Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on darolutamide

CYP3A4 and P-gp inducers
Darolutamide is a substrate of CYP3A4 and P-glycoprotein (P-gp).
Use of strong and moderate CYP3A4 inducers and P-gp inducers (e.g. carbamazepine, phenobarbital, St. John's Wort, phenytoin, and rifampicin) during treatment with darolutamide is not recommended, unless there is no therapeutic alternative. Selection of an alternate concomitant medicinal product, with no or weak potential to induce CYP3A4 or P-gp should be considered.
Repeated administration of rifampicin (600 mg), a strong CYP3A4 and a P-gp inducer, with a single dose of darolutamide (600 mg) together with food, resulted in a decrease of 72% in mean exposure (AUC0-72) and a decrease of 52% in Cmax of darolutamide.

CYP3A4, P-gp and BCRP inhibitors
Darolutamide is a substrate of CYP3A4, P-gp and breast cancer resistance protein (BCRP).
No clinically relevant drug-drug interaction is expected in case of CYP3A4, P-gp or BCRP inhibitor administration. Darolutamide may be given concomitantly with CYP3A4, P-gp or BCRP inhibitors.
Concomitant use of darolutamide with a combined P-gp and strong CYP3A4 inhibitor increases darolutamide exposure which may increase the risk of darolutamide adverse reactions. It is recommended to monitor patients more frequently for darolutamide adverse reactions and modify darolutamide dose as needed.
Administration of itraconazole (200 mg twice daily on day 1 and once daily on the following 7 days), a strong CYP3A4, P-gp and BCRP inhibitor, with a single dose of darolutamide (600 mg on day 5 together with food) resulted in a 1.7-fold increase in mean exposure (AUC0-72) and a 1.4-fold increase of Cmax of darolutamide.

UGT1A9 inhibitors
Darolutamide is a substrate of UGT1A9.
No clinically relevant drug-drug interaction is expected in case of UGT1A9 inhibitor administration.
Darolutamide may be given concomitantly with UGT1A9 inhibitors.
A population pharmacokinetic analysis showed that co-administration of UGT1A9 inhibitors with darolutamide resulted in a 1.2-fold increase in exposure (AUC0-72) of darolutamide.

Docetaxel
Administration of darolutamide in combination with docetaxel resulted in no clinically relevant changes in the pharmacokinetics of darolutamide in mHSPC patients (see section 5.1).

Effects of darolutamide on other medicinal products

BCRP, OATP1B1 and OATP1B3 substrates
Darolutamide is an inhibitor of breast cancer resistance protein (BCRP) and Organic Anion Transporting Polypeptides (OATP) 1B1 and 1B3.
Co-administration of rosuvastatin should be avoided unless there is no therapeutic alternative.
Selection of an alternative concomitant medicinal product with less potential to inhibit BCRP, OATP1B1 and OATP1B3 should be considered.
Administration of darolutamide (600 mg twice daily for 5 days) prior to co-administration of a single dose of rosuvastatin (5 mg) together with food resulted in approximately 5-fold increase in mean exposure (AUC) and Cmax of rosuvastatin.
Co-administration of darolutamide with other BCRP substrates should be avoided where possible.
Co-administration of darolutamide may increase the plasma concentrations of other concomitant BCRP, OATP1B1 and OATP1B3 substrates (e.g. methotrexate, sulfasalazine, fluvastatin, atorvastatin, pitavastatin). Therefore, it is recommended to monitor patients for adverse reactions of BCRP, OATP1B1 and OATP1B3 substrates. In addition, the related recommendation in the product information of these substrates should be followed when co-administered with darolutamide.


P-gp substrates
No clinically relevant drug-drug interaction is expected in case of P-gp substrate administration.
Darolutamide may be given concomitantly with P-gp substrates (e.g. digoxin, verapamil or nifedipine). Co-administration of darolutamide together with the sensitive P-gp substrate dabigatran etexilate did not reveal any increase in exposure (AUC and Cmax) of dabigatran.

CYP3A4 substrates
Darolutamide is a mild inducer of CYP3A4.
No clinically relevant drug-drug interaction is expected in case of CYP substrate administration.
Darolutamide may be given concomitantly with CYP substrates (e.g. warfarin, L-thyroxine, omeprazole).
Administration of darolutamide (600 mg twice daily for 9 days) prior to co-administration of a single dose of the sensitive CYP3A4 substrate midazolam (1 mg) together with food, decreased the mean exposure (AUC) and Cmax of midazolam by 29% and 32%, respectively.
Darolutamide did not inhibit the metabolism of selected CYP substrates in vitro at clinically relevant concentrations.

Docetaxel
Administration of darolutamide in combination with docetaxel resulted in no clinically relevant changes in the pharmacokinetics of docetaxel in mHSPC patients (see section 5.1).

Medicinal products that prolong the QT interval

Since androgen deprivation treatment may prolong the QT interval, the co-administration with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes should be carefully evaluated. These include medicinal products such as class IA (e.g., quinidine, disopyramide) or class III (e.g., amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, and antipsychotics (e.g. haloperidol).