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Phenytoin (Diphenylhydantoin) - Clinical Guidelines

1. Drug Class & Position in Therapy

• Katzung's Basic & Clinical Pharmacology, 16th Ed., p. 651
• Goodman & Gilman's Pharmacological Basis of Therapeutics, p. 411

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2. Indications

• Absence seizures
• Juvenile myoclonic epilepsy (may worsen)
• Dravet syndrome (may worsen)
• Most idiopathic generalized epilepsies with absence component

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3. Mechanism of Action

• Voltage-dependent (greater effect when membrane is depolarized)
• Use-dependent (greater effect during high-frequency firing)

• Goodman & Gilman, p. 392; Tietz Textbook of Laboratory Medicine, 7th Ed., p. 1455

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4. Pharmacokinetics

Key Pharmacokinetic Principle - Zero-Order / Saturation Kinetics

• Small dose increases → disproportionately large rises in plasma concentration
• Risk of rapid, unpredictable toxicity with minor dose adjustments
• Steady-state may not be achieved - plasma levels continue to rise

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5. Therapeutic Drug Monitoring (TDM)

• 10 mcg/mL: 50% seizure response rate

• 15 mcg/mL: 86% seizure suppression

When to Measure Free Phenytoin

• Hypoalbuminemia (liver disease, nephrotic syndrome, malnutrition)
• Elderly (reduced albumin, altered protein binding)
• Neonates
• Renal failure (uremic displacement from protein)
• Co-administration of valproate (competes for binding + inhibits metabolism)
• Suspected toxicity with normal total levels

Corrected phenytoin = Measured phenytoin / [(0.2 × albumin g/dL) + 0.1]

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6. Dosing

Loading Dose (to achieve therapeutic levels rapidly)

• Loading dose ≈ 10-20 mg/L × 0.6 L/kg × 70 kg = 420-840 mg
• Standard IV loading dose: 15-20 mg/kg at a rate not exceeding 50 mg/min (to avoid cardiovascular toxicity)
• Oral loading: 1000 mg in 3 divided doses (400+300+300 mg given q2h) is safer if IV access not available

Maintenance Dosing

• Adults: 300-400 mg/day (4-7 mg/kg/day) in 1-3 divided doses
• Extended-release formulation allows once-daily dosing
• Titrate slowly given saturation kinetics - small increments near target level

IV Administration Rules

• Rate: ≤50 mg/min (≤25 mg/min in elderly/cardiac patients)
• Must be diluted in normal saline (NOT dextrose - precipitates)
• Monitor ECG and blood pressure during infusion
• Watch for "purple glove syndrome" (purplish-black discoloration + edema + pain distal to injection site)

Fosphenytoin (preferred IV/IM prodrug)

• Dosed in phenytoin equivalents (PE)
• Rate: up to 150 mg PE/min IV
• IM administration is reliable (unlike phenytoin)
• Lower incidence of purple glove syndrome and local tissue injury

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7. Adverse Effects

Dose-Related (concentration-dependent)

Chronic/Idiosyncratic Effects (not concentration-dependent)

• Gingival hyperplasia - occurs in ~20% of chronic users; not related to plasma level
• Hirsutism - cosmetically distressing, especially in young women
• Coarsening of facial features
• Peripheral neuropathy - reduced reflexes after years of use
• Osteomalacia/osteoporosis - via CYP induction of vitamin D metabolism
• Megaloblastic anemia - folate deficiency (especially with long-term use)
• Cerebellar atrophy - with long-term toxic levels
• Teratogenicity - "Fetal hydantoin syndrome" (cleft palate, cardiac defects, digit hypoplasia)

Hypersensitivity Reactions

• Maculopapular rash - 5-10%; discontinue immediately
• Steven-Johnson syndrome / toxic epidermal necrolysis (TEN) - rare but serious
• Drug reaction with eosinophilia and systemic symptoms (DRESS)
• HLA-B*15:02 allele (in Han Chinese, Thai, and other Asian populations) significantly increases risk of SJS/TEN - genetic screening recommended before use in these populations per the 2024 DPWG guideline (PMID: 38570725)
• HLA-B*15:02 also relevant for fosphenytoin
• Lupus-like syndrome
• Hepatotoxicity (rare)

IV-Specific (Phenytoin IV)

• Hypotension, bradycardia, cardiac arrhythmias (due to propylene glycol vehicle)
• Purple glove syndrome

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8. Drug Interactions

Drugs That INCREASE Phenytoin Levels (toxicity risk)

Drugs That DECREASE Phenytoin Levels (loss of seizure control)

Drugs Whose Levels Are REDUCED by Phenytoin (inducer effects)

• Oral contraceptives - reduced efficacy (use alternative contraception)
• Warfarin - initially increases, then decreases anticoagulation (complex)
• Corticosteroids
• Cyclosporine/tacrolimus
• Antiretrovirals (PIs, NNRTIs)
• Many chemotherapeutic agents
• Vitamin D - accelerated metabolism leading to osteomalacia
• Folate - reduced absorption/metabolism

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9. Special Populations

Pregnancy

• Category D teratogen - Fetal Hydantoin Syndrome: cleft lip/palate, congenital heart defects, digit/nail hypoplasia, growth restriction, cognitive impairment
• Use only if no safer alternative; supplement with folate 5 mg/day before conception
• Increased clearance during pregnancy - monitor levels closely; dose may need to increase
• Neonates: risk of coagulation defects (give vitamin K to mother before delivery)

Elderly

• Reduced albumin - monitor free phenytoin
• Reduced hepatic metabolism - lower starting doses
• Greater sensitivity to CNS effects

Renal Failure

• Reduced protein binding (uremic compounds displace from albumin)
• Total phenytoin levels are falsely low - must measure free levels
• No dose adjustment for renal clearance (primarily hepatic metabolism)

Hepatic Impairment

• Reduced metabolism and reduced albumin production
• Use with caution; monitor free levels

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10. Formulations

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11. Pharmacogenomics (2024 Guideline Update)

• CYP2C9 poor metabolizers: significantly elevated phenytoin exposure - start with lower doses, monitor closely
• HLA-B*15:02: Screen Asian patients before prescribing - high risk of SJS/TEN
• HLA-A*31:01: Associated with DRESS reaction across multiple ethnic groups

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12. Summary Table

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• Katzung's Basic and Clinical Pharmacology, 16th Edition, pp. 651-654
• Goodman & Gilman's Pharmacological Basis of Therapeutics, pp. 411-413
• Tietz Textbook of Laboratory Medicine, 7th Edition, pp. 1455-1457
• Goldman-Cecil Medicine, International Edition, pp. 257-258
• DPWG 2024 pharmacogenomics guideline: PMID 38570725 (CYP2C9/HLA-B phenytoin gene-drug interactions)