BLACK BOX WARNING
- hepatotoxicity — fatal cases reported, especially in children <2 years and polytherapy
- pancreatitis — may be fatal
- teratogenicity — major congenital malformations including spina bifida; contraindicated for migraine prophylaxis in pregnancy
valproic acid / valproate sodium
Brand: Depakote, Depakene, Depacon
⚠ BBW Beers Criteria TDM Required Prototype Drug
Drug Class: antiepileptic / mood stabilizer
Drug Family: antiepileptic
Subclass: branched-chain fatty acid
Organ Systems: cns
Mechanism of Action
Blocks voltage-gated sodium channels and T-type calcium channels; inhibits GABA transaminase, increasing brain GABA levels; also inhibits histone deacetylase.
voltage-gated sodium channelsGABA transaminase
Indications
- absence seizures (drug of choice)
- generalized tonic-clonic seizures
- bipolar disorder (mania and maintenance)
- migraine prophylaxis
Contraindications
- hepatic disease or significant hepatic dysfunction
- urea cycle disorders
- mitochondrial disorders (Alpers syndrome)
- pregnancy (neural tube defects)
Adverse Effects
Common
- nausea
- vomiting
- weight gain
- tremor
- alopecia
- sedation
- thrombocytopenia
Serious
- hepatotoxicity (especially in children <2 years)
- pancreatitis
- teratogenicity (neural tube defects, spina bifida)
- hyperammonemia encephalopathy
Pharmacokinetics (ADME)
| Absorption | Nearly complete oral absorption; delayed with enteric-coated formulation |
| Distribution | Protein binding ~90% (saturable); Vd 0.1–0.4 L/kg; crosses BBB and placenta |
| Metabolism | Hepatic beta-oxidation and glucuronidation; CYP2C9 minor contributor; also mitochondrial metabolism |
| Excretion | Renal; <3% unchanged |
| Half-life | 9–16 hours |
| Onset | 1–4 days |
| Peak | 1–4 hours (immediate release) |
| Duration | 12–24 hours |
| Protein Binding | ~90% |
| Vd | 0.1–0.4 L/kg |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| carbamazepine | valproate inhibits epoxide hydrolase, increasing carbamazepine-10,11-epoxide toxicity | major |
| phenytoin | valproate displaces phenytoin from protein binding and inhibits metabolism | major |
| lamotrigine | valproate inhibits lamotrigine glucuronidation, doubling lamotrigine levels | major |
Nursing Considerations
- Monitor LFTs at baseline and during the first 6 months; check ammonia levels if altered mental status develops
- Therapeutic serum level: 50–100 mcg/mL (epilepsy) or 50–125 mcg/mL (mania); draw trough levels
- Monitor CBC including platelet count; thrombocytopenia may require dose reduction
- Counsel all women of childbearing age about teratogenicity; ensure adequate folate supplementation and contraception if not trying to conceive
Clinical Pearls
- Drug of choice for absence seizures AND the only antiepileptic effective for all seizure types
- Valproate inhibits lamotrigine metabolism — when adding lamotrigine to valproate, start at half the usual dose to prevent lamotrigine toxicity (Stevens-Johnson syndrome)
Safety Profile
Pregnancy use-with-caution
Lactation use-with-caution
Renal Adjustment Not required
Hepatic Adjustment Required
TDM Required
Concordance Terms
Cross-referenced clinical concepts — click any term to see all content where it appears.