Drug Interaction Report

CONTRAINDICATED: Coadministration with carbamazepine or long-acting barbiturates may significantly reduce the plasma concentrations of voriconazole. Although specific data are lacking, these agents are potent inducers of CYP450 isoenzymes that are responsible for the metabolic clearance of voriconazole and are expected to decrease the systemic exposure to voriconazole. Another potent CYP450 inducer, rifampin (600 mg once daily), decreased the steady-state peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of voriconazole (200 mg every 12 hours for 7 days) by an average of 93% and 96%, respectively, in healthy subjects. According to the manufacturer, doubling the dose of voriconazole did not restore adequate systemic exposure to voriconazole during coadministration with rifampin.

MANAGEMENT: The use of voriconazole with carbamazepine or long-acting barbiturates is considered contraindicated.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of carbamazepine. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

In a small, randomized, crossover study, the administration of carbamazepine with grapefruit juice (compared to water) increased plasma drug concentrations by approximately 40%. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients receiving carbamazepine should be advised to avoid or limit consumption of alcohol. Given the drug's narrow therapeutic index, patients receiving carbamazepine therapy should preferably avoid the regular consumption of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels. Patients should be advised to report signs of carbamazepine toxicity (nausea, visual disturbances, dizziness, or ataxia) to their physicians.

ADJUST DOSING INTERVAL: Food reduces the oral absorption and bioavailability of voriconazole. According to the product labeling, administration of multiple doses of voriconazole with high-fat meals decreased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) by 34% and 24%, respectively, when the drug is administered as a tablet, and by 58% and 37%, respectively, when administered as the oral suspension.

MANAGEMENT: To ensure maximal oral absorption, voriconazole tablets and oral suspension should be taken at least one hour before or after a meal.