Drug Interactions between amoxicillin / clarithromycin / omeprazole and dasatinib

GENERALLY AVOID: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations and pharmacologic effects of dasatinib, which is primarily metabolized by the isoenzyme. In a drug interaction study of 18 patients with solid tumors, coadministration of dasatinib (20 mg once a day) with the potent inhibitor ketoconazole (200 mg twice a day) increased the dasatinib peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 4- and 5-fold, respectively, compared to administration without ketoconazole. Because dasatinib prolongs the QT interval, high plasma levels of dasatinib may increase the risk of ventricular arrhythmias such as torsade de pointes and sudden death. Data are not available for dasatinib in combination with other CYP450 3A4 inhibitors.

MANAGEMENT: Concomitant use of dasatinib with potent CYP450 3A4 inhibitors should generally be avoided. Some authorities recommend avoiding concomitant use of dasatinib during and for 2 weeks after treatment with itraconazole. Close monitoring for toxicity (e.g., myelosuppression, bleeding complications, fluid retention, excessive slowing of heart rate or other conduction disturbances) and a reduction of dasatinib dosage to a range of 20 to 40 mg daily should be considered if there are no alternatives and concomitant use with these agents is necessary.

GENERALLY AVOID: Nonclinical data indicate that the solubility of dasatinib is pH-dependent. Therefore, long-term suppression of gastric acid secretion by H2-receptor antagonists or inhibitors of the proton pump (PPIs or potassium-competitive acid blockers [PCABs]) is likely to reduce dasatinib systemic exposure. In 24 healthy study subjects, administration of a 50 mg dose of dasatinib 10 hours after famotidine was associated with an approximately 60% reduction in dasatinib peak plasma concentration (Cmax) and systemic exposure (AUC). In 14 healthy study subjects, administration of a single 100 mg dose of dasatinib 22 hours following a 40 mg dose of omeprazole at steady state reduced the Cmax and AUC of dasatinib by over 40% each.

MANAGEMENT: Concomitant use of dasatinib with H2-receptor antagonists or inhibitors of the proton pump is not recommended. If gastric acidity management is necessary, antacids should be considered in place of these agents. However, patients treated with dasatinib should avoid taking antacids or oral medications that contain antacids (e.g., didanosine buffered tablets or pediatric oral solution) for at least two hours before and two hours after administration of dasatinib.

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.