Summary

Phenytoin significantly reduces itraconazole plasma concentrations through CYP3A4 enzyme induction, potentially leading to treatment failure of fungal infections. This interaction requires careful monitoring and possible dose adjustments or alternative therapy selection.

Introduction

Itraconazole is a triazole antifungal medication used to treat various systemic and superficial fungal infections, including aspergillosis, candidiasis, and dermatophyte infections. It works by inhibiting fungal cytochrome P450 enzymes, particularly 14α-demethylase. Phenytoin is a hydantoin anticonvulsant primarily used for the treatment and prevention of seizures, including tonic-clonic and partial seizures. It stabilizes neuronal membranes by blocking voltage-dependent sodium channels.

Mechanism of Interaction

The interaction occurs through phenytoin's potent induction of hepatic cytochrome P450 enzymes, particularly CYP3A4, which is the primary enzyme responsible for itraconazole metabolism. Phenytoin increases the expression and activity of CYP3A4, leading to enhanced metabolism and clearance of itraconazole. This results in significantly reduced plasma concentrations of itraconazole and its active metabolite hydroxyitraconazole, potentially compromising antifungal efficacy.

Risks and Symptoms

The primary clinical risk is therapeutic failure of antifungal treatment due to subtherapeutic itraconazole concentrations. This can lead to persistent or recurrent fungal infections, treatment resistance, and potential progression to more severe systemic infections. Patients with serious fungal infections such as invasive aspergillosis or systemic candidiasis are at particular risk for poor outcomes. The interaction may also necessitate prolonged treatment courses or switching to alternative antifungal agents, potentially increasing healthcare costs and patient morbidity.

Management and Precautions

Monitor itraconazole plasma concentrations when used concurrently with phenytoin, with target trough levels typically >0.5-1.0 mg/L for most indications. Consider increasing itraconazole dose by 2-3 fold or switching to alternative antifungal agents such as voriconazole, posaconazole, or amphotericin B formulations. If phenytoin can be safely discontinued or replaced with a non-inducing anticonvulsant (such as levetiracetam or valproic acid), this may be preferred. Closely monitor clinical response and consider therapeutic drug monitoring for both medications. Consult infectious disease and neurology specialists when managing complex cases requiring both medications.

Itraconazole interactions with food and lifestyle

Itraconazole should be taken with food to enhance absorption and bioavailability. The capsule formulation requires an acidic environment for optimal absorption, so it should be taken with a full meal or acidic beverage. Avoid taking itraconazole with antacids, H2 blockers, or proton pump inhibitors as these reduce stomach acid and significantly decrease drug absorption. Grapefruit juice should be avoided as it can increase itraconazole levels and risk of side effects. Alcohol should be used with caution as both itraconazole and alcohol can affect liver function.

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.