II. Indications
- Seizure Disorder
- Non-Seizure Related Conditions
- Migraine Headache Prophylaxis
- Bipolar Disorder (mood stabilizer)
III. Contraindications
- Hepatic dysfunction
- Pregnancy
- Urea cycle disorder
IV. Mechanism
- Synthesized in 1882, but not recognized as an anticonvulsant until 1963
- Synthetic derivative of propylpentanoic acid (short-chain Fatty Acid)
- Anticonvulsant via increasing CNS GABA concentrations
V. Dosing: Adults (and children age >10 years)
-
Seizure Disorder
- Use for age 2 to 10 years is off label at same mg/kg doses listed here (not FDA approved)
- Initial: 10-15 mg/kg/day divided daily to three times daily orally or IV
- Infuse IV doses over 60 minutes (over >20 minutes at minimum)
- Increase in 5 to 10 mg/kg/day increments weekly
- Target dose: 30-60 mg/kg/day (up to 1000-2500 mg/day)
- Divide regular and delayed release dosing two to four times daily
- Extended release may be dosed once daily
-
Status Epilepticus (not a first-line anticonvulsant in Status Epilepticus)
- Has been used for age 2 to 10 years at same mg/kg doses listed here (not FDA approved)
- Dosing recommended in Status Epilepticus is much higher than typical dosing
- Load: 20 mg/kg (up to 40 mg/kg) IV (up to 3000 mg/dose)
- Infuse slowly (no faster than 6 mg/kg/min)
- Maintain: 5 mg/kg/hour or 4 to 8 mg/kg IV three times daily (adjusting based on serum levels)
-
Migraine Headache Prophylaxis
- Initial
- Depakote 250 mg orally twice daily (or ER 500 mg orally daily) for 7 days
- Titrate
- May increase to 1000 mg/day divided twice daily (or ER once daily)
- Initial
-
Bipolar Disorder
- Loading dose in acute mania: 15-20 mg/kg
- Starting dose without load: 500 to 750 mg/day in divided dosing
- Titrate every 2-3 days as tolerated to serum Valproic Acid level of 50 to 125 mcg/ml
- Target dose: 1000 to 3000 mg daily in divided doses
VI. Safety
- Safe in Lactation
- Pregnancy Category X
- Highly Teratogenic (Neural Tube Defects, cognitive defects, neurodevelopmental disorders)
- Small increase in Autism risk
VII. Adverse Effects
- Common (Dose related)
- Nausea and Vomiting (associated with peak levels after dose)
- Tremor
- Ataxia
- Diarrhea
- Lethargy or sedation
- Insomnia
- Mild Liver Function Test abnormalities (AST, ALT)
- Weight gain (may predispose to Metabolic Syndrome)
- Oligomenorrhea
- Serious
- Pancreatitis
- Alopecia
- Thrombocytopenia
- Leukopenia
- Stevens-Johnson Syndrome
- DRESS Syndrome
- Osteoporosis
- Hypothermia
- Hyperammonemia and Hepatic Encephalopathy
- Increased risk with concurrent Topiramate
- Decreased with concurrent administration of L-Carnitine
- Severe Hepatotoxicity (rare with Valproate monotherapy)
- More common in young children (esp. age <2 years)
- May be fatal in rare cases
VIII. Pharmacokinetics
- Rapidly absorbed
- Absorption period prolonged with extended release preparations
- Absorption rates greatest for syrup > capsule > sprinkle or tablet > extended release
- High Protein Binding (decreased in Overdose)
- Hepatic metabolism
- Glucoronidation
- Beta and omega oxidation
- Half-Life is longer in children and underlying liver disease
- Toxicity
- Large therapeutic window
- See Valproic Acid Toxicity
IX. Drug Interactions
- Numerous Drug Interactions
- Valproate levels are decreased by Aspirin, Carbapenems, Estrogen and Cimetidine
- Also reduced by enzyme inducers (e.g. Carbamazepine, Phenytoin, Rifampin)
- Vaproate inhibits epoxide hydrolase and glucuronyltransferase
- Risk of increased levels of other antiiconvulsants (Carbamazepine, Phenytoin, Ethosuximide
X. Monitoring
- Serum Valproate level
- Initial: Every 1-2 weeks
- Later: Every 3-6 months
- Other routine monitoring
- Obtain monthly for 2 months and then every 3 to 12 months
- Complete Blood Count
- Liver Function Tests
XI. Resources
- Valproate Solution (DailyMed)
- Valproate Capsule (DailyMed)
XII. References
- (2022) Presc Lett, Resource #361206, Antiseizure Medications
- Olson (2020) Clinical Pharmacology, Medmaster Miami, p. 56-7
- Hamilton (2020) Tarascon Pocket Pharmacopoeia
- Sun (2017) Crit Dec Emerg Med 31(1): 24
Images: Related links to external sites (from Bing)
Related Studies
| valproic acid (on 12/21/2022 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
| VALPROIC ACID 250 MG CAPSULE | Generic | $0.21 each |
| VALPROIC ACID 250 MG/5 ML SOLN | Generic | $0.02 per ml |
| depakote (on 1/18/2023 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
| DEPAKOTE DR 125 MG SPRINKLE CP | Generic | $0.27 each |
| DEPAKOTE DR 125 MG TABLET | Generic | $0.06 each |
| DEPAKOTE DR 250 MG TABLET | Generic | $0.07 each |
| DEPAKOTE DR 500 MG TABLET | Generic | $0.13 each |
| DEPAKOTE ER 250 MG TABLET | Generic | $0.16 each |
| DEPAKOTE ER 500 MG TABLET | Generic | $0.20 each |
| divalproex (on 12/21/2022 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
| DIVALPROEX DR 125 MG CAP SPRNK | Generic | $0.27 each |
| DIVALPROEX DR 125 MG CP(SPRNK) | Generic | $0.27 each |
| DIVALPROEX SOD DR 125 MG TAB | Generic | $0.06 each |
| DIVALPROEX SOD DR 250 MG TAB | Generic | $0.07 each |
| DIVALPROEX SOD DR 500 MG TAB | Generic | $0.13 each |
| DIVALPROEX SOD ER 250 MG TAB | Generic | $0.18 each |
| DIVALPROEX SOD ER 500 MG TAB | Generic | $0.20 each |