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. |
| Molecular Weight | 252.27 |
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 | Associated with increased risk of congenital malformations including cleft palate, heart defects, and neural tube defects. Use only if benefit outweighs risk. |
| 2nd trimester | May cause fetal hydration syndrome including dysmorphic facies, growth retardation, and cognitive deficits. Monitor fetal growth and consider folic acid supplementation. |
| 3rd trimester | Risk of neonatal hemorrhage due to maternal vitamin K deficiency; administer vitamin K to mother prior to delivery. Neonatal withdrawal may occur. |
Clinical note
Many drugs can increase or decrease phenytoin levels Can cause life-threatening dermatologic reactions like Stevens-Johnson syndrome.
| FDA category | Positive |
| Placental transfer | Crosses placenta readily; cord blood concentrations approximate maternal serum levels. |
■ 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 hydantoinsSinus bradycardiaSinoatrial blockSecond- and third-degree AV blockAdams-Stokes syndrome
| 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. |
Loading safety data…
| Breastfeeding |
| Phenytoin is excreted into breast milk in low concentrations (infant dose <10% of maternal weight-adjusted dose). Monitor infant for drowsiness, poor feeding, and rash. Generally considered compatible with breastfeeding. |
| Lactation Rating | L2 |
| 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. |
| Food/Dietary | Avoid enteral tube feeding formulas and high-protein meals that may reduce phenytoin absorption. Separate dosing by 2-3 hours from tube feeds. Phenytoin may decrease absorption of folic acid and vitamin D; consider supplementation. No specific food interactions, but consistently take with or without food to avoid absorption variability. |
| Clinical Pearls | Extended phenytoin sodium (Dilantin Kapseals) has nonlinear pharmacokinetics; small dose increases can lead to disproportionate rises in serum levels. Fosphenytoin is preferred for IV loading due to lower risk of hypotension and arrhythmias. Always monitor for nystagmus, ataxia, and dysarthria as early signs of toxicity. Phenytoin induces hepatic enzymes (CYP2C9, CYP2C19) and can reduce efficacy of oral contraceptives, warfarin, and antiretrovirals. Caution in hypoalbuminemia or renal impairment: adjust for free phenytoin levels. |
| Patient Advice | Take exactly as prescribed; do not skip doses or double up. Do not stop suddenly as seizure may occur. · Extended-release capsules must be swallowed whole; do not crush or chew. · Avoid alcohol; it can increase side effects and decrease seizure control. · Notify your doctor if you develop rash, fever, swollen glands, or mouth sores; these can signal serious allergic reaction. · Use reliable contraception; phenytoin can reduce effectiveness of birth control pills. · Regular blood tests are needed to monitor drug levels and liver function. · Report symptoms of overdose: blurred vision, double vision, unsteady gait, slurred speech, or severe drowsiness. · Phenytoin may cause gingival hyperplasia; maintain good dental hygiene and see dentist regularly. · Causes vitamin D and folate deficiency; ensure adequate intake or supplementation. · Do not drive or operate machinery until you know how phenytoin affects you; may cause dizziness or drowsiness. |