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. Rare, but potentially severe adverse events include hypersensitivity reactions and drug induced lupus erythematosus and scleroderma.


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 with few case reports published despite use of this agent for half a century. Futhermore, the liver injury in reported cases was usually mild and asymptomatic and a part of a generalized hypersensitivity syndrome with fever, rash, facial edema, lymphadenopathy, and eosinophilia or atypical lymphocytosis. The usual latency to onset of the hypersensitivity syndrome is 2 to 8 weeks. The typical serum enzyme elevations are a mixed-cholestatic-hepatocellular pattern and reported cases have not been jaundiced. While the product labeling for ethosuximide warns of hepatic dysfunction and recommends periodic monitoring of liver tests, clinically apparent liver injury with jaundice from ethosuximide is rare.

Likelihood score: E* (suspected but unproven cause of clinically apparent liver injury).

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 resolves rapidly with discontinuation of ethosuximide 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, but caution and careful monitoring should be used in switching to another anticonvulsant after a hypersensitivity reaction to ethosuximide.

Drug Class: Anticonvulsants



Ethosuximide – Zarontin®




Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 19 February 2018

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