Myoclonus epilepsy with ragged-red fibers
Jun. 18, 2022
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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).
Perampanel has a 2,4-diphenyl-4H-[1,3,4]oxadiazin-5-one core structure, distinguishing it chemically from other AMPA receptor antagonist classes.
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).
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).
Perampanel is approved for the control of partial-onset seizures in both sexes who suffer from epilepsy and who are 12 years of age and older.
In a randomized, double-blind trial, perampanel (4 mg/d) was well-tolerated but did not have a clinically significant effect in improving motor symptoms of L-dopa-treated patients with moderately advanced Parkinson disease and motor fluctuations (13).
Perampanel has shown marked efficacy in Unverricht-Lundborg disease, even in severe cases and particularly against myoclonus, but also against seizures (03). The dose of perampanel is increased by 2 mg steps at 2- to 4-week intervals until 6 mg/day, but its use is limited by behavioral side effects at this dose level.
Contradictions include hypersensitivity to any of the active constituents or excipients in perampanel tablets.
Perampanel is a useful adjunctive treatment option for patients with drug-resistant partial-onset seizures, with or without secondary generalization, and primary generalized tonic-clonic seizures without major problems in safety and drug interactions (04).
Titration of dose to individual requirements facilitates personalized management of epilepsy. In the absence of studies of direct comparison between perampanel and the efficacy as well as tolerability of other licensed antiepileptic drugs, the clinical advantages of perampanel over the other drugs in intractable partial epilepsy remain to be determined (16). Long-term open-label extensions of the 3 pivotal trials are in progress, and interim results indicate safety of use for more than 4 years.
The starting dose is 2 mg orally taken daily at bedtime and should be titrated by 2 mg increments to the dosage range of 4 to 12 mg, based on efficacy for control of seizures as well as tolerance by the patient. The frequency of increment is adjusted according to the co-medications: daily for use with drugs that shorten the half-life of perampanel and every 2 weeks for drugs that do not affect the half-life of perampanel.
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.
Some antiepileptic drugs known to be enzyme inducers—carbamazepine, oxcarbazepine, and phenytoin—increase perampanel clearance and decrease its plasma concentration. In practice, this is compensated by an increased dose of perampanel because it is aimed at clinical response.
In pharmacokinetic analyses of patients with partial-onset seizures receiving perampanel up to 12 mg daily in clinical trials, there was no clinically significant effect on other antiepileptic drugs.
Perampanel 12 mg, but not 4 or 8 mg, enhances the metabolism of the progesterone, which decreases the effectiveness of progesterone-containing oral contraceptives, and use of nonhormonal contraception is recommended.
The Physicians’ Desk Reference should be consulted for a detailed list of interacting drugs.
The most common adverse reactions reported by patients receiving perampanel in clinical trials include dizziness, drowsiness, irritability, falls, weight increase, vertigo, ataxia, blurred vision, dysarthria, asthenia, and irritability (27). Patients with drug-resistant epilepsy who also suffer from intellectual disability may develop an increase in aggressive behavior under perampanel treatment, requiring discontinuation of therapy (01). Findings of a short-term study indicate that perampanel increases aggression as well as depression, but no additional aggression-augmenting effect was seen with concomitant antiepileptic drug administration (06). Somnolence and dizziness are more frequent at higher doses, but serious adverse effects are infrequent, particularly at low doses (19). Dizziness can be avoided by bedtime administration of perampanel.
DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome, which shares features with anticonvulsant hypersensitivity syndrome, is characterized by an extensive rash, fever, lymphadenopathy, hematologic abnormalities, hepatitis, and involvement of the kidneys, lungs, heart, or pancreas. Treatment consists of supportive therapy, corticosteroids, and antihistamines. A case of DRESS associated with use of perampanel has been reported in a child with drug-resistant epilepsy (21).
K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.See Profile
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