Carbamazepine

Carbamazepine is a sodium channel blocking antiseizure medicine used for focal seizures, generalised tonic-clonic seizures, trigeminal neuralgia and as a second-line mood stabiliser. It is a potent enzyme inducer that induces its own metabolism, which drives most of its interactions and dosing quirks.

Mechanism. Blocks voltage-gated sodium channels in a use-dependent way, stabilising hyperexcitable neurons. It can worsen absence and myoclonic seizures.

Pharmacokinetics. Absorption is slow and variable, bioavailability is 75 to 85%, and protein binding is about 75%. It is oxidised by cytochrome P450 3A4 to the active carbamazepine-10,11-epoxide. Autoinduction cuts half-life from 25 to 65 hours at the start to 12 to 17 hours after 3 to 5 weeks, so dose increases are needed during that period.

First-line use. Focal seizures and generalised tonic-clonic seizures. First-line for trigeminal neuralgia. Treatment is long term.

• Adults, oral carbamazepine for epilepsy: start 100 to 200 mg once or twice daily, increase by 100 to 200 mg every week to a usual maintenance of 800 to 1200 mg daily in two or three divided doses (twice daily for prolonged-release). Usual maximum 1600 mg daily; some practice allows up to 2000 mg daily under specialist care.

• Children 6 to 12 years: 100 mg twice daily, increased by 100 mg weekly to a maximum of 1000 mg daily. Under 6 years: 10 to 20 mg/kg daily in two or three doses, increased weekly to a maximum of 35 mg/kg daily.

• Trigeminal neuralgia: 100 mg twice daily, increased by up to 200 mg daily as needed to a usual 400 to 800 mg daily, maximum 1200 mg daily. Attempt dose reduction periodically.

Specialist use. Bipolar disorder (second line): 400 mg daily in divided doses, up to a maximum of 1600 mg daily, with level monitoring.

Kidney, liver, weight and age.

• Kidney: no formal change; use caution and monitor sodium.

• Liver: use caution, and avoid in active hepatic disease.

• Older adults: start 100 mg once or twice daily; hyponatraemia, confusion and falls are more frequent.

Contraindications. Atrioventricular conduction block; history of bone marrow depression; acute intermittent porphyria; hypersensitivity to carbamazepine or tricyclic compounds; monoamine oxidase inhibitors within 14 days; HLA-B*1502 carriers, unless benefit clearly outweighs risk.

Serious adverse effects. Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, aplastic anaemia, agranulocytosis, hyponatraemia, hepatitis, bradyarrhythmia and conduction block, osteomalacia, and foetal malformation.

Common adverse effects. Diplopia, dizziness, ataxia, nausea, drowsiness, and a mild leucopenia.

Interactions.

• Enzyme induction lowers levels of warfarin, direct oral anticoagulants (avoid), hormonal contraceptives (use a copper device or levonorgestrel intrauterine system), lamotrigine, valproate, corticosteroids, efavirenz, dolutegravir (needs 50 mg twice daily), protease inhibitors, rilpivirine (contraindicated), artemether-lumefantrine and praziquantel.

• Raised carbamazepine levels with toxicity: erythromycin, clarithromycin, isoniazid, fluconazole, verapamil, diltiazem, fluoxetine, cimetidine and grapefruit juice.

• Rifampicin and phenytoin lower carbamazepine levels.

Common prescribing errors. Starting a full dose rather than titrating. Missing hyponatraemia. Using it for absence or myoclonic seizures. Giving a macrolide or isoniazid without a dose review.

Special groups.

• Pregnancy: neural tube defect risk about 1%. Give folic acid 5 mg daily before conception. Use the lowest effective dose in divided doses, and give vitamin K to the newborn.

• Breastfeeding: acceptable; monitor the infant for sedation, jaundice, poor feeding and rash.

• Ancestry: HLA-B*1502 (mainly South and Southeast Asian ancestry) and HLA-A*3101 (European and Japanese ancestry) raise the risk of severe skin reactions. Test where available and relevant. Rare in most African populations, but ancestry may be mixed.

• Regional: widely used for epilepsy and neuropathic pain. Interactions with antiretrovirals, antituberculosis drugs and antimalarials are frequent.

Formulations. Tablets 100, 200 and 400 mg. Prolonged-release tablets 200 and 400 mg. Oral liquid 100 mg/5 mL. Give with food. Liquid reaches higher peaks, so divide into smaller, more frequent doses.

Monitoring.

• Baseline: full blood count, sodium, liver function and ECG in older adults or those with cardiac disease. Test HLA-B*1502 in at-risk ancestry where available.

• Ongoing: sodium, full blood count and liver function at about 1, 3 and 6 months, then yearly. Bone health in long-term use.

• Trough level 4 to 12 mg/L, checked after 2 weeks and again after autoinduction at 4 to 5 weeks.

Stopping. Taper over at least 4 weeks. Stop immediately for rash with fever or mucosal involvement, a white cell count under 3 x 10^9/L or neutrophils under 1.5 x 10^9/L, or sodium under 125 mmol/L with symptoms.

Referral and escalation. Refer for persistent seizures, planned pregnancy, or severe skin reaction. Toxicity (nystagmus, ataxia, drowsiness, arrhythmia) needs a level and an ECG.