Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on alectinib
Based on in vitro data, CYP3A4 is the primary enzyme mediating the metabolism of both alectinib and its major active metabolite M4, and CYP3A contributes to 40%  50% of total hepatic metabolism. M4 has shown similar in vitro potency and activity against ALK.

CYP3A inducers
Co-administration of multiple oral doses of 600 mg rifampicin once daily, a strong CYP3A inducer, with a single oral dose of 600 mg alectinib reduced alectinib Cmax, and AUCinf by 51% and 73% respectively and increased M4 Cmax and AUCinf 2.20 and 1.79-fold respectively. The effect on the combined exposure of alectinib and M4 was minor, reducing Cmax and AUCinf by 4% and 18%, respectively. Based on the effects on the combined exposure of alectinib and M4, no dose adjustments are required when Alecensa is co-administered with CYP3A inducers. Appropriate monitoring is recommended for patients taking concomitant strong CYP3A inducers (including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John’s Wort (Hypericum perforatum)).

CYP3A inhibitors
Co-administration of multiple oral doses of 400 mg posaconazole twice daily, a strong CYP3A inhibitor, with a single oral dose of 300 mg alectinib increased alectinib exposure Cmax and AUCinf by 1.18 and 1.75-fold respectively, and reduced M4 Cmax and AUCinf by 71% and 25% respectively. The effect on the combined exposure of alectinib and M4 was minor, reducing Cmax by 7% and increasing AUCinf 1.36-fold. Based on the effects on the combined exposure of alectinib and M4, no dose adjustments are required when Alecensa is co-administered with CYP3A inhibitors. Appropriate monitoring is recommended for patients taking concomitant strong CYP3A inhibitors (including, but not limited to, ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole nefazodone, grapefruit or Seville oranges).

Medicinal products that increase gastric pH
Multiple doses of esomeprazole, a proton pump inhibitor, 40 mg once daily, demonstrated no clinically relevant effect on the combined exposure of alectinib and M4. Therefore, no dose adjustments are required when Alecensa is co-administered with proton pump inhibitors or other medicinal products which raise gastric pH (e.g. H2 receptor antagonists or antacids).

Effect of transporters on alectinib disposition
M4 is a substrate of P-glycoprotein (P-gp). As alectinib inhibits P-gp, it is not expected that co-medication with P-gp inhibitors has a relevant effect on M4 exposure.

Effects of alectinib on other medicinal products

CYP substrates
In vitro, alectinib and M4 show weak time-dependent inhibition of CYP3A4, and alectinib exhibits a weak induction potential of CYP3A4 and CYP2B6 at clinical concentrations.

Multiple doses of 600 mg alectinib had no influence on the exposure of midazolam (2 mg), a sensitive CYP3A substrate. Therefore, no dose adjustment is required for co-administered CYP3A substrates.
A risk for induction of CYP2B6 and pregnane X receptor (PXR) regulated enzymes apart from CYP3A4 cannot be completely excluded. The effectiveness of concomitant administration of oral contraceptives may be reduced.

P-gp substrates
In vitro, alectinib and its major active metabolite M4 are inhibitors of the efflux transporter P-gp. Therefore, alectinib and M4 may have the potential to increase plasma concentrations of co-administered substrates of P-gp. When Alecensa is co-administered with P-gp substrates (e.g., digoxin, dabigatran etexilate, topotecan, sirolimus, everolimus, nilotinib and lapatinib), appropriate monitoring is recommended.

Breast cancer resistance protein (BCRP) substrates
In vitro, alectinib and M4 are inhibitors of the efflux transporter BCRP. Therefore, alectinib and M4 may have the potential to increase plasma concentrations of co-administered substrates of BCRP.
When Alecensa is co-administered with BCRP substrates (e.g., methotrexate, mitoxantrone, topotecan and lapatinib), appropriate monitoring is recommended.