Section 02 · Monograph

Valproate

Reviewed Nov 2026FDA label

DepakoteAED (migraine prevention)

Black Box Warning

Hepatotoxicity: fatal hepatic failure has occurred, typically within the first 6 months of treatment; children under age 2 and patients with mitochondrial disorders (e.g., POLG mutations) are at substantially increased risk and require close monitoring including frequent liver function testing
Pancreatitis: life-threatening cases, including hemorrhagic pancreatitis, have been reported in children and adults, sometimes shortly after initiation or after years of use — evaluate promptly for abdominal pain, nausea, vomiting, or anorexia
Fetal risk: valproate causes major congenital malformations (particularly neural tube defects) and decreased IQ/neurodevelopmental effects in children exposed in utero; malformation rates are several-fold higher than with other antiepileptic monotherapies — contraindicated for migraine prophylaxis in pregnancy

Monotherapy and adjunctive therapy for complex partial seizures, age 10+FDA-labeled
Sole and adjunctive therapy for simple and complex absence seizuresFDA-labeled
Adjunctive therapy for patients with multiple seizure types that include absence seizuresFDA-labeled
Acute treatment of manic or mixed episodes associated with bipolar I disorderFDA-labeled
Prophylaxis of migraine headacheFDA-labeled

Status epilepticus (IV formulation, second/third-line)Off-label
Adjunct in agitation associated with dementia (generally discouraged — evidence of harm without clear benefit)Off-label

Exact mechanism not fully established
Thought to increase brain GABA concentrations/GABAergic transmission
Blocks voltage-gated Na+ channels and T-type Ca2+ channels, reducing neuronal excitability

Seizures: initiate 10–15mg/kg/day, increase by 5–10mg/kg/week to clinical effect, max 60mg/kg/day
Mania: initiate ~750mg/day in divided doses (or 20–25mg/kg/day), titrate to lowest effective dose, max 60mg/kg/day
Migraine prophylaxis: 250mg twice daily, max 1000mg/day
Delayed-release and extended-release formulations are not bioequivalent — do not switch formulations without dose reassessment
Delayed-release tablets/capsules must be swallowed whole, not crushed or chewed
Therapeutic drug monitoring (trough total/free valproate levels) used to guide dosing

Hepatic disease or significant hepatic dysfunction
Known urea cycle disorders
Known or suspected mitochondrial disease caused by POLG mutations in children under 2 years; caution in older patients with suspected POLG-related disorder
Known hypersensitivity to valproate/divalproex
Migraine prophylaxis in pregnant women or women of childbearing potential not using effective contraception

Highly protein-bound; can displace or be displaced by other highly protein-bound drugs
Inhibits glucuronidation of lamotrigine, roughly doubling lamotrigine levels — requires a slower, reduced lamotrigine titration schedule when combined
Carbapenem antibiotics (e.g., meropenem, imipenem) markedly reduce valproate levels and can precipitate breakthrough seizures — avoid coadministration when possible
Enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbital) increase valproate clearance and lower levels
Concomitant topiramate associated with increased risk of hyperammonemia with or without encephalopathy
Increases free fraction/levels of phenytoin and other protein-bound drugs

Common: nausea, vomiting, somnolence, dizziness, tremor, alopecia, weight gain, asthenia
Thrombocytopenia and other blood dyscrasias
Hyperammonemia, with or without encephalopathy — risk increased with urea cycle disorders or concomitant topiramate
Drug reaction with eosinophilia and systemic symptoms (DRESS) and other multiorgan hypersensitivity reactions
Somnolence and cognitive slowing, more pronounced in elderly patients
Suicidal ideation/behavior — monitor for new or worsening depression or mood changes

Liver function tests at baseline and periodically, especially during the first 6 months
Platelet counts and coagulation studies at baseline and periodically
Serum ammonia if unexplained lethargy, vomiting, or mental status changes occur
Valproate trough drug levels
Weight/BMI

Contraindicated for migraine prophylaxis during pregnancy
Associated with major congenital malformations (especially neural tube defects) and decreased IQ/neurodevelopmental effects with in-utero exposure
Use during pregnancy for epilepsy or bipolar disorder only if other treatments have failed or are unacceptable, and only in women of childbearing potential using effective contraception when possible
Consider enrollment in the North American Antiepileptic Drug (NAAED) Pregnancy Registry
Present in breast milk; monitor breastfed infants for signs of liver injury or thrombocytopenia