Summary

Phenytoin and isavuconazole have a clinically significant drug interaction where phenytoin can substantially reduce isavuconazole plasma concentrations, potentially leading to treatment failure. This interaction occurs through phenytoin's induction of CYP3A4 enzymes, which increases isavuconazole metabolism.

Introduction

Phenytoin is a widely used anticonvulsant medication belonging to the hydantoin class, primarily prescribed for the treatment and prevention of seizures in epilepsy and other seizure disorders. It works by blocking voltage-gated sodium channels in neurons, stabilizing neuronal membranes and preventing abnormal electrical activity. Isavuconazole is a newer triazole antifungal agent used to treat serious invasive fungal infections, including invasive aspergillosis and mucormycosis. It functions by inhibiting the fungal enzyme 14α-demethylase, which is essential for ergosterol synthesis in fungal cell membranes.

Mechanism of Interaction

The interaction between phenytoin and isavuconazole occurs through enzyme induction mechanisms. Phenytoin is a potent inducer of cytochrome P450 enzymes, particularly CYP3A4, CYP2C9, and CYP2C19. Isavuconazole is primarily metabolized by CYP3A4 and to a lesser extent by other CYP enzymes. When phenytoin induces CYP3A4 expression, it significantly increases the metabolic clearance of isavuconazole, leading to reduced plasma concentrations and potentially subtherapeutic antifungal levels. This enzyme induction effect typically develops over several days to weeks of concurrent therapy and can persist for weeks after phenytoin discontinuation.

Risks and Symptoms

The primary clinical risk of this interaction is antifungal treatment failure due to subtherapeutic isavuconazole concentrations. Studies have shown that phenytoin can reduce isavuconazole exposure by approximately 90%, which may result in inadequate antifungal coverage and potential progression of invasive fungal infections. This is particularly concerning given that invasive fungal infections are often life-threatening conditions requiring optimal antifungal therapy. Additionally, treatment failure may lead to the development of antifungal resistance, prolonged hospitalization, increased healthcare costs, and potentially fatal outcomes in immunocompromised patients.

Management and Precautions

When concurrent use of phenytoin and isavuconazole is necessary, several management strategies should be considered. First, alternative anticonvulsants that do not significantly induce CYP3A4 (such as levetiracetam, lamotrigine, or valproic acid) should be evaluated if clinically appropriate. If phenytoin cannot be discontinued, alternative antifungal agents with different metabolic pathways, such as liposomal amphotericin B or echinocandins, may be preferred. If the combination must be used, close monitoring of clinical response and consideration of therapeutic drug monitoring for both medications is essential. Isavuconazole dose adjustments are generally not recommended due to the magnitude of the interaction, making alternative therapy the preferred approach.

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.

Isavuconazole interactions with food and lifestyle

Isavuconazole can be taken with or without food, as food does not significantly affect its absorption. However, patients should avoid excessive alcohol consumption while taking isavuconazole, as both substances are metabolized by the liver and concurrent use may increase the risk of liver toxicity. Additionally, patients should be cautious with grapefruit juice consumption, as it may potentially affect the metabolism of isavuconazole through CYP3A4 inhibition, though this interaction is not as well-established as with some other azole antifungals.