Perampanel

Perampanel is a selective non-competitive AMPA receptor antagonist used as adjunct therapy for focal seizures and generalised tonic-clonic seizures. It has a long half-life that allows once daily dosing at night, but carries a boxed-warning-level risk of serious psychiatric and behavioural reactions.

Mechanism. Blocks postsynaptic AMPA-type glutamate receptors, reducing excitatory transmission.

Pharmacokinetics. Bioavailability near 100%, protein binding about 95%, and half-life about 105 hours (25 hours with strong enzyme inducers). Metabolised by cytochrome P450 3A4 and 3A5. Steady state takes about 3 weeks.

Alternative use. Adjunct for focal seizures (age 4 years and over in most labels) and generalised tonic-clonic seizures (age 7 or 12 years and over, depending on the label). Treatment is long term.

• Adults and adolescents, oral perampanel: 2 mg at bedtime (4 mg with strong enzyme inducers), increased by 2 mg no more often than every 2 weeks. Usual maintenance 4 to 8 mg daily for focal seizures, and about 8 mg daily for generalised tonic-clonic seizures. Maximum 12 mg daily.

• Children 4 to 11 years: weight-based, specialist-directed dosing starting at a low bedtime dose.

Kidney, liver, weight and age.

• Kidney: mild impairment, no change. Moderate impairment, slower titration. Not advised in severe impairment or haemodialysis.

• Liver: mild to moderate impairment, start 2 mg and titrate every 2 weeks, with a maximum of 8 mg in mild and 4 mg in moderate impairment. Not advised in severe impairment.

• Older adults: titrate every 2 weeks and watch for falls.

Contraindications. Hypersensitivity.

Serious adverse effects. Serious psychiatric and behavioural reactions (aggression, hostility, irritability, anger, homicidal ideation), suicidal ideation, psychosis, falls, and drug reaction with eosinophilia and systemic symptoms.

Common adverse effects. Dizziness, somnolence, ataxia, gait disturbance, fatigue, irritability, weight gain and falls.

Interactions. Carbamazepine, oxcarbazepine, phenytoin and other inducers lower levels by about half or more. Perampanel at 12 mg daily lowers levonorgestrel exposure, so use alternative contraception. Alcohol and other sedatives worsen dizziness and impaired alertness.

Common prescribing errors. Titrating faster than every 2 weeks. Not warning about mood and aggression. Dosing in the morning rather than at bedtime.

Special groups.

• Pregnancy: limited data; use only if benefit outweighs risk. Give folic acid 5 mg daily before conception.

• Breastfeeding: data are lacking; weigh benefit and risk.

• Regional: seldom available outside specialist centres.

Formulations. Tablets 2, 4, 6, 8, 10 and 12 mg. Oral suspension 0.5 mg/mL in some markets. Take at bedtime, with or without food.

Monitoring. Mood, irritability, aggression and suicidal thoughts at each review, with carer reports. Falls, sedation and weight. Levels are not routine.

Stopping. Reduce gradually. The long half-life gives some self-taper, but reduce by 2 mg at intervals of 1 to 2 weeks. Stop promptly for severe psychiatric reactions.

Referral and escalation. Refer for persistent seizures or psychiatric symptoms. Urgent psychiatric review for suicidal thoughts or violent behaviour.