Valproic acid

FDA label

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Titration Increase by 5-10 mg/kg/day at 1-week intervals

Renal Undefined

Hepatic Contraindicated in hepatic disease or significant hepatic dysfunction

Total daily dose >250 mg: give in divided doses. Thrombocytopenia risk rises at trough >110 mcg/mL (F) / >135 mcg/mL (M).

Instructions

• Swallow capsules whole without chewing (avoids mouth/throat irritation)
• GI irritation: give with food or build dose up slowly from a low level
• Do not discontinue abruptly when preventing major seizures — risk of status epilepticus
• Conversion to monotherapy: reduce concomitant AED ~25% every 2 weeks (may start at valproate initiation or delay 1-2 wk)
• Elderly: reduce starting dose, increase more slowly; monitor fluid/nutrition, somnolence, dehydration
• On rufinamide: start valproate low and titrate to effect
• Missed dose: take ASAP unless near next dose; never double

Contraindications

• Hepatic disease or significant hepatic dysfunction
• Mitochondrial disorders caused by POLG mutations (e.g., Alpers-Huttenlocher); children <2 yr with suspected POLG-related disorder
• Urea cycle disorders
• Migraine prophylaxis: pregnancy, or childbearing potential without effective contraception

Cautions

• Hepatotoxicity, incl. fatal — monitor serum liver tests before and frequently during therapy (esp. first 6 mo); age <2 yr, polytherapy, metabolic/organic brain disease at highest risk
• Fetal risk: neural tube defects, major malformations, decreased IQ/neurodevelopmental disorders — avoid in women of childbearing potential unless other options failed; effective contraception + folate
• Pancreatitis, incl. fatal hemorrhagic — discontinue if diagnosed
• Hyperammonemic encephalopathy (evaluate for urea cycle disorders; risk increased with concomitant topiramate) — measure ammonia if unexplained lethargy/vomiting/mental-status change; hypothermia can co-occur
• Dose-related thrombocytopenia, coagulation abnormalities (low fibrinogen, acquired von Willebrand) — CBC + coags at baseline, periodically, before surgery, and in pregnancy
• Suicidal behavior/ideation (AED class effect, ~2x relative risk) — monitor mood/behavior
• Hypothermia (<35 C), with or without hyperammonemia
• DRESS/multiorgan hypersensitivity — discontinue
• Somnolence in the elderly — reduce starting dose, titrate slowly, monitor intake/dehydration

Adverse reactions

• >5%: nausea, vomiting, abdominal pain, diarrhea, anorexia, dyspepsia
• Tremor (57% high-dose), somnolence, dizziness, asthenia, headache, insomnia
• Thrombocytopenia (24% high-dose), ecchymosis
• Alopecia, weight gain or loss, increased appetite, peripheral edema
• Diplopia/amblyopia, ataxia, nystagmus, tinnitus, emotional lability, abnormal thinking, amnesia
• Post-marketing: SJS/TEN, hyperammonemia, PCOS/menstrual irregularities, decreased bone density/fractures, pancytopenia, cerebral pseudoatrophy (reversible), male infertility

Pregnancy High teratogenicity: neural tube defects ~1-2% (registry major-malformation rate 9-11% at ~1,000 mg/day), craniofacial/cardiac/limb defects, hypospadias; decreased IQ, ASD/ID/ADHD risk; dose-dependent, no safe threshold. Contraindicated for migraine prophylaxis; epilepsy/bipolar only if other drugs failed. Do not stop abruptly (status epilepticus). Folate + NAAED registry (1-888-233-2334).

Lactation Excreted in milk at 1-10% of maternal serum levels (infant serum 0.7-4 mcg/mL, 1-6% of maternal); no adverse developmental/cognitive effects reported through age 6. Monitor breastfed infant for jaundice and unusual bruising/bleeding (hepatic failure and clotting abnormalities reported in valproate-exposed offspring).