Drug Interactions between nilotinib and voriconazole

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of nilotinib, which is primarily metabolized by the isoenzyme. In healthy subjects receiving the potent inhibitor ketoconazole (400 mg once daily for 6 days), nilotinib systemic exposure (AUC) was increased approximately 3-fold. Because nilotinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

MANAGEMENT: Concomitant use of nilotinib with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, posaconazole, voriconazole, conivaptan, nefazodone, cobicistat, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics should generally be avoided. Some authorities recommend avoiding concomitant use of nilotinib during and for 2 weeks after treatment with itraconazole. Should treatment with a potent inhibitor be required, the manufacturer recommends that nilotinib therapy be withheld temporarily. If concomitant use is unavoidable, a reduction of the nilotinib dosage to 400 mg once daily should be considered. Based on pharmacokinetic studies, this dosage is predicted to adjust the nilotinib systemic exposure (AUC) to the range observed without inhibitors. However, clinical data are lacking. Patients should have frequent ECGs and be monitored for arrhythmias when QT interval is prolonged. A QTc interval exceeding 480 msec will require suspension of nilotinib therapy and immediate action to correct any concomitant risk factors before resuming treatment. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. Following discontinuation of the potent CYP450 3A4 inhibitor, a washout period of approximately one week should be allowed before the nilotinib dosage is adjusted upward to the original dosage.

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