Perampanel: A highly selective, non-competitive AMPA-type glutamate receptor antagonist for adjunctive treatment of refractory partial-onset seizures

December 31, 2012

Perampanel is a selective, non-competitive AMPA receptor antagonist that is used as adjunctive therapy for refractory partial-onset seizures and was approved by the FDA on October 22, 2012.

Epilepsy is the repeated incidence of seizures caused by the abnormal hyperexcitation of neurons due to biochemical changes in neurotransmitters and/or their receptors.1 A number of factors may cause a patient to develop seizures, including drugs, genetics, head trauma, stroke, central nervous system infections, dementia, fetal injury, and developmental disorders.1 In about 50% of cases, the cause of the seizure is unknown.1

Seizure episodes involving the loss of consciousness, including tonic clonic and absence seizures, are categorized as generalized seizures.2 When consciousness is not completely lost during a seizure episode, it is categorized as a focal (partial) seizure.2  In addition, partial seizures may be associated with automatism (unconscious, repetitive movements), abnormal behavior, and amnesia where patients have no memory of their seizure episode.2 A focal seizure may also be described as simple or complex. In a simple partial seizure a patient does not lose consciousness and exhibits convulsions typically confined to a single limb.2 Complex partial seizures occur when a patient displays impaired consciousness with behavioral symptoms that correlate with the area of brain experiencing neuronal hyperexcitation.2 Partial seizures can progress to generalized seizures if untreated or uncontrolled. Refractory partial-onset seizures are severe and/or frequent partial seizures, with or without secondary generalization, that are not controlled with treatment.3,4

Most antiepileptic drugs (AEDs) produce their actions via 1 of the following mechanisms: antagonist activity on sodium or calcium channels, agonist activity on the GABA receptors, inhibition of GABA reuptake, or inhibitory effects in the glutamate pathway, though lack of data on the exact mechanism of AEDs contributes to the difficulty of treating patients.5 Clinically, partial seizures respond well to sodium channel blocking AEDs, however approximately one-third of patients do not respond to AED monotherapy.5 Data supporting the use of alternative agents for these cases is limited.4,5 Treatment selection is specific to the type and frequency of seizures.4 Success rate for using an alternative AED following failure with an initial AED is 16%.5  Eleven AEDs are currently approved by FDA approved for adjunct therapy of partial refractory seizures.6 The more commonly used AEDs include carbamazepine, lamotrigine, and levetiracetam.4

Perampanel was developed for the treatment of refractory partial-onset seizure with or without secondary generalized seizures. The European Commission approved perampanel in July 2012. The drug was launched on September 13, 2012.7 FDA accepted a resubmission of the new drug application in March 2012 and perampanel was approved by FDA on October 22, 2012. It is indicated for use as adjunctive therapy for partial-onset seizures (with or without secondary generalization) in patients aged 12 and older.7,8  Perampanel is currently unavailable, pending DEA scheduling classification approval as a controlled substance.8

Chemistry and pharmacology

Glutamate is a key neurotransmitter involved in rapid excitatory neurotransmission. Ionotropic glutamate receptors are subdivided into 3 types: NMDA, kainate, and AMPA receptors. AMPA glutamate receptors are located on the post-synaptic neuron, most highly concentrated in the brain, and mediate synaptic signaling.9 Increased glutamate levels are linked to the propagation of epilepsy and excessive activation of AMPA receptors is linked to neuronal damage.9 The involvement of this receptor in epilepsy and kindled seizures has been established.10

Perampanel is a highly selective, non-competitive AMPA receptor antagonist that blocks excessive excitatory neuronal signaling, preventing the opening of ion channels and ultimately reducing action potential propagation.9 It has a very high affinity for AMPA receptors, and low affinity for kainate and NMDA receptors, which is thought to minimize undesirable effects, including worsening seizure generation.9 The noncompetitive nature of perampanel has been shown to be an advantage over competitive antagonists by exhibiting improved anticonvulsant activity.9

Pharmacokinetics

Perampanel exhibits linear pharmacokinetics and reaches nearly 100% bioavailability following rapid absorption with no significant first-pass metabolism via oral administration over a dose range of 2 mg to 12 mg.11 Peak levels are achieved between 15 minutes and 3 hours, and the terminal half-life is about 70 hours.11,12 Steady state is established at 14 days.11 The volume of distribution is 77 L and 95% of perampanel is protein bound.12 Metabolism of perampanel is primarily through CYP3A4, with 70% excreted in feces and 30% in urine.12

Clinical trials

Phase 1

Two randomized, double-blind, placebo-controlled trials have evaluated the pharmacokinetics and safety of once-daily and multiple-daily dosing of various strengths of perampanel.13 Healthy men aged 18 to 45 years were eligible for enrollment. In the once-daily dosing trial, cohorts of 8 subjects received ascending, sequential single doses of placebo, 0.2 mg, 0.5 mg, 1 mg, 2 mg, 4 mg, 6 mg, or 8 mg of perampanel. In the multiple-daily dosing trial, subjects received 1 mg, 2 mg, 4 mg, or 6 mg of perampanel or placebo for 14 days. Maximal plasma concentration was achieved 1 hour after administration and average half-life was 52 to 129 hours in the once-daily dose trial and 66 to 90 hours in the multiple-daily dose trial. Steady state was reached within 14 days. With respect to safety, perampanel was well tolerated with the most common adverse events described as dizziness, fatigue and somnolence, which were mild to moderate in severity.13

Phase 2

Two randomized, double-blind studies, Study 206 and Study 208, evaluated the tolerability and safety of dose-escalation of perampanel in patients with refractory partial seizures.14 A summary of phase 2 and 3 clinical studies of perampanel are listed in Table 1 (page 21). Subjects were eligible for enrollment in either study if they were aged 18 to 70 years, weighed ≥40 kg, had a diagnosis of epilepsy with partial seizures with or without secondary generalization, and had seizures that were uncontrolled despite treatment with at least 3 different AEDs for any duration during the past 2 years.14 The primary end point for both studies was tolerability at the maximum dose for each study, and safety and efficacy were evaluated as secondary end points.14

Study 206

Study 206 investigated the safety and tolerability of perampanel titrated up to 4 mg daily as a once-daily versus twice-daily administration compared to placebo.14 Eligible subjects were stable on 1 or 2 AEDs for 2 months prior to enrollment, experienced an average of ≥4 partial seizures per month with or without secondary generalization, and were without 21 consecutive seizure-free days.14 Subjects who met the eligibility requirements were required to have ≥3 documented partial seizures during the 4-week baseline period in order to be included in randomization.14 Randomization was carried out in a 1:1:1 ratio between placebo, once-daily perampanel, and twice-daily perampanel, and was stratified based on concomitant use of CYP-inducing and non-CYP-inducing AEDs.14 The dose was initiated at 1 mg daily and titrated by 1 mg daily at intervals of 2 weeks until 4 mg daily was achieved, then maintained for 4 weeks.14 A 2-sided significance level of <.05 was used to determine 80% power and 20% difference between placebo and perampanel treatments.14

Of the 153 randomly assigned subjects, the mean age was 40.2 years with women constituting 56.9% of the sample size and evenly distributed across treatment groups.14 Concomitant use of 2 AEDs was 82.4% in the placebo group and 65.7% in the perampanel group, and of the AEDs used, 47.1% in placebo group and 44.6% in perampanel group were CYP-inducers (specific agents not described).14 Eighty-two percent of patients in all 3 groups tolerated the maximum dose of 4 mg per day.14 The 50% responder rate (defined as the percentage of subjects who experienced ≥50% reduction in seizure frequency during the maintenance phase compared to baseline) was 33% for once-daily dosing of perampanel and 28% for twice-daily dosing. The median reduction in seizure frequency was 25.7% in the perampanel groups and 19.5% in the placebo group (P=.43).14

Study 208

Study 208 examined the safety and tolerability of perampanel 12 mg daily. At the start of the trial, subjects were required to have been taking 1 to 3 AED during the 2 months prior to randomization, have experienced an average of ≥3 partial seizures per month with or without secondary generalization, and have had at least 1 seizure within 21 days of the last episode.14 Eligible subjects were randomly assigned (3:1) to perampanel 12 mg once daily or placebo, and stratified according to concomitant use of CYP-inducing AEDs.14 Perampanel was initiated at 2 mg daily, and titrated by 2 mg every 2 weeks to reach the maintenance dose of 12 mg daily. Subjects remained on the maintenance dose for 4 weeks.14 A Kaplan-Meier analysis was used to determine the number of patients who tolerated perampanel.14

Forty-eight subjects were randomly assigned, with 10 subjects in the placebo group and 38 in the perampanel group.14 The average age was 45.5 years in the placebo group and 40.7 years in the perampanel group, and 50% of subjects in each group were female. Fifty percent of AEDs used in the perampanel group were CYP inducers, compared with 30% in the placebo group.14 Based on the Kaplan-Meier analysis, the probabilities of tolerating 8 mg, 10 mg, and 12 mg perampanel were 0.55, 0.48, and 0.44, respectively, compared with 0.88 for placebo.14 The median percent change in seizure frequency was -39.6% in the perampanel-treated group and +2.1% in the placebo group. Fifty percent responder rates were 22.2% for perampanel and 39.5% for placebo.14

Study 207

Open-label Study 207 examined the long-term tolerability, safety, and efficacy of high-dose (12 mg daily) perampanel over 4 years in patients with refractory partial-onset seizures. Eligible subjects were required to have completed Study 206 or 208, been between aged 18 to 70 years, have a diagnosis of epilepsy with partial-onset seizures with or without secondary generalization, and be uncontrolled while taking 1 to 3 AEDs.15 Patients were all titrated up to 12 mg daily by increasing their last dose in the previous trial by 2 mg every 2 weeks during the titration period.15

In total, 138 subjects were enrolled into the study, 101 from Study 206, and 37 from Study 208, of which 80% had no prior exposure to perampanel.15 Subjects were an average age of 40.7 years (standard deviation=11.9), and were 58% male.15 Twenty-two percent of subjects were taking 1 AED, 68.1% were taking 2 AEDs, and 9.4% were taking 3 AEDs.15 The most common AEDs used were carbamazepine (34.8%), lamotrigine (34.1%), levetiracetam (24.6%), and valproic acid (23.2%).15  The median percent change in seizure frequency per 28 days over 1, 2, 3, or 4 years of perampanel exposure was -43.7%, -52.0%, -49.7%, and -48.4%, respectively, with an overall -39.4% change during the maintenance period.15 In addition, the 50% responder rate over 1, 2, 3, or 4 years was 43.8%, 51.5%, 49.0%, and 50.0%, respectively, and overall 45.8% during the maintenance period.15 Of the 131 subjects with complex partial seizures, 15 subjects (10.9% overall) reported ≥75% reduction in seizure frequency, with 4 of those subjects (2.9% overall) reporting 100% reduction.15

Phase 3

Study 306

The first completed phase 3 trial, Study 306, assessed the safety and efficacy of adjunctive perampanel 2 mg, 4 mg, and 8 mg daily in subjects with epilepsy with refractory partial-onset seizures who were uncontrolled on up to 3 concomitant AEDs. The multinational, randomized, double-blind study included male and female subjects over aged 12 years (18 years in other countries including Germany, Bulgaria, Portugal, Lithuania, India, and China) with uncontrolled refractory partial-onset seizures treated with at least 2 different AEDs in the previous 2 years.16  Immediately prior to randomization, eligible subjects were required to have experienced at least 5 partial seizures without a 25-day seizure-free interval over 6 weeks and have taken up to 3 different AEDs for 3 weeks.16 Subjects were randomly assigned (1:1:1:1) to placebo, 2 mg, 4 mg, or 8 mg perampanel daily.16 Perampanel was initiated at 2 mg daily, titrated up every 2 weeks by 2 mg daily, and maintained for 13 weeks at the assigned dose.16 Primary end points were 50% responder rate and median percent change in seizure frequency per 28 days over the entire duration of the study.16 A target sample size of 170 subjects per treatment arm was estimated to provide 90% power to detect a 21% change in seizure frequency compared to placebo at 2-sided significance level of 0.05.16

The average age of the 706 subjects who completed the study was 33 to 34 years. Approximately 50% of subjects in each treatment arm were female.16 The average percentage of subjects taking 1 concomitant AED was 14.7%, and 85.3% were taking either 2 or 3 AEDs. The median percent change in seizure frequency per 28 days for placebo and perampanel 2 mg, 4 mg, and 8 mg daily was -10.7%, -13.6%, -23.3%, and -30.8%, respectively, and 50% responder rates were 17.9%, 20.6%, 28.5%, and 34.9%, respectively.16 Patients in both the perampanel 4-mg and perampanel 8-mg groups demonstrated statistically significant decreases in seizure frequency (P=.0026, P<.0001, respectively) and improvements in 50% responder rate (P=.0132, P=.0003, respectively).16 There was no statistically significant difference between perampanel 2 mg daily and placebo (P=.420).16

Study 305

Study 305 was a multinational, randomized, double-blind trial investigating the safety and efficacy of perampanel 8 mg and 12 mg daily compared to placebo. Male and female subjects over aged 12 years were eligible to participate if they had a diagnosis of epilepsy of partial-onset seizures with or without secondary generalization, had experienced at least 5 partial seizures without 25 consecutive seizure-free days during the 6-week baseline period, failed at least 2 AEDs in the previous 2 years, and were currently using up to 3 AEDs at the start of the study, of which only one could be a CYP-inducer (such as carbamazepine, phenytoin, phenobarbital, or primidone).17 Excluded subjects included, but were not limited to, those who had: clinically significant of evidence of psychiatric or medical (ie, renal, hepatic, cardiac, respiratory) conditions, drug/alcohol abuse issues, or known suicide attempts in the previous 2 years, progressive central nervous system disease, status epilepticus or primary generalized seizures in the previous 12 months, or scheduled epilepsy surgery.17 Eligible subjects were randomly assigned (1:1:1) to placebo, perampanel 8 mg, or perampanel 12 mg.17 Dosing was initiated at 2 mg daily and titrated up by 2 mg daily at 2-week intervals until the desired dose was achieved and sustained during the 13-week maintenance period.17 The primary efficacy end points were incidence of patients with 50% responder rate and percent change in seizure frequency per 28 days.17 A sample size of 125 subjects per treatment arm was determined to have 90% power to detect a 16% difference in responder rate.17 Due to the multinational data, a Cochran-Mantel-Haenszel test was used to analyze responder rate data and both rank and log transformation-based analyses of covariance (ANCOVA) were calculated for 28-day seizure frequency data.17

Of the 386 randomized subjects, 321 completed the study, 88.2% from the placebo group, 83.7% from the 8-mg perampanel group, and 76.9% from the 12-mg perampanel group.17 The mean age of subjects in the placebo, 8-mg perampanel and 12-mg perampanel groups was  34.4, 36.7, and 35.5 years, respectively, and 47.8%, 49.6%, and 58.7%, respectively, were female.17 Most subjects in each group took 2 AEDs concomitantly (mean 50.5%), followed by 3 AEDs (mean 38.6%) and the fewest were taking only 1 AED (mean 10.9%).17 A 50% responder rate was achieved in 14.7% in the placebo group, compared with 33.3% for 8-mg perampanel-treated patients (P=.002) and 33.9% for 12-mg perampanel-treated patients (P<.001).17 Median percent change in seizure frequency per 28 days over the entire duration of the study was -30.5% for 8 mg perampanel (P<.001 based on rank ANCOVA test, P=.001 based on log transformation ANCOVA test) and -17.6% for 12 mg perampanel (P=.011 based on rank ANCOVA test, P=.025 based on log transformation ANCOVA test) compared to -9.7% for placebo.17 Median difference in percent change was -19.1% for 8 mg perampanel (95% CI, -29.2, -8.4) and -13.7% for 12 mg perampanel (95% CI, -25.2, -2.3) compared to placebo. Fifteen-and-a-half percent and 16.5% of subjects receiving 8 mg and 12 mg perampanel, respectively, experienced >75% seizure reduction, of which 2.3% and 5%, respectively, were seizure-free.17

Study 304

Study 304 was identical in study design and protocol to Study 305, except that it was conducted in different geographical locations, including Argentina, Canada, Chile, and Mexico.18 Three hundred eighty-eight subjects were randomly assigned (1:1:1) to placebo, perampanel 8 mg, or perampanel 12 mg.18 Mean age was 35.6, 35.8, and 36.7 years for placebo, 8 mg and 12 mg perampanel, and 55.4%, 51.1%, and 48.5%, respectively, were female.18 Median percent change in seizure frequency per 28 days over the entire duration of the study was -21.0% for placebo and -25.3% (P=.0261) for perampanel 8 mg and -34.5% (P=.0158) for perampanel 12 mg.18 Responder rates were 37.6% (P=.0760) for perampanel 8 mg and 36.1% (P=.0914) for perampanel 12 mg compared to -17.9% for placebo.18

Study 307

Extension Study 307 examined the long-term safety and tolerability of high-dose perampanel as adjunctive therapy in patients with refractory partial-onset seizures who completed Study 304, 305, or 306. Within 14 days of completion of the double-blind study, subjects began at the last dose received and titrated by 2 mg every 2 weeks up to 12 mg. An open-label maintenance period was planned for 256 weeks.19

Of the 1,264 subjects who completed 1 of the 3 phase 3 trials, 1,218 (96.4%) continued to the extension study and 1,186 completed Study 307.19 The mean age of subjects was 34.3 years and 49.2% were female. In addition to the study medication, subjects used 1 AED (13.4%), 2 AEDs (50.3%) or 3 AEDs (36.3%), with most subjects using carbamazepine (33.7%), valproic acid (33.6%), lamotrigine (31.5%), and/or levetiracetam (29.0%).19 Seizure frequency continued to decrease over the first 26 weeks, then plateaued for the remainder of the extension study.  The median seizure frequency per 28 days was 11.2.19 The median percent change in seizure frequency per 28 days over the entire duration of the study was -47.2% in patients who received treatment for >1 year, and -56.0% in those who received treatment for >2 years.19 The 50% responder rate after 1 year of treatment was 47.6%, and 63.2% after 2 years.19 Seven percent of subjects reported a 1-year seizure-free period after 12 months.19

Adverse events

Most common adverse events were consistent between phase 2 and phase 3 studies.14–19 Data suggest that dizziness may be dose-dependent with rates in placebo-treated patients ranging from 7.4% to 15.7% and rates in perampanel-treated patients as follows: 2 mg: 9.8% to 10%, 4 mg: 16.3% to 17.6%, 8 mg: 26.6% to 37.6%, 12 mg: 38.1% to 47.9%. At clinically effective doses ranging from 4 mg to 12 mg daily, commonly occurring adverse events included (described with rates of occurrence for all doses, with higher rates generally corresponding to higher doses of perampanel) headache (8.5%–21%), somnolence (5.9%–21.4%), and fatigue (5.3%–16.5%). Other adverse events that were exhibited in more than 1 study were contusions, nasopharyngitis, nausea, and gait disturbances (Table 1, page 21). The majority of adverse events were mild and moderate in nature. Dizziness, convulsions, vertigo, irritability, and aggression were common adverse events responsible for discontinuation from studies.14-19 At a dose of perampanel 12 mg daily, increase in anger, confusion, and depression were observed.20 These effects may be observed with concomitant use of alcohol and central nervous system depressants.20 FDA-approved product labeling includes a boxed warning about the risk for serious psychiatric events and requirements specify that perampanel must be dispensed with a medication guide for patients.8

Drug interactions

Perampanel is a substrate for CYP3A4, and therefore it is expected that concomitant use of CYP3A4 inducing agents would reduce perampanel concentrations by increasing its metabolism.20 Studies demonstrated that when perampanel 4 mg, 8 mg, or 12 mg was given concomitantly with CYP3A4 inducing AEDs, 50% response rates were 23.0%, 31.5%, and 30.0%, respectively, compared to 33.3%, 46.5%, and 50.0% when given with non-CYP3A4 inducing AEDs.20,21 Data indicate that strong CYP3A4 inducers, including phenytoin and oxcarbazepine, reduce perampanel concentrations by 50%, and that carbamazepine may reduce concentrations by as much as 66%.20 Perampanel decreased concentrations of other AEDs, including phenobarbital, phenytoin, topiramate, and valproic acid, yet none were clinically relevant.20 Concomitant use of perampanel and oxcarbazepine resulted in a 26% reduction in oxcarbazepine levels, however the mechanism of this effect is unknown.20 Insufficient data are available to establish whether reduced serum albumin concentration or concomitant use of phenytoin influences the pharmacokinetics (notably protein-binding) and effectiveness of perampanel.22

It is recommended by the European Medicines Agency to monitor the addition or withdrawal of CYP450 inducers and inhibitors with concomitant use of perampanel as these agents may decrease or increase perampanel levels.20 A pooled analysis of phase 3 study data demonstrated that seizure frequency decreased in a linear fashion with increasing perampanel exposure, regardless of concomitant AEDs or subjects’ demographic factors.21 The manufacturer cautions that perampanel 12 mg daily may reduce the effectiveness of oral contraceptives and advises that women of childbearing age should consider alternative, reliable methods to prevent pregnancy.20,22

Dosing and administration

Guidance from the European Medicines Agency recommends that perampanel be initiated at 2 mg by mouth daily before bedtime, and titrated by increments of 2 mg until the desired dose is achieved.20 Doses of 4 mg to 8 mg daily have been shown to be effective and well tolerated for the treatment of partial seizures, but doses may be increased to 12 mg daily, if appropriate for clinical response and tolerability.20 Perampanel should be titrated up by 2 mg at 2-week intervals, unless the patient is taking concomitant medications that shorten the half-life of perampanel. In that case, titration should occur at 1-week intervals.20

Patients with mild-to-moderate hepatic impairment should titrate the dose up by 2 mg at 2-week intervals, but should not exceed 8 mg daily.20 Considering that perampanel is metabolized by CYP3A4, perampanel is not recommended for use in patients with severe hepatic impairment due to the risk of insufficient metabolism and increased drug levels.22

A clinical study has not been conducted to establish the effect of renal impairment on perampanel. Phase 3 studies did not demonstrate that mild renal impairment had a significant effect on perampanel, and therefore dose adjustment is not recommended for patients with mild renal impairment.22  Data is not available on the use of perampanel in patients with moderate to severe renal impairment or in those receiving hemodialysis; these populations were excluded from studies.22

Data are insufficient to determine whether elderly patients respond differently to perampanel than younger patients do. A nonepilepsy study that included 905 elderly perampanel users did not report differences in safety profiles due to advanced age, and currently dose adjustments are not recommended.20 However, considerations such as assessment of concomitant medications and comorbid disease states should be undertaken before initiating perampanel.20

Uncontrolled epilepsy has severe clinical, functional and social consequences for patients, and those refractory to conventional treatment often have few options when multidrug regimens fail. Perampanel appears to be an effective and well-tolerated adjunctive AED for the treatment of refractory partial-onset seizures. The drug’s novel mechanism of action on the AMPA receptor suggests a new pathway for providing relief to patients who search for improvement in their seizure control and quality of life.

Formulary Considerations

Perampanel is the first AED that targets AMPA receptors to control seizure generation and has been FDA-approved for use as an adjunctive treatment in patients with refractory partial-onset seizure with or without secondary generalized seizures. It will be available for use in the United States after it has been classified by the DEA as a scheduled drug according to the Controlled Substances Act. Clinical reductions in seizure incidence, including patients reporting at least a 50% reduction (defined as responders), have been reported when perampanel 2 mg to 12 mg by mouth daily has been added to other AEDs such as carbamazepine, phenytoin, valproic acid, lamotrigine, and levetiracetam. Use of perampanel in some patient populations has not been adequately studied, including patients with clinically significant cardiac, respiratory, gastrointestinal, renal, hepatic, or hematologic disease. It is unclear how the severity of these excluded conditions was defined, and the absence of a clear definition may hinder the ability to extrapolate the effects of perampanel to a potentially large number of patients. Long-term efficacy and safety also require further evaluation as efficacy and safety beyond 4 weeks was not assessed in most trials to date.

Perampanel appears to be well tolerated, with the most common adverse effects including dizziness, headache, somnolence, and fatigue. Serious neuropsychiatric adverse events have been reported with perampanel and the drug must be dispensed with a medication guide for patients. Both efficacy and tolerability appear to be dose related. The pharmacokinetics of perampanel allow for once-daily administration, but it is 95% protein bound, which may increase the likelihood of toxicity in patients with decreased albumin. Also, because the drug is metabolized primarily through CYP450 3A4, clinicians must monitor for signs and symptoms of treatment failure with 3A4 inducing agents, and toxicity with 3A4 inhibitors, as the clinical significance of drug interactions is currently unclear.21 Perampanel  represents a new option in the treatment of patients with refractory partial-onset seizures and adds a unique mechanism to complement current options for the treatment of patients with epilepsy.

REFERENCES

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13. Templeton D. Pharmacokinetics of perampanel, a highly selective AMPA-type glutamate receptor antagonist [abstract]. Epilepsia. 2009;50(suppl. 11):98-99.

14. 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.

15. Rektor I, Krauss GL, Bar M, et al. Perampanel study 207: long-term open-label evaluation in patients with epilepsy. Acta Neurol Scand. 2012;126:263–269.

16. Krauss GL, Serratosa JM, Villanueva V, et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology. 2012;78:1408–1415.

17. 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. 2012;1–9.

18. French JA, Krauss GL, Biton V, et al. Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304. Neurology. 2012;79:589–596.

19. Krauss GL, Perucca E, Ben-Menachem E, et al. Perampanel, a selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, as adjunctive therapy for refractory partial-onset seizures: interim results from phase III, extension study 307. Epilepsia. 2012:1–9.

20. Fycompa [summary of product characteristics]. European Medicines Agency. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002434/WC500130815.pdf. Accessed August 30, 2012.

21. Hussein Z, Ferry J, Krauss G, et al. Demographic factors and concomitant antiepileptic drugs have no effect on the pharmacodynamics of perampanel [abstract]. Neurology. 2012;78:6.127.

22. Fycompa, assessment report. European Medicines Agency. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002434/WC500130839.pdf. Accessed September 16, 2012.