally. At short times post-nasal dosing, high PER concentrations were found in olfactory bulbs (olfactory bulbs/plasma ratios of 1.266 ± 0.183 and 0.181 ± 0.027 after IN and intravenous administrations, respectively), suggesting that a fraction of the drug directly reaches brain through the olfactory pathway. In the maximal electroshock seizure test, IN PER protected 60% of mice against seizure development, a substantially higher value than the 20% protected after receiving oral PER. PER also demonstrated anxiolytic effects in open field and elevated plus maze tests. Buried food-seeking test showed no signs of olfactory toxicity. Neuromotor impairment was found in rotarod and open field tests at the times of PER maximum concentrations after IN and oral administrations. Nevertheless, neuromotor performance was improved after repeated administrations. Compared with IN vehicle, PER IN administration decreased brain levels of L-glutamate (0.91 ± 0.13 mg/mL vs 0.64 ± 0.12 mg/mL) and nitric oxide (100 ± 15.62% vs 56.62 ± 4.95%), without interfering in GABA levels. Altogether, these results suggest that the IN PER delivery through the developed SMEDDS can be a safe and promising alternative to the oral treatment, which supports the design of clinical studies to evaluate the IN PER delivery to treat epilepsy and neurological-related conditions as anxiety.

Topics: Animals; Anti-Anxiety Agents; Anticonvulsants; Brain; Drug Delivery Systems; Mice; Seizures; Tissue Distribution

To evaluate the safety and tolerability of adjunctive perampanel in a Japanese subpopulation of Study 311 (NCT02849626), which was a global, multicenter, open-label, single-arm study of children (aged 4 to <12 years) with inadequately controlled focal-onset seizures (FOS), with or without focal to bilateral tonic-clonic seizures (FBTCS) or generalized tonic-clonic seizures (GTCS).. Study 311 comprised a Core Study, Extension A, and Extension B; this report focuses on the Japanese patient subgroup in the Core Study only. In the Core Study, Japanese patients (FOS only) received adjunctive perampanel ≤12 mg/day in a 23-week Treatment Phase. Endpoints included safety/tolerability (primary) and median percent change in seizure frequency per 28 days from baseline. Patients were stratified by age and concomitant enzyme-inducing anti-seizure medication (EIASM) use.. Of 65 enrolled Japanese patients, 56 completed the Core Study and nine withdrew. The most common reason for discontinuation was adverse events (AEs) (n = 4 [6.2%]). The mean (standard deviation) daily dose of perampanel in Japanese FOS patients was 5.8 (2.2) mg/day. During the Core Study, treatment-emergent AEs (TEAEs) were reported by 89% of Japanese patients, most commonly nasopharyngitis (28%) and somnolence (28%). The median percent reduction in seizure frequency per 28 days from baseline was 37% and the lower limit of the 95% CI was greater than 10.5%, satisfying the pre-defined efficacy criteria. Perampanel was effective regardless of age or concomitant EIASM use.. Perampanel as adjunctive therapy is generally safe, well-tolerated, and efficacious in Japanese children aged 4 to <12 years with FOS (with/without FBTCS).

Topics: Anticonvulsants; Child; Child, Preschool; Double-Blind Method; Drug Therapy, Combination; East Asian People; Humans; Pyridones; Seizures; Treatment Outcome

To assess the effectiveness and tolerability of perampanel monotherapy following conversion from adjunctive therapy.. This was a multicenter, retrospective, non-interventional study of Korean patients aged ≥12 years with focal-onset seizures (FOS) with or without focal to bilateral tonic-clonic seizures. Data were extracted from electronic medical records of perampanel-treated patients from 1 February 2016 to 31 October 2020. Kaplan-Meier estimated retention rates, effectiveness, and safety were recorded.. Subjects (n = 66, mean age 46.2 years) were mostly male (68.2%) with focal to bilateral tonic-clonic seizure (71.2%). Mean duration of illness was 86.3 months. Retention rates after conversion to perampanel monotherapy at 3, 6, and 12 months (primary outcome) were 96.0%, 96.0%, and 75.6%, respectively. Overall retention rates in patients receiving perampanel as adjunctive or monotherapy at 3, 6, 12, 18, and 24 months after perampanel add-on were 100%, 98.3%, 95.9%, 92.6%, and 92.6%, respectively. Mean retention duration was 41.2 months (overall perampanel administration) and 21.4 months (monotherapy). Mean seizure frequency/28 days in the Full Analysis Set (n = 61) was comparable for adjunctive and monotherapy (0.2 ± 0.79 vs 0.2 ± 0.64; change between adjunctive and monotherapy periods: 0.0 ± 0.59; p = 0.498). Perampanel was well tolerated and no new safety signals were identified. Dizziness (4.6%), only reported during adjunctive therapy, was the most common treatment-emergent adverse event.. Conversion to perampanel monotherapy from adjunctive therapy showed promising results in subjects with FOS with/without focal to bilateral tonic-clonic seizures; further studies in a larger population are needed to confirm these encouraging data.

Topics: Anticonvulsants; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Pyridones; Republic of Korea; Retrospective Studies; Seizures; Treatment Outcome

Topics: Anticonvulsants; Child; Drug Therapy, Combination; Epilepsy; Humans; Pyridones; Retrospective Studies; Seizures; Treatment Outcome

To assess the effectiveness and tolerability of perampanel (PER) monotherapy in real-world practice for the treatment of focal-onset seizures (FOS) in eastern China.. This is a single-center, retrospective study of patients with FOS, aged ≥ 4 years, who had been prescribed PER as monotherapy. Outcomes included retention, seizure-free, and responder rates at 3, 6 and 12 months and adverse events (AEs) throughout the follow-up period. The efficacy and AEs of PER monotherapy in patients with aged < 14 years old and ≥ 14 years old were also compared.. Sixty-seven patients with FOS who received PER monotherapy and completed a one-year follow-up were included in the analysis. The median maintenance dose was 4 mg. Modified intent-to-treat analysis demonstrated that the retention rates of PER monotherapy at follow-up of 3, 6 and 12months were 75%, 70% and 63%, respectively. At the same points, seizure-free rates of PER monotherapy were 69%, 63% and 52%, and responder rates were 69%, 66% and 61%, respectively. Patients with sleep-related seizures had higher seizure-free rates at 12 months of follow-up. No significant difference in seizure-free and responder rates was found between the aged < 14 years old and the aged ≥ 14 years old. Twenty-one patients (31.3%) had AEs and five patients discontinued using PER because of intolerant AEs. Common AEs were dizziness, irritability and somnolence. The AEs rate in patients < 14 years was 17.9%, significantly lower than patients ≥ 14 years.. Our findings revealed the real-world data of patients in eastern China with FOS using PER as monotherapy. Patients had good retention, seizure-free and responder rates, and relatively low AEs rate at a low dose of PER treatment.

Topics: Adolescent; Anticonvulsants; China; Drug Therapy, Combination; Humans; Pyridones; Retrospective Studies; Seizures; Treatment Outcome

This study determined the 24-month outcomes of perampanel treatment in children and adolescents with epilepsy. The percentage of ≥ 50% responders was 47.3% (139/294) at 12 months and 49.0% (144/294) at 24 months. A 100% reduction in seizures for more than 12 months was observed in 12.2% (36/294). Discontinuation occurred in 39.8% (117/294). The most common reason for discontinuation was adverse events (29.1%, 34/117). Baseline seizure frequency was higher in children aged < 12 years than in patients aged ≥ 12 years; however, the percentage of seizure reduction and ≥ 50% responders did not significantly differ between the two groups. The rate of early discontinuation was higher (p < 0.001) and the duration of perampanel treatment was shorter in children aged < 12 years (p = 0.001). Most children aged < 12 years discontinued PER due to inadequate effectiveness, while adverse event was the most common reason in patients aged ≥ 12 years (p = 0.045). Only slow titration was significantly associated with ≥ 50% of responders. In conclusion, this study showed that perampanel can be utilized effectively and safely for a prolonged period in pediatric patients aged 4 to < 12 years, as well as in patients aged 12 years and older.

Topics: Adolescent; Child; Dental Care; Epilepsy; Humans; Pyridones; Seizures

Efficacy and safety of perampanel monotherapy for treating focal-onset seizures (FOS) has been barely studied in China. This observational study aimed to evaluate the efficacy and safety of perampanel monotherapy in treating Chinese patients with FOS.. This single-center, prospective, real-world observational study enrolled patients aged ≥4 years with FOS who visited the Epilepsy Out-Patient Clinic of Nanjing Brain Hospital affiliated to Nanjing Medical University from January 2020 to December 2021. All patients were treated with perampanel monotherapy. Seizure-freedom rates after 6 and 12 months of treatment were calculated. Adverse events (AEs) were recorded.. Seventy patients with FOS were enrolled. The mean maintenance perampanel dose was 4.64 ± 1.55 mg/day. The 6- and 12-month retention rates of perampanel monotherapy were 78.6% (55/70) and 70.0% (49/70), respectively. The 6- and 12-month seizure-freedom rates were 69.84% (44/63) and 65.08% (41/63), respectively. Patients with focal to bilateral tonic-clonic seizures had significantly higher 6-month and numerically higher 12-month seizure freedom rates than patients with focal impaired awareness seizures (P = 0.046 and P = 0.204, respectively). Twenty-six (37.1%) patients experienced treatment-emergent AEs, and the most common AE was dizziness. Four (5.7%) patients withdrew from the study due to AEs. No new safety concern was observed.. This is the first prospective study on the efficacy and safety of perampanel monotherapy in treating Chinese patients with FOS, and perampanel monotherapy was effective and safe in treating Chinese patients aged ≥4 years with FOS up to 12 months. More multicenter, real-world studies with large sample sizes and longer follow-ups are needed to further evaluate the long-term efficacy and safety of perampanel monotherapy.

Topics: Anticonvulsants; East Asian People; Humans; Outpatients; Prospective Studies; Seizures; Treatment Outcome

Poor medication adherence contributes to increased morbidity and mortality in patients with epilepsy and may be under-addressed in clinical practice. Ethical concerns make it impossible to study the impact of medication nonadherence in clinical trials, but our previous work emphasizes the importance of using preclinical approaches to address these questions. With over 30 clinically available antiseizure medicines (ASM's), it remains an important question to understand the relationship between poor adherence and seizure incidence across mechanistically distinct ASM's, including the broad-spectrum ASM, perampanel (PER).. We formulated PER into chow pellets to deliver to rats in a 100% fully adherent or 50% variable nonadherent paradigm via our novel automated medication-in-food delivery system. Chronic oral dosing was initiated in male rats with chronic epilepsy while monitoring 24/7 for videoEEG evidence of seizures during a 4-week placebo baseline and 4-week treatment phase. PER concentrations were monitored in plasma at 1-week intervals and correlated with degree of seizure control. The relationship between missed doses and extended patterns of nonadherence were correlated with breakthrough seizures.. Fully adherent rats demonstrated a median reduction in seizure frequency of 50%, whereas nonadherent rats had a median increase of 54%. Plasma concentrations of PER were stable over the 4-week treatment period in both fully adherent and nonadherent groups, with levels being twice as high in fully adherent animals. There was no correlation between a single missed dose or series of missed doses and the incidence of breakthrough seizures. However, those animals in the nonadherent group that received PER for every meal during a 24-h period had a reduced likelihood of seizure incidence.. If our preclinical data is supported in the clinic, PER's favorable pharmacokinetic profile in humans, combined with a lowered risk of breakthrough seizures suggests that it may provide a certain forgiveness factor if a dose is missed within a 24-h window.

Topics: Animals; Epilepsy; Forgiveness; Humans; Male; Medication Adherence; Rats; Seizures

Status epilepticus in poststroke epilepsy is a challenging condition because of multiple vascular comorbidities and the advanced age of patients. Data on third-generation antiseizure medication (ASM) in this condition are limited. The aim of this study was to evaluate the efficacy of third-generation ASMs in the second- or third-line therapy of benzodiazepine-refractory status epilepticus in poststroke epilepsy following acute ischemic stroke.. Data on the effectiveness of third-generation ASMs in patients with status epilepticus in poststroke epilepsy were gathered from two German Stroke Registries and the Mainz Epilepsy Registry. We included only cases with epilepsy remote to the ischemic event. No patients with acute symptomatic seizures were included. The following third-generation ASMs were included: brivaracetam, lacosamide, eslicarbazepine, perampanel, topiramate, and zonisamide. The assessment of effectiveness was based on seizure freedom within 48 h since the start of therapy with the respective ASM. Seizure freedom was evaluated both clinically (clinical evaluation at least three times per day) and by daily electroencephalogram records.. Of the 138 patients aged 70.8 ± 8.1 years with benzodiazepine-refractory status epilepticus in ischemic poststroke epilepsy, 33 (23.9%) were treated with lacosamide, 24 (17.4%) with brivaracetam, 23 (16.7%) with eslicarbazepine, 21 (15.2%) with perampanel, 20 (14.5%) with topiramate, and 17 (12.3%) with zonisamide. Seizure freedom within 48 h was achieved in 66.7% of patients with lacosamide, 65.2% with eslicarbazepine, 38.1% with perampanel, 37.5% with brivaracetam, 35.0% with topiramate, and 35.3% with zonisamide (p < 0.05 for comparison of lacosamide or eslicarbazepine to other ASMs).. Based on these data, lacosamide and eslicarbazepine might be more favorable in the treatment of refractory status epilepticus in poststroke epilepsy, when administered as second- or third-line ASMs before anesthesia. Because of the fact that these ASMs share the same mechanism of action (slow inactivation of sodium channels), our findings could motivate further research on the role that this pharmaceutical mechanism of action has in the treatment of poststroke epilepsy.. This study was registered at ClinicalTrials.gov (NCT05267405).

Topics: Aged; Anticonvulsants; Benzodiazepines; Epilepsy; Humans; Ischemic Stroke; Lacosamide; Middle Aged; Retrospective Studies; Seizures; Status Epilepticus; Topiramate; Zonisamide

Real-world data on efficacy and tolerability of perampanel (PER) monotherapy in treatment-naïve patients with focal onset seizures (FOS) and/or focal-to-bilateral tonic-clonic seizures (FBTCS) to assess efficacy effectiveness and tolerability.. This is a retrospective review of study patients with new FOS with or without FBTCS, aged ≥15 years, who had been prescribed PER as monotherapy. Treatment outcome included retention rate, responder, and seizure-free rate at observational point 3, 6, and 12 months (OP3, OP6, and OP12). Treatment-emergent adverse events (TEAEs) and adverse drug reactions were recorded.. A total of 41 patients enrolled in the study (male:female; 17:22, mean age =46.1 ± 21.8 years), with new FOS and/or FBTCS. The proportions of individuals remaining on PER monotherapy at 3, 6, and 12 months were evaluated. The median PER dosage was 4 mg (range 2-8 mg). The retention rates at OP3, OP6, and OP12 were 88%, 73%, and 61%, respectively. The seizure freedom rates at OP3, OP6, and OP12 were 78%, 80%, and 76%, respectively. About 14% had discontinued the PER monotherapy because of lack of efficacy. Sixteen individuals (41%) had TEAEs; common AEs were dizziness, somnolence, and ataxia; and only one case had depression. The AEs with somnolence and ataxia were found higher in elderly (15% and 30%) than adult patients (7% and 3%), respectively. Only 14% had intolerant adverse events, and it was found higher in elderly (23%).. Real-world data of PER monotherapy in treatment-naïve patients with focal onset seizures demonstrated good effectiveness and a good safety profile at relatively low doses. By starting with low dosage and slow titration of PER help to minimize the impact of adverse effects, maximize adherence, and increase patient retention. PER has a once-daily dosing schedule that supports patient adherence contributes to achieving seizure freedom.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Seizures; Thailand; Young Adult

While previous studies have demonstrated the safety and effectiveness of perampanel (PER) in combination with other anti-seizure medications in adult patients, data for older patients are limited. This study aimed to confirm real-world safety and effectiveness of combination treatment with PER in Japanese patients with focal seizures with or without focal to bilateral tonic-clonic seizures (FBTCS) or generalised tonic-clonic seizures (GTCS) according to age subgroups (<65 and ≥65 years of age).. This large-sample prospective post-marketing observational study included a 24-52-week observation period after the first PER treatment. Safety was assessed according to adverse drug reactions (ADRs) and efficacy was evaluated based on the 50% responder rate and rates of overall symptom improvement.. Among the 3,808 patients who were enrolled, 3,716 (3,026 patients aged <65 years and 690 patients aged ≥65 years) and 3,272 were included in the safety and efficacy analysis datasets, respectively. ADRs were reported for 1,247 patients (33.6%) in the safety analysis dataset. Of these, 36.2% and 22.2% were aged <65 years and ≥65 years, respectively, and the most common ADRs were somnolence (11.6%, 5.5%) and dizziness (9.7%, 5.4%). The 50% responder rates in patients aged <65 years and those ≥65 years were 60.1% and 89.0% for those with focal aware seizures (FAS) with motor signs; 48.0% and 60.0% for FAS without motor signs; 47.4% and 80.2% for focal impaired awareness seizures; 70.8% and 93.4% for FBTCS; and 63.6% and 88.9% for GTCS, respectively. The improvement rates of symptoms/conditions were also higher in patients aged ≥65 years than those <65 years.. PER was effective in reducing seizure frequency and was safe, especially in older patients. PER may be a clinical treatment option for older patients with seizure disorders.

Topics: Aged; Anticonvulsants; Epilepsy; Humans; Japan; Middle Aged; Nitriles; Prospective Studies; Pyridones; Seizures; Treatment Outcome

The temporal lobe plays a central role in the regulation of the "Central Autonomic Network" and cardiovascular functions. The blockade of glutamatergic pathways in the temporal lobe affects cardio-autonomic control. Perampanel (PER) is a non-competitive agonist of the AMPA receptor. This study evaluated PER effects on cardiac autonomic control in patients affected by drug-resistant TLE (DRTLE).. We enrolled 40 adults with DRTLE treated with PER as add-on therapy (PER group) and 32 DRTLE age, sex, and seizure-frequency matched controls treated with different additional anti-seizure medication (ASM) as add-on therapy (No-PER group). HRV analysis was performed on 5-minute EKG recording in resting state before and 6-months after the introduction of add-on ASM. Linear Mixed Models (LMM) were used to analyzed HRV variables according to time (baseline and 6-months follow-up) and groups.

Topics: Adult; Drug Resistant Epilepsy; Epilepsy, Temporal Lobe; Heart Rate; Humans; Nitriles; Pyridones; Seizures; Sudden Unexpected Death in Epilepsy; Temporal Lobe

To investigate the effectiveness, safety and tolerability of perampanel (PER) in treating myoclonic seizures in clinical practice, using data from the PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) study.. PERMIT was a pooled analysis of 44 real-world studies from 17 countries, in which patients with focal and generalised epilepsy were treated with PER. This post-hoc analysis included patients with myoclonic seizures at baseline. Retention and effectiveness were assessed after 3, 6, and 12 months; effectiveness was additionally assessed at the last visit (last observation carried forward). Effectiveness assessments included responder rate (≥50% seizure frequency reduction from baseline) and seizure freedom rate (no seizures since at least the prior visit). Safety and tolerability were assessed by evaluating adverse events (AEs) and discontinuation due to AEs.. 156 patients had myoclonic seizures (59.0% female; mean age, 32.1 years; idiopathic generalised epilepsy, 89.1%; Juvenile Myoclonic Epilepsy, 63.1%; monthly median myoclonic seizure frequency [interquartile range], 1.7 [1.0-10.0]; mean [standard deviation] prior antiseizure medications, 2.9 [2.6]). Retention was assessed for 133 patients (mean time, 12.1 months), effectiveness for 142, and safety/tolerability for 156. Responder and seizure freedom rates were, respectively, 89.5% and 68.8% at 12 months, and 85.9% and 63.4% at the last visit. Incidence of AEs was 46.8%, the most frequent being dizziness/vertigo (19.2%), irritability (18.6%) and somnolence (9.6%). AEs led to discontinuation of 14.0% of patients over 12 months.. PER was associated with reduction in myoclonic seizure frequency in patients with myoclonic seizures treated in everyday clinical practice.

Topics: Adult; Anticonvulsants; Drug Therapy, Combination; Female; Humans; Male; Myoclonic Epilepsy, Juvenile; Nitriles; Pyridones; Seizures; Treatment Outcome

Real-world data from adolescents treated with perampanel in a routine clinical setting are lacking in Japan. We evaluated the safety and efficacy of perampanel for adolescent patients (aged 12-17 years) with drug-resistant, refractory epilepsy in real-world settings.. This was a large-scale, prospective, observational post-marketing study, with a 104-week observation period. Safety was assessed by monitoring adverse effects (adverse drug reactions). For efficacy assessments, seizure frequency was compared between the four weeks immediately prior to the last observation and the four weeks before the commencement of perampanel.. In total, 519 patients were enrolled; 505 and 484 patients were included in the safety and efficacy analysis sets, respectively. The mean age was 14.4 years. The mean daily dose of perampanel was 4.4 mg/day. The main reasons for discontinuation at 104 weeks were adverse events (48.4%) and inadequate efficacy (46.8%). The retention rate at 104 weeks was 50.5%. Adverse effect and severe adverse effect incidences were 42.2% and 1.8%, respectively. The most common adverse effects were somnolence (13.5%), irritability (8.5%), dizziness (5.1%), and agitation (4.8%). There were significant differences in the occurrence of adverse effects between the initial titration interval of <2 weeks and 2-4 weeks (odds ratio=0.441, p=0.029) and 4-8 weeks (odds ratio=0.462, p=0.027). The median percent change in seizure frequency at the last observation carried forward was −50.0 for focal aware seizures with motor signs, −73.3 for focal aware seizures without motor signs, −28.6 for focal impaired awareness seizures, −62.6 for focal to bilateral tonic-clonic seizures, and −20.0 for generalized tonic-clonic seizures.. In adolescent patients, perampanel was well tolerated and efficacious in reducing seizure frequency. No unexpected safety issues were observed, and slow titration may reduce the incidence of adverse effects.

Topics: Adolescent; Drug Resistant Epilepsy; Drug-Related Side Effects and Adverse Reactions; Epilepsies, Partial; Epilepsy; Humans; Japan; Nitriles; Prospective Studies; Pyridones; Seizures

To evaluate the effectiveness and tolerability of perampanel (PER) in real-world settings in patients between 1 month and 18 years of age with drug resistant epilepsy (DRE) waiting for epilepsy surgery.. In this multicenter study, patients between 1 month and 18 years of age with DRE treated with PER between January 2020 and June 2021 were selected. The study outcome was effectiveness of PER treatment reported as reduction in seizure frequency and seizure freedom rate. Effectiveness was assessed at 30, 60, 90, 120, 150 and 180 days after initiation of PER. Tolerability profiles were reported as adverse events according to the observations of the patients' family members and physician.. Eighty-five patients treated with PER were included in the study. The mean initial dose and mean maximum dose of adjunctive PER was 2 mg/day and 5.8 mg/day, respectively. The mean seizure frequency (rate/week) was 41.3, 25.4, 18.9, 14.3, 11.2, 11.1 and 8.9 seizures at baseline, 30, 60, 90, 120, 150 and 180 days, respectively; the reduction in the mean seizure frequency at all timepoints was significant compared at the baseline (p<0.001). At 180 days, ≥75% seizure reduction was seen in 64.9% (37/57) of the patients and seizure freedom was achieved in 36.8% (21/57). Drowsiness, ataxia, and behavioral changes were the common adverse events observed, and these improved after the dose of PER was reduced. No discontinuation of PER was required due to side effects or intolerance.. In real-world settings, PER is well tolerated and effective in seizure control in pediatric and adolescent patients with DRE.

Topics: Adolescent; Anticonvulsants; Child; Drug Resistant Epilepsy; Drug Therapy, Combination; Epilepsy; Humans; Nitriles; Pyridones; Seizures; Thailand; Treatment Outcome

Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of syndromes, including Lennox-Gastaut syndrome (LGS), which are refractory to multiple therapies. Perampanel efficacy has been reported in LGS but further real-world evidence is needed in DEEs.. A multicenter, retrospective, 1-year observational study in patients with DEEs on adjuvant perampanel treatment was conducted to assess perampanel safety and effectiveness in this type of patients in a real-world setting. Seizure types [focal onset seizures (FOS), generalized tonic-clonic seizures (GTCS), tonic seizures (TS), atonic seizures (AtS), atypical absences (AA), and myoclonic seizures (MS)] and seizure clusters were divided in different frequency groups: daily, weekly, and monthly seizures, and absent or seizure freedom. Patients could have more than one seizure type. For each frequency group, group change and seizure freedom were analyzed.. Eighty-seven patients diagnosed with DEEs (45 males) of median age 22 [1-70] years were included. The most frequent DEEs were LGS (35.6%) and Lennox-like syndrome (37.9%). At baseline 20 patients had three to five types of seizures, 36 patients had two types of seizures and 31 patients had one predominant type of seizure. The mean number of seizure types per patient at baseline was 2.12 ± 0.97 which was reduced to 1.62 ± 0.91 at 12 months (p < 0.001). Overall, 51.7% of patients had a significant improvement in at least one seizure type. At baseline, 45 patients had GTCS, 42 FOS, 41 TS, 18 AA, 16 AtS, 11 MS, and 30 seizures clusters. Seizure freedom for each specific type at 12 months was significantly achieved by 35% of patients with GTCS (p < 0.001), 17% (p = 0.016) with TS and 37% with seizure clusters (p < 0.001). Patients achieved seizure freedom from other seizure types but with no statistical significance: 7% FOS-free, 28% AA-free, 6% Ats-free, and 18% MS-free. Regarding changes of group at 12 months, 22% of TS and 19% of FOS improved significantly to a group with lower seizure frequency (p = 0.004 and p = 0.02, respectively). In remaining groups (4% of GTCS, 11% of AA, 18% of Ats, 18% of MS, and 13% of seizure clusters), the improvement was not statistically significant. Twenty-nine patients discontinued perampanel: 18 (21%) due to AEs, 8 (9%) due to lack of efficacy, and 3 (3%) due to seizure worsening. Adverse events, mostly mild or moderate, were reported in 53% of patients, and irritability/mood changes (22%) and somnolence (17%) were the most frequent.. This is the first large-scale real-world study with perampanel across different seizure types in patients with DEEs. Perampanel was effective, especially in GTCS, TS, and FOS, as well as in seizure clusters. Perampanel was generally well-tolerated without unexpected AEs.

Topics: Adult; Anticonvulsants; Epilepsies, Myoclonic; Epilepsy, Generalized; Humans; Lennox Gastaut Syndrome; Male; Nitriles; Pyridones; Retrospective Studies; Seizures; Treatment Outcome; Young Adult

Anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor encephalitis is an anti-neuronal surface antigen autoimmune encephalitis and is relatively rare. Our study evaluated a patient who developed anti-AMPA2 receptor encephalitis with memory deficits and refractory focal seizures as paroxysmal jerking on right face as well as dystonic seizure on right hand. On this patient, the combination treatment of levetiracetam, carbamazepine, and clonazepam, monthly periodic intravenous immunoglobin and immunosuppressive therapies for 5 months was not effective for the focal seizures, while his memory loss was slightly improved. However, adjunctive perampanel treatment led to a rapid relief of seizures. Perampanel is suggested in seizures associated with anti-AMPA receptor encephalitis by directly attenuating nerve hyperexcitability caused by glutamate and Ca2+-permeable GluA4 subunit of AMPA receptors.

Topics: Anticonvulsants; Encephalitis; Humans; Nitriles; Pharmaceutical Preparations; Pyridones; Seizures; Treatment Outcome

Perampanel is a new antiepileptic used to treat partial-onset seizures and generalized tonic-clonic seizures in people older than 12 years old. Perampanel is a selective, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, with a prolonged half-life of approximately 105 hours. Few cases of significant toxicity have been reported, and effects in overdose are poorly understood.. This case describes a 20-month-old healthy female who ingested 8 mg of perampanel. She presented to a pediatric emergency department 1 hour after ingestion with ataxia, irritability, and somnolence. Vital signs were: heart rate 130 beats per minute, blood pressure 112/97 mmHg, temperature 99°F, respiratory rate 30 breaths per minute. She was admitted to the pediatric intensive care unit. During the hospitalization, she developed hypotension and bradycardia which improved with stimulation and fluid resuscitation. Intermittent bradycardia persisted for 32 hours after ingestion. Physical examination was notable for somnolence and truncal ataxia with irritability when aroused, all of which improved throughout the hospitalization. A quantitative level obtained on hospital day 3 (HD) was 750ng/ml. On HD 3 the patient was noted to be ataxic but otherwise had an age-appropriate neurologic examination. She was discharged on HD 4 with normal vital signs, return to baseline mental status, and baseline gait. The patient's cardiovascular, neurologic, and behavioral symptoms were attributed to perampanel toxicity. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS ?: Toxicity from a perampanel overdose is poorly understood both in adults and pediatric patients with significant cardiovascular, behavioral, and central nervous system abnormalities.

Topics: Adult; Anticonvulsants; Child; Female; Humans; Infant; Nitriles; Pyridones; Seizures; Treatment Outcome

Leigh syndrome (LS) is a mitochondrial disorder that shows abnormal basal ganglia lesion and psychomotor regression. Although vitamins have been used for LS, we have not found any effective drug.. A 26-year-old man who showed psychomotor delay and short stature at the age of 1 year was diagnosed with LS according to the results of cerebrospinal fluid and high signal intensity in the bilateral striatum on T2-weighted magnetic resonance imaging. He demonstrated psychomotor delay and breathing disorders, but the progression was very slow. His symptoms suddenly worsened at the age of 24 years after acute epididymitis. He showed epileptic seizures simultaneously and his activities of daily living (ADL) significantly worsened. Several antiepileptic drugs were ineffective, but his seizures were suppressed by a low dose of perampanel and his ADL improved.. Our case showed that low-dose perampanel could be a drug for epileptic seizures and improvement of ADL in patients with LS.

Topics: Activities of Daily Living; Adult; Anticonvulsants; Basal Ganglia; Epilepsy; Humans; Leigh Disease; Magnetic Resonance Imaging; Male; Mutation; Nitriles; Pyridones; Seizures; Treatment Outcome

Quantitative EEG (qEEG) is an established technique used as objective measure for evaluating the effect of antiseizure medications (ASMs) on EEG background activity and monitoring cognitive effects of ASMs. Perampanel (PER) has been associated with relatively more tolerable cognitive effects in patients with epilepsy. The primary aim of the present study was to verify the effect of PER as first add-on ASM on qEEG in child and adult patients affected by epilepsy. The secondary aim of this study was to verify the effectiveness of the drug as first add-on treatment in both child and adult patients with epilepsy.. We collected data from 17 adults and 10 children treated with PER as first add-on treatment, who underwent qEEG analysis before starting PER and at 3-month follow-up under stable treatment.. PER resulted with significant effectiveness in reducing seizures in both children and adults. Considering qEEG analysis, we observed at follow-up the significant increase in beta1 and beta total bands both in children and adult patients. In particular, children showed the significant increase of beta band frequencies predominantly in the occipital regions, whereas adults showed a widespread increase of beta activity. Moreover, we documented in both child and adult patients the global reduction of delta bands activity.. This qEEG study documented the relative increase of cortical EEG fast activity in both children and adult patients affected by epilepsy and treated by PER. This result may suggest a potential less negative impact of PER on cognition in patients affected by epilepsy, other than demonstrating effectiveness of the drug when used as first add-on treatment in both children and adult patients.

Topics: Adult; Anticonvulsants; Child; Electroencephalography; Epilepsy; Humans; Nitriles; Pyridones; Seizures

To evaluate the efficacy of perampanel (PER) in patients with a diagnosis of mesial temporal lobe epilepsy (MTLE) taking PER as first add-on option due to inefficacy of first antiepileptic drug (AED), rather than late add-on choice.. Thirty-seven MTLE patients aged ≥ 12 years were recruited consecutively with a minimum duration of follow-up of 1 year and intermediate follow-up of 3 months. Patients were divided into two groups: 20/37 taking PER as first add-on due to inefficacy of first AED (first group) and 17/37 taking PER as late add-on due to inefficacy of ≥ 2 AEDs (second group). Efficacy, retention rate, and safety were evaluated.. At 3 months, the 70% of the first group had a reduction > 50% of seizure frequency, with six patients becoming also seizure free, while in the second group, only the 23.5% had a reduction > 50% of seizure frequency and none became seizure free (p = 0.005). Six patients of first group were also switched to a monotherapy of PER and five out of six remained seizure free at 12 months. At 1 year of follow-up, efficacy of PER was 70% for the first group, while only of 29.4% for the second group (p = 0.014). Retention rate of the first group at 3 months and 1 year was 85%, while for the second group was, respectively, 82.3% and 64.7%.. PER was significantly successful and tolerated in MTLE patients when used as first add-on option rather than as late add-on.

Topics: Aged; Anticonvulsants; Epilepsy, Temporal Lobe; Humans; Nitriles; Pyridones; Seizures; Treatment Outcome

Topics: Epilepsy; Humans; Leigh Disease; Nitriles; Pyridones; Seizures

The antiseizure drugs commonly used as first- and second-line treatments for neonatal seizures display poor efficacy. Thus, drug mechanisms of action that differ from these typical agents might provide better seizure control. Perampanel, an AMPA-receptor antagonist, and brivaracetam, a SV2A ligand, might fill that role.. We utilized methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) to evoke seizures in rats to assess the efficacy of perampanel and brivaracetam treatment in clinically relevant doses.. In postnatal day (P)10 rats, neither perampanel nor brivaracetam suppressed seizure activity. By contrast, in P21 rats, both drugs decreased the severity of seizures. This effect was evident at the 20 and 40 mg/kg doses of brivaracetam and at the 0.9 and 2.7 mg/kg doses of perampanel.. These data indicate that while the efficacy of these drugs may be limited for neonatal seizures, their efficacy increases over early postnatal development.

Topics: Aging; Animals; Anticonvulsants; Carbolines; Convulsants; Female; Nitriles; Pyridones; Pyrrolidinones; Rats; Rats, Sprague-Dawley; Seizures

Perampanel is a new antiepileptic drug with unique mechanism of action - antagonism of AMPA receptors. Its action in immature animals is not yet sufficiently known therefore we started to study anticonvulsant action of perampanel pretreatment (1-20 mg/kg i.p.) against seizures elicited by pentylenetetrazol. Three age groups of rats were examined - 12, 18 and 25 days old. Perampanel selectively suppressed the tonic phase of generalized seizures in the two younger groups and whole tonic-clonic seizures in the 25-day-old group. It exhibited also an anticonvulsant action against minimal clonic seizures present in control 18- and 25-day-old rats. Perampanel is an effective anticonvulsant drug even at very early stages of brain development.

Topics: Animals; Anticonvulsants; Nitriles; Pentylenetetrazole; Pyridones; Rats; Rats, Wistar; Seizures

The aim of this study was to assess the usefulness of perampanel (PER), and to identify the relationship between behavioral impairments and electroencephalogram (EEG) findings in epilepsy patients with autism spectrum disorder (ASD).. Participants were ASD patients with epilepsy recruited between June 1, 2016 and June 30, 2018. Inclusion criteria were: seizures refractory to two appropriate antiseizure medications (ASMs); presence of neuropsychological impairments; and ≥12 months of monitoring. PER was administered once daily, starting at a dose of 2 mg/day, increased to 12 mg/day. Seizure/EEG responders were identified as participants showing a >50 % reduction in seizure/interictal epileptiform discharge (IED) frequency (indicated as complete disappearance and response). Behavioral responders were identified as participants with a ≥50 % reduction in scores of the Japanese manuals for the Aberrant Behavior Checklist (ABC-J).. Eleven (64.7 %) of 17 patients were considered to be both seizure and EEG responders. Five (45.5 %) of these 11 patients with seizure/EEG response were considered as behavioral responders. Mean ABC-J scores were significantly decreased at 12 months after PER administration (p = 0.0002). A correlation between decreased IED frequency and ABC-J score was evident in frontal IEDs, but not in non-frontal IEDs. Participants presenting with frontal IEDs showed a significantly higher correlation between seizures/EEG and behavioral improvements (p = 0.023). Moreover, 2 of 6 patients without seizure/EEG improvement were considered as behavioral responders. No patients discontinued PER.. The results from this study suggest the utility of PER treatment in reducing clinical seizures and IEDs for ASD patients with intractable epilepsy, at least in some patients. Moreover, the present results also indicate the usefulness of PER in improving neuropsychiatric impairments, including behavioral disturbances in ASD related to improvement of clinical seizures/frontal IEDs, but also unrelated to seizure/EEG improvement in at least some ASD patients.

Topics: Autism Spectrum Disorder; Electroencephalography; Epilepsy; Humans; Nitriles; Pyridones; Seizures

Perampanel (PER) is an effective adjunctive therapy for controlling focal-onset seizures (FOS), but few studies have examined its effects as an early add-on for the treatment of FOS in daily clinical practice.. Our retrospective, multicenter, observational study evaluated the effectiveness and safety of PER as an early add-on in 77 patients with FOS, with and without focal to bilateral tonic-clonic seizures (FBTCS) after 3, 6 and 12 months in a real-world setting.. After 12 months of treatment (median dose 6 [4,8] mg/day), the retention rate was 79.2 % and 60 % of patients (39/65) experienced a ≥50 % reduction in seizure frequency relative to baseline. The seizure-free rate was 38.5 % for all seizures (25/65) and 60 % for FBTCS (12/20). The responder rate at 12 months was significantly higher when PER was given with one concomitant AED (72.2 %) compared to when PER was given with two concomitant AEDs (44.8 %). Drug-related adverse events (AEs) were reported in 40.3 % of patients, most of them being mild (64.2 %). Twelve patients (15.6 %) discontinued treatment because of AEs.. PER is an effective and safe early add-on for patients with refractory FOS, especially for those with FBTCS.

Topics: Anticonvulsants; Drug Therapy, Combination; Humans; Nitriles; Pyridones; Retrospective Studies; Seizures; Treatment Outcome

The article is a short review of an observational study that proves the good efficacy and tolerability of perampanel suspension in the adjunctive treatment of epilepsy in children over 4 years of age. The study demonstrated a high level of 50% responders: 47% with focal seizures, 65% with transition of focal seizures to bilateral tonic-clonic seizures, 65% with primary generalized tonic-clonic seizures. Cessation of seizures was achieved in 12%, 19% and 55% of patients, respectively. The most common side-effects were fatigue (26%), nasopharyngitis (19%), lightheadedness, irritability, fever (13% each), and vomiting (11%). There were no significant clinical negative changes in cognitive functions according to the assessment on the Aldenkamp-Baker scale, both on the total score and subscales. Also, there were no significant changes in laboratory data, vital functions and ECG parameters.. Статья представляет собой короткий обзор наблюдательного исследования, которое доказывает хорошую переносимость и эффективность суспензии перампанела в дополнительном лечении эпилепсии у детей старше 4 лет. Исследование продемонстрировало высокий уровень 50% респондеров: при фокальных приступах он был 47%, при фокальных приступах с переходом в билатеральные тонико-клонические — 65%, при первично-генерализованных тонико-клонических — 65%. Прекращение приступов было достигнуто у 12, 19 и 55% пациентов соответственно. Наиболее частыми побочными эффектами были вялость (26%), назофарингит (19%), дурнота, раздражительность, лихорадка (частота каждого 13%) и рвота (11%). Не было обнаружено значительных клинических негативных изменений когнитивных функций согласно оценке по шкале Алденкампа—Бейкера как по общему баллу, так и по отдельным разделам шкалы. Также не было обнаружено существенных изменений со стороны лабораторных данных, витальных функций и параметров ЭКГ.

Topics: Anticonvulsants; Child; Epilepsy, Tonic-Clonic; Humans; Nitriles; Pyridones; Seizures; Treatment Outcome

Status epilepticus (SE) and acute repetitive seizure (ARS) are emergency conditions associated with significant morbidity and mortality in children. Anti-seizure medications (ASMs) need to terminate seizures to prevent brain damage and death. Common challenges that delay the management of SE and ARS in children at Phramongkutklao hospital are difficulty in accessing intravenous route for drug administration and inadequate number of intensive care units (which will be required in case of the use of adverse events to anesthetic ASMs). Oral, non-sedating ASMs could be a potential option to terminate seizures effectively in SE and ARS in children and further studies in this aspect are needed. We performed a prospective, descriptive study in children with SE or ARS < 18 years of age who had contraindication to or their seizures were refractory to the second-line ASMs after benzodiazepine and received oral perampanel. Demographic data, efficacy, and adverse effects of treatment were recorded. Fifteen patients with SE (13.3%) and acute repetitive seizure (86.6%) were enrolled. All patients received an oral perampanel loading dose and the maintenance dose depended on their body weight. The average loading and maintenance dose were 0.24 mg/kg/dose and 0.12 mg/kg/day, respectively. At 48 h after administration of loading dose of perampanel, eight of fifteen patients (53.3%) became seizure free, one patient had seizure reduction of >75% from baseline, and three patients had seizure reduction of 25-50% from baseline. No serious side effects were observed. These results indicate that oral perampanel may be potential treatment option for SE and ARS in children.

Topics: Anticonvulsants; Child; Humans; Nitriles; Prospective Studies; Pyridones; Seizures; Status Epilepticus; Tertiary Care Centers; Thailand; Treatment Outcome

Although 50 % reduction in seizure frequency is a common efficacy endpoint in clinical trials of antiepileptic drugs (AEDs), 75 % or greater reductions may be required to improve patients' health-related quality of life. Identification of clinical factors that are associated with high responder rates may help to inform clinicians on which patients may optimally benefit from treatment. We evaluated potential predictive factors for achieving major treatment responses (≥75 % reduction in seizure frequency per 28 days from study baseline) in patients with drug-resistant focal-onset seizures, with/without focal to bilateral tonic-clonic (FBTC) seizures in perampanel trials designed for regulatory approval.. Univariate analyses using logistic regression were performed using data from three double-blind, placebo-controlled Phase III studies of adjunctive perampanel (Studies 304 [NCT00699972], 305 [NCT00699582], 306 [NCT00700310]), and their open-label extension study (OLEx; Study 307 [NCT00735397]). For the double-blind studies, baseline seizure frequency, number of baseline AEDs, baseline seizure type, baseline concomitant enzyme-inducing AEDs (EIAEDs), baseline carbamazepine, lamotrigine, or valproic acid, age at diagnosis, time since diagnosis, etiology, and perampanel plasma concentration were included individually with study treatment. The same factors were included for the OLEx analysis except for plasma concentration and treatment. Variables found to be significant predictors for a major treatment response in univariate analyses were subsequently included in multivariable analyses using backwards and forwards selection.. In the double-blind studies, 175/1374 patients had a major response to placebo (n = 25) or perampanel (n = 150). The best predictors of a major treatment response in multivariable models with forwards and backwards selection were: the presence of FBTC seizures during baseline (P = 0.0002), higher perampanel plasma concentration (P < 0.0001), older age at diagnosis (P = 0.0024 and 0.0045, respectively), and lower baseline seizure frequency (P = 0.0364 and 0.0127, respectively). In the OLEx, 217/1090 patients had a major treatment response. The best predictors of a major treatment response in the final multivariable model, regardless of backwards or forwards selection, were a lower baseline seizure frequency (P = 0.0022), the absence of focal impaired awareness seizures during baseline (P = 0.0011), the presence of FBTC seizures during baseline (P = 0.0164), lower number(s) of baseline AEDs (P = 0.0002), the absence of EIAEDs during baseline (P = 0.0059), an older age at diagnosis (P = 0.0054), and absence of structural etiologies (P = 0.0138).. These analyses of placebo-controlled and long-term extension trial data identified a number of potential predictive factors for patients with focal-onset seizures achieving a major treatment response. These factors may help guide clinicians when predicting a patient's response to treatment and optimizing individual treatment regimens.

Topics: Anticonvulsants; Clinical Trials, Phase III as Topic; Double-Blind Method; Drug Therapy, Combination; Humans; Nitriles; Pyridones; Quality of Life; Seizures; Treatment Outcome

Chronic post-hypoxic myoclonus is a condition in which the predominant clinical picture is myoclonus following hypoxic brain damage, usually due to cardiorespiratory arrest. It is a condition that is usually treated with antiepileptic drugs, in most cases with a modest clinical response.. We report the case of a patient who started with jerking movements, compatible with myoclonus in the four limbs and the face the day after recovering from a cardiorespiratory arrest. An electroencephalogram was performed during which the myoclonias were recorded with no electrical correlates. During admission, and in successive visits after discharge, different antiepileptic treatments were tried for the myoclonias, which were refractory and affected the patient's quality of life. Two years after onset, treatment with perampanel up to a dose of 4 mg was initiated and the patient reported a significant clinical improvement, as evidenced in the visits.. Perampanel may be an effective alternative for the treatment of myoclonias in patients with chronic post-hypoxic myoclonus.. Respuesta a perampanel en un paciente con mioclono posthipóxico crónico.. Introducción. El mioclono posthipóxico crónico es un cuadro cuya clínica predominante son las mioclonías que acontecen tras un daño cerebral hipóxico, generalmente por parada cardiorrespiratoria. Es una entidad que se trata generalmente con fármacos antiepilépticos, con una modesta respuesta clínica en la mayoría de los casos. Caso clínico. Paciente que comienza con movimientos de sacudidas, compatibles con mioclonías de las cuatro extremidades y faciales al día siguiente de una parada cardiorrespiratoria recuperada. Se realizó un electroencefalograma durante el cual se registraron las mioclonías sin presentar correlato eléctrico. Durante el ingreso, y en sucesivas visitas tras el alta, se probaron diferentes tratamientos antiepilépticos para las mioclonías, que fueron refractarias y comportaron una afectación de la calidad de vida del paciente. Tras dos años de evolución, se inició tratamiento con perampanel hasta una dosis de 4 mg y el paciente refirió una mejoría clínica importante, evidenciada en consultas. Conclusiones. El perampanel puede suponer una alternativa eficaz para el tratamiento de las mioclonías en pacientes con mioclono posthipóxico crónico.

Topics: Anticonvulsants; Carcinoma, Papillary; Clonazepam; Drug Therapy, Combination; Electroencephalography; Heart Arrest; Humans; Hypoxia, Brain; Levetiracetam; Male; Middle Aged; Myoclonus; Nitriles; Postoperative Complications; Pyridones; Seizures; Thyroid Neoplasms; Thyroidectomy; Valproic Acid

Epileptic seizures are frequent in patients with glioma, and anticonvulsive treatment is often indicated. Glioma cells release glutamate via the X

Topics: Animals; Cell Line, Tumor; Glioma; Glucose; Glutamic Acid; Male; Nitriles; Phenotype; Pyridones; Rats; Seizures; Survival Analysis; Xenograft Model Antitumor Assays

Perampanel (PER) has been shown to be effective as an adjunctive therapy for controlling refractory focal-onset seizures (FOS). However, the information as early add-on for the treatment of FOS in the clinical practice is still scarce and must be further assessed.. An observational prospective study was conducted to evaluate the effectiveness of early add-on PER, assessed as 50% responders (seizure frequency reduced by at least 50% during the last 3 months as compared with baseline) rate at 6 and 12 months, in patients with FOS in the routine clinical practice of Spain.. One hundred and thirteen patients (mean age: 40.3 years, 51.3% male) with FOS received PER as early add-on (1st add-on: 37.2% and 2nd: 62.8%) for a mean exposure of 11 months (mean PER dose: 6.3 mg/day at month 12). At 6 months, 50.4% and 20.4% of the patients were responders and seizure-free (respectively) relative to baseline (3 months prior to PER initiation), and at 12 months, 68.1% and 26.5% of the patients were responders and seizure-free (respectively), relative to baseline (3 months prior to PER initiation). The retention rate at 6 and 12 months was 83.2% and 80.5%, respectively. The percentage of seizure-free patients at 12 months was significantly (p = 0.033) higher when PER was added as first vs. second add-on. The number of concomitant antiepileptic drugs (AEDs) was significantly reduced from baseline to 6 and 12 months (p = 0.001). Treatment was simplified in 23.9% of patients at the end of the observation period. Drug-related adverse events (AEs), most mild or moderate, were reported in 30.1% of patients, with irritability (8%) and dizziness (7.1%) as the most frequent ones.. This is the first observational, prospective study to evaluate efficacy and safety of early adjunctive treatment with PER in patients with focal epilepsy at 12 months. Perampanel demonstrated a good efficacy and safety profile when used at a median dose of 6 mg/day, regardless of the combination with other AEDs. Adverse events were mild or moderate, with dizziness being the most frequent one.

Topics: Adult; Anticonvulsants; Dizziness; Drug Therapy, Combination; Epilepsy; Female; Humans; Male; Middle Aged; Nitriles; Prospective Studies; Pyridones; Seizures; Spain; Treatment Outcome; Young Adult

The objective of this study was to evaluate the efficacy and tolerability of perampanel (PER) in late adjunctive treatment of focal epilepsy. We assessed outcomes 1) according to patients' clinical profiles and the broad mechanism of action (MoA) of concomitant antiepileptic drugs (AEDs) and 2) the effects of PER on adverse events, irritability, mood, and quality of life (QOL).. Consecutive patients commenced on PER at two epilepsy centers in Melbourne, Australia were identified. A nested cohort underwent detailed prospective assessment, while the remainder were retrospectively analyzed. Six- and 12-month efficacy endpoints were at least a 50% reduction in seizure frequency (responders) and complete seizure freedom. The prospective cohort underwent standardized validated questionnaires at 0, 1, 3, 6, and 12 months using the modified semi-structured seizure interview (SSI), Liverpool Adverse Events Profile (LAEP), Quality of Life in Epilepsy-Patient-Weighted (QOLIE-10-P), Neurological Disorders Depression Inventory Epilepsy (NDDI-E), and an Irritability Questionnaire.. One hundred sixty patients were followed for a median of 6 months: the mean number of prior AEDs was 6, 99% had drug-resistant epilepsy, and 72% had never experienced a prior seizure-free period of at least 6 months (=continuously refractory epilepsy). Perampanel was associated with responder and seizure freedom rates of 30.6% and 9.4% at 6 months and 19.4% and 4.4% (5.6% adjusted for the titration period) at 12 months. Having "continuously refractory epilepsy" was associated with a reduced likelihood of seizure freedom at 6 months (5% vs. 30%; p = 0.001) and 12 months (3% vs. 13%; p = 0.058). Quality of Life in Epilepsy-Patient-Weighted, irritability, and NDDI-E showed mean improvement at 6 months from baseline.. Even when used as late add-on adjunctive therapy in patients with highly refractory focal epilepsy, PER can result in 12-month seizure freedom of 5.6%. The likelihood of seizure freedom was associated with prior "continuous medication refractoriness". Six months after introduction of PER patients reported improved mood, QOL, and decreased irritability.

Topics: Adult; Affect; Anticonvulsants; Cohort Studies; Drug Resistant Epilepsy; Drug Therapy, Combination; Female; Humans; Irritable Mood; Male; Middle Aged; Nitriles; Prospective Studies; Pyridones; Quality of Life; Retrospective Studies; Seizures; Surveys and Questionnaires; Treatment Outcome; Young Adult

Nonketotic hyperglycinemia is a severe form of early onset epileptic encephalopathy caused by disturbances in the glycine cleavage system; the neurological damage is mainly attributed to overstimulation of the. The patient presented with a severe form of nonketotic hyperglycinemia and experienced frequent epileptic spasms and focal seizures, which were resistant to vigabatrin, adrenocorticotropic hormone therapy, and combined dextromethorphan and sodium benzoate treatments. By 9 months of age, perampanel reduced epileptic spasms by >50%. At 14 months of age, the ketogenic diet markedly reduced focal seizures and glycine levels in the cerebrospinal fluid.. Perampanel reduced fast excitatory neuronal activity, which was induced by an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor, followed by prolonged electrical depolarizations due to an

Topics: Anticonvulsants; Diet, Ketogenic; Humans; Hyperglycinemia, Nonketotic; Infant; Male; Nitriles; Pyridones; Seizures; Treatment Outcome

Epilepsy prevalence is over 20% for those with ID. It is difficult to diagnose and treat and more likely to be treatment resistant. The evidence informing prescribing is sparse, particularly for new drugs such as perampanel (PMP).. This study seeks to strengthen the research evidence regarding PMP for people with ID by pooling information from two isolated and separately conducted studies: the UK-based Epilepsy Database Register (Ep-ID) and the data from the Kempenhaeghe clinic in the Netherlands.. A single data set of comparable data was created and analysed under agreement and supervision of a UK statistician.. Seizure reduction within twelve months was evident in 62% of Dutch and 47% of UK patients. Retention rates were higher for those in the UK (P = .01) and for patients with moderate to profound ID, whilst side effects were more prominent in the Dutch cohort.. Comparable rates of seizure reduction are in line with estimates for non-ID patients, adding to the evidence suggesting that PMP has a similar impact on those with ID. Taking a European perspective and sharing data across centres can help strengthen the evidence for prescribing antiepileptic drugs in the ID population.

Topics: Adolescent; Adult; Anticonvulsants; Cohort Studies; Databases, Factual; Epilepsy; Female; Humans; Intellectual Disability; Male; Middle Aged; Netherlands; Nitriles; Pyridones; Registries; Seizures; Treatment Outcome; United Kingdom; Young Adult

To assess the effectiveness and tolerability of perampanel (PER) monotherapy in routine clinical practice for the treatment of focal onset and generalized tonic-clonic seizures (GTCS).. This multicenter, retrospective, observational study was conducted in patients aged ≥12 years treated with PER as primary monotherapy or converted to PER monotherapy by progressive reduction of background antiepileptic drugs. Outcomes included retention, responder, and seizure-free rate after 3, 6, and 12 months and tolerability throughout the follow-up.. A total of 98 patients (mean age = 49.6 ± 21.7 years, 51% female) with focal seizures and/or GTCS were treated with PER monotherapy for a median exposure of 14 months (range = 1-57) with a median dose of 4 mg (range = 2-10). The retention rates at 3, 6, and 12 months and last follow-up were 93.8%, 89.3%, 80.9%, and 71.4%, respectively. The retention rates according to the type of monotherapy (primary vs conversion) did not differ (log-rank P value = .57). Among the 98 patients, 61.2% patients had seizures throughout the baseline period, with a median seizure frequency of 0.6 seizures per month (range = 0.3-26). Responder rates at 3, 6, and 12 months were 79.6%, 70.1%, and 52.8%, respectively, and seizure freedom rates at the same points were 62.7%, 56.1%, and 41.5%. Regarding the 33 patients who had GTCS in the baseline period, 87.8% were seizure-free at 3 months, 78.1% at 6 months, and 55.1% at 12 months. Over the entire follow-up, PER monotherapy was generally well tolerated, and only 16% of patients discontinued PER due to adverse events (AEs). Female patients were found to be at a higher risk of psychiatric AEs (female vs male odds ratio = 2.85, 95% confidence interval = 1-8.33, P = .046).. PER demonstrated good effectiveness and a good safety profile when used as primary therapy or conversion to monotherapy at relatively low doses, in a clinical setting with patients with focal seizures and GTCS.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Female; Humans; Male; Mental Disorders; Middle Aged; Nitriles; Pyridones; Registries; Retrospective Studies; Seizures; Treatment Outcome; Young Adult

This post hoc analysis assessed the effects of adjunctive perampanel on myoclonic and absence seizure outcomes in patients (aged ≥12 years) with idiopathic generalized epilepsy (IGE) and generalized tonic-clonic seizures during the double-blind (up to 8 mg/day) and open-label extension (OLEx; up to 12 mg/day) phases of Study 332.. Patients experiencing myoclonic and/or absence seizures during study baseline were included. Assessments for myoclonic and absence seizures included: median percent change in seizure frequency, number of seizure days and seizure-free days (all per 28 days), 50 % and 75 % responder rates, seizure-freedom rates, seizure worsening, and monitoring of treatment-emergent adverse events (TEAEs).. During the double-blind phase, myoclonic and/or absence seizures were reported in 47/163 and 60/163 patients, respectively. Median percent reductions in seizure frequency per 28 days from study baseline were 52.5% and 24.5% (myoclonic seizures) and 7.6 % and 41.2 % (absence seizures) for placebo and perampanel, respectively; seizure-freedom rates were 13.0 % and 16.7 % (myoclonic seizures) and 12.1 % and 22.2 % (absence seizures), respectively. During the OLEx phase, 46/138 and 52/138 patients experienced myoclonic and/or absence seizures, respectively. Responses during the double-blind phase were maintained during long-term (>104 weeks) adjunctive perampanel treatment. The frequency/type of TEAEs was consistent with the known safety profile of perampanel.. In this post hoc analysis, adjunctive perampanel was not associated with any overall worsening of absence seizures. Further research is needed to investigate the effect of adjunctive perampanel in IGE patients with myoclonic and/or absence seizures.

Topics: Anticonvulsants; Double-Blind Method; Drug Therapy, Combination; Epilepsy, Generalized; Humans; Nitriles; Pyridones; Seizures; Treatment Outcome

Quantifying epileptiform discharges before and after the initiation of treatment can be useful for evaluating the efficacy of antiepileptic drugs in generalized epilepsy. The aim of this study was to determine if the selective α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist perampanel alters the electroencephalographic signals in patients with drug resistant generalized seizures (primary or secondary). We also assessed the clinical efficacy, safety and tolerability of perampanel as an adjunctive treatment for patients with refractory generalized seizures after 3, 6 and 12 months of treatment to determine if there is an electro-clinical correlation. We carried out a 1-year retrospective, unicentric, observational, descriptive and non-interventional study to analyze changes in epileptiform discharges, seizure frequency and adverse effects in patients with generalized seizures taking perampanel as an add-on treatment. Perampanel significantly reduced the total number, total duration, maximal duration and average duration of epileptiform discharges in patients with primary generalized epilepsy (n = 44). In patients with focal onset epilepsy and secondary generalized seizures (n = 8) significant decreases in the maximal duration and average duration of epileptiform discharges were found. These findings correlate with the significant decrease in seizure frequency and clinical improvement observed after taking perampanel as an adjunctive therapy for 3, 6 and 12 months. To our knowledge, this is the first study to show that perampanel reduces epileptiform activity, and that this effect correlates with patients' clinical improvement. Analysing patients' electroencephalographic activity in response to perampanel could be useful for assessing the drug's efficacy and optimising adjunctive treatments.

Topics: Adult; Anticonvulsants; Drug Resistant Epilepsy; Drug Therapy, Combination; Epilepsies, Partial; Epilepsy; Female; Humans; Male; Nitriles; Pyridones; Seizures; Treatment Outcome

To investigate the efficacy and tolerability of perampanel (PER) when administered as a first add-on therapy to patients with focal epilepsy or idiopathic generalized epilepsy (IGE) taking one other antiseizure drug (ASD).. This multicentre, retrospective, one-year observational study collected data from patients (≥12 years) who initiated treatment with PER as first add-on therapy. Patients had to be experiencing inadequate seizure control on ASD monotherapy and tried ≤3 ASD monotherapies before initiating PER. Multivariate logistic regression analyses were performed, adjusted for the number and type of previous seizures, duration and aetiology of epilepsy.. Of the 149 patients included in the study (mean age 41 years; 54.4 % male), 118 (79.2 %) were still receiving PER as first add-on treatment after 12 months. Mean PER dose was 6.2 mg/day. At 12 months, 45.6 % were seizure-free and 84.6 % responders. A significant difference in seizure freedom rate was found between patients with IGE and patients with focal epilepsy, but not in responders. Reduced seizure control was observed when PER was administered with strong enzyme-inducing ASDs; conversely, increased seizure control was seen when the same dose of PER was combined with enzyme-inhibiting ASDs. The most frequent adverse events were dizziness (15.4 %), irritability (14.1 %) and drowsiness (14.1 %); no differences in tolerance were observed among different combinations.. PER demonstrated a good efficacy and safety profile when used as a first add-on therapy in patients who did not respond to monotherapy. PER dose adjustments may optimize seizure control when combined with strong enzyme-inducing or enzyme-inhibiting ASDs.

Topics: Adult; Anticonvulsants; Epilepsies, Partial; Epilepsy; Female; Humans; Male; Middle Aged; Nitriles; Pharmaceutical Preparations; Pyridones; Retrospective Studies; Seizures; Treatment Outcome

Perampanel (PER) is a novel anti-seizure medication useful in different types of epilepsy. We intended to assess the effectiveness of PER on cortical myoclonus and seizure frequency in patients with progressive myoclonus epilepsy (PME), using quantitative validated scales. Forty-nine patients aged 36.6 ± 15.6 years with PME of various aetiology (18 EPM1, 12 EPM2, five with sialidosis, one with Kufs disease, one with EPM7, and 12 undetermined) were enrolled between January 2017 and June 2018. PER at the dose of 2-12 mg (5.3 ± 2.5) was added to existing therapy. Myoclonus severity was assessed using a minimal myoclonus scale (MMS) in all the patients before and after 4-6 months of steady PER dose, and by means of the Unified Myoclonus Rating Scale (UMRS) in 20 patients. Logistic regression analysis was used to identify the factors potentially predicting treatment efficacy. Four patients dropped out in the first two months due to psychiatric side effects. In the remaining patients, PER reduced myoclonus severity as assessed using MMS (Wilcoxon test: p < 0.001) and UMRS (p < 0.001), with the 'Action myoclonus' section of the UMRS showing the greatest improvement. The patients with EPM1 or EPM1-like phenotype were more likely to improve with PER (p = 0.011). Convulsive seizures which have recurred at least monthly in 17 patients were reduced by >50%. Side effects occurred in 22/49 (44.8%) patients, the most common being irritability followed by drowsiness. PER is effective in treating myoclonus and seizures in PME patients. The frequency of psychiatric side effects suggests the need for careful patient monitoring.

Topics: Adult; Aged; Anticonvulsants; Female; Humans; Male; Middle Aged; Myoclonic Epilepsies, Progressive; Myoclonus; Nitriles; Pyridones; Seizures; Treatment Outcome; Young Adult

Antiepileptic drug side effects are frequent, 42% of them corresponding to cosmetic changes. The most frequent effects are weight gain, gingival hyperplasia, and hair loss. Hair changes in texture or colour are rarely reported in the literature. We present a case of hair curling after the introduction of perampanel. A 13-year-old girl with genetically confirmed Pitt-Hopkins syndrome with uncontrolled seizures, while on treatment with levetiracetam and valproic acid, was started on perampanel, reaching seizure control. After a few weeks of the introduction of the new antiepileptic drug, she developed hair curling. Hair curling is a rare cosmetic side effect, reported mainly in patients under valproic acid treatment. Perampanel is a recently introduced pharmaceutical molecule with no prior reports of hair changes as a side effect. There is no clear explanation for this side effect, but it should be discussed with patients taking valproate whenever perampanel is added to the treatment.

Topics: Adolescent; Anticonvulsants; Epilepsy; Facies; Female; Hair; Humans; Hyperventilation; Intellectual Disability; Nitriles; Pyridones; Seizures; Treatment Outcome; Valproic Acid

Pilocarpine-induced status epilepticus (SE), which results in the development of spontaneous recurrent seizures (SRSs) activates glutamatergic receptors that contribute to seizure sustenance and neuronal cell death. In the current study, we evaluate whether the exposure to perampanel, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker, or amantadine, a N-methyl-D-aspartic acid (NMDA) receptor blocker would reduce the SE-induced long-term consequences. SE was induced in adult male Sprague Dawley rats with pilocarpine. Perampanel or amantadine was injected 10 or 60 min after SE onset. The efficacy of either, in overcoming pilocarpine-induced SE was assessed using electroencephalogram (EEG) recordings. In addition, alterations in cognitive function, development of spontaneous recurrent seizures (SRSs), and hippocampal damage that are generally encountered after SE were also assessed at 72 h and 5 weeks after the induction of SE. Our results indicate that both early and late treatment with perampanel but not amantadine significantly reduced seizure activity. Furthermore, perampanel but not amantadine, reversed the memory deficits in Y-maze and novel object recognition (NOR) tests and retarded the appearance of SRSs. Moreover, perampanel treatment led to reduced SE-induced caspase-3 activation in the hippocampal lysates. Taken together, the data obtained from the study reveals that blocking AMPA receptors by perampanel can modify SE-induced long-term consequences. Our results may provide a proof of principle for the potential therapeutic application of perampanel in clinical use for status epilepticus in future.

Topics: Amantadine; Animals; Astrocytes; Behavior, Animal; Caspase 3; Cell Survival; Cognition Disorders; Disease Models, Animal; Enzyme Activation; Male; Neurons; Nitriles; Pilocarpine; Protein Subunits; Pyridones; Rats, Sprague-Dawley; Receptors, AMPA; Seizures; Status Epilepticus

Novel treatments are needed to control treatment-resistant status epilepticus (SE). We report a summary of clinical cases where perampanel was used in established SE, refractory SE (RSE), or super-refractory SE (SRSE).. Medical records were retrospectively reviewed for perampanel administration in SE at five European hospitals between 2011 and 2015.. Of 1319 patients identified as experiencing SE, 52 (3.9%) received perampanel. Median latency from SE onset to perampanel initiation was 10 days. Patients with SE had previously failed benzodiazepines (when received) and a median of five other antiepileptic drugs (AEDs). Median initial perampanel dose was 6 mg/d, up-titrated to a median maximum dose of 10 mg/d. Perampanel was the last drug added in 32/52 (61.5%) patients, with response attributed to perampanel in 19/52 (36.5%) patients. A greater proportion of perampanel non-responders had SRSE (51.5%; 17/33) vs perampanel responders (31.6%; 6/19), and had failed a higher mean number of AEDs before initiating perampanel (5.9 vs 5.1, respectively). Most commonly reported adverse effects during perampanel treatment were dizziness (n = 1 [1.9%]) and somnolence (n = 1 [1.9%]). No serious adverse effects were documented, and none led to discontinuation of perampanel.. Perampanel was administered to patients with established SE, RSE, or SRSE at greater initial doses than those administered in clinical practice to patients with epilepsy. The SE cases reported here represent a refractory and heterogeneous population, and rate of seizure cessation attributed to perampanel treatment (36.5%) represents a notable response. These data should be confirmed in a larger patient population.

Topics: Adult; Anticonvulsants; Austria; Female; Finland; Germany; Humans; Male; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Seizures; Spain; Status Epilepticus; Treatment Outcome

We report this 1st case because perampanel may be effective against the seizures and abnormal behavior that occur in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.. The patient was a healthy 26-year-old woman who suddenly developed seizures and exhibited abnormal behavior.. NMDAR encephalitis was diagnosed based on positive NMDAR antibody on cerebrospinal fluid analysis.. Treatment with anticonvulsants and sedatives was started immediately, along with steroid pulse therapy and plasmapheresis, but these measures did not adequately control the repeated seizures and abnormal behavior. However, with the addition of oral perampanel, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, the seizures and abnormal behavior promptly disappeared.. The patient was transferred to the rehabilitation hospital and returned to her job.. It appears that perampanel rapidly eliminated these clinical features by inhibiting inflow of abnormal glutamic acid and attenuating nerve hyperexcitability by acting as a selective and noncompetitive antagonist of AMPA receptors that had increased in the postsynaptic membrane due to anti-NMDAR encephalitis. To the best of our knowledge, there are no other reports showing that perampanel was effective against anti-NMDAR encephalitis. This case suggests that perampanel may be effective against the seizures and abnormal behavior that occur in anti-NMDAR encephalitis.

Topics: Adult; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Central Nervous System Agents; Female; Humans; Nitriles; Pyridones; Seizures

Epileptic seizures are frequent in patients with glioblastoma, and anticonvulsive treatment is often necessary. While clinical guidelines recommend all approved anticonvulsants, so far it is still unclear which of the available drugs is the best therapeutic option for treating glioma-associated seizures, also in view of possible anti-tumorigenic effects. In our study, we employed four patient-derived low-passage cell lines of glioblastoma and three cell lines of brain metastases, and challenged these cultures with four anticonvulsants with different mechanisms of action: levetiracetam, valproic acid, carbamazepine and perampanel. Cell proliferation was determined by bromodeoxyuridine incorporation. To further analyze the effects of perampanel, apoptosis induction was measured by caspase 3/7 activation. Glutamate release was quantified and glucose uptake was determined using 18F-fluorodeoxyglucose. Real-time polymerase chain reaction was employed to assess the expression of genes associated with glutamate release and uptake in brain tumor cells. Of the four anticonvulsants, only perampanel showed systematic inhibitory effects on cell proliferation, whereas all other anticonvulsants failed to inhibit glioma and metastasis cell growth in vitro. Metastasis cells were much more resistant to perampanel than glioblastoma cell lines. Glucose uptake was attenuated in all glioblastoma cells after perampanel exposure, whereas cell death via apoptosis was not induced. Extracellular glutamate levels were found to be significantly higher in glioblastoma cell lines as compared to metastasis cell lines, but could be reduced by perampanel exposure. Incubation with perampanel up-regulated glutamine synthetase expression in glioblastoma cells, whereas treatment with valproic acid and levetiracetam downregulated excitatory amino acid transporter-2 expression. Overall, our data suggest that perampanel acts as an anticonvulsive drug and additionally mediated anti-tumorigenic effects.

Topics: Anticonvulsants; Antineoplastic Agents; Apoptosis; Brain; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Epilepsy; Glioblastoma; Glutamic Acid; Humans; Nitriles; Pyridones; Receptors, AMPA; Seizures; Up-Regulation; Valproic Acid

To explore the retention rates and the efficacy and tolerability of perampanel (PER) by using monthly real life data for a period of 12 months.. Longitudinal outcomes of (PER) usage were assessed using actuarial statistics in an observational nonrandomised multicentre study of 181 people with epilepsy (PWE) refractory to first and second line drugs. Graded seizure outcomes, toxicity and the dose of PER were recorded for each month.. PWE were followed for a mean of 15.1 months. The total cumulative probability for retention on PER at 12 months was 61.7% and for ≥50% improvement was 38.2%. Most improvements in seizure control occurred soon after initiation of PER, 17% by one month, 32% by six months and 38% by twelve months, and mostly at low doses 53% on 2 mg and 90% up to 6 mg. Improvements, when they occurred, were sustained. The most common side effects were neuropsychiatric, occurring in 28%. The emergence of side effects did not appear to be dose related. Although people with intellectual disability (ID) were more likely to remain on PER they did not show improved seizure control and also reported more side effects. Patients treated with VNS and PER had a worse outcome.. Overall around a third of people showed a useful, response to PER therapy. The response to PER is noted usually early in the treatment and for the majority of the patients for doses up to 8 mg.

Topics: Actuarial Analysis; Adult; Anticonvulsants; Drug Therapy, Combination; Epilepsy; Female; Humans; Intellectual Disability; Male; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Seizures; Treatment Outcome

A number of antiepileptic drugs (AEDs) with a variety of modes of action, are effective in treating focal seizures. Several AEDs, such as perampanel (PER), levetiracetam (LEV), lacosamide (LCM), lamotrigine (LTG), and carbamazepine (CBZ), have been shown to elevate the seizure threshold in kindling models. These AEDs are clinically effective, but differences exist in the anti-seizure profiles of drugs with similar modes of action. Therefore, we hypothesized that there are differences in how these AEDs affect seizures. Here, we evaluated the effects of AEDs on various seizure parameters in a rat amygdala kindling model upon stimulation at the after-discharge threshold (ADT) and at three-times the ADT (3xADT) to characterize the differences in the effects of these AEDs.. PER, LEV, LCM, LTG, CBZ, or vehicle was administered intraperitoneally to fully kindled rats. Changes in Racine seizure score, after-discharge duration (ADD), and latency to Racine score 4 generalized seizure (S. PER, LEV, LCM, LTG, and CBZ significantly reduced the seizure score from Racine score 5 after stimulation at the ADT; this effect was lost with LEV and LTG after stimulation at 3xADT. PER and LEV significantly shortened the ADD when the seizure focus was stimulated at the ADT, whereas LCM, LTG, and CBZ did not. LEV, LCM, LTG, and CBZ failed to shorten the ADD upon stimulation at 3xADT. PER dose-dependently and significantly increased S. The sodium channel blockers (LCM, LTG, and CBZ) appeared to act by elevation of the seizure threshold via reduction of neuronal excitability, whereas the AMPA receptor antagonist (PER) and the SV2A ligand (LEV), as well as LTG, exerted their effects through the weakening of synaptic transmission in neuronal networks at the seizure focus. Maintenance of the effect of PER even at 3xADT suggests direct and strong modulation of excitatory synaptic transmission by PER, both at the focus and along the seizure propagation route. These findings may provide further rationale for usage of AEDs beyond their respective modes of action.

Topics: Amygdala; Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Kindling, Neurologic; Male; Membrane Glycoproteins; Nerve Tissue Proteins; Nitriles; Pyridones; Rats; Rats, Inbred WKY; Receptors, AMPA; Seizures; Sodium Channel Blockers

Perampanel (PER) is a third generation antiepileptic drug (AED), recently approved as add-on therapy in both focal and generalized seizures. Levetiracetam (LEV) is a second generation AED, widely used in patients with epilepsy because of its favorable safety and efficacy profiles. Perampanel and LEV treatments have been associated with the occurrence of similar adverse events (AEs) (sleepiness, irritability, depression, anxiety, aggressiveness). The aim of the present retrospective single center study was to verify the efficacy and tolerability of PER and LEV used as first add-on therapy in patients with epilepsy affected by secondarily generalized seizures. We collected data from 15 patients treated with PER and 26 patients treated with LEV and followed at our site with follow-up visits at 3, 6, and 12months. This retrospective study documented the comparable efficacy of PER and LEV as first add-on treatments in patients affected by uncontrolled secondarily generalized seizures. However, more patients withdrawn LEV because of AEs compared with PER at the 3- and 12-month follow-up visits. The better tolerability of PER observed in this study could be related to the low therapeutic dose of PER prescribed when it is used as first adjunctive treatment for better controlling secondarily generalized seizures.

Topics: Adult; Aggression; Anticonvulsants; Anxiety; Depression; Dizziness; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Female; Humans; Irritable Mood; Levetiracetam; Male; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Seizures; Treatment Outcome; Wakefulness

Topics: Anticonvulsants; Clinical Trials, Phase III as Topic; Double-Blind Method; Female; Humans; Male; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Seizures; Treatment Outcome

Perampanel is an antiepileptic drug (AED) approved for add-on treatment of focal seizures (with or without generalization) and primary generalized tonic-clonic (GTC) seizures. Our objective was to explore the effectiveness and tolerability of adjunctive perampanel in patients with drug-resistant myoclonic seizures, after failure of other AEDs.. Retrospective, multicenter, observational study. Data were collected from individual patient clinical files and analysed using appropriate descriptive statistics and inferential analyses.. Data are reported for 31 patients with mean age 36.4 years, who had an average epilepsy duration of 18 years, previously taken an average of 5.03 AEDs, and were taking an average of 2.4 AEDs on perampanel initiation. Patients exhibited myoclonic, GTC, absence, tonic and focal seizures, and most had associated cognitive decline and/or ataxia. Median time on perampanel was 6 months, most common dose was 6 mg, and overall retention rate was 84%. The responder rate for myoclonic seizures was defined via reduction of days with myoclonic seizures per month. At 6 months, 15 (48.4%) of the 31 patients were classed as myoclonic seizure responders, 10 (32.3%) were myoclonic seizure free, and 39% saw improvements in functional ability. Of 17 patients with GTC seizures at baseline, 9 (53%) were responders at 6 months, and 8 (47.1%) were seizure free. The most frequent side effects were psychiatric disorders, instability, dizziness and irritability, and mostly resolved with dose reduction. Five patients discontinued perampanel due to side effects.. Perampanel caused clinically meaningful improvements in patients with drug-resistant myoclonic seizures. It was generally well tolerated, but psychiatric and neurological side effects sometimes required follow-up and dose reduction.

Topics: Adult; Aged; Anticonvulsants; Drug Therapy, Combination; Epilepsies, Myoclonic; Female; Humans; Male; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Seizures; Treatment Outcome; Young Adult

Excessive extracellular glutamate activates AMPA-type glutamate receptors (AMPA receptors) and induces seizures. Antagonistic activation of AMPA receptors inhibits epilepsy and glioma growth in in vitro and in vivo studies. This study was conducted to evaluate the clinical impacts of perampanel (PER), a novel AMPA receptor antagonist, on seizures and tumor progression in glioma patients with uncontrollable epilepsy.. Twelve glioma patients with uncontrollable epilepsy were treated with PER. Seizure response, PER concentration, and tumor volume were assessed.. Obvious seizure control was observed in 10 analyzed patients (100%) and 6 patients (60%) became seizure-free. Median plasma concentrations of PER were 296 ng/ml in those with 4 mg/day PER treatment and 518 ng/ml in those with 8 mg/day PER treatment. High-intensity lesions in fluid-attenuated inversion recovery of magnetic resonance imaging (MRI) were volumetrically assessed to analyze tumor size. Volume reduction was detected within 6 months in correlation with increased plasma levels of PER.. PER treatment was effective in uncontrollable epilepsy with gliomas. MRI images showed the inhibition of tumor growth.

Topics: Adult; Aged; Aged, 80 and over; Anticonvulsants; Brain Neoplasms; Disease Progression; Epilepsy; Female; Glioma; Humans; Male; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Seizures

Persistent seizures are associated with physical injury, reduced quality of life, and psychosocial impairment. Perampanel is approved for the adjunctive treatment of primary generalized tonic-clonic seizures (PGTCS).. This study aimed to determine the cost-effectiveness of perampanel as adjunctive therapy to other antiepileptic drugs (AED) compared with AED maintenance therapy alone for the treatment of PGTCS.. We developed a Markov model for PGTCS where transitions were based on treatment response rates. The analysis was conducted over a 33-year time horizon from the Spanish National Health Service (NHS) and societal perspectives. Efficacy data were derived from clinical studies. Resource use, market shares, costs, and utilities were obtained from Kantar Health's National Health and Wellness Survey. Drug costs were obtained from the Consejo General de Colegios Oficiales de Farmacéuticos. One-way and probabilistic sensitivity analyses were performed.. In the base case analysis from the NHS perspective, perampanel was associated with an incremental cost-effectiveness ratio (ICER) of €16,557/quality-adjusted life year (QALY) relative to AED maintenance therapy for the treatment of PGTCS. Incremental costs were €5475 and incremental QALYs were 0.33. In one-way sensitivity analyses, the ICERs were strongly influenced by discounting rate for costs and health effects, with little influence of other parameters, including perampanel cost and utilities. In probabilistic sensitivity analyses, the probability of perampanel being cost-effective at a willingness-to-pay threshold of €30,000/QALY was 89.3%. From the societal perspective, perampanel provided a cost-savings of €5288 per patient compared with AED maintenance therapy alone.. Our study demonstrates that perampanel is likely to be a cost-effective option.

Topics: Anticonvulsants; Cost-Benefit Analysis; Epilepsy, Generalized; Epilepsy, Tonic-Clonic; Humans; Markov Chains; Models, Economic; National Health Programs; Nitriles; Pyridones; Quality of Life; Quality-Adjusted Life Years; Seizures; Spain

Topics: Acoustic Stimulation; Administration, Oral; Animals; Anticonvulsants; Brain; Clobazam; Dose-Response Relationship, Drug; Drug Tolerance; Epilepsy, Reflex; Genetic Predisposition to Disease; Male; Motor Activity; Nitriles; Pyridones; Rats; Seizures

Drug-resistant epilepsy (DRE) occurs commonly in gliomas, possibly due to a shared mechanism of AMPA-activation involving both seizure activity and tumor growth. We tested the AMPA-receptor blocker perampanel (PER) in patients with DRE in low- and high-grade gliomas. Seizure response was defined as 50% drop in seizure frequency or as seizure-freedom. Cognitive function was examined by computerized test on cognitive speed (CTCS), which is sensitive to the type of cognitive dysfunction associated with epilepsy and use of anticonvulsants. Treatment policy included reduction of dose or discontinuation of one or more concurrent AEDs, once a seizure-free response was observed. Twelve patients were included patients, median age 41 years, 9 men versus 3 women and 6 months median duration of follow-up. An objective seizure response (75%) was observed in 9 (75%) out of 12 patients: 50%-seizure response in 3, seizure-freedom in 6, which is plainly more than seen with other types of DRE. Side-effects occurred in six patients. Cognitive function as examined by CTCS improved in six out of eight associated withlowering of concurrent AEDs. The final median dose of PER was 8 mg (varying between 2 and 12 mg). These results of an objective seizure response in 9 (75%) out of 12 patients treated by PER in DRE may be interpreted as a surrogate-marker of tumor response secondary to AMPA blockade, advancing confirmation by MR imaging. These results warrant further study of PER on tumor activity in gliomas.

Topics: Adult; Aged; Anticonvulsants; Cognitive Dysfunction; Dose-Response Relationship, Drug; Drug Resistant Epilepsy; Female; Follow-Up Studies; Glioma; Humans; Male; Middle Aged; Nitriles; Pyridones; Seizures; Treatment Outcome

Psychiatric comorbidities are common in people with epilepsy. A retrospective study of characteristics associated with withdrawal due to psychiatric side effects was undertaken in patients with treated epilepsy participating in prospective audits with new antiepileptic drugs (AEDs). A total of 1058 treated patients with uncontrolled seizures (942 focal-onset seizures, 116 generalized genetic epilepsies [GGEs]) participated in eight prospective, observational audits from 1996 to 2014. These patients were prescribed adjunctive topiramate (n=170), levetiracetam (n=220), pregabalin (n=135), zonisamide (n=203), lacosamide (n=160), eslicarbazepine acetate (n=52), retigabine (n=64), or perampanel (n=54). Doses were titrated according to efficacy and tolerability to optimize zeizure outcomes and reduce side effects. Psychiatric comorbidities were recorded prior to and after the addition of each AED. At baseline, patients with focal-onset seizures (189 of 942; 20.1%) were statistically more likely to have psychiatric diagnoses compared to patients with GGEs (14 of 116, 12.1%; p=0.039). Following adjunctive AED treatment, neuropsychiatric adverse effects led to AED withdrawal in 1.9-16.7% of patients. Patients with a pre-treatment psychiatric history (22 of 209; 10.5%) were statistically more likely to discontinue their new AED due to psychiatric issues compared to patients with no previous psychiatric diagnosis (50 of 849; 5.9%; p=0.017). Patients receiving sodium channel blocking AEDs (4 of 212, 1.9%) were statistically less likely to develop intolerable psychiatric problems, compared to those on AEDs possessing other mechanisms of action (68 of 846, 8.0%; p=0.012). Depression was the commonest problem, leading to discontinuation of AEDs in 2.8% (n=30) patients. Aggression was statistically more common in men (11 of 527, 2.1%) compared to women (1 of 531, 0.2%; p=0.004). Patients with learning disability (12 of 122, 9.8%; p=0.0015) were statistically less likely to have psychiatric issues prior to adjunctive AED treatment compared to other patients (208 of 936, 22.2%), but there were no statistically significant differences once the new AEDs were added (8 of 122 patients with learning disability, 6.6%; 64 of 936 other patients, 6.8%). Awareness of these issues may assist clinicians in avoiding, identifying and treating psychiatric comorbidities in people with epilepsy.

Topics: Acetamides; Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Dibenzazepines; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Female; Fructose; Humans; Lacosamide; Levetiracetam; Male; Medical Audit; Mental Disorders; Middle Aged; Nitriles; Piracetam; Pregabalin; Prospective Studies; Pyridones; Retrospective Studies; Seizures; Sodium Channel Blockers; Topiramate; Young Adult

Report the use of perampanel treatment in children with Lennox-Gastaut syndrome (LGS).. We conducted a prospective study of 13 LGS patients (seven male; mean age, 12.8years) treated with adjunctive perampanel therapy. Perampanel was initiated at 2mg/day and titrated to a median maximum dose of 6mg/day.. After a mean follow-up duration of 10.8months (range, 1-24months), nine patients (69.2%) were responders (≥50% reduction in total seizure frequency) and nine (69.2%) were rated by their physician as "much improved" or "very much improved". Four patients (30.8%) discontinued perampanel due to the lack of efficacy (n=2) and seizure aggravation (n=2). No patients discontinued due to other adverse events (AEs). AEs were reported for six patients (46.2%) and comprised decreased activity/social interaction (n=3), behavior disturbance with agitation (n=2), and/or fatigue (n=2). All AEs became manageable after perampanel dosing was decreased. Improvements in cognitive function and/or behavior were reported for seven patients (53.8%). Introduction of perampanel allowed the dose reduction and/or discontinuation of other treatments in seven patients (53.8%).. Perampanel was efficacious and generally well tolerated as an adjunctive treatment for seizures associated with LGS, supporting further research in this area.

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Cohort Studies; Female; Follow-Up Studies; Humans; Lennox Gastaut Syndrome; Male; Nitriles; Prospective Studies; Pyridones; Seizures; Treatment Outcome

To evaluate the budget impact (BI) of adopting perampanel for adjunctive treatment of partial-onset seizures (POS), with or without secondarily generalized seizures, and the adjunctive treatment of primary generalized tonic-clonic seizures (PGTCS) in patients 12years or older in the United States.. A BI model was developed to estimate the potential BI of adopting adjunctive perampanel from a US payer (direct costs only) and societal (direct and indirect costs) perspective over a 5-year period. Efficacy data for perampanel and antiepileptic drug (AED) maintenance therapy were obtained from perampanel phase III clinical trials. Drug, direct medical (healthcare provider, emergency room, and hospitalizations), and indirect (productivity loss) costs were obtained from appropriate sources (e.g., AnalySource® Online [wholesale acquisition costs], 2013 Optum Insight Clinformatics Database [market share percentages, direct medical costs per unit], and 2011-2013 National Health and Wellness Survey [NHWS; healthcare resource utilization, overall work impairment, and baseline distribution of patients across the 4 health states]). Mapping of seizure frequency to medical resource utilization and work impairment was obtained from Kantar Health's NHWS.. In a hypothetical health plan of 1 million members, 660 (0.066%) members ≥12years old had uncontrolled POS (395 [59.8%]) or PGTCS (265 [40.2%]). During the first 5years of adoption of perampanel, absolute BI (including drug, direct medical, and indirect costs) was $852, $2124, $3855, $5318, and $6397, respectively, for a cumulative absolute BI of $18,545. Drug cost was estimated to increase by $13,888, $34,646, $62,863, $86,728, and $104,326, respectively; however, this cost would be mostly offset by decreases in direct medical ($5041, $12,576, $22,818, $31,481, and $37,869, respectively) and indirect ($7995, $19,946, $36,190, $49,929, and $60,060, respectively) costs. Total per-member-per-month cost (drug and direct medical costs) was estimated to increase by $0.0007, $0.0018, $0.0033, $0.0046, and $0.0055 from years 1 to 5.. Based on results of this BI model, increased cost of adopting perampanel in a health plan of 1 million members would be minimal for payers, and societal costs would be close to neutral.

Topics: Anticonvulsants; Databases, Factual; Drug Therapy, Combination; Female; Health Surveys; Hospitalization; Humans; Male; Models, Economic; Nitriles; Pyridones; Seizures; United States

Perampanel is an AMPA receptor antagonist recently approved for the treatment of partial and generalized epilepsies with tonic-clonic seizures as an add-on therapy.. This single-center postmarketing study retrospectively evaluated the efficacy of perampanel in patients with partial onset and other seizure types, with a special emphasis on its efficacy, safety, and tolerability.. Review of medical records revealed that adequate data were available on 101 patients taking perampanel. Fifty-seven patients were female. Sixteen patients were of pediatric age range. The average dose of perampanel was 6.5mg, and average treatment duration was 8.2months. After treatment, median seizure frequency reduction was 50% overall, 50% in children, and 33% in adults; 44% in primary generalized, 38% in secondarily generalized, and 33% in partial seizures. Responder rate (50% seizure frequency reduction) was 51% overall, 63% in children, and 49% in adults; 60% in partial seizures, 43% in secondarily generalized tonic-clonic seizures, 53% in primary generalized tonic-clonic seizures, and 56% in other seizure types. Seizure freedom was attained in 6% of cases. Most common adverse events were sleepiness/fatigue (35%), behavioral problems (30%), and dizziness (22%). Adverse events were correlated with dosage. Average dose was 7.3mg in patients with adverse events vs. 5.5mg in those without adverse events. Patients who developed fatigue, cognitive decline, headaches, and weight gain were more likely to discontinue perampanel than those patients who experienced coordination issues and behavioral problems.. These findings suggest that perampanel is safe, well-tolerated, and effective in treatment of various types of adult and pediatric epilepsy syndromes. Fatigue, cognitive decline, headache and weight gain were the main causes of perampanel discontinuation.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Child; Child, Preschool; Dose-Response Relationship, Drug; Epilepsies, Partial; Epilepsy, Tonic-Clonic; Fatigue; Female; Humans; Infant; Male; Middle Aged; Nitriles; Product Surveillance, Postmarketing; Pyridones; Receptors, AMPA; Retrospective Studies; Safety; Seizures; Treatment Outcome; Young Adult

The purpose of this study was to evaluate the effectiveness and safety of PER as add-on treatment in patients with severe refractory epilepsy with a particular focus on patients with learning disability and/or psychiatric comorbidity.. We pooled retrospective data from adult patients with refractory epilepsy prescribed perampanel from a tertiary center in France between 1st May 2014 and 3rd June 2015. Data collection was done on February 2016.. One hundred and one patients were included (mean age: 41.2years, 37.6% with learning disability and 49.5% with psychiatric comorbidity). Mean retention was 8.1months (range: 14days to 17months). On final evaluation, a >50% reduction in seizure frequency was reached in 41.6% of patients, and 7 patients (6.9%) became seizure-free. Sixty-three patients (62.4%) experienced adverse effects. The most common adverse effects were irritability, asthenia, aggression, and sedation. Efficacy, retention of treatment, and safety were equally similar in patients with learning disability or psychiatric comorbidity as for those without. The only significant difference was in percentage of seizure-free patients: 11.1% in the group without learning disability compared with 0% in the group with (p=0.043).. Adjunctive PER can achieve clinically meaningful improvement, or even seizure freedom, in more than one-third of patients suffering from severe refractory epilepsies. It seems similarly safe and effective in the subgroup of these patients with learning disability or with psychiatric comorbidity. However, the rate of psychiatric side effects is high,; of note, we asked both patient and caregivers at each visit especially focusing on psychiatric side effects. Patients, caregivers, and families should be informed of potential psychiatric/behavioral risks associated with taking perampanel especially during the initial titration period.

Topics: Adult; Aggression; Anticonvulsants; Drug Resistant Epilepsy; Drug Therapy, Combination; Female; France; Humans; Irritable Mood; Male; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Seizures; Tertiary Care Centers; Treatment Outcome

Real-world data of current antiepileptic drugs (AEDs) used to treat focal seizures is of importance to understand the efficacy and safety outside of the clinical trial setting. Here we report real-world data from a large series of patients treated with perampanel for 1year.. FYDATA was a multicentre, retrospective, 1-year observational study assessing the efficacy and safety of adjuvant perampanel in patients ≥12 years of age with focal epilepsy in a real-world setting. At 12 months, the proportion of patients who were seizure free, median percentage seizure reduction, proportion of responders, retention rate and proportion of patients with adverse events (AEs) were assessed. Analyses were also performed to identify any patient-, medication- and disease-related factors associated with a large clinical response or carry a risk for AEs.. A total of 464 patients were included in the study with a retention rate of 60.6% at 1year. The mean number of prior AEDs was 7.8. The median percentage reduction in overall seizures was 33.3% (75% for secondary generalised seizures) after 1year, with 7.2% of patients achieving seizure freedom. Furthermore, patients on non-enzyme-inducing AEDs were more likely to achieve seizure freedom, and logistic regression revealed that patients aged ≥65 years, those with epilepsy due to a vascular aetiology and those who had received fewer prior AEDs showed a better clinical response to perampanel. A total of 62.9% of the patients experienced AEs at 12 months; dizziness, somnolence and irritability were the most frequent AEs. Patients with prior psychiatric comorbidities (hyperactivity and personality disorder) were more likely to experience psychiatric AEs with perampanel, and slower titration schedules were associated with less AEs overall.. Perampanel, for the treatment of focal epilepsy in a real-world setting in a refractory population, over 1year, demonstrates a similar efficacy and safety profile to that observed in clinical trials. Our results have implications for the optimisation of perampanel use in a clinical setting.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Child; Comorbidity; Epilepsies, Partial; Female; Follow-Up Studies; Humans; Logistic Models; Male; Mental Disorders; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Seizures; Treatment Outcome; Young Adult

The purpose of this study was to evaluate subjective sleep quality and daytime sleepiness in patients receiving adjunctive perampanel for focal seizures.. We conducted a multicenter, prospective, interventional, open-label study in patients aged >16 with focal seizures who received adjunctive perampanel (flexible dosing: 2-12mg). Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and daytime sleepiness with the Epworth Sleepiness Scale (ESS) at baseline and 3 and 6months after initiating perampanel. Patients with modifications in their baseline AEDs or sleep medications were excluded.. In 72 patients with drug-resistant focal seizures, mean baseline PSQI score (±standard deviation) was 7.26 (±4.6), and ESS was 6.19 (±4.2). At 3months (median perampanel dose: 4mg), there was no significant mean change from baseline in ESS score (n=61) and a significant improvement in PSQI (-1.51 points; n=44; p=0.007), driven mainly by improved sleep efficiency (p=0.012). In the 31 patients with 6-month data, ESS (but not PSQI) improved significantly at 6months vs baseline (p=0.029). The only factor significantly correlated with sleep parameters was number of baseline AEDs (higher number correlated with worse daytime sleepiness). Seizure frequency was reduced significantly from baseline at 3 and 6months. In bivariate analysis, neither PSQI nor ESS was associated with seizure frequency, suggesting that the changes in daytime sleepiness and sleep quality may be independent of the direct effect on seizures.. Adjunctive perampanel did not worsen sleep quality or daytime sleepiness at 3months and reduced daytime sleepiness in patients continuing perampanel for 6months. Perampanel may be a suitable AED in patients with sleep disorders, in addition to refractory focal seizures.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Female; Humans; Male; Middle Aged; Nitriles; Prospective Studies; Pyridones; Seizures; Sleep Wake Disorders; Young Adult

To evaluate the efficacy and tolerability of Perampanel (PER) in children and adolescents with refractory epilepsies in daily clinical practice conditions.. This Italian multicenter retrospective observational study was performed in 16 paediatric epilepsy centres. Inclusion criteria were: (i) ≤18 years of age, (ii) history of refractory epilepsy, (iii) a follow-up ≥5 months of PER add-on therapy. Exclusion criteria were: (i) a diagnosis of primary idiopathic generalized epilepsy, (ii) variation of concomitant AEDs during the previous 4 weeks. Response was defined as a ≥50% reduction in monthly seizure frequency compared with the baseline.. 62 patients suffering from various refractory epilepsies were included in this study: 53% were males, the mean age was 14.2 years (range 6-18 years), 8 patients aged <12 years. Mean age at epilepsy onset was 3.4 years and the mean duration of epilepsy was 10.8 years (range 1-16), which ranged from 2 seizures per-month up to several seizures per-day (mean number=96.5). Symptomatic focal epilepsy was reported in 62.9% of cases. Mean number of AEDs used in the past was 7.1; mean number of concomitant AEDs was 2.48, with carbamazepine used in 43.5% of patients. Mean PER daily dose was 7.1mg (2-12mg). After an average of 6.6 months of follow-up (5-13 months), the retention rate was 77.4% (48/62). The response rate was 50%; 16% of patients achieved ≥75% seizure frequency reduction and 5% became completely seizure free. Seizure aggravation was observed in 9.7% of patients. Adverse events were reported in 19 patients (30.6%) and led to PER discontinuation in 4 patients (6.5%). The most common adverse events were behaviour disturbance (irritability and aggressiveness), dizziness, sedation and fatigue.. PER was found to be a safe and effective treatment when used as adjunctive therapy in paediatric patients with uncontrolled epilepsy.

Topics: Adolescent; Anticonvulsants; Child; Drug Resistant Epilepsy; Female; Follow-Up Studies; Humans; Italy; Male; Nitriles; Pyridones; Retrospective Studies; Seizures; Treatment Outcome

Perampanel, a new specific non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor antagonist, has been recently approved in the United States and the European Union for the adjunctive treatment of focal seizures and primary generalized tonic-clonic seizures associated with idiopathic generalized epilepsy. A positive relationship between plasma perampanel concentration and improvement in seizure control has been identified in regulatory trials, suggesting that therapeutic drug monitoring could be useful in optimizing clinical response in patients with epilepsy treated with perampanel. The development of a simple and broadly applicable method for measuring plasma perampanel concentrations is desirable to permit the use of TDM for this drug in clinical practice.. A high-performance liquid chromatographic method with ultraviolet detection for the quantitative determination of perampanel in small aliquots of human plasma (200 μL) has been developed and validated. Sample preparation involves a simple precipitation step followed by solvent evaporation. High-performance liquid chromatographic separation is achieved on 2 reverse-phase monolithic columns in sequence connected to an ultraviolet detector (320 nm), using as mobile phase water/acetonitrile (60:40 vol/vol) mixed with 1 mL/L phosphoric acid, at a flow rate of 1.5 mL/min. Promethazine hydrochloride is used as internal standard.. Calibration curves were linear over a perampanel concentration range of 25-1000 ng/mL, with correlation coefficients equal or greater than 0.998 ± 0.001 and a limit of quantitation set at 25 ng/mL. Intra- and inter-day coefficients of variation did not exceed 7.4%, and the accuracy ranged from 96.4% to 113.3%. No interference was observed from commonly coprescribed drugs.. The present assay is simple, specific, and cost effective with performance characteristics suitable for TDM use.

Topics: Anticonvulsants; Biological Assay; Calibration; Chromatography, High Pressure Liquid; Drug Monitoring; Epilepsy; Humans; Nitriles; Pyridones; Reproducibility of Results; Seizures; Ultraviolet Rays

Pharmacological manipulation of specific neural circuits to optimize therapeutic index is an unrealized goal in neurology and psychiatry. AMPA receptors are important for excitatory synaptic transmission, and their antagonists are antiepileptic. Although efficacious, AMPA-receptor antagonists, including perampanel (Fycompa), the only approved antagonist for epilepsy, induce dizziness and motor impairment. We hypothesized that blockade of forebrain AMPA receptors without blocking cerebellar AMPA receptors would be antiepileptic and devoid of motor impairment. Taking advantage of an AMPA receptor auxiliary protein, TARP γ-8, which is selectively expressed in the forebrain and modulates the pharmacological properties of AMPA receptors, we discovered that LY3130481 selectively antagonized recombinant and native AMPA receptors containing γ-8, but not γ-2 (cerebellum) or other TARP members. Two amino acid residues unique to γ-8 determined this selectivity. We also observed antagonism of AMPA receptors expressed in hippocampal, but not cerebellar, tissue from an patient with epilepsy. Corresponding to this selective activity, LY3130481 prevented multiple seizure types in rats and mice and without motor side effects. These findings demonstrate the first rationally discovered molecule targeting specific neural circuitries for therapeutic advantage.

Topics: Animals; Anticonvulsants; Benzothiazoles; Calcium Channels; Cerebellum; Convulsants; Disease Models, Animal; Dizziness; Epilepsy; Mice; Nitriles; Pentylenetetrazole; Prosencephalon; Pyrazoles; Pyridones; Rats; Receptors, AMPA; Seizures

The AMPA receptor subtype of glutamate receptors, which mediates fast synaptic excitation, is of primary importance in initiating epileptiform discharges, so that AMPA receptor antagonists exert anti-seizure activity in diverse animal models of partial and generalized seizures. Recently, the first AMPA receptor antagonist, perampanel, was approved for use as adjunctive therapy for the treatment of resistant partial seizures in patients. Interestingly, the competitive AMPA receptor antagonist NBQX has recently been reported to prevent development of spontaneous recurrent seizures (SRS) in a neonatal seizure model in rats, indicating the AMPA antagonists may exert also antiepileptogenic effects. This prompted us to evaluate competitive (NBQX) and noncompetitive (perampanel) AMPA receptor antagonists in an adult mouse model of mesial temporal lobe epilepsy. In this model, SRS develop after status epilepticus (SE) induced by intrahippocampal injection of kainate. Focal electrographic seizures in this model are resistant to several major antiepileptic drugs. In line with previous studies, phenytoin was not capable of blocking such seizures in the present experiments, while they were markedly suppressed by NBQX and perampanel. However, perampanel was less tolerable than NBQX in epileptic mice, so that only NBQX was subsequently tested for antiepileptogenic potential. When mice were treated over three days after kainate-induced SE with NBQX (20 mg/kg t.i.d.), no effect on development or frequency of seizures was found in comparison to vehicle controls. These results suggest that AMPA receptor antagonists, while being effective in suppressing resistant focal seizures, are not exerting antiepileptogenic effects in an adult mouse model of partial epilepsy.

Topics: Animals; Anticonvulsants; Chronic Disease; Disease Models, Animal; Electroencephalography; Epilepsy, Temporal Lobe; Female; Hippocampus; Kainic Acid; Mice; Nitriles; Phenytoin; Pyridones; Quinoxalines; Receptors, AMPA; Seizures; Status Epilepticus

Perampanel (PER) has been approved by the European Medicines Agency (EMA) for adjunctive treatment of patients with partial-onset seizures from age 12 years on. It has been introduced to the market in Germany and Austria in 2012. This cross-sectional observational study summarizes the clinical experience of nine centers with adjunctive PER. Patients were consecutively followed from the initiation of PER on. Only patients with a minimum observational period of six months (in case of ongoing treatment) were recruited. Efficacy data reflect the preceding three months at last observation, tolerability data were assessed at the last observation carried forward. 281 patients were included. After six months 169 were still on PER so that a retention rate of 60% resulted. 43 patients were seizure-free for the preceding 3 months (15%). Overall incidence of adverse events was 52.0%. The leading adverse events were somnolence (24.6%) and dizziness (19.6%) followed by ataxia (3.9%), aggression (2.8%), nausea (2.5%) and irritability (2.1%). We conclude that adjunctive PER may lead to at least temporary freedom of seizures in some of these highly difficult-to-treat patients. Adverse events are not uncommon.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Austria; Child; Cross-Sectional Studies; Epilepsies, Partial; Epilepsy; Female; Germany; Humans; Male; Middle Aged; Nitriles; Pyridones; Seizures; Treatment Outcome; Young Adult

Perampanel has recently been approved as an anticonvulsant drug for focal epilepsies. Phase III trials have shown good tolerability, although data regarding effects of high doses of perampanel are not available. Here, we describe the first case of a 34-year-old patient with perampanel intoxication and attempted suicide, in which the recommended daily dose of perampanel was exceeded ten-fold. Clinical signs of the intoxication and possible psychotropic effects are described.

Topics: Adult; Anticonvulsants; Epilepsies, Partial; Epilepsy, Tonic-Clonic; Female; Glasgow Coma Scale; Humans; Nitriles; Pyridones; Seizures; Suicide, Attempted; Tuberous Sclerosis

To assess the pharmacology of perampanel and its antiseizure activity in preclinical models. Perampanel [2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile] is a novel, orally active, prospective antiepileptic agent currently in development for refractory partial-onset seizures.. Perampanel pharmacology was assessed by examining changes in intracellular free Ca(2+) ion concentration ([Ca(2+) ](i) ) in primary rat cortical neurones, and [(3) H]perampanel binding to rat forebrain membranes. Antiseizure activity of orally administered perampanel was examined in amygdala-kindled rats and in mice exhibiting audiogenic, maximal electroshock (MES)-induced, pentylenetetrazole (PTZ) -induced, or 6 Hz-induced seizures.. In cultured rat cortical neurones, perampanel inhibited α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced increases in [Ca(2+) ](i) (IC(50) 93 nm vs. 2 μm AMPA). Perampanel had a minimal effect on N-methyl-d-aspartate (NMDA)-induced increases in [Ca(2+) ](i) , and only at a high concentration (30 μm). [(3) H]Perampanel binding to rat forebrain membranes was not significantly displaced by glutamate or AMPA but was displaced by the noncompetitive AMPA receptor antagonists CP465022 (K(i) 11.2 ± 0.8 nm) and GYKI52466 (K(i) 12.4 ± 1 μm). In mice, perampanel showed protective effects against audiogenic, MES-induced, and PTZ-induced seizures (ED(50) s 0.47, 1.6, and 0.94 mg/kg, respectively). Perampanel also inhibited 6 Hz electroshock-induced seizures when administered alone or in combination with other antiepileptic drugs (AEDs). In amygdala-kindled rats, perampanel significantly increased afterdischarge threshold (p<0.05 vs. vehicle), and significantly reduced motor seizure duration, afterdischarge duration, and seizure severity recorded at 50% higher intensity than afterdischarge threshold current (p<0.05 for all measures vs. vehicle). Perampanel caused dose-dependent motor impairment in both mice (TD(50) 1.8 mg/kg) and rats (TD(50) 9.14 mg/kg), as determined by rotarod tests. In mice, the protective index (TD(50) in rotarod test/ED(50) in seizure test) was 1.1, 3.8, and 1.9 for MES-induced, audiogenic, and PTZ-induced seizures, respectively. In rat, dog, and monkey, perampanel had a half-life of 1.67, 5.34, and 7.55 h and bioavailability of 46.1%, 53.5%, and 74.5%, respectively.. These data suggest that perampanel is an orally active, noncompetitive, selective AMPA receptor antagonist with potential as a broad spectrum antiepileptic agent.

Topics: Amygdala; Animals; Anticonvulsants; Brain; Calcium; Cells, Cultured; Disease Models, Animal; Dogs; Intracellular Space; Male; Mice; Neurons; Nitriles; Pyridones; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, AMPA; Seizures