PHENYTOIN SODIUM
Clinical safety rating: avoid
Many drugs can increase or decrease phenytoin levels Can cause life-threatening dermatologic reactions like Stevens-Johnson syndrome.
Stabilizes neuronal membranes and decreases seizure activity by increasing efflux or decreasing influx of sodium ions across cell membranes in the motor cortex during generation of nerve impulses. Prolongs inactivation of voltage-gated sodium channels, reducing repetitive firing of action potentials.
| Metabolism | Primarily hepatic via CYP2C9 (major) and CYP2C19 (minor). Undergoes saturable (nonlinear) elimination; exhibits dose-dependent pharmacokinetics. Metabolized to inactive metabolites (e.g., parahydroxyphenytoin) conjugated and excreted in urine. |
| Excretion | Primarily hepatic metabolism (CYP2C9, CYP2C19); <5% excreted unchanged in urine. Metabolites (majority p-HPPA) are excreted renally as glucuronide conjugates. Fecal elimination negligible (<2%). |
| Half-life | Mean terminal half-life 22 ± 9 hours (range 7–42 hours), dose-dependent and saturable due to Michaelis-Menten kinetics; half-life increases with higher serum concentrations. Steady state achieved after 7–10 days. |
| Protein binding | 90–95% bound to serum albumin. Binding is saturable; decreased albumin (e.g., uremia, hypoalbuminemia) increases free fraction. |
| Volume of Distribution | 0.6–0.8 L/kg (0.75 L/kg average). Distributes widely with high brain penetration; Vd approximates total body water. |
| Bioavailability | Oral: 85–95% (conventional formulation); extended-release formulations have slightly lower bioavailability (80–90%). Intramuscular: erratic and painful; not recommended. IV: 100%. |
| Onset of Action | Oral: 30–90 minutes (conventional); 2–4 hours (extended-release). IV: 10–30 minutes (loading dose). |
| Duration of Action | Oral: 6–12 hours (conventional); 12–24 hours (extended-release). IV: 4–6 hours for anticonvulsant effect. Maintenance dosing required every 8–24 hours depending on formulation. |
| Molecular Weight | 252.27 |
| Action Class | Sodium channel modulators (AED) |
| Brand Substitutes | Fensant 100mg Injection, Epilet 100mg Injection, Epiwin 100mg Injection |
Loading dose: 15-20 mg/kg IV (not to exceed 50 mg/min) or oral (1000-1500 mg total in divided doses). Maintenance: 300-400 mg/day PO in 1-2 divided doses or IV (100 mg every 6-8 hours).
| Dosage form | INJECTABLE |
| Renal impairment | No dose adjustment required for GFR >10 mL/min. For GFR <10 mL/min, use with caution and monitor free phenytoin levels; consider alternative therapy in severe renal impairment. |
| Liver impairment | Child-Pugh Class A: No adjustment. Child-Pugh Class B: Reduce dose by 25-50%. Child-Pugh Class C: Reduce dose by 50% or consider alternative. |
| Pediatric use | Loading: 15-20 mg/kg IV. Maintenance: 5-7 mg/kg/day PO or IV in 2-3 divided doses; neonates: 5-8 mg/kg/day in 2 divided doses. |
| Geriatric use | Start at lower maintenance dose (200-300 mg/day PO) due to decreased protein binding and metabolism; monitor free phenytoin levels and adjust slowly. |
| 1st trimester | Associated with increased risk of congenital malformations, including orofacial clefts and cardiac defects. Use only if benefit outweighs risk. |
| 2nd trimester | May cause fetal hydantoin syndrome; monitor for growth restriction. Use with caution. |
| 3rd trimester | Risk of neonatal hemorrhage due to vitamin K deficiency; administer vitamin K to mother. Use with caution. |
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 | Readily crosses placenta; fetal plasma concentrations approach maternal levels. Evidence of teratogenicity. |
| Breastfeeding |
■ FDA Black Box Warning
Do not discontinue abruptly; withdrawal may cause increased seizure frequency or status epilepticus. Administer IV slowly (not exceeding 50 mg/min) to avoid cardiovascular collapse.
| Serious Effects |
Hypersensitivity to phenytoin or hydantoinsSinus bradycardiaSinoatrial blockSecond- or third-degree AV blockAdams-Stokes syndrome
| Precautions | Cardiovascular risk: hypotension, bradycardia, and cardiac arrest with IV administration; monitor ECG and blood pressure. Dermatologic reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis; discontinue if rash develops. Hematologic effects: agranulocytosis, thrombocytopenia; monitor CBC. Hypersensitivity: DRESS syndrome. Suicidal ideation/behavior. Cognitive impairment with chronic use. Hepatic injury: monitor liver function. Osteoporosis with long-term use. Fosphenytoin prodrug preferred for IM/IV use due to better tolerability. |
| Food/Dietary | Avoid enteral feeds containing calcium or tube feedings that can reduce absorption; separate administration by 2 hours. Limit intake of foods high in folic acid (e.g., fortified cereals) without supplement. Grapefruit juice may alter metabolism. Ensure adequate vitamin D and calcium intake due to risk of osteomalacia. Alcohol can decrease phenytoin levels. |
Loading safety data…
| Phenytoin is excreted into breast milk in low concentrations (milk-to-plasma ratio ~0.18). No adverse effects reported in infants, but monitor for drowsiness and poor feeding. Generally considered compatible with breastfeeding. |
| Lactation Rating | L2 (Safer) |
| Teratogenic Risk | First trimester: Increased risk of major congenital malformations including cleft lip/palate (odds ratio 7.9), congenital heart defects (OR 2.5-4.5), and neural tube defects. Second/third trimester: Risk of fetal hydantoin syndrome (growth restriction, dysmorphic features, cognitive impairment), neonatal hemorrhage due to vitamin K deficiency, and potential neurodevelopmental delay. Overall risk of major malformations with first-trimester exposure is 6-10% (2-3x baseline). |
| Fetal Monitoring | Maternal: Serum phenytoin concentrations, CBC (especially folate and vitamin K status), liver function tests, signs of toxicity. Fetal: Detailed anatomic ultrasound at 18-20 weeks, echocardiogram if first-trimester exposure. Neonatal: Coagulation profile (vitamin K deficiency), monitoring for withdrawal symptoms (hyperexcitability, jitteriness). |
| Fertility Effects | Phenytoin may decrease fertility in women by inducing hepatic metabolism of sex hormones, potentially reducing efficacy of oral contraceptives. In men, reported cases of decreased sperm count and motility, possibly due to altered gonadotropin secretion. Reversible upon discontinuation. |
| Clinical Pearls | Monitor serum concentrations (target 10-20 mcg/mL); highly protein bound; narrow therapeutic index; fosphenytoin is preferred IV due to less infusion site reactions; induce CYP450 and vitamin D metabolism; risk of purple glove syndrome with IV extravasation; loading dose required for rapid achievement of therapeutic levels; dose adjustments needed in hepatic impairment; use with caution in porphyria. |
| Patient Advice | Take exactly as prescribed; do not stop abruptly to avoid withdrawal seizures. · Do not switch between brands or formulations without consulting your doctor. · Use reliable contraception as phenytoin can reduce the effectiveness of hormonal contraceptives. · Report any skin rash, fever, swollen glands, or mouth sores immediately (risk of Stevens-Johnson syndrome). · Avoid alcohol and limit vitamin D intake; ensure adequate folate supplementation. · Maintain good oral hygiene and regular dental checkups due to risk of gingival hyperplasia. · Phenytoin may cause dizziness or drowsiness; avoid driving until you know how it affects you. · Carry a medical alert ID indicating you take phenytoin. · Do not take antacids within 2 hours of phenytoin. |