Perampanel

• Approved Indications:
• Partial-Onset Seizures (with or without secondarily generalized seizures):
  Indicated as monotherapy or adjunctive therapy in patients ≥4 years of age with focal (partial-onset) seizures.
• Primary Generalized Tonic-Clonic Seizures (PGTCS):
  Approved as adjunctive therapy for the treatment of PGTCS in patients ≥12 years of age with generalized epilepsy.
• Clinically Accepted Off-Label Uses:
• Refractory Epilepsy Syndromes in pediatric patients under close supervision.
• Status Epilepticus (experimental use): Used in refractory or super-refractory cases.

• Route: Oral (tablets or oral suspension)

Adults & Adolescents (≥12 years)

• Partial-Onset Seizures (adjunctive or monotherapy):
  Start with 2 mg once daily at bedtime; may increase by 2 mg/week based on clinical response and tolerability.
  Usual maintenance dose: 4–12 mg once daily.
• Primary Generalized Tonic-Clonic Seizures (adjunctive):
  Start with 2 mg once daily at bedtime; titrate in 2 mg/week steps to a recommended dose of 8 mg/day, up to 12 mg/day if needed.

Children (4–11 years):

• Partial-Onset Seizures (adjunctive):
  Weight-based dosing.
• For 20–30 kg: Start 1 mg/day; titrate cautiously.
• For >30 kg: Start 2 mg/day; increase by 1–2 mg/week as tolerated.

Special Populations:

• Elderly:
  Start at the lowest effective dose with slower titration due to increased sensitivity.
• Hepatic Impairment:
• Mild (Child-Pugh A): Use with caution.
• Moderate (Child-Pugh B): Max dose 8 mg/day.
• Severe (Child-Pugh C): Not recommended.
• Renal Impairment:
  No dosage adjustment required for mild/moderate impairment. Not studied in severe impairment or dialysis patients.
• Concomitant Enzyme-Inducing AEDs (e.g., carbamazepine, phenytoin):
  May require higher maintenance doses due to increased clearance of perampanel.

Perampanel is a selective, non-competitive antagonist of the AMPA-type glutamate receptor located on postsynaptic neurons in the central nervous system. By inhibiting glutamate-mediated excitatory neurotransmission, perampanel reduces neuronal hyperexcitability and prevents seizure propagation. This unique mechanism, distinct from other anti-seizure medications, makes it effective for both focal and generalized seizure types.

• Absorption:
  Rapidly and completely absorbed after oral administration.
  Bioavailability: ~100%
• Time to Peak Concentration:
  ~0.5 to 2.5 hours (faster with suspension)
• Distribution:
  High plasma protein binding (~95–96%)
  Volume of distribution: ~77 L
• Metabolism:
  Extensively metabolized in the liver via CYP3A4.
  Active metabolites are not considered clinically relevant.
• Half-life:
  Approximately 105 hours (long half-life supports once-daily dosing)
• Elimination:
  Primarily via hepatic metabolism; excreted in urine and feces.

• Pregnancy:
• FDA Pregnancy Category: Not assigned (post-2015 rule).
  Animal studies have shown fetal harm (e.g., skeletal malformations). Use only if clearly needed.
  May reduce the efficacy of hormonal contraceptives (especially at doses ≥12 mg/day).
• Lactation:
• Unknown if excreted in human breast milk. Caution is advised; monitor infant for sedation or developmental effects.

• Class: Antiepileptic drug (AED)
• Subclass: AMPA receptor antagonist

• Known hypersensitivity to perampanel or any component of the formulation.
• Severe hepatic impairment (Child-Pugh Class C).

• Neuropsychiatric Adverse Reactions:
  Includes aggression, hostility, irritability, homicidal ideation, and behavioral changes, especially in adolescents. Close monitoring is critical during dose titration.
• CNS Effects:
  Dizziness, somnolence, and fatigue may impair ability to operate machinery or drive.
• Falls:
  Higher incidence of falls reported, particularly in the elderly or those with mobility issues.
• Suicidal Behavior and Ideation:
  As with other AEDs, monitor for mood changes, depression, or suicidal thoughts.
• Withdrawal Seizures:
  Taper gradually to avoid increased seizure frequency.

• Very Common (≥10%):
• Dizziness
• Somnolence
• Fatigue
• Headache
• Irritability
• Common (1–10%):
• Nausea, vomiting
• Ataxia, gait disturbance
• Weight gain
• Anxiety, confusion
• Aggression or hostility (especially in younger patients)
• Rare but Serious:
• Homicidal ideation
• Severe aggression or psychosis
• Suicidal thoughts
• Falls and injuries due to sedation
• Most adverse effects are dose-dependent and more pronounced during titration.

• CYP3A4 Inducers (e.g., carbamazepine, phenytoin, oxcarbazepine):
  ↓ Perampanel plasma levels; may require dose increase.
• CYP3A4 Inhibitors (e.g., ketoconazole):
  ↑ Perampanel exposure; monitor for toxicity.
• Alcohol and other CNS depressants:
  Enhanced CNS effects, including sedation and behavioral changes.
• Hormonal contraceptives (at ≥12 mg/day):
  ↓ Efficacy of progestin-containing contraceptives—use alternative non-hormonal contraception.
• Not a major CYP450 inhibitor or inducer itself.

• Labeling Changes:
  Recent updates emphasize monitoring for aggressive behavior and suicidality, especially in younger patients.
• Expanded Age Indications:
  Now approved for adjunctive use in children as young as 4 years old for focal seizures.
• Research Trends:
  Ongoing studies are exploring potential benefits in epileptic encephalopathies and status epilepticus.

• Tablets and Oral Suspension:
• Store at 20°C to 25°C (68°F to 77°F)
• Excursions permitted: 15°C to 30°C (59°F to 86°F)
• Keep container tightly closed and protect from moisture.
• Do not freeze the oral suspension.
• Shake suspension well before use.