Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Effect of CYP3A inhibitors on belumosudil
The co-administration of multiple doses of itraconazole (a strong CYP3A inhibitor) did not alter exposure to belumosudil to any clinically relevant extent.

Effect of CYP3A inducers on belumosudil

The co-administration of multiple doses of rifampin (a strong CYP3A4 inducer) decreased belumosudil Cmax by 59% and AUC by 72%. The co-administration of strong CYP3A4 inducers with belumosudil may decrease belumosudil exposure. Increase the dose of belumosudil to 200 mg twice daily (see section 4.2).

The co-administration of moderate CYP3A4 inducers e.g., efavirenz is predicted to have a reduced effect on belumosudil as compared to strong CYP3A4 inducers. The co- administration of moderate CYP3A4 inducers with belumosudil may decrease belumosudil exposure. No dose adjustment is recommended.

Effect of proton pump inhibitors on belumosudil

The co-administration of multiple doses of rabeprazole decreased belumosudil Cmax by 87% and AUC by 80%. The co-administration of multiple doses of omeprazole decreased belumosudil Cmax by 68% and AUC by 47%. The co-administration of proton pump inhibitors with belumosudil may decrease belumosudil exposure. Increase the dose of belumosudil to 200 mg twice daily (see section 4.2).

Effect of other gastric acid reducing agents on belumosudil

The co-administration of belumosudil with gastric acid reducing agents other than proton pump inhibitors may decrease belumosudil exposure. No dose adjustment is recommended, however belumosudil and the gastric acid reducing agent should be taken 12 hours apart.

In vitro studies

Effect of belumosudil on CYP3A substrates
The co-administration of belumosudil is predicted to increase midazolam (a sensitive CYP3A substrate) Cmax and AUC approximately 1.3- and 1.5-fold, respectively. No dose adjustment is recommended.

The co-administration of belumosudil may increase exposure of sensitive CYP3A4 substrates with a narrow therapeutic index such as ciclosporin and tacrolimus. No dose adjustment is recommended.
Effect of belumosudil on CYP2C9 substrates

The co-administration of belumosudil is not expected to have clinically meaningful effect on the exposure of CYP2C9 substrates (such as warfarin).

Effect of belumosudil on CYP2C8 substrates

The co-administration of belumosudil is not expected to have clinically meaningful effect on the exposure of CYP2C8 substrates that are not an OATP1B1 substrate.

Effect of belumosudil on UGT1A1 substrates

Belumosudil is a weak inhibitor of UGT1A1, the clinical consequences are not known.
Transporters

Belumosudil is a substrate of P-gp. Belumosudil inhibits BCRP, P-gp, and OATP1B1. The co- administration of oral BCRP, P-gp and OATP1B1 substrates with belumosudil may increase the concentrations of the substrate drugs (such as digoxin and docetaxel).