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valproic acid; n-dipropylacetic acid (Depakene, Depakote, Divalproex, Mylproin, Valontin, Stavzor)

Tradenames: Depakene, Depakote, Divalproex, Stavzor. Aliases: VPA, or n-dipropyl-acetic acid. Indications: 1) seizures: a) absence seizures, atypical absence seizures, myoclonic seizures, tonic-clonic seizures, partial seizures b) the most effective agent for all primary generalized forms of epilepsy 2) migraine prophylaxis 3) mood disorders, bipolar disorder, mania [19] Contraindications: - avoid in patients with liver failure [5] - pregnancy (relative contraindication) [13,14] a) contraindicated for preventing migraine headache during pregnancy [18] b) pregnant women using valproate or other anticonvulsants should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry [18] c) in UK, valproate banned for women of childbearing age unless enrolled in a pregnancy prevention program [24] d) increased risk of autism in offspring [26] - men taking valproate should use contraception & for 3 months & after stopping due to small potential risk of neurodevelopmental disorders in conceived offspring [27] - ineffective in treating psychosis & agitation in the elderly [21] - results in cognitive decline [20] Dosage: 1) start 15 mg/kg/day PO divided BID or TID 2) increase by 5-10 mg/kg/day at weekly intervals until seizures are controlled 3) maximum: 60 mg/kg/day 4) dose should be divided BID or TID to prevent GI side effects 5) Depakote ER: 500-1000 mg PO QD Tabs: 125, 250, 500 mg. Syrup: 250 mg/5 mL. Injection: 100 mg/mL (5 mL). Depakote ER: 250 & 500 mg tabs (Stavzor) - NOT bioequivalent* to Depakote * Depakote ER results in lower serum levels than Depakote [10] 8-20% larger dose of Depakote ER required for similar serum level [10] Dosage adjustment in renal failure: - none - supplemental dose after dialysis uncertain [5] Pharmacokinetics: 1) oral dose is rapidly absorbed 2) absorption of enteric coated tablet is delayed by about 1 hour 3) 84-90% bound to plasma proteins 4) metabolized by the liver 6) excreted in the urine 7) elimination 1/2life is 5-20 hours 8) therapeutic plasma levels are 50-100 ug/mL Monitor: 1) complete blood count (CBC) 2) platelet count & coagulation tests (PT, PTT, INR) a) periodically b) prior to planned surgery c) during pregnancy 3) liver function tests baseline & frequently, especially during the first 6 months of treatment [8,15] - every 6 months [20] 4) plasma ammonia in the event of lethargy, vomiting, mental status change, hypothermia [15] Adverse effects: 1) most common (1-10%) - abdominal cramps, anorexia, diarrhea, nausea/vomiting, change in menstrual cycle, weight gain, tremor, hirsuitism, alopecia, hyperammonemia [5] 2) uncommon (< 1%) - drowsiness, ataxia, irritability, confusion, restlessness, hyperactivity, malaise, headache, erythema multiforme, transient elevated serum transaminases, nystagmus, seeing spots, photosensitivity 3) serious [5] - hepatotoxicity, liver failure, pancreatitis - thrombocytopenia*, platelet dysfunction, aplastic anemia 4) other - osteoporosis [5] - cognitive decline [20] - hypercholesterolemia [5] - polycystic ovary syndrome [5] 5) in utero exposure [11] - teratogenic - fetal valproate syndrome - increase risk of autism [11,17,26] - cognitive impairment [12] - maternal use of valproate associated a decrease in school performance in offspring compared with children unexposed to anticonvulsants & children exposed to lamotrigine [22] - craniofacial defects - cleft palate (5.2) - craniosynostosis (6.8) - atrial septal defect (2.5) - hypospadias (4.8) - polydactyly (2.2) [14] - major congenital malformations: among anticonsulsants valproate with highest risk (25% >1450 mg/day) [23] - 40% risk of developmental disorder [24] 6) increased risk of Parkinson's disease (RR~1.8) [25] * thrombocytopenia may be more common than 1% [9] Drug interactions: 1) do NOT give with clonazepam 2) carbamazepine a) increased carbamazepine metabolites (including active 9,10 epoxide) [9] b) decreased valproate levels 3) phenytoin a) increased free phenytoin b) decreased valproate levels 4) phenobarbital: a) increased phenobarbital levels b) increased CNS effects 5) chlorpromazine, cimetidine, aspirin: increased valproate levels 6) warfarin: increased risk of bleeding 7) rifampin: decreased valproate levels Interactions: - potential interactions with voltage sensitive Na+ channels & possible enhancement of GABA accumulation Laboratory: 1) valproic acid in serum/plasma: a) serum, plasma (EDTA) b) stable at room temperature for several hours c) stable for 1 year at -20 degrees C 2) methods: GLC, GC-MS, EIA, FPIA, FIA Mechanism of action: 1) unknown 2) may be related to increased brain concentrations of GABA 3) may inhibit metabolism of GABA 4) inhibits inositol-3-phosphate synthase

Interactions

drug interactions drug adverse effects (more general classes) monitor with anticonvulsants

Related

fetal valproate syndrome valproic acid in serum/plasma

General

anticonvulsant carboxylate histone decetylase inhibitor mood stabilizer

Properties

MISC-INFO: elimination route LIVER 1/2life 8-15 HOURS therapeutic-range 50-100 UG/ML toxic-range >100 UG/ML protein-binding 84-90% elimination by hemodialysis - peritoneal dialysis - pregnancy-category D safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 701
  3. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  4. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  5. Medical Knowledge Self Assessment Program (MKSAP) 11, 15, 16, 17. American College of Physicians, Philadelphia 1998, 2009, 2012, 2015 - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  6. Prescriber's Letter 7(9):53 2000
  7. Clinical Guide to Laboratory Tests, NW Tietz (ed) 3rd ed, WB Saunders, Philadelpha 1995
  8. Prescriber's Letter 8(8):48, 2001
  9. Small G. In:Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
  10. Prescriber's Letter 10(2):8 2003
  11. Bromley RL et al. Autism spectrum disorders following in utero exposure to antiepileptic drugs. Neurology 2008 Dec 2; 71:1923. PMID: 19047565
  12. Meador KJ et al Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 2009 Apr 16; 360:1597 PMID: 19369666 - Tomson T. Which drug for the pregnant woman with epilepsy? N Engl J Med 2009 Apr 16; 360:1667. PMID: 19369673
  13. FDA MedWatch Valproate Sodium and related products (valproic acid and divalproex sodium): Risk of Birth Defects http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm192788.htm
  14. Jentink J et al Valproic Acid Monotherapy in Pregnancy and Major Congenital Malformations N Engl Med Volume 362:2185-2193, 2010 http://content.nejm.org/cgi/content/short/362/23/2185
  15. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: 260704 (subscription needed) http://www.prescribersletter.com
  16. Fleisher AS et al. Chronic divalproex sodium use and brain atrophy in Alzheimer disease. Neurology 2011 Sep 27; 77:1263. PMID: 21917762
  17. Christensen J et al Prenatal Valproate Exposure and Risk of Autism Spectrum Disorders and Childhood Autism. JAMA. 2013;309(16):1696-1703 PMID: 23613074 http://jama.jamanetwork.com/article.aspx?articleid=1681408 - Meador KJ and Loring DW Risks of In Utero Exposure to Valproate. JAMA. 2013;309(16):1730-1731 PMID: 23613078 http://jama.jamanetwork.com/article.aspx?articleid=1681385
  18. FDA MedWatch Valproate Anti-Seizure Products: Drug Safety Communication - Contraindicated for Pregnant Women for Prevention of Migraine Headaches. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350868.htm
  19. Deprecated Reference
  20. Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013 - Geriatric Review Syllabus, 9th edition (GRS9) Medinal-Walpole A, Pacala JT, Porter JF (eds) American Geriatrics Society, 2016 - Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022
  21. Lonergan E, Luxenberg J. Valproate preparations for agitation in dementia. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD003945. Review. PMID: 19588348
  22. Elkaer LS, Bech BH, Sun Y et al Association Between Prenatal Valproate Exposure and Performance on Standardized Language and Mathematics Tests in School-aged Children JAMA Neurol. Published online February 19, 2018 PMID: 29459981 https://jamanetwork.com/journals/jamaneurology/fullarticle/2672965
  23. Tomson T, Battino D, Bonizzoni E, et al Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry. Lancet Neurology. April 18, 2018 PMID: 29680205 http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(18)30107-8/fulltext - Pennell PB Prescribing antiepileptic drugs to women of reproductive age. Lancet Neurology. April 18, 2018 PMID: 29680207 http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(18)30154-6/fulltext
  24. Medicines and Healthcare products Regulatory Agency. Gov.UK Press release. April 24, 2018 Valproate banned without the pregnancy prevention programme. https://www.gov.uk/government/news/valproate-banned-without-the-pregnancy-prevention-programme
  25. Kneisel K Epilepsy Drugs May Up Risk of Parkinson's. Strongest association seen for sodium valproate. MedPage Today December 27, 2022 https://www.medpagetoday.com/neurology/seizures/102398 - Belete D, Jacobs BM, Simonet C et al Association Between Antiepileptic Drugs and Incident Parkinson Disease in the UK Biobank. JAMA Neurol. Published online December 27, 2022. PMID: 36574240 https://jamanetwork.com/journals/jamaneurology/fullarticle/2799620
  26. Hernandez-Diaz S, Straub L, Bateman BT, et al. Risk of Autism after Prenatal Topiramate, Valproate, or Lamotrigine Exposure. N Engl J Med. 2024 Mar 21;390(12):1069-1079. PMID: 38507750 https://www.nejm.org/doi/10.1056/NEJMoa2309359
  27. Wise J. Valproate: Men are advised to use contraception owing to risk of neurodevelopmental disorders in children. BMJ. 2024 Sep 6;386:q1957. PMID: 39242116
  28. HIGHLIGHTS OF PRESCRIBING INFORMATION DEPAKENE (valproic acid) capsules and oral solution, USP https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018081s056lbl.pdf

Component-of

carbamazepine/lamotrigine/phenobarbital/phenytoin/primidone/valproic acid lamotrigine/valproic acid