Drug Interactions between celecoxib / tramadol and ceritinib

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 celecoxib may increase the plasma concentrations of drugs that are substrates of the CYP450 2D6 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by celecoxib.

MANAGEMENT: Caution is advised if celecoxib must be used concurrently with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever celecoxib is added to or withdrawn from therapy.

MONITOR: Coadministration with inhibitors of CYP450 2C9 may increase the plasma concentrations of celecoxib, which is primarily metabolized by the isoenzyme. The possibility of prolonged and/or increased pharmacologic effects of celecoxib should be considered.

MANAGEMENT: Clinical monitoring for altered effects of celecoxib is recommended following initiation or discontinuation of a CYP450 2C9 inhibitor. Dosage adjustments may be required if an interaction is suspected. Patients should be advised to notify their physician if they experience potential signs and symptoms of celecoxib toxicity such as abdominal pain, black or tarry stools, nausea, vomiting, lethargy, fluid retention, swelling of legs, and worsening heart failure.