fluconazole and phenytoin

Fluconazole inhibits CYP2C9 and CYP2C19, the cytochrome P450 enzymes primarily responsible for phenytoin metabolism. This inhibition reduces phenytoin clearance and increases its plasma concentration. In addition, phenytoin induces CYP3A4, which can increase fluconazole metabolism and slightly decrease fluconazole levels, but the predominant clinically relevant effect is the elevation of phenytoin concentrations.

Elevated phenytoin plasma concentrations can cause dose-related toxicity, including nystagmus, ataxia, confusion, and lethargy; severe intoxication may lead to seizures or coma. The interaction is clinically significant, particularly with higher fluconazole doses or prolonged therapy. Reduced fluconazole exposure may also impair antifungal efficacy, but this is less commonly of concern.

Monitor phenytoin plasma concentrations and clinical signs of toxicity when starting, stopping, or changing the dose of fluconazole. Consider reducing the phenytoin dose if toxicity develops, especially with high-dose or prolonged fluconazole use. Recheck phenytoin levels after any change in the antifungal regimen and adjust the dose accordingly. Antifungal response should also be monitored to ensure adequate efficacy.

This interaction is well documented in multiple case reports and pharmacokinetic studies, particularly with higher fluconazole doses. It is consistently listed in drug interaction databases and standard references.