Summary

Phenytoin significantly reduces voriconazole plasma concentrations through CYP enzyme induction, potentially leading to treatment failure of fungal infections. This interaction requires careful monitoring and possible alternative antifungal therapy.

Introduction

Voriconazole is a triazole antifungal medication used to treat serious invasive fungal infections, including aspergillosis and candidemia. It works by inhibiting fungal cytochrome P450 enzymes essential for ergosterol synthesis. Phenytoin is a first-generation anticonvulsant medication primarily used to treat epilepsy and seizure disorders. It belongs to the hydantoin class of antiepileptic drugs and works by blocking voltage-gated sodium channels in neurons.

Mechanism of Interaction

The interaction between voriconazole and phenytoin occurs through cytochrome P450 enzyme induction. Phenytoin is a potent inducer of CYP2C19, CYP2C9, and CYP3A4 enzymes, which are responsible for voriconazole metabolism. When phenytoin induces these enzymes, it significantly increases the clearance of voriconazole, leading to substantially reduced plasma concentrations. Studies have shown that phenytoin can decrease voriconazole concentrations by up to 70%, potentially compromising antifungal efficacy.

Risks and Symptoms

The primary clinical risk of this interaction is antifungal treatment failure due to subtherapeutic voriconazole levels. Reduced voriconazole concentrations may lead to inadequate treatment of serious fungal infections, potentially resulting in disease progression, increased morbidity, and mortality. Additionally, suboptimal antifungal levels may contribute to the development of antifungal resistance. The interaction is considered clinically significant and may occur within days of initiating phenytoin therapy in patients already receiving voriconazole.

Management and Precautions

Key management strategies include: 1) Consider alternative antifungal agents such as amphotericin B, caspofungin, or micafungin that are not significantly affected by phenytoin. 2) If voriconazole must be continued, increase the dose and monitor voriconazole plasma levels closely, targeting therapeutic concentrations of 1-5.5 mg/L. 3) Monitor clinical response and fungal culture results more frequently. 4) Consider alternative anticonvulsants such as levetiracetam or valproic acid if seizure control permits. 5) Consult with infectious disease specialists and neurologists for optimal management. 6) If phenytoin is discontinued, reduce voriconazole dose to prevent toxicity as enzyme induction reverses over 1-2 weeks.

Voriconazole interactions with food and lifestyle

Voriconazole should be taken on an empty stomach, at least 1 hour before or 2 hours after meals, as food significantly reduces absorption and bioavailability. High-fat meals can decrease voriconazole absorption by up to 22%. Patients should avoid grapefruit and grapefruit juice during treatment, as these can increase voriconazole blood levels and risk of toxicity. Alcohol consumption should be avoided or limited, as both voriconazole and alcohol are metabolized by the liver and concurrent use may increase the risk of liver toxicity. Patients should also avoid prolonged sun exposure and use adequate sun protection, as voriconazole can cause photosensitivity reactions and increase risk of skin cancer with long-term use.

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.