Sodium Valproate

Sodium valproate is a broad-spectrum antiseizure medicine and mood stabiliser, and the first-choice drug for generalised epilepsies in men and in women who cannot become pregnant. It carries a boxed-warning-level risk of foetal malformation and neurodevelopmental harm, as well as hepatotoxicity and pancreatitis, which restrict its use in women and girls of childbearing potential.

Mechanism. Raises brain GABA, blocks voltage-gated sodium channels and T-type calcium channels, and inhibits histone deacetylase.

Pharmacokinetics. Bioavailability is near 100%. Protein binding is about 90% at low concentrations but saturable, so the free fraction rises at high doses, in hypoalbuminaemia, in uraemia and in liver disease. Half-life is 9 to 16 hours, shorter with enzyme inducers and in children. It is cleared by glucuronidation, beta-oxidation and cytochrome P450 2C9 and 2C19, and it inhibits glucuronidation and epoxide hydrolase.

First-line use. Generalised epilepsies (tonic-clonic, absence, myoclonic, juvenile myoclonic epilepsy), unclassified epilepsy, and photosensitive epilepsy, in men and in women unable to become pregnant. Treatment is long term.

• Adults, oral sodium valproate: start 300 mg twice daily (or 10 mg/kg daily), increase by 200 mg every 3 days to a usual maintenance of 1000 to 2000 mg daily (20 to 30 mg/kg daily) in two divided doses. Usual maximum 2500 mg daily; some labels allow up to 60 mg/kg daily.

• Children over 20 kg: 400 mg daily start, titrated to a usual 20 to 30 mg/kg daily, up to 35 mg/kg daily with level monitoring. Under 20 kg: 20 mg/kg daily, increased with monitoring.

• Children under 2 years: avoid unless specialist care is available, because of a high risk of fatal hepatotoxicity, particularly with mitochondrial disease.

Alternative and specialist use.

• Manic episodes of bipolar disorder: 750 mg daily in divided doses, titrated within 1 to 3 days to a usual 1000 to 2000 mg daily, maximum 60 mg/kg daily, aiming for a level of 50 to 125 mg/L. Not for women of childbearing potential.

• Migraine prophylaxis: 250 mg twice daily, increased to 500 to 1000 mg daily. Not for women of childbearing potential.

Emergency use. Status epilepticus after benzodiazepine failure, when levetiracetam or phenytoin are unsuitable or have failed, in men and women not able to become pregnant:

• Sodium valproate intravenous 40 mg/kg (maximum 3000 mg) over 10 minutes, once. Then continue the usual daily dose intravenously.

Kidney, liver, weight and age.

• Kidney: no total dose change is needed, but free valproate rises with uraemia, so interpret total levels with caution.

• Liver: contraindicated in active liver disease. Avoid in significant hepatic dysfunction.

• Older adults: start low and titrate slowly; tremor, parkinsonism and hyperammonaemic encephalopathy are more frequent.

Contraindications. Active liver disease or family history of severe hepatic dysfunction; porphyria; urea cycle disorders; mitochondrial disease due to POLG mutations; carnitine disorders; hypersensitivity. Contraindicated in pregnancy for epilepsy unless there is no suitable alternative, and in women and girls of childbearing potential unless the conditions of a pregnancy prevention programme are met.

Serious adverse effects. Hepatotoxicity (including fatal liver failure), pancreatitis, hyperammonaemic encephalopathy, thrombocytopenia and platelet dysfunction, bleeding, polycystic ovary syndrome, bone loss, severe skin reactions, and foetal malformation.

Common adverse effects. Tremor, weight gain, nausea, hair thinning, peripheral oedema, drowsiness and menstrual disturbance.

Interactions.

• Lamotrigine: valproate roughly doubles lamotrigine half-life and raises rash risk, so lamotrigine doses must be halved.

• Carbapenems (meropenem, imipenem): fall in valproate levels of 60 to 100% within 24 hours with seizure breakthrough, so the combination is avoided.

• Phenytoin: free phenytoin rises while total phenytoin may fall. Phenobarbital and primidone levels rise. Enzyme inducers and rifampicin lower valproate levels.

• Aspirin and warfarin: displaced from albumin, raising bleeding risk. Zidovudine levels rise.

Common prescribing errors. Starting in a woman of childbearing potential without pregnancy testing and counselling. Using the total level to adjust dose in hypoalbuminaemia. Prescribing with meropenem. Forgetting folic acid.

Special groups.

• Pregnancy: major malformation risk is about 10%, neural tube defects about 1 to 2%, and neurodevelopmental disorders up to 30 to 40% of exposed children. If a woman is already pregnant on valproate, use the lowest effective dose, divided doses with prolonged-release tablets, folic acid 5 mg daily, and specialist review. Do not stop abruptly.

• Men: counsel that a possible small neurodevelopmental risk after paternal exposure is under review, and use contraception advice and specialist review.

• Breastfeeding: milk levels are low and use is usually acceptable. Monitor the infant for jaundice, bruising and drowsiness.

• Children: highest hepatotoxicity risk under 2 years, on several antiseizure medicines, or with metabolic disease.

• Regional: avoid in unexplained developmental delay or recurrent vomiting with encephalopathy until a metabolic disorder is excluded.

Formulations. Gastro-resistant tablets 200 and 500 mg. Prolonged-release tablets 300 and 500 mg. Oral solution 200 mg/5 mL. Intravenous solution 100 mg/mL. Give with food to reduce gastric upset. Daily intravenous and oral doses are equal.

Preparation. Give intravenous valproate as a slow injection over 3 to 5 minutes, or as an infusion in 0.9% sodium chloride or 5% glucose over 60 minutes at not over 20 mg/min. A continuous infusion of 1 to 2 mg/kg/hour is an alternative.

Monitoring.

• Baseline: pregnancy test, liver function, full blood count with platelets, weight, and coagulation if bleeding or surgery is planned.

• Ongoing: liver function monthly for the first 6 months, then when clinically indicated. Check ammonia in unexplained vomiting, lethargy or confusion. Total trough level 50 to 100 mg/L for epilepsy is a guide only.

Stopping. Reduce slowly over at least 4 weeks to avoid seizure relapse.

Referral and escalation. Refer any woman of childbearing potential for specialist review of alternatives. Stop and urgently assess for jaundice, persistent vomiting, abdominal pain, or bleeding. Hyperammonaemic encephalopathy with a normal liver profile warrants stopping valproate.