Belumosudil

Strong CYP3A Inducers : Increase REZUROCK dosage to 200 mg twice daily. ( 7.1 , 2.3 ) Proton Pump Inhibitors : Increase REZUROCK dosage to 200 mg twice daily. ( 7.1 , 2.3 ) BCRP Substrates: Avoid concomitant use with drugs that are BCRP substrates where possible. If used together, monitor patients more frequently for adverse reactions and decrease the substrates dosage(s) in accordance with the respective Prescribing Information. ( 7.2 ) OATP1B1 Substrates: If used together, monitor patients more frequently for adverse reactions and decrease the substrates dosage(s) in accordance with the respective Prescribing Information.

( 7.2 ) Certain CYP1A2, CYP3A, P-gp or UGT1A1 Substrates : Avoid concomitant use with these substrates for which minimal concentration changes may lead to serious toxicities. If concomitant use cannot be avoided, decrease the substrates dosage(s) in accordance with the respective Prescribing Information. ( 7.2 )

7.1 Effect of Other Drugs on REZUROCK Proton Pump Inhibitors Belumosudil exhibits pH-dependent solubility. Concomitant use of REZUROCK with proton pump inhibitors decreases belumosudil exposure [see Clinical Pharmacology (12.3) ] , which may reduce the efficacy of REZUROCK. Increase the dosage of REZUROCK when used concomitantly with proton pump inhibitors [see Dosage and Administration (2.3) ]. Strong CYP3A Inducers Belumosudil is a CYP3A substrate. Concomitant use of REZUROCK with strong CYP3A inducers decreases belumosudil exposure [see Clinical Pharmacology (12.3) ] , which may reduce the efficacy of REZUROCK.

Increase the dosage of REZUROCK when used concomitantly with strong CYP3A inducers [see Dosage and Administration (2.3) ].

7.2 Effect of REZUROCK on Other Drugs BCRP and OATP1B1 Substrates Avoid concomitant use with drugs that are BCRP substrates where possible. If used together, monitor patients more frequently for adverse reactions and decrease the BCRP substrates dosage(s) in accordance with the respective Prescribing Information. Belumosudil is a BCRP inhibitor. Concomitant use of REZUROCK with BCRP substrates increases their plasma concentrations [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates. Belumosudil is an OATP1B1 inhibitor. Concomitant use of REZUROCK with OATP1B1 substrates may increase their plasma concentrations.

Monitor patients more frequently for adverse reactions of these substrates and decrease the OATP1B1 substrates dosage(s) in accordance with the respective Prescribing Information [see Clinical Pharmacology (12.3) ] . Certain CYP1A2 Substrates Avoid concomitant use of REZUROCK with drugs that are sensitive CYP1A2 substrates, for which minimal concentration changes may lead to serious toxicities. If concomitant use cannot be avoided, decrease the CYP1A2 substrate dosage(s) in accordance with the respective Prescribing Information. Belumosudil is a CYP1A2 inhibitor.

Concomitant use of REZUROCK with sensitive CYP1A2 substrates (e.g., caffeine) is predicted to increase CYP1A2 substrate exposure [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates. Certain CYP3A Substrates Avoid concomitant use of REZUROCK with drugs that are sensitive CYP3A substrates, for which minimal concentration changes may lead to serious toxicities. If concomitant use cannot be avoided, decrease the CYP3A substrate dosage(s) in accordance with the respective Prescribing Information. Belumosudil is a CYP3A inhibitor.

Concomitant use of REZUROCK with sensitive CYP3A substrates (e.g., midazolam) is predicted to increase CYP3A substrate exposure [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates. Certain UGT1A1 Substrates Avoid concomitant use of REZUROCK with drugs that are UGT1A1 substrates, for which minimal concentration changes may lead to serious toxicities. If concomitant use cannot be avoided, decrease the UGT1A1 substrates dosage(s) in accordance with the respective Prescribing Information. Belumosudil is a UGT1A1 inhibitor.

Concomitant use of REZUROCK with a UGT1A1 substrate decreased plasma concentrations of the glucuronide metabolite of the UGT1A1 substrate [see Clinical Pharmacology (12.3) ]. Concomitant use of belumosudil with other UGT1A1 substrates may increase their plasma concentrations, which may increase the risk of adverse reactions related to these substrates. Certain P-gp Substrates Avoid concomitant use of REZUROCK with drugs that are P-gp substrates, for which minimal concentration changes may lead to serious toxicities. If concomitant use cannot be avoided, decrease the P-gp substrates dosage(s) in accordance with the respective Prescribing Information. Belumosudil is a P-gp inhibitor.

Concomitant use of REZUROCK with P-gp substrates increased their plasma concentrations [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates.

8.1 Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action [see Clinical Pharmacology (12.1) ] , REZUROCK can cause fetal harm when administered to pregnant women. There are no available human data on REZUROCK use in pregnant women to evaluate for a drug-associated risk.

In animal reproduction studies, administration of belumosudil to pregnant rats and rabbits during the period of organogenesis resulted in adverse developmental outcomes, including alterations to growth, embryo-fetal mortality, and embryo-fetal malformations at maternal exposures (AUC) approximately ≥1.4 (rat) and ≥0.08 (rabbit) times the human exposure (AUC) at the recommended dose (see Data ) . Advise pregnant women and females of reproductive potential of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data Animal data Embryo-fetal development studies were conducted in rats with administration of belumosudil to pregnant animals during the period of organogenesis at oral doses of 25, 50, 150, and 300 mg/kg/day in a pilot study and doses of 15, 50, and 150 mg/kg/day in a pivotal study. In the pilot study, maternal toxicity and embryo-fetal developmental effects were observed. Maternal toxicity (reduced body weight gain) occurred at 150 and 300 mg/kg/day doses. Increased post-implantation loss occurred at 50 and 300 mg/kg/day. Fetal-malformations were observed at ≥50 mg/kg/day and included absence of anus and tail, omphalocele, and dome shaped head.

The exposure (AUC) at 50 mg/kg/day in rats is approximately 1.4 times the human exposure at the recommended dose of 200 mg. In an embryo-fetal developmental study in rabbits, pregnant animals administered oral doses of belumosudil at 50, 125, and 225 mg/kg/day during the period of organogenesis resulted in maternal toxicity and embryo-fetal developmental effects. Maternal toxicity (body weight loss and mortality) was observed at doses ≥125 mg/kg/day. Embryo-fetal effects were observed at doses ≥50 mg/kg/day and included spontaneous abortion, increased post-implantation loss, decreased percentage of live fetuses, malformations, and decreased fetal body weight.

Malformations included those in the tail (short), ribs (branched, fused or deformed), sternebrae (fused), and neural arches (fused, misaligned, and deformed). The exposure (AUC) at 50 mg/kg/day in rabbits is approximately 0.08 times the human exposure at the recommended dose of 200 mg.