Drug Interactions between amoxicillin / clarithromycin / omeprazole and ceritinib

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of ceritinib, which is a substrate of the isoenzyme. In 19 healthy subjects, administration of a single 450 mg dose of ceritinib with the potent CYP450 3A4 inhibitor ketoconazole (200 mg twice daily for 14 days) increased ceritinib peak plasma concentration (Cmax) by 22% and systemic exposure (AUC) by 2.9-fold. The steady-state AUC of ceritinib at reduced doses after coadministration with ketoconazole 200 mg twice daily for 14 days was predicted by simulations to be similar to the steady-state AUC of ceritinib administered alone. Because ceritinib 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. Other, more common side effects such as diarrhea, nausea, vomiting, abdominal pain, hyperglycemia, and bradycardia may also increase.

MANAGEMENT: Concomitant use of ceritinib with potent CYP450 3A4 inhibitors should generally be avoided. Some authorities recommend avoiding concomitant use of ceritinib during and for 2 weeks after treatment with itraconazole. If coadministration is required, the manufacturer recommends a reduction of the ceritinib dosage by approximately one-third, rounded to the nearest 150 mg dosage strength. Patients should have periodic ECGs and be monitored for arrhythmias when QT interval is prolonged. A QTc interval exceeding 500 msec on at least two separate ECGs will require suspension of ceritinib therapy and immediate action to correct any concomitant risk factors before resuming treatment with a 150 mg dosage reduction. 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, ceritinib therapy should be resumed at the dosage that was taken prior to initiating the CYP450 3A4 inhibitor.

MONITOR: Drugs that alter the pH of the upper gastrointestinal tract may affect the solubility of ceritinib and reduce its bioavailability. The interaction has not been formally studied; however, the solubility of ceritinib has been found to be pH-dependent in vitro and the drug becomes poorly soluble as pH increases.

MANAGEMENT: Until more information is available, caution is advised if ceritinib is used with drugs that can alter the gastric pH such as proton pump inhibitors, H2-receptor antagonists, and antacids. The potential for diminished therapeutic effects of ceritinib should be considered, and pharmacologic response should be closely monitored.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.