Drug Interactions between amoxicillin / clarithromycin / omeprazole and sotorasib

GENERALLY AVOID: Coadministration with drugs that increase gastric pH may significantly decrease the oral bioavailability of sotorasib and reduce its concentrations in plasma. According to the product labeling, the aqueous solubility of sotorasib decreases from 1.3 mg/mL at pH 1.2 to 0.03 mg/mL at pH 6.8. When a single 960 mg dose of sotorasib was coadministered with multiple doses of the proton pump inhibitor omeprazole, sotorasib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 65% and 57%, respectively, under fed conditions, and by 57% and 42%, respectively, under fasted conditions. Coadministration of a single dose of the H2-receptor antagonist famotidine given 10 hours before and 2 hours after a single 960 mg dose of sotorasib under fed conditions decreased sotorasib Cmax by 35% and AUC by 38%. The interaction may similarly occur with other acid reducing or neutralizing agents, which may reduce the efficacy of sotorasib.

MANAGEMENT: Concomitant use of sotorasib with proton pump inhibitors, H2-receptor antagonists, or other acid reducing agents should generally be avoided. If acid suppression therapy is required, locally acting antacids may be considered. The manufacturer recommends taking sotorasib 4 hours before or 10 hours after administration of a locally acting antacid.

MONITOR: Coadministration with sotorasib may decrease the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The proposed mechanism is increased metabolic clearance due to induction of CYP450 3A4 by sotorasib. When midazolam, a sensitive CYP450 3A4 substrate, was coadministered with sotorasib, midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 48% and 53%, respectively. These results suggest moderate induction of CYP450 3A4 by sotorasib.

MANAGEMENT: Caution is advised when sotorasib is used concomitantly with drugs that are substrates of CYP450 3A4, particularly sensitive substrates or those with a narrow therapeutic range. The prescribing information recommends avoiding coadministration of sotorasib with CYP450 3A4 substrates for which minimal concentration changes may lead to therapeutic failure. If coadministration is required, dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever sotorasib is added to or withdrawn from therapy. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration of a moderate CYP450 3A4 inducer like sotorasib and for any dosage adjustments that may be required.

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.