Drug Interactions between ceritinib and dexamethasone / moxifloxacin

MONITOR CLOSELY: Concomitant administration of corticosteroids may potentiate the risk of tendinitis and tendon rupture associated with fluoroquinolone treatment. The mechanism is unknown. Tendinitis and tendon rupture have most frequently involved the Achilles tendon, although cases involving the rotator cuff (the shoulder), the hand, the biceps, and the thumb have also been reported. Some have required surgical repair or resulted in prolonged disability. Tendon rupture can occur during or up to several months after completion of fluoroquinolone therapy.

MANAGEMENT: Caution is recommended if fluoroquinolones are prescribed in combination with corticosteroids, particularly in patients with other concomitant risk factors (e.g., age over 60 years; recipient of kidney, heart, and/or lung transplant). Patients should be advised to stop taking the fluoroquinolone, avoid exercise and use of the affected area, and promptly contact their physician if they experience pain, swelling, or inflammation of a tendon. In general, fluoroquinolones should only be used to treat conditions that are proven or strongly suspected to be caused by bacteria and only if the benefits outweigh the risks.

MONITOR CLOSELY: Ceritinib can cause concentration-dependent prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. Across the development program for ceritinib, one of 304 patients (less than 1%) treated with dosages ranging from 50 mg to 750 mg was found to have a QTc greater than 500 msec and 10 patients (3%) had an increase from baseline QTc greater than 60 msec. A central tendency analysis of the QTc data at average steady-state concentrations predicted a QTc increase of 16 msec at the 750 mg dose. A pharmacokinetic/pharmacodynamic analysis suggested concentration-dependent QTc prolongation. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia). Moreover, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is recommended if ceritinib is used in combination with other drugs that can prolong the QT interval. ECG and serum electrolytes, including potassium, magnesium and calcium, should be monitored before starting ceritinib therapy and periodically during treatment. Ceritinib should not be started if baseline QTc is greater than 500 msec. Likewise, treatment should be withheld in patients who develop a QTc interval greater than 500 msec on at least 2 separate ECGs until the QTc interval is less than 481 msec or recovery to baseline (if the QTc interval is greater than or equal to 481 msec), then resume ceritinib with a 150 mg dosage reduction. Permanently discontinue ceritinib therapy if QTc prolongation develops in combination with torsade de pointes or polymorphic ventricular tachycardia or signs and symptoms of serious arrhythmia. 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.

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of ceritinib, which is a substrate of the isoenzyme. In 19 healthy subjects, administration of a single 750 mg dose of ceritinib with the potent CYP450 3A4 inducer rifampin (600 mg daily for 14 days) decreased ceritinib peak plasma concentration (Cmax) by 44% and systemic exposure (AUC) by 70%. Data are not available for ceritinib in combination with other, less potent CYP450 3A4 inducers.

MANAGEMENT: Patients receiving ceritinib with CYP450 3A4 inducers should be monitored for potentially diminished pharmacologic response to ceritinib. Concomitant use should be avoided if an interaction is suspected.