Perampanel …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 10.07.2021
Released 06.26.2013
Expires For CME 10.07.2024

Perampanel

Author: K K Jain MD†

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Perampanel

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Introduction

Historical note and terminology

Perampanel, an aminomethyl propionic acid (AMPA) receptor antagonist, has been studied for various clinical indications, including epilepsy and Parkinson disease. The drug is currently approved in the United States and the European Union as adjunct treatment for control of partial-onset seizures in those who are 12 years of age and older. Perampanel has the potential for addiction. The Drug Enforcement Administration has placed perampanel into schedule III drug (ie, persons who handle this drug are subject to regulatory controls and administrative, civil, and criminal sanctions applicable to schedule III controlled substances).

Pharmacology

Perampanel has a 2,4-diphenyl-4H-[1,3,4]oxadiazin-5-one core structure, distinguishing it chemically from other AMPA receptor antagonist classes.

Perampanel (chemical structure)

(Contributed by Dr. K K Jain.)

Pharmacodynamics. Perampanel is a highly selective, noncompetitive, AMPA receptor antagonist that reduces neuronal hyperexcitation associated with seizures by targeting glutamate activity at postsynaptic AMPA receptors, which are the major subtype of ionotropic glutamate receptors. It has no significant affinity for NMDA or kainate receptors. Results of studies in animal models suggest that perampanel is an orally active, noncompetitive, selective AMPA receptor antagonist with potential as a broad spectrum antiepileptic agent (07). Concentrations of perampanel required to reduce AMPA receptor-mediated responses are like those in plasma following anticonvulsant doses and are consistent, with AMPA receptor antagonism being its primary mode of action (02).

Pharmacokinetics. Important features of the pharmacokinetics of perampanel are:

	• Perampanel has high oral bioavailability. It is rapidly absorbed after ingestion, and kinetics are proportional to the dose.
	• Peak plasma level is reached in 0.5 to 2.5 hours.
	• It undergoes oxidative metabolism in the liver via CYP3A4, followed by glucuronidation.
	• The terminal half-life of perampanel in humans is 105 hours, but it may be reduced in the presence of a strong CYP3A4 inducer, such as carbamazepine (17). The calculated effective half-life is 48 hours, which enables once-daily dosing to improve patient compliance and in the event of a missed dose, will have minimal impact on seizure control (12).
	• Protein binding is 95% to 96%, with mainly albumin and alfa1-acid glycoprotein.
	• Approximately half of the dose is excreted in the feces.
	• Renal clearance is 12 mL/min, and about 20% is excreted into the urine.

Therapeutic drug monitoring. Individual reference ranges of perampanel vary widely with no reliable therapeutic range for plasma concentrations, but therapeutic drug monitoring may still be useful in some clinical situations (22).

Clinical trials

Phase I and II clinical trials showed that perampanel had a favorable safety and tolerability profile and provided proof of concept for its mechanism of action in patients with treatment-resistant partial-onset seizures. Median reductions in seizure frequency in phase 3 trials were 23.3% (4 mg), 26.3% to 30.8% (8 mg), and 17.6% to 34.5% (12 mg) versus 9.7% to 21.0% for placebo, whereas responder rates were 28.5% (4 mg), 33.3% to 37.6% (8 mg), and 33.9% to 36.1% (12 mg) versus 14.7% to 26.4% for placebo (14).

Two long-term safety extension studies have a secondary objective of evaluating the maintenance of efficacy of adjunctive perampanel in the treatment of refractory partial-onset seizures (15; 10). Overall, these clinical trials have demonstrated that adjunctive perampanel 4, 8, or 12 mg/day, can significantly improve responder rates in patients with refractory partial-onset seizures. In extension studies of these trials, no new safety signals emerged during up to 3 years of perampanel exposure, with marked reductions, particularly in secondary generalized seizures (11). These studies also demonstrate how careful dose titration can be used to optimize treatment for individual patients. Extension of phase III studies has shown that increasing perampanel dose from 8 to 12 mg can produce additional benefits in seizure control in some patients who tolerate the higher dose (09). A multicenter, double-blind study provides Class I evidence that adjunctive perampanel reduces primary generalized tonic-clonic seizure frequency, compared with placebo, in patients with drug-resistant primary generalized tonic-clonic seizures in idiopathic generalized epilepsy (05). In a multicenter, retrospective, 1-year observational study on patients with idiopathic generalized epilepsy, perampanel improved seizure outcomes for generalized tonic-clonic seizures, myoclonic seizures, and absence seizures, with few discontinuations due to adverse events (26). A multicenter, retrospective, 1-year observational study showed that perampanel had a good efficacy and safety profile when used as a first add-on therapy in patients who did not respond to monotherapy, and dose adjustments may optimize seizure control when combined with strong enzyme-inducing or enzyme-inhibiting antiepileptic drugs (20).

Post hoc analysis of four randomized, double-blind, placebo-controlled, phase 3 studies of adjunctive perampanel in patients aged 12 years or older with focal seizures, with and without focal to bilateral tonic-clonic seizures, showed that 4 mg/d dose was effective and well-tolerated and that this dose may be a valuable treatment option in patients unable to tolerate higher perampanel doses up to 12 mg/d (23).

Special considerations

Perampanel’s label has a boxed warning to alert prescribers and patients about the risk of serious neuropsychiatric events. Some of these events were reported as life-threatening. Violent thoughts or threatening behavior (including homicidal ideation) was observed in a few patients. Health care professionals should closely monitor patients during the titration period when higher doses are used.

Dose adjustment is not required in mild renal impairment. Perampanel is not recommended for use in patients with moderate or severe renal impairment and those on hemodialysis.

Pediatric. No data are available on the safety and efficacy of perampanel in children below the age of 12 years. Perampanel is associated with a relatively high incidence of behavioral adverse events, mostly in adolescents with refractory epilepsy, which is the reason for the high discontinuation rate (08). Data gathered via an online questionnaire sent to pediatric neurologists in the UK indicate that perampanel was fairly effective in children and adolescents with refractory epilepsy, but the rate of adverse events leading to discontinuation was considerable (24).

Geriatric. There were not enough subjects 65 years of age or older in clinical trials, but those who were studied did not show any differences in safety profile from younger subjects. Caution should be exercised in using perampanel in elderly patients on polypharmacy.

Pregnancy. Perampanel is designated Pregnancy Category C. Administration of perampanel to pregnant rats throughout organogenesis resulted in an increase in visceral abnormalities. Perampanel is generally not recommended for women of childbearing age without contraception, and reduced efficacy of progesterone-containing oral contraceptives by interaction with perampanel should be considered (18). Potential benefits may warrant use of the drug in pregnant women despite potential risks, but perampanel should be used only if clearly needed and the benefit outweighs potential risk. Pregnant patients taking perampanel should enroll in the North American Antiepileptic Drug Pregnancy Registry. Clinical data have been collected from reports of perampanel exposure during pregnancy from routine clinical settings, interventional studies, and noninterventional postmarketing studies, and events coded to Medical Dictionary for Regulatory Activities (MedDRA) (Vazquez et al 2121). These data should be interpreted with caution, and further outcome data are required to estimate the prevalence of adverse pregnancy outcomes with perampanel exposure.

Perampanel is excreted into animal milk, but it is not known whether perampanel is distributed in human breast milk. The effects in nursing infants are unknown.

Anesthesia. No information is available about use of anesthesia in subjects on perampanel therapy.

References

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02: Ceolin L, Bortolotto ZA, Bannister N, Collingridge GL, Lodge D, Volianskis A. A novel anti-epileptic agent, perampanel, selectively inhibits AMPA receptor-mediated synaptic transmission in the hippocampus. Neurochem Int 2012;61(4):517-22. PMID 22433907
03: Crespel A, Gelisse P, Tang NP, Genton P. Perampanel in 12 patients with Unverricht-Lundborg disease. Epilepsia 2017;58(4):543-7.** PMID 28166365
04: Frampton JE. Perampanel: a review in drug-resistant epilepsy. Drugs 2015;75(14):1657-68. PMID 26370209
05: French JA, Krauss GL, Wechsler RT, et al. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy: a randomized trial. Neurology 2015;85(11):950-7. PMID 26296511
06: Goji H, Kanemoto K. The effect of perampanel on aggression and depression in patients with epilepsy: a short-term prospective study. Seizure 2019;67:1-4. PMID 30826629
07: Hanada T, Hashizume Y, Tokuhara N, et al. Perampanel: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy. Epilepsia 2011;52(7):1331-40. PMID 21635236
08: Heyman E, Lahat E, Levin N, et al. Tolerability and efficacy of perampanel in children with refractory epilepsy. Dev Med Child Neurol 2017;59(4):441-4. PMID 27935018
09: Kramer LD, Satlin A, Krauss GL, et al. Perampanel for adjunctive treatment of partial-onset seizures: a pooled dose-response analysis of phase III studies. Epilepsia 2014;55(3):423-31. PMID 24605793
10: 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 2013;54(1):126-34. PMID 22905878
11: Krauss GL, Perucca E, Ben-Menachem E, et al. Long-term safety of perampanel and seizure outcomes in refractory partial-onset seizures and secondarily generalized seizures: results from phase III extension study 307. Epilepsia 2014;55(7):1058-68. PMID 24867391
12: Patsalos PN. The clinical pharmacology profile of the new antiepileptic drug perampanel: A novel noncompetitive AMPA receptor antagonist. Epilepsia 2015;56(1):12-27. PMID 25495693
13: Rascol O, Barone P, Behari M, et al. Perampanel in Parkinson disease fluctuations: a double-blind randomized trial with placebo and entacapone. Clin Neuropharmacol 2012;35(1):15-20. PMID 22222634
14: Rektor I. Perampanel, a novel, non-competitive, selective AMPA receptor antagonist as adjunctive therapy for treatment-resistant partial-onset seizures. Expert Opin Pharmacother 2013;14(2):225-35. PMID 23259931
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(4):263-9. PMID 22913800
16: Rheims S, Ryvlin P. Profile of perampanel and its potential in the treatment of partial onset seizures. Neuropsychiatr Dis Treat 2013;9:629-37. PMID 23717043
17: Rogawski MA, Hanada T. Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist. Acta Neurol Scand Suppl 2013;(197):19-24. PMID 23480152
18: Rohracher A, Brigo F, Höfler J, et al. Perampanel for the treatment of primary generalized tonic-clonic seizures in idiopathic generalized epilepsy. Expert Opin Pharmacother 2016;17(10):1403-11. PMID 27267634
19: Rugg-Gunn F. Adverse effects and safety profile of perampanel: a review of pooled data. Epilepsia 2014;55 Suppl 1:13-5. PMID 24400692
20: Santamarina E, Bertol V, Garayoa V, et al. Efficacy and tolerability of perampanel as a first add-on therapy with different anti-seizure drugs. Seizure 2020;83:48-56. PMID 33096456
21: Shimabukuro K, Gibbon F, Kerstetter J, Tinsley C, Ashwal S. DRESS associated with perampanel administration in a child with drug-resistant epilepsy. Neurology 2014;83(23):2188. PMID 25361780
22: Steinhoff BJ, Hübers E, Kurth C, Jürges Kehl-Kork U. Plasma concentration and clinical effects of perampanel-The Kork experience. Seizure 2019;67:18-22. PMID 30852267
23: Steinhoff BJ, Patten A, Williams B, Malhotra M. Efficacy and safety of adjunctive perampanel 4 mg/d for the treatment of focal seizures: a pooled post hoc analysis of four randomized, double-blind, phase III studies. Epilepsia 2020;61(2):278-86.** PMID 31944276
24: Swiderska N, Tan HJ, Rajai A, Silwal A, Desurkar A, Martland T. Effectiveness and tolerability of perampanel in children, adolescents and young adults with refractory epilepsy: a UK national multicentre study. Seizure 2017;52:63-70. PMID 28992560
25: Vazquez B, Tomson T, Dobrinsky C, Schuck E, O'Brien TJ. Perampanel and pregnancy. Epilepsia 2021;62(3):698-708. PMID 33666943
26: Villanueva V, Montoya J, Castillo A, et al. Perampanel in routine clinical use in idiopathic generalized epilepsy: The 12-month GENERAL study. Epilepsia 2018;59(9):1740-52. PMID 30062784
27: Zaccara G, Giovannelli F, Cincotta M, Verrotti A, Grillo E. The adverse event profile of perampanel: meta-analysis of randomized controlled trials. Eur J Neurol 2013;20(8):1204-11. PMID 23607817

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Perampanel

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Perampanel …

Perampanel

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Drug-induced myasthenic syndromes

Epilepsy with auditory features

Alcohol withdrawal seizures

Acupuncture

Epileptic lesions due to malformation of cortical development

Epileptic spasms

Perampanel

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Drug-induced myasthenic syndromes

Epilepsy with auditory features

Alcohol withdrawal seizures

Acupuncture

Epileptic lesions due to malformation of cortical development

Epileptic spasms

This is an article preview.
Start a Free Account
to access the full version.