Peganone

Anticonvulsants, Hydantoins

A MedGuide will be available that discusses the risk of suicidal thoughts and behaviors associated with the use of anticonvulsant medications.

Oral Administration

Ethotoin is administered orally. Administer each dose after food, usually in 4—6 divided doses daily.
Doses should be administered at regularly spaced intervals at roughly the same time each day.

Severe

suicidal ideation / Delayed / Incidence not known
megaloblastic anemia / Delayed / Incidence not known
pancytopenia / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
lupus-like symptoms / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known

Moderate

depression / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
leukopenia / Delayed / Incidence not known
confusion / Early / Incidence not known
ataxia / Delayed / Incidence not known
dysarthria / Delayed / Incidence not known
nystagmus / Delayed / Incidence not known
lymphadenopathy / Delayed / Incidence not known
gingival hyperplasia / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
chest pain (unspecified) / Early / Incidence not known

Mild

diplopia / Early / Incidence not known
fatigue / Early / Incidence not known
headache / Early / Incidence not known
insomnia / Early / Incidence not known
dizziness / Early / Incidence not known
drowsiness / Early / Incidence not known
diarrhea / Early / Incidence not known
vomiting / Early / Incidence not known
nausea / Early / Incidence not known
rash / Early / Incidence not known
fever / Early / Incidence not known

Peganone

Rx

Oral hydantoin anticonvulsant used to control tonic-clonic (grand mal) and complex partial (psychomotor) seizures; also an adjunct to control combined absence and tonic-clonic seizures; often used with other anticonvulsants; not effective monotherapy for absence seizures; close monitoring for emerging or worsening suicidal thoughts/behavior or depression is recommended.

For the treatment of generalized tonic-clonic seizures and complex-partial seizures (as a second line or adjunct therapy).
NOTE: Ethotoin is usually administered with other anticonvulsants.
Oral dosage Adults

Initially, 250 mg PO 4 times per day; may be increased over several days to 3 g/day PO given in divided doses as needed to obtain seizure control. Maintenance dosages of less than 2 g/day generally have been ineffective in adults. Geriatric patients may metabolize ethotoin more slowly and may require careful titration.

Children and Adolescents

Initially, do not exceed 750 mg/day PO given in divided doses (usually 4 times per day). Usual maintenance dose is 500 mg—1 g/day PO given in 4—6 divided doses. Alternative dosing includes 80 mg/kg/day PO or 2.5 g/m2/day PO, given in divided doses.

Hepatic Impairment

Specific dosing parameters in hepatic impairment are not available; however, ethotoin is extensively metabolized and downward dose adjustments may be needed.

Renal Impairment

No dosage adjustment needed; only a small fraction of ethotoin is excreted unchanged.

Acetaminophen: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Aspirin: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Aspirin; Diphenhydramine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Caffeine: (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Chlorpheniramine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Codeine: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Dextromethorphan: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Dextromethorphan; Doxylamine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Phenytoin theoretically can add to the CNS-depressant effects of other CNS depressants. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Diphenhydramine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Guaifenesin; Phenylephrine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Hydrocodone: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Oxycodone: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Pamabrom; Pyrilamine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Pentazocine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Pseudoephedrine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acyclovir: (Minor) In a single case report, the addition of acyclovir to a regimen of phenytoin and valproate led to a clinically significant decrease in phenytoin serum concentrations and loss of seizure control. Acyclovir did not appear to affect valproate concentrations in this report. Until more data are known, clinicians should be prepared to make adjustments in hydantoin dosing if acyclovir therapy is added or discontinued.
Albendazole: (Minor) Antiepileptic drugs (AEDs) are often administered concomitantly with albendazole for the treatment of neurocysticercosis. Hydantoins appear to induce the oxidative metabolism of albendazole. Notably, a significant reduction in the plasma concentration of the active albendazole sulfoxide metabolite may occur. Monitor patient clinical response closely during treatment.
Alendronate; Cholecalciferol: (Moderate) Phenytoin and fosphenytoin can decrease the activity of vitamin D (e.g., cholecalciferol) by increasing its metabolism. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia. Vitamin D supplementation or dosage adjustments may be required in patients who are receiving chronic treatment with anticonvulsants.
Alfentanil: (Moderate) Drugs that induce CYP3A4, including phenytoin or fosphenytoin (and possibly ethotoin), may decrease the effectiveness of alfentanil. Alfentanil is a substrate for the cytochrome (CYP) 3A4 isoenzyme. Induction of alfentanil metabolism may take several days. In addition, additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists.
Aliskiren; Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Alogliptin: (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Alogliptin; Metformin: (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients. (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Alogliptin; Pioglitazone: (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Alosetron: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of aolsetron, leading to reduced efficacy of alosetron.
Alpha-glucosidase Inhibitors: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Alprazolam: (Moderate) Monitor for reduced efficacy of alprazolam and signs of benzodiazepine withdrawal if coadministration with hydantoins is necessary. Alprazolam is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. Concomitant use with CYP3A4 inducers can decrease alprazolam concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Aluminum Hydroxide: (Major) Aluminum hydroxide inhibits the absorption of ethotoin. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Aluminum Hydroxide; Magnesium Carbonate: (Major) Aluminum hydroxide inhibits the absorption of ethotoin. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Aluminum Hydroxide; Magnesium Hydroxide: (Major) Aluminum hydroxide inhibits the absorption of ethotoin. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction. (Major) Magnesium hydroxide inhibits the absorption of ethotoin. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) Aluminum hydroxide inhibits the absorption of ethotoin. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction. (Major) Magnesium hydroxide inhibits the absorption of ethotoin. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Aluminum Hydroxide; Magnesium Trisilicate: (Major) Aluminum hydroxide inhibits the absorption of ethotoin. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Amitriptyline: (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Atorvastatin: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine. (Moderate) Monitor for a decrease in atorvastatin efficacy if concomitant use with phenytoin is necessary. Concomitant use may decrease atorvastatin exposure. Atorvastatin is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Amlodipine; Benazepril: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Celecoxib: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Olmesartan: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Valsartan: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amobarbital: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking.
Amoxapine: (Moderate) Amoxapine, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Pharmacokinetic interactions may occur, since hydantoins may induce hepatic metabolism of certain antidepressants. Monitor patients on anticonvulsants carefully when amoxapine is used concurrently.
Aprepitant, Fosaprepitant: (Major) Avoid the concurrent use of ethotoin with aprepitant, fosaprepitant due to substantially decreased exposure of aprepitant. If these drugs must be coadministered, monitor for a decrease in the efficacy of aprepitant as well as an increase in ethotoin-related adverse effects for several days after administration of a multi-day aprepitant regimen. Ethotoin is a strong CYP3A4 inducer and aprepitant is a CYP3A4 substrate. When a single dose of aprepitant (375 mg, or 3 times the maximum recommended dose) was administered on day 9 of a 14-day rifampin regimen (a strong CYP3A4 inducer), the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased by 3-fold. Additionally, ethotoin is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may also increase plasma concentrations of ethotoin. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Finally, aprepitant is a CYP2C9 inducer and ethotoin is a CYP2C9 substrate. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant.
Armodafinil: (Moderate) Since armodafinil is metabolized by the CYP3A4 isoenzyme, and hydantoins (e.g., phenytoin, fosphenytoin) are CYP3A4 inducers. decreased armodafinil efficacy may result from increased armodafinil metabolism. In addition, armodafinil is an inhibitor of the CYP2C19 and CYP2C9 isoenzymes. Hydantoins are substrates of CYP2C19, and phenytoin is a substrate of CYP2C9. Hydantoin concentrations may increase. Monitor carefully for signs of toxicity; phenytoin concentration monitoring may be helpful.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking. (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination.
Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists. (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking. (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination.
Aspirin, ASA; Caffeine: (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Major) The oral absorption of ethotoin may be reduced by antacids. Separating the administration of ethotoin and antacids by at least 2 hours will help minimize the possibility of interaction.
Atazanavir: (Major) Ethotoin may increase the metabolism of atazanavir and lead to decreased antiretroviral efficacy. The appropriate drug-dose adjustments necessary to ensure optimum levels of both antiretroviral and anticonvulsant drugs are unknown. Consider using alternative anticonvulsant, or monitoring atazanavir concentrations and boosting with ritonavir if necessary. If atazanavir is added to anticonvulsant therapy, the patient should be observed for changes in the clinical efficacy of the antiretroviral regimen or seizure control. Monitoring of serum concentrations of these drugs is recommended when given concomitantly with atazanavir.
Atazanavir; Cobicistat: (Major) Ethotoin may increase the metabolism of atazanavir and lead to decreased antiretroviral efficacy. The appropriate drug-dose adjustments necessary to ensure optimum levels of both antiretroviral and anticonvulsant drugs are unknown. Consider using alternative anticonvulsant, or monitoring atazanavir concentrations and boosting with ritonavir if necessary. If atazanavir is added to anticonvulsant therapy, the patient should be observed for changes in the clinical efficacy of the antiretroviral regimen or seizure control. Monitoring of serum concentrations of these drugs is recommended when given concomitantly with atazanavir.
Atorvastatin: (Moderate) Monitor for a decrease in atorvastatin efficacy if concomitant use with phenytoin is necessary. Concomitant use may decrease atorvastatin exposure. Atorvastatin is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Atorvastatin; Ezetimibe: (Moderate) Monitor for a decrease in atorvastatin efficacy if concomitant use with phenytoin is necessary. Concomitant use may decrease atorvastatin exposure. Atorvastatin is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with hydantoins can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
Barbiturates: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking.
Belladonna; Opium: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists. Methadone is a primary substrate for the CYP3A4 isoenzyme. Serum concentrations of methadone may decrease due to CYP3A4 induction by phenytoin; withdrawal symptoms may occur.
Benzhydrocodone; Acetaminophen: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Bleomycin: (Major) Patients receiving antineoplastic agents concurrently with hydantoins may be at risk for toxicity or loss of clinical efficacy and seizures; anticonvulsant therapy should be monitored closely during and after administration of antineoplastic agents. Concurrent therapy with phenytoin and bleomycin has been associated with subtherapeutic phenytoin serum concentrations and seizure activity. Phenytoin dosage increases of 20 to 100% have been required in some patients, depending on the chemotherapy administered.
Bortezomib: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, including bortezomib, leading to reduced efficacy of the concomitant medication.
Bosentan: (Moderate) Bosentan is a significant inducer of CYP2C9 hepatic enzymes. Theoretically, bosentan can increase ethotoin clearance via hepatic induction. Monitor ethotoin levels.
Brexpiprazole: (Major) Because brexpiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the brexpiprazole dose be doubled over 1 to 2 weeks when a strong CYP3A4 inducer, such as ethotoin, phenytoin, or fosphenytoin, is added to brexpiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in brexpiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the brexpiprazole dose should be reduced to the original level over 1 to 2 weeks.
Bupivacaine Liposomal: (Minor) Bupivacaine is metabolized by CYP3A4. Hydantoins induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
Bupivacaine: (Minor) Bupivacaine is metabolized by CYP3A4. Hydantoins induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
Bupivacaine; Epinephrine: (Minor) Bupivacaine is metabolized by CYP3A4. Hydantoins induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
Bupivacaine; Lidocaine: (Moderate) Lidocaine is a substrate for the cytochrome P450 isoenzymes 1A2 and 3A4. Ethotoin may enhance lidocaine clearance by inducing cytochrome P-450 enzymes. (Minor) Bupivacaine is metabolized by CYP3A4. Hydantoins induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
Bupivacaine; Meloxicam: (Minor) Bupivacaine is metabolized by CYP3A4. Hydantoins induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
Busulfan: (Moderate) Ethotoin may increase the clearance of busulfan due to the induction of glutathione-S-transferase.
Butabarbital: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking.
Butalbital; Acetaminophen: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Butalbital; Acetaminophen; Caffeine: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking. (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists. (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking. (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Caffeine: (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination.
Caffeine; Sodium Benzoate: (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination.
Calcitriol: (Moderate) Dosage adjustments of vitamin D analogs may be required during coadministration with phenytoin and fosphenytoin (which is metabolized to phenytoin). Phenytoin can increase the metabolism of endogenous vitamin D, thereby lowering serum concentrations and decreasing its activity. In rare cases, this has caused antiepileptic drug-induced rickets and osteomalacia.
Calcium: (Major) Oral absorption of phenytoin can be reduced by calcium salts. Calcium salts can form complexes that are nonabsorbable. Separating the administration of phenytoin and calcium salts by at least 2 hours to help avoid this interaction. A similar interaction may occur with ethotoin.
Calcium; Vitamin D: (Moderate) Phenytoin and fosphenytoin can decrease the activity of vitamin D (e.g., cholecalciferol) by increasing its metabolism. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia. Vitamin D supplementation or dosage adjustments may be required in patients who are receiving chronic treatment with anticonvulsants.
Canagliflozin: (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Canagliflozin; Metformin: (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients. (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Carbamazepine: (Moderate) Monitor carbamazepine and phenytoin concentrations closely during coadministration; dose adjustments may be needed. Concomitant use may decrease carbamazepine or phenytoin concentrations. Carbamazepine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. Hydantoins are CYP2C9 and CYP2C19 substrates and carbamazepine is a moderate CYP2C9 and CYP2C19 inducer.
Carbonic anhydrase inhibitors: (Minor) Acetazolamide or methazolamide can induce osteomalacia in patients being concomitantly treated with hydantoin anticonvulsants. The carbonic anhydrase inhibitors increase the rate of urinary calcium excretion; phenytoin increases the metabolism of the D vitamins. When combined, the effects on bone catabolism can be additive.
Carboplatin: (Major) Patients receiving antineoplastic agents concurrently with hydantoins may be at risk for toxicity or loss of clinical efficacy and seizures; anticonvulsant therapy should be monitored closely during and after administration of antineoplastic agents. Concurrent therapy with phenytoin and carboplatin has been associated with subtherapeutic phenytoin serum concentrations and seizure activity. Phenytoin dosage increases of 20 to 100% have been required in some patients, depending on the chemotherapy administered.
Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Concurrent use of cariprazine with CYP3A4 inducers, such as ethotoin, has not been evaluated and is not recommended because the net effect on active drug and metabolites is unclear.
Caspofungin: (Major) Consider dosing caspofungin as 70 mg IV once daily in adult patients and 70 mg/m2 IV once daily (Max: 70 mg/day) in pediatric patients receiving ethotoin. Administering inducers of hepatic cytochrome P450, such as ethotoin, concurrently with caspofungin may reduce the plasma concentrations of caspofungin.
Celecoxib; Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with hydantoins is necessary; consider increasing the dose of tramadol as needed. If hydantoins are discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and hydantoins are strong CYP3A inducers. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Charcoal: (Major) Charcoal exerts a nonspecific effect, and many medications can be adsorbed by activated charcoal. In some drug overdoses (e.g., fosphenytoin or phenytoin), multiple-doses of charcoal slurries may be an effective therapeutic adjunct. Patients who ingest activated charcoal in non-overdose situations for flatulence or other purposes should be aware that the effectiveness of other regularly taken medications (e.g., oral phenytoin) might be decreased.
Chloramphenicol: (Moderate) Chloramphenicol inhibits the cytochrome P-450 enzyme system and can affect the hepatic metabolism of hydantoins. It is also possible that plasma concentrations of chloramphenicol can be reduced by concomitant use of hydantoin.
Chlordiazepoxide: (Moderate) Hydantoin anticonvulsants can theoretically increase the clearance of chlordiazepoxide, leading to lower benzodiazepine concentrations. Chlordiazepoxide may also have an unpredictable effect on phenytoin serum concentrations.
Chlordiazepoxide; Amitriptyline: (Moderate) Hydantoin anticonvulsants can theoretically increase the clearance of chlordiazepoxide, leading to lower benzodiazepine concentrations. Chlordiazepoxide may also have an unpredictable effect on phenytoin serum concentrations. (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Chlordiazepoxide; Clidinium: (Moderate) Hydantoin anticonvulsants can theoretically increase the clearance of chlordiazepoxide, leading to lower benzodiazepine concentrations. Chlordiazepoxide may also have an unpredictable effect on phenytoin serum concentrations.
Chlorpheniramine; Codeine: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists.
Clomipramine: (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Clonazepam: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS-depressant effects of other CNS depressants. Also, hepatic enzyme inducers such as hydantoins can theoretically increase the clearance of clonazepam.
Clorazepate: (Moderate) Hydantoins are hepatic inducers and can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, leading to lower benzodiazepine concentrations.
Clozapine: (Moderate) Ethotoin may increase the metabolism of clozapine through CYP1A2 and/or CYP3A4 induction, leading to increased clearance of clozapine. When initiating clozapine or adding a weak to moderate CYP1A2 or CYP3A4 inducer to pre-existing clozapine treatment, monitor for decreased effectiveness and consider increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions and consider reducing the clozapine dose if necessary. In addition, clozapine lowers the seizure threshold and may reduce the effectiveness of ethotoin in treating seizures. Monitor for increased seizure activity and consider alternative treatment or make dose adjustments accordingly.
Codeine: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists.
Codeine; Guaifenesin: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists.
Codeine; Phenylephrine; Promethazine: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists.
Codeine; Promethazine: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists.
Colesevelam: (Moderate) Colesevelam may decrease the bioavailability of the hydantoin anticonvulsants. To minimize potential for interactions, consider administering oral anticonvulsants at least 1 hour before or at least 4 hours after colesevelam. Although colesevelam was found to have no significant effect on the bioavailability of phenytoin in an in vivo pharmacokinetic study, there have been post-marketing reports of increased seizure activity or decreased phenytoin concentrations in patients receiving concomitant colesevelam therapy. Hydantoins should be administered at least 4 hours before colesevelam. The manufacturer recommends that when administering other drugs with a narrow therapeutic index, consideration should be given to separating the administration of the drug with colesevelam. Although not specifically studied, it may be prudent to administer other anticonvulsants at least 4 hours before colesevelam. Additionally, drug response and/or serum concentrations should also be monitored.
Conjugated Estrogens; Medroxyprogesterone: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Cyclosporine: (Moderate) Hydantoin anticonvulsants (i.e, phenytoin, fosphenytoin, and ethotoin) can induce the hepatic cytochrome P-450 enzyme system, thus decreasing plasma concentrations of cyclosporine. If a hydantoin anticonvulsant is added to a cyclosporine-containing regimens, cyclosporine concentrations should be closely monitored and adjusted as needed until a new steady-state is achieved. Conversely, if the anticonvulsant is discontinued, cyclosporine concentrations could increase and result in toxicity.
Dapagliflozin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Dapagliflozin; Metformin: (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Dapagliflozin; Saxagliptin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid concomitant use of ritonavir and hydantoins. Concomitant use may decrease the exposure of ritonavir and hydantoins, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the hydantoin. A dose increase of the hydantoin may be necessary. Ritonavir is a CYP3A substrate and inducer and hydantoins are CYP3A inducers. (Major) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with ethotoin should be undertaken with extreme caution due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposure to dasabuvir, ombitasvir, paritaprevir and ritonavir. Although specific data are unavailable regarding cytochrome P450 enzyme involvement with ethotoin metabolism or enzyme induction, interactions that are documented with phenytoin may theoretically occur with ethotoin. Phenytoin is a potent inducer and substrate of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, phenytoin may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates.
Desipramine: (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Desogestrel; Ethinyl Estradiol: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Dexamethasone: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of dexamethasone, leading to reduced efficacy. Depending on the individual clinical situation and the indication for the interacting medication, enzyme-induction interactions may not always produce reductions in treatment efficacy.
Dexlansoprazole: (Moderate) Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and proton pump inhibitors (PPIs). Fosphenytoin induces hepatic cytochrome P-450 enzymes, including those responsible for the metabolism of PPIs (e.g., CYP3A4, CYP2C19). A reduction in PPI concentrations may increase the risk of gastrointestinal (GI) adverse events such as GI bleeding. If fosphenytoin and PPIs must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy.
Dextromethorphan; Quinidine: (Major) Quinidine is eliminated primarily via hepatic metabolism, primarily by the CYP3A4 isoenzyme. Inducers of CYP3A4, such as fosphenytoin or phenytoin, may increase hepatic elimination of quinidine and decrease its serum concentrations. Quinidine concentrations should be monitored closely after the anticonvulsant is added to the treatment regimen. No special precautions appear necessary if these agents are begun several weeks before quinidine is added but quinidine doses may require adjustment if one of these agents is added or discontinued during quinidine therapy.
Diazepam: (Moderate) Et

hotoin is a hepatic enzyme inducer and thus may accelerate the metabolism of several other anticonvulsants, and can theoretically add to the CNS-depressant effects of other CNS depressants, including the anxiolytics, sedatives, and hypnotics which may be used concomitantly for seizure control or as psychotropics. Ethotoin should be used cautiously with diazepam, as decreased diazepam serum concentrations may be seen when coadministered with phenytoin. In addition, diazepam has been reported to have an unpredictable effect on phenytoin serum concentrations (e.g., to increase, decrease, or cause no change in phenytoin serum concentrations). Conflicting results may have been observed due to saturable phenytoin metabolism and/or other conditions associated with the reported data. Since definitive controlled trial data are lacking, phenytoin concentrations should be monitored more closely when diazepam is added or discontinued.
Diazoxide: (Moderate) Diazoxide may increase the hepatic metabolism of phenytoin, but the mechanism and incidence of the interaction is not certain. Subtherapeutic phenytoin concentrations have been documented in three children when coadministered with diazoxide; in two cases, the phenytoin serum concentrations were undetectable. In addition, the risk of developing hyperglycemia is increased when diazoxide is given concomitantly with phenytoin. Until further data are available, use caution when hydantoins such as phenytoin, fosphenytoin, or ethotoin are prescribed with diazoxide. It is prudent to monitor serum drug concentrations and clinical response during concomitant therapy.
Dienogest; Estradiol valerate: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Diphenhydramine; Naproxen: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with hydantoins, monitor patients for toxicity from either drug.
Diphenoxylate; Atropine: (Moderate) Concurrent administration of diphenoxylate/difenoxin with hydantoins can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
Disopyramide: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, including disopyramide, leading to reduced efficacy of the concomitant medication. Patients should be monitored for loss of disopyramide activity if a hydantoin is added. In addition, disopyramide doses may need to be reduced if a hydantoin is stopped and disopyramide therapy is continued. Serum disopyramide concentrations should be monitored closely if hepatic enzyme inducers are either added or discontinued during disopyramide therapy.
Disulfiram: (Major) Disulfiram can interfere with the metabolism of hydantoin anticonvulsants, particularly phenytoin, resulting in increased serum concentrations and possible phenytoin toxicity (i.e., ataxia, hyperreflexia, nystagmus, tremor). The mechanism is most likely due to inhibition of CYP2C9 by disulfiram. Phenytoin serum concentrations should be performed prior to and during disulfiram administration, and dosages of either agent should be adjusted accordingly. This interaction may not occur if disulfiram therapy is initiated prior to beginning phenytoin, but, in this scenario, if disulfiram therapy is discontinued, subtherapeutic phenytoin concentrations can ensue. A similar interaction may occur with fosphenytoin or ethotoin.
Doxepin: (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Doxercalciferol: (Moderate) Although these interactions have not been specifically studied, hepatic enzyme inducers such as phenytoin and fosphenytoin may affect the 25-hydroxylation of doxercalciferol and may necessitate dosage adjustments of doxercalciferol. Phenytoin can decrease the activity of vitamin D by increasing its metabolism. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia. Vitamin D supplementation or dosage adjustments may be required in patients who are receiving chronic treatment with anticonvulsants.
Doxorubicin Liposomal: (Major) Patients receiving antineoplastic agents concurrently with hydantoins may be at risk for toxicity or loss of clinical efficacy and seizures; anticonvulsant therapy should be monitored closely during and after administration of antineoplastic agents. Phenytoin concentrations may be decreased by doxorubicin. Fosphenytoin, a prodrug of phenytoin, may also be susceptible to this interaction with doxorubicin; as well as ethotoin, another anticonvulsant hydantoin. Additionally, phenytoin and fosphenytoin are potent inducers of CYP3A4; doxorubicin is a major CYP3A4 substrate. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of doxorubicin with phenytoin or fosphenytoin if possible. If not possible, monitor doxorubicin closely for efficacy.
Doxorubicin: (Major) Patients receiving antineoplastic agents concurrently with hydantoins may be at risk for toxicity or loss of clinical efficacy and seizures; anticonvulsant therapy should be monitored closely during and after administration of antineoplastic agents. Phenytoin concentrations may be decreased by doxorubicin. Fosphenytoin, a prodrug of phenytoin, may also be susceptible to this interaction with doxorubicin; as well as ethotoin, another anticonvulsant hydantoin. Additionally, phenytoin and fosphenytoin are potent inducers of CYP3A4; doxorubicin is a major CYP3A4 substrate. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of doxorubicin with phenytoin or fosphenytoin if possible. If not possible, monitor doxorubicin closely for efficacy.
Doxycycline: (Moderate) Monitor for decreased efficacy of doxycycline if coadministered with hydantoins. Hydantoins decrease the half-life of doxycycline.
Droperidol: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the droperidol.
Drospirenone: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Drospirenone; Estetrol: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Drospirenone; Estradiol: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Drospirenone; Ethinyl Estradiol: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Efavirenz: (Major) Complex interactions may occur when hydantoins (phenytoin, fosphenytoin, and possibly ethotoin) are administered to patients receiving treatment for HIV infection; if possible, a different anticonvulsant should be used. The combination regimens used to treat HIV often include substrates, inducers, and inhibitors of several CYP isoenzymes. If phenytoin is used in patients being treated for HIV, the patient must be closely monitored for antiviral efficacy and seizure control; appropriate dose adjustments for phenytoin or the antiretroviral medications are unknown. Efavirenz is a substrate and inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19. Phenytoin is a substrate and inducer of CYP3A4, CYP2C9, and CYP2C19. Use of these drugs in combination may decrease the serum concentrations of both phenytoin and efavirenz.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Complex interactions may occur when hydantoins (phenytoin, fosphenytoin, and possibly ethotoin) are administered to patients receiving treatment for HIV infection; if possible, a different anticonvulsant should be used. The combination regimens used to treat HIV often include substrates, inducers, and inhibitors of several CYP isoenzymes. If phenytoin is used in patients being treated for HIV, the patient must be closely monitored for antiviral efficacy and seizure control; appropriate dose adjustments for phenytoin or the antiretroviral medications are unknown. Efavirenz is a substrate and inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19. Phenytoin is a substrate and inducer of CYP3A4, CYP2C9, and CYP2C19. Use of these drugs in combination may decrease the serum concentrations of both phenytoin and efavirenz.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Complex interactions may occur when hydantoins (phenytoin, fosphenytoin, and possibly ethotoin) are administered to patients receiving treatment for HIV infection; if possible, a different anticonvulsant should be used. The combination regimens used to treat HIV often include substrates, inducers, and inhibitors of several CYP isoenzymes. If phenytoin is used in patients being treated for HIV, the patient must be closely monitored for antiviral efficacy and seizure control; appropriate dose adjustments for phenytoin or the antiretroviral medications are unknown. Efavirenz is a substrate and inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19. Phenytoin is a substrate and inducer of CYP3A4, CYP2C9, and CYP2C19. Use of these drugs in combination may decrease the serum concentrations of both phenytoin and efavirenz.
Elagolix; Estradiol; Norethindrone acetate: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Empagliflozin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Empagliflozin; Linagliptin: (Moderate) Phenytoin, fosphenytoin, or ethotoin can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. In addition, potent inducers of CYP3A4 (e.g.,phenytoin, fosphenytoin) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of phenytoin or fosphenytoin, an alternative to linagliptin is strongly recommended. Patients receiving linagliptin should be closely monitored for signs indicating loss of diabetic control when co-use of any of these hydantoins is necessary. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy is discontinued. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Empagliflozin; Linagliptin; Metformin: (Moderate) Phenytoin, fosphenytoin, or ethotoin can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. In addition, potent inducers of CYP3A4 (e.g.,phenytoin, fosphenytoin) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of phenytoin or fosphenytoin, an alternative to linagliptin is strongly recommended. Patients receiving linagliptin should be closely monitored for signs indicating loss of diabetic control when co-use of any of these hydantoins is necessary. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy is discontinued. (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Empagliflozin; Metformin: (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Enalapril; Felodipine: (Moderate) Hydantoin anticonvulsants (i.e., phenytoin, fosphenytoin, or ethotoin) induce CYP3A4 and may significantly enhance the hepatic metabolism of felodipine. Higher doses of felodipine may be necessary in epileptic patients receiving any of these anticonvulsants.
Ergotamine; Caffeine: (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination.
Ertugliflozin; Metformin: (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Ertugliflozin; Sitagliptin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Estazolam: (Moderate) Hydantoin anticonvulsants are hepatic inducers and can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, possibly leading to reduced benzodiazepine concentrations.
Estradiol Cypionate; Medroxyprogesterone: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Estradiol; Levonorgestrel: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Estradiol; Norethindrone: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Estradiol; Norgestimate: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Estradiol; Progesterone: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Estramustine: (Moderate) Estrogens are metabolized by CYP3A4. Concurrent administration of hepatic enzyme inducers with estrogens, including hydantoin anticonvulsants, may increase the elimination of estrogen.
Eszopiclone: (Moderate) Potent inducers of CYP3A4, such as hydantoins, may increase the rate of eszopiclone metabolism. The serum concentration and clinical effect of eszopiclone may be reduced. An alternative hypnotic agent may be more prudent in patients taking CYP3A4 inducers.
Ethanol: (Major) Phenytoin theoretically can add to the CNS-depressant effects of alcohol. Chronic ingestion of alcohol induces hepatic microsomal isozymes and increases the clearance of phenytoin. Alcohol also exhibits epileptogenic potential. Alcohol should generally be avoided in patients on fosphenytoin or phenytoin. Acute ingestion of small amounts of ethanol in non-alcoholic patients does not appear to affect the hepatic metabolism of phenytoin to a clinically significant degree.
Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Ethinyl Estradiol; Norelgestromin: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Ethinyl Estradiol; Norethindrone Acetate: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Ethinyl Estradiol; Norgestrel: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Etonogestrel: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Etonogestrel; Ethinyl Estradiol: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Ezetimibe; Simvastatin: (Moderate) Monitor for a decrease in simvastatin efficacy if concomitant use with phenytoin is necessary. Concomitant use may decrease simvastatin exposure. Simvastatin is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Felbamate: (Moderate) Hydantoins are hepatic enzyme inducers and thus may accelerate the metabolism of several other anticonvulsants, including felbamate.
Felodipine: (Moderate) Hydantoin anticonvulsants (i.e., phenytoin, fosphenytoin, or ethotoin) induce CYP3A4 and may significantly enhance the hepatic metabolism of felodipine. Higher doses of felodipine may be necessary in epileptic patients receiving any of these anticonvulsants.
Fenoprofen: (Minor) As fenoprofen is 99% bound to albumin, an interaction may occur between fenoprofen and hydantoins. Fenoprofen may displace other highly protein bound drugs from albumin or vice versa. If fenoprofen is used concurrently with hydantoins, monitor patients for toxicity from any of the drugs.
Flibanserin: (Major) The concomitant use of flibanserin with CYP3A4 inducers significantly decreases flibanserin exposure compared to the use of flibanserin alone. Therefore, concurrent use of flibanserin and CYP3A4 inducers, such as ethotoin, is not recommended.
Fluconazole: (Major) Fluconazole can decrease the metabolism of phenytoin. A mean increase of 88% in phenytoin serum AUC has been seen in some normal male volunteers taking both fluconazole and phenytoin. Concentrations of phenytoin should be carefully monitored if fluconazole is added. A similar interaction would be expected with ethotoin.
Fluorouracil, 5-FU: (Major) Alterations in phenytoin serum concentrations have been reported in patients previously stabilized on phenytoin who receive systemic fluorouracil, 5-FU. Most commonly, decreased phenytoin serum concentrations are reported in the literature, however, increased levels of phenytoin have been reported in a small number of patients. Similar interactions may be expected between 5-FU and fosphenytoin or ethotoin.
Flurazepam: (Moderate) Monitor patients for decreased efficacy of flurazepam if coadministration with phenytoin/fosphenytoin is necessary. Concurrent use may decrease flurazepam exposure. Flurazepam is a CYP3A substrate and phenytoin/fosphenytoin are strong CYP3A inducers.
Food: (Major) Advise patients to avoid cannabis use during phenytoin/fosphenytoin treatment. Concomitant use may decrease the concentration of some cannabinoids and alter their effects. The cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A substrates and phenytoin/fosphenytoin are strong CYP3A inducers. Concomitant use of a cannabinoid product containing THC and CBD at an approximate 1:1 ratio with another strong CYP3A inducer decreased THC, 11-OH-THC, and CBD peak exposures by 36%, 87%, and 52% respectively.
Fosamprenavir: (Major) Anticonvulsants, such as hydantoin anticonvulsants (e.g., phenytoin, ethotoin, fosphenytoin), may increase the metabolism of amprenavir and lead to decreased efficacy of fosamprenavir. Additionally, fosamprenavir is usually administered with low-dose ritonavir; this combination could result in decreased phenytoin concentrations. The appropriate drug-dose adjustments necessary to ensure optimum levels of both antiretroviral and anticonvulsant drugs are unknown. If fosamprenavir is added to anticonvulsant therapy, the patient should be observed for changes in the clinical efficacy of the antiretroviral regimen or seizure control. Monitoring of serum concentrations of these agents is recommended when given concomitantly with fosamprenavir.
Glipizide; Metformin: (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Glyburide; Metformin: (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Green Tea: (Minor) Some green tea products contain caffeine. The metabolism of caffeine can be increased by concurrent use with hydantoin anticonvulsants.
Haloperidol: (Major) Haloperidol is metabolized in the liver; hydantoin anticonvulsants are known to induce certain hepatic enzymes. Clinicians should monitor for reduced haloperidol effectiveness if a hydantoin is used concurrently. Conversely, the discontinuation of these drugs may produce an increase in haloperidol concentrations. Additionally, antipsychotic use may lower the seizure threshold in patients receiving anticonvulsants, although the risk is less with haloperidol than with the phenothiazines. Additional CNS depression may occur when haloperidol is given with anticonvulsant drugs.
Hydromorphone: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists. Methadone is a primary substrate for the CYP3A4 isoenzyme. Serum concentrations of methadone may decrease due to CYP3A4 induction by phenytoin; withdrawal symptoms may occur.
Hydroxychloroquine: (Moderate) Caution is warranted with the coadministration of hydroxychloroquine and antiepileptic drugs, such as ethotoin. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
Imipramine: (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Incretin Mimetics: (Minor) Ethotoin can decrease the hypoglycemic effects of incretin mimetics by producing an increase in blood glucose levels. Patients receiving incretin mimetics should be closely monitored for signs indicating loss of diabetic control when therapy with a hydantoin is instituted. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy with a hydantoin is discontinued.
Indinavir: (Major) Hydantoins like phenytoin, ethotoin, fosphenytoin may increase the metabolism of indinavir and lead to decreased efficacy. In addition, indinavir may inhibit the CYP metabolism of hydantoins, resulting in increased hydantoin concentrations.
Insulins: (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of ethotoin. Dosages of ethotoin may need to be adjusted while the patient is receiving rifampin.
Isoniazid, INH; Rifampin: (Major) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of ethotoin. Dosages of ethotoin may need to be adjusted while the patient is receiving rifampin.
Isradipine: (Moderate) Because isradipine is a substrate of CYP3A4 , the concomitant use of drugs that induce CYP3A4, such as hydantoin anticonvulsants (i.e., phenytoin, fosphenytoin, or ethotoin), may cause a reduction in the bioavailability and thus decreased therapeutic effect of isradipine. Until more data are available, patients should be monitored for potential loss of therapeutic effect when hepatic enzyme inducers are added to isradipine therapy.
Lansoprazole; Naproxen: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with hydantoins, monitor patients for toxicity from either drug.
Lanthanum Carbonate: (Major) Oral compounds known to interact with antacids, like ethotoin, should not be taken within 2 hours of dosing with lanthanum carbonate. If these agents are used concomitantly, space the dosing intervals appropriately. Monitor serum concentrations and clinical condition.
Leuprolide; Norethindrone: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Levamlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Levonorgestrel: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Levonorgestrel; Ethinyl Estradiol: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Levorphanol: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists. Methadone is a primary substrate for the CYP3A4 isoenzyme. Serum concentrations of methadone may decrease due to CYP3A4 induction by phenytoin; withdrawal symptoms may occur.
Levothyroxine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of thyroid hormones, leading to reduced efficacy of the thyroid hormone.
Levothyroxine; Liothyronine (Porcine): (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of thyroid hormones, leading to reduced efficacy of the thyroid hormone.
Levothyroxine; Liothyronine (Synthetic): (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of thyroid hormones, leading to reduced efficacy of the thyroid hormone.
Lidocaine: (Moderate) Lidocaine is a substrate for the cytochrome P450 isoenzymes 1A2 and 3A4. Ethotoin may enhance lidocaine clearance by inducing cytochrome P-450 enzymes.
Lidocaine; Epinephrine: (Moderate) Lidocaine is a substrate for the cytochrome P450 isoenzymes 1A2 and 3A4. Ethotoin may enhance lidocaine clearance by inducing cytochrome P-450 enzymes.
Lidocaine; Prilocaine: (Moderate) Lidocaine is a substrate for the cytochrome P450 isoenzymes 1A2 and 3A4. Ethotoin may enhance lidocaine clearance by inducing cytochrome P-450 enzymes.
Linagliptin: (Moderate) Phenytoin, fosphenytoin, or ethotoin can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. In addition, potent inducers of CYP3A4 (e.g.,phenytoin, fosphenytoin) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of phenytoin or fosphenytoin, an alternative to linagliptin is strongly recommended. Patients receiving linagliptin should be closely monitored for signs indicating loss of diabetic control when co-use of any of these hydantoins is necessary. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy is discontinued.
Linagliptin; Metformin: (Moderate) Phenytoin, fosphenytoin, or ethotoin can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations. In addition, potent inducers of CYP3A4 (e.g.,phenytoin, fosphenytoin) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of phenytoin or fosphenytoin, an alternative to linagliptin is strongly recommended. Patients receiving linagliptin should be closely monitored for signs indicating loss of diabetic control when co-use of any of these hydantoins is necessary. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy is discontinued. (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Liothyronine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of thyroid hormones, leading to reduced efficacy of the thyroid hormone.
Lopinavir; Ritonavir: (Major) Avoid concomitant use of lopinavir; ritonavir and hydantoins. If concomitant use is necessary, do not use once daily dosing of lopinavir; ritonavir. Concomitant use may decrease lopinavir plasma concentrations, resulting in reduced efficacy. Lopinavir is a CYP3A substrate and hydantoins are CYP3A inducers. (Major) Avoid concomitant use of ritonavir and hydantoins. Concomitant use may decrease the exposure of ritonavir and hydantoins, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the hydantoin. A dose increase of the hydantoin may be necessary. Ritonavir is a CYP3A substrate and inducer and hydantoins are CYP3A inducers.
Loxapine: (Major) Hydantoins may induce hepatic microsomal enzymes, leading to increased clearance of antipsychotic agents including loxapine. Also, loxapine may lower the seizure threshold. Adequate dosages of the anticonvulsant should be continued when an antipsychotic drug is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either drug.
Lurasidone: (Moderate) Because lurasidone is primarily metabolized by CYP3A4, decreased plasma concentrations of lurasidone may occur when the drug is co-administered with inducers of CYP3A4 such as ethotoin. A decrease in efficacy of lurasidone is possible. If lurasidone is used with a moderate CYP3A4 inducer, it may be necessary to increase the lurasidone dose after chronic treatment (7 days or more). Antipsychotics may also increase CNS depression and lower the seizure threshold, producing a pharmacodynamic interaction with anticonvulsants. Adequate dosages of the anticonvulsant should be continued when an antipsychotic drug is added; patients should be monitored for evidence of loss of seizure control or the need for dosage adjustments of either drug.
Magnesium Hydroxide: (Major) Magnesium hydroxide inhibits the absorption of ethotoin. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
Maprotiline: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. Ethotoin, phenytoin or fosphenytoin may increase antidepressant metabolism. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
Medroxyprogesterone: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Mefloquine: (Moderate) The hydantoin anticonvulsants induce CYP3A4 and may increase the metabolism of mefloquine if coadministered. Concomitant administration can reduce the clinical efficacy of mefloquine, increasing the risk of Plasmodium falciparum resistance during treatment of malaria. Coadministration of mefloquine and hydantoin anticonvulsants may also result in lower than expected anticonvulsant concentrations and loss of seizure control. Monitoring of the hydantoin (e.g., phenytoin) anticonvulsant serum concentration, if the drug is monitored via therapeutic drug monitoring, is recommended. Mefloquine may cause CNS side effects that may cause seizures or alter moods or behaviors.
Meperidine: (Major) The coadministration of phenytoin, fosphenytoin, or ethotoin with meperidine may result in reduced analgesic efficacy of meperidine and increased meperidine/normeperidine related CNS adverse effects. Phenytoin may stimulate the metabolism of meperidine to its more toxic metabolite normeperidine. While the clinical relevance of this interaction is uncertain, concurrent use should be undertaken with care.
Meperidine; Promethazine: (Major) The coadministration of phenytoin, fosphenytoin, or ethotoin with meperidine may result in reduced analgesic efficacy of meperidine and increased meperidine/normeperidine related CNS adverse effects. Phenytoin may stimulate the metabolism of meperidine to its more toxic metabolite normeperidine. While the clinical relevance of this interaction is uncertain, concurrent use should be undertaken with care.
Mestranol; Norethindrone: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Metformin: (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Metformin; Repaglinide: (Moderate) Coadministration of repaglinide with hydantoins may increase or decrease blood glucose; if coadministration is necessary, repaglinide dosage adjustment may be required and an increased frequency of glucose monitoring is recommended. Hydantoins are potent CYP3A4 inducers and repaglinide is a CYP3A4 substrate. In addition, phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Metformin; Rosiglitazone: (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Metformin; Saxagliptin: (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Metformin; Sitagliptin: (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Methadone: (Moderate) Additive CNS depression including respiratory depression, hypotension, profound sedation, or coma may occur with the combined use of the hydantoin (e.g., phenytoin, fosphenytoin, and ethotoin) and methadone. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; in opioid-naive adults, use an initial methadone dose of 2.5 mg every 12 hours. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Methadone is a primary substrate for the CYP3A4 isoenzyme. Serum concentrations of methadone may decrease due to CYP3A4 induction by phenytoin, fosphenytoin, and possibly ethotoin; withdrawal symptoms may occur.
Methamphetamine: (Major) Methamphetamine may delay the intestinal absorption of orally-administered phenytoin; the extent of phenytoin absorption is not known to be effected. Monitor the patient's neurologic status closely, as the amphetamines may also lower the seizure threshold in some patients on phenytoin or fosphenytoin.
Methohexital: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking.
Methoxsalen: (Major) Hydantoins may increase the clearance of methoxsalen. The mechanism may be due to phenytoin induction of hepatic metabolizing enzymes resulting in reduced methoxsalen serum concentrations.
Methsuximide: (Moderate) Concurrent administration of methsuximide and phenytoin may increase phenytoin concentrations resulting in side effects or toxicity. Other hydantoins such as ethotoin may be similarly affected by methsuximide.
Mexiletine: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, such as mexiletine, leading to reduced efficacy of the concomitant medication.
Midazolam: (Moderate) Hydantoins are potent inducers of the hepatic isoenzyme CYP3A4, one of the pathways responsible for the hepatic metabolism of midazolam. Patients receiving these drugs may require higher doses of midazolam to achieve the desired clinical effect.
Modafinil: (Moderate) Since modafinil is metabolized by the CYP3A4 isoenzyme, and hydantoins (e.g., phenytoin, fosphenytoin) are CYP3A4 inducers, decreased modafinil efficacy may result from increased modafinil metabolism. In addition, modafinil is an inhibitor of the CYP2C19 and CYP2C9 isoenzymes. Hydantoins are substrates of CYP2C19, and phenytoin is a substrate of CYP2C9. Hydantoin concentrations may increase. Monitor carefully for signs of toxicity; phenytoin concentration monitoring may be helpful.
Molindone: (Moderate) The hydantoins may induce hepatic microsomal enzymes, leading to increased clearance of the antipsychotic agents, such as molindone. Clinicians should monitor for reduced effectiveness of the antipsychotic agent if hydantoin therapy is added. Antipsychotics may also increase CNS depression and also may lower the seizure threshold, producing a pharmacodynamic interaction with anticonvulsants. Adequate dosages of the anticonvulsant should be continued when an antipsychotic drug is added.
Montelukast: (Minor) Hydantoin anticonvulsants may reduce the systemic exposure of montelukast. However, dosage adjustment is not likely to be needed. If used together, the manufacturer recommends monitoring for proper montelukast effectiveness as a precaution. Hydantoin anticonvulsants are a strong CYP3A inducers. Montelukast is metabolized by CYP2C8 (primary), and also CYP2C9 and CYP3A4.
Morphine: (Moderate) Additive CNS depression could be seen with the combined use of the ethotoin and morphine.
Morphine; Naltrexone: (Moderate) Additive CNS depression could be seen with the combined use of the ethotoin and morphine.
Naldemedine: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as hydantoins, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
Naproxen: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with hydantoins, monitor patients for toxicity from either drug.
Naproxen; Esomeprazole: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with hydantoins, monitor patients for toxicity from either drug.
Naproxen; Pseudoephedrine: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with hydantoins, monitor patients for toxicity from either drug.
Nateglinide: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Nelfinavir: (Major) The coadministration of nelfinavir and phenytoin results in decreased phenytoin concentrations. Hydantoins may also increase the metabolism of nelfinavir, leading to decreased antiretroviral efficacy. Careful monitoring is warranted with coadministration of nelfinavir with hydantoin anticonvulsants.
Nevirapine: (Major) Coadministration of phenytoin or fosphenytoin and nevirapine is not recommended due to the potential for loss of virologic response and possible resistance to nevirapine. Nevirapine may also decrease plasma concentrations of phenytoin/fosphenytoin. If concurrent use is necessary, monitor phenytoin concentrations and virologic response. Nevirapine is a CYP3A substrate and phenytoin/fosphenytoin are strong CYP3A inducers.
Niacin; Simvastatin: (Moderate) Monitor for a decrease in simvastatin efficacy if concomitant use with phenytoin is necessary. Concomitant use may decrease simvastatin exposure. Simvastatin is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Nicardipine: (Moderate) Hydantoin anticonvulsants (i.e., phenytoin, fosphenytoin, or ethotoin) may induce the CYP3A4 metabolism of calcium-channel blockers and thereby reduce their oral bioavailability. The dosage requirements of nicardipine may be increased in patients receiving concurrent hydantoin anticonvulsants.
Nimodipine: (Moderate) Limited data suggest that nimodipine may potentiate the effects of phenytoin. Because fosphenytoin is metabolized to phenytoin, additive effects are possible with concomitant nimodipine and fosphenytoin therapy. In addition, in epileptic patients taking phenytoin, there is a 7-fold decrease in the AUC of nimodipine due to hepatic enzyme induction. Monitor closely for therapeutic effectiveness and toxicity of both drugs.
Nirmatrelvir; Ritonavir: (Major) Avoid concomitant use of ritonavir and hydantoins. Concomitant use may decrease the exposure of ritonavir and hydantoins, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the hydantoin. A dose increase of the hydantoin may be necessary. Ritonavir is a CYP3A substrate and inducer and hydantoins are CYP3A inducers.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Norethindrone: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Norethindrone; Ethinyl Estradiol: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Norgestimate; Ethinyl Estradiol: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Norgestrel: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Nortriptyline: (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Olanzapine: (Major) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme, such as hydantoins, may increase olanzapine clearance. Clinicians should monitor for reduced effectiveness of the antipsychotic agent if hydantoin therapy is added.
Olanzapine; Fluoxetine: (Major) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme, such as hydantoins, may increase olanzapine clearance. Clinicians should monitor for reduced effectiveness of the antipsychotic agent if hydantoin therapy is added.
Olanzapine; Samidorphan: (Major) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme, such as hydantoins, may increase olanzapine clearance. Clinicians should monitor for reduced effectiveness of the antipsychotic agent if hydantoin therapy is added.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid concomitant use of ritonavir and hydantoins. Concomitant use may decrease the exposure of ritonavir and hydantoins, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the hydantoin. A dose increase of the hydantoin may be necessary. Ritonavir is a CYP3A substrate and inducer and hydantoins are CYP3A inducers. (Major) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with ethotoin should be undertaken with extreme caution due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposure to dasabuvir, ombitasvir, paritaprevir and ritonavir. Although specific data are unavailable regarding cytochrome P450 enzyme involvement with ethotoin metabolism or enzyme induction, interactions that are documented with phenytoin may theoretically occur with ethotoin. Phenytoin is a potent inducer and substrate of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, phenytoin may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Drugs that induce hepatic microsomal enzymes, particularly those drugs that increase CYP2C9 or CYP2C19 metabolism, such as rifamycins, can accelerate hydantoin anticonvulsant clearance.
Omeprazole; Sodium Bicarbonate: (Major) The oral absorption of ethotoin may be reduced by antacids. Separating the administration of ethotoin and antacids by at least 2 hours will help minimize the possibility of interaction.
Oxazepam: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS-depressant effects of other CNS depressants including oxazepam. In addition to additive pharmacodynamic effects, potential hepatic enzyme inducers such as hydantoins can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, leading to lower benzodiazepine concentrations.
Oxymorphone: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists. Methadone is a primary substrate for the CYP3A4 isoenzyme. Serum concentrations of methadone may decrease due to CYP3A4 induction by phenytoin; withdrawal symptoms may occur.
Paclitaxel: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 isoenzymes 2C8 and 3A4. Potential interactions may occur in vivo with any agent that induces CYP2C8 or CYP3A4 isoenzymes including hydantoins. This combination could potentially decrease chemotherapy efficacy.
Paliperidone: (Major) Avoid using a strong inducer of CYP3A4 if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of strong CYP3A4 inducers such as hydantions is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. A dosage increase of oral paliperidone may be required during coadministration of a strong inducer of both CYP3A4 and P-gp. However, concurrent use of oral paliperidone with a strong CYP3A4 inducer alone may not be clinically relevant since this isoenzyme contributes to only a small fraction of total body clearance of the drug.
Paricalcitol: (Moderate) Antiepileptic drugs, such as barbiturates (i.e., phenobarbital and primidone), and phenytoin (or fosphenytoin which is metabolized to phenytoin) can increase the metabolism of endogenous vitamin D, thereby lowering serum concentrations and decreasing its activity. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia. In addition, hydantoins are CYP3A4 inducers and thus may further lower serum concentrations of paricalcitol through increased CYP3A4-mediated metabolism. Dosage adjustments of vitamin D analogs may be required in patients who are receiving chronic treatment with antiepileptic drugs.
Pentobarbital: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking.
Perindopril; Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Perphenazine; Amitriptyline: (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Phenicol Derivatives: (Moderate) Chloramphenicol inhibits the cytochrome P-450 enzyme system and can affect the hepatic metabolism of hydantoins. It is also possible that plasma concentrations of chloramphenicol can be reduced by concomitant use of hydantoin.
Phenobarbital: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking.
Phentermine; Topiramate: (Moderate) A dosage adjustment may be needed during coadministration of topiramate and hydantoins, closely monitor patients appropriately for increased adverse effects or altered clinical response to therapy. Serum phenytoin concentration may be needed for optimal dosage adjustments. Hydantoins have been shown to reduce topiramate serum concentrations.Topiramate may increase phenytoin concentrations through its inhibitory effects on CYP2C19. In some patients receiving phenytoin concurrently with topiramate, plasma concentrations of phenytoin were increased by 25% and topiramate plasma concentrations were decreased by 48%. These patients were generally receiving dosage regimens of phenytoin twice-daily. Other patients experienced a change of less than 10% in phenytoin plasma concentrations. A similar reaction would be expected with fosphenytoin.
Pioglitazone; Metformin: (Minor) Ethotoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Pramlintide: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Primidone: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking.
Progesterone: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Progestins: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Protriptyline: (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Quazepam: (Moderate) Hydantoins are hepatic inducers and can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, leading to lower benzodiazepine concentrations.
Quinidine: (Major) Quinidine is eliminated primarily via hepatic metabolism, primarily by the CYP3A4 isoenzyme. Inducers of CYP3A4, such as fosphenytoin or phenytoin, may increase hepatic elimination of quinidine and decrease its serum concentrations. Quinidine concentrations should be monitored closely after the anticonvulsant is added to the treatment regimen. No special precautions appear necessary if these agents are begun several weeks before quinidine is added but quinidine doses may require adjustment if one of these agents is added or discontinued during quinidine therapy.
Rabeprazole: (Moderate) Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and proton pump inhibitors (PPIs). Phenytoin induces hepatic cytochrome P-450 enzymes, including those responsible for the metabolism of PPIs (e.g., CYP3A4, CYP2C19). A reduction in PPI concentrations may increase the risk of gastrointestinal (GI) adverse events such as GI bleeding. If phenytoin and PPIs must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy.
Relugolix; Estradiol; Norethindrone acetate: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Remifentanil: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists. Methadone is a primary substrate for the CYP3A4 isoenzyme. Serum concentrations of methadone may decrease due to CYP3A4 induction by phenytoin; withdrawal symptoms may occur.
Repaglinide: (Moderate) Coadministration of repaglinide with hydantoins may increase or decrease blood glucose; if coadministration is necessary, repaglinide dosage adjustment may be required and an increased frequency of glucose monitoring is recommended. Hydantoins are potent CYP3A4 inducers and repaglinide is a CYP3A4 substrate. In addition, phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically.
Rifabutin: (Moderate) Drugs that induce hepatic microsomal enzymes, particularly those drugs that increase CYP2C9 or CYP2C19 metabolism, such as rifamycins, can accelerate hydantoin anticonvulsant clearance.
Rifampin: (Major) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of ethotoin. Dosages of ethotoin may need to be adjusted while the patient is receiving rifampin.
Risperidone: (Major) Because antipsychotics such as risperidone can lower the seizure threshold, the effectiveness of ethotoin as an anticonvulsant may be reduced. In addition, inducers of CYP3A4, such as ethotoin, may decrease plasma concentrations of risperidone and its active metabolite. Therefore, the manufacturer of oral risperidone recommends a slow upward titration of the risperidone dose as needed up to double the patient's usual dose during use of a 3A4 inducer. When using Risperdal Consta, the patient will require close monitoring for 4 to 8 weeks when starting an inducer. A lower dose of Risperdal Consta may be prescribed between 2 to 4 weeks before the planned discontinuation of the inducer to adjust for the expected increase in plasma concentrations of risperidone and its active metabolite. For patients treated with the recommended dose of Risperdal Consta 25 mg and discontinuing the inducer, it is recommended to continue the 25 mg dose unless a reduction to 12.5 mg or discontinuation of treatment is indicated. The efficacy of the 12.5 mg dose has not been studied in clinical trials.
Ritonavir: (Major) Avoid concomitant use of ritonavir and hydantoins. Concomitant use may decrease the exposure of ritonavir and hydantoins, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the hydantoin. A dose increase of the hydantoin may be necessary. Ritonavir is a CYP3A substrate and inducer and hydantoins are CYP3A inducers.
Salicylates: (Minor) Large doses of salicylates can displace hydantoins from plasma protein-binding sites. Although increased serum concentrations of unbound phenytoin may lead to phenytoin toxicity, the liver may also more rapidly clear unbound drug.
Saquinavir: (Major) Complex interactions may occur when phenytoin or fosphenytoin are administered to patients receiving treatment for HIV infection. The combination regimens used to treat HIV often include substrates, inducers, and inhibitors of several CYP isoenzymes. An alternative anticonvulsant should be considered when possible. If phenytoin is used in patients being treated for HIV, the patient must be closely monitored for antiviral efficacy and seizure control; appropriate dose adjustments for phenytoin or the antiretroviral medications are unknown. Phenytoin will likely increase the metabolism of anti-retroviral protease inhibitors (PIs), leading to decreased antiretroviral efficacy. In addition, PIs may inhibit the CYP metabolism of phenytoin, resulting in increased phenytoin concentrations.
Saxagliptin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Secobarbital: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking.
Segesterone Acetate; Ethinyl Estradiol: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Sildenafil: (Moderate) Monitor for decreased efficacy of sildenafil if coadministration with phenytoin is necessary as concurrent use may decrease sildenafil exposure. Sildenafil is a sensitive CYP3A substrate and phenytoin is a strong CYP3A inducer. Concomitant administration of strong CYP3A inducers is expected to substantially decrease plasma concentrations of sildenafil.
Simvastatin: (Moderate) Monitor for a decrease in simvastatin efficacy if concomitant use with phenytoin is necessary. Concomitant use may decrease simvastatin exposure. Simvastatin is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Simvastatin; Sitagliptin: (Moderate) Monitor for a decrease in simvastatin efficacy if concomitant use with phenytoin is necessary. Concomitant use may decrease simvastatin exposure. Simvastatin is a CYP3A substrate and phenytoin is a strong CYP3A inducer. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Sitagliptin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Sodium Bicarbonate: (Major) The oral absorption of ethotoin may be reduced by antacids. Separating the administration of ethotoin and antacids by at least 2 hours will help minimize the possibility of interaction.
St. John's Wort, Hypericum perforatum: (Major) Avoid if possible; St. John's wort could decrease the efficacy of hydantoins metabolized by CYP450 enzymes, including hydantoins as St. John's wort induces CYP2C9 and other CYP450 enzymes. Clinicians should observe patients closely if St. John's wort is used; careful monitoring of anticonvulsant drug concentrations may be needed.
Sucralfate: (Major) The oral absorption of ethotoin may be reduced by sucralfate. Although the magnitude of this interactions is not great, an occasional patient may be affected and the interaction may lead to subtherapeutic ethotoin concentrations. Sucralfate should be given 2 hours before or after the ethotoin.
Sulfonylureas: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. In addition, coadministration may result in decreased serum concentrations of chlorpropamide. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Sumatriptan; Naproxen: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with hydantoins, monitor patients for toxicity from either drug.
Tasimelteon: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as hydantoins, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%.
Telmisartan; Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Temazepam: (Moderate) Hydantoins may increase the hepatic clearance of benzodiazepines. Interactions have been documented with benzodiazepines metabolized by oxidation or conjugation.
Theophylline, Aminophylline: (Moderate) Theophylline is primarily metabolized in the liver by the CYP1A2 isoenzyme, and also by the CYP3A4 isoenzyme. Medications that cause induction of hepatic CYP450 enzymes, such as phenytoin, ethotoin, or fosphenytoin, may increase the hepatic oxidative metabolism of theophylline or aminophylline. Theophylline doses may need to be increased if hydantoin anticonvulsants are added. More importantly, serious theophylline toxicity can result if any of these drugs are discontinued and the dose of theophylline is not correspondingly decreased. Also, theophylline may inhibit the oral absorption of phenytoin.
Thiazolidinediones: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Thiothixene: (Major) Thiothixene, when used concomitantly with various anticonvulsants can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when thiothixene is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the neuroleptic or the anticonvulsant.
Thyroid hormones: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of thyroid hormones, leading to reduced efficacy of the thyroid hormone.
Tiagabine: (Moderate) Population pharmacokinetic analyses indicate that tiagabine clearance is increased by about 60% when taken concomitantly with phenytoin (or fosphenytoin) or other hepatic enzyme-inducing antiepileptic drugs. Tiagabine had no effect on the steady-state plasma concentrations of phenytoin when evaluated in patients with epilepsy. Tiagabine does not appear to be an inducer or inhibitor of the hepatic microsomal enzyme system. Use of tiagabine WITHOUT enzyme-inducing antiepileptic drugs results in blood levels about two times those attained in the studies on which dosing recommendations for partial seizures are based. If tiagabine is used in patients that are not taking enzyme-inducing drugs, whether it be for the partial seizure indication or for other off-label uses, the dose of tiagabine must be adjusted down. Paradoxical seizures have occurred in patients receiving tiagabine for off-label (primarily psychiatric) indications; these seizures may be dose-related. However, many of these patients were also taking medications that can lower the seizure threshold and the FDA strongly discourage the use of tiagabine for off-label indications.
Ticlopidine: (Moderate) Ticlopidine is an inhibitor of the hepatic isoenzyme CYP2C19 and has been shown to reduce the clearance of phenytoin in patients previously on a stable phenytoin dosage regimen. Hydantoin dosage adjustments may be necessary in some patients who receive ticlopidine concurrently.
Tipranavir: (Major) Hydantoin anticonvulsants increase the metabolism of the protease inhibitors and may lead to decreased efficacy of these medications. In addition, tipranavir may inhibit the CYP metabolism of hydantoins, resulting in increased hydantoin concentrations.
Topiramate: (Moderate) A dosage adjustment may be needed during coadministration of topiramate and hydantoins, closely monitor patients appropriately for increased adverse effects or altered clinical response to therapy. Serum phenytoin concentration may be needed for optimal dosage adjustments. Hydantoins have been shown to reduce topiramate serum concentrations.Topiramate may increase phenytoin concentrations through its inhibitory effects on CYP2C19. In some patients receiving phenytoin concurrently with topiramate, plasma concentrations of phenytoin were increased by 25% and topiramate plasma concentrations were decreased by 48%. These patients were generally receiving dosage regimens of phenytoin twice-daily. Other patients experienced a change of less than 10% in phenytoin plasma concentrations. A similar reaction would be expected with fosphenytoin.
Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with hydantoins is necessary; consider increasing the dose of tramadol as needed. If hydantoins are discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and hydantoins are strong CYP3A inducers. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Tramadol; Acetaminophen: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with hydantoins is necessary; consider increasing the dose of tramadol as needed. If hydantoins are discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and hydantoins are strong CYP3A inducers. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Trandolapril; Verapamil: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with hydantoins is necessary. Concomitant use may decrease plasma concentrations of verapamil. Verapamil is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers.
Triazolam: (Moderate) Monitor for withdrawal symptoms or lack of triazolam efficacy if coadministration with phenytoin/fosphenytoin is necessary. Triazolam is a CYP3A substrate and phenytoin/fosphenytoin are strong CYP3A inducers.
Tricyclic antidepressants: (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Trimipramine: (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Verapamil: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with hydantoins is necessary. Concomitant use may decrease plasma concentrations of verapamil. Verapamil is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers.
Vitamin D: (Moderate) Phenytoin and fosphenytoin can decrease the activity of vitamin D (e.g., cholecalciferol) by increasing its metabolism. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia. Vitamin D supplementation or dosage adjustments may be required in patients who are receiving chronic treatment with anticonvulsants. (Moderate) Phenytoin and fosphenytoin can decrease the activity of vitamin D (e.g., cholecalciferol, ergocalciferol) by increasing its metabolism. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia. Vitamin D supplementation or dosage adjustments may be required in patients who are receiving chronic treatment with anticonvulsants.
Voriconazole: (Major) Phenytoin and fosphenytoin clearance can be decreased by drugs that significantly inhibit the cytochrome P450 2C subset of isoenzymes (e.g., CYP2C9 or 2C19), like voriconazole. In a pharmacokinetic study using volunteers, voriconazole increased the mean Cmax and AUC of phenytoin by approximately 70% and 80%, respectively. Frequent monitoring of plasma phenytoin concentrations and observation of the patient for phenytoin toxicity is recommended. In the same study, phenytoin reduced the mean Cmax and AUC of voriconazole by approximately 50% and 70%, respectively. This reduction was due to CYP3A4 or CYP2C9 induction by phenytoin. Recommendations from the manufacturer of voriconazole state that phenytoin or fosphenytoin can be given with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg IV every 12 hours or to 400 mg PO every 12 hours (or 200 mg PO every 12 hours in patients >= 12 years old and weighing < 40 kg). This interaction has not been specifically studied with ethotoin, another hydantoin anticonvulsant.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with hydantoins is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Hydantoins are CYP1A2, moderate CYP2C9, and strong CYP3A4 inducers and the enantiomers of warfarin are substrates of CYP1A2/CYP2C9/CYP3A4. Additionally, an immediate interaction may occur as phenytoin can displace warfarin from protein binding sites causing rapid increases in the INR. Warfarin dosage adjustments may also be necessary on discontinuation of the anticonvulsant.
Ziprasidone: (Major) Hydantoins may induce hepatic microsomal enzymes, leading to increased clearance of ziprasidone. Some antipsychotics may also increase CNS depression and also may lower the seizure threshold, producing a pharmacodynamic interaction with anticonvulsants. Adequate dosages of the anticonvulsant should be continued when an antipsychotic drug is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either drug.
Zolpidem: (Major) Avoid concurrent use of zolpidem with potent CYP3A4 inducers, such as hydantoins, if possible due to the potential for decreased zolpidem exposure and potential reduction of efficacy. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during coadministration with another potent CYP3A4 inducer. Consider if an alternative sleep agent would be appropriate for the patient.
Zonisamide: (Moderate) Hydantoins are hepatic enzyme inducers and thus may accelerate the metabolism of several other anticonvulsants, including zonisamide.

Peganone Oral Tab: 250mg

As with all anticonvulsant-type medications, particularly those with narrow therapeutic windows, ethotoin dosage must be individualized.

Anticonvulsant drugs can elevate the seizure threshold and/or limit the spread of seizure discharge. Ethotoin exerts its anticonvulsant effect mainly by limiting the spread of seizure activity and reducing seizure propagation, unlike phenobarbital and carbamazepine, which elevate the seizure threshold. Ethotoin's anticonvulsant effects are mediated through effects on sodium channels on the neuronal cell membrane. Ethotoin exerts its anticonvulsant effects with less CNS sedation than does phenobarbital. Ethotoin's utility as an anticonvulsant appears to be less than phenytoin, possibly due to the need for multiple daily doses. Unlike phenytoin, ethotoin exhibits no antiarrhythmic effects mediated by effects on sodium channels or Purkinje fibers.
 
 

Ethotoin is administered orally.
 
Ethotoin metabolites are produced by the hepatic microsomal enzyme system and excretion of the metabolites is via the kidneys. The isozymes involved in hepatic oxidation have not been described. The drug exhibits saturable metabolism (primarily via hydroxylation) with respect to the formation of N-de-ethyl and P-hydroxyl-ethotoin, the major metabolites. When plasma concentrations are below 8 mcg/ml, the elimination half-life is in the range of 3 to 9 hours. A study comparing single tablet doses of 500, 1000, and 1500 mg demonstrated that ethotoin, and to a lesser extent 5-phenylhydantoin, another major metabolite, exhibit substantial nonlinear kinetics. The degree of nonlinearity with multiple dosing may be increased over that seen after a single dose, given the likelihood of plasma accumulation with multiple dosing at intervals of 4 to 6 hours. The 5-phenylhydantoin metabolite is eliminated with a significantly longer half-life (18.7 +/- 6.1 h) than that of ethotoin. Only a small fraction of ethotoin is excreted unchanged.
 
Affected cytochrome P450 isoenzymes: none
No data are available regarding cytochrome P450 enzymes involvement with ethotoin metabolism or enzyme induction.

Oral Route

Ethotoin is fairly rapidly absorbed; the extent of oral absorption is not known. The time to maximum concentration (Tmax) is roughly 2 hours. Experience suggests that therapeutic plasma concentrations fall in the range of 15 to 50 mcg/ml; however, this range is not as extensively documented as those quoted for other antiepileptics that have been studied in greater detail.

Pregnancy

Ethotoin may cause fetal harm when administered to a pregnant woman. Other hydantoins, such as phenytoin are known teratogens, and a recognizable pattern of malformations has been observed. Congenital malformations (e.g., orofacial clefts, cardiac defects) and abnormalities characteristic of fetal hydantoin syndrome (i.e., dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities, cognitive deficits) have been observed. Several cases of malignancies, including neuroblastoma, have been reported in pediatric patients whose mothers received phenytoin during pregnancy. Cleft lip and palate have been reported with the use of ethotoin during pregnancy. Additionally, neonatal coagulation defects have been reported in neonates born to mothers receiving antiepileptic drugs and appear to result from drug-induced vitamin K deficiency in the fetus. Administration of vitamin K to the mother before obstetric delivery and to the neonate at birth has been shown to prevent or correct this defect. There is some evidence suggesting that hydantoin-like compounds may interfere with folic acid metabolism, precipitating a folate deficiency megaloblastic anemia. As in any pregnancy, folic acid supplementation should be instituted prior to and during pregnancy and lactation. Counsel pregnant women and women of childbearing potential that use of ethotoin during pregnancy can cause fetal harm, and when appropriate, about alternative therapeutic options. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to ethotoin; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.