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Drug Reference

sodium valproate

Anticonvulsant· Brands: Epilim, Depakine, StavzorIVPO

Mechanism of action
Sodium valproate increases the central nervous system availability of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, and may also modulate voltage-gated sodium channels and possibly potassium channels. These actions stabilise neuronal membranes and reduce hyperexcitability, contributing to its anticonvulsant and mood-stabilising effects.
Pharmacokinetics
Sodium valproate is well absorbed after oral administration and extensively bound to plasma proteins. It is metabolised primarily in the liver by glucuronidation and beta-oxidation. The elimination half-life is generally 8 to 20 hours, but may be shorter in patients on enzyme-inducing drugs. Valproate and its metabolites are excreted mainly in the urine. Therapeutic serum concentrations are typically 40 to 100 mg/L, although the correlation with clinical response is variable.
Indications & dosing

Epilepsy (generalized tonic-clonic, partial, or myoclonic seizures)

Start 600 mg daily, increase by 200-300 mg every 3 days. Usual maintenance 1-2 g/day in divided doses. Max 3 g/day.

  • adult · PO: 500–1000 mg twice daily · Start 600 mg daily, increase by 200-300 mg every 3 days. Usual maintenance 1-2 g/day in divided doses. Max 3 g/day.

Epilepsy (absence seizures)

Same as generalized seizures. May use once daily with modified release.

  • adult · PO: 500–1000 mg twice daily · Same as generalized seizures. May use once daily with modified release.

Bipolar disorder (acute mania)

Start 500 mg daily, titrate to response. Usual range 1-2 g/day. Therapeutic drug monitoring advisable.

  • adult · PO: 500–1000 mg twice daily · Start 500 mg daily, titrate to response. Usual range 1-2 g/day. Therapeutic drug monitoring advisable.

Migraine prophylaxisoff-label

Start 500 mg/day, usual range 500-1000 mg/day. Not licensed in all countries; evidence varies.

  • adult · PO: 250–500 mg twice daily · Start 500 mg/day, usual range 500-1000 mg/day. Not licensed in all countries; evidence varies.

Epilepsy (all types)

Starting 15 mg/kg/day, increase weekly. Max dose 30 mg/kg/day.

  • pediatric · PO: 20–30 mg/kg/day in 2 divided doses · Starting 15 mg/kg/day, increase weekly. Max dose 30 mg/kg/day.
Contraindications & precautions
  • Active liver disease or hepatic impairment · Valproate is hepatotoxic; avoid in active liver disease.
  • Porphyria · Valproate may exacerbate porphyria.
  • Known mitochondrial disorders (e.g., Alpers-Huttenlocher syndrome) · Risk of severe hepatotoxicity.
  • Urea cycle disorders · Risk of hyperammonaemia and encephalopathy.
  • Pregnancy · Teratogenic; use only if no alternative and a pregnancy prevention programme is in place.
  • Hypersensitivity to valproate · Avoid in previous allergic reaction.
  • Monitor liver function tests before and during treatment, especially during the first 6 months; discontinue if signs of hepatic dysfunction.
  • Avoid in women of childbearing potential unless effective contraception and a pregnancy prevention programme are in place; use the lowest effective dose.
  • Monitor platelet count and coagulation parameters, especially before surgery or if bleeding occurs.
  • Use with caution in renal impairment; reduce dose as needed.
  • Beware of interactions with enzyme inducers and aspirin; adjust doses accordingly.
  • Do not stop abruptly; taper gradually to avoid rebound seizures.
Adverse effects
  • Nausea and vomiting
  • Weight gain
  • Tremor
  • Alopecia (hair loss)
  • Somnolence (sedation)
  • Hepatotoxicityserious
  • Pancreatitisserious
  • Thrombocytopeniaserious
  • Hyperammonaemia with encephalopathyserious
  • Teratogenicity (e.g., neural tube defects)serious
Renal & hepatic adjustment
  • Hepatic impairment (mild): Use with caution; consider dose reduction and monitor liver function tests regularly.
  • Hepatic impairment (moderate): Use with extreme caution at the lowest effective dose; monitor LFTs frequently; consider alternative therapy if possible.
  • Hepatic impairment (severe): Contraindicated; avoid in active liver disease or severe hepatic impairment. (avoid)
Monitoring, pregnancy & toxicity
  • Serum valproate concentration · Before dose (trough), periodically; more often if toxicity suspected or after dose changes.
  • Liver function tests (ALT, AST) · Baseline, then every 1-3 months for first 6 months, then periodic.
  • Full blood count with platelets · Baseline and every 3-6 months.
  • Coagulation profile (PT, aPTT) · Baseline before surgery or if bleeding symptoms.
  • Plasma ammonia · If symptoms of hyperammonemia (e.g. confusion, vomiting).
  • Pregnancy test · Before starting in women of childbearing potential and monthly during treatment.
  • Pregnancy: Sodium valproate is teratogenic; it is contraindicated in pregnancy for migraine and bipolar disorder. For epilepsy, it should only be used if no effective alternative is available, at the lowest effective dose, with high-dose folic acid (5 mg daily) and specialist supervision. Women of childbearing potential must use effective contraception. Pregnancy must be excluded before starting treatment and during therapy.
  • Toxicity: CNS depression, respiratory depression, coma, metabolic acidosis, and hyperammonemia; may be fatal. · Supportive care with airway management; activated charcoal if within 1 hour; consider haemodialysis for severe toxicity (e.g. hyperammonemia, metabolic acidosis).
  • Toxicity: Liver injury, ranging from mild transaminitis to fatal hepatic failure, particularly in young children and those with mitochondrial disease. · Discontinue treatment immediately and monitor LFTs; assess for other causes.
  • Toxicity: Confusion, lethargy, vomiting, and altered consciousness due to elevated ammonia, often without hepatotoxicity. · Stop valproate, provide supportive care; consider lactulose, L-carnitine (in severe cases), and haemodialysis if unresponsive.
  • Toxicity: Acute pancreatitis with severe abdominal pain, nausea, vomiting, and elevated serum amylase/lipase. · Discontinue valproate; supportive care with pain management and IV fluids.
Antidotes & reversal
  • L-carnitine · For hyperammonaemic encephalopathy and high-risk overdose; repeated charcoal and haemodialysis in severe cases.
Clinical notes
Sodium valproate is used for the treatment of generalised and partial epilepsies, including absence seizures, myoclonic seizures and tonic-clonic seizures. It is also licensed for bipolar disorder and migraine prophylaxis. Monitoring of serum valproate levels, liver function tests and full blood counts is required, especially during the first six months of therapy. It is highly teratogenic, and is contraindicated in pregnancy for epilepsy unless there are no alternatives. Valproate should be withdrawn gradually to avoid rebound seizures. It inhibits the metabolism of lamotrigine, increasing its plasma concentration, and its own clearance is increased by enzyme inducers such as phenytoin and carbamazepine. Prescribers must follow local guidelines for its use in women and girls of childbearing age.

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BNF; local formulary