Phenytoin - Drug Monograph

Introduction

Phenytoin is a widely used anticonvulsant medication that has been a cornerstone of epilepsy treatment since its approval by the FDA in 1938. As a hydantoin derivative, it represents one of the oldest and most extensively studied antiepileptic drugs in clinical practice. Phenytoin remains particularly valuable for managing acute seizures and providing long-term seizure prophylaxis in various epilepsy syndromes.

Mechanism of Action

Phenytoin exerts its anticonvulsant effects primarily through use-dependent blockade of voltage-gated sodium channels. The drug binds to these channels in their inactive state, stabilizing them and preventing recovery to the resting state. This mechanism reduces the ability of neurons to fire at high frequencies, thereby limiting the spread of seizure activity from epileptogenic foci without completely suppressing normal neuronal transmission. Additionally, phenytoin may modulate calcium channels and inhibit glutamate release while potentiating GABAergic inhibition.

Indications

• Treatment of generalized tonic-clonic seizures and complex partial seizures
• Prevention and treatment of seizures occurring during or following neurosurgery
• Management of status epilepticus (IV formulation)
• Prophylaxis of seizures following traumatic brain injury
• Off-label uses include: trigeminal neuralgia, certain cardiac arrhythmias, and migraine prophylaxis

Dosage and Administration

• Initial dose: 100 mg PO three times daily
• Maintenance: 300-400 mg/day (may be given once daily due to extended half-life)
• Loading dose: 15-20 mg/kg IV for status epilepticus

• Initial: 5 mg/kg/day in 2-3 divided doses
• Maintenance: 4-8 mg/kg/day

• Hepatic impairment: Reduce dose and monitor closely
• Renal impairment: Use caution; free phenytoin levels may be elevated
• Elderly: Lower doses may be required due to altered pharmacokinetics

• IV administration: Must not exceed 50 mg/min due to risk of cardiovascular collapse
• IM administration: Not recommended due to erratic absorption and precipitation at injection site
• Switching between formulations: Requires careful monitoring due to potential bioavailability differences

Pharmacokinetics

Contraindications

• Hypersensitivity to phenytoin, other hydantoins, or any component of the formulation
• Sinus bradycardia, sinoatrial block, second- or third-degree AV block
• Adams-Stokes syndrome
• History of prior acute hepatotoxicity due to phenytoin

Warnings and Precautions

• IV administration: Risk of serious cardiovascular events including hypotension and arrhythmias, especially at rapid infusion rates

• Withdrawal may precipitate status epilepticus
• Suicidal behavior and ideation
• Serious dermatologic reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis)
• Hematologic complications (agranulocytosis, pancytopenia)
• Hepatic injury and acute hepatic failure
• Teratogenicity and fetal harm
• Lymphadenopathy and pseudolymphoma
• Osteomalacia and decreased bone mineral density

Drug Interactions

• Warfarin: Increased anticoagulant effect
• Oral contraceptives: Reduced efficacy
• Cimetidine: Increased phenytoin levels
• Valproic acid: Complex interaction; both increased and decreased phenytoin levels possible
• Carbamazepine: Decreased phenytoin levels
• Phenobarbital: Variable effects
• Fluconazole, voriconazole: Increased phenytoin levels
• Rifampin: Decreased phenytoin levels
• Theophylline: Decreased theophylline levels
• Folic acid: Decreased phenytoin levels

Adverse Effects

• Nystagmus
• Ataxia
• Slurred speech
• Dizziness
• Drowsiness
• Gingival hyperplasia
• Coarsening of facial features

• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Drug reaction with eosinophilia and systemic symptoms (DRESS)
• Hepatic necrosis
• Blood dyscrasias
• Cerebellar atrophy
• Cardiovascular collapse (with rapid IV administration)
• Purple glove syndrome (with IV extravasation)

Monitoring Parameters

• Serum phenytoin levels (therapeutic range: 10-20 mcg/mL)
• CBC with differential (baseline and periodically)
• Liver function tests (baseline and periodically)
• Vitamin D levels and bone density (long-term therapy)
• Signs of hematologic, dermatologic, or hepatic toxicity
• Neurological examination for cerebellar signs
• Oral examination for gingival hyperplasia
• Free phenytoin levels in patients with renal impairment, hypoalbuminemia, or uremia

Patient Education

• Take consistently with regard to meals
• Do not abruptly discontinue medication
• Maintain good oral hygiene to minimize gingival hyperplasia
• Avoid alcohol consumption
• Use effective contraception (phenytoin reduces efficacy of hormonal contraceptives)
• Report any rash, fever, sore throat, easy bruising, or yellowing of skin/eyes immediately
• Be aware of potential cognitive effects when driving or operating machinery
• Carry medical identification indicating epilepsy diagnosis and medication use
• Regular dental checkups are essential
• Notify all healthcare providers of phenytoin use before any new prescriptions

References

1. Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013;54(3):551-563.

2. Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008;49(7):1239-1276.

3. FDA Prescribing Information: Dilantin (phenytoin). Accessed January 2023.

4. Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol. 2006;61(3):246-255.

5. Löscher W, Schmidt D. Epilepsy: perampanel—new promise for refractory epilepsy? Nat Rev Neurol. 2012;8(12):661-662.

6. McNamara JO. Pharmacotherapy of the epilepsies. In: Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics. 13th ed. McGraw-Hill; 2017.

7. Epilepsy Foundation. Treatment: Medications. Accessed January 2023.

8. American Epilepsy Society Guidelines. Evidence-based guideline: treatment of convulsive status epilepticus in children and adults. Epilepsy Currents. 2016;16(1):48-61.