Perampanel

Introduction Overview

Generic Name

perampanel

Brand Name

Fycompa

Dosage Form

Oral tablet and oral suspension

Drug Class

AMPA receptor antagonists

Pharmacokinetics

Absorption:
Perampanel is rapidly absorbed from the gastrointestinal tract following oral administration, with peak plasma concentrations typically occurring between 0.5 to 2.5 hours post-dose. The absolute bioavailability of perampanel is high due to its efficient absorption. Food intake does not significantly affect the extent of absorption, but it may slightly delay the time to peak concentration. The oral suspension formulation is designed to be bioequivalent to tablets, facilitating administration in patients who have difficulty swallowing.

Distribution:
Perampanel is extensively distributed throughout the body, demonstrating a large volume of distribution approximately 77 L. It is highly protein-bound (~95%), primarily to albumin, which limits free drug concentration but may impact drug-drug interactions with other highly protein-bound medications. The penetration of perampanel across the blood-brain barrier is adequate to exert its therapeutic anticonvulsant effect on central nervous system AMPA receptors. Animal studies suggest significant CNS distribution, consistent with clinical efficacy in seizure control.

Metabolism:
Perampanel undergoes extensive metabolism primarily via hepatic cytochrome P450 enzymes, predominantly CYP3A4 and CYP3A5 isoforms. The principal metabolic pathways include oxidative metabolism leading to multiple inactive metabolites. The involvement of CYP3A isoenzymes dictates that inducers or inhibitors of these enzymes can significantly alter perampanel plasma concentrations, necessitating dosing adjustments. Enzyme-inducing antiepileptic drugs (AEDs) such as carbamazepine, phenytoin, and oxcarbazepine reduce perampanel levels via CYP3A induction.

Elimination:
The elimination half-life of perampanel in healthy adults ranges from approximately 70 to 110 hours, which allows once-daily dosing, typically administered at bedtime. Excretion occurs mainly through feces (~70%) and to a lesser extent through urine (~30%) as metabolites, with less than 2% of unchanged drug excreted renally. The prolonged elimination half-life contributes to a steady plasma concentration with chronic dosing but also requires careful consideration during dose titration and discontinuation to avoid accumulation or withdrawal seizures respectively. In patients with moderate to severe hepatic impairment, elimination may be altered, requiring dosage modifications and close monitoring.

Dosage Forms

Available Dosage Forms:
Fycompa is available as oral tablets and as an oral suspension:
- Oral tablets: film-coated tablets typically available in strengths including 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg.
- Oral suspension (liquid): contains 0.5 mg/mL perampanel, supplied in bottles with dosing syringes for precise measurement.

Dosages for Adults and Adolescents:
Fycompa dosing is individualized and titrated based on therapeutic response and tolerability. For patients aged 12 years and older:
- Initial dose without enzyme-inducing AEDs: 2 mg orally once daily at bedtime.
- Dose increments: increased by 2 mg increments, no more frequently than every week.
- Maintenance dose: usually 4 to 12 mg once daily.
- Maximum dose: 12 mg once daily at bedtime.
- In presence of enzyme-inducing AEDs (such as carbamazepine, phenytoin, oxcarbazepine), initial dose is 4 mg once daily, with dose adjustments as needed.

Specific Patient Populations:
- Pediatrics (≥12 years): same dosing regimen as adults with appropriate monitoring.
- Liver or kidney impairment: caution is advised; perampanel dose adjustments may be necessary although specific guidelines require consultation.
- Elderly patients: increased risk of falls; start at lower doses and titrate cautiously.

Clinical guidelines recommend bedtime administration to minimize central nervous system adverse effects such as dizziness or somnolence. The oral suspension formulation is especially useful for patients who have difficulty swallowing tablets, facilitating adherence in pediatric or elderly populations.

Mechanism Of Action

Perampanel is a highly selective, non-competitive antagonist of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of glutamate receptors located on postsynaptic neurons. By binding allosterically to AMPA receptors, perampanel inhibits the receptor’s ion channel function without competing with glutamate directly, thereby reducing excitatory neurotransmission in the central nervous system.

This mechanism results in decreased calcium and sodium ion influx at neuronal synapses, attenuating abnormal neuronal firing associated with epileptic seizures. This suppression of excitatory postsynaptic potentials stabilizes neuronal membranes and reduces the spread of seizure activity in the brain.

Compared to other antiepileptics, which may modulate sodium channels, GABAergic activity, or other receptor subtypes, perampanel’s selective antagonism of AMPA receptors provides a unique mode of action targeting glutamatergic excitatory pathways. This novel mechanism contributes to its efficacy as adjunctive therapy for partial-onset seizures and primary generalized tonic-clonic seizures.

Clinical studies have demonstrated that perampanel’s antagonism of AMPA receptors effectively reduces seizure frequency. Additionally, its long half-life allows for sustained receptor blockade with once-daily dosing. Ongoing research explores the drug’s potential neuroprotective effects due to modulation of excitotoxic pathways implicated in epilepsy and other neurological disorders.

Pharmacological Actions

Selective non-competitive antagonism of AMPA glutamate receptors in the CNS.
Reduction of excitatory neurotransmission associated with seizure activity.
Stabilization of neuronal membranes by inhibiting ion influx through AMPA receptor channels.
Adjunctive anticonvulsant activity for controlling partial-onset seizures with or without secondary generalization.
Adjunctive treatment for primary generalized tonic-clonic seizures in patients 12 years and older.
Minimal affinity for other receptor types, reducing potential for off-target effects.
Produces dose-dependent central nervous system depressant effects such as dizziness and somnolence.
Exhibits slow elimination kinetics supporting once-daily dosing.
Demonstrates potential neuroprotective effects by mitigating glutamate-induced excitotoxicity.
Does not significantly inhibit or induce major cytochrome P450 enzymes but is metabolized via CYP3A4/5.

Therapeutic Or Clinical Uses

Adjunctive treatment of partial-onset seizures (with or without secondarily generalized seizures) in patients with epilepsy aged 12 years and older.
Adjunctive therapy for primary generalized tonic-clonic (PGTC) seizures in patients 12 years of age and older.
Management of refractory seizures when added to other antiepileptic drugs.
Use in pediatric patients ≥12 years for seizure control with individualized dosing.
Potential investigational use in other neurological disorders involving glutamatergic excitotoxicity (under research).
Treatment of epilepsy patients with complex partial seizures unresponsive to first-line therapies.
Reduction of seizure frequency and severity in combination antiepileptic regimens.
Alternative therapy for patients intolerant to other antiepileptic drugs due to its unique mechanism.
Use as a once-daily, bedtime oral medication to improve compliance and minimize daytime sedation.
Reduction in seizures contributes to improved quality of life and reduced morbidity in epilepsy patients.

Side Or Adverse Effects

Dizziness and vertigo, commonly reported and sometimes severe enough to cause falls, especially in elderly patients.
Somnolence and drowsiness impacting alertness and motor coordination.
Headache of varying intensity.
Fatigue, tiredness, or general weakness.
Nausea, vomiting, and abdominal discomfort.
Weight gain observed in approximately 4% of patients on higher doses (8-12 mg).
Behavioral and psychiatric effects including irritability, aggression, hostility, anxiety, and mood changes.
Serious psychotic reactions such as hallucinations, paranoia, and homicidal or suicidal ideations, particularly during treatment initiation or dose titration.
Loss of coordination and ataxia leading to impaired balance.
Bruising and bleeding tendencies reported rarely.
Memory impairment, confusion, and cognitive effects in some patients.
Increased risk of accidental falls due to CNS depressant effects.
Allergic reactions including rash, urticaria, and angioedema are rare but serious.
Potential for dependence and misuse; caution advised in patients with history of drug addiction.
Withdrawal seizures risk if the drug is abruptly discontinued.

Precautions

Monitor closely for mood and behavior changes, especially suicidal ideation or aggressive behavior.
Use with caution in patients with history of psychiatric disorders including depression and psychosis.
Avoid abrupt discontinuation to prevent increased seizure frequency or status epilepticus.
Dose adjustments are necessary if used concomitantly with enzyme-inducing AEDs to maintain therapeutic efficacy.
Caution in elderly due to increased risk of falls and resultant injuries.
Avoid or limit alcohol due to additive CNS depressant effects.
Consider alternative contraception methods as perampanel may reduce effectiveness of hormonal birth control.
Use cautiously in patients with moderate to severe hepatic impairment; dose modification may be necessary.
Regular liver and kidney function monitoring recommended during prolonged therapy.
Careful dose titration to reduce the incidence of CNS-related adverse effects.
Advise patients to avoid driving or operating heavy machinery until they know how the drug affects them.
Evaluate risk-benefit in pregnant women; informed pregnancy registry participation is recommended.
Avoid use in patients with known hypersensitivity to perampanel or any formulation excipients.
Store medication securely to prevent misuse or accidental ingestion, especially in households with children or individuals at risk of abuse.
Periodic assessment for weight changes and metabolic side effects during treatment.

Warnings

Risk of serious psychiatric adverse effects, including psychosis, hostility, aggression, and suicidal thoughts.
Potential for habit-forming properties; misuse can lead to addiction, overdose, or death.
Abrupt withdrawal of Fycompa may result in increased seizure frequency or status epilepticus.
Not recommended to initiate or discontinue during pregnancy without medical supervision due to risk to mother and fetus.
May cause dizziness and somnolence; patients should not engage in hazardous activities until stable dosage response is confirmed.
Reduced efficacy of hormonal contraceptives; non-hormonal contraception should be considered to prevent unintended pregnancy.
Serious skin reactions and hypersensitivity are rare but require immediate medical attention.
Monitoring is required when introduced in combination with enzyme-inducing AEDs due to altered pharmacokinetics.
Risk of falls and related injuries is increased, particularly in older adults.
Alcohol consumption can potentiate CNS depressive effects and should be avoided.
Potential for cognitive impairment and memory disturbances; caution in activities requiring mental alertness.
Use with caution in patients with a history of addiction or substance abuse.
Patients and caregivers should be educated about signs of mood or behavior changes requiring rapid medical attention.
Dose titration should be performed gradually to minimize adverse neurologic or psychiatric effects.
Sudden discontinuation can exacerbate seizures and is strongly discouraged.

Contraindication

Known hypersensitivity or allergy to perampanel or any component of the formulation.
Use in patients with a history of psychotic disorders without close monitoring due to risk of exacerbation.
Concomitant use with drugs or substances known to severely alter CYP3A4 activity that cannot be monitored may be contraindicated.
Patients with active suicidal ideation or behaviors until stabilized under supervision.
Inability to adhere to prescribed dosing or monitoring schedule, increasing risk of adverse effects or toxicity.
Severe hepatic impairment without appropriate dose adjustment and medical oversight.
Use during pregnancy unless clearly needed and under rigorous medical supervision.
Known drug abuse or addiction history without adequate safeguards to prevent misuse.
Patients with severe coordination or balance problems at high risk for falls may require alternative therapies.
Known intolerance to similar AMPA receptor antagonists if applicable.
Concomitant use with potent CYP3A inducers like rifampin without dose adjustments or monitoring.
Children under 4 years of age, as safety and efficacy have not been established.
Use with caution or avoidance in breastfeeding mothers until risk assessment is done.
Contraindicated in patients with serious dermatologic reactions suspected to be related to perampanel.
Patients with history of severe allergic reactions to other antiepileptic drugs until risk-benefit analysis is performed.

Drug Interactions

Carbamazepine, oxcarbazepine, and phenytoin significantly induce CYP3A4 enzymes, decreasing perampanel plasma concentrations and reducing its efficacy.
Rifampin, a potent CYP3A4 inducer, markedly reduces perampanel levels, necessitating dose adjustment.
St. John's wort, an herbal CYP3A4 inducer, also diminishes perampanel exposure.
Hormonal contraceptives may have reduced efficacy due to perampanel-induced enzyme induction, requiring alternative contraceptive methods.
Concurrent use with central nervous system depressants such as opioids, benzodiazepines, or muscle relaxants can exacerbate sedation and dizziness.
Co-administration with other antiepileptic medications may necessitate dose monitoring to avoid additive adverse effects.
Strong CYP3A4 inhibitors may increase perampanel plasma levels, heightening risk of toxicity, though clinical data is limited.
No significant interaction with CYP2C19, CYP1A2, or other common metabolic pathways.
Potential pharmacodynamic interaction with alcohol leading to enhanced CNS depression and impaired motor function.
Concomitant use with drugs affecting protein binding may alter free perampanel concentrations.
Perampanel does not significantly alter the metabolism of other drugs but clinical vigilance is warranted.
Adjustments may be needed if enzyme-inducing AEDs are added or withdrawn from the regimen due to impact on perampanel clearance.
Possible interaction with warfarin and other anticoagulants requiring monitoring of coagulation parameters.
Interactions with vitamin supplements and herbal products should be assessed case-by-case.
Patients should disclose all prescription, over-the-counter, and herbal medications to healthcare providers to avoid harmful interactions.

Preparations Of The Drug

Film-coated oral tablets supplied in various strengths (2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg) for flexible dosing.
Oral suspension (0.5 mg/mL) in bottles with dosing syringe for accurate measurement, suitable for pediatric and patients with swallowing difficulties.
Packaging designed to maintain stability at room temperature, avoiding moisture and heat exposure; do not freeze suspension.
Each preparation includes patient information leaflets detailing dosing instructions, side effects, and cautions.
Prescription-only availability due to potential for misuse and serious adverse effects.
Controlled substance scheduling (Schedule III) with regulations on dispensing and storage.
Specific labeling for warnings regarding CNS depression, psychiatric effects, and pregnancy considerations.
Tamper-evident packaging to reduce risk of misuse or diversion.
Batch and expiry information included to ensure drug stability and efficacy.
Dosing syringes calibrated for oral suspension to ensure accurate administration.
Suspension requires shaking before use to maintain uniform drug concentration.
Tablets are film-coated to facilitate swallowing and protect active ingredient.
No currently available intravenous or alternative parenteral formulations; oral administration only.
Storage guidance emphasizes disposal of unused suspension 90 days after opening to maintain safety and efficacy.
Educational materials available for healthcare providers to guide proper prescription and monitoring.