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Perampanel

Perampanel, sold under the brand name Fycompa among others, is a non-competitive and selective antagonist of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) glutamate receptors indicated as an antiepileptic drug for the treatment of certain seizure disorders in patients with epilepsy.^[1]^[2] It is approved for use as adjunctive or monotherapy in partial-onset seizures with or without secondarily generalized seizures in patients aged 4 years and older, and as adjunctive therapy for primary generalized tonic-clonic seizures in patients aged 12 years and older.^[1]^[3] Originally developed by Eisai Co., Ltd., perampanel received initial U.S. Food and Drug Administration (FDA) approval on October 22, 2012, for adjunctive treatment of partial-onset seizures in patients aged 12 years and older, marking it as the first-in-class AMPA receptor antagonist for epilepsy.^[4] Subsequent approvals expanded its indications to include younger patients and primary generalized tonic-clonic seizures, with formulations available as oral tablets (2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg) and oral suspension (0.5 mg/mL). Generic versions became available in the United States in May 2025.^[1]^[3] The recommended starting dosage is 2 mg once daily at bedtime, titrated upward by 2 mg increments weekly to a maintenance dose of 8–12 mg daily for partial-onset seizures or 8 mg daily for tonic-clonic seizures, with adjustments for hepatic or renal impairment and concomitant use of CYP3A4 inducers.^[1] While the precise mechanism by which perampanel exerts its antiepileptic effects is not fully understood, it selectively blocks AMPA receptors on postsynaptic neurons, thereby reducing neuronal excitability and seizure propagation without significantly affecting GABA-mediated inhibition.^[1]^[2] Efficacy was demonstrated in randomized, double-blind, placebo-controlled trials, such as Studies 1–3 for partial-onset seizures (showing median seizure reductions of 23–31.8% at 8–12 mg doses versus 14.4–17.1% for placebo) and Study 4 for primary generalized tonic-clonic seizures (76% seizure reduction at 8 mg versus 38% for placebo).^[1] As a Schedule III controlled substance due to abuse potential, perampanel carries a boxed warning for serious psychiatric and behavioral reactions, including aggression, hostility, and homicidal ideation, as well as risks of suicidal ideation, dizziness, somnolence, and falls; abrupt discontinuation may precipitate status epilepticus.^[1]^[3]

Clinical Use

Indications

Perampanel is approved in the United States as both monotherapy and adjunctive therapy for the treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy aged 4 years and older.^[5] In the European Union, it is approved as adjunctive therapy for the same seizure type in patients aged 4 years and older.^[6] This approval reflects its role in managing focal epilepsies, where perampanel's selective antagonism of AMPA receptors helps control seizure propagation without broadly affecting other glutamate receptors. For primary generalized tonic-clonic seizures, perampanel is approved as adjunctive therapy in patients aged 12 years and older in both the United States and the European Union.^[5]^[6] In the EU, this indication extends to patients from 7 years of age in idiopathic generalized epilepsy.^[6] Monotherapy use is approved in the US for partial-onset seizures in patients aged 4 years and older, supported by clinical evidence and extrapolation demonstrating efficacy comparable to adjunctive use.^[5] Perampanel is not approved for the treatment of absence or myoclonic seizures.^[5]^[6] Although evidence for its use in genetic generalized epilepsy remains limited, emerging data from 2025 retrospective studies indicate potential efficacy in reducing seizure frequency in syndromes like juvenile myoclonic epilepsy and genetic tonic-clonic seizures, with responder rates up to 83% at low doses, though further prospective trials are needed for broader approval.^[7]

Contraindications

Perampanel is contraindicated in patients with known hypersensitivity to the active substance or to any of the excipients.^[8] Use during pregnancy is not recommended unless the potential benefit justifies the potential risk to the fetus. Animal studies have demonstrated developmental toxicity, including increased embryofetal lethality and reduced fetal body weights, likely related to its non-competitive antagonism of AMPA receptors critical for neuronal development and synaptic plasticity; there are limited human data available.^[5] Women of childbearing potential taking perampanel must use effective contraception, and discontinuation should be considered if pregnancy occurs, with enrollment in the North American Antiepileptic Drug Pregnancy Registry recommended for monitoring.^[5] Perampanel is not recommended in patients with severe hepatic impairment (Child-Pugh class C), as the drug undergoes extensive hepatic metabolism primarily via CYP3A4 enzymes, leading to significantly elevated plasma concentrations and increased risk of adverse effects in this population.^[5] Similarly, it is not recommended for patients with severe renal impairment (creatinine clearance <30 mL/min) or those on hemodialysis, due to limited data on safety and potential for drug accumulation.^[5] Caution is advised in patients with a history of psychotic disorders, as clinical trials excluded those with active psychosis, and the drug carries a risk of exacerbating psychiatric symptoms, including aggression, hostility, and hallucinations, potentially through its effects on glutamate signaling; prescribers should monitor closely.^[5] In pediatric populations, perampanel is not indicated for children under 4 years of age for partial-onset seizures or under 12 years for primary generalized tonic-clonic seizures, owing to insufficient data on safety and efficacy in these younger age groups.^[5]

Dosage and Administration

Perampanel is administered orally once daily at bedtime, either as tablets or oral suspension, and may be taken with or without food.^[5] For adults and adolescents aged 12 years and older, the recommended initial dose is 2 mg once daily.^[5] In pediatric patients aged 4 to 11 years, the initial dose is also 2 mg once daily (equivalent to 4 mL of the 0.5 mg/mL oral suspension).^[5] The oral suspension must be shaken well before each administration, and the provided adapter and graduated oral dosing syringe should be used for accurate measurement.^[5] Dose titration should occur in increments of 2 mg once weekly, based on clinical response and tolerability, to reach a maintenance dose of 8 to 12 mg once daily.^[5] Some patients may achieve adequate seizure control at 4 mg daily, while the maximum recommended dose is 12 mg once daily.^[5] In patients concomitantly using moderate or strong CYP3A4 inducers, the initial dose should be increased to 4 mg once daily, with subsequent titration and monitoring to a maximum of 12 mg, as lower exposures may occur without adjustment.^[5] For patients with mild hepatic impairment (Child-Pugh A), the maximum dose is reduced to 6 mg once daily, with titration increments every 2 weeks; in moderate impairment (Child-Pugh B), the maximum is 4 mg once daily, also titrated every 2 weeks; perampanel is not recommended in severe hepatic impairment (Child-Pugh C).^[5] In elderly patients (aged 65 years and older), dose increases should occur no more frequently than every 2 weeks due to potential differences in tolerability.^[5] For renal impairment, no specific dose adjustment is required in mild or moderate cases without dialysis, but close monitoring is advised with slower titration if needed; perampanel is not recommended in severe renal impairment or patients on hemodialysis.^[5] The oral suspension should be discarded 90 days after first opening.^[5]

Safety Profile

Side Effects

Perampanel is associated with a range of adverse effects, the most common of which (≥10% incidence) include dizziness (up to 47%), somnolence (18%), fatigue (12%), and irritability (12%). Other effects occurring in 1-10% include nausea (8%) and weight increase (4%).^[9]^[10]^[11] Serious adverse reactions include psychiatric and behavioral changes such as aggression, hostility, and homicidal ideation, which prompted a black box warning from the FDA due to their potential to be life-threatening.^[12]^[13]^[14] Falls, often resulting from ataxia or vertigo, represent another serious risk, particularly in elderly patients.^[12]^[15] Additionally, as with other antiepileptic drugs, perampanel carries a class warning for suicidal ideation and behavior.^[12]^[16] The incidence of dizziness and psychiatric effects increases in a dose-related manner, with higher rates observed at daily doses of 8-12 mg compared to lower doses.^[12]^[17]^[18] A 2025 long-term study found adjunctive perampanel generally well tolerated in pediatric patients (ages 4-12 years) with epilepsy over up to 52 weeks, with treatment-emergent adverse events in 69% but high completion rate (90%) and no clinical concerns in cognition, growth, development, or quality of life.^[19] Somnolence is a commonly reported adverse effect in pediatric patients across studies.^[20] Perampanel's abuse potential, evidenced by euphoric effects at supratherapeutic doses, contributed to its classification as a Schedule III controlled substance by the DEA in 2013.^[21]^[12] As of the FDA label update in September 2024 and 2025 studies, the safety profile remains consistent with earlier data, with no new serious risks identified.^[9] Management of side effects typically involves dose reduction or discontinuation in severe cases, along with close monitoring for central nervous system depression; slow titration is recommended to minimize risks.^[12]^[22] Effects may be enhanced when perampanel is combined with CNS depressants such as alcohol.^[12]

Drug Interactions

Perampanel is primarily metabolized by the cytochrome P450 enzyme CYP3A4, leading to significant pharmacokinetic interactions with strong inducers and inhibitors of this pathway.^[12] Strong CYP3A4 inducers such as rifampin, carbamazepine, phenytoin, and oxcarbazepine reduce perampanel plasma concentrations by 50-67%, potentially decreasing its efficacy.^[12] In such cases, therapy should be initiated at 2 mg/day (or 4 mg/day for patients on carbamazepine, phenytoin, or oxcarbazepine), with dose increases limited to a maximum of 12 mg/day, and close monitoring for clinical response is recommended when adding or withdrawing these agents.^[12] Conversely, strong CYP3A4 inhibitors like ketoconazole can increase perampanel exposure by 3- to 5-fold, heightening the risk of adverse effects; dose reduction by up to 50% is advised during concomitant use, with further adjustments based on tolerability.^[12] Perampanel may also interact with hormonal contraceptives, reducing the area under the curve (AUC) of levonorgestrel by approximately 40%, which could compromise contraceptive efficacy.^[12] Women of childbearing potential using levonorgestrel-containing contraceptives should employ additional non-hormonal methods or alternative contraception during perampanel treatment and for at least one month after discontinuation.^[12] Pharmacodynamic interactions occur with central nervous system (CNS) depressants, including alcohol, benzodiazepines, and opioids, resulting in additive effects that exacerbate dizziness, somnolence, and impaired psychomotor function.^[12] Concomitant alcohol use with perampanel at 12 mg/day has been shown to worsen mood, increase anger and confusion, and further impair vigilance and alertness; patients are advised to avoid alcohol or limit activities requiring mental acuity until the combined effects are known.^[12] Among other antiepileptic drugs, no major pharmacokinetic interactions have been observed with valproate or levetiracetam, though valproate may modestly increase perampanel concentrations without necessitating routine dose adjustments.^[23]^[24] For phenytoin, monitoring is recommended due to its inductive effects on CYP3A4.^[12] Food does not significantly affect perampanel absorption or bioavailability, allowing administration with or without meals.^[12] However, grapefruit juice, as a moderate CYP3A4 inhibitor, may increase perampanel levels, and its regular consumption should be avoided or monitored.^[25] Protein binding displacement interactions with other highly bound drugs are not considered clinically significant.^[12]

Pharmacology

Mechanism of Action

Perampanel is a selective, non-competitive antagonist of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of ionotropic glutamate receptors, which are key mediators of fast excitatory synaptic transmission in the central nervous system. By binding to an allosteric site distinct from the glutamate-binding domain, perampanel inhibits AMPA receptor activation without directly competing with the endogenous ligand glutamate, thereby stabilizing the receptor in a closed conformation and preventing ion channel opening. This binding occurs at a novel site in the transmembrane domain, specifically involving interactions with the pre-M1 linker and the extracellular portions of transmembrane segments M3 and M4, as revealed by crystallographic studies of the rat GluA2 AMPA receptor.^[26]^[27] The antagonism exerted by perampanel reduces glutamate-mediated excitatory postsynaptic currents, limiting neuronal depolarization and thereby attenuating excessive excitatory neurotransmission that underlies seizure activity in epilepsy. This mechanism decreases neuronal hyperexcitability by suppressing the propagation of seizure discharges, as demonstrated in preclinical models such as amygdala-kindled rats, where perampanel elevates the afterdischarge threshold and shortens seizure duration. Physiologically, this selective modulation of AMPA receptors helps restore the balance between excitation and inhibition in epileptic circuits without broadly disrupting normal synaptic function.^[27]^[28] Perampanel exhibits high selectivity for AMPA receptors, showing no significant affinity for γ-aminobutyric acid (GABA) receptors, N-methyl-D-aspartate (NMDA) receptors, or kainate receptors, the other major subtypes of ionotropic glutamate receptors. Concentrations up to 30 μM produce minimal inhibition of NMDA- or kainate-induced responses, confirming its targeted action on AMPA-mediated pathways. Additionally, perampanel has minimal effects on voltage-gated ion channels, with no notable modulation observed at concentrations up to 28.6 μM, further underscoring its specificity for glutamatergic signaling. Its primary site of action is within the brain, where it exerts central antiepileptic effects.^[28]^[27]^[29]

Pharmacokinetics

Perampanel exhibits favorable pharmacokinetic properties that support once-daily oral dosing for the management of epilepsy. Following oral administration, the drug demonstrates rapid and complete absorption with high bioavailability approaching 100%, and its pharmacokinetics are linear over the clinically relevant dose range up to 12 mg.^[12]^[30] Absorption of perampanel is rapid, with median peak plasma concentrations (T_max) achieved within 0.5 to 2 hours under fasting conditions, though a high-fat meal can delay T_max by 1 to 3 hours and reduce C_max by up to 40% without affecting overall exposure.^[12] The drug undergoes negligible first-pass metabolism, contributing to its near-complete bioavailability.^[30] In terms of distribution, perampanel is approximately 95-96% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein, across a wide concentration range. Its apparent volume of distribution is about 1 L/kg, indicating moderate tissue distribution, and the drug readily crosses the blood-brain barrier to exert its antiseizure effects.^[12]^[31]^[30] Metabolism of perampanel occurs primarily in the liver through oxidation mediated by cytochrome P450 enzyme CYP3A4, producing inactive metabolites, with minor contributions from CYP1A2 and CYP2B6.^[12]^[32] Unchanged perampanel accounts for 74-80% of circulating radioactivity, highlighting limited biotransformation relative to total exposure.^[12] Elimination of perampanel is characterized by a long terminal half-life of approximately 105 hours (with interindividual variability ranging from 40 to 176 hours), enabling steady-state concentrations to be reached in about 14 days.^[12]^[30] Excretion occurs via feces (about 48%, primarily as metabolites) and urine (about 22%, primarily as metabolites), with less than 2% eliminated unchanged.^[32]^[12] In special populations, hepatic impairment significantly reduces clearance and prolongs the half-life—for instance, moderate impairment can extend it to around 295 hours—necessitating dose adjustments.^[12] In contrast, mild renal impairment results in only a modest 27% reduction in clearance with no major clinical impact, though data for severe renal dysfunction are limited.^[12]

Chemistry

Chemical Structure and Properties

Perampanel is an organic compound with the molecular formula C₂₃H₁₅N₃O and a molar mass of 349.39 g/mol for the anhydrous form.^[33]^[12] The compound is typically encountered as a hemisesquihydrate (C₂₃H₁₅N₃O • ¾H₂O), with a corresponding molecular weight of 362.90 g/mol.^[12] The IUPAC name of perampanel is 2-(2-oxo-1-phenyl-5-pyridin-2-yl-3-pyridinyl)benzonitrile, reflecting its structure as a member of the bipyridine class.^[33] It features a [2,3'-bipyridin-6'-one] core, substituted at the 1' position by a phenyl group and at the 5' position by a 2-cyanophenyl group, which contributes to its overall rigidity and planarity.^[33] The SMILES notation for perampanel is C1=CC=C(C=C1)N2C=C(C=C(C2=O)C3=CC=CC=C3C#N)C4=CC=CC=N4, providing a linear representation of its connectivity.^[33] Physically, perampanel appears as a white to yellowish-white crystalline powder that is nonhygroscopic.^[12]^[34] It exhibits low aqueous solubility, being practically insoluble in water but slightly soluble under acidic conditions due to its basic pKa of 3.24 associated with the pyridine nitrogen.^[12]^[28] In organic solvents, perampanel is freely soluble in 1-methyl-2-pyrrolidinone, sparingly soluble in acetonitrile and acetone, and slightly soluble in methanol, ethanol, and ethyl acetate.^[12] The compound remains stable under normal storage conditions, with no significant degradation reported in standard pharmaceutical environments.^[34] This bipyridinone core structure underlies perampanel's selective binding to AMPA receptors.^[33]

Pharmaceutical Formulations

Perampanel is available in two primary oral dosage forms: film-coated tablets and an oral suspension, both designed for once-daily administration. The tablets are supplied in strengths of 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg, which align with typical titration increments for dose adjustment. These tablets are round and biconvex, with colors varying by strength—orange for 2 mg, red for 4 mg, pink for 6 mg, white for 8 mg, blue for 10 mg, and green for 12 mg—and are debossed with the strength on one side and "Є 275" on the other. The inactive ingredients in the tablets include lactose monohydrate, low-substituted hydroxypropyl cellulose, povidone, microcrystalline cellulose, magnesium stearate, hypromellose, polyethylene glycol, talc, and titanium dioxide, along with specific colorants such as yellow ferric oxide (for 2 mg and 10 mg), red ferric oxide (for 2 mg, 4 mg, 6 mg, and 8 mg), black ferric oxide (for 8 mg), FD&C Blue No. 2 aluminum lake (for 10 mg), and FD&C Blue No. 1 aluminum lake (for 12 mg).^[12] The oral suspension is formulated at a concentration of 0.5 mg/mL as a white to off-white opaque liquid, primarily intended for pediatric patients or those who have difficulty swallowing tablets to facilitate precise dosing. It contains the following inactive ingredients: sorbitol, microcrystalline cellulose, carboxymethylcellulose sodium, poloxamer, simethicone, citric acid, sodium benzoate, and purified water. The suspension is supplied in 340 mL amber polyethylene terephthalate (PET) bottles with child-resistant closures, accompanied by a push-in bottle adapter and two 20-mL graduated oral dosing syringes for accurate measurement; it must be shaken well before use and is not interchangeable with household measuring devices.^[35] Storage recommendations for both formulations emphasize room temperature conditions to maintain stability. Tablets should be kept at 20°C to 25°C (68°F to 77°F), with excursions permitted between 15°C and 30°C (59°F to 86°F), in tight containers. The oral suspension requires storage below 30°C (86°F), without freezing, and remains stable for 90 days after first opening, after which any remainder must be discarded.^[12]^[35] Generic versions of perampanel tablets and suspension were approved by the FDA in 2025, with the first generic tablet approval granted to Teva Pharmaceuticals on May 23, 2025; these generics demonstrate bioequivalence to the branded Fycompa formulation under steady-state conditions, supporting interchangeable use. No intravenous or other non-oral formulations are available.^[36]^[12]

Development and Research

History

Perampanel was discovered and developed by Eisai Co. through a focused high-throughput screening program at its research laboratories in the early 2000s, targeting non-competitive antagonists of AMPA-type glutamate receptors to address unmet needs in epilepsy treatment.^[37] The compound emerged from optimization of a 1,3,5-triaryl-1H-pyridin-2-one structure, demonstrating potent antiseizure activity in preclinical models.^[37] Eisai advanced perampanel into clinical development, completing three pivotal Phase III trials (Studies 304, 305, and 306) by 2011, which enrolled over 1,400 patients with refractory partial-onset seizures and supported its efficacy as adjunctive therapy.^[38]^[37] Regulatory milestones followed rapidly. The European Medicines Agency granted marketing authorization for perampanel (as Fycompa) on July 23, 2012, for adjunctive treatment of partial-onset seizures with or without secondarily generalized seizures in patients aged 12 years and older.^[39] In the United States, the FDA approved perampanel tablets on October 22, 2012, under New Drug Application (NDA) 202834, for the same indication in patients aged 12 years and older.^[40] Indications expanded over time: to adjunctive therapy for primary generalized tonic-clonic seizures on June 22, 2015; to monotherapy for partial-onset seizures on July 26, 2017;^[41] and to both adjunctive and monotherapy use for partial-onset seizures in pediatric patients aged 4 years and older on September 28, 2018.^[42] An oral suspension formulation was approved by the FDA on April 29, 2016, to improve administration options for patients with swallowing difficulties.^[43] Post-approval updates addressed safety and regulatory status. A black box warning for serious psychiatric and behavioral reactions, including aggression, hostility, and homicidal ideation, was included in the initial U.S. prescribing information in 2012 and updated in 2013 to emphasize risks.^[4]^[44] The U.S. Drug Enforcement Administration classified perampanel as a Schedule III controlled substance on December 2, 2013, due to its potential for abuse and moderate psychological dependence.^[21] Generic versions of perampanel tablets became available in the United States following FDA approvals starting in May 2025, enabling production by multiple manufacturers such as Teva Pharmaceuticals.^[45]

Clinical Studies

Perampanel's approval for adjunctive treatment of partial-onset seizures was supported by three pivotal phase III randomized, double-blind, placebo-controlled trials (studies 304, 305, and 306) conducted between 2011 and 2012, involving over 1,400 adults with refractory epilepsy.^[46] These trials evaluated perampanel at doses of 2-12 mg/day over a 19-week period, including a 6-week titration and 13-week maintenance phase. In pooled analyses, the 50% responder rates (≥50% reduction in seizure frequency) ranged from 23% to 34% for 8-12 mg doses compared to 12% for placebo, with median seizure frequency reductions of 30-40% versus 13% for placebo.^[47] Efficacy was dose-dependent, with higher doses showing greater reductions in complex partial and secondarily generalized seizures, though benefits plateaued beyond 8 mg in some subgroups.^[48] The FREEDOM study, a phase III trial published in 2015, extended perampanel's evidence to primary generalized tonic-clonic (PGTC) seizures in idiopathic generalized epilepsy, randomizing 164 patients aged ≥12 years to 8 mg/day or placebo over 19 weeks.^[49] Adjunctive perampanel achieved a median 68% reduction in PGTC seizure frequency per 28 days compared to 28% for placebo, with 64% of perampanel-treated patients achieving ≥50% responder status versus 35% on placebo.^[49] Seizure freedom rates were 21% for perampanel versus 0% for placebo during the maintenance period, establishing its role in reducing convulsive seizures in drug-resistant cases.^[50] Pediatric data from the open-label extension of study 311 (NCT02849626), reported in 2025, evaluated long-term adjunctive perampanel (up to 12 mg/day) in children aged 4-11 years with inadequately controlled focal-onset or generalized tonic-clonic seizures over ≤52 weeks.^[51] Retention rates reached approximately 90% at 12 months, reflecting sustained tolerability, while median percent reductions in seizure frequency ranged from 69% to 100% across seizure types, with no new safety signals emerging, supporting its use in younger patients irrespective of concomitant enzyme-inducing antiepileptic drugs.^[51]^[19] Recent studies from 2023-2025 further refined perampanel's profile. The phase 4 study 512 (NCT04252846), a 12-month prospective observational trial completed in 2025, assessed perampanel as first add-on therapy in patients aged ≥12 years with focal or generalized epilepsy, reporting a 64% responder rate and 74% retention at 12 months.^[52] Similarly, study 338 (NCT02834793), a phase 3 trial reported in 2024, confirmed safety in patients aged ≥2 years with Lennox-Gastaut syndrome or other uncontrolled seizures, achieving median reductions of 23-49% in drop and total seizures.^[53] A 2025 real-world post-hoc analysis from routine clinical practice highlighted perampanel's efficacy as early add-on therapy, with responder rates exceeding 50% in both focal and generalized epilepsy cohorts over 6-12 months.^[54] Meta-analyses have synthesized these findings. A 2013 systematic review of phase III trials confirmed perampanel's superiority over placebo in reducing seizure frequency (odds ratios for 50% response: 1.5-1.8) with comparable tolerability to other adjunctive antiepileptics, though psychiatric adverse events were noted.^[55] An updated 2024 meta-analysis of real-world and extension studies reinforced these results, showing sustained efficacy (responder rates 40-60%) but noted behavioral side effects limiting long-term use in some patients.^[56] Despite robust evidence, limitations include the predominantly short-term (≤19 weeks) design of core trials, reliance on adjunctive rather than monotherapy contexts, and absence of head-to-head comparisons with other antiepileptics to clarify relative efficacy.^[57] Long-term extensions address durability but highlight needs for broader pediatric and monotherapy data.^[56]

Society and Culture

Names

Perampanel is the generic name and International Nonproprietary Name (INN) for this antiepileptic medication.^[6]^[58] The primary brand name is Fycompa, developed by Eisai Co., Ltd. and marketed by Eisai outside the United States and by Catalyst Pharmaceuticals in the United States following a 2022 transfer of commercial rights.^[59]^[60]^[61] Fycompa is approved and available in numerous countries, including the United States, European Union member states, Canada, Japan, Australia, and Russia.^[62] No combination products containing perampanel have been approved; it is indicated for use as monotherapy or adjunctive therapy with other antiepileptic drugs.^[3] The pronunciation of perampanel is /pəˈræmpənɛl/ (per-AM-pa-nel).^[13] Fycompa is available in branded formulations as oral tablets and suspension.^[6]

Legal Status

In the United States, perampanel is classified as a Schedule III controlled substance under the Controlled Substances Act by the Drug Enforcement Administration (DEA), a designation effective since December 12, 2013, due to its potential for abuse, including reports of euphoria and psychological dependence at supratherapeutic doses.^[21] This classification imposes strict regulations on its manufacture, distribution, and prescription, requiring DEA registration for handlers and limiting refills to prevent diversion.^[63] In the European Union, perampanel is authorized for medical use as a prescription-only medicine (Rx-only) by the European Medicines Agency (EMA), without designation as a controlled substance, though it is subject to enhanced pharmacovigilance monitoring for associated psychiatric and behavioral risks, such as aggression and irritability.^[6] The drug's marketing authorization, granted in 2012 and expanded in subsequent years, mandates its use solely as adjunctive therapy under specialist supervision. In Canada, perampanel was approved by Health Canada in 2013 as a prescription drug for adjunctive treatment of partial-onset seizures, but it is not classified as a controlled substance under the Controlled Drugs and Substances Act.^[64] Prescribing follows standard narcotic control regulations for non-controlled prescription medications, with oversight focused on its potential for serious adverse psychiatric effects.^[65] Internationally, perampanel's regulatory status varies; for example, in Japan, it is approved as a prescription-only medicine since 2010 for partial-onset seizures, with no controlled substance classification but requirements for careful monitoring of behavioral side effects.^[66] These differences reflect national assessments of abuse liability and therapeutic need, often influenced by the drug's black box warning for psychiatric risks, which heightens scrutiny in prescribing practices worldwide.^[12] Overall, perampanel requires specialized prescribing protocols in most jurisdictions to mitigate misuse risks, including dependence and off-label recreational use.^[67]

Availability

Perampanel has been widely available in major markets including the United States, European Union, Canada, Japan, and Australia since its initial approvals between 2012 and 2013.^[62] In the United States, the branded product was priced at approximately $1,000 to $1,300 per month prior to generic entry, but generic versions launched in 2025 by manufacturers such as Teva Pharmaceuticals (approved May 23, 2025, for tablets) and MSN Laboratories (approved July 11, 2025, for oral suspension), resulting in cost reductions of around 75% for patients using discount programs.^[36]^[68] In the European Union, perampanel is accessible through national health systems with monthly pricing typically ranging from €200 to €300, depending on the country and dosage.^[69] Access remains limited in many developing countries due to high costs and supply chain challenges, though efforts to improve procurement through international organizations help bridge gaps for eligible patients.^[70] Occasional shortages of perampanel were reported in select markets, such as Canada, during 2023-2024, primarily attributed to manufacturing issues, but these have been largely resolved following the introduction of generic supplies in 2025.^[71] In the United States, Catalyst Pharmaceuticals offers a patient assistance program providing free medication to eligible uninsured or underinsured patients who meet income criteria.^[72] As a Schedule III controlled substance, its dispensing requires adherence to federal regulations on prescriptions and record-keeping.^[21]

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Feb 7, 2025 · Dizziness, somnolence, fatigue, and gait disturbance events appear to be dose-related and occurred mostly during the titration phase.Precautions · For Healthcare Professionals · Psychiatric
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https://onlinelibrary.wiley.com/doi/10.1111/epi.18242
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Schedules of Controlled Substances: Placement of Perampanel into ...
Dec 2, 2013 · 3. Abuse of perampanel may lead to moderate or low physical dependence or high psychological dependence. Based on these findings, the Deputy ...
[21]
Fycompa: Side effects and how to manage them - MedicalNewsToday
Jul 1, 2024 · Mild side effects of Fycompa · dizziness · fatigue · abdominal pain · nausea or vomiting · difficulty walking · anxiety · sleepiness · vertigo ( ...
[22]
Impact of perampanel on pharmacokinetics of concomitant ... - NIH
No significant impact of perampanel on clearance was found for clonazepam (n = 81), levetiracetam (n = 330), phenobarbital (n = 54), phenytoin (n = 90), ...
[23]
Effect of valproic acid on perampanel pharmacokinetics in patients ...
We prospectively examined the effect of antiepileptic (AED) cotherapy on steady state plasma concentrations of perampanel (PMP) in epileptic patients.
[24]
Perampanel | Epilepsy clinician handbook
Inhibitors of CYP3A4 drug metabolism including ketoconazole or grapefruit juice may cause modest increases in perampanel concentrations.
[25]
https://www.schn.health.nsw.gov.au/epilepsy-clinician-handbook/medications/perampanel
[26]
Perampanel: A novel, orally active, noncompetitive AMPA‐receptor ...
Jun 2, 2011 · Perampanel is an orally active, noncompetitive, selective AMPA receptor antagonist with potential as a broad spectrum antiepileptic agent.
[27]
Preclinical pharmacology of perampanel, a selective non ...
Hence, these blood–brain barrier transporters are unlikely to limit access of perampanel to the brain. Oral perampanel is rapidly and almost completely ...
[28]
None
### Summary of FYCOMPA (Perampanel) from FDA Labeling (10/22/2012)
[29]
Perampanel (Fycompa): A Review of Clinical Efficacy and Safety in ...
This medication is classified as pregnancy category C, indicating it may cause fetal harm based on animal studies; however, due to the lack of well-controlled ...
[30]
Perampanel | SpringerLink
Jul 27, 2016 · The volume of distribution is 1.1 L/kg and protein binding is 95 %. Biotransformation. Perampanel undergoes extensive metabolism in the liver ...
[31]
Perampanel | C23H15N3O | CID 9924495 - PubChem - NIH
Perampanel is a member of the class of bipyridines that is 2,3'-bipyridin-6'-one substituted at positions 1' and 5' by phenyl and 2-cyanophenyl groups ...Missing: stability | Show results with:stability
[32]
Perampanel chemical structure. - ResearchGate
Perampanel exists as a white to slightly colored nonhygroscopic powder and is insoluble in water and slightly soluble in acidic conditions, with a basic pKa of ...
[33]
[PDF] Fycompa Oral Suspension - accessdata.fda.gov
Oral Suspension. FYCOMPA oral suspension is a white to off-white opaque liquid providing perampanel in a concentration of 0.5 mg/mL. The oral suspension ...Missing: 2025 | Show results with:2025
[34]
Generic Fycompa Availability - Drugs.com
Oct 8, 2025 · Yes, the FDA has approved a generic version of Fycompa. However, FDA approval doesn't guarantee the generic will be available in pharmacies.
[35]
The discovery and development of perampanel for the treatment of ...
Feb 24, 2014 · Perampanel is a novel AMPA receptor antagonist, approved in over 35 countries as an adjunctive therapy for the treatment of partial-onset seizures.
[36]
Results of Phase III Study for Perampanel Presented at 2011 ...
Aug 30, 2011 · “This third Phase III study demonstrated the statistical and clinical efficacy of perampanel for reducing partial-onset seizures among epilepsy ...
[37]
[PDF] Fycompa (perampanel) - European Medicines Agency
Fycompa is taken by mouth once a day at bedtime. Fycompa tablets can be taken with or without food and should not be chewed, crushed or split.
[38]
Drug Approval Package: Brand Name (Generic Name) NDA #
Nov 28, 2012 · Drug Approval Package: FYCOMPA (perampanel) Tablets. Company: Eisai, Inc. Application No.: 202834. Approval Date: 10/22/2012.
[39]
FDA Approves Eisai's FYCOMPA® (perampanel) for Use as ...
Jul 26, 2017 · In addition to the new monotherapy use in POS, FYCOMPA is approved for adjunctive use for POS and primary generalized tonic-clonic seizures ( ...
[40]
Eisai Announces FDA Approval Of FYCOMPA® in Pediatric Patients ...
Sep 28, 2018 · Eisai Announces FDA Approval Of FYCOMPA® in Pediatric Patients As Young As 4 Years Old For The Treatment Of Partial-Onset Seizures - Sep 28, ...
[41]
Eisai Announces FDA Approval of FYCOMPA® (perampanel) Oral ...
May 2, 2016 · The US Food and Drug Administration (FDA) has approved FYCOMPA (perampanel) CIII Oral Suspension as adjunctive therapy for the treatment of partial-onset ...Missing: April | Show results with:April
[42]
[PDF] 3323136 This label may not be the latest approved by FDA. For ...
Serious or life-threatening psychiatric and behavioral adverse reactions including aggression, hostility, irritability, anger, and homicidal ideation.
[43]
RxNews - OptumRx | Healthcare professionals portal
May 29, 2025. Fycompa® (perampanel) – First-time generic. May 29, 2025 - Teva launched an AB-rated generic version of Catalyst's Fycompa (perampanel) tablets.<|separator|>
[44]
Efficacy of perampanel: a review of clinical trial data - Kerling - 2013
Mar 11, 2013 · In all three studies, perampanel 4, 8, and 12 mg/day consistently provided significant reductions in the frequency of partial-onset seizures ...
[45]
results of randomized global phase III study 305 - PubMed
This phase III trial demonstrated that adjunctive treatment with once-daily perampanel at 8 mg and 12 mg was effective in improving seizure control in ...Missing: studies 304 306
[46]
Analysis of pooled phase III trials of adjunctive perampanel for ...
In accordance with previously reported analyses, median reductions in seizure frequency and 50% responder rates were generally greater in patients randomized ...
[47]
Perampanel for Tonic-Clonic Seizures in Idiopathic Generalized ...
Sep 15, 2015 · This study provides Class I evidence that adjunctive perampanel reduces PGTC seizure frequency, compared with placebo, in patients with drug-resistant PGTC ...
[48]
Perampanel for tonic-clonic seizures in idiopathic generalized ...
This interventional study provides Class I evidence that adjunctive perampanel 8 mg significantly reduces PGTC seizure frequency and improves 50% PGTC seizure ...Perampanel For Tonic-Clonic... · Abstract · Safety
[49]
Long-term safety and efficacy of adjunctive perampanel in pediatric ...
Feb 11, 2025 · These findings support long-term (≤52 weeks) use of adjunctive perampanel in children with epilepsy, irrespective of seizure type, age, or EIASM use.Missing: studies | Show results with:studies
[50]
A Phase 4, multicenter, prospective, non-interventional ... - PubMed
Introduction: Study 512 aimed to assess the efficacy and safety of perampanel (PER) as the first add-on therapy. Methods: In this 12-month, prospective ...
[51]
Efficacy and safety of perampanel in patients with seizures ...
Nov 22, 2024 · Objectives: The Phase 3 Study 338 (NCT02834793) assessed long-term clinical outcomes of adjunctive perampanel in patients ≥2 years of age ...
[52]
Perampanel as Early Add-On Therapy for Focal and Generalised ...
May 21, 2025 · Perampanel is indicated for the adjunctive treatment of focal onset seizures with or without secondarily generalised seizures in patients from 4 years of age.Missing: indications | Show results with:indications<|separator|>
[53]
Systematic Review and Meta-Analysis of the Efficacy and Safety of ...
Perampanel is a first-in-class antiepileptic drug approved for adjunctive treatment of partial-onset seizure in patients aged 12 years or older.
[54]
A meta-analysis with at least 1-year follow-up - Seizure
Sep 18, 2024 · Perampanel is generally well tolerated and effective in the treatment of epilepsy in children and adolescents with mid-long-term follow-up. The ...<|separator|>
[55]
Efficacy and safety of perampanel in epilepsy: A systematic review ...
This systematic review reports significant reduction in seizures and a potential dose-based increase in discontinuations due to TEAE.
[56]
[PDF] source/international-nonproprietary-names-(inn)/rl59.
perampanel pérampanel perampanel. INN: List 59 peretinoin pérétinoïne peretinoína. C30H29CIN6O3. H3C. H3C. WHO Drug Information, Vol. 22, No. 1, 2008. N. CH3.
[57]
antiepileptic drug fycompa® injection formulation launched in ... - Eisai
Apr 17, 2024 · The usual starting dose for adults and children ≥4 years old is 2 mg of perampanel once daily, which may then be increased by 2 mg at intervals ...
[58]
[PDF] 202834 Perampanel Clinical PREA - FDA
Mar 27, 2012 · Perampanel Fycompa Anticonvulsant Eisai, Inc. Perampanel is safe and effective at doses of 4mg to 8mg daily. It is recommended for approval on ...
[59]
[PDF] Fycompa Approval Status Worldwide (Country/ Region) April, 2021
Fycompa Approval Status Worldwide (Country/ Region). April, 2021. Note: The ... Russia. Aug-2013. Ecuador. Oct-2020. Lithuania. Jul-2012. Saudi Arabia. Jul-2017.
[60]
Is Fycompa a controlled substance? - Drugs.com
Oct 3, 2024 · Fycompa is classified as a Schedule 3 controlled substance by the DEA because it may be habit-forming. Misuse of this medicine can cause addiction, overdose, ...Missing: III | Show results with:III
[61]
Regulatory Decision Summary for Fycompa
Fycompa (perampanel) is currently approved in Canada as adjunctive therapy for the treatment of partial-onset seizures (POS) and primary generalized ...Missing: classification | Show results with:classification
[62]
[PDF] FYCOMPA (perampanel) Product Monograph
Feb 24, 2020 · This means that i) doses above 12 mg/day cannot be recommended for any patients; and ii) there is inadequate information about the maximum ...
[63]
antiepileptic drug fycompa® injection formulation approved in ... - Eisai
Jan 18, 2024 · Perampanel is currently approved in more than 75 countries and territories, including Japan, China, and other countries in Europe and in Asia as ...Missing: legal | Show results with:legal
[64]
Schedules of Controlled Substances: Placement of Perampanel into ...
Oct 22, 2013 · As stated in HHS's review, the results of a human abuse potential study indicate that perampanel has an abuse potential comparable to or greater ...
[65]
https://pdf.hres.ca/dpd_pm/00055181.PDF
[66]
[PDF] A Systematic Review of the Cost-effectiveness of Perampanel in the ...
136.58 Euro, and the price per mg was 0.6097. Euro. Saku Väätäinen et al. [15] showed that the perampanel drug cost was 222.74 Euro/28 days. It should be ...
[67]
Value of Perampanel as Adjunctive Treatment for Partial-Onset ...
Jul 5, 2021 · However, in developing countries, most epileptic patients cannot receive reasonable and effective treatment. In China, the treatment gap for ...
[68]
https://www.goodrx.com/fycompa
[69]
[PDF] EISAI ASSISTANCE PROGRAM FOR FYCOMPA® (perampanel) CIII
To enroll in the Fycompa Patient Assistance Program, check the box and complete section 1. Financial documentation is required. Call 1-855-347-2448.Missing: uninsured | Show results with:uninsured