Ethotoin

Risk of hepatotoxicity from a single toxic dose or prolonged use of acetaminophen may be increased and therapeutic efficacy may be decreased in patients regularly taking other hepatic enzyme-inducing agents such as phenytoin. /Hydantoin anticonvulsants/

Concurrent use of alcohol or CNS depression-producing medications with hydantoin anticonvulsants may enhance CNS depression. Chronic use of alcohol may decrease serum concentrations and effectiveness of hydantoins; concurrent use of hydantoin anticonvulsants with acute alcohol intake may increase serum hydantoin concentrations. /Hydantoin anticonvulsants/

Concurrent use of amiodarone with phenytoin and possibly with other hydantoin anticonvulsants may increase plasma concentrations of the hydantoin, resulting in increased effects and/or toxicity. /Hydantoin anticonvulsants/

Concurrent use with coumarin- or indandione-derivative anticoagulants, chloramphenicol, cimetidine, disulfiram, influenza virus vaccine, isoniazid, methylphenidate, phenylbutazone, ranitidine, salicylates, or sulfonamide may increase serum concentrations of hydantoin anticonvulsants because of decreased metabolism, thereby increasing the hydantoins' effects and/or toxicity. /Hydantoin anticonvulsants/

For more Interactions (Complete) data for ETHOTOIN (22 total), please visit the HSDB record page.

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.

The mechanism of action is probably very similar to that of phenytoin. The latter drug appears to stabilize rather than to raise the normal seizure threshold, and to prevent the spread of seizure activity rather than to abolish the primary focus of seizure discharges. Ethotoin inhibits nerve impulses in the motor cortex by lowering sodium ion influx, limiting tetanic stimulation.

/SIGNS AND SYMPTOMS/ Clinical effects of overdose include ataxia (clumsiness or unsteadiness) or staggering walk, blurred or double vision, severe confusion, severe dizziness or drowsiness, dysarthria (stuttering) or slurred speech, hyperreflexia, nausea and vomiting, nystagmus (continuous, uncontrolled back-and-forth and/or rolling eye movements), tremor, and unusual tiredness or weakness. /Hydantoin anticonvulsants/

/OTHER TOXICITY INFORMATION/ The fetal hydantoin syndrome has been associated with the use of the more potent phenytoins. Only six reports describing the use of ethotoin during the first trimester have been located. Congenital malformations observed in two of these cases included cleft lip/plate and patent ductus arteriosus. No cause-and-effect relationship was established. Although the toxicity of ethotoin appears to be lower than the more potent phenytoin, the occurrence of congenital defects in two fetuses exposed to ethotoin suggests that a teratogenic potential may exist.

/OTHER TOXICITY INFORMATION/ Because acute attacks of porphyria may be precipitated by anticonvulsants, a therapeutic dilemma arises when seizures complicate hepatic porphyria. The list of unsafe agents includes barbiturates, primidone, phenytoin, mephenytoin, ethotoin, ethosuximide, methsuximide, phensuximide, and trimethadione. Agents are considered unsafe if they induce experimental porphyria in animals, and short trials in patients are unreliable for screening.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Ethotoin

Ambiguous-DILI-concern

3

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Pregnant Sprague-Dawley CD rats were orally administered either phenytoin (PHT, 200 mg/kg), mephenytoin (MPH, 100 mg/kg), ethotoin (ETH, 600 mg/kg), hydantoin (HYD, 1,200 mg/kg) or vehicle (propylene glycol) on days 7-18 of gestation. Mean (+/- S.E.) maternal serum concentrations of PHT, MPH, and ETH 1 hr after dosing on gestational day 18 were 16.0 +/- 3.3, 10.7 +/- 3.0, and 65.2 +/- 10.45, respectively, and free fractions were 16%, 18%, and 11% respectively. The free fraction for PHT is similar, but was lower for both MPH and ETH than that seen in humans. Preweaning mortality for PHT, MPH, ETH, HYD, and controls was 25%, 6.3%, 12.5%, 2.0% and 0.8%, respectively. The MPH and ETH exposed animals weighed approximately 6.6% less than controls throughout the study; the other groups did not differ significantly. PHT offspring showed incr early locomotor activity. Only PHT exposed animals (27%) exhibited abnormal circling behavior after weaning. PHT-circlers accounted for higher levels of activity in an open field test and for longer straight channel swimming times. PHT-circlers and noncirclers differed from one another and controls on performance of a complex (Cincinnati) maze and on the development of the air-righting reflex. Offspring prenatally exposed to MPH showed an early delay in air-righting. ETH and HYD offspring were not consistently different from controls in behavior. The data suggest the following ordinal relationship among the drugs for behavioral teratogenesis: PHT much greater than MPH greater than ETH congruent to HYD congruent to CON. The effects of PHT are consistent with previous findings. Data on the other drugs suggest that other hydantoins do not possess the behavioral teratogenic efficacy of PHT and that PHT may be unique in its effects on CNS development.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl ethotoin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Therapeutic Category: Anticonvulsant.

Medication

For the control of tonic-clonic (grand mal) and complex partial (psychomotor) seizures.

Prepared by heating the potassium salt of 5-phenylhydantoin with ethyl bromide in alcohol at 100 °C in a sealed tube: Pinner, Ber 21, 2320 (1888).

Reaction of ethyl isocyanate and alpha-amino-alpha-phenylacetic acid followed by acid-catalyzed cyclodehydration.