VA Class:CN400

AHFS Class:

• Hydantoins 28:12.12

Generic Name(s):

• Ethotoin

Ethotoin is a hydantoin-derivative anticonvulsant.

Ethotoin is used for the prophylactic management of tonic-clonic (grand mal) seizures and partial seizures with complex symptomatology (psychomotor seizures). Ethotoin is less effective and less toxic than phenytoin. The drug is usually administered concomitantly with other anticonvulsants such as phenytoin or phenobarbital. Before proceeding to the use of the more toxic anticonvulsants, ethotoin therapy may be indicated for patients whose seizures have not been satisfactorily controlled by the primary anticonvulsants. Although ethotoin is usually ineffective in the management of absence (petit mal) seizures, it may be used in conjunction with succinimide-derivative or oxazolidinedione-derivative anticonvulsants in patients with combined absence and tonic-clonic seizures.

Administration

Ethotoin is administered orally. The drug should be taken after food in 4-6 divided doses daily.

Patients who are currently receiving or beginning therapy with ethotoin and/or any other anticonvulsant should be closely monitored for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.100,101,102 (See Cautions: CNS Effects and see Cautions: Precautions and Contraindications, in the Anticonvulsants General Statement 28:12.)

Dosage

Ethotoin dosage must be carefully and slowly adjusted according to individual requirements and response. The drug should be withdrawn slowly to avoid precipitating seizures or status epilepticus.

The initial dosage of ethotoin for adults is 1 g or less daily with subsequent gradual dosage increases over a period of several days. The usual maintenance dosage for adults is 2-3 g daily; dosages less than 2 g daily are ineffective in most adults. The initial dosage of ethotoin for pediatric patients should not exceed 750 mg daily. The usual maintenance dosage for children is 500 mg to 1 g daily, although occasionally 2 g daily or rarely 3 g daily may be necessary. Some clinicians recommend pediatric dosages of 80 mg/kg daily or 2.5 g/m² daily.

Ethotoin shares the toxic potentials of the hydantoin-derivative anticonvulsants, and the usual precautions of anticonvulsant therapy should be observed. (See Cautions in the Anticonvulsants General Statement 28:12.)

Clinicians should inform patients, their families, and caregivers about the potential for an increased risk of suicidal thinking and behavior (suicidality) associated with anticonvulsant therapy.100 For a complete discussion, see Cautions: CNS Effects and see Cautions: Precautions and Contraindications, in the Anticonvulsants General Statement 28:12.

Ethotoin is contraindicated in patients with hepatic abnormalities or hematologic disorders.

Although the etiologic role of ethotoin has not been definitely established, blood dyscrasias have been reported in patients receiving the drug, and clinicians should be alert to the possibility of their occurrence. Patients should be advised to report immediately any sign or symptom indicative of hematologic toxicity (e.g., sore throat, fever, malaise, petechiae, easy bruising, epistaxis). Complete blood cell counts should be performed before and at monthly intervals for several months after initiation of ethotoin therapy. The drug should be discontinued if marked depression of blood cell count occurs.

Liver function tests should be performed in patients receiving ethotoin if there is clinical evidence of possible hepatic dysfunction. If signs of hepatotoxicity occur during ethotoin therapy, the drug should be discontinued.

Ataxia and gingival hyperplasia have been reported only rarely during ethotoin therapy and usually only in patients receiving an additional hydantoin derivative. When ethotoin has replaced other hydantoin-derivative anticonvulsants, both of these reactions have subsided in some patients.

Lymphadenopathy has occurred during ethotoin administration, and this effect subsided when the drug was discontinued. In addition, a few cases of systemic lupus erythematosus have occurred in patients receiving other hydantoin derivatives. The possibility of lymphadenopathy and systemic lupus erythematosus should be kept in mind, and if a lymphoma-like syndrome develops, ethotoin should be discontinued.

Other adverse effects which have occurred during ethotoin therapy are nausea or vomiting, diarrhea, chest pain, nystagmus, diplopia, dizziness, fever, headache, insomnia, fatigue, numbness, and rash. Although the etiologic role of ethotoin has not been definitely established, blood dyscrasias have been reported in patients receiving the drug.

It is not known whether ethotoin is carcinogenic in animals or humans.

Safe use of ethotoin during pregnancy has not been established. Ethotoin should be used during pregnancy only when clearly needed. (See Cautions: Pregnancy and Lactation, in the Anticonvulsants General Statement 28:12.)

Ethotoin is distributed into milk. Because of the potential for serious adverse reactions from ethotoin in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Extreme paranoid symptoms have developed in patients receiving ethotoin and phenacemide concurrently; however, phenacemide is no longer commercially available in the US.

Pharmacology

Ethotoin shares the actions of the hydantoin-derivative anticonvulsants; however, the drug apparently does not have the antiarrhythmic properties demonstrated by phenytoin.

Pharmacokinetics

Absorption

Ethotoin is fairly rapidly absorbed from the GI tract following oral administration; the extent of absorption is not known.

A therapeutic range for plasma ethotoin concentrations has not been clearly established; however, a therapeutic range of 15-50 mcg/mL has been suggested.

Distribution

Ethotoin is distributed into milk.

Elimination

Ethotoin is metabolized by the liver to p -hydroxylated and m -hydroxylated derivatives following N -deethylation; these metabolites are conjugated with glucuronic acid. The N -deethylated metabolite may also be metabolized to 2-phenylhydantoic acid. Ethotoin appears to exhibit saturable metabolism with respect to the formation of the p -hydroxylated and N -deethylated metabolites. At plasma concentrations less than about 8 mcg/mL, ethotoin reportedly has an elimination half-life of 3-9 hours. Limited data suggest that ethotoin and, to a lesser degree, 5-phenylhydantoin (the N -deethylated metabolite) may exhibit nonlinear pharmacokinetics following oral administration of single 500-, 1000-, and 1500-mg doses of ethotoin. The degree of nonlinearity may increase following oral administration of multiple doses (with a dosing interval of 4-6 hours) of ethotoin when compared with single doses, probably secondary to accumulation of the drug in plasma. Ethotoin and its metabolites are excreted in urine and feces; small quantities also appear in saliva. Only a small fraction is eliminated unchanged.

Chemistry and Stability

Chemistry

Ethotoin is a hydantoin-derivative anticonvulsant. The drug occurs as a white, crystalline powder and is insoluble in water and freely soluble in dehydrated alcohol.

Stability

Commercially available ethotoin tablets should be stored in tight containers at a temperature less than 40°C, preferably between 15-30°C. Ethotoin darkens on exposure to light or extreme heat.

Additional Information

For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, acute toxicity, drug interactions, and dosage and administration of ethotoin, see the Anticonvulsants General Statement 28:12.

Only references cited for selected revisions after 1984 are available electronically.

100. Food and Drug Administration. FDA Alert. Information for healthcare professionals: suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website. [Web]

101. Food and Drug Administration. FDA News: FDA alerts health care providers to risk of suicidal thoughts and behavior with antiepileptic medications. Rockville, MD; 2008 Jan 31. From the FDA website. [Web]

102. Food and Drug Administration. FDA Alert: Suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website. [Web]