Drug Interactions between phenytoin and Vfend

ADJUST DOSE: Coadministration of phenytoin and voriconazole may significantly reduce the plasma concentrations of voriconazole and increase the plasma concentrations of phenytoin. The mechanism involves phenytoin induction of voriconazole metabolism via CYP450 2C19, 2C9 and 3A4, and voriconazole inhibition of phenytoin metabolism via CYP450 2C9 and 2C19. In healthy male subjects, administration of voriconazole (200 mg orally every 12 hours) with phenytoin (300 mg once daily) for 14 days decreased the mean steady-state voriconazole peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 49% and 69%, respectively, compared to administration with placebo. Doubling the dosage of voriconazole and giving it with the same dosage of phenytoin for 7 days resulted in steady-state voriconazole Cmax and AUC that were comparable to those observed when voriconazole was administered alone at 200 mg twice daily or with placebo. However, in a case report of a 27-year-old woman receiving phenytoin 400 mg/day and voriconazole 400 mg orally twice daily for suspected central nervous system Aspergillus infection, the patient developed breakthrough oral candidiasis after six weeks of cotreatment. A dosage increase of voriconazole to 400 mg orally three times a day was required, whereupon the patient's condition stabilized and no toxicity was observed. Conversely, administration of phenytoin (300 mg once daily) with voriconazole (400 mg twice daily) for 10 days increased the mean Cmax and AUC of phenytoin by approximately 67% and 81%, respectively, compared to administration with placebo. The increases may be expected to be as high as two times the values observed when phenytoin is given without voriconazole. The combination was generally well tolerated in study patients, with most adverse effects classified as either mild or moderate.

MANAGEMENT: During concomitant therapy with phenytoin, the manufacturer recommends that maintenance dosage of voriconazole be increased from 4 mg/kg to 5 mg/kg every 12 hours when given intravenously, and from 200 mg to 400 mg every 12 hours when given orally (or from 100 mg to 200 mg every 12 hours in patients who weigh less than 40 kg). Frequent monitoring of plasma phenytoin levels and phenytoin-related adverse effects is recommended. Patients should be advised to contact their doctor if they experience symptoms of phenytoin toxicity such as nausea, vomiting, tremor, ataxia, lethargy, slurred speech, visual disturbances, and/or changes in mental status. Some experts also recommend monitoring plasma voriconazole levels, particularly in critically ill patients. Inadequate levels of voriconazole in the presence of phenytoin have been reported rarely, despite increasing voriconazole dosage as recommended. Additionally, measuring voriconazole levels following withdrawal of phenytoin can help to determine when to readjust voriconazole dosage.

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