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Effect of other medicinal products on momelotinib: Momelotinib undergoes metabolism though multiple CYP enzymes (including CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP1A2) and aldehyde oxidase, with CYP3A4 having the greatest contribution.
Strong CYP3A4 inducers: Multiple doses of rifampicin (600 mg daily for 7 days) decreased momelotinib Cmax by 29.4% and AUCinf by 46.1% when compared with momelotinib (200 mg single dose) plus rifampicin single‑dose (600 mg), to capture the induction effect of rifampicin. Co-administration of strong CYP3A4 inducers may lead to decreased momelotinib exposure and consequently a risk for reduced efficacy. Therefore, additional monitoring of the clinical signs and symptoms of myelofibrosis is recommended with concomitant use of momelotinib and strong CYP3A4 inducers (including but not limited to carbamazepine, phenobarbital, phenytoin, and St John's wort [Hypericum perforatum]).
Multiple doses of rifampicin (600 mg daily for 7 days) did not change momelotinib Cmax and decreased momelotinib AUCinf by 15.3% when compared with momelotinib alone (200 mg single dose), capturing the combined effect of CYP3A4 induction and organic anion transporting peptide (OATP)1B1 and OATP1B3 inhibition. Momelotinib can be co-administered with rifampicin without a dose modification.
Transporters: Momelotinib is a substrate of OATP1B1 and OATP1B3 transporters. Co-administration with a single dose of rifampicin, capturing the OATP1B1/1B3 inhibition effect, moderately increased momelotinib exposure (Cmax by 40.4% and AUCinf by 57.1%). Therefore, caution and monitoring for adverse reactions is advised with concomitant use of OATP1B1/1B3 inhibitors, including ciclosporin.
Effect of momelotinib on other medicinal products: Transporters: Momelotinib is an inhibitor of BCRP in vitro. Co-administration of a single dose of rosuvastatin at 10 mg (a BCRP substrate) with multiple doses of momelotinib (200 mg once daily) increased rosuvastatin Cmax by 3.2-fold and AUC by 2.7-fold, which may increase the risk of adverse reactions of rosuvastatin. Tmax and t1/2 of rosuvastatin remained unchanged. Momelotinib may increase exposure to other sensitive BCRP substrates, including sulfasalazine.
Momelotinib may inhibit P-gp in the gut and increase exposure to P-gp substrates. Therefore, caution is advised when administering momelotinib with P-gp substrates with a narrow therapeutic index.
Momelotinib may inhibit organic cation transporter 1 (OCT1). The active metabolite of momelotinib, M21, may inhibit multidrug and toxic compound extrusion transporter 1 (MATE1). Momelotinib and M21 have not been evaluated for MATE2-K inhibition. Therefore, caution is advised when administering momelotinib with sensitive substrates of OCT1, MATE1 and MATE2-K (e.g., metformin).
CYP450 substrates: Momelotinib may induce CYP1A2 and CYP2B6 and may inhibit CYP2B6. Therefore, narrow therapeutic index or sensitive substrate medicinal products of CYP1A2 (e.g., theophylline, tizanidine) or CYP2B6 (e.g., cyclophosphamide) should be co-administered with momelotinib with caution.
Hormonal contraceptives: Multiple doses of momelotinib had no influence on the exposure of midazolam, a sensitive CYP3A substrate. However, a risk for induction of other pregnane X receptor (PXR) regulated enzymes apart from CYP3A4 cannot be completely excluded and the effectiveness of concomitant administration of oral contraceptives may be reduced (see Precautions and Pharmacology: Pharmacokinetics under Actions).
