DRUG INTERACTIONS

1 Effect of Other Drugs on REZUROCK Strong CYP3A Inducers-

Coadministration 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 coadministered with strong CYP3A inducers

Proton Pump Inhibitors-                                                                                    Coadministration of REZUROCK with proton pump inhibitors decreases belumosudil exposure , which may reduce the efficacy of REZUROCK.

Increase the dosage of REZUROCK when coadministered with proton pump inhibitors 

BRIEF SUMMARY

BELUMOSUDIL- (July 2021)

Indn-   to treat chronic graft-versus-host disease   after failure of systemic therapy                                                                                                                                     

Comp- Tablet: 200 mg.  Recommended Dosage: 200 mg taken orally once daily with food.

ADR-  the most common (= 20%) adverse reactions, including laboratory abnormalities, were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain.

CI-   None.

WARNINGS -

 Embryo-Fetal Toxicity:                                                                                                 Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.

Pat Inform-

Embryo-fetal Toxicity: • Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy 

• Advise females of reproductive potential to use effective contraceptive during treatment with and for at least one week after the last dose

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U.S.  APPROVED DRUGS SURING 2021                                     

Serial No 31

Name-        REZUROCK

Active  Ingredient -  Belumosudil

Pharmacological clssificiation-        To treat chronic graft-versus-host disease                                                                       after failure of systemic therapy                                                                                                                                                                                                                                                                                                                       Date of Approved-         7/16/2021

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                   REZUROCK safely and effectively.

See full prescribing information for REZUROCK. REZUROCK™ (belumosudil) tablets, for oral use

Initial U.S. Approval: 2021

INDICATIONS AND USAGE

 REZUROCK is a kinase inhibitor indicated for the treatment of adult and pediatric patients 12 years and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy.

ADVERSE REACTIONS -

 The most common (= 20%) adverse reactions, including laboratory abnormalities, were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, phosphate decreased, gamma glutamyl transferase increased, lymphocytes decreased, and hypertension.

CONTRAINDICATIONS-

 None.

WARNINGS AND PRECAUTIONS-

 Embryo-Fetal Toxicity:                                                                                                 Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.)

---ADVERSE REACTIONS ---------------------------- The most common (= 20%) adverse reactions, including laboratory abnormalities, were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, phosphate decreased, gamma glutamyl transferase increased, lymphocytes decreased, and hypertension. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Kadmon Pharmaceuticals, LLC at 1-877-377-7862 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -----------------------USE IN SPECIFIC POPULATIONS ---------------------- Lactation: Advise not to breastfeed. (8.2)

DOSAGE AND ADMINISTRATION

Recommended Dosage: 200 mg taken orally once daily with food.

DOSAGE FORMS AND STRENGTHS -

 Tablet: 200 mg. 

PATIENT COUNSELING INFORMATION-

 Advise the patient to read the FDA-approved patient labeling (Patient Information).

Embryo-fetal Toxicity: • Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy 

• Advise females of reproductive potential to use effective contraceptive during treatment with REZUROCK and for at least one week after the last dose

• Advise males with female partners of reproductive potential to use effective contraceptive during treatment with REZUROCK and for at least one week after the last dose

Lactation

• Advise women not to breastfeed during treatment with REZUROCK and for at least one week after the last dose 

Infertility                                                                                                                              • Advise males and females of reproductive potential that REZUROCK may impair fertility 

Administration                                                                                                                   • Inform patients to take REZUROCK orally once daily with food according to their physician's instructions and that the oral dosage (tablets) should be swallowed whole with a glass of water without cutting, crushing or chewing the tablets approximately the same time each day [

• Advise patients that in the event of a missed daily dose of REZUROCK, it should be taken as soon as possible on the same day with a return to the normal schedule the following day.

Patients should not take extra doses to make up the missed dose 

Drug Interactions

• Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products  Active ingredient made in India.

Distributed and marketed by: Kadmon Pharmaceuticals, LLC Warrendale, PA 15086 1-877-377-7862 REZUROCK™ is a trademark of Kadmon Pharmaceuticals, LLC. © 2021 Kadmon Pharmaceuticals, LLC, Warrendale, PA 15086. All rights reserved. 1

  CLINICAL PHARMACOLOGY

1. Mechanism of Action

Belumosudil is an inhibitor of rho-associated, coiled-coil containing protein kinase (ROCK) which inhibits ROCK2 and ROCK1 with IC50 values of approximately 100 nM and 3 µM, respectively.

 Belumosudil also inhibited aberrant pro-fibrotic signaling, in vitro. In vivo, belumosudil demonstrated activity in animal models of chronic GVHD.

2 Pharmacodynamics Belumosudil exposure-response relationships and the time course of pharmacodynamic response are not established.

3 Pharmacokinetics The following pharmacokinetic parameters are presented for chronic GVHD patients administered belumosudil 200 mg once daily, unless otherwise specified.

Absorption- Median Tmax of belumosudil at steady state was 1.26 to 2.53 hours following administration of 200 mg once daily or twice daily in patients.

The mean (%CV) bioavailability was 64% (17%) following a single belumosudil dose in healthy subjects.

Effect of Food Belumosudil Cmax and AUC increased 2.2 times and 2 times, respectively, following administration of a single belumosudil dose with a high-fat and high-calorie meal (800 to 1,000 calories with approximately 50% of total caloric content of the meal from fat) compared to the fasted state in healthy subjects. Median Tmax was delayed 0.5 hours.

Distribution- The geometric mean volume of distribution after a single dose of belumosudil in healthy subjects was 184 L (geo CV% 67.7%).

Belumosudil binding to human serum albumin and human a1-acid glycoprotein was 99.9% and 98.6%, respectively, in vitro.

Elimination The mean (%CV) elimination half-life of belumosudil was 19 hours (39%), and clearance was 9.83 L/hours (46%) in patients. Metabolism Belumosudil is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8, CYP2D6, and UGT1A9, in vitro.

Excretion Following a single oral dose of radiolabeled belumosudil in healthy subjects, 85% of radioactivity was recovered in feces (30% as unchanged) and less than 5% in urine.

Specific Populations No clinically significant differences in belumosudil pharmacokinetics were observed with regard to age (18 to 77 years), sex, weight (38.6 to 143 kg), or mild to moderate renal impairment (eGFR = 60 and < 90 mL/min/1.72m2 to eGFR = 30 and < 60 mL/min/1.72m2).

The effect of severe renal impairment on the pharmacokinetics of belumosudil has not been studied.

Drug Interaction Studies Clinical Studies and Model-Informed Approaches

Effects of Other Drugs on Belumosudil Strong Cytochrome P450 (CYP) 3A Inhibitors: There was no clinically meaningful effect on belumosudil exposure when coadministered with itraconazole in healthy subjects.

Strong CYP3A Inducers: Coadministration of rifampin decreased belumosudil Cmax by 59% and AUC by 72% in healthy subjects.

Proton Pump Inhibitors: Coadministration of rabeprazole decreased belumosudil Cmax by 87% and AUC by 80%, and omeprazole decreased belumosudil Cmax by 68% and AUC by 47% in healthy subjects.

Effects of Belumosudil on Other Drugs CYP3A Substrates: Coadministration of belumosudil is predicted to increase midazolam (a sensitive CYP3A substrate) Cmax and AUC approximately 1.3-and 1.5-fold, respectively. CYP2C9 Substrates:

CYP2C8 Substrates: Coadministration of belumosudil is not expected to have clinically meaningful effect on the exposure of CYP2C8 substrates that are not an OATP1B1 substrate.

In Vitro Studies Transporter Systems: Belumosudil is a substrate of P-gp. Belumosudil inhibits BCRP, P-gp, and OATP1B1 at clinically relevant concentrations.

USE IN SPECIFIC POPULATIONS

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.

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.

2 Lactation Risk Summary

There are no data available on the presence of belumosudil or its metabolites in human milk or the effects on the breastfed child, or milk production. Because of the potential for serious adverse reactions from belumosudil in the breastfed child, advise lactating women not to breastfeed during treatment with REZUROCK and for at least one week after the last dose. 

3 Females and Males of Reproductive Potential REZUROCK can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating treatment with REZUROCK.

Contraception Females Advise females of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose of REZUROCK. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus.

Males Advise males with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose of REZUROCK.

Infertility- Females Based on findings from rats, REZUROCK may impair female fertility. The effect on fertility is reversible.

Males Based on findings from rats and dogs, REZUROCK may impair male fertility. The effects on fertility are reversible

4 Pediatric Use The safety and effectiveness of REZUROCK have been established in pediatric patients 12 years and older.

The safety and effectiveness of REZUROCK in pediatric patients less than 12 years old have not been established.

5 Geriatric Use- Of the 186 patients with chronic GVHD in clinical studies of REZUROCK, 26% were 65 years and older. No clinically meaningful differences in safety or effectiveness of REZUROCK were observed in comparison to younger patients