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 |
Ontology: Valproic Acid (C0042291)
| Definition (CHV) | a kind of epilepsy treatment drug |
| Definition (CHV) | a kind of epilepsy treatment drug |
| Definition (CHV) | a kind of epilepsy treatment drug |
| Definition (CHV) | a kind of epilepsy treatment drug |
| Definition (CHV) | a kind of epilepsy treatment drug |
| Definition (NCI_NCI-GLOSS) | A drug used to treat epileptic seizures and bipolar disorder and to prevent migraine headaches. It is also being studied in the treatment of several types of cancer. It blocks an enzyme that cells need to grow and may cause cancer cells to die. It also blocks the growth of new blood vessels that tumors need to grow. It is a type of anticonvulsant, histone deacetylase (HDAC) inhibitor, antimaniacal, migraine headache prophylactic, and antiangiogenesis agent. |
| Definition (NCI) | A synthetic derivative of propylpentanoic acid with antiepileptic properties and potential antineoplastic and antiangiogenesis activities. In epilepsy, valproic acid appears to act by increasing the concentration of gamma-aminobutyric acid (GABA) in the brain. This agent's antitumor and antiangiogenesis activities may be related to the inhibition of histone deacetylases and nitric oxide synthase, which results in the inhibition of nitric oxide synthesis. (NCI04) |
| Definition (MSH) | A fatty acid with anticonvulsant properties used in the treatment of epilepsy. The mechanisms of its therapeutic actions are not well understood. It may act by increasing GAMMA-AMINOBUTYRIC ACID levels in the brain or by altering the properties of voltage dependent sodium channels. |
| Definition (PDQ) | A synthetic derivative of propylpentanoic acid with antiepileptic properties and potential antineoplastic and antiangiogenesis activities. In epilepsy, valproic acid appears to act by increasing the concentration of gamma-aminobutyric acid (GABA) in the brain. This agent's antitumor and antiangiogenesis activities may be related to the inhibition of histone deacetylases and nitric oxide synthase, which results in the inhibition of nitric oxide synthesis. Check for "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=350047&idtype=1" active clinical trials or "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=350047&idtype=1&closed=1" closed clinical trials using this agent. ("http://nciterms.nci.nih.gov:80/NCIBrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&code=C29536" NCI Thesaurus) |
| Concepts | Pharmacologic Substance (T121) , Organic Chemical (T109) |
| MSH | D014635 |
| SnomedCT | 13965000, 387080000 |
| English | Acid, Valproic, Divalproex, Valproic Acid, 2 Propylpentanoic Acid, 2-Propylpentanoic Acid, Pentanoic acid, 2-propyl-, 2-Propylvaleric Acid, Di-n-propylacetic Acid, valproic acid, DIVALPROEX, valproic acid (medication), VALPROIC ACID, Valproic Acid [Chemical/Ingredient], Acid, Propylisopropylacetic, Propylisopropylacetic Acid, dipropylacetic acid, dipropylacetic acid (DPA), dpa, divalproex, DPA, DPA - dipropylacetic acid, 2-Propylpentanoic acid, 2-Propylvaleric acid, Dipropylacetic acid, Valproic acid, Valproic acid (product), Valproic acid (substance), VA |
| Swedish | Valproinsyra |
| Czech | kyselina valproová |
| Finnish | Valproiinihappo |
| Russian | NATRIIA VALPROAT, VAL'PROEVAIA KISLOTA, VALPROATY, DIPROPILATSETAT, VALPROEVAIA KISLOTA, VAL'PROATY, ВАЛПРОАТЫ, ВАЛПРОЕВАЯ КИСЛОТА, ВАЛЬПРОАТЫ, ВАЛЬПРОЕВАЯ КИСЛОТА, ДИПРОПИЛАЦЕТАТ, НАТРИЯ ВАЛПРОАТ |
| Japanese | ダイバルプロエクス, バルプロ酸ナトリウム, ジプロピル酢酸, ジプロピルアセテート, ジバルプロエクス, バルプロ酸, 酢酸ジプロピル |
| French | Acide valproïque, Acide 2-propylpentanoïque, Acide 2-propyl-pentanoïque |
| Polish | Kwas walproinowy, Walproinian sodowy, Octan dipropylu, Divalproex |
| Portuguese | Ácido Valproico, Divalproex |
| Spanish | ácido 2-propilpentanoico, ácido 2-propilvalérico, ácido dipropilacético, ácido valproico (producto), ácido valproico (sustancia), ácido valproico, Divalproex, Ácido Valproico |
| German | Divalproex, Valproinsäure |
| Italian | Acido valproico |
Ontology: Valproate (C0080356)
| Definition (CSP) | fatty acid with anticonvulsant properties. |
| Concepts | Pharmacologic Substance (T121) , Lipid (T119) |
| MSH | D014635 |
| SnomedCT | 264325000, 372812003, 67477004 |
| LNC | LP16305-2, MTHU005126 |
| English | 2 propylvalerate, valproate, Valproate product, Valproate (product), Valproate (substance), Valproate |
| French | Valproate |
| Spanish | valproato (producto), valproato (sustancia), valproato |
Ontology: Depakene (C0700661)
| Concepts | Pharmacologic Substance (T121) , Lipid (T119) |
| MSH | D014635 |
| English | Depakine, depakene, depakine, Depakene |
Ontology: Depakote (C0719751)
| Definition (CHV) | a kind of epilepsy treatment drug |
| Concepts | Pharmacologic Substance (T121) , Lipid (T119) |
| MSH | D014635 |
| English | depakote, Depakote |
