Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Effects of entrectinib on other medicinal products
Effect of entrectinib on CYP substrates
Entrectinib is a weak inhibitor of CYP3A4. Co-administration of entrectinib 600 mg once daily with oral midazolam (a sensitive CYP3A substrate) in patients increased the midazolam AUC by 50% but reduced midazolam Cmax by 21%. Caution is advised when entrectinib is administered together with sensitive CYP3A4 substrates with a narrow therapeutic range (e.g., cisapride, cyclosporin, ergotamine, fentanyl, pimozide, quinidine, tacrolimus, alfentanil and sirolimus), due to the increased risk of adverse drug reactions.

Effect of entrectinib on P-gp substrates
In vitro data suggest that entrectinib has inhibitory potential towards P-glycoprotein (P-gp).

Co-administration of a single 600 mg dose of entrectinib with digoxin (a sensitive P-gp substrate) increased digoxin Cmax by 28% and AUC by 18%. The renal clearance of digoxin was similar between treatments of digoxin alone and digoxin co-administered with entrectinib, indicating minimal effect of entrectinib on renal clearance of digoxin.

The effect of entrectinib on digoxin absorption is not considered clinically relevant, but it is unknown whether the effect of entrectinib may be larger on more sensitive oral P-gp substrates such as dabigatran etexilate.

Effect of entrectinib on BCRP substrates
Inhibition of BCRP was observed in in vitro studies.
The clinical relevance of this inhibition is unknown, but caution is advised when sensitive oral BCRP substrates (e.g. methotrexate, mitoxantrone, topotecan, lapatinib) are co-administered with entrectinib, due to the risk of increased absorption.

Effect of entrectinib on other transporter substrates
In vitro data indicate that entrectinib has weak inhibitory potential towards organic anion-transporting polypeptide (OATP)1B1. The clinical relevance of this inhibition is unknown, but caution is advised when sensitive oral OATP1B1 substrates (e.g. atorvastatin, pravastatin, rosuvastatin repaglinide, bosentan) are co-administered with entrectinib, due to the risk of increased absorption.



Effect of entrectinib on substrates of PXR regulated enzymes
In vitro studies indicate that entrectinib may induce pregnane X receptor (PXR) regulated enzymes (e.g. CYP2C family and UGT). Co-administration of entrectinib with CYP2C8, CYP2C9 or CYP2C19 substrates (e.g. repaglinide, warfarin, tolbutamide or omeprazole) may decrease their exposure.

Oral contraceptives
It is currently unknown whether entrectinib may reduce the effectiveness of systemically acting hormonal contraceptives. Therefore, women using systemically acting hormonal contraceptives are advised to add a barrier method (see section 4.6).

Effects of other medicinal products on entrectinib

Based on in vitro data, CYP3A4 is the predominant enzyme mediating the metabolism of entrectinib and formation of its major active metabolite M5.

Effect of CYP3A or P-gp inducers on entrectinib
Co-administration of multiple oral doses of rifampin, a strong CYP3A inducer, with a single oral dose of entrectinib reduced entrectinib AUCinf by 77% and Cmax by 56%.

Co-administration of entrectinib with CYP3A/P-gp inducers (including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, St. John's Wort -Hypericum perforatum-, apalutamide, ritonavir) should be avoided.

Effect of CYP3A or P-gp inhibitors on entrectinib
Co-administration of itraconazole, a strong CYP3A4 inhibitor, with a single oral dose of entrectinib increased AUCinf by 600% and Cmax by 173%.

Co-administration of strong and moderate CYP3A inhibitors (including, but not limited to, ritonavir, saquinavir, ketoconazole, itraconazole, voriconazole, posaconazole, grapefruit or Seville oranges) should be avoided. If concurrent use of strong or moderate inhibitors of CYP3A4 is unavoidable, dose adjustment of entrectinib is required (see section 4.2).

Although, a marked effect of inhibitory P-gp medicinal products on entrectinib pharmacokinetics is not expected, caution is advised when treatment with strong or moderate P-gp inhibitors (e.g.
verapamil, nifedipine, felodipine, fluvoxamine, paroxetine) are co-administered with entrectinib due to risk of increased entrectinib exposure (see section 5.2).

Effect of medicinal products that increase gastric pH on entrectinib
Co-administration of a proton pump inhibitor (PPI), lansoprazole with a single 600 mg entrectinib dose reduced entrectinib AUC by 25% and Cmax by 23%.

No dose adjustments are required when entrectinib is co-administered with PPIs or other drugs that raise gastric pH (e.g., H2 receptor antagonists or antacids).