Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Effects of other agents on larotrectinib
Effect of CYP3A, P-gp and BCRP inhibitors on larotrectinib
Larotrectinib is a substrate of cytochrome P450 (CYP) 3A, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Co-administration of VITRAKVI with strong or moderate CYP3A inhibitors, P-gp and BCRP inhibitors (e.g. atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole or grapefruit) may increase larotrectinib plasma concentrations (see section 4.2).
Clinical data in healthy adult subjects indicate that co-administration of a single 100 mg VITRAKVI dose with itraconazole (a strong CYP3A inhibitor and P-gp and BCRP inhibitor) 200 mg once daily for 7 days increased larotrectinib Cmax and AUC by 2.8-fold and 4.3-fold, respectively.
Clinical data in healthy adult subjects indicate that co-administration of a single 100 mg VITRAKVI dose with a single dose of 600 mg rifampin (a P-gp and BCRP inhibitor) increased larotrectinib Cmax and AUC by 1.8-fold and 1.7-fold, respectively.

Effect of CYP3A and P-gp inducers on larotrectinib
Co-administration of VITRAKVI with strong or moderate CYP3A inducers and strong P-gp inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, or St. John’s Wort) may decrease larotrectinib plasma concentrations and should be avoided (see section 4.4).
Clinical data in healthy adult subjects indicate that co-administration of a single 100 mg VITRAKVI dose with rifampin (a strong CYP3A and P-gp inducer) 600 mg once daily for 11 days decreased larotrectinib Cmax and AUC by 71% and 81%, respectively. No clinical data is available on the effect of a moderate inducer, but a decrease in larotrectinib exposure is expected.

Effects of larotrectinib on other agents

Effect of larotrectinib on CYP3A substrates
Clinical data in healthy adult subjects indicate that co-administration of VITRAKVI (100 mg twice daily for 10 days) increased the Cmax and AUC of oral midazolam 1.7-fold compared to midazolam alone, suggesting that larotrectinib is a weak inhibitor of CYP3A.
Exercise caution with concomitant use of CYP3A substrates with narrow therapeutic range (e.g.
alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, or tacrolimus) in patients taking VITRAKVI. If concomitant use of these CYP3A substrates with narrow therapeutic range is required in patients taking VITRAKVI, dose reductions of the CYP3A substrates may be required due to adverse reactions.


Effect of larotrectinib on CYP2B6 substrates
In vitro studies indicate that larotrectinib induces CYP2B6. Co-administration of larotrectinib with CYP2B6 substrates (e.g. bupropion, efavirenz) may decrease their exposure.

Effect of larotrectinib on other transporter substrates
In vitro studies indicate that larotrectinib is an inhibitor of OATP1B1. No clinical studies have been performed to investigate interactions with OATP1B1 substrates. Therefore, it cannot be excluded whether co-administration of larotrectinib with OATP1B1 substrates (e.g. valsartan, statins) may increase their exposure.

Effect of larotrectinib on substrates of PXR regulated enzymes
In vitro studies indicate that larotrectinib is a weak inducer of PXR regulated enzymes (e.g. CYP2C family and UGT). Co-administration of larotrectinib with CYP2C8, CYP2C9 or CYP2C19 substrates (e.g. repaglinide, warfarin, tolbutamide or omeprazole) may decrease their exposure.

Hormonal contraceptives
It is currently unknown whether larotrectinib may reduce the effectiveness of systemically acting hormonal contraceptives. Therefore, women using systemically acting hormonal contraceptives should be advised to add a barrier method.