EXTENDED PHENYTOIN SODIUM
Clinical safety rating: avoid
Many drugs can increase or decrease phenytoin levels Can cause life-threatening dermatologic reactions like Stevens-Johnson syndrome.
Phenytoin stabilizes neuronal membranes by promoting sodium channel inactivation, reducing repetitive firing of action potentials, and decreasing synaptic transmission.
| Metabolism | Primarily metabolized by hepatic CYP2C9 and to a lesser extent CYP2C19; exhibits saturable (Michaelis-Menten) pharmacokinetics; major metabolite is 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH) which is glucuronidated and excreted in urine. |
| Excretion | Primarily hepatic metabolism (CYP2C9/CYP2C19), with <5% excreted unchanged renally. Fecal excretion accounts for minor elimination. |
| Half-life | 22–32 hours (mean 24 hours) in adults, dose-dependent due to saturable metabolism; may exceed 60 hours at high concentrations. |
| Protein binding | 90–95% bound to albumin; free fraction increases in hypoalbuminemia or uremia. |
| Volume of Distribution | 0.6–1.0 L/kg; distributes widely with higher concentrations in brain and liver. |
| Bioavailability | Extended-release oral: 90–100%; IV: 100%. |
| Onset of Action | Oral extended-release: 2–4 hours; IV loading: 15–30 minutes. |
| Duration of Action | 24 hours for seizure control; steady-state reached in 7–10 days with oral dosing. |
Oral: 100 mg three times daily; intravenous: 10-20 mg/kg loading dose at a maximum rate of 50 mg/min, then 100 mg every 6-8 hours maintenance.
| Dosage form | CAPSULE |
| Renal impairment | GFR 10-50 mL/min: no adjustment; GFR <10 mL/min: administer every 8-12 hours. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 25-50%; Child-Pugh C: avoid use or reduce dose by 50-75%. |
| Pediatric use | Loading dose: 15-20 mg/kg IV or oral; maintenance: 5-10 mg/kg/day in 2-3 divided doses. |
| Geriatric use | Start at lower end of dosing range (e.g., 100 mg orally once daily) due to decreased clearance; monitor serum levels and adjust based on response and toxicity. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Many drugs can increase or decrease phenytoin levels Can cause life-threatening dermatologic reactions like Stevens-Johnson syndrome.
| FDA category | Positive |
| Breastfeeding | Phenytoin is excreted into breast milk with M/P ratio approximately 0.18–0.45. Infant serum levels are low, typically less than 10% of maternal levels. However, cases of infant drowsiness and poor feeding have been reported. American Academy of Pediatrics considers phenytoin compatible with breastfeeding, but monitor infant for sedation and poor sucking. Breastfeed just before maternal dose to minimize infant exposure. |
■ FDA Black Box Warning
Intravenous administration may cause cardiovascular collapse and/or CNS depression. Rapid infusion is associated with severe hypotension and cardiac arrhythmias. Continuous monitoring of ECG and vital signs is required during IV loading.
| Common Effects | Gingival hyperplasia |
| Serious Effects |
Hypersensitivity to phenytoin or hydantoins; sinus bradycardia; sinoatrial block; second- or third-degree AV block; Adams-Stokes syndrome; co-administration with delavirdine due to reduced antiretroviral efficacy.
| Precautions | Cardiovascular risk with IV administration (hypotension, bradycardia, and arrhythmias); CNS adverse effects (nystagmus, ataxia, sedation, cognitive impairment); hepatotoxicity; hematologic disorders (agranulocytosis, thrombocytopenia); hypersensitivity reactions (including Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms [DRESS]); osteomalacia and osteoporosis due to vitamin D metabolism induction; teratogenicity (fetal hydantoin syndrome); caution with hepatic impairment; avoid abrupt withdrawal to prevent rebound seizures; use with caution in elderly and debilitated patients due to increased risk of toxicity. |
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| Teratogenic Risk |
| Phenytoin is associated with fetal hydantoin syndrome, including craniofacial anomalies, growth restriction, and neurodevelopmental impairment. First trimester exposure increases risk of major congenital malformations (cleft palate, heart defects). Second and third trimester exposure risks include hemorrhage due to vitamin K deficiency and decreased fetal clotting factors. Risk of neural tube defects is elevated. Use only if benefits outweigh risks; consider folic acid supplementation 5 mg/day before and during pregnancy. |
| Fetal Monitoring | Monitor maternal serum phenytoin concentrations every 2–4 weeks during pregnancy and postpartum. Assess for signs of toxicity (nystagmus, ataxia, sedation). Fetal monitoring includes ultrasound for structural anomalies (18-22 weeks), fetal growth scans in third trimester. Monitor neonatal for withdrawal symptoms, coagulopathy (administer vitamin K 1 mg IM at birth). Check infant CBC and liver function if maternal toxicity suspected. |
| Fertility Effects | Phenytoin may decrease fertility in females by inducing hepatic enzymes, altering sex hormone metabolism, and causing menstrual irregularities. In males, reports of decreased libido and erectile dysfunction; sperm abnormalities (reduced motility, abnormal morphology) have been described. Effects are generally reversible upon discontinuation. |