Summary

Fluconazole significantly increases phenytoin blood levels by inhibiting its metabolism, potentially leading to phenytoin toxicity. This interaction requires careful monitoring and possible dose adjustments when these medications are used together.

Introduction

Phenytoin is an antiepileptic drug (AED) commonly used to treat seizures and prevent seizure recurrence. It belongs to the hydantoin class of anticonvulsants and works by blocking sodium channels in the brain. Fluconazole is a triazole antifungal medication used to treat various fungal infections, including candidiasis and cryptococcal infections. It works by inhibiting fungal cytochrome P450 enzymes, particularly 14α-demethylase, which is essential for ergosterol synthesis in fungal cell membranes.

Mechanism of Interaction

The interaction between phenytoin and fluconazole occurs through cytochrome P450 enzyme inhibition. Fluconazole is a potent inhibitor of CYP2C9 and CYP2C19 enzymes, which are primarily responsible for phenytoin metabolism. When fluconazole inhibits these enzymes, phenytoin clearance is significantly reduced, leading to increased plasma concentrations and prolonged half-life. This metabolic inhibition can result in phenytoin levels increasing by 75-100% or more, depending on the fluconazole dose and duration of therapy.

Risks and Symptoms

The primary risk of this interaction is phenytoin toxicity, which can manifest as neurological symptoms including ataxia, diplopia, nystagmus, confusion, slurred speech, and drowsiness. Severe toxicity may lead to coma or respiratory depression. Additionally, elevated phenytoin levels can cause cardiac arrhythmias, particularly in patients with underlying heart conditions. The interaction is dose-dependent, with higher fluconazole doses (≥200 mg daily) posing greater risk. Patients with pre-existing high phenytoin levels or those receiving maximum phenytoin doses are at increased risk for toxicity.

Management and Precautions

When concurrent use is necessary, phenytoin levels should be monitored closely, with baseline levels obtained before starting fluconazole. Consider reducing phenytoin dose by 25-50% when initiating fluconazole therapy, particularly with doses ≥200 mg daily. Monitor phenytoin serum concentrations within 3-5 days of starting fluconazole and adjust doses accordingly to maintain therapeutic levels (10-20 mg/L). Watch for signs of phenytoin toxicity throughout treatment. When discontinuing fluconazole, phenytoin levels may decrease, requiring dose increases to prevent breakthrough seizures. Alternative antifungal agents with less CYP450 inhibition, such as terbinafine or amphotericin B, should be considered when clinically appropriate.

Phenytoin interactions with food and lifestyle

Phenytoin has several important food and lifestyle interactions that patients should be aware of. Alcohol consumption can significantly affect phenytoin levels - chronic alcohol use may decrease phenytoin effectiveness by increasing metabolism, while acute alcohol intoxication can increase phenytoin levels and toxicity risk. Patients should discuss alcohol use with their healthcare provider. Enteral nutrition (tube feeding) can significantly reduce phenytoin absorption, requiring dosing adjustments and timing considerations. Folic acid supplementation may decrease phenytoin levels, as phenytoin can cause folate deficiency but supplementation can reduce drug effectiveness. Vitamin D supplementation may be necessary as phenytoin can cause vitamin D deficiency and bone problems. Smoking may increase phenytoin metabolism, potentially requiring dose adjustments. Patients should maintain consistent dietary habits and discuss any significant dietary changes with their healthcare provider, as phenytoin levels can be affected by nutritional status.

Fluconazole interactions with food and lifestyle

Fluconazole can be taken with or without food as food does not significantly affect its absorption. However, patients should avoid excessive alcohol consumption while taking fluconazole, as both substances can potentially affect liver function. While moderate alcohol intake is generally considered acceptable, patients with liver conditions or those taking fluconazole for extended periods should discuss alcohol use with their healthcare provider. No specific dietary restrictions are required with fluconazole therapy.