Sodium Valproate 20.Sep.2018-Expires: 7 days - Do not archive DESCRIPTION SUBSTANCE NAME Sodium Valproate   SUBSTANCE CLASS Antiepileptic   Carboxylic Acid Derivative   Antipsychotic   INTERVENTION CRITERIA Intervention Level Acute Child and Adult Medical assessment and observation at an emergency department is recommended for: - Ingestions greater than 50 mg/kg - Symptomatic cases - Exposures with intent to self-harm   Decontamination, if appropriate, and medical observation at an emergency department is recommended for: - Ingestions greater than 400 mg/kg   Acute On Chronic Medical assessment and observation at an emergency department is recommended for: - Ingestions 50 mg/kg greater than the patients usual single therapeutic dose - Symptomatic cases - Exposures with intent to self-harm   Decontamination, if appropriate, and medical observation at an emergency department is recommended for: - Ingestions 400 mg/kg greater than the patients usual single therapeutic dose is ingested   Chronic Medical assessment and observation is recommended for:  - Any symptomatic chronic ingestion   Observation Period Observation at Home If the exposure does not meet the intervention level and the patient is asymptomatic, they can be observed at home in the care of a reliable observer. The patient should be observed for 6 hours following ingestion of a standard preparation or for 24 hours if a sustained release formulation has been ingested.   The patient should be medically assessed if any symptoms develop, including: Vomiting Drowsiness Confusion Unconsciousness Tremor   Medical Observation If the patient’s ingested dose is above the intervention criteria: - Observe for development of symptoms for a minimum period of 6 hours when a standard-release preparation has been ingested - Observe for development of symptoms for a minimum period of 12 hours when an enteric-coated or sustained-release preparation has been ingested   If the patient remains asymptomatic throughout the observation period, and any necessary decontamination and investigations have been carried out: - Discharge into the care of a reliable observer, or - Refer for psychiatric assessment (if the overdose was intentional)   If the patient is symptomatic on presentation they should be observed until there has been resolution of signs of valproate toxicity and serum concentrations have fallen into the therapeutic range.   Investigations Levels Valproic acid serum concentrations should be measured following ingestion of immediate- and sustained release-preparations when the suspected dose is > 200 mg/kg.   Serum concentrations should be taken on presentation and repeated at 3 to 4 hour intervals (to identify the onset of peak concentrations and ensure that the serum concentrations are falling)[1][2][3] In particular, patients ingesting enteric coated formulations of valproic acid may have slowed absorption or form concretions in the GI tract. Absorption may be delayed and prolonged. Hence, serial serum valproate estimations may be useful to ascertain ongoing absorption and guide the need for further GI decontamination and extracorporeal elimination.   Click here to link to toxic serum levels   Monitoring Monitor: Level of consciousness Respiratory rate Oxygen saturations Heart rate Blood pressure ECG Seizure activity Arterial blood gases Blood glucose Urea and electrolytes   Admission Criteria Hospital admission is recommended when: - >400 mg/kg or more is ingested - Serum concentration is greater than 5,908 umol/L (850 mg/L) valproic acid - Following symptoms occur  Any decreased level of consciousness Respiratory depression Hypotension Hypoglycemia Recurrent seizures - Following conditions are present Electrolyte disturbances (hypernatremia) Metabolic acidosis Encephalopathy Hepatotoxicity Pancreatitis   TREATMENT TREATMENT SUMMARY Severe toxicity is unlikely in the majority of overdoses. However, emergency stabilization may occasionally be required following exposure to massive amounts of valproate, when treatment of cardio-respiratory arrest, seizures, or metabolic acidosis may be necessary.   Decontamination with activated charcoal is recommended for ingestions over 400 mg/kg sodium valproate.   There are no proven antidotes for valproic acid intoxication, although L-carnitine may be considered an adjunct to standard management.[4][5] Multiple dose activated charcoal and hemodialysis may be useful in severe toxicity.[6] Valproic acid concentrations should be monitored.   Acute treatment is primarily symptomatic and supportive, focussing mainly on CNS and respiratory depression. Treatment of encephalopathy, seizures, hypotension, electrolyte disturbances, thrombocytopenia, metabolic acidosis, bone marrow suppression, and hypothermia may sometimes be required following large to massive overdoses. Hepatotoxicity and pancreatitis are uncommon with overdose, but do occur with therapeutic doses and may be fatal. Delayed cerebral edema may occur. Ammonia concentrations should be checked if encephalopathy is suspected.   Patients with chronic valproate toxicity will require referral to their a neurologist for dosage adjustment and monitoring of their ongoing therapy.   Emergency Stabilization Ensure adequate cardiorespiratory function Cardiac arrest Seizure Metabolic acidosis Emergency monitoring Decontamination Ingestion Single dose activated charcoal Exclude bezoar Antidote(s) None recommended L-Carnitine Enhanced Elimination Multiple dose activated charcoal Hemodialysis Supportive Care Monitoring Neurologic CNS depression Seizure Encephalopathy Cerebral edema Respiratory Respiratory depression Cardiovascular Hypotension Metabolic Hypoglycemia Metabolic acidosis Fluid and electrolytes Electrolyte abnormalities Hematologic Thrombocytopenia Bone marrow suppression Hepatic Hepatotoxicity Gastrointestinal Pancreatitis EMERGENCY STABILIZATION Ensure Adequate Cardiopulmonary Function Endotracheal intubation maybe required for airway protection and adequate ventilation of the obtunded patient following overdose. Ensure that the patient is well perfused and hemodynamically stable.   Immediately establish secure intravenous access.   Seizure Seizures are uncommon with valproate overdose.   Most toxic seizures are short-lived and often do not require intervention.[7]   Administer a benzodiazepine as first-line treatment to patients with seizure activity.[7]   Blood glucose concentration should be promptly determined. If the result indicates hypoglycemia, or is unobtainable, 50% dextrose should be administered IV (preceded by thiamine in adults).   If seizure activity continues or if there is need for maintenance dosing proceed to further supportive care of toxic seizure.   Metabolic Acidosis Follow standard protocols for the management of metabolic acidosis. Emergency Monitoring Level of consciousness Respiratory rate Heart rate ECG Blood pressure Seizure activity Acid-base balance   DECONTAMINATION Ingestion Single Dose Activated Charcoal Decontamination with activated charcoal is recommended for ingestions over 400 mg/kg sodium valproate.   CNS depression is a likely consequence of significant overdose. Gastrointestinal decontamination should be undertaken with appropriate airway protection.   Administration of activated charcoal may be considered if a patient has ingested a potentially toxic amount of a solid formulation (e.g. tablet or capsule) up to 2 hours previously.   Single dose activated charcoal[8] CHILD 1 to 2 g/kg orally ADULT 50 to 100 g orally   Nasogastric Administration Nasogastric instillation of activated charcoal is not recommended unless the ingestion is considered potentially severely toxic. If endotracheal intubation is otherwise required, activated charcoal can be administered following intubation, however, intubation should not be performed solely for the purpose of then administering charcoal.   Exclude Bezoar While bezoar formation is unlikely following valproate overdose, the possibility should be considered with the ingestion of enteric-coated or modified-release formulations.   Suspect a bezoar or tablet concretion where serum valproate concentration remains persistently elevated or plateaued despite apparently adequate GI decontamination.   Pharmacobezoars (drug concretions) may occur following an ingested overdose of various drugs and, particularly, modified release (e.g. sustained release) or enteric-coated preparations. Such masses may significantly extend or increase the duration of toxicity.[9]   Investigation for the presence of a tablet mass in the upper GI tract may be of benefit in the patient with life-threatening toxicity, but negative imaging studies do not exclude the presence of a bezoar.   Bezoars may be detected by: - Gastroscopy (can only view stomach and duodenum and impractical if charcoal has been administered as the bezoar may be hidden) - Abdominal CT scanning with oral contrast - Plain X-ray examination (but only for radio-opaque concretions) - Ultrasound examination   If found, the risk and practicality of removal should be weighed against use of supportive care with or without the addition of whole bowel irrigation.   If the bezoar is located in the stomach or duodenum, removal may be attempted endoscopically. Bezoars in the small intestine are inherently difficult to localize and impossible to remove without laparotomy.   ANTIDOTE(S) There Are No Antidotes For This Substance No clinically established antidotes exist for the treatment of valproic acid overdose. However, naloxone and L-carnitine have both been used in a number of cases with varying results.   Naloxone has been used successfully in a small number of cases to reverse valproate-induced CNS depression[10][11][12][13][14][15]This appears to have been more effective in patients with minimally elevated serum concentrations,[16][17]with other reports showing no effect in patients with much higher concentrations.[18][19][20]Any effect may be due to reversal of valproate blockade of GABA cellular uptake or reversal of valproate-induced release of endogenous opioids.[16][21]   L-Carnitine Evidence supporting clinical efficacy and safety of L-carnitine in acute valproic acid poisoning is limited.[4] The primary route of metabolism of valproic acid by beta-oxidation is inhibited by hypocarnitemia,[22] a state which is commonly observed in chronic, supratherapeutic valproic acid poisoning. Administration of L-carnitine is thought to normalize metabolism[23]  and has well established clinical benefit in reversing hyperammonemia in these patients. It is strongly recommended prophylactically in “at-risk” patients on valproic acid therapy.[24][25]   In acute poisoning there is some, albeit scant, evidence that valproic acid metabolism is similarly inhibited and that administration of L-carnitine similarly normalizes metabolism.[22][26][4] There are also anecdotal reports of reversal of hyperammonemia in acute poisoning.[27][28][29] L-carnitine does not appear to have any effect on neurological toxicity.[26]   L-carnitine may be considered in acute valproic acid poisoning as an adjunct to standard management where hyperammonemia or decreased level of consciousness is present.[4][5]   Indications L-carnitine administration is indicated in patients with: Decreased level of consciousness[4][5] Hyperammonemia[30][26][5][31] Some authors also recommend considering L-carnitine administration if severe toxicity is present or likely: Ingestions > 100 mg/kg valproic  acid[4] Serum valproic acid concentrations > 3,128 umol/L (> 450 mg/L)[4][5][32] Hepatotoxicity[25][26]   Dose and Administration Note that the recommended L-carnitine dose for acute valproic acid poisoning is higher[4][5][27][28][22] than that used for chronic, supratherapeutic poisoning[30][25][5] or mild hypocarnitemia. Case reports indicate that L-carnitine infusion may be required for up to 3 to 4 days.[4][28]   L-Carnitine Dosage in Acute Valproic Acid Poisoning   CHILD and ADULT IV Loading dose: 100 mg/kg (bolus over 2 to 3 minutes or infusion over 15 to 30 minutes)[4][5] Maximum dose 3 g[4](up to 6 g has been given)[5] Maintenance dose: 50 mg/kg every 8 hours[4] or 15 mg/kg every 4 hours[5] Doses given either as bolus over 2 to 3 minutes or infusion over 15 to 30 minutes[4][5] End Point: Ammonia levels decreasing, patient demonstrates clinical improvement, or significant adverse effects occur.[4][5]   Precautions Seizures have occurred in patients taking L-carnitine therapeutically; caution is recommended in patients with underlying seizure disorder. Adequate hydration and a good renal output must be maintained as there is potential for accumulation of toxic metabolites of L-carnitine (trimethylamine and trimethylamine-N-oxide) in patients with renal impairment.[33][34]   Contra-indications L-carnitine does not have any contraindications.[33][34]   Adverse Effects Seizures are reported, both in patients with or without a prior history of convulsive disorder.[33][34] Tachydysrhythmias, hypertension, and hypotension are also noted.[4] Gastrointestinal upset[34] and an unpleasant, fishy body odor may occur.[26][30] No allergic reactions or adverse effects were observed when L-carnitine was administered in 215 acute valproic acid poisoning cases.[31]   SIGNS AND SYMPTOMS Sodium valproate is rapidly metabolized to valproic acid in vivo.   CNS depression, ranging from drowsiness to coma, is the most frequent sign after valproic acid overdose; with ingestions less than 200 mg/kg asymptomatic or displaying mild drowsiness and ataxia only. Ingestions from 200 to 400 mg/kg are likely to present varying levels of consciousness. Significant CNS depression is likely with multi-organ involvement as dose increases between 400 and 1,000 mg/kg. Massive overdoses (> 1,000 mg/kg) can result in serious CNS and respiratory depression, hypotension, metabolic acidosis, and bone marrow depression. Severe hyperammonemic encephalopathy, cerebral edema, and clinically significant thrombocytopenia may develop; hypernatremia, hypoglycemia, hypocalcemia and other electrolyte disturbances may be severe and prolonged.[35] Delayed cerebral edema may occur though is not common. Death is rare, and usually results from cardiac or respiratory arrest.   Individuals with underlying genetic urea cycle disorders, such as ornithine transcarbamylase deficiency, are at increased risk of developing hyperammonemic encephalopathy. This may occur with therapeutic dosing.   Hepatotoxicity, pancreatitis and other adverse effects seen with therapeutic doses may occasionally occur with overdose.   There is a risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in patients starting carbamazepine therapy.[36]   Onset/Duration of Symptoms Symptoms would usually be expected to develop within four hours of ingestion with most standard preparations of valproate. Delayed toxicity may occur with ingestion of sustained release or enteric-coated formulations, with CNS depression occurring as long as 8 to 13 hours post-ingestion.[37][38]   Metabolic disturbances usually present early, and may be severe and prolonged. The development of cerebral edema may also be delayed, presenting two to three days or more post-ingestion. Bone marrow suppression may present three to five days after a massive overdose, and usually resolves spontaneously a few days later.   Severity of Poisoning Mild Valproate Toxicity Moderate Valproate Toxicity Severe Valproate Toxicity Mild drowsiness Confusion Nausea Vomiting Tachycardia Increased drowsiness Electrolyte disturbances Hypoglycemia Thrombocytopenia Unconsciousness / coma Cerebral edema Hypotension Respiratory depression Respiratory or metabolic acidosis Seizures Cardiac or respiratory arrest   CHRONIC EFFECTS Adverse Effects Adverse effects in patients taking valproate drugs therapeutically are not uncommon, and may also occur in overdose. Some effects such as increases in hepatic enzymes, bone marrow suppression, sedation or ataxia may be misleading, suggesting a higher degree of toxicity following overdose than is present.   There are also some serious adverse effects that occur at therapeutic doses which may occur in overdose. These include fatal hepatotoxicity such as toxic cholestatic hepatitis and hepatocellular necrosis,[24][39]pancreatitis,[40]and severe hyperammonemic encephalopathy.[41][42]   Hepatotoxicity, and rarely hepatic failure, occur most commonly in the first few months of treatment. Young children with multiple medical problems, on multiple antiepileptic agents are at highest risk of fatal hepatotoxicity. Fatalities due to pancreatitis have also occurred.[39][43][44][45]   Individuals with underlying genetic urea cycle disorders, such as ornithine transcarbamylase deficiency, may develop hyperammonemic encephalopathy following initiation of valproate therapy at normal doses.[46]   REFERENCES [1] Payen C, Frantz P, Martin O, Parant F, Moulsma M, Pulce C, Descotes J. Delayed toxicity following acute ingestion of valpromide. Hum Exp Toxicol 2004 Mar; 23 (3): 145-8. [2] Graudins A, Aaron CK. Delayed peak serum valproic acid in massive divalproex overdose--treatment with charcoal hemoperfusion. J Toxicol Clin Toxicol 1996; 34 (3): 335-41. [3] Ingels M, Beauchamp J, Clark RF, Williams SR. Delayed valproic acid toxicity: a retrospective case series. Ann Emerg Med 2002 Jun; 39 (6): 616-21. [4] Perrott J, Murphy NG, Zed PJ. L-carnitine for acute valproic acid overdose: a systematic review of published cases. Ann Pharmacother 2010 Jul-Aug; 44 (7-8): 1287-93. [5] Russell S. Carnitine as an antidote for acute valproate toxicity in children. Curr Opin Pediatr 2007 Apr; 19 (2): 206-10. [6] Ghannoum M, Laliberté M, Nolin TD, MacTier R, Lavergne V, Hoffman RS, Gosselin S. Extracorporeal treatment for valproic acid poisoning: Systematic review and recommendations from the EXTRIP workgroup. Clin Toxicol (Phila) 2015 Jun; 53 (5): 454-65. [7] Chen HY, Albertson TE, Olson KR. Treatment of drug-induced seizures. Br J Clin Pharmacol 2016 Mar; 81 (3): 412-9. [8] Fountain JS, Beasley DM. Activated charcoal supercedes ipecac as gastric decontaminant. N Z Med J 1998 Oct 23; 111 (1076): 402-4. [9] Rankin RJ, Edwards IR. Overdose of sustained release verapamil. [Letter] N Z Med J 1990 Apr 11; 103 (887): 165. [10] Montero FJ. Naloxone in the reversal of coma induced by sodium valproate. [Letter] Ann Emerg Med 1999 Mar; 33 (3): 357-8. [11] Alberto G, Erickson T, Popiel R, Narayanan M, Hryhorczuk D. Central nervous system manifestations of a valproic acid overdose responsive to naloxone. Ann Emerg Med 1989 Aug; 18 (8): 889-91. [12] Espinoza O, Maradei I, Ramirez M, Pascuzzo-Lima C. An unusual presentation of opioid-like syndrome in pediatric valproic acid poisoning. Vet Hum Toxicol 2001 Jun; 43 (3): 178-9. [13] Steiman GS, Woerpel RW, Sherard ES Jr. Treatment of accidental sodium valproate overdose with an opiate antagonist. Ann Neurol 1979 Sep; 6 (3): 274. [14] Roberge RJ, Francis EH 3rd. Use of naloxone in valproic acid overdose: case report and review. J Emerg Med 2002 Jan; 22 (1): 67-70. [15] Popiel R, Erickson T, Leikin JB. Valproic acid overdose: response to naloxone [abstract]. Vet Hum Toxicol 1989; 31: 368. [16] Dingledine R, Iversen LL, Breuker E. Naloxone as a GABA antagonist: evidence from iontophoretic, receptor binding and convulsant studies. Eur J Pharmacol 1978 Jan 1; 47 (1): 19-27. [17] Hyden H, Cupello A, Palm A. Naloxone reverses the inhibition by sodium valproate of GABA transport across the Deiters' neuronal plasma membrane. [Letter] Ann Neurol 1987 Apr; 21 (4): 416-7. [18] Connacher AA, Macnab MS, Moody JP, Jung RT. Fatality due to massive overdose of sodium valproate. Scott Med J 1987 Jun; 32 (3): 85-6. [19] Mortensen PB, Hansen HE, Pedersen B, Hartmann-Andersen F, Husted SE. Acute valproate intoxication: biochemical investigations and hemodialysis treatment. Int J Clin Pharmacol Ther Toxicol 1983 Feb; 21 (2): 64-8. [20] Palatnick W, Honcharik N, Roberts D. Coma, anion gap, and metabolic derangements associated with massive valproic acid overdose [abstract] Vet Hum Toxicol 1989; 31:368. [21] Gruol DL, Barker JL, Smith TG. Naloxone antagonism of GABA-evoked membrane polarizations in cultured mouse spinal cord neurons. Brain Res 1980 Oct 6; 198 (2): 323-32. [22] Ishikura H, Matsuo N, Matsubara M, Ishihara T, Takeyama N, Tanaka T. Valproic acid overdose and L-carnitine therapy. J Anal Toxicol 1996 Jan-Feb; 20 (1): 55-8. [23] Lheureux PE, Penaloza A, Zahir S, Gris M. Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence? Crit Care 2005 Oct 5; 9 (5): 431-40. [24] Raskind JY, El-Chaar GM. The role of carnitine supplementation during valproic acid therapy. Ann Pharmacother 2000 May; 34 (5): 630-8. [25] De Vivo DC, Bohan TP, Coulter DL, Dreifuss FE, Greenwood RS, Nordli DR Jr, Shields WD, Stafstrom CE, Tein I. L-carnitine supplementation in childhood epilepsy: current perspectives. Epilepsia 1998 Nov; 39 (11): 1216-25. [26] Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila) 2009 Feb; 47 (2): 101-11. [27] Jung J, Eo E, Ahn KO. A case of hemoperfusion and L-carnitine management in valproic acid overdose. Am J Emerg Med 2008 Mar; 26 (3): 388.e3-4. [28] Chan YC, Tse ML, Lau FL. Two cases of valproic acid poisoning treated with L-carnitine. Hum Exp Toxicol 2007 Dec; 26 (12): 967-9. [29] Auinger K, Müller V, Rudiger A, Maggiorini M. Valproic acid intoxication imitating brain death. Am J Emerg Med 2009 Nov; 27 (9): 1177.e5-6. [30] Sztajnkrycer MD. Valproic acid toxicity: overview and management. J Toxicol Clin Toxicol 2002; 40 (6): 789-801. [31] LoVecchio F, Shriki J, Samaddar R. L-carnitine was safely administered in the setting of valproate toxicity. Am J Emerg Med 2005 May; 23 (3): 321-2. [32] Perez A, McKay CA. Role of carnitine in valproic acid toxicity. [Letter] J Toxicol Clin Toxicol 2003; 41 (6): 899; author reply 901-2. [33] Carnitor IV Prescribing Information, United States of America: Sigma-Tau Pharmaceuticals; 2011; [cited 26 January 2012]. URL: http://www.sigmatau.com. [34] Carnitor Oral Prescribing Information, United States of America: Sigma-Tau Pharmaceuticals; June 2006; [cited 26 January 2012]. URL: http://www.fda.gov. [35] Murray L, Daly F, Little M, Cadogan M. Toxicology handbook. Marrickville, Australia: Churchill Livingstone; 2007. p. 277-9. [36] Mockenhaupt M, Messenheimer J, Tennis P, Schlingmann J. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology 2005 Apr 12; 64 (7): 1134-8. [37] Brubacher JR, Dahghani P, McKnight D. Delayed toxicity following ingestion of enteric-coated divalproex sodium (Epival). J Emerg Med 1999 May-Jun; 17 (3): 463-7. [38] Houghton BL, Bowers JB. Valproic acid overdose: a case report and review of therapy. MedGenMed 2003 Jan 14; 5 (1): 5. [39] Dreifuss FE, Santilli N, Langer DH, Sweeney KP, Moline KA, Menander KB. Valproic acid hepatic fatalities: a retrospective review. Neurology 1987 Mar; 37 (3): 379-85. [40] Wyllie E, Wyllie R, Cruse RP, Erenberg G, Rothner AD. Pancreatitis associated with valproic acid therapy. Am J Dis Child 1984 Oct; 138 (10): 912-4. [41] Chen WT, Yen DJ, Yu HY, Liao KK. Valproate-induced encephalopathy. Zhonghua Yi Xue Za Zhi (Taipei) 2001 Aug; 64 (8): 474-8. [42] Ziyeh S, Thiel T, Spreer J, Klisch J, Schumacher M. Valproate-induced encephalopathy: assessment with MR imaging and 1H MR spectroscopy. Epilepsia 2002 Sep; 43 (9): 1101-5. [43] Dreifuss FE, Langer DH, Moline KA, Maxwell JE. Valproic acid hepatic fatalities. II. US experience since 1984. Neurology 1989 Feb; 39 (2 Pt 1): 201-7. [44] Lewis JR. Valproic acid (Depakene). A new anticonvulsant agent. JAMA 1978 Nov 10; 240 (20): 2190-2. [45] Powell-Jackson PR, Tredger JM, Williams R. Hepatotoxicity to sodium valproate: a review. Gut 1984 Jun; 25 (6): 673-81. [46] Epilim Medicines Data Sheet, New Zealand: Sanofi-Synthelabo (NZ) Ltd; 2003; [cited 2003 September 5]. URL: http://www.medsafe.govt.nz. Do Not Archive. This document is current on day of issue, NZ: 20.Sep.2018

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