PHENYTOIN SODIUM

Clinical safety rating: avoid

Many drugs can increase or decrease phenytoin levels Can cause life-threatening dermatologic reactions like Stevens-Johnson syndrome.

How it works

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.

What the body does with it

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.

Classification & Brands

Action Class	Sodium channel modulators (AED)
Brand Substitutes	Fensant 100mg Injection, Epilet 100mg Injection, Epiwin 100mg Injection

Dosing & administration

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.

Use during pregnancy

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 reported M/P ratio of 0.18-0.45. Infant serum levels are typically subtherapeutic (<4 mcg/mL). Risk of adverse effects is low, but monitor infant for drowsiness, poor feeding, or rash. American Academy of Pediatrics considers compatible with breastfeeding.
Teratogenic Risk

Warnings & precautions

■ 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.

Side Effect Profile

Serious Effects

Absolute Contraindications

Hypersensitivity to hydantoins (including phenytoin, fosphenytoin, or ethotoin). History of prior acute hepatotoxicity with phenytoin. Sinus bradycardia, sinoatrial block, second- and third-degree AV block, or Adams-Stokes syndrome (IV formulation). Coadministration with delavirdine (reduces antiretroviral levels and increases phenytoin toxicity).

Clinical Precautions

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.

Clinical Tips & Counseling

Drug interactions

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PHENYTOIN SODIUM

Clinical safety rating: avoid

Many drugs can increase or decrease phenytoin levels Can cause life-threatening dermatologic reactions like Stevens-Johnson syndrome.

How it works

What the body does with it

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.

Classification & Brands

Action Class	Sodium channel modulators (AED)
Brand Substitutes	Fensant 100mg Injection, Epilet 100mg Injection, Epiwin 100mg Injection

Dosing & administration

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.

Use during pregnancy

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 reported M/P ratio of 0.18-0.45. Infant serum levels are typically subtherapeutic (<4 mcg/mL). Risk of adverse effects is low, but monitor infant for drowsiness, poor feeding, or rash. American Academy of Pediatrics considers compatible with breastfeeding.
Teratogenic Risk

Warnings & precautions

■ 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.