Topiramate

Topiramate is a sulfamate-substituted monosaccharide antiseizure medicine used for focal and generalised seizures, Lennox-Gastaut syndrome and migraine prophylaxis. It causes cognitive slowing, weight loss, metabolic acidosis and kidney stones, and is teratogenic.

Mechanism. Blocks voltage-gated sodium channels, enhances GABA-A activity, antagonises AMPA and kainate receptors and weakly inhibits carbonic anhydrase.

Pharmacokinetics. Bioavailability about 80%, protein binding 15 to 41%, half-life about 21 hours. About 70% is excreted unchanged in urine. Enzyme inducers cut levels by about half. At doses of 200 mg daily or more it reduces ethinylestradiol exposure.

First-line use. Focal and generalised tonic-clonic seizures as monotherapy or adjunct. Treatment is long term.

• Adults, oral topiramate for epilepsy: 25 mg at night for 1 week, then 25 to 50 mg daily in two doses, increased by 25 to 50 mg every 1 to 2 weeks. Monotherapy target 100 mg daily, usual 100 to 200 mg daily in two doses, maximum 500 mg daily. Adjunct usual 200 to 400 mg daily, maximum 800 mg daily in some practice; most keep to 400 mg daily.

• Children 2 to under 16 years: 0.5 to 1 mg/kg at night, increased by 0.5 to 1 mg/kg every 1 to 2 weeks. Adjunct target 5 to 9 mg/kg daily in two doses. Monotherapy target about 100 mg daily.

Alternative use. Migraine prophylaxis in adults: 25 mg at night for 1 week, then 25 mg twice daily, then 25 mg in the morning and 50 mg at night, then 50 mg twice daily. Target 100 mg daily in two doses. Maximum 200 mg daily. Not for women of childbearing potential unless contraception is reliable.

Kidney, liver, weight and age.

• Kidney: with creatinine clearance under 70 mL/min, halve the usual dose and titrate slowly. Haemodialysis removes much of the drug, so give a supplemental dose after dialysis.

• Liver: reduced clearance; use caution and titrate slowly.

• Older adults: dose by kidney function.

Contraindications. Hypersensitivity. Pregnancy and women of childbearing potential not using effective contraception for migraine prophylaxis.

Serious adverse effects. Acute myopia with secondary angle-closure glaucoma (usually within the first month), metabolic acidosis, kidney stones, oligohidrosis and hyperthermia in children, hyperammonaemic encephalopathy (especially with valproate), suicidal ideation, severe skin reactions, and foetal harm (oral clefts, small-for-gestational-age infants).

Common adverse effects. Cognitive slowing, word-finding difficulty, paraesthesia, fatigue, weight loss, taste change and mood disturbance.

Interactions. Phenytoin and carbamazepine lower topiramate levels, and topiramate may raise phenytoin. Valproate increases hyperammonaemia and encephalopathy risk. Metformin, acetazolamide and other carbonic anhydrase inhibitors add acidosis and stone risk. Topiramate lowers oestrogen contraceptive efficacy at higher doses, and may raise lithium levels at high doses.

Common prescribing errors. Starting at too high a dose. Not warning about cognitive effects. Missing acidosis. Not discussing contraception.

Special groups.

• Pregnancy: increased risk of oral clefts (about 1.4% against 0.4% background) and low birth weight. Avoid unless no alternative. Give folic acid 5 mg daily before conception.

• Breastfeeding: considerable milk transfer. Monitor the infant for diarrhoea, drowsiness and poor feeding.

• Children: monitor temperature and sweating in hot weather.

Formulations. Tablets 25, 50, 100 and 200 mg. Sprinkle capsules 15, 25 and 50 mg. Swallow tablets whole because of bitterness. Food does not matter. Encourage fluid intake of about 2 litres daily to lower stone risk.

Monitoring.

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

• Ongoing: bicarbonate periodically. Reduce the dose or taper if it stays persistently under 20 mmol/L. Review mood, cognition and eye symptoms. Drug levels are not routinely used.

Stopping. Reduce by 25 to 50 mg weekly. Stop promptly for acute visual loss or eye pain.

Referral and escalation. Urgent ophthalmology review for new visual blurring or eye pain. Refer for kidney stones, persistent acidosis, or when pregnancy is planned.