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Andrea E. Cavanna

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Ethosuximide is a first-generation antiepileptic drug (AED; Fig. 5.1) known under the proprietary brand name of Zarontin® (Pfizer, New York, NY) in the UK (oral solution) and USA (Fig. 5.2).

Fig. 5.1 Chronology of the clinical use of ethosuximide

Fig. 5.1 Chronology of the clinical use of ethosuximide

Fig. 5.2 Chemical structure of ethosuximide

Fig. 5.2 Chemical structure of ethosuximide



Ethosuximide 250 mg (56-cap pack).

Oral solution

Ethosuximide 50 mg/mL (200 mL).

Generic formulation

MHRA/CHM advice to minimize risk when switching patients with epilepsy between different manufacturers’ products (including generic products):

  • Category 3: it is usually unnecessary to ensure that patients are maintained on a specific manufacturer’s product unless there are specific concerns, such as patient anxiety and risk of confusion/dosing error.


Epilepsy: monotherapy and adjunctive therapy of absence seizures; adjunctive therapy of generalized tonic-clonic seizures.

Recommendations summarized from NICE (2012)

  • Seizure types: first line (absence seizures), adjunctive (absence seizures).

  • Epilepsy types: first line (absence syndromes), adjunctive (absence syndromes).

Dose titration

250 mg bd, then increased in steps of 250 mg every 5–7 days; usual maintenance 1000–1500 mg daily, divided into two doses (max. 2000 mg daily).

Plasma levels monitoring

Monitoring ethosuximide plasma levels can be useful in selected cases, although the evidence for a therapeutic plasma range is limited (suggested therapeutic plasma concentrations 40–100 mg/L) and a toxic limit has not been consistently defined.


Patients with acute porphyrias.

Adverse effects

Ethosuximide can be associated with adverse effects at the level the nervous system and other systems (Table 5.1).

Table 5.1 Estimated frequency of adverse effects of ethosuximide

Very common (>1 in 10 patients on ethosuximide)

Nervous system

Other systems

Common (>1 in 100 patients on ethosuximide)

Nervous system

Other systems

  • abdominal pain

  • anorexia

  • diarrhoea

  • gastro-intestinal disturbances

  • nausea and vomiting

  • weight loss

Uncommon (>1 in 1,000 patients on ethosuximide)

Nervous system

  • aggression

  • ataxia

  • dizziness

  • drowsiness

  • euphoria

  • fatigue

  • headache

  • impaired concentration

  • irritability

Other systems

  • hiccup

Rare (>1 in 10,000 patients on ethosuximide)

Nervous system:

  • depression

  • dyskinesia

  • increased libido

  • myopia

  • photophobia

  • psychosis

  • sleep disturbances

Other systems:

  • gingival hypertrophy

  • rash

  • tongue swelling

  • vaginal bleeding

Very rare (<1 in 10,000 patients on ethosuximide)

Nervous system

Other systems


With AEDs

  • Plasma concentration of ethosuximide is reduced by the glucuronidation inducers carbamazepine, phenytoin, phenobarbital, and primidone.

  • Plasma concentration of ethosuximide has been reported to be both increased and decreased by valproate.

  • Ethosuximide can raise serum levels of phenytoin.

With other drugs

Metabolism of ethosuximide is inhibited by isoniazid, resulting in increased plasma concentration and risk of toxicity.

With alcohol/food

There are no known specific interactions between alcohol and ethosuximide, and there are no specific foods that must be excluded from diet when taking ethosuximide.

Special populations

Hepatic impairment

Use with caution.

Renal impairment

Use with caution.


  • The dose of ethosuximide should be monitored carefully during pregnancy and after delivery, and adjustments made on a clinical basis.

  • Ethosuximide crosses the placenta and cases of birth defects have been reported. Therefore, the prescribing physician should weigh the benefits versus the risks of ethosuximide in treating or counselling epileptic women of childbearing age.

  • Ethosuximide is excreted in breastmilk and the effects of ethosuximide on the nursing infant are unknown. Therefore, ethosuximide should be used in nursing mothers only if the benefits clearly outweigh the risks and breastfeeding is best avoided.

Behavioural and cognitive effects in patients with epilepsy

Adverse behavioural effects can be of clinical significance, and include the possible induction of anxiety, depression, confusion, irritability, aggression, hallucinations, and intermittent impairment of consciousness These episodes can occur following cessation of seizures and normalization of the electroencephalogram (EEG), and resolve with discontinuation of ethosuximide and seizure recurrence (alternative psychosis in the context of forced normalization). Among first-generation AEDs, ethosuximide is characterized by a relatively favourable cognitive profile, with low incidence of cognitive adverse effects.

Psychiatric use

Ethosuximide as adjunctive treatment of bipolar disorder was found to be ineffective in patients with acute mania. This AED has no approved indications or clinical uses in psychiatry (Fig. 5.3).

Fig. 5.3 Level of evidence supporting the psychiatric use of ethosuximide in patients with behavioural symptoms

Fig. 5.3 Level of evidence supporting the psychiatric use of ethosuximide in patients with behavioural symptoms

Overall rating

Ethosuximide is characterized by few antiepileptic indications, with an acceptable interaction profile in polytherapy. It has a good behavioural tolerability profile, but no psychiatric uses (Table 5.2).

Table 5.2 Overall rating of ethosuximide

Antiepileptic indications

Interactions in polytherapy

Behavioural tolerability


Psychiatric use

Key: ☺☺☺ = very good; ☺☺ = good; ☺ = acceptable.