CLINICAL REVIEW
Perampanel
CLINICAL REVIEW
Perampanel: A new agent for adjunctive treatment of partial seizures Michele A. Faulkner
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erampanel (per am´ pa nel; Fycompa, Esai) was recently approved for use as adjunctive therapy for the treatment of partial seizures with or without secondary generalization. The drug received marketing authorization approval from the European Commission on July 27, 2012, and Food and Drug Administration (FDA) approval on October 22, 2012, for use as addon therapy in patients with partial seizures age 12 years and older. This review summarizes the currently available efficacy and safety data on perampanel and describes the potential role of the drug in the treatment of refractory partial seizures. Background Epilepsy affects over 50 million people worldwide, approximately 60% of whom experience partial seizures.1 Monotherapeutic options often fail, and even when adjunctive treatment with one or more medications with activity against partial seizures is used, 25–33% of patients continue to experience seizure activity.2,3 The consequences for patients, caregivers, and society are substantial, as increased morbidity and mortality and decreased quality
Purpose. The pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of perampanel are reviewed. Summary. 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 a-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (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 secondar y generalization. Drug interactions have been noted with agents that induce cytochrome P-450 hepatic enzymes, includ-
of life are common among those with uncontrolled seizures. Although some practitioners use antiepileptic drugs for off-label indications (e.g., adjunctive therapies are sometimes used as monotherapy), the drugs are specifically designated
Michele A. Faulkner, Pharm.D., is Associate Professor of Pharmacy Practice, School of Pharmacy and Health Professions, and Associate Professor of Medicine, Department of Neurology, School of Medicine, Creighton University, Omaha, NE ([email protected]).
ing 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. Conclusion. 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. Am J Health-Syst Pharm. 2014; 71:191-8
by FDA for use as monotherapy or adjunct therapy. FDA-approved agents for monotherapy of partial seizures include older medications such as phenytoin, valproic acid, carbamazepine, and phenobarbital, as well as the second-generation anti-
The author has declared no potential conflicts of interest. Copyright © 2014, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/14/0201-0191$06.00. DOI 10.2146/ajhp130203
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epileptics oxcarbazepine, topiramate, felbamate, and lamotrigine (which is approved for monotherapy after converting from carbamazepine, phenytoin, phenobarbital, primidone, or valproic acid). FDA-approved adjunct therapies include gabapentin, pregabalin, tiagabine, levetiracetam, zonisamide, lacosamide, vigabatrin, and ezogabine. These antiepileptics work by inhibiting voltage-gated sodium and calcium channels or enhancing g-aminobutyric acid.4 However, a few of the newer antiepileptic agents have unique or novel targets for their action (either as a primary or secondary mechanism) including gabapentin and pregabalin (a 2dsubunit of L-type voltage-regulated calcium channels), lamotrigine (Hcurrent), levetiracetam (synaptic vesicle protein 2A), and ezogabine (Kv7 potassium channels). 4 Two antiepileptics have nonselective antagonistic activity at ionotropic glutamate receptors: felbamate at the N-methyl-d-aspartate (NMDA) receptor and topiramate at the kainite receptor, though their glutaminergic activity is very much secondary to other mechanisms of action.5,6 The prospect of targeting glutamate as a primary mechanism for decreasing seizure activity has been a subject of much interest and study in recent years. Glutamate is the primary excitatory neurotransmitter in the brain; as such, manipulation of glutaminergic pathways may be a rational approach to the control of epilepsy. Increased glutamate concentrations have long been suspected to trigger seizures.7 Elevated and sustained extracellular glutamate concentrations in the hippocampus have been noted both before and during seizure activity.8 Previous attempts to use NMDA receptors as an antiepileptic target were met with disappointment, largely due to the propensity for medicinal manipulation of the receptors to cause adverse neuropsychiatric effects in humans.9,10 In fact, NMDA 192
receptors are the target of several drugs with a known potential for abuse (e.g., phencyclidine, ketamine, nitrous oxide, dextromethorphan). However, another type of ionotropic glutamate receptor—the a-amino3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) receptor—has a significant role in the development and propagation of seizures and appears to have a broader spectrum of activity compared with NMDA and kainite receptors.10 AMPA receptors are the predominant mediators of excitatory neurotransmission in the brain and are the most commonly identified receptors throughout the nervous system.10,11 Animal models have demonstrated that exogenous administration of AMPA can induce profound seizure activity.12 AMPA receptors are both glutamate receptors and ligand-gated cation channels.11 Four agonist-binding sites are found on each receptor; when more than one site is occupied simultaneously, the channel opens with a current speed that is relative to the number of sites bound at any given time.13,14 Because cation channels open and close rapidly, AMPA receptors are believed to be responsible for the majority of fast excitatory transmission throughout the central nervous system. Overstimulation of AMPA receptors by glutamate may lead to ionic imbalance by inducing calcium overload in cells, resulting in excitotoxicity stemming from excessive glutamate-induced neurotransmission.15,16 Thus, a drug with the capacity to inhibit this excessive glutamate-driven receptor stimulation may deter seizure activity and possibly provide neuroprotection. Pharmacology Perampanel is a selective antagonist of excitatory postsynaptic AMPA glutamate receptors.11 Unlike most antiepileptic drugs, which were discovered to have antiseizure activity after random drug screening, by manipulating existing antiepileptic
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compounds, or purely by serendipity, perampanel was created by deliberate design based on known mechanisms of seizure occurrence and propagation.17 As a noncompetitive inhibitor, it binds to receptor sites other than those targeted by glutamate and thus cannot be displaced, even in the presence of high glutamate concentrations (Figure 1).18 Glutamate can still bind to AMPA receptors, but the expected response is inhibited by the presence of perampanel. Pharmacokinetics Perampanel exhibits a linear pharmacokinetic profile best described as a one-compartment model with first-order elimination.19-21 The drug is rapidly and nearly completely absorbed after oral administration, achieving its maximum serum concentration (Cmax) in approximately 1 hour.22 Food does not appear to alter the extent of oral absorption, though it may double or triple the time to reach Cmax.23,24 The mean half-life of perampanel was 52–129 hours after the administration of a single dose and 66–90 hours after 14 days of daily administration in Phase I trials conducted in healthy men age 18–45 years.22 Steady-state concentration was achieved by administration day 14. A pooled analysis of 19 additional Phase I trials revealed the drug’s halflife to be approximately 105 hours.24 Perampanel is highly bound to plasma protein (approximately 95%). Perampanel metabolism, which is extensive, is primarily accomplished through oxidation via cytochrome P-450 isoenzymes 3A4 and 3A5, followed by subsequent glucuronidation.24 First-pass metabolism is negligible. The administration of radiolabeled perampanel to elderly volunteers who were otherwise healthy resulted in 30% of the drug being recovered in the urine and 70% in the stool.24 No dosage alterations have been recommended based on age alone. Use of perampanel in patients with mild-to-moderate
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Perampanel
Figure 1. Mechanism of action of perampanel. The neurotransmitter glutamate is released into the synaptic space during depolarization of presynaptic neurons. The action potential of presynaptic neurons is associated with changes in intracellular ion concentrations. Binding of glutamate to postsynaptic receptors elicits an excitatory postsynaptic potential (EPSP). Perampanel binds to a site on the postsynaptic a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR) for glutamate and inhibits excessive glutamate-induced neurotransmission; this inhibition may reduce seizure activity. Reprinted from reference 18 with permission from Elsevier (www.journals. elsevier.com/pharmacological-research).
hepatic disease revealed a decrease in clearance of approximately onehalf compared with healthy subjects. Dosage adjustments for persons with Child-Pugh scores A and B have subsequently been recommended.24 Perampanel labeling further suggests the drug should be avoided in individuals with severe liver disease. Although no study has specifically evaluated perampanel in persons with severe renal disease, the drug should also be avoided in individuals with severely compromised kidney function, including those undergoing hemodialysis.24 Clinical use and efficacy 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. Study 304. The first of these, study 304, was a randomized, doubleblind, placebo-controlled, Phase III trial that included enrollment at centers in Argentina, Canada, Chile, Mexico, and the United States.25 All patients were 12 years of age or older, consistent with the eventual approval of the drug by FDA. Up to three additional antiepileptic drugs per patient were allowed (the majority were taking two or three). A total of 387 individuals who did not respond to at least two other antiepileptic agents were randomized in a 1:1:1 ratio to receive placebo, perampanel 8 mg daily, or perampanel 12 mg daily. Eligible patients were required to have experienced at least five seizures over a six-week time frame (the
baseline period) despite being on a regimen of up to three antiseizure medications. The baseline median seizure frequency was 12.0–14.3 per 28 days. The baseline phase was followed by an escalation phase during which the daily dose was increased by 2 mg weekly over 6 weeks until achievement of the target dosage. If a patient could not tolerate the medication, dosage escalation could be temporarily deferred or the dosage decreased. Patients were maintained on their assigned treatment for an additional 13 weeks, and posttreatment efficacy and safety data were collected 4 weeks later. The primary outcome measures defined for the trial included the change in seizure frequency per 28 days during the entire 19-week double-blind phase as compared with baseline and the re-
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sponder rate (defined as a minimum 50% decrease in seizure occurrence). The median change in seizure activity from baseline for the placebo group was particularly robust, with a reduction of 21%. Patients in the perampanel 8- and 12-mg groups achieved decreases of 26.3% (p = 0.026) and 34.5% (p = 0.016) in seizure activity, respectively. The median differences (95% confidence interval [CI]) of the two doses compared with placebo were –13.5% (–26.2% to –1.9%) for the 8-mg group and –14.2% (–25% to –2.7%) for the 12-mg group. All seizure types were associated with a positive dose–response relationship. Considering complex-partial seizures and secondarily generalized seizures together, the reductions in seizure activity from baseline were 17.9% in the placebo group, 33% in the 8-mg group (p = 0.002), and 33.1% in the 12-mg group (p = 0.008). When all patients were evaluated together, the 50% responder rates for those taking perampanel 8 mg daily (37.6%) and 12 mg daily (36.1%) did not differ significantly from the rate for the placebo group (26.4%) (p = 0.076 and p = 0.091, respectively). However, when North American patients (n = 227) were considered separately, the responder rate for perampaneltreated recipients was significantly higher than for those who received placebo (p < 0.05 for both perampanel dosages). Conversely, among Central and South American patients, the responder rate did not differ between perampanel and placebo groups. Theories regarding this discrepancy include issues related to the selection of participants or investigator conduct, but no definitive explanation has been given. Overall, only 5% of patients who received placebo achieved a decrease of 75–100% in seizure frequency, while 18.8% of those receiving perampanel 8 mg daily and 17.3% of those receiving 12 mg daily met this criterion (p = 0.001 for both). Dur194
ing the maintenance phase, 2.2% and 1.5% of patients taking the 8- and 12-mg/day dosages, respectively, achieved full seizure freedom. No patient receiving placebo was seizure free. Study 305. Study 305, the only high-dose trial to include both European and Central Asian patients, was also a Phase III trial and its design was identical to that of Study 304.26 A total of 386 patients were enrolled, and most were receiving two additional medications for seizures (one to three additional medications were allowed). The baseline median seizure frequency was 11.8–13.7 per 28 days. During the double-blind phase, the median change in seizure frequency was –30.5% for the 8-mg/ day group (p < 0.001) and –17.6% for the 12-mg/day group (p = 0.011). Compared with placebo, the 8- and 12-mg/day dosages were associated with significant reductions in median seizure frequency (–19.1% [95% CI, –29.2% to –8.4%] and –13.7% [95% CI, –25.2% to –2.3%], respectively). The responder rate was also significantly higher for the 8-mg/ day (33.3%) and the 12-mg/day dosages (33.9%) compared with placebo (14.7%; p = 0.002 and p < 0.001 compared with the 8- and 12-mg/ day dosages). A decrease in seizure activity of 75–100% was experienced by 15.5%, 16.5%, and 4.4% of those receiving perampanel 8 mg/day, perampanel 12 mg/day, and placebo, respectively. Seizure-free status was achieved by 2.3% and 5% of patients taking perampanel 8 and 12 mg/day, respectively, versus 1.5% of patients receiving placebo. Study 306. A third Phase III trial, Study 306, was conducted in centers located throughout Europe, Central Asia, Australia, and North America.27 Inclusion criteria and study design were identical to the previous two studies; however, this trial included low and medium daily doses of perampanel (2, 4, and 8 mg) for comparison with placebo. A total of
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705 patients were enrolled, with the majority taking two or three antiepileptic medications concomitantly. The median frequency of seizures at baseline was 9.3–10.9 per 28 days. Compared with placebo, the median percentage change in seizure frequency was nonsignificant for the 2-mg/day group but significant in the 4- and 8-mg/day groups (decreases of 23.3% [p = 0.03] and 30.8% [p < 0.001], respectively). A positive correlation with dosage was noted with all seizure types. The 8-mg/day dose was consistently favorable compared with the 4-mg/day dose, regardless of the number of concomitant antiepileptic agents. For patients receiving one additional medication, seizure frequency decreased by 29% with the 4-mg/day dosage and by 46.4% with the 8-mg/day dosage. When two concomitant medications were used, seizure frequency decreased by 18.6% (4 mg/day) and 28.5% (8 mg/ day). For individuals taking three additional medications for seizure control, the difference between the two dosages was less robust, but the reduction in seizures in the 8-mg/ day group was still better than in the 4-mg/day group (30% versus 26.2%). The 50% responder rates for placebo, perampanel 2 mg/day, perampanel 4 mg/day, and perampanel 8 mg/ day were 17.9%, 20.6%, 28.5% (p = 0.013, number needed to treat = 8), and 34.9% (p < 0.001, number needed to treat = 6), respectively. Seizurefree rates during the maintenance period were 1.2% (placebo), 1.9% (2 mg/day), 4.4% (4 mg/day), and 4.8% (8 mg/day). Study 307. Study 307 is an ongoing extension of the three studies previously detailed.28 Initially, a 16week blinded conversion period was undertaken during which patients receiving placebo or low-to-medium dose perampanel were switched to the active drug or had their dosage increased by 2 mg/day biweekly to their personal level of tolerance (up to 12 mg/day). This will be fol-
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lowed by a maximum 256-week study period during which patients receive perampanel in an open-label fashion. Manipulation of concurrent antiepileptic medication is allowed within the parameters of the study. Endpoints are defined as the change in 28-day seizure frequency and 50% response rate as compared with baseline before the active drug was given. Efficacy is being assessed at 13-week intervals. A total of 1218 (96.4%) of the participants from the other studies have been enrolled. Of those, 380 were converted to perampanel from placebo. At the time the interim results were reported, 70.8% of those who originally enrolled remained in the study. Of the patients who discontinued their participation, 7.4% did so claiming lack of efficacy of perampanel. In the majority of patients (91.4%), dosage was increased to the higher end of the dosing spectrum (mean ± S.D. dose, 10.1 ± 2.3 mg/day). Overall, seizure frequency was noted to decrease over the first 26 weeks, and the decrease has been maintained. The 588 patients who had at least one year of exposure at the time of interim data analysis demonstrated a change in seizure frequency of –47.2% during the final 13 weeks of exposure before reporting. The 19 patients who had been participants for at least two years exhibited a decrease of 56%. In general, seizure frequency continues to decrease as the study progresses while responder rates increase. However, the number of participants has declined, and it is not possible to rule out the effects of other antiepileptic agents as concomitant medications may be freely manipulated while patients are enrolled. In addition, this trial does not examine loss of initial efficacy in individuals. Pooled analysis. A pooled analysis of Phase III studies of perampanel demonstrated a consistent decrease in median seizure frequency, regardless of which other antiepileptic medications were being used con-
comitantly.29 The five most commonly used antiepileptic medications in the trials were carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, and valproic acid. Changes in seizure frequency associated with placebo ranged from –5% to –18%, compared with high-dose perampanel (12 mg/day) which generated changes of –18% (when given with carbamazepine) to –39% (when given with levetiracetam). Adverse events Two Phase II studies enrolling patients age 18–70 years with uncontrolled seizures after trials of at least three antiepileptic medications were undertaken to examine the safety and tolerability of perampanel. The first, Study 206, randomized patients to receive perampanel 4 mg daily (given either as a single dose or divided twice daily) or placebo.30 The safety analysis included 153 patients. After a four-week baseline period, patients were randomized to one of the three groups in a 1:1:1 fashion. The study medication was administered with food. The dosage of perampanel was adjusted at biweekly intervals over eight weeks. Once-daily and twice-daily administrations were tolerated equally well. Six patients withdrew from the study due to adverse effects, including 3 in the placebo group, 2 in the perampanel twice-daily group, and 1 in the perampanel once-daily group. The overall rates of adverse events did not significantly differ between the placebo group (62.7%) and the two treatment groups (66.7%). Over 80% of patients tolerated the 4-mg/day dosage. Of the four serious adverse events reported, two occurred in the placebo group, and all were related to seizure activity. No deaths occurred, and no abnormal test or laboratory values were reported. The second trial, Study 208 (n = 48), was similar in design to Study 206; however, perampanel dosages of up to 12 mg/day were given.30 Ran-
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domization was done in a 3:1 manner (perampanel to placebo) and was stratified according to whether the subject was using enzyme-inducing antiepileptic medications concurrently. Patients in this study also took their medications with food. Dosages were increased 2 mg/day every two weeks. Of those receiving active medication, 32% achieved the maximum dosage compared with 60% of those receiving placebo. One patient in the placebo group and 2 in the perampanel group withdrew from the study due to adverse reactions. Overall, the percentage of adverse events was similar between groups (80% in the placebo group, 84.2% in the perampanel group). One patient in each group reported a serious adverse event, neither of which was believed to be treatment related. No deaths occurred, and no significant changes in laboratory data were reported. The most commonly reported adverse events (occurring in more than 10% of patients) reported in perampanel-treated patients in both of the Phase II studies were dizziness and somnolence.30 Most of the adverse events experienced are common among patients taking antiepileptics, so it is difficult to determine if perampanel was the causative agent in any of the study participants. Study 207 is an extension trial of Study 206 and Study 208.6 The study is ongoing, but preliminary results demonstrate a high frequency of mild-to-moderate adverse events (93.5%). Serious adverse events possibly related to drug therapy include convulsions, schizophrenia, status epilepticus, and tonic–clonic seizures. The death of one patient, a morbidly obese 48-year old who suffered cardiac arrest, was recorded in Study 207. Although the patient’s death is unlikely related to drug therapy, sudden unexpected death in epilepsy (SUDEP) cannot be ruled out. Of the patients enrolled in any of the Phase III trials or extension Study 307, 87.4% experienced an adverse
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event.25-28 Of these adverse events, 78.2% were attributed to treatment, and positive dosage–response relationships were evident for most cases. The vast majority of adverse events were characterized as mild to moderate in intensity (73%). Withdrawal of medication was necessary in 13.2% of patients, with dizziness, irritability, and aggression each resulting in study discontinuation by at least 1% of participants. Falls were noted in roughly 1 in 10 individuals receiving perampanel 12 mg daily.22 An additional 36.1% of patients required a dosage reduction, and another 3.3% of patients required interruption of medication administration. The most common reasons for alterations in dosing were dizziness (20.7%), somnolence (7.3%), ataxia (3.3%), fatigue (2.9%), headache (2.3%,) and gait disturbance (2%). The only serious adverse events that occurred in more than 1% of study participants were related to epileptic seizure activity.27 No cases of SUDEP were noted in the Phase III trials25-27; one case of SUDEP was reported in Study 307.28 Suicidality was experienced by 2 patients (1 receiving placebo, 1 receiving perampanel 8 mg/day) in Study 304, 1 patient (receiving placebo) in Study 305, and 1 patient (receiving 2 mg/day) in Study 306.25-27 Increased weight of >7% above baseline was noted in 11.6–19.2% of patients receiving perampanel in the Phase III trials versus 4.4–8.3% in those receiving placebo. Weight gain did not appear to be dosage related. Abnormal laboratory values noted in the extension study were minimal, and it is unclear if any were attributable to the study medication.28 Specifically, serum alanine transaminase or aspartate transaminase levels exceeding three times the upper limit of normal were noted in fewer than 1% of enrollees, and creatine kinase levels exceeding five times the upper limit of normal were observed in 1.7% of patients. Of those individuals demonstrating abnormal laboratory 196
test values, most were also receiving concurrent antiepileptic drugs that may have influenced the results (carbamazepine, oxcarbazepine, and valproic acid). Changes in blood pressure occurred in fewer than 2% of patients, and no clinically important changes in electrocardiogram results were seen. A boxed warning has been placed in the FDA-approved labeling for perampanel.24 Specifically, serious or life-threatening neuropsychiatric reactions including aggression, hostility, irritability, anger, and homicidal ideation and threats are purported to have occurred in patients receiving the drug, though rates reported in clinical trials were low. In Study 304, aggression was noted in 1.9% of patients receiving perampanel versus none in the placebo group.23 Severity ratings placed 1 subject each in the mild and severe groups, while 3 patients were determined to have experienced moderate aggression. In Study 305, fewer than 1% of patients experienced aggression in the placebo and perampanel 12-mg/day groups; 1.6% of patients in the 8-mg/ day group reported aggression. Anger was reported by 1.7% of patients in the 12-mg/day group.24 In addition, 10 participants in Study 307, or fewer than 1% of the study sample, reported aggression. 26 Homicidal ideation was not noted in any of the published data for the Phase II and III trials. Dosage reductions or drug discontinuation is recommended if signs of these reactions become apparent during therapy.24 Drug interactions Studies have consistently shown that antiepileptic drugs that induce cytochrome P-450 hepatic enzymes have a significant effect on plasma perampanel concentrations. Specifically, carbamazepine, phenytoin, and oxcarbazepine reduce perampanel levels by up to 67%.24 However, phenobarbital has not been found to alter perampanel concentrations.
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There are no reports of clinically significant drug interactions with other antiepileptics. As a general recommendation, the manufacturer suggests that the perampanel dosage may need to be increased when given with strong cytochrome P-450 inducers (e.g., rifampin, St. John’s wort).24 Interactions with other drugs have also been noted. When used at the maximum recommended 12-mg/day dosage, perampanel has been shown to decrease serum concentrations of levonorgestrel, a common ingredient in oral and implantable contraceptive preparations, by 40%. 24 It is unknown whether this interaction decreases contraceptive effectiveness, but a backup method of birth control is recommended when the two drugs are used simultaneously. Midazolam coadministration with perampanel has been shown to decrease concentrations of the latter by approximately 14%. Ketoconazole, a strong cytochrome P-450 inhibitor, may increase perampanel concentrations by about 20%. The significance of these interactions, if any, remains to be determined; however, no specific dosage recommendations are currently advised when the combinations are used. Dosage and administration Perampanel should be initiated at 2 mg/day, and the drug should be taken at bedtime to minimize the effect of adverse events.24 However, for individuals who are receiving therapy with known hepatic enzyme inducers, the initial dose should be doubled to 4 mg/day. Slow upward adjustment of the perampanel dosage (2-mg/day increments once weekly) is recommended to decrease the frequency of adverse effects. Increasing the adjustment interval to once every other week is suggested for elderly patients. The maximum recommended dose is 12 mg/day for patients with normal renal and hepatic functions. The maximum daily
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dose is 6 mg for individuals with mild hepatic impairment or 4 mg for those with moderate hepatic impairment. Dosage adjustment should occur at biweekly intervals for patients in either category. As previously stated, the drug should be avoided in individuals with severe hepatic or renal impairment, including those undergoing hemodialysis. Because of the long half-life of the drug, if a dose is missed, the patient may continue therapy with the next scheduled dose. Currently, the Drug Enforcement Administration is conducting a controlled-substance scheduling review of perampanel.31 As such, the drug is not yet marketed, and pricing data are currently unavailable. Although the prescribing information states that euphoric effects may be induced when supratherapeutic doses are used, no abuse or diversion has been reported to date. Place in therapy Perampanel is a first-in-class antiepileptic agent. Well over a dozen antiepileptic medications have come to market in the past several decades, many of which also possess unique mechanisms of action. However, none of these agents, when compared with others, has been shown to have a substantial effect on refractory partial seizures.17 Perampanel has shown promising efficacy in treatmentresistant epilepsy that is at least equivalent to other drugs approved for adjunctive therapy. In addition, perampanel’s early approval for adolescent patients makes it somewhat unique. It remains to be seen whether perampanel will prove to have neuroprotective attributes as a result of its ability to reduce sustained seizure activity. The drug has not been studied as a monotherapeutic option, and its potential role as a standalone agent for partial seizures is unknown. In general, the drug appears to be well tolerated, though slow and deliberate dosage escalation in conjunction with bedtime administra-
tion will likely increase its acceptance by patients. Patients need to be monitored for changes in behavior. At this time there is no information on whether individuals with a history of psychiatric diagnoses are more prone to experience behavioral issues compared with patients with no such history. Perampanel has an uncomplicated pharmacokinetic profile. It exhibits relatively complete bioavailability, and the length of the drug’s half-life may make the issue of breakthrough seizure activity due to missed doses less of a concern while the ability to administer the drug once daily may make adherence to therapy easier. Drug interactions with enzyme-inducing antiepileptic agents have been identified, and simple compensatory dosing recommendations have been established. Conclusion 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.
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24. 25.
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seizure in the conscious human brain. Lancet. 1993; 341:1607-10. Le DA, Lipton SA. Potential and current use of N-methyl-d-aspartate (NMDA) receptor antagonists in diseases of aging. Drugs Aging. 2001; 18:717-24. Rogawski MA. Revisiting AMPA receptors as an antiepileptic drug target. Epilepsy Curr. 2011; 11:56-63. Plosker GL. Perampanel as adjunctive therapy in patients with partial onset seizures. CNS Drugs. 2012; 26:1085-96. Meldrum BS, Rogawski MA. Molecular targets for antiepileptic drug development. Neurotherapeutics. 2007; 4:18-61. Mayer ML. Glutamate receptor ion channels. Curr Opin Neurobiol. 2005; 15: 282-8. Rosenmund C, Stern-Bach Y, Stevens CF. The tetrameric structure of a glutamate receptor channel. Science. 1998; 280:1596-9. Meldrum BS. Implications for neuroprotective treatments. Prog Brain Res. 2002; 135:487-95. Frandsen A, Schousboe A. AMPA receptormediated neurotoxicity: role of Ca2+ and desensitization. Neurochem Res. 2003; 28:1495-9. Löscher W, Schmidt D. Perampanel— new promise for refractory epilepsy? Nat Rev Neurol. 2012; 8:661-2. News. Franco V, Crema F, Iudice A et al. Novel treatment options for epilepsy: focus on perampanel. Pharmacol Res. 2013; 70:35-40. Hussein Z, Ferry J, Krauss G et al. Demographic factors and concomitant antiepileptic drugs have no effect on the pharmacodynamics of perampanel. Presented at 64th Annual Meeting of the American Academy of Neurology. New Orleans, LA; 2012 Apr 26. Hussein Z, Critchley D, Ferry J et al. Population pharmacokinetics of perampanel, a selective, noncompetitive AMPA receptor antagonist, in patients with refractory partial-onset seizures participating in a randomized, double-blind, placebocontrolled phase III study. Epilepsia. 2011; 52(suppl 6):248-9. Abstract. Fuseau E, Templeton D, Hussein Z. Population pharmacokinetics and pharmacodynamics of perampanel in patients with refractory partial seizures. Epilepsy Curr. 2011; 11(suppl 1):1.254. Abstract. Templeton D. Pharmacokinetics of perampanel, a highly selective AMPA-type glutamate receptor antagonist. Epilepsia. 2009; 50(suppl 11):98. Abstract. Laurenza A, Ferry J, Hussein Z. Population pharmacokinetics and pharmacodynamics of perampanel: a pooled analysis from three phase III trials. Epilepsy Curr. 2012; 12(suppl 1):2.231. Abstract. Fycompa (perampanel) package insert. Woodcliff Lake, NJ: Esai; 2012 Oct. French JA, Krauss GL, Biton V et al. Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304. Neurology. 2012; 79: 589-96.
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26. French JA, Krauss GL, Steinhoff BJ et al. Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305. Epilepsia. 2013; 54:117-25. 27. Krauss GL, Serratosa JM, Villanueva V. Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 306. Neurology. 2012; 78:140815. 28. Krauss GL, Perucca E, Ben-Menachem E et al. Perampanel, a selective, noncompetitive a-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid receptor antagonist, as adjunctive therapy for refractory partial-onset seizures: interim results from phase III, extension study 307. Epilepsia. 2013; 54:126-34. 29. Trinka E, Straub H, Squillacote D et al. Analysis of seizure frequency reduction by concomitant antiepileptic drug (AED) use with adjunctive perampanel: pooled phase III results. Epilepsia. 2012; 53(suppl 5):194-5. Abstract. 30. Krauss GL, Bar M, Biton V et al. Tolerability and safety of perampanel: two randomized dose-escalation studies. Acta Neurol Scand. 2012; 125:8-15. 31. Gilbert JA. Eisai files a writ of mandamus as a last resort to get DEA to schedule Fycompa. www.fdalawblog.net/fda_law_ blog_hyman_phelps/2013/08/eisai-filesa-writ-of-mandamus-as-a-last-resortto-get-dea-to-schedule-fycompa-.html (accessed 2013 Nov 1).
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Perampanel: A new agent for adjunctive treatment of partial seizures Michele A. Faulkner
P
erampanel (per am´ pa nel; Fycompa, Esai) was recently approved for use as adjunctive therapy for the treatment of partial seizures with or without secondary generalization. The drug received marketing authorization approval from the European Commission on July 27, 2012, and Food and Drug Administration (FDA) approval on October 22, 2012, for use as addon therapy in patients with partial seizures age 12 years and older. This review summarizes the currently available efficacy and safety data on perampanel and describes the potential role of the drug in the treatment of refractory partial seizures. Background Epilepsy affects over 50 million people worldwide, approximately 60% of whom experience partial seizures.1 Monotherapeutic options often fail, and even when adjunctive treatment with one or more medications with activity against partial seizures is used, 25–33% of patients continue to experience seizure activity.2,3 The consequences for patients, caregivers, and society are substantial, as increased morbidity and mortality and decreased quality
Purpose. The pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of perampanel are reviewed. Summary. 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 a-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (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 secondar y generalization. Drug interactions have been noted with agents that induce cytochrome P-450 hepatic enzymes, includ-
of life are common among those with uncontrolled seizures. Although some practitioners use antiepileptic drugs for off-label indications (e.g., adjunctive therapies are sometimes used as monotherapy), the drugs are specifically designated
Michele A. Faulkner, Pharm.D., is Associate Professor of Pharmacy Practice, School of Pharmacy and Health Professions, and Associate Professor of Medicine, Department of Neurology, School of Medicine, Creighton University, Omaha, NE ([email protected]).
ing 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. Conclusion. 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. Am J Health-Syst Pharm. 2014; 71:191-8
by FDA for use as monotherapy or adjunct therapy. FDA-approved agents for monotherapy of partial seizures include older medications such as phenytoin, valproic acid, carbamazepine, and phenobarbital, as well as the second-generation anti-
The author has declared no potential conflicts of interest. Copyright © 2014, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/14/0201-0191$06.00. DOI 10.2146/ajhp130203
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epileptics oxcarbazepine, topiramate, felbamate, and lamotrigine (which is approved for monotherapy after converting from carbamazepine, phenytoin, phenobarbital, primidone, or valproic acid). FDA-approved adjunct therapies include gabapentin, pregabalin, tiagabine, levetiracetam, zonisamide, lacosamide, vigabatrin, and ezogabine. These antiepileptics work by inhibiting voltage-gated sodium and calcium channels or enhancing g-aminobutyric acid.4 However, a few of the newer antiepileptic agents have unique or novel targets for their action (either as a primary or secondary mechanism) including gabapentin and pregabalin (a 2dsubunit of L-type voltage-regulated calcium channels), lamotrigine (Hcurrent), levetiracetam (synaptic vesicle protein 2A), and ezogabine (Kv7 potassium channels). 4 Two antiepileptics have nonselective antagonistic activity at ionotropic glutamate receptors: felbamate at the N-methyl-d-aspartate (NMDA) receptor and topiramate at the kainite receptor, though their glutaminergic activity is very much secondary to other mechanisms of action.5,6 The prospect of targeting glutamate as a primary mechanism for decreasing seizure activity has been a subject of much interest and study in recent years. Glutamate is the primary excitatory neurotransmitter in the brain; as such, manipulation of glutaminergic pathways may be a rational approach to the control of epilepsy. Increased glutamate concentrations have long been suspected to trigger seizures.7 Elevated and sustained extracellular glutamate concentrations in the hippocampus have been noted both before and during seizure activity.8 Previous attempts to use NMDA receptors as an antiepileptic target were met with disappointment, largely due to the propensity for medicinal manipulation of the receptors to cause adverse neuropsychiatric effects in humans.9,10 In fact, NMDA 192
receptors are the target of several drugs with a known potential for abuse (e.g., phencyclidine, ketamine, nitrous oxide, dextromethorphan). However, another type of ionotropic glutamate receptor—the a-amino3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) receptor—has a significant role in the development and propagation of seizures and appears to have a broader spectrum of activity compared with NMDA and kainite receptors.10 AMPA receptors are the predominant mediators of excitatory neurotransmission in the brain and are the most commonly identified receptors throughout the nervous system.10,11 Animal models have demonstrated that exogenous administration of AMPA can induce profound seizure activity.12 AMPA receptors are both glutamate receptors and ligand-gated cation channels.11 Four agonist-binding sites are found on each receptor; when more than one site is occupied simultaneously, the channel opens with a current speed that is relative to the number of sites bound at any given time.13,14 Because cation channels open and close rapidly, AMPA receptors are believed to be responsible for the majority of fast excitatory transmission throughout the central nervous system. Overstimulation of AMPA receptors by glutamate may lead to ionic imbalance by inducing calcium overload in cells, resulting in excitotoxicity stemming from excessive glutamate-induced neurotransmission.15,16 Thus, a drug with the capacity to inhibit this excessive glutamate-driven receptor stimulation may deter seizure activity and possibly provide neuroprotection. Pharmacology Perampanel is a selective antagonist of excitatory postsynaptic AMPA glutamate receptors.11 Unlike most antiepileptic drugs, which were discovered to have antiseizure activity after random drug screening, by manipulating existing antiepileptic
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compounds, or purely by serendipity, perampanel was created by deliberate design based on known mechanisms of seizure occurrence and propagation.17 As a noncompetitive inhibitor, it binds to receptor sites other than those targeted by glutamate and thus cannot be displaced, even in the presence of high glutamate concentrations (Figure 1).18 Glutamate can still bind to AMPA receptors, but the expected response is inhibited by the presence of perampanel. Pharmacokinetics Perampanel exhibits a linear pharmacokinetic profile best described as a one-compartment model with first-order elimination.19-21 The drug is rapidly and nearly completely absorbed after oral administration, achieving its maximum serum concentration (Cmax) in approximately 1 hour.22 Food does not appear to alter the extent of oral absorption, though it may double or triple the time to reach Cmax.23,24 The mean half-life of perampanel was 52–129 hours after the administration of a single dose and 66–90 hours after 14 days of daily administration in Phase I trials conducted in healthy men age 18–45 years.22 Steady-state concentration was achieved by administration day 14. A pooled analysis of 19 additional Phase I trials revealed the drug’s halflife to be approximately 105 hours.24 Perampanel is highly bound to plasma protein (approximately 95%). Perampanel metabolism, which is extensive, is primarily accomplished through oxidation via cytochrome P-450 isoenzymes 3A4 and 3A5, followed by subsequent glucuronidation.24 First-pass metabolism is negligible. The administration of radiolabeled perampanel to elderly volunteers who were otherwise healthy resulted in 30% of the drug being recovered in the urine and 70% in the stool.24 No dosage alterations have been recommended based on age alone. Use of perampanel in patients with mild-to-moderate
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Figure 1. Mechanism of action of perampanel. The neurotransmitter glutamate is released into the synaptic space during depolarization of presynaptic neurons. The action potential of presynaptic neurons is associated with changes in intracellular ion concentrations. Binding of glutamate to postsynaptic receptors elicits an excitatory postsynaptic potential (EPSP). Perampanel binds to a site on the postsynaptic a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR) for glutamate and inhibits excessive glutamate-induced neurotransmission; this inhibition may reduce seizure activity. Reprinted from reference 18 with permission from Elsevier (www.journals. elsevier.com/pharmacological-research).
hepatic disease revealed a decrease in clearance of approximately onehalf compared with healthy subjects. Dosage adjustments for persons with Child-Pugh scores A and B have subsequently been recommended.24 Perampanel labeling further suggests the drug should be avoided in individuals with severe liver disease. Although no study has specifically evaluated perampanel in persons with severe renal disease, the drug should also be avoided in individuals with severely compromised kidney function, including those undergoing hemodialysis.24 Clinical use and efficacy 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. Study 304. The first of these, study 304, was a randomized, doubleblind, placebo-controlled, Phase III trial that included enrollment at centers in Argentina, Canada, Chile, Mexico, and the United States.25 All patients were 12 years of age or older, consistent with the eventual approval of the drug by FDA. Up to three additional antiepileptic drugs per patient were allowed (the majority were taking two or three). A total of 387 individuals who did not respond to at least two other antiepileptic agents were randomized in a 1:1:1 ratio to receive placebo, perampanel 8 mg daily, or perampanel 12 mg daily. Eligible patients were required to have experienced at least five seizures over a six-week time frame (the
baseline period) despite being on a regimen of up to three antiseizure medications. The baseline median seizure frequency was 12.0–14.3 per 28 days. The baseline phase was followed by an escalation phase during which the daily dose was increased by 2 mg weekly over 6 weeks until achievement of the target dosage. If a patient could not tolerate the medication, dosage escalation could be temporarily deferred or the dosage decreased. Patients were maintained on their assigned treatment for an additional 13 weeks, and posttreatment efficacy and safety data were collected 4 weeks later. The primary outcome measures defined for the trial included the change in seizure frequency per 28 days during the entire 19-week double-blind phase as compared with baseline and the re-
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sponder rate (defined as a minimum 50% decrease in seizure occurrence). The median change in seizure activity from baseline for the placebo group was particularly robust, with a reduction of 21%. Patients in the perampanel 8- and 12-mg groups achieved decreases of 26.3% (p = 0.026) and 34.5% (p = 0.016) in seizure activity, respectively. The median differences (95% confidence interval [CI]) of the two doses compared with placebo were –13.5% (–26.2% to –1.9%) for the 8-mg group and –14.2% (–25% to –2.7%) for the 12-mg group. All seizure types were associated with a positive dose–response relationship. Considering complex-partial seizures and secondarily generalized seizures together, the reductions in seizure activity from baseline were 17.9% in the placebo group, 33% in the 8-mg group (p = 0.002), and 33.1% in the 12-mg group (p = 0.008). When all patients were evaluated together, the 50% responder rates for those taking perampanel 8 mg daily (37.6%) and 12 mg daily (36.1%) did not differ significantly from the rate for the placebo group (26.4%) (p = 0.076 and p = 0.091, respectively). However, when North American patients (n = 227) were considered separately, the responder rate for perampaneltreated recipients was significantly higher than for those who received placebo (p < 0.05 for both perampanel dosages). Conversely, among Central and South American patients, the responder rate did not differ between perampanel and placebo groups. Theories regarding this discrepancy include issues related to the selection of participants or investigator conduct, but no definitive explanation has been given. Overall, only 5% of patients who received placebo achieved a decrease of 75–100% in seizure frequency, while 18.8% of those receiving perampanel 8 mg daily and 17.3% of those receiving 12 mg daily met this criterion (p = 0.001 for both). Dur194
ing the maintenance phase, 2.2% and 1.5% of patients taking the 8- and 12-mg/day dosages, respectively, achieved full seizure freedom. No patient receiving placebo was seizure free. Study 305. Study 305, the only high-dose trial to include both European and Central Asian patients, was also a Phase III trial and its design was identical to that of Study 304.26 A total of 386 patients were enrolled, and most were receiving two additional medications for seizures (one to three additional medications were allowed). The baseline median seizure frequency was 11.8–13.7 per 28 days. During the double-blind phase, the median change in seizure frequency was –30.5% for the 8-mg/ day group (p < 0.001) and –17.6% for the 12-mg/day group (p = 0.011). Compared with placebo, the 8- and 12-mg/day dosages were associated with significant reductions in median seizure frequency (–19.1% [95% CI, –29.2% to –8.4%] and –13.7% [95% CI, –25.2% to –2.3%], respectively). The responder rate was also significantly higher for the 8-mg/ day (33.3%) and the 12-mg/day dosages (33.9%) compared with placebo (14.7%; p = 0.002 and p < 0.001 compared with the 8- and 12-mg/ day dosages). A decrease in seizure activity of 75–100% was experienced by 15.5%, 16.5%, and 4.4% of those receiving perampanel 8 mg/day, perampanel 12 mg/day, and placebo, respectively. Seizure-free status was achieved by 2.3% and 5% of patients taking perampanel 8 and 12 mg/day, respectively, versus 1.5% of patients receiving placebo. Study 306. A third Phase III trial, Study 306, was conducted in centers located throughout Europe, Central Asia, Australia, and North America.27 Inclusion criteria and study design were identical to the previous two studies; however, this trial included low and medium daily doses of perampanel (2, 4, and 8 mg) for comparison with placebo. A total of
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705 patients were enrolled, with the majority taking two or three antiepileptic medications concomitantly. The median frequency of seizures at baseline was 9.3–10.9 per 28 days. Compared with placebo, the median percentage change in seizure frequency was nonsignificant for the 2-mg/day group but significant in the 4- and 8-mg/day groups (decreases of 23.3% [p = 0.03] and 30.8% [p < 0.001], respectively). A positive correlation with dosage was noted with all seizure types. The 8-mg/day dose was consistently favorable compared with the 4-mg/day dose, regardless of the number of concomitant antiepileptic agents. For patients receiving one additional medication, seizure frequency decreased by 29% with the 4-mg/day dosage and by 46.4% with the 8-mg/day dosage. When two concomitant medications were used, seizure frequency decreased by 18.6% (4 mg/day) and 28.5% (8 mg/ day). For individuals taking three additional medications for seizure control, the difference between the two dosages was less robust, but the reduction in seizures in the 8-mg/ day group was still better than in the 4-mg/day group (30% versus 26.2%). The 50% responder rates for placebo, perampanel 2 mg/day, perampanel 4 mg/day, and perampanel 8 mg/ day were 17.9%, 20.6%, 28.5% (p = 0.013, number needed to treat = 8), and 34.9% (p < 0.001, number needed to treat = 6), respectively. Seizurefree rates during the maintenance period were 1.2% (placebo), 1.9% (2 mg/day), 4.4% (4 mg/day), and 4.8% (8 mg/day). Study 307. Study 307 is an ongoing extension of the three studies previously detailed.28 Initially, a 16week blinded conversion period was undertaken during which patients receiving placebo or low-to-medium dose perampanel were switched to the active drug or had their dosage increased by 2 mg/day biweekly to their personal level of tolerance (up to 12 mg/day). This will be fol-
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lowed by a maximum 256-week study period during which patients receive perampanel in an open-label fashion. Manipulation of concurrent antiepileptic medication is allowed within the parameters of the study. Endpoints are defined as the change in 28-day seizure frequency and 50% response rate as compared with baseline before the active drug was given. Efficacy is being assessed at 13-week intervals. A total of 1218 (96.4%) of the participants from the other studies have been enrolled. Of those, 380 were converted to perampanel from placebo. At the time the interim results were reported, 70.8% of those who originally enrolled remained in the study. Of the patients who discontinued their participation, 7.4% did so claiming lack of efficacy of perampanel. In the majority of patients (91.4%), dosage was increased to the higher end of the dosing spectrum (mean ± S.D. dose, 10.1 ± 2.3 mg/day). Overall, seizure frequency was noted to decrease over the first 26 weeks, and the decrease has been maintained. The 588 patients who had at least one year of exposure at the time of interim data analysis demonstrated a change in seizure frequency of –47.2% during the final 13 weeks of exposure before reporting. The 19 patients who had been participants for at least two years exhibited a decrease of 56%. In general, seizure frequency continues to decrease as the study progresses while responder rates increase. However, the number of participants has declined, and it is not possible to rule out the effects of other antiepileptic agents as concomitant medications may be freely manipulated while patients are enrolled. In addition, this trial does not examine loss of initial efficacy in individuals. Pooled analysis. A pooled analysis of Phase III studies of perampanel demonstrated a consistent decrease in median seizure frequency, regardless of which other antiepileptic medications were being used con-
comitantly.29 The five most commonly used antiepileptic medications in the trials were carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, and valproic acid. Changes in seizure frequency associated with placebo ranged from –5% to –18%, compared with high-dose perampanel (12 mg/day) which generated changes of –18% (when given with carbamazepine) to –39% (when given with levetiracetam). Adverse events Two Phase II studies enrolling patients age 18–70 years with uncontrolled seizures after trials of at least three antiepileptic medications were undertaken to examine the safety and tolerability of perampanel. The first, Study 206, randomized patients to receive perampanel 4 mg daily (given either as a single dose or divided twice daily) or placebo.30 The safety analysis included 153 patients. After a four-week baseline period, patients were randomized to one of the three groups in a 1:1:1 fashion. The study medication was administered with food. The dosage of perampanel was adjusted at biweekly intervals over eight weeks. Once-daily and twice-daily administrations were tolerated equally well. Six patients withdrew from the study due to adverse effects, including 3 in the placebo group, 2 in the perampanel twice-daily group, and 1 in the perampanel once-daily group. The overall rates of adverse events did not significantly differ between the placebo group (62.7%) and the two treatment groups (66.7%). Over 80% of patients tolerated the 4-mg/day dosage. Of the four serious adverse events reported, two occurred in the placebo group, and all were related to seizure activity. No deaths occurred, and no abnormal test or laboratory values were reported. The second trial, Study 208 (n = 48), was similar in design to Study 206; however, perampanel dosages of up to 12 mg/day were given.30 Ran-
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domization was done in a 3:1 manner (perampanel to placebo) and was stratified according to whether the subject was using enzyme-inducing antiepileptic medications concurrently. Patients in this study also took their medications with food. Dosages were increased 2 mg/day every two weeks. Of those receiving active medication, 32% achieved the maximum dosage compared with 60% of those receiving placebo. One patient in the placebo group and 2 in the perampanel group withdrew from the study due to adverse reactions. Overall, the percentage of adverse events was similar between groups (80% in the placebo group, 84.2% in the perampanel group). One patient in each group reported a serious adverse event, neither of which was believed to be treatment related. No deaths occurred, and no significant changes in laboratory data were reported. The most commonly reported adverse events (occurring in more than 10% of patients) reported in perampanel-treated patients in both of the Phase II studies were dizziness and somnolence.30 Most of the adverse events experienced are common among patients taking antiepileptics, so it is difficult to determine if perampanel was the causative agent in any of the study participants. Study 207 is an extension trial of Study 206 and Study 208.6 The study is ongoing, but preliminary results demonstrate a high frequency of mild-to-moderate adverse events (93.5%). Serious adverse events possibly related to drug therapy include convulsions, schizophrenia, status epilepticus, and tonic–clonic seizures. The death of one patient, a morbidly obese 48-year old who suffered cardiac arrest, was recorded in Study 207. Although the patient’s death is unlikely related to drug therapy, sudden unexpected death in epilepsy (SUDEP) cannot be ruled out. Of the patients enrolled in any of the Phase III trials or extension Study 307, 87.4% experienced an adverse
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event.25-28 Of these adverse events, 78.2% were attributed to treatment, and positive dosage–response relationships were evident for most cases. The vast majority of adverse events were characterized as mild to moderate in intensity (73%). Withdrawal of medication was necessary in 13.2% of patients, with dizziness, irritability, and aggression each resulting in study discontinuation by at least 1% of participants. Falls were noted in roughly 1 in 10 individuals receiving perampanel 12 mg daily.22 An additional 36.1% of patients required a dosage reduction, and another 3.3% of patients required interruption of medication administration. The most common reasons for alterations in dosing were dizziness (20.7%), somnolence (7.3%), ataxia (3.3%), fatigue (2.9%), headache (2.3%,) and gait disturbance (2%). The only serious adverse events that occurred in more than 1% of study participants were related to epileptic seizure activity.27 No cases of SUDEP were noted in the Phase III trials25-27; one case of SUDEP was reported in Study 307.28 Suicidality was experienced by 2 patients (1 receiving placebo, 1 receiving perampanel 8 mg/day) in Study 304, 1 patient (receiving placebo) in Study 305, and 1 patient (receiving 2 mg/day) in Study 306.25-27 Increased weight of >7% above baseline was noted in 11.6–19.2% of patients receiving perampanel in the Phase III trials versus 4.4–8.3% in those receiving placebo. Weight gain did not appear to be dosage related. Abnormal laboratory values noted in the extension study were minimal, and it is unclear if any were attributable to the study medication.28 Specifically, serum alanine transaminase or aspartate transaminase levels exceeding three times the upper limit of normal were noted in fewer than 1% of enrollees, and creatine kinase levels exceeding five times the upper limit of normal were observed in 1.7% of patients. Of those individuals demonstrating abnormal laboratory 196
test values, most were also receiving concurrent antiepileptic drugs that may have influenced the results (carbamazepine, oxcarbazepine, and valproic acid). Changes in blood pressure occurred in fewer than 2% of patients, and no clinically important changes in electrocardiogram results were seen. A boxed warning has been placed in the FDA-approved labeling for perampanel.24 Specifically, serious or life-threatening neuropsychiatric reactions including aggression, hostility, irritability, anger, and homicidal ideation and threats are purported to have occurred in patients receiving the drug, though rates reported in clinical trials were low. In Study 304, aggression was noted in 1.9% of patients receiving perampanel versus none in the placebo group.23 Severity ratings placed 1 subject each in the mild and severe groups, while 3 patients were determined to have experienced moderate aggression. In Study 305, fewer than 1% of patients experienced aggression in the placebo and perampanel 12-mg/day groups; 1.6% of patients in the 8-mg/ day group reported aggression. Anger was reported by 1.7% of patients in the 12-mg/day group.24 In addition, 10 participants in Study 307, or fewer than 1% of the study sample, reported aggression. 26 Homicidal ideation was not noted in any of the published data for the Phase II and III trials. Dosage reductions or drug discontinuation is recommended if signs of these reactions become apparent during therapy.24 Drug interactions Studies have consistently shown that antiepileptic drugs that induce cytochrome P-450 hepatic enzymes have a significant effect on plasma perampanel concentrations. Specifically, carbamazepine, phenytoin, and oxcarbazepine reduce perampanel levels by up to 67%.24 However, phenobarbital has not been found to alter perampanel concentrations.
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There are no reports of clinically significant drug interactions with other antiepileptics. As a general recommendation, the manufacturer suggests that the perampanel dosage may need to be increased when given with strong cytochrome P-450 inducers (e.g., rifampin, St. John’s wort).24 Interactions with other drugs have also been noted. When used at the maximum recommended 12-mg/day dosage, perampanel has been shown to decrease serum concentrations of levonorgestrel, a common ingredient in oral and implantable contraceptive preparations, by 40%. 24 It is unknown whether this interaction decreases contraceptive effectiveness, but a backup method of birth control is recommended when the two drugs are used simultaneously. Midazolam coadministration with perampanel has been shown to decrease concentrations of the latter by approximately 14%. Ketoconazole, a strong cytochrome P-450 inhibitor, may increase perampanel concentrations by about 20%. The significance of these interactions, if any, remains to be determined; however, no specific dosage recommendations are currently advised when the combinations are used. Dosage and administration Perampanel should be initiated at 2 mg/day, and the drug should be taken at bedtime to minimize the effect of adverse events.24 However, for individuals who are receiving therapy with known hepatic enzyme inducers, the initial dose should be doubled to 4 mg/day. Slow upward adjustment of the perampanel dosage (2-mg/day increments once weekly) is recommended to decrease the frequency of adverse effects. Increasing the adjustment interval to once every other week is suggested for elderly patients. The maximum recommended dose is 12 mg/day for patients with normal renal and hepatic functions. The maximum daily
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dose is 6 mg for individuals with mild hepatic impairment or 4 mg for those with moderate hepatic impairment. Dosage adjustment should occur at biweekly intervals for patients in either category. As previously stated, the drug should be avoided in individuals with severe hepatic or renal impairment, including those undergoing hemodialysis. Because of the long half-life of the drug, if a dose is missed, the patient may continue therapy with the next scheduled dose. Currently, the Drug Enforcement Administration is conducting a controlled-substance scheduling review of perampanel.31 As such, the drug is not yet marketed, and pricing data are currently unavailable. Although the prescribing information states that euphoric effects may be induced when supratherapeutic doses are used, no abuse or diversion has been reported to date. Place in therapy Perampanel is a first-in-class antiepileptic agent. Well over a dozen antiepileptic medications have come to market in the past several decades, many of which also possess unique mechanisms of action. However, none of these agents, when compared with others, has been shown to have a substantial effect on refractory partial seizures.17 Perampanel has shown promising efficacy in treatmentresistant epilepsy that is at least equivalent to other drugs approved for adjunctive therapy. In addition, perampanel’s early approval for adolescent patients makes it somewhat unique. It remains to be seen whether perampanel will prove to have neuroprotective attributes as a result of its ability to reduce sustained seizure activity. The drug has not been studied as a monotherapeutic option, and its potential role as a standalone agent for partial seizures is unknown. In general, the drug appears to be well tolerated, though slow and deliberate dosage escalation in conjunction with bedtime administra-
tion will likely increase its acceptance by patients. Patients need to be monitored for changes in behavior. At this time there is no information on whether individuals with a history of psychiatric diagnoses are more prone to experience behavioral issues compared with patients with no such history. Perampanel has an uncomplicated pharmacokinetic profile. It exhibits relatively complete bioavailability, and the length of the drug’s half-life may make the issue of breakthrough seizure activity due to missed doses less of a concern while the ability to administer the drug once daily may make adherence to therapy easier. Drug interactions with enzyme-inducing antiepileptic agents have been identified, and simple compensatory dosing recommendations have been established. Conclusion 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.
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