Drug Interactions between amoxicillin / clarithromycin / omeprazole 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 larotrectinib may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. In study subjects, coadministration of midazolam, a sensitive CYP450 3A4 substrate, with larotrectinib 100 mg twice daily increased midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.7-fold each compared to administration of midazolam alone. The Cmax and AUC of 1-hydroxymidazolam, the main metabolite of midazolam, were both increased by 1.4-fold.

MANAGEMENT: Caution is advised when larotrectinib is used concomitantly with drugs that are substrates of CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever larotrectinib is added to or withdrawn from therapy. Patients should be monitored for the development of adverse effects. Some authorities recommend avoiding concomitant use of larotrectinib and sensitive CYP450 3A4 substrates or substrates with narrow therapeutic ranges. These drugs include, but are not limited to: alfentanil, cisapride, colchicine, cyclosporine, fentanyl, ivacaftor, lovastatin, simvastatin, oral midazolam, triazolam, pimozide, quinidine, sildenafil, ergot derivatives, macrolide immunosuppressants, and vinca alkaloids.

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.