DILANTIN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for DILANTIN (DILANTIN).
Phenytoin 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. It acts by blocking voltage-dependent sodium channels, thereby inhibiting the spread of seizure activity.
| Metabolism | Primarily metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19. Phenytoin exhibits saturable (Michaelis-Menten) pharmacokinetics with dose-dependent elimination. Major metabolite is 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH), which is glucuronidated and excreted in urine. |
| Excretion | Primarily hepatic metabolism to inactive metabolites (p-hydroxyphenyltoin and glucuronide conjugate). Less than 5% excreted unchanged in urine. Fecal excretion minimal (<2%). |
| Half-life | Average 22 hours (range 7-42 hours) in adults. Dose-dependent; increases with higher concentrations due to saturable metabolism. In neonates: 10-15 hours. In chronic use, half-life may increase. |
| Protein binding | 90-95% bound to albumin. Hypoalbuminemia or uremia can decrease binding, increasing free fraction. |
| Volume of Distribution | 0.6-0.8 L/kg. Reflects distribution into total body water and tissues; higher in neonates and children (up to 1 L/kg). |
| Bioavailability | Oral: 90-100% (capsules, chewable tablets). Extended-release: 85-95%. IM: poor and erratic; not for routine use. Suspension: 90-100% but absorption may be slower. |
| Onset of Action | IV: 0.5-1 hour (peak effect). Oral: 2-4 hours (therapeutic effect). IM: not recommended due to erratic absorption and tissue damage. |
| Duration of Action | 12-24 hours for seizure control after single dose; therapeutic effect persists with chronic dosing due to long half-life. |
| Action Class | Sodium channel modulators (AED) |
300–400 mg/day orally in 2–3 divided doses; IV loading dose 15–20 mg/kg at max 50 mg/min, then 300 mg/day IV divided 2–3 times daily.
| Dosage form | TABLET, CHEWABLE |
| Renal impairment | No dose adjustment required for GFR >10 mL/min. For GFR <10 mL/min, reduce dose by 25–50% and monitor levels. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 50%. Child-Pugh C: reduce dose by 75% or avoid use. |
| Pediatric use | Loading: 15–20 mg/kg IV. Maintenance: 5–10 mg/kg/day orally in 2–3 divided doses; max 300 mg/day. |
| Geriatric use | Start at 200 mg/day orally in 2 divided doses; titrate slowly; monitor free phenytoin levels (due to reduced albumin). |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for DILANTIN (DILANTIN).
| Breastfeeding | Phenytoin is excreted into breast milk in low concentrations. Milk-to-plasma (M/P) ratio is approximately 0.15-0.4. Exclusively breastfed infants receive about 1-5% of the maternal weight-adjusted dose. Adverse effects in infants are rare but may include sedation, poor feeding, or rash. Benefits of breastfeeding generally outweigh minimal risk, but monitor infant for drowsiness and adequate weight gain. |
| Teratogenic Risk | Phenytoin (DILANTIN) is classified as FDA Pregnancy Category D. First trimester exposure is associated with a 2-3 fold increased risk of major malformations, including orofacial clefts, congenital heart defects, and the fetal hydantoin syndrome (craniofacial dysmorphisms, nail hypoplasia, growth deficiency, neurodevelopmental delays). Second and third trimester exposure may cause decreased fetal growth, microcephaly, and cognitive deficits. Risk is dose-dependent and increased with polytherapy. |
■ FDA Black Box Warning
Intravenous administration of phenytoin may cause cardiovascular adverse reactions including severe hypotension and cardiac arrhythmias. Continuous monitoring of ECG and vital signs is required during IV administration. Parenteral phenytoin should not be given faster than 50 mg per minute in adults or 1-3 mg/kg per minute in neonates.
| Serious Effects |
["Hypersensitivity to phenytoin or any hydantoin product","Sinus bradycardia, sinoatrial block, second- or third-degree AV block, or Adam-Stokes syndrome (IV formulation)","Coadministration with delayirdine"]
| Precautions | ["Cardiovascular risk: hypotension, arrhythmias with IV administration","Neurological effects: sedation, ataxia, nystagmus, cognitive impairment","Hematological effects: agranulocytosis, thrombocytopenia, leukopenia","Dermatological reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS syndrome","Hepatic injury: acute hepatotoxicity, hepatitis","Teratogenicity: fetal hydantoin syndrome if used during pregnancy","Hyperglycemia, osteomalacia, lymphadenopathy","Supratherapeutic levels can cause toxicity; therapeutic monitoring required"] |
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| Fetal Monitoring | Monitor maternal phenytoin serum concentrations regularly (before and during pregnancy). Assess folate status and supplement with folic acid (0.4-5 mg/day) preconception and throughout pregnancy. Obtain maternal alpha-fetoprotein screening at 16-18 weeks. Perform targeted fetal ultrasound at 18-22 weeks for structural anomalies. Consider fetal echocardiogram. Monitor fetal growth by serial ultrasounds in third trimester. Monitor for neonatal bleeding and administer vitamin K (1 mg IM) at birth due to phenytoin-induced vitamin K deficiency. |
| Fertility Effects | Phenytoin may reduce fertility due to effects on sex hormones. It induces hepatic CYP450 enzymes, increasing clearance of estrogen and progesterone, potentially causing menstrual irregularities, amenorrhea, and ovulation dysfunction. This may impair fertility in women. In men, phenytoin may cause decreased sperm count and motility. Reversible upon discontinuation. |