Ethotoin

Pronunciation: (ETH-oh-toin)
Class: Hydantoin

Trade Names

Peganone
- Tablets 250 mg

Pharmacology

May act at motor cortex to inhibit spread of seizure activity. Possibly works by promoting sodium efflux from neurons, thereby stabilizing threshold against hyperexcitability. Also decreases posttetanic potentiation at synapse.

Pharmacokinetics

Absorption

Fairly rapidly absorbed.

Metabolism

Major metabolites are to N-deethyl and p-hydroxyl-ethotoin.

Elimination

Elimination half-life ranges from 3 to 9 h.

Indications and Usage

Control of tonic-clonic (grand mal) and complex partial (psychomotor) seizures.

Contraindications

Hepatic abnormalities or hematologic disorders.

Dosage and Administration

Adults

PO Start with 1 g/day or less (in 4 to 6 divided doses daily), with subsequent gradual dosage increases over a period of several days. Optimum dosage is based on individual response. Usual maintenance dosage is 2 to 3 g/day. Doses less than 2 g have not been found to be effective in most adults.

Children

PO Dose depends on age and weight of patient. Initial dosage should not exceed 750 mg/day administered in 4 to 6 divided doses. Usual maintenance dose is 500 mg to 1 g; although, occasionally, 2 g or, rarely, 3 g may be necessary.

General Advice

Administer after food.
Separate doses as evenly as practical.
Therapeutic plasma concentrations are 15 to 50 mcg/mL.

Storage/Stability

Store below 77°F. Protect from light.

Drug Interactions

The following ethotoin drug interactions are based on documentation for phenytoin drug interactions. Based on pharmacologic and pharmacokinetic considerations, the occurrence of similar drug-class interactions are anticipated with both ethotoin and phenytoin.

Acetaminophen

Plasma concentrations and pharmacologic response may be reduced by ethotoin. At usual therapeutic doses, no special precautions are needed.

Amiodarone, azole antifungal agents (eg, itraconazole), benzodiazepines (eg, midazolam, oxazepam), felbamate, hormonal contraceptives, SSRIs (eg, sertraline), succinimides (eg, methsuximide), topiramate, valproic acid

Serum concentrations may be reduced by ethotoin, decreasing the pharmacologic effects, while ethotoin concentrations may be elevated, increasing the pharmacologic effects. Monitor the clinical response of the patient when these agents are coadministered. Use of an alternative, nonhormonal method of contraception is advisable.

Antineoplastic agents (eg, bleomycin), colesevelam, diazoxide, rifamycins (eg, rifampin)

Plasma concentrations and therapeutic effectiveness of ethotoin may be reduced. Frequency of seizures may be increased. Monitor the clinical response to ethotoin during coadministration of these agents. Adjust the ethotoin dosage as needed.

Barbiturates (eg, phenobarbital)

Ethotoin may increase barbiturate serum concentrations. The effect of barbiturates on ethotoin is unpredictable. Monitor barbiturate serum concentrations of both drugs, seizure activity, and clinical symptoms when starting or stopping either drug.

Carbamazepine

The pharmacologic effects are difficult to predict. Increased and decreased ethotoin plasma concentrations and decreased carbamazepine plasma concentrations may occur. Carefully monitor carbamazepine serum concentrations, adverse effects, and seizure control when starting, stopping, or changing the dose of either drug.

Chloramphenicol

The pharmacologic effects of ethotoin may be increased. Elevated plasma ethotoin concentrations with toxicity may occur. Chloramphenicol concentrations may be increased or decreased. Monitor the patient for signs of ethotoin toxicity. Adjust the dosage of either drug as needed.

Cimetidine, disulfiram, fluorouracil, isoniazid, omeprazole, phenacemide, sulfonamides (eg, sulfadiazine), ticlopidine, trimethoprim

Serum ethotoin levels may be elevated, increasing the pharmacologic effects and risk of toxicity. Monitor the patient for signs of toxicity. Adjust the ethotoin dose as needed.

Corticosteroids

Plasma concentrations and therapeutic effects of ethotoin may be decreased. Pharmacologic effects of corticosteroids may be reduced. Monitor the clinical response of the patient. Higher dosages of either drug may be needed during coadministration.

Cyclosporine

Cyclosporine blood or plasma concentrations may be reduced, decreasing the pharmacologic effects. Monitor cyclosporine blood or plasma concentrations and monitor for evidence of graft rejection; adjust the cyclosporine dose cyclosporine as needed.

Disopyramide

The anticholinergic adverse effects of disopyramide may be increased, while its therapeutic effects might be decreased. Adjust the disopyramide dosage to provide the max therapeutic benefit with a minimum of adverse reactions.

Dronedarone, nisoldipine, NNRT inhibitors (eg, etravirine), tolvaptan

Pharmacologic effects may be reduced by ethotoin. Avoid coadministration.

Drugs known to adversely affect the hematopoietic system

Avoid coadministration.

Estrogens

Effects of estrogens may be decreased. If an interaction is suspected, consider increasing the estrogen dose. If the estrogenic compound is being used for contraception, use of a nonhormonal form of contraception should be considered.

Felodipine, gefitinib, levodopa, methadone, metyrapone, mexiletine, mirtazapine, praziquantel, quetiapine, quinidine

Pharmacologic effects may be decreased by ethotoin. Increased doses of these agents may be needed during ethotoin coadministration.

Folic acid

Serum ethotoin concentrations may be reduced, resulting in a possible decrease of pharmacologic effects. Monitor the patient for loss of seizure control. Adjust the ethotoin dose as needed. Hydantoin-like compounds may interfere with folic acid metabolism, precipitating megaloblastic anemia.

Primidone

Ethotoin may increase serum concentrations of primidone and its metabolites. Monitor primidone and primidone metabolites closely following any alteration in ethotoin therapy. Adjust the ethotoin dose as needed.

Warfarin

Anticoagulant and ethotoin effects may be increased. Adjust the dose of either drug as needed.

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

Dizziness, fatigue, headache, insomnia.

Dermatologic

Skin rash, Stevens-Johnson syndrome.

EENT

Diplopia, nystagmus.

GI

Diarrhea, nausea, vomiting.

Hematologic-Lymphatic

Blood dyscrasias, lymphadenopathy.

Miscellaneous

Chest pain, fever, numbness, systemic lupus erythematosus.

Precautions

Monitor

Monitor all patients for the emergence or worsening of depression, suicidal thoughts or behaviors, and/or any unusual changes in mood or behavior. Monitor LFTs if clinical evidence suggests the possibility of hepatic function impairment. Monitor patient for skin rash, fever, or other signs of infection; sores in the mouth; unusual bruising or bleeding; and petechiae. Ensure that urinalysis and CBC with differential are performed before starting therapy and at monthly intervals for several months during therapy.

Pregnancy

Category D .

Lactation

Excreted in breast milk.

Children

Safety and efficacy in children younger than 1 yr of age have not been established.

Elderly

Use with caution, usually starting at the low end of the dosage range, because of the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant diseases or other drug therapy.

Blood dyscrasias

May occur. Discontinue if marked blood cell count depression develops. In addition, there is some evidence that hydantoin-like compounds may interfere with folic acid metabolism, precipitating megaloblastic anemia. Ensure that folic acid levels are periodically evaluated during prolonged therapy. Be prepared to supplement folic acid to prevent megaloblastic anemia.

Hepatic function impairment

Ensure that medication is discontinued in patients who develop hepatic impairment.

Lymphadenopathy

May occur. Withdrawal of therapy has resulted in remission of clinical and pathological findings. If a lymphoma-like syndrome develops, withdraw therapy and closely observe the patient for regression of signs and symptoms before resuming treatment.

Simultaneous antiepileptic therapy

In patients receiving another antiepileptic drug, it should not be discontinued when starting ethotoin. The dosage of the other drug should be reduced gradually as the dose of ethotoin is increased. Ethotoin may replace the other drug or the optimal dosage of both drugs may be established.

Suicide

The risk of suicidal thoughts and behaviors is increased.

Withdrawal

Do not discontinue treatment in pregnant patients in whom the drug is administered to prevent major seizures because of the possibility of precipitating status epilepticus with hypoxia and risk to both the mother and fetus.

Overdosage

Symptoms

Ataxia, coma, drowsiness, nausea, visual disturbances.

Patient Information

Instruct patient to continue to take other antiepileptic medications as prescribed by health care provider.
Advise patient that each dose should be taken after food and to space the doses as evenly as possible.
Advise patient that if medication needs to be discontinued, it will be slowly withdrawn over a period of several weeks unless safety concerns (eg, rash) require a more rapid withdrawal.
Caution patient that drug may cause dizziness and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
Advise women of childbearing potential to use effective contraception during treatment with ethotoin.
Instruct patients to inform health care provider immediately if easy bruising, epistaxis, fever, malaise, petechiae, skin rash, sore throat, or other signs of infection or bleeding tendency develop.
Instruct patient to inform health care provider if seizures get worse or if new types of seizures occur.
Advise patient to carry medical identification (eg, card, bracelet) indicating epilepsy and medication use.
Advise patients, caregivers, and families that antiepileptic drugs, including ethotoin, may increase the risk of suicidal thoughts and behaviors and that they should be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm.