What are the potential interactions with Phenytoin and how can they be managed?

Phenytoin Drug Interactions and Management

Key Interactions and Management Strategies

Phenytoin has numerous significant drug interactions that can affect its efficacy and safety. Careful monitoring of drug levels and appropriate dosage adjustments are essential to prevent treatment failure or toxicity.

Major Drug-Drug Interactions

Enzyme Inducers (Decrease Phenytoin Levels)

• Rifampin, carbamazepine, phenobarbital: Strong inducers that significantly decrease phenytoin plasma concentrations 1
• St. John's wort: Potent P-gp inducer that decreases phenytoin efficacy 1
• Other inducers: Rifabutin, oxcarbazepine, rifapentine, modafinil 1

Enzyme Inhibitors (Increase Phenytoin Levels)

• Azole antifungals, cimetidine, fluoxetine, fluvoxamine: Inhibit CYP2C9, increasing phenytoin levels 2
• Amiodarone, chloramphenicol, isoniazid: Significantly increase phenytoin levels 2
• Valproic acid: Displaces phenytoin from protein binding sites and inhibits metabolism 1

Medications Affected by Phenytoin

• Warfarin: Phenytoin increases warfarin metabolism, reducing anticoagulant effect 1
• Oral contraceptives: Reduced efficacy due to increased estrogen metabolism 1, 2
• Corticosteroids, doxycycline: Reduced efficacy due to increased metabolism 2

Biphasic Interactions

• Phenytoin-valproate: Valproate initially displaces phenytoin from protein binding sites (transiently increasing free phenytoin), then inhibits metabolism (increasing total phenytoin) 3
• Phenytoin-phenobarbital: Complex interaction with unpredictable effects on serum levels of both drugs 2

Monitoring and Management Approach

1. Baseline Assessment

• Obtain baseline phenytoin level before adding potentially interacting medications
• Target therapeutic range: 10-20 mcg/mL 4
• Consider free phenytoin levels in patients with hypoalbuminemia, renal failure, or when taking highly protein-bound drugs 5

2. Dose Adjustment Strategy

• When adding enzyme inducers: Increase phenytoin dose by 25-50% and monitor levels closely
• When adding enzyme inhibitors: Reduce phenytoin dose by 25-30% and monitor for toxicity
• For patients with subtherapeutic levels: Increase daily dose by approximately 100 mg 4
• For patients with levels near toxic range: Decrease dose by 30-50 mg/day 4

3. Monitoring Protocol

• Check phenytoin levels 7-10 days after any dose adjustment or addition of interacting medication 4
• Monitor more frequently in patients with risk factors (renal/hepatic impairment, multiple medications)
• Watch for clinical signs of toxicity: nystagmus, ataxia, slurred speech, confusion 2

Special Considerations

Hepatitis C Treatment

• Sofosbuvir-based regimens are contraindicated with phenytoin due to significant reduction in sofosbuvir levels 1
• Velpatasvir concentrations are significantly reduced by phenytoin, potentially causing treatment failure 1

Tuberculosis Treatment

• Rifampin: Significantly decreases phenytoin levels through enzyme induction 1, 5
• Isoniazid: Increases phenytoin levels by inhibiting metabolism 1
• When both drugs are used together, the net effect is unpredictable and requires close monitoring 5

Anticoagulant Therapy

• TMP-SMX in combination with phenytoin increases risk of phenytoin toxicity 1
• Phenytoin decreases warfarin efficacy by increasing its metabolism 1
• Monitor INR more frequently when starting, stopping, or adjusting phenytoin dose in patients on warfarin 1

Genetic Considerations

• HLA-B*15:02 testing is recommended before phenytoin use in patients of Asian ancestry due to increased risk of Stevens-Johnson syndrome 2, 6
• CYP2C9 genetic variants affect phenytoin metabolism and dosing requirements 6

Common Pitfalls and Caveats

• Protein binding displacement: Total phenytoin levels may decrease while free (active) levels remain therapeutic in patients taking valproate or with hypoalbuminemia 3
• Delayed effects: Some interactions may take 2-3 weeks to fully manifest due to phenytoin's long half-life 2
• Saturable metabolism: Small changes in dose can lead to disproportionate changes in serum levels due to phenytoin's non-linear pharmacokinetics 3
• Formulation differences: Different phenytoin products may have different bioavailability; maintain consistent formulation 2
• Enteral feeding: Can significantly reduce phenytoin absorption; separate administration times by at least 2 hours 2

Phenytoin's narrow therapeutic index and complex pharmacokinetics make it particularly susceptible to clinically significant drug interactions. Regular therapeutic drug monitoring and appropriate dose adjustments are essential for maintaining efficacy while avoiding toxicity when adding or removing interacting medications.