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 seizure disorders and prevent seizures following neurosurgery. It belongs to the hydantoin class of anticonvulsants and works by blocking voltage-gated sodium channels in neurons. Fluconazole is a triazole antifungal medication used to treat various fungal infections, including candidiasis, cryptococcal meningitis, and other systemic mycoses. 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. Studies have shown that fluconazole can increase phenytoin levels by 75-100%, with the effect being dose-dependent and more pronounced with higher fluconazole doses (≥200 mg daily).

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. In severe cases, patients may experience seizures paradoxically due to phenytoin toxicity. The interaction is considered clinically significant and can occur within 2-5 days of starting fluconazole therapy. Patients with baseline high phenytoin levels or those receiving higher fluconazole doses are at increased risk. The interaction may persist for several days after discontinuing fluconazole due to its long half-life and the time required for enzyme recovery.

Management and Precautions

When concurrent use is necessary, several management strategies should be implemented: 1) Monitor phenytoin serum levels closely, with baseline levels obtained before starting fluconazole and follow-up levels within 3-5 days; 2) Consider reducing phenytoin dose by 25-50% when initiating fluconazole therapy, particularly with doses ≥200 mg daily; 3) Monitor patients for signs and symptoms of phenytoin toxicity including neurological changes; 4) Consider alternative antifungal agents with less CYP450 inhibition potential, such as terbinafine or echinocandins, when clinically appropriate; 5) If fluconazole is discontinued, monitor for potential phenytoin level decreases and seizure breakthrough, as phenytoin doses may need to be increased back to previous levels; 6) Maintain therapeutic drug monitoring throughout the treatment course and for several days after fluconazole discontinuation.

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.