Drugs Ther Perspect (2013) 29:189–193 DOI 10.1007/s40267-013-0050-z

ADIS DRUG CLINICAL Q&A

Perampanel: a guide to its use in partial-onset seizures Lesley J. Scott • Katherine A. Lyseng-Williamson Greg L. Plosker

•

Published online: 5 June 2013  Springer International Publishing Switzerland 2013

Abstract Perampanel (Fycompa), a novel selective, noncompetitive antagonist of a-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid-type glutamate receptors on post-synaptic neurons, is indicated as adjunctive therapy for patients aged C12 years with partial-onset seizures with or without secondarily generalized seizures. In this patient population, adjunctive once-daily perampanel is more effective than adjunctive placebo in reducing seizure frequency and is generally well-tolerated.

Adis evaluation of perampanel in patients with partial-onset seizures What are its key clinical benefits? Novel (first-in-class) antiepileptic drug Effective in reducing seizure frequency Benefits sustained with long-term treatment Generally well-tolerated What are its key clinical limitations? Potential to cause aggression Not recommended in patients with moderate to severe renal impairment or severe hepatic impairment

L. J. Scott (&)
K. A. Lyseng-Williamson
G. L. Plosker Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, 0754 Auckland, New Zealand e-mail: [email protected]

What is the rationale for developing the drug? Epilepsy is the most common of all neurological conditions and affects more than 50 million people worldwide, or about 1 % of the population [1, 2]. Partial seizures, also known as focal seizures because they originate in only part of the brain, are more common than generalized seizures, especially in adult-onset epilepsy [1, 2]. In industrialized countries, partial seizures occur in &60 % of individuals with epilepsy [1]. They can be categorized as either simple partial seizures, which are not associated with loss of consciousness, or complex partial seizures, which result in altered or loss of consciousness [3, 4]. In some cases, partial-onset seizures can become secondarily generalized, such that epileptic activity spreads to both hemispheres of the brain, resulting in loss of consciousness and often tonicclonic seizures [4]. A wide range of antiepileptic drugs (AEDs) is available to control seizures in patients with epilepsy, although about one-quarter to one-third of patients will continue to have seizures despite receiving adequate trials of AEDs alone or in combination [5]. Moreover, epilepsy in general and refractory epilepsy in particular, is associated with increased mortality and morbidity, as well as reduced health-related quality of life. The need for AEDs with improved efficacy and favourable tolerability profiles has led to the development of a number of new AEDs in recent years, many of which are used as adjunctive treatment of partial-onset seizures [5]. One such agent is perampanel (Fycompa).

How does the drug work? Perampanel is a selective, noncompetitive antagonist of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

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(AMPA)-type glutamate receptors. It is the first agent in this new class of AEDs [6]. AMPA receptors are ligandgated ion channels activated by glutamate, the major excitatory neurotransmitter in the CNS, which is thought to have an important role in inducing seizures [5]. However, the precise mechanism by which perampanel exerts its antiepileptic effects is not yet fully known [6, 7].

For whom is the drug indicated? Oral perampanel is indicated as adjunctive treatment for partial-onset seizures with or without secondarily generalized seizures in patients aged C12 years with epilepsy [6, 7]. Table 1 provides a summary of the EU prescribing information [6] for the use of perampanel in this indication.

What is its clinical efficacy in short-term trials … In double-blind, phase III trials, patients (aged C12 years) with simple or complex partial-onset seizures, with or without secondary generalization, were randomized to receive adjunctive once-daily perampanel or placebo for 19 weeks, which included a 6-week titration period and a 13-week maintenance period [8–10]. All patients also received one to three AEDs. During the titration phase of the trials, perampanel dosage was increased from 2 mg/day (by increments of 2 mg/day at weekly intervals) up to the target dosage. Adjunctive therapy with perampanel 4–12 mg/day was superior to that with adjunctive placebo in terms of the 50 % responder rate for all partial-onset seizures (defined as the proportion of patients who experienced at least a 50 % reduction in seizure frequency) during the 13-week double-blind maintenance period and/or in reducing the frequency of partial-onset seizures during the 19-week double-blind period across the three studies (Table 2) [8– 10]. In study 305 [9], perampanel 8 and 12 mg/day were statistically superior to placebo for both of these endpoints, as were perampanel 4 and 8 mg/day in study 306 (Table 2) [10]. In Study 304 [8], perampanel 8 and 12 mg/day were associated with significantly greater median percentage reductions in partial-onset seizure frequency than placebo, but there were no statistically significant between-group differences for the 50 % responder rates for all partial seizures (Table 2). A subanalysis of 50 % responder rates for partial-onset seizures in study 304 showed regional differences in the efficacy of perampanel [8]. The 50 % responder rate was significantly (p \ 0.05) greater with perampanel 8 and 12 mg/day than with placebo in the North American cohort (n = 227) [40.5 and 40.0 vs.

21.9 %), but not in the Central and South American cohort (n = 160) [33.9 and 30.2 vs. 33.3 %]. In a pooled analysis of studies 304, 305 and 306 (n = 1,478) [11], 50 % responder rates for partial-onset seizures over the 13-week double-blind maintenance period were significantly (p \ 0.05) greater with perampanel 4, 8 and 12 mg/day than with placebo (28.5, 35.3 and 35.0 vs. 19.3 %, respectively), as were 75 % responder rates for partial-onset seizures (12.2, 17.4 and 16.9 vs. 6.1 %). The median percentage changes from baseline in partial-onset seizure frequency over the 19-week double-blind period were also significantly (p \ 0.01) greater with perampanel 4, 8 and 12 mg/day than with placebo (-23.3, -28.8 and -27.2 vs. -12.8 %, respectively) [11]. An important secondary endpoint in all three trials was the median percentage change in the frequency of complex partial plus secondarily generalized seizures (present in &65–75 % of patients at baseline) [8–10]. In the pooled analysis [11], 50 % responder rates for complex partial plus secondarily generalized seizures were significantly (p \ 0.01) greater with perampanel 4, 8 and 12 mg/day than with placebo (36.3, 39.4 and 38.2 vs. 23.2 %, respectively). Median percentage changes from baseline in the frequency of these seizures per 28 days were significantly (p \ 0.001) greater with perampanel 4, 8 and 12 mg/day than with placebo (-31.2, -35.6 and -28.6 vs. -13.9 %). Perampanel was also associated with reductions in the frequency of secondarily generalized seizures in the pooled analysis [11]. Significantly (p \ 0.01) greater 50 % responder rates for secondarily generalized seizures were shown with perampanel 8 and 12 mg/day than with placebo (60.5 and 53.7 vs. 37.0 %), and median percentage changes from baseline in their frequency were significantly (p \ 0.01) greater with perampanel 4, 8 and 12 mg/day than with placebo (-48.6, -62.9 and -53.3 vs. -19.4 %) [11]. …and an extension study? Patients completing the phase III trials [8–10] could enter an open-label extension study [12]. This study included an initial 16-week blinded conversion period during which patients who had received placebo or perampanel \12 mg/ day in the phase III trials had their perampanel dosage titrated upwards in increments of 2 mg/day every 2 weeks to the maximum tolerated dosage (up to 12 mg/day). Patients who had been receiving 12 mg/day in the phase III trials were maintained on this dosage. The on-going extension study includes a planned 256-week open-label maintenance period and a 4-week follow-up phase. At a specified cut-off date for interim analysis, efficacy data were available for 1,207 patients in the intent-to-treat analysis set, which included 1006, 588 and 19 patients who received perampanel for C26 weeks, C1 year and

191 Table 1 Prescribing summary of oral perampanel (Fycompa) in patients aged C12 years with epilepsy in the EU [6]. Consult local prescribing information for further details What is its approved indication? Adjunctive treatment of partial-onset seizures with or without secondarily generalized seizures in pts aged C12 years with epilepsy What is its administration regimen? Dosage

4–12 mg once daily before bedtime

Titration

Initial dosage: 2 mg/day Dosage titration: increase by increments of 2 mg based on clinical response and tolerability to a maintenance dosage of 4–8 mg/day; depending on the efficacy and tolerability of 8 mg/day, the dosage may be increased by increments of 2 mg to 12 mg/day Interval between incremental increases: no more frequently than every 2 weeks in pts taking concomitant drugs that do not shorten the half-life of perampanel, and no more frequently than every 1 week in pts taking concomitant drugs (e.g. carbamazepine, oxcarbazepine, phenytoin) that shorten the half-life of perampanel

Discontinuation

Discontinue treatment gradually to reduce the risk of rebound seizures If absolutely needed, treatment may be abruptly discontinued, as perampanel has a long half-life

How is it available? Film-coated tablets containing 2, 4, 6, 8, 10 or 12 mg perampanel What is its pharmacokinetic profile? Absorption

Readily absorbed (food delays the rate, but not the extent, of absorption)

Metabolism

Extensively metabolized by CYP3A (and possibly other pathways) with subsequent glucuronidation

Elimination

Primarily as metabolites in the urine (30 %) and faeces (70 %) Half-life &105 h (reduced to &25 h with concurrent carbamazepine)

How should it be used in special populations? Pts aged C65 years

No dosage adjustment required Use with caution, taking into account the drug interaction potential in pts receiving polypharmacy

Pts with renal impairment

Mild impairment: no dosage adjustment required Moderate to severe impairment or pts undergoing haemodialysis: use is not recommended

Pts with hepatic impairment

Mild to moderate impairment, initiate dosage titration at 2 mg/day and titrate at 2-week intervals, based on efficacy and tolerability, to a maximum dosage of 8 mg/day

Female pts

Women of childbearing potential not using contraception: use is not recommended unless clearly necessary

Severe impairment: use is not recommended Pregnant women: use is not recommended Breast-feeding women: discontinue breast feeding or discontinue/abstain from perampanel based on the benefits of breast feeding for the child and perampanel for the woman Pts with a history of substance abuse

Use with caution Monitor pts for symptoms of perampanel abuse

What are other special warnings and precautions concerning its use? Suicidal ideation

Suicidal ideation and behaviour have been reported with AEDs and the available data do not exclude the possibility of an increased risk for perampanel Monitor pts for signs of suicidal ideation and behaviour and consider appropriate treatment Advise pts and their caregivers to seek medical advice if signs of suicidal ideation or behaviour emerge

Ability to drive and use machines

The ability to drive or use machines may be influenced by perampanel-induced dizziness and somnolence

Falls

The risk of falls, particularly in the elderly, appears to be increased (underlying reason is unclear)

Aggression

Cases of aggression have occurred during perampanel treatment and are related to dose

Advise pts not to drive a vehicle, operate complex machinery or engage in other potentially hazardous activities until it is known whether perampanel affects their ability to perform these tasks

Consider dosage reduction in cases of persistence of aggressive symptoms What are its potential clinically relevant drug interactions? Progestogen-containing oral contraceptives

Perampanel 12 mg/day may reduce the efficacy of progestogen-containing oral contraceptives

Concomitant CYP3A-inducing AEDs

Response rates to perampanel may be reduced in pts receiving concomitant CYP3A-inducing AEDs (e.g. carbamazepine, oxcarbazepine, phenytoin)

Advise women receiving perampanel 12 mg/day to use an additional non-hormonal contraception method

Monitor pt response and adjust dosage accordingly when switching from concomitant CYP3A-inducing AEDs to concomitant non-inducer AEDs, and vice versa Other CYP-inducing or inhibiting drugs

Concomitant use of these agents may decrease or increase perampanel plasma concentrations Monitor pts closely when adding or removing CYP inducers or inhibitors, and adjust perampanel dosage accordingly

AEDs anti-epileptic drugs, CYP cytochrome P450, pt(s) patient(s)

192 Table 2 Main findings in the intent-to-treat populations of key phase III trials with oral perampanel as adjunctive therapy in patients (aged C12 years) with partial-onset seizures

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Median baseline seizure frequency per 28 days 14.3

50 % responder ratea over the 13-week double-blind maintenance period 37.6

Perampanel 12

133

12.0

36.1

-34.5*

Placebo

121

13.7

26.4

-21.0

Trial

Regimen (mg/day)

No. of patients

Study 304 [8]

Perampanel 8

Study 305 [9]

Study 306 [10]

Perampanel 8

129

13.0

33.3**

-30.5***

Perampanel 12

121

13.7

33.9***

-17.6*

Placebo

136

11.8

14.7

Perampanel 2

180

10.1

20.6

-13.6

Perampanel 4

172

10.0

28.5*

-23.3**

Perampanel 8

169

10.9

34.9***

-30.8***

17.9

-10.7

Placebo 184 * p \ 0.05, ** p \ 0.01, *** p \ 0.001 vs. placebo a

Median % change from baseline in seizure frequency over the 19-week double-blind period -26.3*

9.3

-9.7

Percentage of patients who experienced at least a 50 % reduction in partial-onset seizure frequency

C2 years, respectively. The majority of patients ([90 %) received perampanel at dosages of 10 or 12 mg/day [12]. Compared with the pre-perampanel baseline period of the phase III trials, seizure frequency per 28 days was reduced by a median of &42 % at the end of the 16-week blinded conversion period; there was no apparent difference between patients initially randomized to placebo (-42.4 %, n = 369) and those initially randomized to perampanel (-41.5 %, n = 817) [12]. The group response for reduction in seizure frequency was similar during the open-label maintenance period. For example, among the 588 patients with at least 1 year of perampanel exposure, the median reduction in seizure frequency per 28 days during the last 13 weeks of exposure compared with the pre-perampanel baseline period was 47.2 %. The corresponding value for the small number of patients with at least 2 years’ exposure was 56.0 %. Similar results were reported for the 50 % responder rates [12]. At the end of the blinded conversion period, the proportions of patients with a C50 % reduction in seizure frequency compared with baseline were 44.2 and 43.3 % for those initially randomized to placebo and perampanel, respectively. Group responses for 50 % responder rates were also similar during the open-label maintenance period. However, the extension study did not examine loss of initial efficacy (i.e. development of tolerance) and patients were allowed to change their concomitant medication to maintain efficacy [12].

What is its tolerability profile? According to the EU summary of product characteristics [6], dizziness and somnolence are the most frequently reported adverse events with oral perampanel (incidence C10 %), as well as the most common adverse events leading to

discontinuation of perampanel (C1 % of patients). Pooled data from the phase III clinical trials with perampanel in patients with refractory partial-onset seizures indicate that 1.7, 4.2 and 13.7 % of patients randomized to perampanel 4, 8 and 12 mg/day, respectively, discontinued treatment because of an adverse drug reaction [6]. Adverse events reported were largely mild or moderate in severity [8–10]. Based on interim results from the long-term extension study (n = 1186) [6], dizziness, somnolence, headache and fatigue were the most frequently reported treatmentemergent adverse events (Fig. 1). In general, the longer-

Fig. 1 Tolerability of oral perampanel in an open-label extension of phase III trials (as reported by Krauss et al. [12]). Treatment-emergent adverse events occurring in at least 5 % of patients in the safety analysis set of 1186 individuals with refractory partial-onset seizures who completed the phase III trials and received oral perampanel for up to &2 years (median 51.4 weeks). Most patients received perampanel 10 or 12 mg/day (in addition to concurrent antiepileptic drugs). URTI upper respiratory tract infection

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term tolerability profile of perampanel as adjunctive therapy was similar to that reported in the shorter-term phase III clinical trials. Almost half of the patients (48.9 %) received perampanel for [52 weeks and 21.1 % were exposed to perampanel for [76 weeks. The median duration of exposure to perampanel was 51.4 weeks and most patients (91.4 %) received perampanel 10 or 12 mg/day [12]. In the individual phase III trials [8–10], there were no clinically important mean changes in laboratory values or ECG findings. In particular, perampanel up to 12 mg/day did not prolong the corrected QT interval and did not affect QRS duration [6]. There are several warnings and precautions regarding the use of perampanel and the risk for certain adverse events (e.g. suicidal ideation, aggression, falls and dizziness and somnolence; Table 1) [6, 7]. In phase III trials, suicidal ideation was reported in two patients receiving perampanel (one randomized to 8 mg/day [8] and one randomized to 2 mg/day [10]) and two patients receiving placebo [8, 9]. Interim results of the extension study reported six cases of suicidal ideation with perampanel (\1 %), including four patients who required hospitalization [12].

What is its current positioning? Perampanel is a useful option for the adjunctive treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy aged 12 years and older. It has a novel mechanism of action, as it is the first in a new class of AEDs known as AMPA receptor antagonists. In clinical trials in patients with refractory partial-onset seizures, once-daily perampanel, as adjunctive therapy with one to three AEDs, was superior to adjunctive placebo in reducing seizure frequency and was well-tolerated. The efficacy and tolerability profiles of perampanel were maintained with long-term treatment in an extension study. Acknowledgement The manuscript was reviewed by: A. Husain, Duke University Medical Center, Medicine (Neurology), Durham, NC, USA.

Disclosure This article was updated from CNS Drugs 2012;26(12):1085–96 [5]. The preparation of these reviews was not supported by any external funding. During the review process, the manufacturer of the agent under review was offered an opportunity to comment on the articles. Changes resulting from comments received were made by the authors on the basis of scientific and editorial merit.

References 1. Neligan A, Hauser WA, Sander JW. The epidemiology of the epilepsies. Handb Clin Neurol. 2012;107(3rd series):113–33. 2. Figueroa Garcia A. Partial epilepsies. 2012. http://emedicine. medscape.com/article/1186635-overview. Accessed 27 Feb 2013. 3. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia. 2010;51(4):676–85. 4. The National Society for Epilepsy. Epilepsy: an introduction to epileptic seizures. 2012. http://www.epilepsysociety.org.uk/ AboutEpilepsy/Whatisepilepsy/Seizures. Accessed 27 Feb 2013. 5. Plosker GL. Perampanel as adjunctive therapy in patients with partial-onset seizures. CNS Drugs. 2012;26(12):1085–96. 6. Fycompa (perampanel) film-coated tablet: summary of product characteristics. London: European Medicines Agency; 2012. 7. Fycompa (perampanel) tablets: US prescribing information. Woodcliff Lake (NJ): Eisai Inc.; 2012. 8. French JA, Krauss GL, Biton V, et al. Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304. Neurology. 2012;79(6):589–96. 9. 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(1):117–25. 10. Krauss GL, Serratosa JM, Villanueva V, et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology. 2012;78(18):1408–15. 11. Steinhoff BJ, Ben-Menachem E, Ryvlin P, et al. Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: a pooled analysis of three phase III studies. Epilepsia. Epub 2013 May 10. 12. Krauss GL, Perucca E, Ben-Menachem E, et al. Perampanel, a selective, noncompetitive a-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. 2013;54(1):126–34.