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Drug Reference

valproic acid

antiepileptic drug (broad-spectrum)· Brands: Epilim, Depakote, Episenta, Depakene, Convulex, OrfirilIVPOPR

Mechanism of action
Valproate acts on several targets rather than one. It prolongs inactivation of voltage-gated sodium channels, limiting high-frequency neuronal firing, which is the mechanism it shares with phenytoin and carbamazepine. It raises brain GABA by inhibiting GABA transaminase and succinic semialdehyde dehydrogenase and by weakly inhibiting GABA reuptake. It also modulates T-type calcium currents, which contributes to activity in absence seizures, and inhibits histone deacetylases, an effect of uncertain clinical relevance. The combination gives broad-spectrum activity against focal-onset and generalised seizures, including absence and myoclonic seizures, and mood-stabilising activity in bipolar disorder. No single mechanism accounts for either its efficacy or its toxicity.
Pharmacokinetics
Oral absorption is rapid and near complete for sodium valproate, though food slows the rate without much reducing the extent; valproic acid, sodium valproate and semisodium valproate formulations differ in salt content and release profile. Protein binding is concentration dependent, about 90 per cent at low total concentrations and falling as binding saturates, so free drug rises disproportionately and toxicity can occur when the total level looks acceptable, particularly in hypoalbuminaemia, renal or hepatic impairment, and pregnancy. Volume of distribution is roughly 0.1 to 0.4 L/kg. Metabolism is hepatic, mainly glucuronidation (UGT1A6, UGT2B7) and mitochondrial beta-oxidation, with minor CYP2C9, CYP2A6 and CYP2B6 contributions; the metabolite 2-propyl-4-pentenoic acid contributes to hepatotoxicity. Half-life is typically 9 to 16 hours in monotherapy and shorter with enzyme-inducing co-medication. Elimination is renal. Target total trough concentrations are commonly quoted as about 50 to 100 mg/L (350 to 700 micromol/L), with free level measurement when protein binding is disturbed.
Indications & dosing

Generalised tonic-clonic seizures and focal (partial) seizures, adults

Start 600 mg daily in divided doses and increase by about 200 mg every 3 days. Usual maintenance 1000 to 2000 mg daily. Check trough levels if seizures persist or toxicity is suspected.

  • adult · PO: 300–500 mg BD · Start 600 mg daily in divided doses and increase by about 200 mg every 3 days. Usual maintenance 1000 to 2000 mg daily. Check trough levels if seizures persist or toxicity is suspected.

Epilepsy in children, including absence and myoclonic seizures

Start 10 to 15 mg/kg/day in divided doses, increasing weekly to a usual 25 to 30 mg/kg/day, maximum 60 mg/kg/day. Avoid under 2 years unless unavoidable because of hepatotoxicity risk.

  • pediatric · PO: 5–10 mg/kg BD · Start 10 to 15 mg/kg/day in divided doses, increasing weekly to a usual 25 to 30 mg/kg/day, maximum 60 mg/kg/day. Avoid under 2 years unless unavoidable because of hepatotoxicity risk.

Status epilepticus after benzodiazepine failureoff-label

Loading dose by slow IV injection over 5 to 10 minutes, then infusion of 1 to 2 mg/kg/hour. Rapid injection causes hypotension and arrhythmia. Monitor for hyperammonaemia and encephalopathy.

  • adult · IV: 15–40 mg/kg once · Loading dose by slow IV injection over 5 to 10 minutes, then infusion of 1 to 2 mg/kg/hour. Rapid injection causes hypotension and arrhythmia. Monitor for hyperammonaemia and encephalopathy.

Acute manic episode in bipolar disorder

Usual licensed range 750 to 1500 mg daily, titrated slowly. Not first-line for most patients; specialist initiation and monitoring are usual. Different salts are not interchangeable without checking the formulation.

  • adult · PO: 250–500 mg BD · Usual licensed range 750 to 1500 mg daily, titrated slowly. Not first-line for most patients; specialist initiation and monitoring are usual. Different salts are not interchangeable without checking the formulation.

Juvenile myoclonic epilepsy (myoclonic seizures)

Highly effective for this syndrome but avoided in women of childbearing potential; levetiracetam, lamotrigine or topiramate are preferred alternatives despite poorer myoclonic control.

  • adult · PO: 250–500 mg BD · Highly effective for this syndrome but avoided in women of childbearing potential; levetiracetam, lamotrigine or topiramate are preferred alternatives despite poorer myoclonic control.

Migraine prophylaxisoff-label

Unlicensed for this indication in many formularies. Usual range 400 to 1000 mg daily; benefit may take several weeks. Not for use in pregnancy or in women who could become pregnant.

  • adult · PO: 250–500 mg BD · Unlicensed for this indication in many formularies. Usual range 400 to 1000 mg daily; benefit may take several weeks. Not for use in pregnancy or in women who could become pregnant.
Contraindications & precautions
  • Known mitochondrial disorder or POLG-related disease (for example Alpers-Huttenlocher syndrome) · Valproate can precipitate acute liver failure and death in these patients. Take a family history before starting and avoid the drug if mitochondrial disease is suspected.
  • Active or severe liver disease, or a family history of severe hepatic dysfunction · Hepatotoxicity risk is markedly increased. Baseline liver function tests are mandatory before starting and during early treatment.
  • Urea cycle disorder or known hyperammonaemia · Valproate inhibits urea cycle enzymes and can cause hyperammonaemic encephalopathy, which may be fatal.
  • Pregnancy for bipolar disorder or migraine prophylaxis · Regulators regard the fetal risk as unacceptable for these indications. Do not use in pregnancy or in women who could become pregnant for these indications.
  • Pregnancy in epilepsy unless there is no suitable alternative · Use in pregnancy only if alternatives have failed and after specialist advice, because of teratogenicity and neurodevelopmental harm.
  • Women or girls of childbearing potential who are not in a pregnancy prevention programme · Requires negative pregnancy tests, effective contraception, specialist review at least annually and documented counselling about fetal risk.
  • Hypersensitivity to valproate or to any excipient in the formulation · Rash, hypersensitivity reactions and, rarely, eosinophilia with systemic symptoms have been reported.
  • Known thrombocytopenia or a bleeding disorder, or concomitant mefloquine · Valproate can worsen thrombocytopenia and coagulopathy; mefloquine antagonises its anticonvulsant effect and lowers plasma levels. Use only with clear justification and monitoring.
  • Check full blood count, liver function and coagulation before starting, then at intervals during the first six months. Children under three and children on multiple antiepileptics carry a higher risk of fatal hepatotoxicity.
  • Apply the pregnancy prevention programme: document counselling, negative pregnancy tests and effective contraception. Discuss fetal risk with all patients of childbearing potential, and note that valproate can affect male fertility.
  • Warn patients to report malaise, anorexia, vomiting, jaundice, oedema or worsening seizures, which may signal hepatic failure requiring immediate withdrawal and investigation.
  • Advise patients to report severe abdominal pain, especially radiating to the back, with nausea or vomiting, as this may indicate pancreatitis.
  • Do not stop the drug abruptly: taper under medical supervision to avoid withdrawal seizures or rebound seizures.
  • Monitor plasma concentrations after dose changes and check ammonia if drowsiness, confusion or vomiting occurs. Watch interactions: lamotrigine (rash risk), carbapenems and rifampicin lower levels, while valproate raises levels of several drugs. Practice varies by formulary.
Adverse effects
  • Nausea, vomiting, abdominal discomfort, diarrhoea
  • Tremor
  • Weight gain and increased appetite
  • Hair loss (alopecia) and nail changes
  • Sedation, dizziness and ataxia
  • Thrombocytopenia and prolonged bleeding timeserious
  • Hyperammonaemia, with or without encephalopathyserious
  • Hepatotoxicity, including fatal hepatic failureserious
  • Acute pancreatitisserious
  • Teratogenicity and neurodevelopmental harm after in-utero exposureserious
Interactions
  • lamotriginemajorWhen valproic acid and lamotrigine are co-prescribed, the starting dose of lamotrigine should be reduced to approximately half of the standard initiating dose, and the subsequent titration should be slower, with increments every alternate week. The dose of valproic acid may also need adjustment. Prescribers should monitor the patient for signs of rash, fever, or other hypersensitivity reactions, especially during the first few months of therapy. Routine monitoring of lamotrigine serum concentrations can be helpful, though not universally available. If a rash develops, lamotrigine should be discontinued immediately. This combination is best managed by a specialist with expertise in epilepsy.
  • meropenemcontraindicatedAvoid concurrent use of meropenem and valproic acid. Select an alternative antibiotic if possible. If meropenem is unavoidable, consider an alternative anticonvulsant. If no alternative exists, monitor valproic acid concentrations closely and adjust the dose, although this is frequently ineffective. Seek specialist advice and warn patients to report any increase in seizure frequency.
  • aspirinmajorAvoid co-prescription if possible. If combined therapy is necessary, monitor the patient closely for signs of valproate toxicity and consider monitoring free valproic acid concentration (if available) in addition to total levels. Reduce the valproic acid dose as clinically indicated. Educate the patient about symptoms of toxicity and bleeding. Alternative analgesics or antiplatelet agents should be considered.
  • phenytoinmajorMonitor total and, where available, free phenytoin concentrations, as well as valproic acid levels, when initiating, adjusting, or discontinuing either drug. Consider reducing the phenytoin dose when valproic acid is added, and increase it when valproic acid is withdrawn. Observe the patient for clinical signs of phenytoin toxicity and adjust the dose accordingly.
  • carbamazepinemajorMonitor serum concentrations of both valproic acid and carbamazepine (including free carbamazepine if feasible) at baseline and after any dose change, and monitor for clinical signs of toxicity or inadequate seizure control. Adjust valproic acid dose upwards if levels fall, and consider reducing carbamazepine dose if epoxide toxicity develops. Consider alternative antiepileptic drugs if monitoring is not available or if the interaction proves difficult to manage.
Renal & hepatic adjustment
  • Hepatic impairment (mild): Use with caution; consider a lower starting dose and slower titration, with close monitoring of liver enzymes and clinical response.
  • Hepatic impairment (moderate): Use with caution; reduce dose and monitor closely. Avoid if there is active liver disease, acute hepatitis, or worsening hepatic function.
  • Hepatic impairment (severe): Contraindicated in severe hepatic impairment, active liver disease, or acute hepatitis; avoid valproic acid and choose an alternative. (avoid)
Monitoring, pregnancy & toxicity
  • Serum valproate concentration · Baseline, after dose changes, and if toxicity or poor seizure control is suspected.
  • Liver function tests, including transaminases and bilirubin · Baseline, then periodically during the first 6 months and when clinically indicated.
  • Full blood count including platelet count · Baseline and periodically, especially before surgery or if bleeding or infection occurs.
  • Ammonia · If unexplained encephalopathy, vomiting, or lethargy, especially in patients with urea cycle disorders.
  • Coagulation screen, including PT/INR and fibrinogen · Before surgery and if bleeding or bruising occurs.
  • Pregnancy test · Before starting treatment and periodically in people of childbearing potential.
  • Pregnancy: Valproate is highly teratogenic and increases the risk of major congenital malformations and neurodevelopmental disorders. Avoid in pregnancy and in people of childbearing potential unless no suitable alternative exists and pregnancy prevention programme conditions are met. In epilepsy, use only under specialist supervision at the lowest effective dose, preferably as monotherapy, with effective contraception. Avoid for migraine and bipolar disorder. If pregnancy occurs, seek urgent specialist advice and do not stop treatment abruptly.
  • Toxicity: Nausea, vomiting, abdominal pain, dizziness, drowsiness and confusion, which may progress to coma and respiratory depression. · Supportive care, airway protection, continuous monitoring, and activated charcoal if within 1 to 2 hours of ingestion and the airway is protected. Naloxone has been used but is not reliably effective.
  • Toxicity: Hyperammonaemia, which can cause encephalopathy, vomiting, lethargy and seizures, even with normal liver enzymes and therapeutic valproate levels. · Stop valproate, give L-carnitine if severe, and consider haemodialysis for refractory hyperammonaemia or severe overdose.
  • Toxicity: Metabolic acidosis, hypernatraemia, hypocalcaemia and cerebral oedema. · Supportive care with correction of electrolyte and acid-base abnormalities as needed; haemodialysis may be required for severe toxicity.
  • Toxicity: Hepatotoxicity, including fatal hepatic failure, and pancreatitis. · Stop valproate, monitor liver function and pancreatic enzymes, and provide supportive care. Avoid re-exposure.
Clinical notes
Valproate is used for focal-onset and generalised seizures, including absence and myoclonic seizures, as a mood stabiliser in bipolar disorder, and for migraine prophylaxis. It is teratogenic: intrauterine exposure causes neural tube defects and other malformations and is associated with poorer neurodevelopmental outcomes, so in many regions it is contraindicated in pregnancy and in women and girls of childbearing potential unless the conditions of a pregnancy prevention programme are met, and migraine prophylaxis is generally excluded in that group. It carries warnings for fatal hepatotoxicity, particularly in children under two years and in inherited metabolic disorders such as POLG-related disease, and for pancreatitis, which can occur at any time and requires discontinuation. Other harms include hyperammonaemic encephalopathy with normal transaminases, thrombocytopenia and other blood dyscrasias, weight gain, tremor, alopecia, sedation and hyponatraemia. Valproate inhibits lamotrigine metabolism and raises its levels, increasing the risk of serious rash, while enzyme-inducing antiepileptics lower valproate levels. Monitor liver function, full blood count and clinical state, and check ammonia if encephalopathy is suspected. Teaching examples only: 500 mg orally daily in divided doses, titrated to response; sodium valproate 40 mg/kg intravenously (maximum 3000 mg) for convulsive status epilepticus after a benzodiazepine. Practice varies by indication, formulation and region, so verify against current guidance.

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BNF; current product literature or SmPC; national valproate pregnancy prevention programme guidance (for example MHRA or EMA); local formulary and therapeutic drug monitoring service.