perampanel and Epilepsies--Partial

In the present meta-analysis, the efficacy and safety of perampanel (PER) for the treatment of adolescents with epilepsy were assessed.. Keyword searches were performed in Embase, PubMed, Cochrane Library, Web of Science, EBSCO and CNKI from 1 January 2020 to 10 October 2020. The randomized controlled trials (RCTs) and case-control studies in which PER was compared with other Anti-seizure drugs (ASDs) and/or placebo in children with epilepsy, were considered eligible studies. Odds ratio (OR) with 95% confidence interval (95% CI) for the dichotomous outcome statistic was calculated using a fixed-effects or random-effects model.. Three RCTs with a total of 372 adolescents' patients were included in this meta-analysis. Placebo was used as a control in these studies. Compared with placebo, PER showed better efficacy in median seizure frequency reduction from baseline per 28 days (OR = 2.49, 95% CI: 1.25-4.96,. Based on the results in this study, PER showed better efficacy than placebo therapy in children with epilepsy and the AEs were similar in PER group and placebo group. PER showed good efficacy and a low risk of AEs, and might be a promising medication for the treatment of pediatric epilepsy. In the future, well-designed and large-scale RCTs are necessary to validate the present findings.

Topics: Adolescent; Anticonvulsants; Child; Epilepsies, Partial; Epilepsy; Humans; Treatment Outcome

To investigate the safety of perampanel in different disorders and doses.. Embase, the Cochrane Library, Medline, and ClinicalTrials.gov were searched from inception to July 2022 for randomized controlled trials (RCTs). The meta-analysis was performed by using Review Manager 5.3 and R 4.2.1 software.. A total of 17 RCTs with 5711 subjects were included in the final analysis. The double-blind treatment phase was from 12 weeks to 48 weeks. Our results showed that 11 adverse events (aggression, ataxia, balance disorder, dizziness, fall, fatigue, irritability, rash, somnolence, vertigo, and weight increase) were statistically significantly associated with perampanel, and 4 of them (ataxia, dizziness, fatigue, and somnolence) showed a clear dose-response relationship. Psychiatric adverse events occurred most frequently among serious treatment-emergent adverse events (TEAEs). At 8 mg/day, seven adverse events (aggression, balance disorder, dizziness, fatigue, irritability, vertigo, and weight increase) occurred more frequently in patients with epilepsy than in patients with other disorders, whereas dose discontinuation rates due to adverse events were lower in patients with epilepsy than in patients with other disorders.. The safety profile of perampanel is dependent on diseases and dose. The risk of adverse events was statistically significantly higher, with doses exceeding 4 mg/day. Despite a higher risk of adverse events, patients with epilepsy had a lower perampanel discontinuation rate than patients with other disorders.

Topics: Anticonvulsants; Ataxia; Dizziness; Double-Blind Method; Drug Therapy, Combination; Epilepsies, Partial; Epilepsy; Fatigue; Humans; Pyridones; Randomized Controlled Trials as Topic; Sleepiness; Treatment Outcome; Vertigo

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

The aim of the study was to summarize the findings of the studies documenting the efficacy and safety of perampanel when used in children/adolescents or adults, either as add-on therapy or as monotherapy.. A systematic search was conducted using PubMed, EMBASE and Scopus. Only studies with a cohort-based approach (either prospective or retrospective) were included. We were interested in real-world studies and therefore, studies with a highly regulated environment, such as randomized controlled trials, were excluded. The primary outcomes of interest were retention rates, response rates and seizure-free rates. Random effects model was used for the analysis. Effect sizes were reported as pooled prevalence along with 95% confidence intervals.. A total of 34 studies were included. The retention rates, within 24 months from initiation of treatment as an add-on therapy, ranged between 65% to 77% among children and adolescents. For adults, the retention rate varied between 56 to 77% within 24 months from initiation of treatment. The response rate was around 70% in children/adolescents and 52% in adults at 24 months of follow-up. Around 25% of children and adolescents and 37% of adults were seizure-free at 24 months follow-up period. The proportion of children/adolescents and adults reporting any treatment-related adverse effects was 29% and 41%, respectively. The commonly reported adverse effects were dizziness/drowsiness, somnolence, behavioral problems (irritability, aggression, anxiety, mood changes), postural instability/gait problems, fatigue and weight gain.. Perampanel might be an effective anti-epileptic drug in both children/adolescents and adults when used as an adjunct therapy. More data is required to comment on its use as monotherapy. Careful monitoring for psychiatric problems and behavioral disturbances is required, both prior to initiating treatment as well as during the course of management. Studies with long-term follow-up may are needed to confirm the findings of this meta-analysis.

Topics: Adolescent; Adult; Anticonvulsants; Child; Epilepsies, Partial; Epilepsy; Humans; Nitriles; Prospective Studies; Retrospective Studies; Treatment Outcome

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

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

Eslicarbazepine (ESL), Lacosamide (LAC), Perampanel (PER) and Brivaracetam (BRV), have recently been marketed as third-generation antiepileptic drugs (AEDs). We conducted a meta-analysis to indirectly compare overall efficacy and tolerability between third-generation AEDs in uncontrolled focal epilepsy.. We performed an online database search using Pubmed, Embase, Cochrane Online Library, and Clinicaltrial.gov for all available randomized controlled trials (RCTs) that investigated the therapeutic effects over a range of AED doses versus placebo. We then compared clinical efficacy and tolerability between these newer AEDs using Indirect Treatment Comparison software.. Nineteen RCTs with a total of 7245 patients were included in our study. There were no significant differences in the risk difference of 50% responder rates and seizure free rates between third generation AEDs, regardless of dose. The risk of treatment emergent adverse events was significantly higher with ESL and PER treatment compared to BRV at all doses combined. Withdrawal rates due to adverse events were also significantly higher in patients treated with the highest doses of LAC and PER versus BRV, while treatment with ESL or LAC was related to higher withdrawal rates versus BRV when all doses were combined.. Our analysis suggested there were no significant differences in efficacy between third generation AEDs in uncontrolled focal epilepsy. BRV may have the best tolerability profile. The other AEDs were associated with a higher risk for intolerable adverse, especially when taken at a high doses. The results from these indirect comparisons warrant further examination and verification through future well-designed trials.

Topics: Anticonvulsants; Dibenzazepines; Epilepsies, Partial; Humans; Lacosamide; Nitriles; Pyridones; Pyrrolidinones; Randomized Controlled Trials as Topic

To estimate the comparative efficacy among antiepileptic drugs in the pediatric population (0-18 years).. Using the Embase and MEDLINE databases, we updated to February 2017 the search strategy of the National Institute for Health and Care Excellence guidelines for epilepsy. We only included randomized clinical trials conducted in children and mixed-age populations. According to the PRISMA network meta-analysis guideline, the study-level quality assessment was made with the Cochrane risk-of-bias tool. Three investigators independently selected articles. The efficacy outcome was considered to be seizure freedom or ≥50% seizure reduction.. We selected 46 randomized clinical trials. A total of 5652 individuals were randomized to 22 antiepileptic drugs and placebo. The point estimates of carbamazepine and lamotrigine efficacy showed their superiority with respect to all comparator antiepileptic drugs for the treatment of newly diagnosed focal epilepsy. In refractory focal epilepsy, levetiracetam (odds ratio [OR] = 3.3, 95% credible interval [CrI] = 1.3-7.6) and perampanel (OR = 2.5, 95% CrI = 1.1-5.8) were more effective compared to placebo. Ethosuximide and valproic acid were both superior to lamotrigine against absence seizures. The OR point estimate showed the superiority of adrenocorticotropic hormone over all comparators in infantile spasms. A wide heterogeneity in the length of follow-up was observed among the studies.. This network meta-analysis suggests that the quality of studies should be improved through the use of comparative designs, relevant outcomes, appropriate follow-up length, and more reliable inclusion criteria.

Topics: Adolescent; Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Anticonvulsants; Carbamazepine; Child; Child, Preschool; Drug Resistant Epilepsy; Epilepsies, Partial; Epilepsy; Epilepsy, Absence; Ethosuximide; Hormones; Humans; Infant; Lamotrigine; Levetiracetam; Network Meta-Analysis; Nitriles; Odds Ratio; Piracetam; Pyridones; Spasms, Infantile; Treatment Outcome; Triazines; Valproic Acid

In 4 Phase III registration trials (3 in patients with partial seizures, N=1480; 1 in patients with PGTCS, N=163), perampanel administered to patients already receiving 1-3 concomitant antiepileptic drugs (AEDs) demonstrated statistically superior efficacy compared to placebo in reducing seizure frequency. However, use of perampanel in these studies was associated with a risk of psychiatric and behavioral adverse reactions, including aggression, hostility, irritability, anger, and homicidal ideation and threats. The present study is a post hoc analysis of pooled data from these 4 trials to determine if concomitant treatment with levetiracetam and/or topiramate increased the risk of hostility- and aggression-related AEs. Treatment-emergent AEs (TEAEs) were determined using a "Narrow & Broad" search based on the Medical Dictionary for Regulatory Activities (MedDRA) standard MedDRA query (SMQ) for hostility- and aggression-related events. The rate of hostility- and aggression-related TEAEs was observed to be similar among perampanel-treated patients: a) receiving levetiracetam (N=340) compared to those not receiving levetiracetam (N=779); b) receiving topiramate (N=223) compared to those not receiving topiramate (N=896); and c) receiving both levetiracetam and topiramate (N=47) compared to those not receiving levetiracetam and topiramate (N=1072). Severe and serious TEAEs related to hostility and aggression were rare and occurred at a similar rate regardless of concomitant levetiracetam and/or topiramate therapy. Taken together, these results suggest that concomitant treatment with levetiracetam and/or topiramate has no appreciable effect on the occurrence of hostility- or aggression-related TEAEs in patients receiving perampanel.

Topics: Adolescent; Adult; Aged; Aggression; Anticonvulsants; Child; Drug Therapy, Combination; Epilepsies, Partial; Fructose; Hostility; Humans; Levetiracetam; Middle Aged; Nitriles; Piracetam; Pyridones; Topiramate; Treatment Outcome; Young Adult

Perampanel is approved for adjunctive therapy of focal epilepsy with or without secondarily generalized seizures in patients aged >12 years. This narrative review uses real-world and clinical trial data to elucidate perampanel's role in the clinic. Audit data show good tolerability with perampanel and higher freedom-from-seizure rates in elderly vs younger patients. When using perampanel in elderly patients, special attention should be given to comorbidities and co-medication to avoid potential interactions or adverse events. Slower titration is generally recommended, and seizure control should be reassessed at a dose of 4 mg before further dose increases. Perampanel efficacy is similar in adolescents and adults; however, somnolence, nasopharyngitis, and aggression are more frequent in adolescents vs the overall population. Individualized and slow-dose titration can minimize adverse events. Low serum concentrations of perampanel may occur in patients also receiving some enzyme-inducing anti-epileptic drugs; a perampanel dose increase may be required. Adverse events of importance with perampanel include dizziness; anger, aggression, and hostile behavior (particularly in adolescents); and falls (particularly in patients >65 years). An individualized approach to dosing, including slower up-titration and bedtime dosing, reduces dizziness risk. Other drugs may cause or aggravate dizziness; reducing concomitant drugs may be necessary when up-titrating perampanel. It would seem clinically appropriate to give due consideration to avoiding use in patients with a history of anger or hostile/aggressive behavior. The possibility of such behaviors should be discussed with patients before starting perampanel, with monitoring during up-titration. Slower up-titration of perampanel in older patients helps reduce fall risk.

Topics: Adolescent; Adult; Anticonvulsants; Clinical Trials as Topic; Epilepsies, Partial; Female; Humans; Male; Nitriles; Pyridones; Randomized Controlled Trials as Topic

To evaluate the impact of perampanel and demographics on clearance of concomitant antiepileptic drugs (AEDs), in patients with refractory partial-onset seizures.. Pooled data from three Phase III clinical studies with adjunctive perampanel were used. Blood samples for evaluation of 11 concomitant AEDs were taken during baseline (before perampanel initiation), and at weeks 10, 14, and 19 during the maintenance phase of perampanel treatment (2-12 mg/day, once daily at bedtime). Models estimating apparent clearance of each concomitant AED were fitted to the data, and the effects of perampanel and demographic variables on clearance were determined. Final models were assessed with goodness of fit plots including population predictions and individual predictions against observations.. No significant impact of perampanel on clearance was found for clonazepam (n = 81), levetiracetam (n = 330), phenobarbital (n = 54), phenytoin (n = 90), topiramate (n = 226) or zonisamide (n = 93). Statistically significant, but small and not clinically relevant increases in model-predicted clearance were detected for carbamazepine (+4.3% with 12 mg perampanel; n = 379), clobazam (+3.4% males, +7.7% females, 12 mg; n = 114), lamotrigine (+9.3%, 12 mg; n = 356), and valproic acid (+5.0%, 12 mg; n = 349). Oxcarbazepine clearance was reduced (26%; n = 200), but the clinical relevance is unclear as levels of the active metabolite (the monohydroxy derivative of oxcarbazepine) were not measured.. Population PK data show that perampanel (2-12 mg/day, once daily at bedtime) has no relevant impact on the clearance of the most commonly used concomitant AEDs.

Topics: Adult; Anticonvulsants; Clinical Trials, Phase III as Topic; Drug Interactions; Drug Therapy, Combination; Epilepsies, Partial; Female; Humans; Male; Middle Aged; Models, Biological; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Young Adult

Brivaracetam (BRV), eslicarbazepine acetate (ESL), lacosamide (LCM), and perampanel (PER) have been recently marketed as adjunctive treatments for focal onset seizures. To date, no randomized controlled trial (RCT) has directly compared BRV with ESL, LCM, or PER.. To compare BRV with the other add-on AEDs in patients with uncontrolled focal epilepsy, estimating their efficacy and tolerability through an adjusted, common-reference based indirect comparison meta-analysis.. We systematically searched RCTs in which add-on treatment with ESL or LCM in patients with focal onset seizures have been compared with placebo. Efficacy and tolerability outcomes were considered. Random-effects Mantel-Haenszel meta-analyses were performed to obtain odds ratios (ORs) for the efficacy of BRV, LCM, ESL, or PER versus placebo. Adjusted indirect comparisons were then made between BRV and the other three AEDs using the obtained results, comparing the minimum and the highest effective recommended daily dose of each drug.. Seventeen RCTs, with a total of 4971 patients were included. After adjusting for dose-effects, indirect comparisons showed no difference between BRV and LCM, ESL, or PER for responder rate and seizure freedom. Lower adverse events were observed with high dose BRV compared to high dose ESL or PER, but no difference was found in withdrawing because of adverse events.. Indirect comparisons do not demonstrate a significant difference in efficacy between add-on BRV and LCM, ESL, or PER in focal epilepsy, and might suggest a better tolerability of BRV than ESL, and possibly also PER, at the highest effective recommended dose.

Topics: Acetamides; Anticonvulsants; Dibenzazepines; Drug Therapy, Combination; Epilepsies, Partial; Humans; Lacosamide; Nitriles; Pyridones; Pyrrolidinones; Randomized Controlled Trials as Topic

Epilepsies are among the most common diseases of the CNS. As available antiepileptic drugs do not successfully control seizures in one-third of these patients, the development of drugs with new mechanisms of action is an urgent requirement.. Preclinical and clinical data of the recently released antiepileptic drug perampanel are reviewed based on search in medical databases with special reference to its mechanism of action and to its pharmacokinetic properties relevant for clinical treatment. Pharmacodynamically, perampanel is a noncompetitive AMPA-receptor antagonist exerting its antiepileptic properties by modulating glutamatergic synaptic excitation. Pharmacokinetically, perampanel is characterized by a short Tmax but slow hepatic metabolism and a mean plasma half-life of 105 h, allowing for once-daily dosing. Perampanel has shown antiepileptic properties in several animal models of seizures and epilepsy, and in clinical studies significantly reducing partial-onset seizures in a dose range from 4 to 12 mg/day both in blinded short-term and in open-label long-term extension trials even in highly pharmacoresistant patients. Aside from adverse effects of dizziness and somnolence, neuropsychiatric disturbances have been reported in patient subgroups, making careful clinical monitoring during uptitration recommendable.. The use of perampanel focusing on control of abnormal synaptic excitation profits from favorable pharmacokinetics and from proven efficacy and overall good tolerability also in patient populations nonresponsive to treatment with previously available antiepileptic drugs.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Epilepsies, Partial; Half-Life; Humans; Nitriles; Pyridones; Receptors, AMPA

Perampanel is the latest approved antiepileptic drug in focal and generalized epilepsies and has a distinct and selective mode of action on AMPA-receptors. Several thousand patients have received perampanel within randomized placebo-controlled trials, open-label extension trials and post-marketing observational studies. Significant median partial-onset seizure reduction rates of 23% for 4 mg/day, 26-31% for 8 mg/day and 18-35% for 12 mg/day were reported. Likewise 50 percent responder rates were 29% for 4 mg/day, 33-38% for 8 mg/day and 34-36% for 12 mg/day. Primary generalized tonic-clonic seizures were reduced by 76.5% (8 mg) vs 38.4% (placebo) in a recent controlled trial. Overall, perampanel is well tolerated and the main adverse events are dizziness, somnolence and fatigue. There are also anecdotal reports on use in progressive myoclonic epilepsies and status epilepticus. Perampanel will likely remain an important, possibly broad-spectrum AED with a significant market share, especially in patients with drug-refractory epilepsies.

Topics: Animals; Anticonvulsants; Epilepsies, Partial; Epilepsy, Generalized; Humans; Nitriles; Pyridones; Receptors, AMPA; Status Epilepticus

This article lays the background for, and discusses the practical issues surrounding, the adjunctive use of the last four antiepileptic drugs (AEDs) to be licensed for the treatment of pharmacoresistant focal seizures in the UK and elsewhere. More than 30% of adolescent and adult patients will not be fully controlled on the currently available therapeutic armamentarium. After not responding to their first three AED schedules, only a handful of patients attained seizure freedom on subsequent regimens. To optimise the response to any new AED in this setting, it is often necessary to reduce the existing drug burden. The pharmacology, tolerability and safety, and everyday use of lacosamide, eslicarbazepine acetate, retigabine (ezogabine) and perampanel will be reviewed and discussed. This will be accompanied by data from prospective audits with each drug undertaken at the Western Infirmary in Glasgow, Scotland, and a report of their successful introduction in an illustrative case. Overall, there is a large variation in the course of refractory epilepsy and the effect of AED therapy on this process seems minimal. Nevertheless, a number of patients will benefit from the introduction of each new AED, with some becoming seizure-free.

Topics: Acetamides; Adult; Aged; Animals; Anticonvulsants; Carbamates; Dibenzazepines; Drug Resistant Epilepsy; Epilepsies, Partial; Female; Humans; Lacosamide; Male; Middle Aged; Nitriles; Phenylenediamines; Pyridones

The pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of perampanel are reviewed.. Perampanel, a first-in-class antiepileptic agent, was recently approved for use as adjunctive therapy for the treatment of resistant partial seizures in patients 12 years of age and older. It acts as a selective, noncompetitive antagonist at postsynaptic α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors. Perampanel exhibits linear pharmacokinetics and has a half-life of approximately 105 hours. The drug is rapidly and nearly completely absorbed after oral administration, achieving its maximum serum concentration in approximately 1 hour. Its bioavailability is nearly complete. Several efficacy studies have consistently demonstrated the utility of perampanel as adjunctive therapy for the treatment of refractory partial seizures with or without secondary generalization. Drug interactions have been noted with agents that induce cytochrome P-450 hepatic enzymes, including other antiepileptics, and alterations in perampanel dosing may be necessary when these medications are used concurrently. Adverse effects associated with perampanel use are primarily related to the central nervous system, and slow dosage adjustment and bedtime administration are recommended to maximize patient tolerance. The drug's labeling includes a boxed warning about the possible induction of serious adverse psychiatric and behavioral reactions that necessitate close monitoring. Perampanel is not recommended for individuals with severe liver disease or severely compromised kidney function, including those undergoing hemodialysis.. Perampanel is a novel antiepileptic agent specifically designed to exhibit selective noncompetitive antagonist activity at AMPA receptors. Perampanel has consistently demonstrated the ability to control treatment-refractory partial seizures in many patients.

Topics: Administration, Oral; Animals; Anticonvulsants; Biological Availability; Drug Interactions; Drug Labeling; Epilepsies, Partial; Half-Life; Humans; Nitriles; Pyridones; Receptors, AMPA

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 evaluate the efficacy of adjunctive, once-daily perampanel against secondarily generalized (SG) seizures in three Phase III trials (studies 304, 305, and 306) and their extension (study 307). The Phase III studies enrolled patients (≥ 12 years) with uncontrolled partial-onset seizures despite treatment with 1-3 concomitant antiepileptic drugs. Patients completing the core Phase III studies were eligible for the extension study. Endpoints included median percent change in SG seizure frequency, 50% responder (proportion of patients achieving a ≥ 50% reduction in SG seizure frequency), 75% response, and seizure-freedom rates. In total, 1480 patients were randomized and treated in the three perampanel Phase III trials. At baseline, 71.9% of placebo-treated and 68.4% of perampanel-treated patients had a history of SG seizures. In the individual core Phase III studies, perampanel (4-12 mg) reduced seizure frequency and improved responder rates. Consistent with this, in pooled analyses of the Phase III data, the median percent change in SG seizure frequency was -48.6%, -62.9%, and -53.3% with perampanel 4, 8, and 12 mg, respectively, vs -19.4% with placebo; 50% responder rates were 49.3%, 60.5%, and 53.7% vs 37.0% with placebo. More perampanel-treated patients had ≥ 75% reductions in SG seizure frequency, and seizure-freedom rates improved, compared with placebo. Improvements in seizure frequency and responder rate were maintained during the extension study. Perampanel consistently demonstrated efficacy against SG seizures when assessed using various endpoints. Furthermore, reductions in seizure frequency and improvements in responder rate were sustained with long-term perampanel treatment.

Topics: Anticonvulsants; Clinical Trials, Phase III as Topic; Epilepsies, Partial; Epilepsy, Generalized; Humans; Nitriles; Pyridones

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

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

Topics: Anticonvulsants; Databases, Factual; Dose-Response Relationship, Drug; Epilepsies, Partial; Humans; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Research Design; Treatment Outcome

In the search for new antiepileptic drugs (AEDs), AMPA-type receptor antagonists have a novel target and the potential to improve seizure control in patients with refractory seizures. This article reviews preclinical and clinical data for 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile, perampanel , a new chemical entity developed for the treatment of partial-onset seizures.. Perampanel is a selective, non-competitive AMPA receptor antagonist. The preclinical profile of perampanel and its clinical development are reviewed.. Unlike many traditional AEDs, perampanel demonstrated efficacy in a broad spectrum of preclinical seizure models. Phase I and II clinical studies suggested perampanel had a favorable safety and tolerability profile and demonstrated proof of concept for its mechanism of action in patients with treatment-resistant partial-onset seizures. Three Phase III studies have additionally demonstrated that adjunctive perampanel 4 - 12 mg/day is well-tolerated and significantly improves seizure control in these patients. Median reductions in seizure frequency were 23.3% (4 mg), 26.3 - 30.8% (8 mg) and 17.6 - 34.5% (12 mg) versus 9.7 - 21.0% for placebo. Responder rates were 28.5% (4 mg), 33.3 - 37.6% (8 mg) and 33.9 - 36.1% (12 mg) versus 14.7 - 26.4% for placebo. Perampanel may offer an alternative treatment option in the management of patients with refractory partial-onset seizures.

Topics: Animals; Anticonvulsants; Clinical Trials as Topic; Drug Evaluation, Preclinical; Epilepsies, Partial; Humans; Molecular Targeted Therapy; Nitriles; Pyridones; Receptors, AMPA; Treatment Outcome

Perampanel is a selective noncompetitive AMPA-type glutamate receptor antagonist which has demonstrated anticonvulsant activity in experimental seizure models and antiepileptic activity in clinical trials. Perampanel has a long mean elimination half-life of 105 hours but this may be reduced in the presence of enzyme-inducing antiepileptic drugs. Adjunctive use of perampanel at 4-12 mg/day in refractory partial-onset seizures reduced seizures by 23-34% in short-term, double-blind, placebo-controlled trials. These reductions were maintained long-term in open-label extension studies lasting up to 4 years. Dizziness, somnolence and headache were the most common treatment-emergent adverse events; discontinuation rates due to adverse events approximated 13% in long-term studies. Perampanel's efficacy and tolerability outcomes are broadly comparable with other agents licensed for adjunctive use in refractory partial onset seizures.

Topics: Animals; Anticonvulsants; Brain; Drug Interactions; Epilepsies, Partial; Excitatory Amino Acid Antagonists; Humans; Nitriles; Pyridones; Receptors, AMPA; Treatment Outcome

This study aimed to determine the efficacy and safety of perampanel added to monotherapy in patients with focal-onset seizures, with or without secondarily generalized tonic-clonic seizures.. In this multicentre, open-label trial, enrolled patients were treated with perampanel monotherapy. During a 12-week titration period, perampanel was incrementally increased by 2 mg/d over ≥2-week intervals. Patients then entered a 24-week maintenance period. The primary objective was to investigate the 50% responder rate in total seizure frequency, with 75% and 100% responder rates as secondary objectives. Treatment-emergent adverse events (TEAEs) and adverse drug reactions were recorded. A post hoc analysis was performed to investigate the effect of titration speed and different concomitant AEDs on the efficacy and safety of perampanel.. Of the 85 patients analysed, seizure reductions of 50%, 75% and 100% were observed in 80.0% (95% confidence interval [CI]: 69.9-87.9), 71.8% (95% CI: 61.0-81.0) and 47.1% (95% CI: 36.1-58.2) during the maintenance period, respectively. The 50%, 75% and 100% response rates in patients with secondarily generalized tonic-clonic seizures were 87.5% (95% CI: 61.7-98.5), 87.5% (95% CI: 61.7-98.5) and 75.0% (95% CI: 47.6-92.7), respectively. The most common TEAEs were dizziness (50.0%), somnolence (9.8%) and headache (8.8%). The efficacy outcomes and safety profile of perampanel were more favourable with slow titration and relatively consistent when stratified by concomitant AEDs.. Perampanel was effective and well tolerated as a first add-on to monotherapy in patients with focal-onset seizures, with or without secondarily generalized seizures.

Topics: Adult; Aged; Anticonvulsants; Epilepsies, Partial; Female; Humans; Male; Middle Aged; Nitriles; Prospective Studies; Pyridones; Treatment Outcome; Young Adult

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 of six randomized, double-blind, Phase II and III studies evaluated efficacy and safety of adjunctive perampanel (2-12 mg/day) in adolescent patients (aged ≥12 to ≤17 years) with uncontrolled partial-onset seizures, with or without secondarily generalized (SG) seizures, or primary generalized tonic-clonic (PGTC) seizures.. Adolescent patients from Studies 304 (NCT00699972), 305 (NCT00699582), 306 (NCT00700310), 335 (NCT01618695), 235 (NCT01161524), and 332 (NCT01393743) were included. Efficacy assessments (split by seizure type) included median percent change in seizure frequency per 28 days from baseline and seizure-freedom rates. Safety assessments (all seizure types combined) included monitoring of treatment-emergent adverse events (TEAEs).. The Safety Analysis Set included 372 adolescent patients (placebo, n = 114; perampanel, n = 258); the Full Analysis Set included 346 patients with partial-onset seizures (placebo, n = 103; perampanel, n = 243), of whom 125 experienced SG seizures during baseline (placebo, n = 37; perampanel, n = 88), and 22 with PGTC seizures (placebo, n = 9; perampanel, n = 13). Compared with placebo, perampanel 8 and 12 mg/day conferred greater median percent reductions in seizure frequency per 28 days for partial-onset seizures (18.0% vs 35.9% and 53.8% [both P < 0.01]) and SG seizures (24.4% vs 72.8% [P < 0.001] and 57.8% [P < 0.01]), and greater seizure-freedom rates (partial-onset: 7.8% vs 13.2% and 11.8% [not statistically significant]; SG: 8.1% vs 40.7% [P < 0.001] and 41.7% [P < 0.01]). For PGTC seizures, and compared with placebo, perampanel 8 mg/day was also associated with greater median percent reductions in seizure frequency per 28 days (29.8% vs 88.0%) and greater seizure-freedom rates (11.1% vs 23.1%). Treatment-emergent adverse events were reported in 76 (66.7%) placebo- and 192 (74.4%) perampanel-treated patients (most common: dizziness, somnolence, headache, and nasopharyngitis). Serious TEAEs occurred in 5 (4.4%) placebo- and 11 (4.3%) perampanel-treated patients.. Adjunctive perampanel was efficacious and generally well tolerated in adolescent patients with partial-onset, SG, or PGTC seizures and represents a potentially beneficial treatment option for adolescents with uncontrolled epilepsy.

Topics: Adolescent; Adult; Anticonvulsants; Dizziness; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Epilepsies, Partial; Female; Headache; Humans; Male; Nitriles; Pyridones; Sleepiness; 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

Assess cognitive effects of adjunctive perampanel in adolescents.. In this double-blind study (ClinicalTrials.gov identifier: NCT01161524), patients aged 12 to <18 years with partial-onset seizures despite receiving 1-3 antiepileptic drugs were randomized (2:1) to perampanel or placebo. Perampanel was increased weekly in 2-mg increments to 8-12 mg/day (6-week titration; 13-week maintenance). Changes in neuropsychological outcomes were assessed at end of maintenance: Cognitive Drug Research (CDR) System Global Cognition Score (primary end point), five CDR System domain T-scores (secondary end points), letter fluency, category fluency, and Lafayette Grooved Pegboard Test (LGPT).. One hundred thirty-three patients were randomized. In the full analysis set, there were no differences of perampanel (n = 79) vs. placebo (n = 44) in CDR System Global Cognition Score (least squares mean change, -0.6 vs. 1.6; p = 0.145), Quality of Working Memory (1.1 vs. 2.0; p = 0.579), or Power of Attention (-6.9 vs. -2.7; p = 0.219). There were small differences with perampanel vs. placebo in other CDR System domains: improvements in Quality of Episodic Memory (3.0 vs. -1.2; p = 0.012), and worsening in Continuity of Attention (-3.3 vs. 1.6; p = 0.013) and Speed of Memory (0.3 vs. 7.0; p = 0.032). Letter fluency, category fluency, and LGPT were not significantly different between groups. The most frequent adverse events with perampanel were dizziness (30.6%) and somnolence (15.3%).. Perampanel did not differ from placebo in the global cognitive score, two of five subdomains, and four other cognitive measures. Perampanel was worse on two and better on one subdomain.

Topics: Acetamides; Adolescent; Anticonvulsants; Attention; Carbamazepine; Child; Cognition; Double-Blind Method; Drug Therapy, Combination; Epilepsies, Partial; Female; Fructose; Humans; Lacosamide; Lamotrigine; Levetiracetam; Male; Memory, Short-Term; Neuropsychological Tests; Nitriles; Oxcarbazepine; Piracetam; Pyridones; Topiramate; Treatment Outcome; Triazines; Valproic Acid

The noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist perampanel was shown in phase III trials to be an effective and well-tolerated adjunctive treatment for partial-onset seizures. In adolescents, it is necessary to characterize cognitive, neuropsychological, and behavioral side effects of antiepileptic drugs (AEDs). The current analysis focuses on behavioral outcomes, efficacy, and safety of perampanel in adolescents.. Adolescents (12-17 years) on a stable regimen of 1-3 AEDs for partial-onset seizures were randomized (2:1 ratio) to receive up to 12 mg/day perampanel or placebo. Alongside efficacy, cognitive, and neuropsychological assessments, behavioral outcomes were measured with the Child Behavior Checklist (CBCL) before and after a 19-week titration and maintenance phase.. Of the randomized patients, 85 received perampanel and 48 received placebo. Median reduction in seizure frequency from baseline was 58.0% for perampanel and 24.0% for placebo (p = 0.079). More patients had seizure frequency reduced by 50% after perampanel (n = 49 [59.0%]) than placebo (n = 17 [37.0%]; p = 0.0144). Changes in behavior were minimal, and there were no differences between groups on competency (p = 0.619) or problems (p = 0.174). A greater proportion of placebo patients were classified in the CBCL "clinical" range for competency at end of treatment, whereas the number in the perampanel group remained unchanged. The overall safety profile was similar to that reported previously for perampanel; most frequently reported adverse events (AEs) were dizziness (26 patients [30.6% vs. 14.6% placebo]), somnolence (13 patients [15.3% vs. 4.2%]), and headache (nine patients [10.6% vs. 14.6%]). Aggression was reported in seven patients receiving perampanel (8.2% vs. 2.1% placebo); two of these were serious AEs, with neither requiring treatment discontinuation.. Adjunctive perampanel is efficacious and well tolerated in adolescents with partial-onset seizures, and appears to have no clinically important impact on behavior measured using the CBCL.

Topics: Adolescent; Anticonvulsants; Child; Child Behavior; Cognition; Double-Blind Method; Epilepsies, Partial; Female; Follow-Up Studies; Humans; Male; Neuropsychological Tests; Nitriles; Outcome Assessment, Health Care; Pyridones; Statistics as Topic; Surveys and Questionnaires; 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

Perampanel is a selective, noncompetitive AMPA receptor antagonist approved as adjunctive treatment for partial seizures. To assess potential for delayed cardiac repolarization, a Phase I thorough QT study was performed, supplemented by plasma concentration-QT data modeled from 3 pooled Phase III studies.. The Phase I thorough QT study (double-blind, combined fixed-sequence, parallel-group) quantified the effect of perampanel (6 mg once daily for 7 days, followed by dose escalation to a single 8-mg dose, a single 10-mg dose, then 12 mg once daily for 7 days), moxifloxacin positive control (single 400-mg dose on Day 16), and placebo on QT interval duration in healthy subjects (N = 261). Electrocardiograms were recorded at baseline, Day 7 (post 6 mg dose), and Day 16 (post 12 mg dose). Statistical comparisons were between the highest approved perampanel dose (12 mg) versus placebo, a "mid-therapeutic" dose (6 mg) versus placebo, and moxifloxacin versus placebo. Acknowledging that the Phase I thorough QT study could not incorporate a true "supratherapeutic" dose due to length of titration and tolerability concerns in healthy subjects, Phase III studies of perampanel included expanded electrocardiogram safety evaluations specifically intended to support concentration-QT response modeling. The lack of effect of perampanel on the QT interval is shown from pooled analysis of 3 double-blind, placebo-controlled, 19-week, Phase III studies with perampanel doses ≤ 12 mg (N = 1038, total perampanel; and N=442, placebo) in patients with partial seizures. QT measures were corrected for heart rate using Fridericia's (QTcF; the primary endpoint) and Bazett's (QTcB) formulas.. In the Phase I thorough QT study, the positive control moxifloxacin caused peak time-matched, baseline-adjusted, placebo-corrected (ΔΔ) QTcF of 12.15 ms at 4h postdose, confirming a drug effect on QTc interval and study assessment sensitivity. Mean baseline-adjusted (Δ) QTcF versus nominal time curves were comparable between perampanel 12 mg and placebo, with most ΔQTcF values being slightly negative. Healthy subjects receiving perampanel 6 and 12 mg doses for 7 days showed no evidence of effects on cardiac repolarization. Peak ΔΔQTcF was 2.34 ms at 1.5h postdose for perampanel 6 mg and 3.92 ms at 0.5h postdose for perampanel 12 mg. At every time point, the upper 95% confidence limit of ΔΔQTcF for perampanel 6 and 12 mg was <10 ms. Phase III studies revealed no clinically significant difference between patients with partial seizures treated with perampanel or placebo in QTcF and QTcB values >450 ms, with no dose-dependent increases or large incremental changes from baseline of >60 ms. Regression analysis of individual plasma perampanel concentrations versus corresponding QTc interval values in Phase I thorough QT and Phase III studies demonstrated no relationship between perampanel concentrations and QT interval duration.. Treatment with perampanel 6 mg and 12 mg for 7 days did not delay cardiac repolarization in healthy volunteers. In a population analysis of 1480 patients with partial seizures treated with perampanel doses ≤ 12 mg or placebo, no clinically significant trends in QT interval data were noted. Based on the thorough QT study and evaluations from pooled Phase III studies, there is no evidence of prolonged QT interval duration with perampanel treatment.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Anticonvulsants; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions; Electrocardiography; Epilepsies, Partial; Female; Fluoroquinolones; Heart Rate; Humans; Long QT Syndrome; Male; Middle Aged; Moxifloxacin; Nitriles; Pyridones; Reference Values; Young Adult

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

The antiepileptic drug (AED) perampanel is approved in ≥40 countries as adjunctive therapy for drug-resistant partial seizures in patients with epilepsy. This post hoc analysis of pooled data from three phase III, double-blind, randomized studies of perampanel examines between-gender differences in perampanel efficacy and safety. Of the 1,478 subjects in the pooled analysis (719 male, 759 female), 1,109 were included in the pharmacokinetic/pharmacodynamic analysis. Perampanel oral clearance was 17% lower in female than in male patients not receiving enzyme-inducing AEDs. Pooled efficacy analysis revealed that seizure frequency was reduced with perampanel treatment regardless of gender; a greater numerical reduction in seizure frequency and increased responder rates occurred in female participants at perampanel doses of 4, 8, and 12 mg. Tolerability was similar between groups, although common adverse events such as dizziness and headache occurred more frequently in female subjects. Modest elevations in perampanel exposure in female patients may result in meaningful between-gender differences in efficacy and safety; therefore, dosing should be individualized and clinical response monitored.

Topics: Adult; Dizziness; Double-Blind Method; Epilepsies, Partial; Female; Humans; Male; Nitriles; Pyridones; Treatment Outcome

Perampanel, a selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist, is indicated for adjunctive treatment of partial seizures in patients ≥12 years based on three phase III clinical studies. The perampanel U.S. Prescribing Information includes a boxed warning for serious psychiatric and behavioral adverse reactions. To provide context for this warning, detail on psychiatric and behavioral safety data from perampanel clinical studies is presented.. An analysis of pooled safety data from three phase III studies in patients with partial seizures is presented. Data from phase I and phase II studies in patients with and without epilepsy were also analyzed. Psychiatric and behavioral treatment-emergent adverse events (TEAEs) were evaluated according to Medical Dictionary for Regulatory Activities (MedDRA) terms, using "narrow" and "narrow-and-broad" standardized MedDRA queries (SMQs) for TEAEs suggestive of hostility/aggression.. From the three phase III partial-seizure studies, the overall rate of psychiatric TEAEs was higher in the 8 mg (17.2%) and 12 mg (22.4%) perampanel groups versus placebo (12.4%). In the "narrow" SMQ, hostility/aggression TEAEs were observed in 2.8% for 8 mg and 6.3% for 12 mg perampanel groups, versus 0.7% of placebo patients. "Narrow-and-broad" SMQs for hostility/aggression TEAE rates were 12.3% for 8 mg and 20.4% for 12 mg perampanel groups, versus 5.7% for placebo; rates for events resulting in discontinuation were perampanel = 1.6% versus placebo = 0.7%. For events reported as serious AEs (SAEs), rates were perampanel = 0.7% versus placebo = 0.2%. In nonepilepsy patients, psychiatric TEAEs were similar between patients receiving perampanel and placebo. In phase I subjects/volunteers, all psychiatric TEAEs were mild or moderate. These analyses suggest that psychiatric adverse effects are associated with use of perampanel.. Patients and caregivers should be counseled regarding the potential risk of psychiatric and behavioral events with perampanel in patients with partial seizures; patients should be monitored for these events during treatment, especially during titration and at higher doses.

Topics: Adolescent; Adult; Aggression; Anticonvulsants; Child; Dose-Response Relationship, Drug; Epilepsies, Partial; Female; Hostility; Humans; Male; Mental Disorders; Middle Aged; Nitriles; Pyridones; Young Adult

To better understand the relationship between efficacy and perampanel dose, integrated actual (last) dose data from three phase III trials and an extension study (blinded Conversion Period; open-label Maintenance Period) were analyzed.. Seizure frequency data were analyzed in patients who were randomized to and completed the 13-week Maintenance Period of the phase III studies on perampanel 8 mg, and who received an actual (last) dose of 12 mg during (1) the extension 16-week blinded Conversion Period or (2) weeks 1-13 of the extension Maintenance Period. Due to a treatment-by-region interaction (p = 0.042), analyses excluded patients from the Latin America region (n = 162/1,480; 10.9% of the treated cohort).. Of 372 patients randomized to 8 mg in the phase III studies, 273 completed the Maintenance Period at 8 mg and 267 entered the extension study. In patients who then had an actual (last) dose of 12 mg during the extension blinded Conversion Period (n = 217), median percent change in seizure frequency per 28 days improved from -32.4% (8 mg, phase III Maintenance Period) to -44.2% (12 mg, extension blinded Conversion Period); 50% responder rates increased slightly from 37.3% to 42.9%. In patients who completed the phase III studies on 8 mg and had an actual (last) dose of 12 mg during weeks 1-13 of the extension Maintenance Period (n = 181), median percent change in seizure frequency per 28 days improved from -34.1% (phase III Maintenance Period) to -46.0% (weeks 1-13 extension Maintenance Period); 50% responder rates were 39.2% and 46.4%. Seizure control remained substantially unchanged in patients who completed the phase III studies at 12 mg and continued on that dose during the extension.. Increasing perampanel dose from 8 to 12 mg can produce additional benefits in seizure control in at least some patients who tolerate the higher dose.

Topics: Adult; Anticonvulsants; Cohort Studies; Dizziness; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Epilepsies, Partial; Female; Humans; Male; Middle Aged; Nitriles; Pyridones; Treatment Outcome; Young Adult

Perampanel is a selective AMPA receptor antagonist approved for adjunctive therapy in patients with refractory partial-onset seizures. Perampanel is metabolized primarily via CYP3A4, yet it has a relatively long half-life of 105h; it is, therefore, recommended that perampanel be given once daily (preferably at bedtime). Many patients occasionally have less-than-perfect adherence to their drug regimen, and given the known pharmacokinetic interactions of perampanel with commonly used enzyme-inducing antiepileptic drugs (EIAEDs), we explored the effects of a missed dose on steady-state perampanel plasma concentrations and the ramifications of "make up" doses in these patients. Although perampanel is approved for once-daily dosing, some clinicians may elect to give perampanel as a divided dose (i.e., twice daily), so we also sought to examine the pharmacokinetic impact of twice- versus once-daily dosing.. Pharmacokinetic simulations were performed using validated perampanel pharmacokinetic parameters, derived from 19 phase I studies in 606 subjects, to investigate the effect on perampanel plasma concentration of (1) missing a dose of perampanel followed by delayed replacement of the missed dose, (2) missing a dose followed by resumption of scheduled therapy, and (3) missing a dose in the presence/absence of carbamazepine. Simulations were done for a typical patient receiving an 8-mg once-daily or a 4-mg twice-daily dose using the nonlinear mixed effects program, NONMEM v7.2, in conjunction with PDx-pop v5.. Our results corroborate that given the pharmacokinetic characteristics of perampanel, a missed dose is unlikely to cause as much fluctuation in plasma concentration as would be expected for a drug with a short half-life. Importantly, simulations suggest that supplementing a missed dose 6-12h later, followed by continuation of the regular schedule, may not result in any significant "spikes" in perampanel plasma concentrations. Simulations demonstrated that twice-daily dosing offered little advantage in further flattening the concentration-time profile of perampanel in the adherent patient. However, fluctuations in plasma concentrations are minimized by twice-daily dosing in patients receiving concomitant EIAEDs.. These pharmacokinetic simulations suggest that the long half-life of perampanel may be advantageous in conferring a relatively smooth concentration-time profile with a once-daily or twice-daily dosing, even in the presence of concomitant EIAEDs. However, the results of the present study suggest that perampanel replacement is recommended for patients taking an EIAED to mitigate the potential risks associated with reduced exposure. Confirmation of the ultimate clinical impact of these findings will require further study.

Topics: Anticonvulsants; Biomedical Research; Carbamazepine; Computer Simulation; Dose-Response Relationship, Drug; Drug Administration Schedule; Epilepsies, Partial; Female; Humans; Male; Medication Adherence; Models, Biological; Nitriles; Pharmacokinetics; Pyridones; Time Factors

To evaluate safety, tolerability, seizure frequency, and regional variations in treatment responses with the AMPA antagonist, perampanel, in a large extension study during up to 3 years of treatment.. Patients ≥ 12 years old with partial-onset seizures despite treatment with 1-3 antiepileptic drugs at baseline completed a perampanel phase III trial and entered extension study 307 (NCT00735397). Patients were titrated to 12 mg/day (or their individual maximum tolerated dose) during the blinded conversion period, followed by open-label maintenance. Exposure, safety (adverse events [AEs], vital signs, weight, electrocardiography [ECG], laboratory values) and seizure outcomes were analyzed; key measures were assessed by geographic regions.. Among 1,216 patients, median exposure was 1.5 years (range 1 week to 3.3 years), with >300 patients treated for >2 years. Treatment retention was 58.5% at cutoff. AEs reported in ≥ 10% of patients were dizziness, somnolence, headache, fatigue, irritability, and weight increase. Only dizziness and irritability caused discontinuation in >1% of patients (3.9% and 1.3%, respectively). The only serious AEs reported in >1% of patients were epilepsy-related (convulsion, 3.0%; status epilepticus, 1.1%). No clinically relevant changes in vital signs, ECG or laboratory parameters were seen. After titration/conversion, responder rate and median percentage change from baseline in seizure frequency were stable: 46% for both measures at 9 months (in 980 patients with ≥ 9 months' exposure) and 58% and 60%, respectively, at 2 years (in the 337 patients with 2 years' exposure). Median percentage reduction in frequency of secondarily generalized (SG) seizures ranged from 77% at 9 months (N = 422) to 90% at 2 years (N = 141). Among the 694 patients with maintenance data ≥ 1 year, 5.3% were seizure-free for the entire year.. No new safety signals emerged during up to 3 years of perampanel exposure in 39 countries. Seizure responses remained stable, with marked reductions, particularly in SG seizures.

Topics: Adolescent; Adult; Anticonvulsants; Child; Double-Blind Method; Epilepsies, Partial; Epilepsy, Generalized; Female; Humans; Male; Mental Disorders; Middle Aged; Nitriles; Pyridones; Time Factors; Treatment Outcome; Young Adult

Despite availability of many AEDs, failure rate of first AED used in children with newly diagnosed epilepsy remains as high as 20-40%. Although likelihood of seizure freedom declines with successive AEDs, almost 1 in 5 patients become seizure free with the addition of an alternative AED after failure of 2-5 agents. New AED - perampanel (PER) was developed as a selective, non-competitive AMPA receptor antagonist to target post-synaptic glutamate transmission.. Efficacy and tolerability of PER in adolescents and adults with refractory partial seizures secondarily generalized and without generalization was assessed in international (global) randomized placebo-controlled prospective phase III trials with prolonged open follow-up phase. 1478 patients aged older than 12 years were included. All of them were unsuccessfully pretreated with 1-3 AEDs. Patients were randomized either to placebo or to 2, 4, 8, 12 mg of PER daily respectively. After completing the double blind phase they were transferred to open extension phase with titration of daily dose of PER up to 12 mg.. PER in doses of 4, 8, and 12 mg/day provided reductions in the frequency of partial-onset seizures compared with placebo. Percentage of patients achieving ≤ 50% reduction from baseline in seizure frequency/28 days on doses 4, 8 and 12 mg daily was 29%, 35% and 35% respectively vs. 19% in placebo group (p<0,01). Median% change from baseline in seizure frequency/28 days saw also more evident in PER group. Adverse events (AEs) occurred in 65-89% of patients receiving any dose of PER vs. 67% patients receiving placebo. Most AEs were of mild or moderate intensity (dose related). Most frequently reported AEs were dizziness, somnolence and aggression. 1218 pts were enrolled in the open-label extension study. 91% of patients reached 10 or 12 mg/day of PER. Efficacy was maintained with long-term treatment with responder rates of 62.7% during Weeks 92-104. Frequency and character of AEs were consistent with that in double blind phase.. The presented data indicate that PER at a daily dose of 4, 8 or 12 mg is efficacious as additional treatment of adolescents and adults with refractory partial seizures secondarily generalized and without generalization with acceptable tolerability.

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

Three phase III studies (304 [ClinicalTrials.gov identifier: NCT00699972], 305 [NCT00699582], 306 [NCT00700310]) evaluated perampanel, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, as adjunctive therapy for refractory partial seizures. We report post hoc analyses of pooled study data by randomized dose.. Patients with partial seizures despite receiving 1-3 antiepileptic drugs were randomized to once-daily placebo, perampanel 8 or 12 mg (studies 304, 305), or placebo, perampanel 2, 4, or 8 mg (study 306). Studies included a 6-week baseline period and double-blind treatment phase (6-week titration; 13-week maintenance). Primary end points were median change in partial seizure frequency (baseline vs. double-blind phase) and percentage of patients achieving ≥ 50% reduction in seizure frequency (baseline vs. maintenance). Here, these end points, together with secondary, exploratory, and safety end points, were assessed using pooled study data.. The pooled intent-to-treat analysis set (randomized, treated patients with any seizure data) included 1,478 patients. Median changes in partial seizure frequency were greater with perampanel than placebo (perampanel 4 mg, -23.3%; 8 mg, -28.8%; 12 mg, -27.2%; placebo, -12.8%; p < 0.01, each dose vs. placebo), as were 50% responder rates (perampanel 4 mg, 28.5%; 8 mg, 35.3%; 12 mg, 35.0%; placebo, 19.3%; p < 0.05, each dose vs. placebo). In addition, median changes in complex partial plus secondary generalized seizure frequency were also greater with perampanel than placebo (perampanel 4 mg, -31.2%; 8 mg, -35.6%; 12 mg, -28.6%; placebo, -13.9%). Perampanel was generally well tolerated. The most frequent treatment-emergent adverse events (TEAEs) were dizziness, somnolence, and headache. Most TEAEs were mild/moderate; relatively few patients experienced severe TEAEs (placebo, 5.4%; perampanel, 8.9%) or serious TEAEs (placebo, 5.0%; perampanel, 5.5%). There were no deaths and no clinically important mean changes in laboratory values, electrocardiography (ECG) findings, or vital signs.. Perampanel reduced partial seizure frequency and improved responder rates compared with placebo, with an acceptable tolerability profile.

Topics: Adult; Anticonvulsants; Confidence Intervals; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsies, Partial; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nitriles; Pyridones; Treatment Outcome; Young Adult

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

Topics: Adolescent; Adult; Aged; Anticonvulsants; Child; Chromatography, High Pressure Liquid; Disorders of Excessive Somnolence; Dizziness; Dose-Response Relationship, Drug; Double-Blind Method; Epilepsies, Partial; Female; Gait Disorders, Neurologic; Humans; Male; Middle Aged; Nitriles; Pyridones; Tandem Mass Spectrometry; Treatment Outcome; Young Adult

To assess the efficacy and safety of once-daily doses of perampanel 8 and 12 mg when added to 1-3 concomitantly administered, approved antiepileptic drugs (AEDs) in patients with uncontrolled partial-onset seizures.. Study 305 was a multicenter, double-blind, placebo-controlled trial in patients aged 12 years and older with ongoing seizures despite prior therapy with at least two AEDs, and currently receiving 1-3 AEDs. Equal randomization to once-daily oral perampanel 8 or 12 mg, or placebo was performed. Patients entered a 19-week double-blind treatment phase comprising a 6-week titration period, with weekly 2-mg dose increments, followed by a 13-week maintenance period. Primary efficacy end points were the responder rate (proportion of patients who had a ≥50% reduction in seizure frequency during treatment per 28 days relative to baseline), and the percent change in seizure frequency per 28 days relative to pre-perampanel baseline. A secondary end point was percent change in the frequency of complex partial plus secondarily generalized seizures. Adverse events (AEs) were monitored throughout the study.. Three hundred eighty-six patients were randomized and treated with study medication. Of these, 321 patients completed the study. The 50% responder rates (intent-to-treat analysis) were 14.7%, 33.3%, and 33.9%, respectively, for placebo, perampanel 8 mg, and perampanel 12 mg, with significant improvements over placebo for both perampanel 8 mg (p = 0.002) and 12 mg (p < 0.001). The median percent change from baseline in seizure frequency per 28 days (intent-to-treat analysis) was -9.7%, -30.5%, and -17.6% for placebo, 8 mg, and 12 mg, respectively, with significant reductions compared with placebo for both 8 mg (p < 0.001) and 12 mg (p = 0.011). For complex partial seizures plus partial seizures that secondarily generalized, the median percent change in frequency was -32.7% (8 mg), -21.9 (12 mg), and -8.1% (placebo), with significant reductions for both 8 mg (p < 0.001) and 12 mg (p = 0.005). The most frequent (occurring in ≥10% of patients in any treatment group) treatment-emergent AEs were dizziness, somnolence, fatigue, and headache, with an apparent dose effect suggested for all except headache.. This phase III trial demonstrated that adjunctive treatment with once-daily perampanel at 8 mg and 12 mg was effective in improving seizure control in patients 12 years and older with refractory partial-onset seizures. These study results also demonstrated that once-daily doses of 8 mg and 12 mg were safe and acceptably tolerated in this study. Perampanel demonstrated a favorable risk/benefit ratio in this population.

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

To evaluate safety, tolerability, and seizure outcome data during long-term treatment with once-daily adjunctive perampanel (up to 12 mg/day) in patients with refractory partial-onset seizures.. Study 307 was an extension study for patients completing the double-blind phase of three pivotal phase III trials (studies 304, 305, and 306). The study consisted of two phases: an open-label treatment phase (including a 16-week blinded conversion period and a planned 256-week maintenance period) and a 4-week follow-up phase. Patients were blindly titrated during the conversion period to their individual maximum tolerated dose (maximum 12 mg/day). Adverse events (AEs) were monitored throughout the study and seizure frequency recorded. The interim data cutoff date for analyses was December 1, 2010.. In total, 1,218 patients were enrolled in the study. At the interim cutoff date, 1,186 patients were in the safety analysis set; 1,089 (91.8%) patients had >16 weeks of exposure to perampanel, 580 (48.9%) patients had >1 year of exposure, and 19 (1.6%) patients had >2 years of exposure. At the interim analysis, 840 (70.8%) patients remained on perampanel treatment. The large majority of patients (n = 1,084 [91%]) were titrated to 10 mg or 12 mg/day. Median (range) duration of exposure was 51.4 (1.1-128.1) weeks. Treatment-emergent AEs were reported in 87.4% of patients. The most frequent were dizziness (43.9%), somnolence (20.2%), headache (16.7%), and fatigue (12.1%). Serious AEs were reported in 13.2% of patients. In the intent-to-treat analysis set (n = 1,207), the frequency of all seizures decreased over the first 26 weeks of perampanel treatment in patients with at least 26 weeks of exposure to perampanel (n = 1,006 [83.3%]); this reduction was maintained in patients with at least 1 year of exposure (n = 588 [48.7%]). The overall median percent changes in seizure frequency in patients included in each 13-week interval of perampanel treatment were -39.2% for weeks 14-26 (n = 1,114), -46.5% for weeks 40-52 (n = 731), and -58.1% for weeks 92-104 (n = 59). Overall responder rates in patients included in each 13-week interval of perampanel treatment were 41.4% for weeks 14-26 (n = 1,114), 46.9% for weeks 40-52 (n = 731), and 62.7% for weeks 92-104 (n = 59). During the blinded conversion period, the reduction in seizure frequency in patients previously randomized to placebo (-42.4%, n = 369) was similar to that in patients previously randomized to perampanel (-41.5%, n = 817).. Consistent with pivotal phase III trials, these interim results demonstrated that perampanel had a favorable tolerability profile in patients with refractory partial-onset seizures over the longer term. The decrease in seizure frequency was consistent and maintained in those patients over at least 1 year of perampanel exposure.

Topics: Adult; Anticonvulsants; Double-Blind Method; Drug Therapy, Combination; Epilepsies, Partial; Female; Humans; Male; Nitriles; Pyridones; Receptors, AMPA; Treatment Outcome

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

Topics: Adolescent; Adult; Aged; Anticonvulsants; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Epilepsies, Partial; Female; Humans; Male; Middle Aged; Nitriles; Pyridones; Treatment Outcome

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

Topics: Adolescent; Adult; Anticonvulsants; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Electroencephalography; Epilepsies, Partial; Epilepsy, Complex Partial; Female; Humans; Intention to Treat Analysis; Male; Nitriles; Pyridones; 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

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

Topics: Anticonvulsants; Child; Drug Therapy, Combination; Epilepsies, Partial; Humans; Nitriles; Pyridones; Treatment Outcome

Topics: Epilepsia Partialis Continua; Epilepsies, Partial; Female; Humans; Male; Nitriles; Pyridones; Turner Syndrome

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

Perampanel (PER) has previously been shown to be effective and tolerable when used as an adjunctive therapy for patients with focal-onset seizures (FOS). This study aimed to evaluate the effect of PER as adjunctive therapy for patients with FOS in the Chinese population under real-world conditions for 1 year.. A prospective, single-center, 1-year observational study was conducted at Huashan Hospital, enrolling both under age (≥4 years old) and adult patients with FOS. Response to PER was assessed at 3-, 6-, and 12-month checkpoints by analyzing the 50 % responder rate, the seizure-free rate, and reduction in seizure frequency.. One hundred and eight patients (mean age: 26.6 years, 56.5 % males) with FOS were included, with seventy-six patients finishing the 1-year follow-up (retention rate: 70.4 %, mean PER dose: 4.3 mg/day). The seizure frequency was reduced significantly at 3, 6, and 12 months relative to baseline (p < 0.001 for each seizure type). At 12 months, the responder rate was 65.8 %, and the seizure-free rate was 39.5 %. A significantly higher responder rate was found in patients with focal to bilateral tonic-clonic seizures (p = 0.024), among which the percentage of patients with sleep-related epilepsy was significantly high (p = 0.045). Responders had a lower number of concomitant anti-seizure medications (ASMs) than the non-responders (p = 0.009). Drug-related adverse events (AEs) were reported in 37 % of patients, mostly mild or moderate, and the patients who experienced AEs had a higher daily dose of PER than those who did not (p = 0.026).. Perampanel, an add-on therapy for focal-onset seizures, was found to be effective and tolerable in Chinese patients at 12 months.

Topics: Adult; Anticonvulsants; Child, Preschool; China; Drug Therapy, Combination; Epilepsies, Partial; Female; Humans; Male; Prospective Studies; Pyridones; Treatment Outcome

We investigated the long-term efficacy and safety of perampanel as a first add-on therapy in patients with focal epilepsy.. This retrospective study represented the 3-year extension phase of a multicenter, open-label, phase 4, prospective study of perampanel as a first add-on therapy in patients with focal epilepsy. Seizure and safety outcomes were assessed annually from the start of the extension study, and the retention rate was calculated from the start of perampanel exposure in the original study.. The 50% responder and seizure freedom rates were 84.8% and 58.7%, respectively, during the third year and 71.7% and 32.6%, respectively, during the entire 3-year period of the extension study. The 1-, 2-, and 3-year retention rates were 62.5%, 53.1%, and 52.1%, respectively. Efficacies were higher in patients that were aged >55 years, male, and receiving ≤4 mg of perampanel. Perampanel was generally well tolerated; 47.3% of patients experienced at least one adverse event during the 3 years of extension (46 adverse events (AEs) in 35 patients). The most common AEs were dizziness (33.8%), somnolence (5.4%), anger (4.1%), and irritability (4.1%). AEs were resolved with perampanel dose reduction or discontinuation in 10 (13.5%) and 12 (16.2%) patients, respectively.. Long-term treatment with perampanel as a first add-on therapy did not raise new safety signals in patients with focal epilepsy. Especially at low perampanel doses (≤4 mg/day), sustained improvement in seizure control was achieved, which could potentially avoid adverse drug reactions.

Topics: Anticonvulsants; Drug Therapy, Combination; Epilepsies, Partial; Humans; Male; Nitriles; Prospective Studies; Pyridones; Retrospective Studies; Treatment Outcome

To compare the 12-month retention rate, effectiveness and tolerability of perampanel (PER) as a first or late add-on treatment in adult patients with focal-onset seizures (FOS), including focal to bilateral tonic-clonic seizures (FBTCS).. This retrospective, observational, multicenter study was carried out in patients with FOS that received PER as a late add-on (n = 60), after failure of > 3 AEDs, and a group that received PER as a first add-on treatment (n = 21).. At 12 months, the retention (90.5 % vs. 48.3 %; p = 0.001), seizure-freedom (71.4 % vs. 13.3 %; p < 0.001) and responder (85.7 % vs. 28.3 %; p < 0.001) rates were significantly higher in the first add-on group compared with the late add-on group. In patients with FBTCS, the 12-month retention rate did not differ significantly between the first and late add-on groups (93.8 % vs. 66.7 %); however, seizure-freedom (81.2 % vs. 27.8 %; p = 0.002) and responder rate response (93.8 % vs. 44.4 %; p = 0.002) were significantly higher in the first add-on group. There were no significant differences in tolerability between the two groups, including in patients with FBTCS. Adverse events were reported in 54.3 % of patients (44/81), most were mild or moderate, with dizziness being the most frequent one.. Overall, retention rate and effectiveness at 12 months were significantly higher in patients taking PER as a first add-on than as a late add-on, and the tolerability of PER did not differ significantly between groups. PER demonstrated high effectiveness in patients with FBTCS, even as a late add-on treatment.

Topics: Anticonvulsants; Epilepsies, Partial; Humans; Nitriles; Pyridones; Retrospective Studies; Treatment Outcome

With an elimination half-life of 105 hours, perampanel (PER) allows a once-daily dosing regimen. In pivotal trials, when PER was tapered, it was therefore usually discontinued abruptly. Thus, in our hospital we have always practiced abrupt cessation. In this case series, we investigated how long PER serum concentrations still remain measurable after abrupt discontinuation of PER and whether withdrawal symptoms, such as an increase in seizures or status epilepticus, occur. PER serum levels and the clinical course of 15 adult in-patients were monitored for three weeks based on a retrospective study design following abrupt discontinuation of PER. After one week, PER was still detected in 13 of 15 patients, after two weeks in 10, and after three weeks in three. Neither a severe increase in seizure frequency nor status epilepticus occurred. However, modifications of the concomitant antiseizure drugs were necessary. The abrupt discontinuation of PER leads to a slow decrease in plasma concentration, thus resembling self-evident gradual discontinuation of PER. In some cases, PER may still be measurable and thus clinically active even weeks after its discontinuation. Efficacy and safety of other antiseizure drugs can be estimated appropriately only thereafter.

Topics: Adult; Anticonvulsants; Drug Administration Schedule; Drug Tapering; Epilepsies, Partial; Epilepsy; Humans; Nitriles; Pyridones; Retrospective Studies

Quantitative Encephalography (qEEG) depicts synthetically the features of EEG signal and represents a promising tool in the assessment of neurophysiological changes brought about by Anti-Seizure Medications (ASMs). In this study we characterized qEEG alterations related to add-on therapy with Perampanel (PER). PER is the only ASM presenting a direct glutamatergic antagonism, hence the characterization of PER induced EEG changes could help to better understand its large spectrum of efficacy.. We analysed standard-19 channel-EEG from 25 People with Epilepsy (PwE) both before (T0) and after (T1) the introduction of PER as add-on treatment. Normal values were obtained in 30 healthy controls (HC) matched for sex and age. EEGs were analysed using Matlab™ and the EEGlab and Brainstorm toolkits. We extracted spectral power and connectivity (Phase locking Value) of EEG signal and then compared these features between T0 and T1 and across groups (PwE, HC), we also evaluated the correlations with clinical features.. PwE showed increased theta power (p = 0.036) after the introduction of PER but no significant change of EEG connectivity. We also found that PwE have reduced beta power (p = 0.012) and increased connectivity in delta (p = 0.013) and theta (p = 0.007) range as compared to HC, but no significant change was observed between T0 and T1 in PwE. Finally, we found that PwE classified as drug responders to PER have greater alpha power both at T0 and at T1 (p = 0.024) suggesting that this parameter may predict response to treatment.. PER causes slight increase of theta activity and does not alter connectivity as assessed by standard EEG. Moreover, greater alpha power could be a good marker of response to PER therapy, and potentially ASM therapy in general.. Our results corroborate the hypothesis that pharmaco-EEG is a viable tool to study neurophysiological changes induced by ASM. Additionally, our work highlights the role of alpha power as a marker of ASM therapeutic response.

Topics: Adult; Aged; Anticonvulsants; Brain; Drug Therapy, Combination; Electroencephalography; Epilepsies, Partial; Female; Humans; Longitudinal Studies; Male; Middle Aged; Nerve Net; Nitriles; Prospective Studies; Pyridones; Treatment Outcome

Clinical trials have demonstrated the efficacy of perampanel for the treatment of epilepsy. However, patients treated with this and other antiepileptic drugs often exhibit aggressive behaviors. We investigated the clinical factors contributing to aggression in patients with refractory focal epilepsy during 6 months of adjunctive perampanel treatment.. This was a single-center longitudinal study involving patients treated with perampanel (starting dose, 2 mg/day; maximal dose, 12 mg/day). Patients were assessed with an aggression questionnaire (Korean version of Aggression Questionnaire [AQ-K]) and the hospital anxiety depression scale (HADS) at the beginning of the study and after receiving treatment for 6 months. Paired t-tests were used to compare AQ-K and HADS scores at the beginning of the study with those recorded at the end, and stepwise linear regression models were applied to identify predictive factors.. Thirty-two patients (mean age, 42.4 ± 10.3 years) successfully completed the 6-month study. The AQ-K and HADS scores increased after 6 months of adjunctive perampanel treatment (p < .1). The HADS scores related to depression at baseline predicted changes in total AQ-K scores, whereas the change in this HADS score was a predictor of physical and verbal aggression. A perampanel dose of ≥8 mg was a predictive factor for changes in anger and HADS scores related to depression after 6 months. Unexpectedly, concomitant use of topiramate had protective effects on AQ-K scores (including for verbal aggression and anger) in patients receiving perampanel.. Depressive symptoms and a high dose of perampanel are potential predictors for aggression, whereas concomitant use of topiramate is protective against aggression in patients receiving perampanel for focal epilepsy.

Topics: Adult; Aggression; Anticonvulsants; Drug Resistant Epilepsy; Epilepsies, Partial; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Middle Aged; Nitriles; Pyridones; Surveys and Questionnaires; Treatment Outcome

Perampanel (PER) is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist recently approved for focal and generalized epilepsies as an add-on therapy. It is well tolerated and effective as treatment of various pediatric epilepsy syndromes; PER does not seem to negatively affect the cognitive profile of children and adolescents, but its influence on executive functions is still to be assessed.. Our sample included 37 children aged 12-18 years, with focal pharmacoresistant epilepsy already in therapy with 2 or 3 antiepileptic drug (AED); PER was added with 1 mg/week increments up to a dose of 2-4 mg/day. Changes in executive functions were assessed by the EpiTrack Junior test. Emotional and behavioral aspects were evaluated through the interview for parents Child Behavior Checklist (CBCL). Both tests were performed before taking PER and after 6 and 12 months of treatment.. After 12 months of PER in 22/30 patients, global score of the EpiTrack Junior test remained almost unchanged; in 7/30 patients, this score improved. The CBCL did not show significant changes in emotional or behavioral problems.. Adjunctive treatment with PER did not negatively affect executive functions that could also be improved. No emotional/behavioral negative effects have been reported, and this suggests a good tolerability in the middle/long term.

Topics: Adolescent; Adolescent Behavior; Anticonvulsants; Child; Child Behavior; Drug Therapy, Combination; Epilepsies, Partial; Excitatory Amino Acid Antagonists; Executive Function; Female; Humans; Male; Nitriles; Pyridones; 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 newly introduced antiepileptic drug (AED) and is used in over 50 countries. In the current study, we analyzed the efficacy of PER for patients with partial epilepsy who were recruited from two hospitals that had both an epilepsy center and a general neurosurgical unit over a 1-year period.. The present study was a retrospective observational study that evaluated the effects of PER for the treatment of partial epilepsy in 51 patients. We analyzed the effects of PER at two checkpoints, i.e., 6 and 12 months after starting adjunctive PER treatment. Following this, we analyzed the effects of PER as a first add-on (only one prior AED) and late add-on (≥2 prior AEDs) therapy, and focused on the characteristics of the patients who achieved seizure freedom.. Of the initial 51 patients, 45 and 39 patients were evaluated at the 6- and 12-month checkpoints, respectively. Overall, after starting treatment with PER, 29% (13/45) and 28% (11/39) of patients were seizure-free at 6 and 12 months, respectively. The tolerance rate of PER was 67% (30/45) at 6 months and 53.8% (21/39) at 12 months following treatment. The seizure-free rate of the 30 patients who were continuously treated with PER for 6 months was significantly higher in the patients who used PER as a first add-on treatment (75.0%, 6/8) than it was in the patients who used PER as a late add-on treatment (31.8%, 7/22) (p = 0.049). The seizure-free rate of the 21 patients who were continuously treated with PER for 12 months was significantly higher in the patients who used PER as a first add-on treatment (100%, 5/5) than it was in the patients who used PER as a late add-on treatment (37.5%, 6/16) (p = 0.035). Among the patients who achieved seizure freedom, the most frequently administered dose of PER was 2 mg at 6 (62%, 8/13) and 12 months (64%, 7/11). Levetiracetam was the most frequently administered concomitant AED at both 6 (92%, 12/13) and 12 months (91%, 10/11).. This retrospective observational study provides evidence supporting the effectiveness of PER as a first add-on therapy in patients with partial epilepsy. Importantly, the seizure-free rate was better when PER was used as a first, rather than a second or later, add-on treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Child; Drug Administration Schedule; Drug Therapy, Combination; Epilepsies, Partial; Female; Humans; Longitudinal Studies; Male; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Treatment Outcome; Young Adult

Perampanel (PER) is a new antiepileptic drug (AED) with a novel mechanism of action. Investigations of the efficacy and safety of PER in pediatric and adult patients have increased recently. Although the clinical usefulness and pharmacokinetics of PER have been investigated in adolescent and adult populations, similar studies have not been performed in children.. We retrospectively reviewed the medical records of patients treated with PER for more than 6 months in the Department of Pediatrics, Hiroshima University Hospital, between September 2016 and November 2018. We obtained demographic and clinical data including age, sex, epilepsy type, seizure type, seizure frequency before and after treatment initiation, adverse events, reasons for discontinuing PER treatment, doses at evaluation points, serum concentrations, concomitant AEDs, intellectual status, and epilepsy etiology. Seizure types and epilepsy syndromes were classified according to the criteria of the International League Against Epilepsy.. Perampanel is effective against various types of seizures, including ES, in pediatric patients with refractory epilepsy. Furthermore, PER has good tolerability when the dose is adjusted based on serum concentrations. The PER CD ratio was lower in pediatric patients than in adolescents and adults; therefore, clinicians must consider the CD ratio when treating children with PER.

Topics: Adolescent; Anticonvulsants; Carbamazepine; Child; Child, Preschool; Dizziness; Drug Resistant Epilepsy; Drug Therapy, Combination; Epilepsies, Partial; Epilepsy, Absence; Female; Humans; Infant; Male; Nitriles; Phenobarbital; Phenytoin; Pyridones; Retrospective Studies; Treatment Outcome

Topics: Adult; Anticonvulsants; Carbamazepine; Drug Resistant Epilepsy; Drug Therapy, Combination; Epilepsies, Partial; Epilepsy, Tonic-Clonic; Humans; Male; Nitriles; Oxcarbazepine; Pyridones; Self Mutilation

Topics: Anticonvulsants; Cognition; Drug Resistant Epilepsy; Epilepsies, Partial; Humans; Nitriles; Pyridones

Topics: Anticonvulsants; Epilepsies, Partial; Humans; Nitriles; Pyridones; Treatment Outcome

Topics: Anticonvulsants; Cognition; Drug Resistant Epilepsy; Epilepsies, Partial; Humans; Nitriles; Pyridones

Perampanel (PER) was first licensed in the United Kingdom in 2012 for the adjunctive treatment of focal seizures with or without secondary generalization in adults and children over 12years of age. It has recently also been approved for use as add-on therapy for patients with primary generalized tonic-clonic seizures. This prospective audit reports preliminary outcomes with adjunctive PER in patients with focal-onset seizures in everyday clinical practice using a standard design.. To date, 54 patients (38 males, 16 females; 21-65years, median: 48years) have completed the study. The median monthly seizure frequency was 4 (range: 1-60). At baseline, patients were taking a median of 2 other antiepileptic drugs (range: 1-4 drugs), with their seizures having previously failed to improve on a median of 3 schedules (range: 1-15 schedules). After 12weeks of stable dosing, PER was added, aiming at a target range of 6-12mg/daily. Review took place every 6-8weeks until one of 4 endpoints was reached: seizure freedom for ≥6months on a given PER dose, ≥50% (responder) or <50% (marginal effect) seizure reduction over 6months, compared with the prospective baseline, on the highest tolerated PER dose, or withdrawal of PER due to a lack of efficacy or side effects.. Three (5.6%) patients have remained seizure-free, with 8 (14.8%) demonstrating a ≥50% response and a further 17 (31.5%) reporting a marginal effect. Of the 26 (48.1%) dropping out of PER treatment, 21 (38.9%) did so because of side effects. The commonest problems were nausea, vomiting, ataxia, dizziness, and sedation. Overall, 6 (11%) patients developed neuropsychiatric problems, with 3 reporting irritability and/or aggression. Two patients had substantial weight gain, and another patient suffered recurrent falls. Treatment with enzyme-inducing AEDs had no effect on PER dosing in patients responding to PER or withdrawing due to side effects.. These data support the value of adjunctive PER in some patients with pharmacoresistant epilepsy in everyday clinical practice.

Topics: Adult; Aged; Aggression; Anticonvulsants; Ataxia; Drug Therapy, Combination; Epilepsies, Partial; Female; Humans; Male; Middle Aged; Nitriles; Prospective Studies; Pyridones; Treatment Outcome; United Kingdom; Vomiting; Weight Gain; Young Adult

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

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

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

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

To document reversible cognitive deterioration associated to high doses of zonisamide, using the Reliable Change Index to control practice effects derived from repetitive neuropsychological assessments.. A 11 year-old boy with tuberous sclerosis complex and left frontal refractory epilepsy, evaluated within a paediatric epilepsy surgery program. The epileptogenic zone was found to be related with a tuber situated on the left inferior frontal gyrus. The effects of high doses of zonisamide simulate a disturbance of eloquent cortex within the epileptogenic zone and the impact of uncontrolled seizures on cognitive functioning over the language-dominant hemisphere. Drug withdrawal significantly improved total intelligence index, verbal comprehension intellectual index and specific language-sustained cognitive abilities, beyond practice effects.. The differentiation between cognitive effects of drugs and functional deficits resulting from eloquent cortex involvement within the epileptogenic zone can be of crucial importance in the decision-making process for epilepsy surgery.. Deterioro neuropsicologico reversible asociado a zonisamida en un paciente pediatrico con esclerosis tuberosa.. Objetivo. Documentar el deterioro cognitivo reversible asociado a altas dosis de zonisamida, utilizando indices de cambio fiable para controlar los efectos de practica derivados de evaluaciones neuropsicologicas repetidas. Caso clinico. Niño de 11 años con complejo esclerosis tuberosa y epilepsia refractaria del lobulo frontal izquierdo, evaluado en el contexto de un programa de cirugia de la epilepsia pediatrica. La zona epileptogena se relaciono con un tuber epileptogeno localizado en el giro frontal inferior del hemisferio izquierdo. Los efectos de altas dosis de zonisamida mimetizaron una afectacion de la corteza elocuente en la zona epileptogena y un impacto de las crisis no controladas en el funcionamiento cognitivo asociado al hemisferio dominante para el lenguaje. La retirada del farmaco mejoro significativamente, mas alla de los efectos de practica, el cociente intelectual total, el indice intelectual de comprension verbal y habilidades cognitivas especificas sustentadas en el lenguaje. Conclusiones. La diferenciacion entre los efectos cognitivos de los farmacos y la existencia de un deficit funcional por afectacion de la corteza elocuente en el area epileptogena puede ser crucial para la toma de decisiones en cirugia de la epilepsia.

Topics: Acetamides; Anticonvulsants; Benzodiazepines; Child; Clobazam; Cognition Disorders; Dibenzazepines; Drug Substitution; Drug Therapy, Combination; Epilepsies, Partial; Frontal Lobe; Humans; Isoxazoles; Lacosamide; Language Disorders; Learning Disabilities; Male; Memory Disorders; Neuroimaging; Nitriles; Pyridones; Tuberous Sclerosis; Zonisamide

The liver plays a major role in the metabolism and elimination of many antiepileptic drugs (AEDs), including perampanel. Some of the metabolites identified for perampanel are likely formed via reactive intermediates, which have the potential to covalently bind to protein and cause idiosyncratic toxicities, including hepatotoxicity. The approved AED perampanel is a selective, noncompetitive AMPA receptor antagonist. The safety and tolerability of perampanel have been well documented in 3 double-blind, randomized, placebo-controlled, phase III studies. Here we report the effects of perampanel on liver function in patients from the phase III studies to assess the potential for liver toxicity.. Following 6-week baseline, patients (≥12 years old) with drug-resistant partial seizures were randomized to once-daily double-blind treatment (6-week titration, 13-week maintenance) with 2, 4, 8, or 12mg perampanel (n=1038) or with placebo (n=442). Clinical laboratory tests for hepatobiliary laboratory parameters were evaluated at baseline and at end of treatment. These included alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyl transpeptidase, and total bilirubin. Treatment-emergent markedly abnormal values (an increase in NCI-CTC grade relative to baseline and a grade ≥2) and treatment-emergent adverse events (TEAEs) related to hepatobiliary parameters were also recorded.. Mean hepatobiliary values were within normal ranges at baseline and end of treatment for all perampanel groups and placebo. Mean changes from baseline to end of treatment were small. The incidence of markedly abnormal results was very low for perampanel and placebo. TEAEs related to hepatobiliary parameters occurred in 0.4% of perampanel patients and 0% of placebo patients. Hepatobiliary disorders included cholelithiasis (n=3 in perampanel) and abnormal hepatic function (n=1 in perampanel). None of the events were serious or led to perampanel discontinuation. No subject had values that met the criteria for Hy's Law.. Hepatobiliary laboratory data and related TEAEs were not notably different between perampanel and placebo treatment groups, and no dose-related trends were observed. Based on the laboratory results from the 3 Phase III studies, perampanel (2, 4, 8, and 12mg) demonstrated no clinically important effects on liver function tests, indicating perampanel is an AED with a low potential for drug-induced liver toxicity.

Topics: Adolescent; Adult; Alkaline Phosphatase; Anticonvulsants; CD13 Antigens; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Epilepsies, Partial; Female; Follow-Up Studies; gamma-Glutamyltransferase; Glutamyl Aminopeptidase; Humans; Liver; Liver Function Tests; Male; Multicenter Studies as Topic; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Retrospective Studies; Treatment Outcome; Young Adult

Malignant gliomas like glioblastoma multiforme (GBM) release glutamate which causes excitotoxic death to surrounding neurons, thereby vacating room for tumor expansion. We report the case of a patient with GBM treated with the AMPA receptor blocker Perampanel (PER) in combination therapy for partial seizures. Histological work-up of a biopsy showed the tissue of a GBM without mutation of the isocitrate dehydrogenase 1 (IDH1) and without promotor methylation of the O6-methylguanine-DNA methyltransferase (MGMT). In a group of patients with IDH 1 wild type and non-methylated MGMT a median survival of 199 days after surgery (i. e. 6.5 months) was described. Our patient lived about one year longer. PER rendered our patient seizure-free for at least the last seven months of his life. It was well tolerated and did not increase the toxicity of temozolomide. When choosing an antiepileptic drug (AED) for the treatment of seizures in patients with malignant brain tumors, the efficacy, the tolerability and perhaps possible effects on tumor progression of the AED should be taken into account.

Topics: Alkylating Agents; Brain Neoplasms; Dacarbazine; Epilepsies, Partial; Excitatory Amino Acid Antagonists; Glioblastoma; Humans; Isocitrate Dehydrogenase; Magnetic Resonance Imaging; Male; Methylation; Middle Aged; Mutation; Nitriles; O(6)-Methylguanine-DNA Methyltransferase; Promoter Regions, Genetic; Pyridones; Survival Analysis; Temozolomide

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

Nearly a dozen antiepileptic drugs have been shown to prevent attacks in patients with partial epilepsy, whether used alone, or in combination when successive single-agent well-conducted treatments have failed. Perampanel (Fycompa, Eisai) an AMPA glutamate receptor antagonist, has been granted marketing authorisation in the European Union and United States, for use in combination with other antiepileptic drugs in patients aged 12 years or older with partial epilepsy. Perampanel has not been compared with other antiepileptic drugs in clinical trials. Its evaluation is based on three comparative, double-blind, placebo-controlled trials, in which perampanel was added to other antiepileptic drugs considered to be inadequately effective. In these trials, after 19 weeks of treatment, its efficacy was only modest: the response rate was at best only about 20% higher than with placebo. Indirect comparison, albeit inherently unreliable, suggests that perampanel is no better than other antiepileptic drugs. Perampanel has frequent and often dose-dependent adverse effects; they mainly include irritability, aggression, impaired alertness and coordination, and weight gain. Cardiac disorders were observed during a long-term trial of perampanel. This possible adverse effect requires further study. Perampanel led to stunted growth in experimental animals. It is not known whether adolescents are also at risk. Perampanel does not appear to be a potent inducer or inhibitor of the cytochrome P450 enzyme system, but its drug interaction profile requires further evaluation. In animal studies, perampanel exposure resulted in increased perinatal mortality. In practice, there is no evidence that perampanel represents a therapeutic advance for patients with partial epilepsy. In addition to its known adverse effects, there are concerns over possible long-term cardiac toxicity and a deleterious effect on growth. Other acceptable solutions, based on better-known drugs, should be discussed with epileptic patients.

Topics: Anticonvulsants; Epilepsies, Partial; Humans; Nitriles; Pyridones

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