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Valproate

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Valproate, Valproic Acid, Depakote, Depakene, Divalproex

  • See Also
  1. Valproic Acid Toxicity
  2. Seizure Disorder
  3. Anticonvulsant
  • Indications
  1. Seizure Disorder
    1. Generalized Tonic Clonic Seizures
    2. Absence Seizures
    3. Myoclonic Seizures
    4. Simple Partial Seizures
    5. Complex Partial Seizures
  2. Non-Seizure Related Conditions
    1. Migraine Headache Prophylaxis
    2. Bipolar Disorder (mood stabilizer)
  • Contraindications
  1. Hepatic dysfunction
  2. Pregnancy
  3. Urea cycle disorder
  • Mechanism
  1. Synthesized in 1882, but not recognized as an anticonvulsant until 1963
  2. Synthetic derivative of propylpentanoic acid (short-chain Fatty Acid)
  3. Anticonvulsant via increasing CNS GABA concentrations
  • Dosing
  • Adults (and children age >10 years)
  1. Seizure Disorder
    1. Use for age 2 to 10 years is off label at same mg/kg doses listed here (not FDA approved)
    2. Initial: 10-15 mg/kg/day divided daily to three times daily orally or IV
      1. Infuse IV doses over 60 minutes (over >20 minutes at minimum)
    3. Increase in 5 to 10 mg/kg/day increments weekly
    4. Target dose: 30-60 mg/kg/day (up to 1000-2500 mg/day)
      1. Divide regular and delayed release dosing two to four times daily
      2. Extended release may be dosed once daily
  2. Status Epilepticus (not a first-line anticonvulsant in Status Epilepticus)
    1. Has been used for age 2 to 10 years at same mg/kg doses listed here (not FDA approved)
    2. Dosing recommended in Status Epilepticus is much higher than typical dosing
    3. Load: 20 mg/kg (up to 40 mg/kg) IV (up to 3000 mg/dose)
      1. Infuse slowly (no faster than 6 mg/kg/min)
    4. Maintain: 5 mg/kg/hour or 4 to 8 mg/kg IV three times daily (adjusting based on serum levels)
  3. Migraine Headache Prophylaxis
    1. Initial
      1. Depakote 250 mg orally twice daily (or ER 500 mg orally daily) for 7 days
    2. Titrate
      1. May increase to 1000 mg/day divided twice daily (or ER once daily)
  4. Bipolar Disorder
    1. Loading dose in acute mania: 15-20 mg/kg
    2. Starting dose without load: 500 to 750 mg/day in divided dosing
    3. Titrate every 2-3 days as tolerated to serum Valproic Acid level of 50 to 125 mcg/ml
    4. Target dose: 1000 to 3000 mg daily in divided doses
  • Safety
  1. Safe in Lactation
  2. Pregnancy Category X
    1. Highly Teratogenic (Neural Tube Defects, cognitive defects, neurodevelopmental disorders)
    2. Small increase in Autism risk
      1. Hernandez-Diaz (2024) N Engl J Med 390(12):1069-79 +PMID: 38507750 [PubMed]
  • Adverse Effects
  1. Common (Dose related)
    1. Nausea and Vomiting (associated with peak levels after dose)
    2. Tremor
    3. Ataxia
    4. Diarrhea
    5. Lethargy or sedation
    6. Insomnia
    7. Mild Liver Function Test abnormalities (AST, ALT)
    8. Weight gain (may predispose to Metabolic Syndrome)
    9. Oligomenorrhea
  2. Serious
    1. Pancreatitis
    2. Alopecia
      1. Centrum A-Zinc daily prevents associated Hair Loss
    3. Thrombocytopenia
    4. Leukopenia
    5. Stevens-Johnson Syndrome
    6. DRESS Syndrome
    7. Osteoporosis
    8. Hypothermia
    9. Hyperammonemia and Hepatic Encephalopathy
      1. Increased risk with concurrent Topiramate
      2. Decreased with concurrent administration of L-Carnitine
    10. Severe Hepatotoxicity (rare with Valproate monotherapy)
      1. More common in young children (esp. age <2 years)
      2. May be fatal in rare cases
  • Pharmacokinetics
  1. Rapidly absorbed
    1. Absorption period prolonged with extended release preparations
    2. Absorption rates greatest for syrup > capsule > sprinkle or tablet > extended release
  2. High Protein Binding (decreased in Overdose)
  3. Hepatic metabolism
    1. Glucoronidation
    2. Beta and omega oxidation
  4. Half-Life is longer in children and underlying liver disease
  5. Toxicity
    1. Large therapeutic window
    2. See Valproic Acid Toxicity
  • Drug Interactions
  1. Numerous Drug Interactions
  2. Valproate levels are decreased by Aspirin, Carbapenems, Estrogen and Cimetidine
    1. Also reduced by enzyme inducers (e.g. Carbamazepine, Phenytoin, Rifampin)
  3. Vaproate inhibits epoxide hydrolase and glucuronyltransferase
    1. Risk of increased levels of other antiiconvulsants (Carbamazepine, Phenytoin, Ethosuximide
  • Monitoring
  1. Serum Valproate level
    1. Initial: Every 1-2 weeks
    2. Later: Every 3-6 months
  2. Other routine monitoring
    1. Obtain monthly for 2 months and then every 3 to 12 months
    2. Complete Blood Count
    3. Liver Function Tests
  • Resources
  1. Valproate Solution (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3dfb6da1-f66a-4618-9f74-d2d6c16c0b58
  2. Valproate Capsule (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3904177b-8a26-4356-9080-d2a2e3f468af
  • References
  1. (2022) Presc Lett, Resource #361206, Antiseizure Medications
  2. Olson (2020) Clinical Pharmacology, Medmaster Miami, p. 56-7
  3. Hamilton (2020) Tarascon Pocket Pharmacopoeia
  4. Sun (2017) Crit Dec Emerg Med 31(1): 24