Drug Interaction Report

MONITOR: Itraconazole has been reported to inhibit the clearance of busulfan. The mechanism of interaction has not been established. Itraconazole is a potent inhibitor of the CYP450 3A4 isoenzyme and P-glycoprotein (P-gp) efflux transporter, although there is little evidence to suggest that busulfan is a substrate of either. In one study, mean busulfan clearance decreased by approximately 18% in bone marrow transplant patients who received itraconazole 6 mg/kg once daily compared to matched controls who did not receive itraconazole, resulting in 24% higher steady-state concentrations. The clinical significance of these changes is unknown. In contrast, patients who received fluconazole showed no difference in busulfan clearance relative to controls. Whether, or how, other azole antifungal agents may affect the clearance of busulfan is uncertain. In a study of 136 pediatric autologous bone marrow transplant patients who received high-dose busulfan as part of a conditioning regimen, concomitant ketoconazole therapy was identified as a risk factor for the development of hepatic veno-occlusive disease (HVOD). Since HVOD may be a concentration-dependent toxicity of busulfan, the study data would suggest a pharmacokinetic interaction with ketoconazole. No data are available for posaconazole or voriconazole, which are known inhibitors of CYP450 3A4 but not P-gp, although posaconazole is a substrate for P-gp.

MANAGEMENT: Patients prescribed busulfan with itraconazole or ketoconazole should be monitored for potentially increased myelotoxic, hepatotoxic, neurotoxic, and gastrointestinal toxic effects. Some experts also recommend the same precaution during coadministration with posaconazole or voriconazole, although clinical data are lacking.

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.