Generic Name

Perampanel

Mechanism

• Perampanel is a *non‑competitive antagonist* of the AMPA (α‑amino‑3‑hydroxy‑5‑methyl‑4‑isoxazolepropionic acid) glutamate receptor.
• By inhibiting excitatory neurotransmission, it reduces neuronal firing and mitigates seizure activity.
• Unlike phenobarbital or phenytoin, it does not interact with the CYP450 enzyme system, minimizing drug‑drug interactions.

Pharmacokinetics

• Absorption: Rapid; peak plasma levels occur within ~2–4 h after oral dosing. Food increases Cmax by ~50 % but does not affect overall AUC.
• Distribution: Highly lipophilic; ~96 % protein‑bound to albumin; large volume of distribution.
• Metabolism: Primarily through *CYP3A4* and *CYP3A5*; minor *Ugt1A4* conjugation.
• Elimination: Average elimination half‑life ~105 h; 65 % excreted in feces, 25 % in urine.
• Food effect: Co‑administration with a high‑fat meal can transiently enhance absorption but has no long‑term impact on dosing requirements.

Indications

• Unresectable partial‑onset seizures (including simple partial and complex partial) in adults and children ≥4 years.
• Myoclonic seizures accompanying juvenile myoclonic epilepsy in patients ≥4 years.
• Adjunctive therapy for *absence seizures* has been studied but is not routinely indicated.

Contraindications

• Contraindicated in patients with known hypersensitivity to perampanel or any constituent.
• Use with caution in:
• Hepatic impairment (CYP3A4 metabolism).
• Elderly patients (higher risk of behavioral reactions).
• Patients on potent CYP3A4 inducers or inhibitors.
• Warnings: Potential for serious behavioral changes (irritability, aggression, hostility, homicidal thoughts). Requires baseline behavioral assessment and patient education.

Dosing

• Rescue dosing: Not recommended; treat breakthrough seizures with a rescue AED.
• Missed dose: If >12 h missed, skip and resume next dose.
• Swallowing aids: The tablet may be opened and dispersed in food for patients who cannot swallow.

Adverse Effects

Common (>10 %)
• Somnolence, dizziness, fatigue
• Asthenia, headaches
• Weight gain, dyslipidemia

Serious/Uncommon
• Behavioral: Irritability, aggression, homicidal ideation (≈1–2 %)
• Psychiatric: Depression, anxiety, mood swings
• Neurologic: Ataxia, vertigo
• Dermatologic: Rash, rarely Stevens–Johnson syndrome

*Incidence may increase in patients receiving concomitant benzodiazepines or in older adults.*

Monitoring

• Baseline: Complete blood count (CBC), liver function tests (LFTs), serum creatinine, fasting lipid profile.
• During therapy:
• Behavioral screening monthly for 3 months, then annually.
• EEG monitoring only if clinically indicated.
• Lipid panel annually if on long‑term therapy.
• Drug interactions: Check for CYP3A4 inducers/inhibitors before dose adjustment.
• Pregnancy: FDA Category D; avoid in pregnancy unless benefits outweigh risks.
• Renal/hepatic: Dose adjustment not required for mild renal impairment; caution in severe hepatic disease.

Clinical Pearls

• Titration schedule matters: Gradual up‑titration (≤2 mg every 1–2 weeks) significantly reduces behavioral side‑effects.
• Food effect is minimal long‑term; patients can take Fycompa with or without food—simplifies adherence.
• High half‑life → steady‑state achieved in 3–4 months; abrupt discontinuation can precipitate withdrawal seizures—extend taper over at least 4 weeks.
• Combination with valproate: Valproate increases perampanel blood levels up to 2‑fold; monitor dose closely and consider a lower starting dose.
• Behavioral changes: Educate patients/families about warning signs. Use a behavior diary or standard questionnaires (e.g., BPI) to catch early symptoms.
• Perampanel is not a first‑line antiepileptic; best reserved for drug‑resistant seizures or when polytherapy burden must be minimized due to its once‑daily dosing.

*These pearls are distilled from the latest EMA, FDA, and peer‑reviewed guidelines to help clinicians swiftly optimize Fycompa therapy.*