Ethosuximide is an succinimide based anticonvulsant commonly used for absence (petit mal) seizures in both adults and children. Ethosuximide has been associated with rare instances of serum enzyme elevations during treatment but has not been linked to cases of clinically apparent liver injury with jaundice.
Ethosuximide (eth' oh sux" a mide) is a succinimide derivative and potent anticonvulsant that has been used to treat absence (petit mal) seizures for more than 50 years. Ethosuximde reduces theshold calcium currents in thalamic neurons and suppresses the paroxysmal spike and wave activity that is associated with lapses of consciousness that occur with absence seizures. Ethosuximide was approved for use in epilepsy in 1960 for use alone or in combination with other agents to treat absence seizures. Ethosuximide is available as tablets of 250 mg and as syrup for pediatric use in several generic forms and under the brand name of Zarontin. The recommended initial dose in adults and children above the age of 6 years is 250 mg twice daily with dose escalation weekly based upon tolerance and effect. Common side effects include dizziness, somnolence, ataxia, fatigue, irritability, anorexia and epigastric discomfort.
Prospective studies suggest that chronic ethosuximide therapy is not accompanied by significant elevations in serum aminotransferase levels, but can increase gamma glutamyltranspeptidase levels. Clinically apparent hepatotoxicity from ethosuximide is very rare and only a few case reports have been published, usually as a part of a hypersensitivity syndrome with fever, rash, facial edema, lymphadenopathy, and eosinophilia or atypical lymphocytosis. The usual latency is 2 to 8 weeks. The typical serum enzyme elevations are a mixed-cholestatic-hepatocellular pattern, but reported cases have not been jaundiced. While the product labelling for ethosuximide warns of hepatic dysfunction and recommends periodic liver function studies, clinically apparent liver injury from ethosuximide must be very rare.
Mechanism of Injury
Ethosuximide is metabolized to inactive intermediates in the liver via the cytochrome P450 system (CYP 3A4). The mechanism of ethosuximide hepatotoxicity is unknown but is likely to be hypersensitivity to an metabolic intermediate.
Outcome and Management
Reported instances of liver injury from ethosuximide have consisted of transient, asymptomatic serum enzyme elevations or mild liver injury accompanying skin rash and systemic hypersensivity reactions. Ethosuximide has not been linked to cases of chronic hepatitis, vanishing bile duct syndrome or acute liver failure. The liver injury associated with ethosuximide resolves rapidly with discontinuation of the anticonvulsant and typically recurs rapidly with reexposure, which should be avoided. There does not appear to be cross-reactivity to hypersensitivity reactions or liver injury between ethosuximide and other antiseizure medications including the aromatic anticonvulsants.
REPRESENTATIVE TRADE NAMES
Ethosuximide – Zarontin®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 07 April 2014
Zimmerman HJ. Anticonvulsants. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999: pp. 498-516. (Expert review of anticonvulsants and liver injury published in 1999; ethosuximide is not discussed).
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McNamara JO. Pharmacology of the epilepsies. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 583-607. (Textbook of pharmacology and therapeutics).
Reynolds NC Jr, Miska RM. Safety of anticonvulsants in hepatic porphyrias. Neurology 1981; 31: 480-4. PubMed Citation (Mentions that ethosuximide has been associated with triggering attacks of acute intermittent porphyria).
Coulter DL. Ethosuximide-induced liver dysfunction. Arch Neurol 1983; 40: 393-4. PubMed Citation (1 year old boy developed ALT elevations one month after ethosuximide was added to a chronic regimen of valproate and phenobarbital that continued to worsen after stopping valproate [bilirubin normal, ALT 69 rising 229 U/L, GGT 175 U/], and resolved rapidly when ethosuximide was stopped).
Wyllie E, Wyllie R. Routine laboratory monitoring for serious adverse effects of antiepileptic medications: the controversy. Epilepsia 1991; 32 Suppl 5: S74-9. PubMed Citation (Review of adverse effects of phenytoin, valproate, carbamazepine and ethosuximide with discussion of potential role of routine monitoring of laboratory results such as ALT; most information indicates that such monitoring is unlikely to be effective in avoiding the rare instance of severe idiosyncratic hepatic injury from anticonvulsants because of their rarity and rapidity of onset and the frequent, insignificant ALT elevations found; mentions aplastic anemia and leucopenia as being due to ethosuximide, but not hepatic injury).
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syndrome due to 2 anticonvulsant drugs. Contact Dermatitis 1999; 41: 141-4. PubMed Citation (6 year old boy with petit mal developed rash, fever, lymphadenopathy and eosinophilia a month after starting ethionamide and valproate [bilirubin not given, AST 70 U/L, GGT 50 U/L], redeveloping rash within a day of restarting ethosuximide, later tolerating lamotrigine and clonazepam).
Knowles SR, Shapiro LE, Shear NH. Anticonvulsant hypersensitivity syndrome: incidence, prevention and management. Drug Saf 1999; 21: 489– 501. PubMed Citation (Review of anticonvulsant hypersensitivity syndrome: triad of fever, rash and internal organ injury occurring 1-8 weeks after exposure to anticonvulsant; liver being most common internal organ involved. Occurs in 1:1000-1:10,000 initial exposures to phenytoin, carbamazepine, phenobarbital or lamotrigine, unrelated to dose, perhaps predisposed by valproate; liver injury arises 1-4 weeks after onset of rash and ranges in severity from asymptomatic ALT elevations to icteric hepatitis to ALF; high mortality rate with jaundice; other organs include muscle, kidney, brain, heart and lung. Pseudolymphoma syndrome and serum sickness like syndrome are separate complications of anticonvulsants; role of corticosteroids uncertain; cross reactivity among the agents should be assumed; ethosuximide is not mentioned).
Hamer HM, Morris HH. Hypersensitivity syndrome to antiepileptic drugs: a review including new anticonvulsants. Clevel Clin J Med 1999; 66: 239-45. PubMed Citation (Clinical review of anticonvulsant syndrome, which occurs in 1-5/10,000 users, higher risk in African Americans and affected siblings; liver involvement common, but most cases are anicteric; other manifestations include facial edema, lymphadenopathy, bone marrow aplasia, pseudolymphoma, thyroiditis, interstitial nephritis, switching to valproate, levetiracetam or benzodiazepines is safe; ethosuximide is not mentioned).
Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl 2004; 10: 1018-23. PubMed Citation (Among ~50,000 liver transplants done in the United States between 1990 and 2002, 137 [0.2%] were done for idiosyncratic drug induced acute liver failure, of which 10 were attributed to phenytoin, 10 to valproate and 1 to carbamazepine, but none to ethosuximide or other anticonvulsants).
Björnsson E. Hepatotoxicity associated with antiepileptic drugs. Acta Neurol Scan 2008; 118: 281-90. PubMed Citation (Review of all anticonvulsants; mentions that there is no known clinically significant hepatotoxicity associated with ethosuximide).
Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, valproate accounted for 6 cases, lamotrigine 5, phenytoin 5, gabapentin and topiramate 1 each; none were due to ethosuximide).
Posner E. Absence seizures in children. Clin Evid (Online) 2008 Jan 10;2008.
PubMed Citation (Review of evidence of efficacy and safety of drugs for petit mal seizures in children; ethosuximide is considered effective, but there are no randomized controlled trials to support this consensus; mentions that hepatic impairment, aplastic anaemia and serious skin reactions are rare adverse effects of ethosuximide).
Penovich PE, Willmore LJ. Use of a new antiepileptic drug or an old one as first drug for treatment of absence epilepsy. Epilepsia 2009; 50 Suppl
8:37-41. PubMed Citation (Review of the therapy of absence seizures, mentions that side effects of ethosuximide "tend to be a challenge"; no mention of hepatotoxicity).
Knowles SR, Dewhurst N, Shear NH. Anticonvulsant hypersensitivity syndrome:
an update. Expert Opin Drug Saf 2012; 11: 767-78. PubMed Citation (Updated review of anticonvulsant hypersensitivity syndrome; associated with phenytoin, phenobarbital, lamotrigine and carbamazepine and rarely with zonisamide, valproate and oxcarbazepine; ethosuximide not mentioned).
Drugs for epilepsy. Treat Guidel Med Lett 2013; 11: 9-18. PubMed Citation (Concise review of indications and side effects of anticonvulsants: ethosuximide is approved for treatment of absence seizures, but is not effective in generalized tonic-clonic or partial seizures; rare side effects include severe skin and generalized hypersensitivity reactions; no mention of hepatotoxicity).
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