PROMPT 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, thereby reducing repetitive firing of action potentials and inhibiting the spread of seizure activity.
| Metabolism | Primarily hepatic metabolism by CYP2C9 and CYP2C19; major metabolite is HPPA (5-(4-hydroxyphenyl)-5-phenylhydantoin) which is excreted in urine. Exhibits saturable (zero-order) pharmacokinetics at therapeutic concentrations. |
| Excretion | Primarily hepatic metabolism (CYP2C9) to inactive p-HPPH. Renal excretion as p-HPPH glucuronide (~60-70%) and unchanged drug (5%), with ~30% biliary/fecal elimination. |
| Half-life | 30-100 hours (average 40 hours) following IV administration; prolonged in hepatic impairment, neonates, and with enzyme inhibitors; shorter in children and with enzyme inducers. |
| Protein binding | 90-95% bound to albumin; saturable binding leads to nonlinear pharmacokinetics at higher concentrations. |
| Volume of Distribution | 0.5-0.8 L/kg (average 0.64 L/kg); crosses blood-brain barrier and placenta; distributes into cerebrospinal fluid (CSF). |
| Bioavailability | IV: 100%; Oral: 90-95% (phenytoin sodium capsules) with variable absorption depending on formulation; IM: 70-90% due to precipitation at injection site. |
| Onset of Action | IV: 10-30 minutes for anticonvulsant effect; IM: 30-60 minutes (faster than oral); Oral: 2-4 hours. |
| Duration of Action | IV: 12-24 hours; Oral: 12-24 hours; sustained due to long half-life; requires monitoring for toxicity. |
Loading dose: 15-20 mg/kg (max 1500 mg) IV at a rate not exceeding 50 mg/min. Maintenance dose: 300-600 mg/day IV or orally in 3 divided doses. Adjust per therapeutic drug monitoring (target total phenytoin 10-20 mcg/mL).
| Dosage form | CAPSULE |
| Renal impairment | For GFR <10 mL/min: reduce maintenance dose by 25-50% or use alternative; monitor free phenytoin levels. For dialysis: supplement 1-2 mg/kg IV post-dialysis; avoid loading doses. No adjustment for GFR >10 mL/min. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce maintenance dose by 25-50%. Child-Pugh C: reduce dose by 50-75% with close monitoring of free phenytoin levels. |
| Pediatric use | Loading dose: 15-20 mg/kg IV (max 1500 mg) at max rate 1-3 mg/kg/min (neonates 0.5-1 mg/kg/min). Maintenance: 5-10 mg/kg/day IV or orally in 2-3 divided doses; infants: 8-15 mg/kg/day; children: 4-8 mg/kg/day. Adjust per levels. |
| Geriatric use | Start with lower maintenance doses (e.g., 200-300 mg/day orally or IV) and increase slowly due to reduced protein binding and clearance. Monitor free phenytoin levels (target 1-2 mcg/mL). Avoid loading doses due to cardiac risks. |
| 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; M/P ratio is approximately 0.18-0.45. Concentrations in breast milk are low, and adverse effects in breastfed infants are rare. However, monitor for potential sedation, poor feeding, or rash. American Academy of Pediatrics considers phenytoin usually compatible with breastfeeding. |
| Teratogenic Risk |
■ FDA Black Box Warning
Intravenous administration: Must be administered continuously with ECG monitoring due to risk of cardiovascular collapse and severe hypotension; rate should not exceed 50 mg/min in adults. Central nervous system toxicity and cardiovascular collapse have occurred with too rapid IV administration.
| Common Effects | Gingival hyperplasia |
| Serious Effects |
Hypersensitivity to phenytoin or hydantoins; sinus bradycardia, sinoatrial block, second- and third-degree AV block, Adams-Stokes syndrome (IV form); concomitant use with delavirdine.
| Precautions | Risk of teratogenicity (fetal hydantoin syndrome); may cause exfoliative dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis); abrupt withdrawal may precipitate status epilepticus; may cause hypersensitivity reactions; caution in hepatic impairment, porphyria; monitor for nystagmus, ataxia, slurred speech as signs of toxicity; hyperglycemia; decreased bone mineral density; lymphadenopathy; drug interactions (e.g., warfarin, oral contraceptives). |
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| First trimester: Increased risk of major congenital malformations, including orofacial clefts, neural tube defects, congenital heart defects, and urogenital anomalies, known as fetal hydantoin syndrome. Second and third trimesters: Risk of intrauterine growth restriction, microcephaly, cognitive impairment, and bleeding disorders due to vitamin K deficiency. Risk of neonatal hemorrhage is increased. |
| Fetal Monitoring | Maternal: Serum phenytoin concentrations every 1-2 months, especially during the third trimester and postpartum; liver function tests, complete blood count, folate levels, and bleeding times. Fetal: Ultrasound for structural anomalies (e.g., neural tube defects, congenital heart defects) at 18-20 weeks; consider fetal echocardiogram. Neonatal: Monitor for withdrawal symptoms, bleeding (vitamin K prophylaxis recommended), and coagulopathy. |
| Fertility Effects | Phenytoin may affect fertility in both sexes. In women, it can cause menstrual irregularities, anovulation, and reduced fertility due to altered hormone metabolism. In men, reports of decreased libido, impotence, and reduced sperm count and motility, likely due to effects on sex hormone metabolism. |