Primidone

Primidone is a barbiturate-related antiseizure medicine used for focal and generalised tonic-clonic seizures and widely for essential tremor. It is metabolised to phenobarbital and phenylethylmalonamide, so it shares the sedation, enzyme induction and teratogenicity of phenobarbital.

Mechanism. Primidone and its two active metabolites (phenobarbital and phenylethylmalonamide) reduce neuronal excitability. Phenobarbital enhances GABA-A chloride channel opening.

Pharmacokinetics. Bioavailability about 90%. Half-life is 5 to 15 hours for primidone, about 16 hours for phenylethylmalonamide, and 75 to 120 hours for phenobarbital. Excretion is partly renal as unchanged drug.

First-line use. Focal and generalised tonic-clonic seizures where phenobarbital-type therapy is chosen. Treatment is long term.

• Adults, oral primidone for epilepsy: 125 mg at bedtime for 3 days, then 125 mg twice daily for 3 days, then 250 mg twice daily for 3 days, then 250 mg three times daily. Usual maintenance 750 to 1500 mg daily in two or three doses. Usual maximum 1500 mg daily; some labels allow 2000 mg daily.

• Children under 8 years: 50 mg at bedtime for 3 days, 50 mg twice daily for 3 days, 100 mg twice daily for 3 days, then 125 to 250 mg three times daily (10 to 25 mg/kg daily).

Alternative use. Essential tremor (off-label): 12.5 to 25 mg at night, increased by 25 mg every 1 to 2 weeks to a usual 50 to 250 mg daily in one or two doses. Reduce the starting dose in older adults because first-dose sedation and nausea are common.

Kidney, liver, weight and age.

• Kidney: extend the dosing interval to 12 to 24 hours in severe impairment.

• Liver: reduce the dose; avoid in severe impairment.

• Older adults: start at 12.5 to 25 mg and titrate slowly.

Contraindications. Porphyria and hypersensitivity to primidone or phenobarbital.

Serious adverse effects. Severe skin reactions, megaloblastic anaemia, respiratory depression with sedatives, osteomalacia, dependence, withdrawal seizures and foetal malformation.

Common adverse effects. Drowsiness, ataxia, dizziness, nausea and vomiting (especially at initiation), visual disturbance and behavioural change.

Interactions. Like phenobarbital, it induces enzymes and lowers warfarin, direct oral anticoagulants, hormonal contraceptives, corticosteroids, doxycycline, dolutegravir, efavirenz and protease inhibitors. Valproate raises phenobarbital derived from primidone. Isoniazid and alcohol add risk. Phenytoin increases conversion to phenobarbital.

Common prescribing errors. Starting at the full dose. Prescribing both primidone and phenobarbital. Not warning about first-dose sedation.

Special groups.

• Pregnancy: teratogenic and linked to neonatal bleeding and withdrawal. Give folic acid 5 mg daily before conception and vitamin K 1 mg to the newborn.

• Breastfeeding: infant sedation and poor feeding; monitor or avoid.

• Regional: availability varies; phenobarbital is often the practical alternative.

Formulations. Tablets 50 and 250 mg (market dependent). Oral suspension 250 mg/5 mL in some markets. Take with food to limit nausea.

Monitoring.

• Baseline: full blood count, liver function and a sedation and fall risk review.

• Ongoing: primidone trough 5 to 12 mg/L and phenobarbital level 15 to 40 mg/L. Review folate, calcium and vitamin D in long-term use.

Stopping. Taper over several weeks to avoid withdrawal seizures or rebound tremor.

Referral and escalation. Refer for persistent seizures, planned pregnancy, or excessive sedation. For essential tremor, refer when propranolol and primidone fail or are not tolerated.