Interactions : אינטראקציות

4.5    Interaction with other medicinal products and other forms of interaction

In vitro studies indicate that sotorasib is metabolised by cytochrome P450 (CYP) 2C8, CYP3A4, and CYP3A5, and is a substrate of P-glycoprotein (P-gp). Sotorasib was an inducer of CYP3A4, CYP2B6, CYP2C8, CYP2C9, and CYP2C19 in vitro. Sotorasib is an in vitro inhibitor of CYP2C8, CYP2D6, and CYP3A. In vitro studies indicate that sotorasib is an inhibitor of human organic anion transporter (OAT)1/3, OATP1B1, Breast Cancer Resistance Protein (BCRP) and P-gp.

Effects of other medicinal products on sotorasib

Acid-reducing agents
Co-administration of sotorasib with a PPI (omeprazole) or an H2 receptor antagonist (famotidine) led to a decrease in sotorasib concentrations.

Under fed conditions (standard-calorie moderate-fat meals), co-administration of multiple doses of omeprazole with a single dose of 960 mg sotorasib decreased sotorasib Cmax by 65% and AUC by 57%. Co-administration of a single dose of famotidine given 10 hours prior and 2 hours after a single dose of 960 mg sotorasib decreased sotorasib Cmax by 35% and AUC by 38%.

Under fasted conditions, co-administration of multiple doses of omeprazole with a single dose of 960 mg sotorasib decreased sotorasib Cmax by 57% and AUC by 42%.

Co-administration of PPIs and H2 receptor antagonists with LUMYKRAS is not recommended because the impact on sotorasib efficacy is unknown. If treatment with an acid-reducing agent is required, LUMYKRAS should be taken 4 hours before or 10 hours after administration of a local antacid (see section 4.2).

Co-administration of multiple dose itraconazole (a strong CYP3A4 and P-gp inhibitor) did not increase sotorasib exposures to a clinically significant extent. No dose adjustment of LUMYKRAS is recommended when co-administered with CYP3A4 inhibitors.

Strong CYP3A4 inducers
Co-administration of sotorasib with multiple doses of a strong CYP3A4 inducer (rifampicin) decreased sotorasib Cmax by 35% and AUC by 51%. Co-administration of strong CYP3A4 inducers 
(e.g. rifampicin, carbamazepine, enzalutamide, mitotane, phenytoin and St. John’s wort) with LUMYKRAS is not recommended because they may decrease sotorasib exposure.

Effect of sotorasib on other medicinal products

CYP3A4 substrates
Sotorasib is a moderate CYP3A4 inducer. Co-administration of sotorasib with CYP3A4 substrates led to a decrease in their plasma concentrations, which may reduce the efficacy of these substrates.

Co-administration of sotorasib with midazolam (a sensitive CYP3A4 substrate) decreased midazolam Cmax by 48% and AUC by 53%.

Avoid co-administration of LUMYKRAS with CYP3A4 substrates with narrow therapeutic indices, including but not limited to alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, hormonal contraceptives, pimozide, quinidine, sirolimus and tacrolimus. If co-administration cannot be avoided, adjust the CYP3A4 substrate dose in accordance with the current summary of product characteristics.

CYP2B6, CYP2C8, CYP2C9 and CYP2C19 substrates
In vitro data indicated that sotorasib may have the potential to induce CYP2B6, CYP2C8, CYP2C9 and CYP2C19; the clinical relevance of these findings is unknown. When sotorasib is co-administered with medicinal products metabolised by these enzymes, appropriate monitoring is recommended.

CYP2D6 substrates
In vitro data indicated that sotorasib may have the potential to inhibit CYP2D6, the clinical relevance of these findings is unknown. When LUMYKRAS is co-administered with CYP2D6 substrates (e.g.
flecainide, propafenone, metoprolol), appropriate monitoring is recommended.

BCRP substrates
LUMYKRAS is a weak BCRP inhibitor. Co-administration of LUMYKRAS with a BCRP substrate led to an increase in the plasma concentrations of the BCRP substrate, which may increase the effect of the substrate.

Co-administration of LUMYKRAS with rosuvastatin (a BCRP substrate) increased the rosuvastatin Cmax by 70% and AUC by 34%.

When LUMYKRAS is co-administered with a BCRP substrates, including but not limited to lapatinib, methotrexate, mitoxantrone, rosuvastatin and topotecan, monitor for adverse reactions of the BCRP substrate and reduce the BCRP substrate dose in accordance with its current summary of product characteristics.

Effect of sotorasib on P-gp substrates
Co-administration of sotorasib with digoxin (a P-glycoprotein [P-gp] substrate) increased digoxin Cmax by 1.9-fold and AUCinf by 1.2-fold of digoxin administered alone. Co-administration of LUMYKRAS with P-gp substrates with narrow therapeutic indices is not recommended. If co-administration cannot be avoided, adjust the P-gp substrate dosage in accordance with the current summary of product characteristics.