Lamotrigine

Lamotrigine is a phenyltriazine antiseizure medicine and mood stabiliser used for focal and generalised epilepsy and for prevention of depressive episodes in bipolar disorder. It is well tolerated and relatively favourable in pregnancy, but it needs slow titration because of the risk of serious rash, and its levels are changed by valproate, enzyme inducers and oestrogen.

Mechanism. Blocks voltage-gated sodium channels and reduces release of glutamate.

Pharmacokinetics. Bioavailability about 98%, protein binding 55%. Cleared by glucuronidation. Half-life is 25 to 33 hours alone, 48 to 70 hours with valproate, and 13 to 14 hours with enzyme inducers. Oestrogen-containing contraceptives roughly halve levels, and pregnancy increases clearance 2 to 3 times.

First-line use. Focal seizures, generalised tonic-clonic seizures, absence seizures (second choice) and Lennox-Gastaut syndrome. Treatment is long term.

• Adults, oral lamotrigine alone: 25 mg daily for 2 weeks, 50 mg daily for 2 weeks, then increase by 50 to 100 mg every 1 to 2 weeks. Usual maintenance 100 to 200 mg daily, once or twice daily. Maximum 500 mg daily.

• With valproate: 25 mg on alternate days for 2 weeks, 25 mg daily for 2 weeks, then increase by 25 to 50 mg every 1 to 2 weeks. Usual maintenance 100 to 200 mg daily.

• With enzyme inducers (carbamazepine, phenytoin, phenobarbital, primidone) but no valproate: 50 mg daily for 2 weeks, 100 mg daily in two doses for 2 weeks, then increase by up to 100 mg every 1 to 2 weeks. Usual maintenance 200 to 400 mg daily, up to 700 mg.

• Children 2 to 12 years, alone: 0.3 mg/kg daily for 2 weeks, 0.6 mg/kg daily for 2 weeks, then 0.6 mg/kg every 1 to 2 weeks to a usual 4.5 to 7.5 mg/kg daily, maximum 300 mg daily. With valproate: 0.15 mg/kg daily, then 0.3 mg/kg daily, increasing by 0.3 mg/kg to a usual 1 to 5 mg/kg daily. With inducers: 0.6 mg/kg daily, then 1.2 mg/kg daily, up to 5 to 15 mg/kg daily.

• If stopped for more than 5 half-lives, restart from the initial titration.

Specialist use. Bipolar disorder maintenance: titrate to a target of 200 mg daily alone, 100 mg daily with valproate, and 400 mg daily with enzyme inducers.

Kidney, liver, weight and age.

• Kidney: lower maintenance doses may suffice in significant impairment. Haemodialysis removes about 20%.

• Liver: reduce initial, escalation and maintenance doses by about 25% in moderate to severe impairment without ascites, and by 50% in severe impairment with ascites.

• Older adults: start at the lower titration steps.

Contraindications. Hypersensitivity. Avoid in structural heart disease or conduction disease because of class 1B antiarrhythmic activity.

Serious adverse effects. Stevens-Johnson syndrome and toxic epidermal necrolysis (boxed-warning-level risk, highest with valproate, fast titration, over-dosing at start and in children), usually within 2 to 8 weeks. Haemophagocytic lymphohistiocytosis, aseptic meningitis, blood dyscrasias and multi-organ hypersensitivity.

Common adverse effects. Headache, dizziness, diplopia, ataxia, tremor, nausea, insomnia and benign rash.

Interactions.

• Valproate roughly doubles levels. Enzyme inducers, rifampicin and lopinavir-ritonavir or atazanavir-ritonavir lower levels. Ethinylestradiol-containing contraceptives lower levels, so the dose may need to double, and levels rise in the pill-free week.

• Lamotrigine does not meaningfully induce other drugs, but may lower levonorgestrel-only contraceptive levels slightly.

Common prescribing errors. Rapid titration. Forgetting to halve the start dose with valproate. Restarting at full dose after a missed week. Name confusion with similar-sounding medicines.

Special groups.

• Pregnancy: lower malformation risk than most alternatives. Levels fall markedly, so titrate to seizure control and return to the pre-pregnancy dose within days to weeks after delivery to avoid toxicity. Give folic acid 5 mg daily before conception.

• Breastfeeding: infant levels reach 20 to 50% of maternal. Use is usually acceptable with monitoring of the infant for rash, drowsiness and apnoea.

• Contraception: stopping or starting an oestrogen contraceptive needs dose review.

Formulations. Tablets 25, 50, 100, 150 and 200 mg. Dispersible tablets 5, 25 and 100 mg. Orodispersible tablets and prolonged-release tablets exist. Take with or without food.

Monitoring.

• Baseline: history of rash on any antiseizure medicine; consider cardiac assessment if risk.

• Ongoing: skin at each visit and counsel to report any rash, fever or mouth ulcers immediately. Levels are not routine, but a guide range is 3 to 15 mg/L; check in pregnancy and with contraceptive changes.

Stopping. Taper over at least 2 weeks. Stop immediately for rash with systemic features, unless clearly unrelated.

Referral and escalation. Refer any rash with fever, mucosal involvement, blistering or lymphadenopathy for urgent assessment. Refer for persistent seizures or pregnancy planning.