Drug Interactions between fluconazole and fosphenytoin

MONITOR CLOSELY: The concomitant use of fluconazole may increase serum hydantoin levels and risk of hydantoin toxicity. The mechanism is inhibition of CYP450 2C9 and 2C19 hepatic metabolism. In 10 healthy male volunteers, a mean increase in phenytoin AUC of 88% (with a range of 16% to 247%) was observed after 4 days of phenytoin administration (200 mg orally per day for 3 days followed by 250 mg IV once) with fluconazole (200 mg orally per day for 16 days) compared to phenytoin administration alone. Repeated concomitant administration of phenytoin (250 mg IV) and fluconazole (200 mg) also resulted in increased phenytoin AUC24 and Cmin by 75% and 128%, respectively.

MANAGEMENT: Close clinical monitoring of patient response, tolerance, and serum hydantoin concentrations is recommended whenever fluconazole is added, discontinued, or the dose changed. Patients should be advised to notify their doctor if they experience symptoms of toxicity (drowsiness, visual disturbances, change in mental status, nausea, or ataxia). A reduction in hydantoin dosage may be necessary.