Drug Interactions between amoxicillin / clarithromycin / vonoprazan and mobocertinib

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of mobocertinib, which is primarily metabolized by the isoenzyme. Elevated plasma concentrations of mobocertinib may increase the risk for adverse effects such as QT prolongation, heart failure or reduced ejection fraction, cardiomyopathy, heart block, diarrhea, rash, stomatitis, fatigue, and musculoskeletal pain. The risk of QT prolongation in particular may be increased with concomitant use of potent CYP450 3A4 inhibitors that are also known to prolong the QT interval (e.g., adagrasib, ceritinib, clarithromycin, mifepristone, saquinavir, telithromycin, some azole antifungals). Based on drug interaction studies using model-informed approaches, coadministration of mobocertinib with repeated doses of the potent CYP450 3A4 inhibitors, itraconazole or ketoconazole, is predicted to increase the steady-state combined molar AUC (systemic exposure) of mobocertinib and its active metabolites by 374% to 419%.

MANAGEMENT: Concomitant use of mobocertinib with potent CYP450 3A4 inhibitors is not recommended.

GENERALLY AVOID: Coadministration with mobocertinib may decrease the plasma concentrations and therapeutic effects of drugs that are substrates of CYP450 3A4. The interaction may be significant for sensitive CYP450 3A4 substrates or those that demonstrate a narrow therapeutic index. The proposed mechanism is increased clearance due to mobocertinib-mediated induction of CYP450 3A4. Concomitant use of mobocertinib 160 mg once daily with oral or intravenous midazolam (a sensitive CYP450 3A4 substrate) decreased the midazolam systemic exposure (AUC) by 32% and 16%, respectively.

MANAGEMENT: Use of mobocertinib with sensitive CYP450 3A4 substrates or those that demonstrate a narrow therapeutic index (e.g., cisapride, ergot alkaloids, colchicine, fentanyl, macrolide immunosuppressants, midazolam, pimozide, triazolam, vinca alkaloids) should generally be avoided. If coadministration is required, patients should be monitored for diminished therapeutic effects. Clinical and laboratory monitoring should be considered whenever mobocertinib is added to or withdrawn from therapy with these drugs, and the dosage of the sensitive CYP450 3A4 substrate drug adjusted in accordance with the approved product label.

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.