Ethosuximide

(BAN, USAN, rINN)
Ethosuximide Chemical formula
Synonyms: CI-366; CN-10395; Ethosuximid; Éthosuximide; Ethosuximidum; Etosüksimid; Etosuksimidas; Etosuksimidi; Etosuksymid; Etosuximid; Etosuximida; Etoszuximid; NSC-64013; PM-671. 2-Ethyl-2methylsuccinimide.
Cyrillic synonym: Этосуксимид.

💊 Chemical information

Chemical formula: C7H11NO2 = 141.2.
CAS — 77-67-8.
ATC — N03AD01.
ATC Vet — QN03AD01.

Pharmacopoeias.

In Chin., Eur., Int., Jpn, and US.

Ph. Eur. 6.2

(Ethosuximide). A white or almost white powder or waxy solid. It exhibits polymorphism. Freely soluble in water; very soluble in alcohol and in dichloromethane. Protect from light.

USP 31

(Ethosuximide). A white to off-white crystalline powder or waxy solid, having a characteristic odour. Freely soluble in water and in chloroform; very soluble in alcohol and in ether; very slightly soluble in petroleum spirit. Store in airtight containers.

💊 Adverse Effects and Treatment

Gastrointestinal adverse effects including nausea, vomiting, diarrhoea, anorexia, gastric upset, and abdominal pain occur quite often with ethosuximide. Other effects that may occur include headache, fatigue, lethargy, drowsiness, dizziness, ataxia, hiccup, and mild euphoria. More rarely dyskinesias, personality changes, depression, psychosis, sleep disturbances including night terrors, skin rashes, erythema multiforme or StevensJohnson syndrome, SLE, photophobia, gum hypertrophy, tongue swelling, myopia, increased libido, and vaginal bleeding have been reported. There are a few reports of blood disorders including eosinophilia, leucopenia, agranulocytosis, thrombocytopenia, pancytopenia, and aplastic anaemia; fatalities have occurred. Abnormal renal and liver function values have been recorded.

Effects on mental function.

For the effects of antiepileptic therapy on cognition and mood, including the risk of suicidal ideation.

💊 Precautions

Ethosuximide should be used with caution in patients with impaired hepatic or renal function. Licensed product information recommends regular hepatic and renalfunction tests (and some suggest blood counts) during treatment with ethosuximide, although the practical value of such monitoring has been questioned. Patients or their carers should be told how to recognise signs of blood toxicity and they should be advised to seek immediate medical attention if symptoms such as fever, sore throat, mouth ulcers, bruising, or bleeding develop. Care is required when withdrawing ethosuximide therapy—see also Uses and Administration, below.

Breast feeding.

Ethosuximide is distributed in significant amounts into breast milk; hyperexcitability and poor suckling have been reported in the infant. Although licensed product information recommends that breast feeding should be avoided, the American Academy of Pediatrics1 considers that ethosuximide is usually compatible with breast feeding. For further comment on antiepileptic therapy and breast feeding.
1. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. Correction. ibid.; 1029. Also available at: http://aappolicy.aappublications.org/cgi/content/full/ pediatrics%3b108/3/776 (accessed 09/06/08)

Driving.

For a comment on antiepileptic drugs and driving.

Porphyria.

Ethosuximide has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

Pregnancy.

For comments on the management of epilepsy during pregnancy.

💊 Interactions

There are complex interactions between antiepileptics and toxicity may be enhanced without a corresponding increase in antiepileptic activity. Such interactions are very variable and unpredictable and plasma monitoring is often advisable with combination therapy.

Antibacterials.

Isoniazid raises the plasma concentration of ethosuximide and increases the risk of toxicity. Psychotic behaviour has been reported1 in a patient stabilised on ethosuximide and sodium valproate, after the introduction of isoniazid. Serumethosuximide concentrations rose substantially until both ethosuximide and isoniazid were stopped.
1. van Wieringen A, Vrijlandt CM. Ethosuximide intoxication caused by interaction with isoniazid. Neurology 1983; 33: 1227–8.

Antidepressants.

As with all antiepileptics, antidepressants may antagonise the antiepileptic activity of ethosuximide by lowering the convulsive threshold.

Antiepileptics.

Since ethosuximide has a limited spectrum of antiepileptic action, patients with mixed seizure syndromes may require addition of other antiepileptics. Carbamazepine, phenobarbital, and phenytoin have all been shown1 to increase the clearance of ethosuximide and thus reduce plasma concentrations. This interaction is likely to be clinically relevant and higher ethosuximide dosages may be necessary to achieve therapeutic drug levels. The effect of valproic acid on ethosuximide concentrations is unclear. One study2 showed a marked increase in serum ethosuximide concentrations once valproate was added to combination therapies; increases in ethosuximide concentrations have also been noted in healthy subjects when taken with valproic acid.3 Conversely, other studies have reported reductions4 or no significant changes in serum ethosuximide concentrations5,6with valproic acid. For the effect of ethosuximide on valproic acid.
1. Giaccone M, et al. Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients. Br J Clin Pharmacol 1996; 41: 575–9
2. Mattson RH, Cramer JA. Valproic acid and ethosuximide interaction. Ann Neurol 1980; 7: 583–4
3. Pisani F, et al. Valproic acid-ethosuximide interaction: a pharmacokinetic study. Epilepsia 1984; 25: 229–33
4. Battino D, et al. Ethosuximide plasma concentrations: influence of age and associated concomitant therapy. Clin Pharmacokinet 1982; 7: 176–80
5. Fowler GW. Effect of dipropylacetate on serum levels of anticonvulsants in children. Proc West Pharmacol Soc 1978; 21: 37–40
6. Bauer LA, et al. Ethosuximide kinetics: possible interaction with valproic acid. Clin Pharmacol Ther 1982; 31: 741–5.

Antipsychotics.

As with all antiepileptics, antipsychotics may antagonise the antiepileptic activity of ethosuximide by lowering the convulsive threshold.

💊 Pharmacokinetics

Ethosuximide is readily absorbed from the gastrointestinal tract and extensively hydroxylated in the liver to its principal metabolite which is reported to be inactive. Ethosuximide is excreted in the urine mainly in the form of its metabolites, either free or conjugated, but about 12 to 20% is also excreted unchanged. Ethosuximide is widely distributed throughout the body, but is not significantly bound to plasma proteins. A half-life of about 40 to 60 hours has been reported for adults with a shorter half-life of about 30 hours in children. Monitoring of plasma concentrations has been suggested as an aid in assessing control and the therapeutic range of ethosuximide is usually quoted as being 40 to 100 micrograms/mL (about 300 to 700 micromoles/litre); concentrations in saliva and tears have also been measured. Ethosuximide crosses the placental barrier, and is distributed into breast milk. The pharmacokinetics of ethosuximide are affected by use with other antiepileptics (see under Interactions, above).

💊 Uses and Administration

Ethosuximide is a succinimide antiepileptic used in the treatment of absence seizures (below). It may also be used for myoclonic seizures. Ethosuximide is ineffective against tonic-clonic seizures and may unmask them if given alone in mixed seizure types. A plasma-ethosuximide concentration of 40 to 100 micrograms/mL (about 300 to 700 micromoles/litre) appears to be generally necessary. The initial dose is 500 mg daily by mouth. The dosage is then adjusted in steps of 250 mg every 4 to 7 days, according to response. Control of seizures is usually produced with a daily dose of 1 to 1.5 g, although some patients may require doses of up to 2 g; strict supervision is necessary when the dose exceeds 1.5 g. Daily doses at the higher end of the range should be given in 2 divided doses. For doses in children, see below. As with other antiepileptics, withdrawal of ethosuximide therapy or transition to or from another type of antiepileptic therapy should be made gradually to avoid precipitating an increase in the frequency of seizures. For a discussion on whether or not to withdraw antiepileptic therapy in seizure-free patients.

Administration in children.

Ethosuximide may be used in the treatment of absence (petit mal) seizures and for myoclonic seizures in infants and children. In the UK, the following recommended oral doses are given according to age:
up to 6 years of age: an initial dose of 250 mg daily, increased gradually in small steps every few days to a usual dose of 20 mg/kg daily; licensed information for one product (Emeside; Chemidex, UK) recommends that the dose should not exceed 1 g. (Similar dosages are recommended in the USA for children aged between 3 to 6 years). The BNFC suggests giving the daily dose as 2, or if necessary 3, divided doses
aged 6 years and above: usual adult doses (see above)

Epilepsy.

Ethosuximide is a drug of choice in the treatment of absence seizures; it may also be used for myoclonic, atonic, and tonic seizures but is ineffective in other forms of epilepsy. Ethosuximide may be given with other antiepileptics in the treatment of mixed-seizure syndromes that include absences. It has been suggested that ethosuximide may provoke tonic-clonic seizures, but there is not a great deal of evidence for this. One early report indicated that 22 of 85 patients receiving a regimen of ethosuximide, mesuximide, and trimethadione for absence seizures developed tonic-clonic seizures1 and another of similar vintage reported exacerbation of mixed-seizure types in 7 patients receiving ethosuximide.2 However, it is recognised that patients with absence seizures have a high incidence of generalised tonic-clonic seizures3 and it would presumably be difficult to distinguish such attacks from any putative effect of ethosuximide. Furthermore, ethosuximide is not effective against tonic-clonic seizures, and in patients with mixed-seizure types it might be expected to unmask the non-absence components of the disease. Ethosuximide has also been tried in the management of absence status epilepticus.
1. Friedel B, Lempp R. Grand-mal-Provokation bei der Behandlung kindlicher petit-mal mit Oxazolidinen oder Succinimiden und ihre therapeutischen Konsequenzen. Z Kinderheilk 1962; 87: 42–51
2. de Haas AML, Kuilman M. Ethosuximide (α-ethyl-α-methylsuccinimide) and grand mal. Epilepsia 1964; 5: 90–6
3. Glauser TA. Succinimides: Adverse Effects. In: Levy RG, et al., eds. Antiepileptic drugs 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2002; 658–64.

💊 Preparations

BP 2008: Ethosuximide Capsules; Ethosuximide Oral Solution; USP 31: Ethosuximide Capsules; Ethosuximide Oral Solution.

Proprietary Preparations

Arg.: Zarontin; Austral.: Zarontin; Austria: Petinimid; Suxinutin; Belg.: Zarontin; Canad.: Zarontin; Chile: Suxinutin; Cz.: Petinimid; Suxilep†; Denm.: Zarondan; Fin.: Suxinutin; Fr.: Zarontin; Ger.: Petnidan; Suxilep; Suxinutin†; Gr.: Zarontin; Hung.: Petnidan; Suxinutin†; Irl.: Zarontin; Israel: Zarontin†; Ital.: Zarontin; Mex.: Fluozoid; Neth.: Ethymal; Zarontin†; NZ: Zarontin; Pol.: Petinimid; Rus.: Suxilep (Суксилеп); S.Afr.: Zarontin; Spain: Zarontin†; Swed.: Suxinutin; Switz.: Petinimid; Suxinutin†; UK: Emeside; Zarontin; USA: Zarontin.
Published October 21, 2018.