PEGANONE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for PEGANONE (PEGANONE).
Ethotoin, a hydantoin derivative, stabilizes neuronal membranes by promoting sodium efflux and reducing sodium influx, decreasing post-tetanic potentiation and seizure spread.
| Metabolism | Hepatic metabolism via cytochrome P450 enzymes (predominantly CYP2C9 and CYP2C19); metabolites are excreted in urine as glucuronide conjugates. |
| Excretion | Primarily hepatic metabolism; less than 5% excreted unchanged in urine. Renal elimination of metabolites accounts for ~40-60% of an oral dose; biliary/fecal elimination accounts for ~10-20%. |
| Half-life | Terminal elimination half-life of ethotoin (PEGANONE) is approximately 5-8 hours in adults; variable due to saturable metabolism. Shorter half-life requires multiple daily dosing to maintain therapeutic levels (therapeutic range 15-50 mcg/mL). |
| Protein binding | Ethotoin is approximately 40-60% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Volume of distribution is approximately 0.5-0.7 L/kg, suggesting distribution into total body water with minimal tissue binding. |
| Bioavailability | Oral bioavailability is nearly 100% based on complete absorption from the gastrointestinal tract. |
| Onset of Action | Oral: 30-60 minutes for absorption; clinical effect (seizure control) typically occurs within 1-2 hours after a loading dose. |
| Duration of Action | Duration of anticonvulsant effect is 6-12 hours after a single oral dose due to short half-life; requires dosing 3-4 times daily to maintain consistent therapeutic levels. |
500-1000 mg orally 2 to 4 times daily (maximum 4000 mg/day).
| Dosage form | TABLET |
| Renal impairment | eGFR <50 mL/min: not recommended due risk of toxicity; no specific dosing guidelines available. |
| Liver impairment | Contraindicated in severe hepatic impairment; use with caution in mild-moderate impairment, reduce dose by 25-50% based on response. |
| Pediatric use | 1-10 mg/kg/day orally in divided doses every 6-8 hours; maximum 1000 mg/day. |
| Geriatric use | Start at lower end of dosing range (500 mg twice daily) due to decreased clearance; monitor for CNS effects. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for PEGANONE (PEGANONE).
| Breastfeeding | Ethotoin is excreted into breast milk. The milk-to-plasma (M/P) ratio is approximately 0.5-0.8. Estimated infant dose is 2.5-5% of maternal weight-adjusted dose. Use with caution; monitor infant for sedation, poor feeding, and rash. Consider benefits of breastfeeding versus potential risks. |
| Teratogenic Risk | PEGANONE (ethotoin) is a hydantoin anticonvulsant. First trimester: Associated with increased risk of major congenital malformations, including neural tube defects, cardiac defects, and orofacial clefts (fetal hydantoin syndrome). Second and third trimesters: Risk of fetal growth restriction, developmental delay, and coagulopathy due to vitamin K deficiency. |
■ FDA Black Box Warning
No FDA black box warning.
| Serious Effects |
Hypersensitivity to ethotoin or other hydantoins; history of hematologic disorders; hepatic porphyria; during pregnancy (risk of teratogenicity outweighs benefits unless seizure control is essential).
| Precautions | Hypersensitivity reactions including rash, Stevens-Johnson syndrome, and lupus-like syndrome; hematopoietic effects (agranulocytosis, thrombocytopenia, leukopenia) require monitoring; lymphadenopathy; teratogenicity (fetal hydantoin syndrome); acute intermittent porphyria; withdrawal seizures upon abrupt discontinuation. |
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| Fetal Monitoring | Monitor maternal serum ethotoin levels at least monthly; adjust dose to maintain therapeutic range (typically 15-50 mcg/mL). Perform fetal ultrasound at 18-20 weeks for structural anomalies. Consider fetal echocardiography. Monitor maternal liver function tests, complete blood count, and signs of folate deficiency. Administer vitamin K 10 mg/day orally during last month of pregnancy and 1 mg IM to neonate at birth. |
| Fertility Effects | PEGANONE may impair female fertility by disrupting menstrual cycles and ovulation due to enzyme-inducing effects on sex hormone metabolism. In males, reports of decreased libido and spermatogenesis abnormalities. Consider preconception counseling and alternative agents in patients planning pregnancy. |