Zonisamide

Zonisamide is a sulphonamide-derived antiseizure medicine used for focal seizures, with once daily dosing and a long half-life. Its notable risks are metabolic acidosis, kidney stones, weight loss, mood effects and heat-related problems in children.

Mechanism. Blocks voltage-gated sodium channels and T-type calcium channels, and weakly inhibits carbonic anhydrase.

Pharmacokinetics. Bioavailability is near 100%. Protein binding is 40 to 50%, and it binds extensively to red cells. Half-life is about 63 hours, falling to 27 to 38 hours with enzyme inducers. It is cleared by cytochrome P450 3A4 and acetylation, and about 35% is excreted unchanged.

First-line use. Focal seizures with or without secondary generalisation, as monotherapy or adjunct. Treatment is long term.

• Adults, oral zonisamide as monotherapy: 100 mg daily for 2 weeks, 200 mg daily for 2 weeks, 300 mg daily for 2 weeks, then 400 mg daily if needed. Usual maintenance 300 mg daily. Usual maximum 500 mg daily; some labels allow 600 mg daily.

• Adjunct: 50 mg daily in two doses for 1 week, then 100 mg daily, then increase by 100 mg weekly. Usual maintenance 300 to 500 mg daily, once or twice daily.

• Children 6 to 17 years, adjunct: 1 mg/kg daily for 1 week, increasing by 1 mg/kg weekly to a usual 6 to 8 mg/kg daily. Maximum 500 mg daily.

Kidney, liver, weight and age.

• Kidney: titrate more slowly, with intervals of 2 weeks. Use is not advised when creatinine clearance is under 20 mL/min.

• Liver: titrate more slowly and use caution.

• Older adults: start low and monitor weight and fluid intake.

Contraindications. Hypersensitivity to zonisamide or sulphonamides.

Serious adverse effects. Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, aplastic anaemia, agranulocytosis, metabolic acidosis, kidney stones, oligohidrosis and hyperthermia in children, psychosis and suicidal ideation, rhabdomyolysis and acute myopia with angle closure.

Common adverse effects. Somnolence, dizziness, anorexia, weight loss, irritability, depression and cognitive slowing.

Interactions. Carbamazepine, phenytoin and phenobarbital shorten half-life. Topiramate and acetazolamide add acidosis and stone risk. Strong cytochrome P450 3A4 inhibitors raise levels modestly.

Common prescribing errors. Prescribing to someone with sulphonamide allergy. Fast titration. Missing acidosis. Not advising adequate fluids.

Special groups.

• Pregnancy: avoid unless essential, and ensure effective contraception during and for 1 month after treatment. Give folic acid 5 mg daily before conception.

• Breastfeeding: avoid during and for 1 month after stopping, because of the long half-life.

• Children: warn about reduced sweating and fever in hot weather.

Formulations. Capsules 25, 50 and 100 mg. Oral suspension in some markets. Take with or without food, and swallow capsules whole.

Monitoring.

• Baseline: serum bicarbonate, creatinine, weight and mood.

• Ongoing: bicarbonate and weight periodically. Reduce or stop if persistent acidosis develops. Encourage about 2 litres of fluid daily. A guide level is 10 to 40 mg/L.

Stopping. Taper gradually, for example reducing by 100 mg each week. Stop at once for rash, blood dyscrasia or acute visual symptoms.

Referral and escalation. Refer for persistent seizures, kidney stones, severe acidosis, psychiatric symptoms or planned pregnancy.