Drug Interactions between ivacaftor / lumacaftor and nilotinib

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of nilotinib, which is primarily metabolized by the isoenzyme. In healthy subjects receiving the potent inducer rifampin (600 mg once daily for 12 days), nilotinib systemic exposure (AUC) was decreased approximately 80%. Data are not available for nilotinib in combination with other, less potent CYP450 3A4 inducers.

MANAGEMENT: Concomitant use of nilotinib with potent CYP450 3A4 inducers should generally be avoided due to the potential for reduced efficacy. If coadministration is required, a dosage increase for nilotinib may be necessary depending on patient tolerability. The dosage should be reduced to the indicated dosage following discontinuation of the potent CYP450 3A4 inducer.

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MONITOR: Coadministration with inhibitors of CYP450 3A4 and/or P-glycoprotein may increase the plasma concentrations of nilotinib, which is a substrate of both the isoenzyme and the efflux transporter. 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. Data are not available for nilotinib in combination with other CYP450 3A4 or P-glycoprotein inhibitors. Theoretically, a reverse interaction may also occur, since many CYP450 3A4 and P-glycoprotein inhibitors are also substrates, and nilotinib is an inhibitor of both.

MANAGEMENT: Caution is advised if nilotinib is prescribed in combination with CYP450 3A4 and/or P-glycoprotein inhibitors. Pharmacologic response to nilotinib should be monitored more closely whenever a CYP450 3A4 or P-glycoprotein inhibitor is added to or withdrawn from therapy, and the nilotinib dosage adjusted as necessary. 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. Patients should also be monitored for altered efficacy and safety of the concomitant administered drug.

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