Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Valproic acid poisoning

Matthew D Sztajnkrycer, MD, PhD
Section Editor
Stephen J Traub, MD
Deputy Editor
Jonathan Grayzel, MD, FAAEM


Valproic acid (2-propylpentanoic acid; VPA) is a branched-chain carboxylic acid introduced as an anti-epileptic drug in 1978 in the United States. It is used to treat partial and generalized seizures and acute mania, and as prophylaxis for bipolar disorder and migraine headaches. Although acute VPA intoxication frequently results in mild, self-limited central nervous system depression, serious toxicity and death may occur.

The clinical features and treatment of VPA intoxication are reviewed here. A summary table to facilitate the emergency management of VPA overdose is provided (table 1). The use of VPA as an antiepileptic agent is detailed separately. (See "Overview of the management of epilepsy in adults".)


Although not fully elucidated, the anti-epileptic effects of VPA appear to be mediated by several mechanisms. The pharmacology of VPA is discussed separately. (See "Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects", section on 'Valproate'.)


Valproic acid (VPA) is available in immediate-release and enteric-coated, delayed-release (12 hour) and extended release (24 hour) oral preparations, as well as an intravenous formulation. Delayed and extended release products are typically formulated as divalproex sodium. Therapeutic daily doses range from 500 mg to 2 g in adults or 15 to 60 mg/kg in children [1].

Nonenteric-coated preparations of VPA are rapidly and nearly completely absorbed from the gastrointestinal tract; peak plasma concentrations are observed from one to four hours after ingestion [1]. Peak plasma concentrations occur four to five hours after therapeutic doses of enteric-coated tablets but may be markedly delayed following overdose [1,2]. A multicenter study of VPA ingestions revealed a mean time to peak plasma concentration of 7.4±3.9 hours; 14 percent of patients had peak concentrations delayed greater than 10 hours [3]. In one case report, peak plasma VPA concentrations occurred 17 hours following overdose of divalproex sodium [4].


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Aug 22, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. McNamara JO. Drugs effective in the therapy of the epilepsies. In: Goodman & Gilman's The Pharmacological basis of therapeutics, Hardman JG, Limbird LE, Molinoff PB et al. (Eds), McGraw-Hill, New York 1996. p.476.
  2. Ingels M, Beauchamp J, Clark RF, Williams SR. Delayed valproic acid toxicity: a retrospective case series. Ann Emerg Med 2002; 39:616.
  3. Spiller HA, Krenzelok EP, Klein-Schwartz W, et al. Multicenter case series of valproic acid ingestion: serum concentrations and toxicity. J Toxicol Clin Toxicol 2000; 38:755.
  4. Graudins A, Aaron CK. Delayed peak serum valproic acid in massive divalproex overdose--treatment with charcoal hemoperfusion. J Toxicol Clin Toxicol 1996; 34:335.
  5. Chadwick DW. Concentration-effect relationships of valproic acid. Clin Pharmacokinet 1985; 10:155.
  6. Gugler R, von Unruh GE. Clinical pharmacokinetics of valproic acid. Clin Pharmacokinet 1980; 5:67.
  7. Gram L, Bentsen KD. Valproate: an updated review. Acta Neurol Scand 1985; 72:129.
  8. Dupuis RE, Lichtman SN, Pollack GM. Acute valproic acid overdose. Clinical course and pharmacokinetic disposition of valproic acid and metabolites. Drug Saf 1990; 5:65.
  9. Coulter DL, Allen RJ. Secondary hyperammonaemia: a possible mechanism for valproate encephalopathy. Lancet 1980; 1:1310.
  10. Khoo SH, Leyland MJ. Cerebral edema following acute sodium valproate overdose. J Toxicol Clin Toxicol 1992; 30:209.
  11. Anderson, GO, Ritland, S. Life threatening intoxication with sodium valproate. Clin Toxicol 1995; 33:279.
  12. Ishikura H, Matsuo N, Matsubara M, et al. Valproic acid overdose and L-carnitine therapy. J Anal Toxicol 1996; 20:55.
  13. Bryant AE 3rd, Dreifuss FE. Valproic acid hepatic fatalities. III. U.S. experience since 1986. Neurology 1996; 46:465.
  14. Coulter DL, Allen RJ. Hyperammonemia with valproic acid therapy. J Pediatr 1981; 99:317.
  15. Mortensen PB, Hansen HE, Pedersen B, et al. Acute valproate intoxication: biochemical investigations and hemodialysis treatment. Int J Clin Pharmacol Ther Toxicol 1983; 21:64.
  16. Jones AL, Proudfoot AT. Features and management of poisoning with modern drugs used to treat epilepsy. QJM 1998; 91:325.
  17. Tønnesen E. Delirium tremens and hypokalemia. Lancet 1982; 2:97.
  18. Silver M, Factor SA. Valproic acid-induced parkinsonism: levodopa responsiveness with dyskinesia. Parkinsonism Relat Disord 2013; 19:758.
  19. Mahmoud F, Tampi RR. Valproic acid-induced parkinsonism in the elderly: a comprehensive review of the literature. Am J Geriatr Pharmacother 2011; 9:405.
  20. Berthelot-Moritz F, Chadda K, Chanavaz I, et al. Fatal sodium valproate poisoning. Intensive Care Med 1997; 23:599.
  21. Rupasinghe J, Jasinarachchi M. Progressive encephalopathy with cerebral oedema and infarctions associated with valproate and diazepam overdose. J Clin Neurosci 2011; 18:710.
  22. Ohtani Y, Endo F, Matsuda I. Carnitine deficiency and hyperammonemia associated with valproic acid therapy. J Pediatr 1982; 101:782.
  23. Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila) 2009; 47:101.
  24. Murphy JV, Marquardt K. Asymptomatic hyperammonemia in patients receiving valproic acid. Arch Neurol 1982; 39:591.
  25. Chicharro AV, de Marinis AJ, Kanner AM. The measurement of ammonia blood levels in patients taking valproic acid: looking for problems where they do not exist? Epilepsy Behav 2007; 11:361.
  26. Dealberto MJ. Valproate-induced hyperammonaemic encephalopathy: review of 14 cases in the psychiatric setting. Int Clin Psychopharmacol 2007; 22:330.
  27. Gidal BE, Inglese CM, Meyer JF, et al. Diet- and valproate-induced transient hyperammonemia: effect of L-carnitine. Pediatr Neurol 1997; 16:301.
  28. Marescaux C, Warter JM, Micheletti G, et al. Stuporous episodes during treatment with sodium valproate: report of seven cases. Epilepsia 1982; 23:297.
  29. Zaret BS, Beckner RR, Marini AM, et al. Sodium valproate-induced hyperammonemia without clinical hepatic dysfunction. Neurology 1982; 32:206.
  30. Batshaw ML, Brusilow SW. Valproate-induced hyperammonemia. Ann Neurol 1982; 11:319.
  31. Duarte J, Macias S, Coria F, et al. Valproate-induced coma: case report and literature review. Ann Pharmacother 1993; 27:582.
  32. Verrotti A, Trotta D, Morgese G, Chiarelli F. Valproate-induced hyperammonemic encephalopathy. Metab Brain Dis 2002; 17:367.
  33. Auinger K, Müller V, Rudiger A, Maggiorini M. Valproic acid intoxication imitating brain death. Am J Emerg Med 2009; 27:1177.e5.
  34. Cheng M, Tang X, Wen S, et al. Valproate (VPA)-associated hyperammonemic encephalopathy independent of elevated serum VPA levels: 21 cases in China from May 2000 to May 2012. Compr Psychiatry 2013; 54:562.
  35. Eubanks AL, Aguirre B, Bourgeois JA. Severe acute hyperammonemia after brief exposure to valproate. Psychosomatics 2008; 49:82.
  36. Yehya N, Saldarini CT, Koski ME, Davanzo P. Valproate-induced hyperammonemic encephalopathy. J Am Acad Child Adolesc Psychiatry 2004; 43:926.
  37. Camilleri C, Albertson T, Offerman S. Fatal cerebral edema after moderate valproic acid overdose. Ann Emerg Med 2005; 45:337.
  38. Sackellares JC, Lee SI, Dreifuss FE. Stupor following administration of valproic acid to patients receiving other antiepileptic drugs. Epilepsia 1979; 20:697.
  39. Yamamoto Y, Takahashi Y, Imai K, et al. Risk factors for hyperammonemia in pediatric patients with epilepsy. Epilepsia 2013; 54:983.
  40. Powell-Jackson PR, Tredger JM, Williams R. Hepatotoxicity to sodium valproate: a review. Gut 1984; 25:673.
  41. Pinkston R, Walker LA. Multiorgan system failure caused by valproic acid toxicity. Am J Emerg Med 1997; 15:504.
  42. Koenig SA, Buesing D, Longin E, et al. Valproic acid-induced hepatopathy: nine new fatalities in Germany from 1994 to 2003. Epilepsia 2006; 47:2027.
  43. Star K, Edwards IR, Choonara I. Valproic acid and fatalities in children: a review of individual case safety reports in VigiBase. PLoS One 2014; 9:e108970.
  44. Schmid MM, Freudenmann RW, Keller F, et al. Non-fatal and fatal liver failure associated with valproic acid. Pharmacopsychiatry 2013; 46:63.
  45. Mindikoglu AL, King D, Magder LS, et al. Valproic acid-associated acute liver failure in children: case report and analysis of liver transplantation outcomes in the United States. J Pediatr 2011; 158:802.
  46. Matsumoto J, Ogawa H, Maeyama R, et al. Successful treatment by direct hemoperfusion of coma possibly resulting from mitochondrial dysfunction in acute valproate intoxication. Epilepsia 1997; 38:950.
  47. Raza M, Al-Bekairi AM, Ageel AM, Qureshi S. Biochemical basis of sodium valproate hepatotoxicity and renal tubular disorder: time dependence of peroxidative injury. Pharmacol Res 1997; 35:153.
  48. Alberto G, Erickson T, Popiel R, et al. Central nervous system manifestations of a valproic acid overdose responsive to naloxone. Ann Emerg Med 1989; 18:889.
  49. Steiman GS, Woerpel RW, Sherard ES Jr. Treatment of accidental sodium valproate overdose with an opiate antagonist. Ann Neurol 1979; 6:274.
  50. Montero FJ. Naloxone in the reversal of coma induced by sodium valproate. Ann Emerg Med 1999; 33:357.
  51. Dingledine R, Iversen LL, Breuker E. Naloxone as a GABA antagonist: evidence from iontophoretic, receptor binding and convulsant studies. Eur J Pharmacol 1978; 47:19.
  52. Connacher AA, Macnab MS, Moody JP, Jung RT. Fatality due to massive overdose of sodium valproate. Scott Med J 1987; 32:85.
  53. Farrar HC, Herold DA, Reed MD. Acute valproic acid intoxication: enhanced drug clearance with oral-activated charcoal. Crit Care Med 1993; 21:299.
  54. Perrott J, Murphy NG, Zed PJ. L-carnitine for acute valproic acid overdose: a systematic review of published cases. Ann Pharmacother 2010; 44:1287.
  55. Howland MA. L-Carnitine. In: Goldfrank's Toxicological Emergencies, 9th, McGraw Hill Medical, New York 2011. p.711.
  56. Russell S. Carnitine as an antidote for acute valproate toxicity in children. Curr Opin Pediatr 2007; 19:206.
  57. Mock CM, Schwetschenau KH. Levocarnitine for valproic-acid-induced hyperammonemic encephalopathy. Am J Health Syst Pharm 2012; 69:35.
  58. Raby WN. Carnitine for valproic acid-induced hyperammonemia. Am J Psychiatry 1997; 154:1168.
  59. Murakami K, Sugimoto T, Woo M, et al. Effect of L-carnitine supplementation on acute valproate intoxication. Epilepsia 1996; 37:687.
  60. Bohan TP, Helton E, McDonald I, et al. Effect of L-carnitine treatment for valproate-induced hepatotoxicity. Neurology 2001; 56:1405.
  61. Zeiler FA, Sader N, Gillman LM, West M. Levocarnitine induced seizures in patients on valproic acid: A negative systematic review. Seizure 2016; 36:36.
  62. al-Shareef A, Buss DC, Shetty HG, et al. The effect of repeated-dose activated charcoal on the pharmacokinetics of sodium valproate in healthy volunteers. Br J Clin Pharmacol 1997; 43:109.
  63. Ghannoum M, Laliberté M, Nolin TD, et al. Extracorporeal treatment for valproic acid poisoning: systematic review and recommendations from the EXTRIP workgroup. Clin Toxicol (Phila) 2015; 53:454.
  64. Marbury, TC, Lee, CS, Bruni, J. Hemodialysis of valproic acid in uremic patients. Dial Transplant 1980; 9:961.
  65. Klotz U, Antonin KH. Pharmacokinetics and bioavailability of sodium valproate. Clin Pharmacol Ther 1977; 21:736.
  66. Bowdle AT, Patel IH, Levy RH, Wilensky AJ. Valproic acid dosage and plasma protein binding and clearance. Clin Pharmacol Ther 1980; 28:486.
  67. van der Merwe AC, Albrecht CF, Brink MS, Coetzee AR. Sodium valproate poisoning. A case report. S Afr Med J 1985; 67:735.
  68. Roodhooft AM, Van Dam K, Haentjens D, et al. Acute sodium valproate intoxication: occurrence of renal failure and treatment with haemoperfusion-haemodialysis. Eur J Pediatr 1990; 149:363.
  69. Tank JE, Palmer BF. Simultaneous "in series" hemodialysis and hemoperfusion in the management of valproic acid overdose. Am J Kidney Dis 1993; 22:341.
  70. Williams, SR, Clark, RF. Hemodialysis of a valproic acid poisoning (abstract). J Toxicol Clin Toxicol 1995; 33:491.
  71. Fernandez MC, Walter FG, Kloster JC, et al. Hemodialysis and hemoperfusion for treatment of valproic acid and gabapentin poisoning. Vet Hum Toxicol 1996; 38:438.
  72. Kay TD, Playford HR, Johnson DW. Hemodialysis versus continuous veno-venous hemodiafiltration in the management of severe valproate overdose. Clin Nephrol 2003; 59:56.
  73. Al Aly Z, Yalamanchili P, Gonzalez E. Extracorporeal management of valproic acid toxicity: a case report and review of the literature. Semin Dial 2005; 18:62.
  74. Licari E, Calzavacca P, Warrillow SJ, Bellomo R. Life-threatening sodium valproate overdose: a comparison of two approaches to treatment. Crit Care Med 2009; 37:3161.
  75. van den Broek MP, Sikma MA, Ververs TF, Meulenbelt J. Severe valproic acid intoxication: case study on the unbound fraction and the applicability of extracorporeal elimination. Eur J Emerg Med 2009; 16:330.
  76. Kandrotas RJ, Love JM, Gal P, Oles KS. The effect of hemodialysis and hemoperfusion on serum valproic acid concentration. Neurology 1990; 40:1456.
  77. Manoguerra AS, Erdman AR, Woolf AD, et al. Valproic acid poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2008; 46:661.