VALPROIC ACID
Clinical safety rating: avoid
CYP450 enzyme inducers may decrease levels Can cause severe hepatotoxicity and teratogenic effects including neural tube defects.
Increases GABA concentration in the brain by inhibiting GABA transaminase and succinic semialdehyde dehydrogenase; also blocks voltage-gated sodium channels and T-type calcium channels.
| Metabolism | Primarily hepatic via glucuronidation (30-50%), mitochondrial β-oxidation (40%), and CYP-mediated oxidation (CYP2C9, CYP2A6). |
| Excretion | Primarily hepatic metabolism (>95%), with less than 3% excreted unchanged in urine. Minor fecal excretion (~5%). |
| Half-life | Terminal elimination half-life is 9–16 hours in adults; shorter in children (6–9 hours) and longer in neonates (20–30 hours), elderly, or hepatic impairment (up to 18 hours). |
| Protein binding | Highly protein-bound (88–95%), primarily to albumin. Protein binding is saturable and decreases at high concentrations. |
| Volume of Distribution | 0.13–0.23 L/kg. Low volume of distribution indicates limited tissue uptake; reflects mainly plasma and extracellular fluid. |
| Bioavailability | Oral (immediate-release): ~100%; enteric-coated: 80–90%; extended-release: 90–95% relative to immediate-release. Rectal: 80–100%; IV: 100%. |
| Onset of Action | Oral: 3–5 days to steady-state therapeutic effect; IV: within 1 hour for seizure cessation; Rectal: 15–60 minutes for seizure control. |
| Duration of Action | Duration varies with formulation: oral extended-release lasts 24 hours; immediate-release lasts 6–12 hours. Anticonvulsant effect persists with steady-state dosing. |
| Molecular Weight | 144.21 |
Initial: 10-15 mg/kg/day orally (divided 2-3 times), increase by 5-10 mg/kg/week; maintenance: 30-60 mg/kg/day. IV infusion: same oral dose, rate ≤20 mg/min.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for renal impairment; hemodialysis removes ~20% of dose, supplemental dose may be needed post-dialysis. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh C). In mild-moderate (Child-Pugh A/B): reduce dose by 50% and monitor ammonia/coagulation. |
| Pediatric use | Initial: 15-30 mg/kg/day (divided 2-3 times), up to 60 mg/kg/day for seizure control. Monitor LFTs; avoid in <2 years unless high risk. |
| Geriatric use | Start at lower end (10-15 mg/kg/day) due to reduced clearance; monitor for tremors, sedation, and thrombocytopenia. Reduce dose with hypoalbuminemia. |
| 1st trimester | High risk of neural tube defects (1-2%), cardiac malformations, cleft palate; avoid use unless no alternative. folic acid supplementation recommended. |
| 2nd trimester | Risk of fetal anomalies persists; avoid if possible. Consider alternative anticonvulsants. |
| 3rd trimester | Risk of neonatal hemorrhage due to vitamin K deficiency; maternal bleeding complications. Avoid near term. |
Clinical note
CYP450 enzyme inducers may decrease levels Can cause severe hepatotoxicity and teratogenic effects including neural tube defects.
| FDA category | Positive |
| Placental transfer | Crosses placenta readily; fetal serum concentrations may reach 100-200% of maternal levels. |
| Breastfeeding |
■ FDA Black Box Warning
Hepatotoxicity, including fatal hepatic failure; pancreatitis, including fatal hemorrhagic pancreatitis; teratogenicity, including neural tube defects (e.g., spina bifida).
| Common Effects | bipolar disorder |
| Serious Effects |
Hepatic disease or significant liver dysfunctionUrea cycle disordersKnown hypersensitivity to valproatePorphyria
| Precautions | Liver dysfunction, pancreatitis, thrombocytopenia, hyperammonemia, hypothermia, drug reaction with eosinophilia and systemic symptoms (DRESS), suicidal thoughts/behavior, multi-organ hypersensitivity reactions, monitoring of liver function and platelets required. |
| Food/Dietary | No specific food restrictions. However, valproic acid absorption is slightly delayed with food, but not significantly affected. Avoid alcohol. Monitor caffeine intake; excessive caffeine may lower seizure threshold. No restrictions on grapefruit juice. |
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| Valproic acid is excreted into breast milk in low concentrations (1-10% of maternal serum level). Generally considered compatible with breastfeeding, but monitor infant for sedation, poor feeding, and hepatic dysfunction. |
| Lactation Rating | L2 (Safer) |
| Teratogenic Risk | First trimester: Major congenital malformations (neural tube defects, craniofacial defects, cardiovascular malformations) in 5-9% of exposed fetuses, dose-dependent. Second and third trimesters: Fetal valproate syndrome, developmental delay, autism spectrum disorder, reduced IQ. Late pregnancy: Neonatal hemorrhage, hepatic toxicity, withdrawal symptoms. |
| Fetal Monitoring | Maternal: Serum valproic acid trough levels (therapeutic range 50-100 mcg/mL), liver function tests, complete blood count, coagulation profile. Fetal: High-resolution ultrasound at 16-18 weeks for neural tube defects; fetal echocardiography; consider maternal serum alpha-fetoprotein screening. |
| Fertility Effects | Valproic acid is associated with polycystic ovary syndrome (PCOS)-like changes, menstrual irregularities, anovulation, and reduced fertility in women. In men, reversible sperm abnormalities (decreased count, motility) have been reported. |
| Clinical Pearls | Valproic acid is contraindicated in patients with mitochondrial disorders (e.g., POLG mutations) due to risk of acute liver failure. Monitor ammonia levels if encephalopathy occurs, as hyperammonemia can develop even without hepatotoxicity. Adjust dose in hepatic impairment; avoid in severe liver disease. Depakote sprinkle capsules can be opened and sprinkled on soft food for patients with swallowing difficulties. Therapeutic drug monitoring: serum trough levels 50-100 mcg/mL for epilepsy; for bipolar disorder, lower levels may be effective. |
| Patient Advice | Take exactly as prescribed; do not change dose or stop without consulting your doctor. · Do not crush or chew extended-release tablets; swallow whole. · Avoid alcohol while taking this medication as it increases risk of liver damage. · Report immediately: fatigue, vomiting, abdominal pain, yellowing of skin/eyes (signs of liver injury), easy bruising/bleeding, or unusual weakness. · May cause drowsiness or dizziness; avoid driving until you know how you react. · Use effective contraception if of childbearing potential; valproic acid can cause severe birth defects (neural tube defects). · Do not take with other drugs that contain valproic acid (e.g., divalproex). · Store at room temperature away from moisture and heat. |