valproic acid; n-dipropylacetic acid (Depakene, Depakote, Divalproex, Mylproin, Valontin, Stavzor)
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Introduction
Tradenames: Depakene, Depakote, Divalproex, Stavzor. Aliases: VPA, or n-dipropyl-acetic acid.
Indications
- seizures:
- absence seizures, atypical absence seizures, myoclonic seizures, tonic-clonic seizures, partial seizures
- the most effective agent for all primary generalized forms of epilepsy
- migraine prophylaxis
- mood disorders, bipolar disorder, mania[19]
Contraindications
- avoid in patients with liver failure[5]
- pregnancy (relative contraindication)[13][14]
- contraindicated for preventing migraine headache during pregnancy[18]
- pregnant women using valproate or other anticonvulsants should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry[18]
- in UK, valproate banned for women of childbearing age unless enrolled in a pregnancy prevention program[24]
- increased risk of autism in offspring[26]
- ineffective in treating psychosis & agitation in the elderly[21]
- results in cognitive decline[20]
Dosage
- start 15 mg/kg/day PO divided BID or TID
- increase by 5-10 mg/kg/day at weekly intervals until seizures are controlled
- maximum: 60 mg/kg/day
- dose should be divided BID or TID to prevent GI side effects
- Depakote ER: 500-1000 mg PO QD
Tabs: 125, 250, 500 mg.
Syrup: 250 mg/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
Pharmacokinetics
- oral dose is rapidly absorbed
- absorption of enteric coated tablet is delayed by about 1 hour
- 84-90% bound to plasma proteins
- metabolized by the liver
- excreted in the urine
- elimination 1/2life is 5-20 hours
- therapeutic plasma levels are 50-100 ug/mL
elimination via liver
1/2life = 8-15 hours
protein binding = 84-90 %
elimination by hemodialysis = -
elimination by peritoneal dialysis = -
Monitor
- complete blood count (CBC)
- platelet count & coagulation tests (PT, PTT, INR)
- periodically
- prior to planned surgery
- during pregnancy
- liver function tests baseline & frequently, especially during the first 6 months of treatment[8][15]
- every 6 months[20]
- plasma ammonia in the event of lethargy, vomiting, mental status change, hypothermia[15]
Adverse effects
- most common (1-10%)
- abdominal cramps, anorexia, diarrhea, nausea/vomiting, change in menstrual cycle, weight gain, tremor, hirsuitism, alopecia, hyperammonemia[5]
- uncommon (< 1%)
- drowsiness, ataxia, irritability, confusion, restlessness, hyperactivity, malaise, headache, erythema multiforme, transient elevated serum transaminases, nystagmus, seeing spots, photosensitivity
- serious[5]
- hepatotoxicity, liver failure, pancreatitis
- thrombocytopenia*, platelet dysfunction, aplastic anemia
- other
- 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]
- increased risk of Parkinson's disease (RR~1.8)[25]
* thrombocytopenia may be more common than 1%[9]
Drug interactions
- do NOT give with clonazepam
- carbamazepine
- increased carbamazepine metabolites (including active 9,10 epoxide)[9]
- decreased valproate levels
- phenytoin
- increased free phenytoin
- decreased valproate levels
- phenobarbital:
- increased phenobarbital levels
- increased CNS effects
- chlorpromazine, cimetidine, aspirin: increased valproate levels
- warfarin: increased risk of bleeding
- rifampin: decreased valproate levels Interactions:
- potential interactions with voltage sensitive Na+ channels & possible enhancement of GABA accumulation
- drug interaction(s) anticonvulsants with anti-bacterial agents
- drug interaction(s) anticonvulsants with statins
Laboratory
- valproic acid in serum/plasma:
- serum, plasma (EDTA)
- stable at room temperature for several hours
- stable for 1 year at -20 degrees C
- methods: GLC, GC-MS, EIA, FPIA, FIA
Mechanism of action
- unknown
- may be related to increased brain concentrations of GABA
- may inhibit metabolism of GABA
- inhibits inositol-3-phosphate synthase
More general terms
Additional terms
Component of
References
- ↑ The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
- ↑ Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 701
- ↑ Kaiser Permanente Northern California Regional Drug Formulary, 1998
- ↑ Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 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 - ↑ Prescriber's Letter 7(9):53 2000
- ↑ Clinical Guide to Laboratory Tests, NW Tietz (ed) 3rd ed, WB Saunders, Philadelpha 1995
- ↑ 8.0 8.1 Prescriber's Letter 8(8):48, 2001
- ↑ 9.0 9.1 9.2 Small G. In:Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
- ↑ 10.0 10.1 10.2 Prescriber's Letter 10(2):8 2003
- ↑ 11.0 11.1 11.2 Bromley RL et al. Autism spectrum disorders following in utero exposure to antiepileptic drugs. Neurology 2008 Dec 2; 71:1923. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19047565
- ↑ 12.0 12.1 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: https://www.ncbi.nlm.nih.gov/pubmed/19369666
Tomson T. Which drug for the pregnant woman with epilepsy? N Engl J Med 2009 Apr 16; 360:1667. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19369673 - ↑ 13.0 13.1 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
- ↑ 14.0 14.1 14.2 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
- ↑ 15.0 15.1 15.2 Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=260704&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ Fleisher AS et al. Chronic divalproex sodium use and brain atrophy in Alzheimer disease. Neurology 2011 Sep 27; 77:1263. PMID: https://www.ncbi.nlm.nih.gov/pubmed/21917762
- ↑ 17.0 17.1 Christensen J et al Prenatal Valproate Exposure and Risk of Autism Spectrum Disorders and Childhood Autism. JAMA. 2013;309(16):1696-1703 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23613074 <Internet> 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23613078 <Internet> http://jama.jamanetwork.com/article.aspx?articleid=1681385 - ↑ 18.0 18.1 18.2 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
- ↑ 19.0 19.1 Deprecated Reference
- ↑ 20.0 20.1 20.2 20.3 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 - ↑ 21.0 21.1 Lonergan E, Luxenberg J. Valproate preparations for agitation in dementia. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD003945. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19588348
- ↑ 22.0 22.1 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: https://www.ncbi.nlm.nih.gov/pubmed/29459981 https://jamanetwork.com/journals/jamaneurology/fullarticle/2672965
- ↑ 23.0 23.1 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/29680205 <Internet> 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/29680207 <Internet> http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(18)30154-6/fulltext - ↑ 24.0 24.1 24.2 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
- ↑ 25.0 25.1 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: https://www.ncbi.nlm.nih.gov/pubmed/36574240 https://jamanetwork.com/journals/jamaneurology/fullarticle/2799620 - ↑ 26.0 26.1 26.2 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: https://www.ncbi.nlm.nih.gov/pubmed/38507750 https://www.nejm.org/doi/10.1056/NEJMoa2309359
- ↑ HIGHLIGHTS OF PRESCRIBING INFORMATION DEPAKENE (valproic acid) capsules and oral solution, USP https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018081s056lbl.pdf
Database
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3121
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=147515
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=86480
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=53519
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=14047