Drug Interactions between Omeclamox-Pak and ponatinib

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of ponatinib, which is a substrate of the isoenzyme. In 22 healthy volunteers, administration of a single 15 mg oral dose of ponatinib in combination with the potent CYP450 3A4 inhibitor ketoconazole (400 mg daily) increased ponatinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 47% and 78%, respectively, compared to administration of ponatinib alone.

MANAGEMENT: Caution is recommended if concomitant use is required, and the dosage of ponatinib should be reduced according to the manufacturer's recommendations. Patients may be at increased risk for adverse effects such as thromboembolism, ischemia, congestive heart failure, hypertension, hepatotoxicity, pancreatitis, myelosuppression, hemorrhage, and fluid retention. Some authorities recommend that, following discontinuation and after an appropriate washout period of the CYP450 3A4 inhibitor (i.e., 3 to 5 half-lives), the ponatinib dosage taken prior to initiating the potent CYP450 3A4 inhibitor may be resumed (US).

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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.

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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.

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Coadministration with drugs that elevate the gastric pH such as proton pump inhibitors, H2-receptor antagonists, and antacids may decrease the oral bioavailability of ponatinib and reduce its concentrations in plasma. The aqueous solubility of ponatinib has been shown to be pH-dependent, with higher pH resulting in decreased solubility. However, in a drug interaction study in healthy volunteers, coadministration of ponatinib after multiple doses of lansoprazole resulted in a minor reduction in ponatinib Cmax but no change in overall systemic exposure (AUC) compared to ponatinib administered alone. Therefore, ponatinib may be coadministered with medicines that increase gastric pH without dose adjustment or separation of administration.

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