Drug Interactions between amoxicillin / clarithromycin / vonoprazan and larotrectinib

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of larotrectinib, which is primarily metabolized by the isoenzyme. When a single 100 mg dose of larotrectinib was coadministered with the potent CYP450 3A4 inhibitor itraconazole (200 mg once daily for 7 days), larotrectinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2.8- and 4.3-fold, respectively, compared to administration of larotrectinib alone. Increased exposure to larotrectinib may increase the risk of adverse effects such as neurotoxicity (delirium, dysarthria, dizziness, gait disturbance, paresthesia, encephalopathy, memory impairment, tremor) and hepatotoxicity (elevations in liver transaminases).

MANAGEMENT: Concomitant use of larotrectinib with potent CYP450 3A4 inhibitors should generally be avoided. If coadministration is required, the manufacturer recommends reducing the larotrectinib dose by 50%. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, the larotrectinib dose that was taken prior to initiating the inhibitor may be resumed.

MONITOR: Coadministration with inhibitors of CYP450 3A4, P-glycoprotein (P-gp), and/or breast cancer resistance protein (BCRP) may increase the plasma concentrations of larotrectinib. According to the prescribing information, larotrectinib is metabolized primarily by the CYP450 3A4 isoenzyme and is a substrate of the P-gp and BCRP efflux transporters in vitro. When a single 100 mg dose of larotrectinib was coadministered with itraconazole (200 mg once daily for 7 days), a potent CYP450 3A4 inhibitor and P-gp/BCRP inhibitor, larotrectinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2.8- and 4.3-fold, respectively, compared to administration of larotrectinib alone. When a single 100 mg dose of larotrectinib was administered in healthy adult subjects with a single 600 mg dose of rifampin (a P-gp and BCRP inhibitor during initial use, but an inducer of CYP450 3A4 and P-gp following chronic use), larotrectinib Cmax and AUC increased by 1.8- and 1.7-fold, respectively. Coadministration with fluconazole, a moderate CYP450 3A4 inhibitor, is predicted to increase larotrectinib steady-state Cmax by 1.9-fold and AUC by 2.7-fold.

MANAGEMENT: Caution is advised when larotrectinib is used with CYP450 3A4, P-gp, and/or BCRP inhibitors. Patients should be monitored more frequently for adverse effects such as neurotoxicity (delirium, dysarthria, dizziness, gait disturbance, paraesthesia, encephalopathy, memory impairment, tremor) and hepatotoxicity (elevations in liver transaminases), and the larotrectinib dosage adjusted based on severity of emergent adverse reactions in accordance with the product labeling.

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.