Label: REZUROCK- belumosudil tablet
- NDC Code(s): 79802-200-30
- Packager: Kadmon Pharmaceuticals, LLC
- Category: HUMAN PRESCRIPTION DRUG LABEL
- DEA Schedule: None
- Marketing Status: New Drug Application
Drug Label Information
Updated January 8, 2025
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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: 2021INDICATIONS 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. (1)
DOSAGE FORMS AND STRENGTHS
Tablet: 200 mg. (3)
CONTRAINDICATIONS
None. (4)
WARNINGS AND PRECAUTIONS
ADVERSE REACTIONS
The most common (≥20%) adverse reactions, including laboratory abnormalities, are 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 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
- 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)
- Certain P-gp, OATP1B1, BCRP, and UGT1A1 substrates: Avoid concomitant use with these substrates for which minimal concentration changes may lead to serious toxicities. If coadministration cannot be avoided, decrease the substrates dosage(s) in accordance with the respective Prescribing Information. (7.2)
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 12/2024
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Table of Contents
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
2.2 Dosage Modifications for Adverse Reactions
2.3 Dosage Modification Due to Drug Interactions
2.4 Recommended Dosage in Patients with Hepatic Impairment
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Embryo-Fetal Toxicity
6 ADVERSE REACTIONS
6.1 Clinical Trial Experience
7 DRUG INTERACTIONS
7.1 Effect of Other Drugs on REZUROCK
7.2 Effect of REZUROCK on Other Drugs
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Chronic Graft versus Host Disease
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
- *
- Sections or subsections omitted from the full prescribing information are not listed.
- 1 INDICATIONS AND USAGE
-
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
The recommended dose of REZUROCK is 200 mg given orally once daily until progression of chronic GVHD that requires new systemic therapy.
Instruct the patient on the following:
- Swallow REZUROCK tablets whole. Do not cut, crush, or chew tablets.
- Take REZUROCK with a meal at approximately the same time each day [see Clinical Pharmacology (12.3)].
- If a dose of REZUROCK is missed, instruct the patient to not take extra doses to make up the missed dose.
Treatment with REZUROCK has not been studied in patients with pre-existing severe renal impairment. For patients with pre-existing severe renal impairment, consider the risks and potential benefits before initiating treatment with REZUROCK [see Clinical Pharmacology (12.3)].
2.2 Dosage Modifications for Adverse Reactions
Monitor total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) at least monthly.
Modify the REZUROCK dosage for adverse reactions as per Table 1.
Table 1: Recommended Dosage Modifications for REZUROCK for Adverse Reactions Adverse Reaction Severity* REZUROCK Dosage Modifications - *
- Based on CTCAE v 4.03
Hepatotoxicity [see Adverse Reactions (6.1)] Grade 3 AST or ALT (5× to 20× ULN) or Grade 2 bilirubin (1.5× to 3× ULN) Hold REZUROCK until recovery of bilirubin, AST and ALT to Grade 0–1, then resume REZUROCK at the recommended dose. Grade 4 AST or ALT (more than 20× ULN) or Grade ≥3 bilirubin (more than 3× ULN) Discontinue REZUROCK permanently. Other adverse reactions [see Adverse Reactions (6.1)] Grade 3 Hold REZUROCK until recovery to Grade 0–1, then resume REZUROCK at the recommended dose level. Grade 4 Discontinue REZUROCK permanently. 2.3 Dosage Modification Due to Drug Interactions
Strong CYP3A Inducers
Increase the dosage of REZUROCK to 200 mg twice daily when coadministered with strong CYP3A inducers [see Drug Interactions (7.1)].
Proton Pump Inhibitors
Increase the dosage of REZUROCK to 200 mg twice daily when coadministered with proton pump inhibitors [see Drug Interactions (7.1)].
2.4 Recommended Dosage in Patients with Hepatic Impairment
Avoid use in patients with moderate hepatic impairment (Child-Pugh B) or severe hepatic impairment (Child-Pugh C) without liver GVHD [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
No dosage adjustment is recommended when administering REZUROCK to patients with mild hepatic impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
- 3 DOSAGE FORMS AND STRENGTHS
- 4 CONTRAINDICATIONS
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5 WARNINGS AND PRECAUTIONS
5.1 Embryo-Fetal Toxicity
Based on findings in animals and its mechanism of action, REZUROCK can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of belumosudil to pregnant rats and rabbits during the period of organogenesis caused adverse developmental outcomes including embryo-fetal mortality and malformations at maternal exposures (AUC) less than those in patients at the recommended dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for one week after the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].
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6 ADVERSE REACTIONS
6.1 Clinical Trial Experience
Because clinical trials are conducted under widely variable conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice.
Chronic Graft versus Host Disease
In two clinical trials (Study KD025-213 and Study KD025-208), 83 adult patients with chronic GVHD were treated with REZUROCK 200 mg once daily [see Clinical Studies (14.1)]. The median duration of treatment was 9.2 months (range 0.5 to 44.7 months).
Fatal adverse reaction was reported in one patient with severe nausea, vomiting, diarrhea and multi-organ failure.
Permanent discontinuation of REZUROCK due to adverse reactions occurred in 18% of patients. The adverse reactions which resulted in permanent discontinuation of REZUROCK in >3% of patients included nausea (4%). Adverse reactions leading to dose interruption occurred in 29% of patients. The adverse reactions leading to dose interruption in ≥2% were infections (11%), diarrhea (4%), and asthenia, dyspnea, hemorrhage, hypotension, liver function test abnormal, nausea, pyrexia, edema, and renal failure with (2% each).
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.
Table 2 summarizes the nonlaboratory adverse reactions.
Table 2: Nonlaboratory Adverse Reactions in ≥10% Patients with Chronic GVHD Treated with REZUROCK Adverse Reaction REZUROCK
200 mg once daily
(N=83)All Grades (%) Grades 3–4 (%) - *
- infection with an unspecified pathogen includes acute sinusitis, device related infection, ear infection, folliculitis, gastroenteritis, gastrointestinal infection, hordeolum, infectious colitis, lung infection, skin infection, tooth infection, urinary tract infection, wound infection, upper respiratory tract infection, pneumonia, conjunctivitis, sinusitis, respiratory tract infection, bronchitis, sepsis, septic shock.
- †
- includes influenza, rhinovirus infection, gastroenteritis viral, viral upper respiratory tract infection, bronchitis viral, Epstein-Barr viremia, Epstein-Barr virus infection, parainfluenzae virus infection, Varicella zoster virus infection, viral infection.
- ‡
- includes cellulitis, Helicobacter infection, Staphylococcal bacteremia, catheter site cellulitis, Clostridium difficile colitis, Escherichia urinary tract infection, gastroenteritis Escherichia coli, Pseudomonas infection, urinary tract infection bacterial.
- §
- includes fatigue, asthenia, malaise.
- ¶
- includes edema peripheral, generalized edema, face edema, localized edema, edema.
- #
- includes nausea, vomiting.
- Þ
- includes abdominal pain, abdominal pain upper, abdominal pain lower.
- ß
- includes dyspnea, dyspnea exertional, apnea, orthopnea, sleep apnea syndrome.
- à
- includes cough, productive cough.
- è
- includes contusion, hematoma, epistaxis, increased tendency to bruise, conjunctival hemorrhage, hematochezia, mouth hemorrhage, catheter site hemorrhage, hematuria, hemothorax, purpura.
- ð
- includes pain in extremity, back pain, flank pain, limb discomfort, musculoskeletal chest pain, neck pain, musculoskeletal pain.
- ø
- includes headache, migraine.
- ý
- includes rash, rash maculo-papular, rash erythematous, rash generalized, dermatitis exfoliative.
- £
- includes pruritus, pruritus generalized.
Infections and infestations Infection (pathogen not specified)* 53 16 Viral infection† 19 4 Bacterial infection‡ 16 4 General disorders and administration site conditions Asthenia§ 46 4 Edema¶ 27 1 Pyrexia 18 1 Gastrointestinal Nausea# 42 4 Diarrhea 35 5 Abdominal painÞ 22 1 Dysphagia 16 0 Respiratory, thoracic and mediastinal Dyspneaß 33 5 Coughà 30 0 Nasal congestion 12 0 Vascular Hemorrhageè 23 5 Hypertension 21 7 Musculoskeletal and connective tissue Musculoskeletal painð 22 4 Muscle spasm 17 0 Arthralgia 15 2 Nervous system Headacheø 21 0 Metabolism and nutrition Decreased appetite 17 1 Skin and subcutaneous Rashý 12 0 Pruritus£ 11 0 Table 3 summarizes the laboratory abnormalities in REZUROCK.
Table 3: Selected Laboratory Abnormalities in Patients with Chronic GVHD Treated with REZUROCK REZUROCK
200 mg once dailyGrade 0–1
BaselineGrade 2–4
Max PostGrade 3–4
Max PostParameter (N) (%) (%) Chemistry Phosphate decreased 76 28 7 Gamma Glutamyl Transferase increased 47 21 11 Calcium decreased 82 12 1 Alkaline Phosphatase increased 80 9 0 Potassium increased 82 7 1 Alanine Aminotransferase increased 83 7 2 Creatinine increased 83 4 0 Hematology Lymphocytes decreased 62 29 13 Hemoglobin decreased 79 11 1 Platelets decreased 82 10 5 Neutrophil Count decreased 83 8 4 -
7 DRUG INTERACTIONS
7.1 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 [see Dosage and Administration (2.3)].
Proton Pump Inhibitors
Coadministration 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 coadministered with proton pump inhibitors [see Dosage and Administration (2.3)].
7.2 Effect of REZUROCK on Other Drugs
Certain UGT1A1 substrates
Avoid coadministration of REZUROCK with UGT1A1 substrates, for which minimal concentration changes may lead to serious toxicities. If coadministration cannot be avoided, decrease the UGT1A1 substrates dosage(s) in accordance with the respective Prescribing Information.
REZUROCK is an inhibitor of UGT1A1. Coadministration of REZUROCK with a UGT1A1 substrate decreased plasma concentrations of the glucuronide metabolite [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to sensitive substrates of UGT1A1.
Certain P-gp, OATP1B1, and BCRP substrates
Avoid coadministration of REZUROCK with P-gp, OATP1B1, and BCRP substrates, for which minimal concentration changes may lead to serious toxicities. If coadministration cannot be avoided, decrease the P-gp, OATP1B1, and BCRP substrates dosage(s) in accordance with the respective Prescribing Information.
REZUROCK is an inhibitor of P-gp, OATP1B1, and BCRP. Coadministration of REZUROCK with P-gp, OATP1B1, and BCRP substrates increased their plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates.
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8 USE IN SPECIFIC POPULATIONS
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.
8.2 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 one week after the last dose.
8.3 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 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.
Infertility
Females
Based on findings from rats, REZUROCK may impair female fertility [see Nonclinical Toxicology (13.1)].
Males
Based on findings from rats and dogs, REZUROCK may impair male fertility [see Nonclinical Toxicology (13.1)].
8.4 Pediatric Use
The safety and effectiveness of REZUROCK have been established in pediatric patients 12 years and older. Use of REZUROCK in this age group is supported by evidence from adequate and well-controlled studies of REZUROCK in adults with additional population pharmacokinetic data demonstrating that age and body weight had no clinically meaningful effect on the pharmacokinetics of drug substance, that the exposure of drug substance is expected to be similar between adults and pediatric patients age 12 years and older, and that the course of disease is sufficiently similar in adult and pediatric patients to allow extrapolation of data in adults to pediatric patients.
The safety and effectiveness of REZUROCK in pediatric patients less than 12 years old have not been established.
8.5 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.
8.6 Renal Impairment
Treatment with REZUROCK has not been studied in patients with pre-existing severe renal impairment. For patients with pre-existing severe renal impairment, consider the risks and potential benefits before initiating treatment with REZUROCK [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
Avoid use in patients with moderate hepatic impairment (Child-Pugh B) or severe hepatic impairment (Child-Pugh C) without liver GVHD [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A) [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
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11 DESCRIPTION
Belumosudil is a kinase inhibitor. The active pharmaceutical ingredient is belumosudil mesylate with the molecular formula C27H28N6O5S and the molecular weight is 548.62 g/mol. The chemical name for belumosudil mesylate is 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl) acetamide methanesulfonate (1:1). The chemical structure is as follows:
Belumosudil mesylate is a yellow powder that is practically insoluble in water, slightly soluble in methanol and DMF and soluble in DMSO.
REZUROCK tablets are for oral administration. Each tablet contains 200 mg of the free base equivalent to 242.5 mg of belumosudil mesylate. The tablet also contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, and microcrystalline cellulose.
The tablet film consists of polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide and yellow iron oxide.
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12 CLINICAL PHARMACOLOGY
12.1 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 down-regulated proinflammatory responses via regulation of STAT3/STAT5 phosphorylation and shifting Th17/Treg balance in ex-vivo or in vitro-human T cell assays. Belumosudil also inhibited aberrant pro-fibrotic signaling, in vitro. In vivo, belumosudil demonstrated activity in animal models of chronic GVHD.
12.2 Pharmacodynamics
Belumosudil exposure-response relationships and the time course of pharmacodynamic response are not established.
12.3 Pharmacokinetics
The following pharmacokinetic parameters are presented for chronic GVHD patients administered belumosudil 200 mg once daily, unless otherwise specified. The mean (% coefficient of variation, %CV) steady-state AUC and Cmax of belumosudil was 22,700 (48%) h∙ng/mL and 2390 (44%) ng/mL, respectively. Belumosudil Cmax and AUC increased in an approximately proportional manner over a dosage range of 200 and 400 mg (1 to 2 times once daily recommended dosage). The accumulation ratio of belumosudil was 1.4.
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 α1-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.
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.
Patients with Hepatic Impairment
Following a single 200 mg dose of belumosudil, changes in belumosudil exposure in subjects with varying degrees of hepatic impairment based on Child-Pugh score without liver GVHD relative to subjects with normal hepatic function is shown in Table 4.
Table 4: Effect of Varying Degrees of Hepatic Impairment on Belumosudil Exposure Hepatic Impairment Category Changes in Belumosudil Exposure in Subjects with Hepatic Impairment Compared to Subjects with Normal Hepatic Function Total (Free + Bound) Concentrations Free Concentrations Cmax AUC Cmax AUC Mild (Child-Pugh A) 1.2-fold increase 1.4-fold increase 14% decrease 19% decrease Moderate (Child-Pugh B) 6% decrease 1.5-fold increase 12% decrease 1.4-fold increase Severe (Child-Pugh C) 1.3-fold increase 4.2-fold increase 5.4-fold increase 16-fold increase 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.
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: Coadministration of belumosudil is not expected to have clinically meaningful effect on the exposure of CYP2C9 substrates (such as warfarin).
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13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Belumosudil did not result in any carcinogenic effect in a 6-month CByB6F1-Tg (HRAS)2Jic hemizygous mouse study at oral doses up to 15 mg/kg/day in female and 30 mg/kg/day in male mice.
Mutagenesis
Belumosudil was not genotoxic in an in vitro bacterial mutagenicity (Ames) assay, in vitro chromosome aberration assay in human peripheral blood lymphocytes (HPBL) or an in vivo rat bone marrow micronucleus assay.
Impairment of Fertility
In a combined male and female rat fertility and early embryonic development study, belumosudil-treated male animals were mated with untreated females, or untreated males were mated with belumosudil-treated females. Belumosudil was administered orally at doses of 50, 150 or 275 mg/kg/day to male rats 70 days prior to and throughout the mating period, and to female rats 14 days prior to mating and up to Gestation Day 7. At the dose of 275 mg/kg/day, adverse findings in female rats (treated with belumosudil or untreated but mated with treated males) regarding early embryonic development included increased pre- or post-implantation loss and decreased number of viable embryos. Administration of belumosudil to male rats at a dose of 275 mg/kg/day resulted in abnormal sperm findings (reduced motility, reduced count, and increased percentage of abnormal sperm), and testes/epididymis organ changes (reduced weight and degeneration). Fertility was reduced in both treated males or females at the 275 mg/kg/day dose and reached statistical significance in males. Adverse changes in male and female reproductive organs also occurred in general 3-month and 6-month toxicology studies. In males, findings included spermatozoa degeneration at a belumosudil dose of 50 mg/kg/day in rats and 35 mg/kg/day in dogs. The exposure (AUC) at the doses of 50 mg/kg/day in male rats and 35 mg/kg/day in male dogs is approximately equivalent to the clinical exposure at the recommended dose of 200 mg/day. Changes were reversible in dogs but not fully reversible in rats. In female rats, changes included decreased follicular development in ovaries and lower uterine weights that correlated with uterine/cervical hypoplasia at 275 mg/kg/day [corresponding to 9 times exposure in patients at the recommended dose of 200 mg/day]. Changes were fully reversed during the 4-week recovery period.
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14 CLINICAL STUDIES
14.1 Chronic Graft versus Host Disease
Study KD025-213 (NCT03640481) was a randomized, open-label, multicenter study of REZUROCK for treatment of patients with chronic GVHD who had received 2 to 5 prior lines of systemic therapy and required additional treatment. Patients were excluded from the studies if platelets were <50 × 109/L; absolute neutrophil count <1.5 × 109/L; AST or ALT >3 × ULN; total bilirubin >1.5 × ULN; QTc(F) >480 ms; eGFR <30 mL/min/1.73 m2; or FEV1 ≤39%. There were 66 patients treated with REZUROCK 200 mg taken orally once daily. Concomitant treatment with supportive care therapies for chronic GVHD was permitted. Concomitant treatment with GVHD prophylaxis and standard care systemic chronic GVHD therapies was permitted as long as the subject has been on a stable dose for at least 2 weeks prior to study. Initiation of new systemic chronic GVHD therapy while on study was not permitted.
Demographics and baseline characteristics are summarized in Table 5.
Table 5: Demographics and Baseline Characteristics of Patients with Chronic GVHD REZUROCK
200 mg once daily
(N=65)Age, Median, Years (minimum, maximum) 53 (21, 77) Age ≥65 Years, n (%) 17 (26) Male, n (%) 42 (65) Race, n (%) White 54 (83) Black 6 (9) Other or Not Reported 5 (8) Median (range) time (months) from Chronic GVHD Diagnosis 25.3 (1.9, 162.4) ≥4 Organs Involved, n (%) 31 (48) Median (range) Number of Prior Lines of Therapy 3 (2, 6) Number of Prior Lines of Therapy, n (%) 2 23 (35) 3 12 (19) 4 15 (23) ≥5 15 (23) Prior chronic GVHD treatment with ibrutinib, n (%) 21 (32) Prior chronic GVHD treatment with ruxolitinib, n (%) 20 (31) Refractory to Last Therapy, n (%*) 43/55 (78) Severe chronic GVHD, n (%) 46 (71) Median (range) Global Severity Rating 7 (2, 9) Median (range) Lee Symptom Scale Score at baseline 27 (7, 56) Median (range) Corticosteroid dose at baseline (PE/kg)† 0.19 (0.03, 0.95) The efficacy of REZUROCK was based on overall response rate (ORR) through Cycle 7 Day 1 where overall response included complete response or partial response according to the 2014 NIH Response Criteria. The ORR results are presented in Table 6. The ORR was 75% (95% CI: 63, 85). The median duration of response, calculated from first response to progression, death, or new systemic therapies for chronic GVHD, was 1.9 months (95% CI: 1.2, 2.9). The median time to first response was 1.8 months (95% CI: 1.0, 1.9). In patients who achieved response, no death or new systemic therapy initiation occurred in 62% (95% CI: 46, 74) of patients for at least 12 months since response.
Table 6: Overall Response Rate through Cycle 7 Day 1 for Patients with Chronic GVHD in Study KD025-213 REZUROCK
200 mg once daily
(N=65)- *
- Estimated using Clopper-Pearson method
Overall Response Rate (ORR) 49 (75%) 95% Confidence Interval* (63%, 85%) Complete Response 4 (6%) Partial Response 45 (69%) ORR results were supported by exploratory analyses of patient-reported symptom bother which showed at least a 7-point decrease in the Lee Symptom Scale summary score through Cycle 7 Day 1 in 52% (95% CI: 40, 65) of patients.
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16 HOW SUPPLIED/STORAGE AND HANDLING
REZUROCK 200 mg tablets are supplied as pale yellow film-coated oblong tablets containing 200 mg of belumosudil (equivalent to 242.5 mg belumosudil mesylate). Each tablet is debossed with "KDM" on one side and "200" on the other side and is packaged as follows:
- 200 mg tablets in 30 count bottle: NDC 79802-200-30
Store at room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Dispense to patient in original container only. Store in original container to protect from moisture. Replace cap securely each time after opening. Do not discard desiccant.
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17 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 [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)].
- Advise females of reproductive potential to use effective contraceptive during treatment with REZUROCK and for one week after the last dose [see Warnings and Precautions (5.1)].
- Advise males with female partners of reproductive potential to use effective contraceptive during treatment with REZUROCK and for one week after the last dose [see Use in Specific Populations (8.3)].
Lactation
- Advise women not to breastfeed during treatment with REZUROCK and for one week after the last dose [see Use in Specific Populations (8.2)].
Infertility
- Advise males and females of reproductive potential that REZUROCK may impair fertility [see Use in Specific Populations (8.3)].
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 [see Dosage and Administration (2.1)].
- 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 [see Dosage and Administration (2.1)].
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 [see Drug Interactions (7)].
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SPL UNCLASSIFIED SECTION
Distributed and marketed by:
Kadmon Pharmaceuticals, LLC
Bridgewater, NJ 08807
A SANOFI COMPANY
1-800-633-1610REZUROCK® is a registered trademark of Kadmon Pharmaceuticals, LLC.
© 2024 Kadmon Pharmaceuticals, LLC. All rights reserved.For patent information: https://www.sanofi.us/en/products-and-resources/patents
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PATIENT PACKAGE INSERT
This Patient Information has been approved by the U.S. Food and Drug Administration Issued: 12/2024 PATIENT INFORMATION
REZUROCK (REZ-ur-ok)
(belumosudil)
tabletsWhat is REZUROCK? REZUROCK is a prescription medicine used to treat adults and children 12 years of age and older with chronic graft-versus-host disease (chronic GVHD) after you have received at least 2 prior treatments (systemic therapy) and they did not work.
It is not known if REZUROCK is safe and effective in children less than 12 years old.Before taking REZUROCK, tell your healthcare provider about all of your medical conditions, including if you: - have kidney or liver problems.
- are pregnant or plan to become pregnant. REZUROCK can harm your unborn baby. If you are able to become pregnant, your healthcare provider will do a pregnancy test before starting treatment with REZUROCK. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with REZUROCK.
- Females who can become pregnant should use effective birth control during treatment with REZUROCK and for 1 week after the last dose.
- Males with female partners who can become pregnant should use effective birth control during treatment with REZUROCK and for 1 week after the last dose.
- are breastfeeding or plan to breastfeed. It is not known if REZUROCK passes into breast milk. Do not breastfeed during treatment with REZUROCK and for 1 week after the last dose.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.How should I take REZUROCK? - Take REZUROCK exactly as your healthcare provider tells you to take it.
- Do not change your dose or stop taking REZUROCK without first talking to your healthcare provider.
- Take REZUROCK 1 time a day with a meal.
- Take REZUROCK at about the same time each day.
- Swallow REZUROCK tablets whole with a glass of water.
- Do not cut, crush, or chew REZUROCK tablets.
- Your healthcare provider will do blood tests to check your liver at least 1 time a month during treatment with REZUROCK.
- If you miss a dose of REZUROCK, take it as soon as you remember on the same day. Take your next dose of REZUROCK at your regular time on the next day. Do not take extra doses of REZUROCK to make up for a missed dose.
- If you take too much REZUROCK, call your healthcare provider or go to the nearest hospital emergency room right away.
What are the possible side effects of REZUROCK?
The most common side effects of REZUROCK include:- infections
- tiredness or weakness
- nausea
- diarrhea
- shortness of breath
- cough
- swelling
- bleeding
- stomach (abdominal) pain
- muscle or bone pain
- headache
- high blood pressure
Your healthcare provider may change your dose of REZUROCK, temporarily stop, or permanently stop treatment with REZUROCK if you have certain side effects.
REZUROCK may affect fertility in males and females. Talk to your healthcare provider if this is a concern for you.
These are not all the possible side effects of REZUROCK.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Kadmon Pharmaceuticals, LLC at 1-800-633-1610.How should I store REZUROCK? - Store REZUROCK at room temperature between 68°F to 77°F (20°C to 25°C).
- Keep REZUROCK in its original container. The REZUROCK bottle contains a desiccant packet to help keep your tablets dry (protect from moisture). Keep the desiccant in the bottle.
- Tightly close the REZUROCK bottle after you take your dose.
General information about the safe and effective use of REZUROCK.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use REZUROCK for a condition for which it was not prescribed. Do not give REZUROCK to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about REZUROCK that is written for health professionals.What are the ingredients in REZUROCK?
Active ingredient: belumosudil mesylate
Inactive ingredients:
Tablet core: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, and microcrystalline cellulose.
Tablet coating: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide and yellow iron oxide.
Distributed and marketed by Kadmon Pharmaceuticals, LLC, Bridgewater, NJ 08807, A SANOFI COMPANY
REZUROCK® is a registered trademark of Kadmon Pharmaceuticals, LLC
© 2024 Kadmon Pharmaceuticals, LLC.
All rights reserved.
For more information, call 1-800-633-1610 or go to www.REZUROCK.com. - PRINCIPAL DISPLAY PANEL - 200 mg Tablet Bottle Carton
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INGREDIENTS AND APPEARANCE
REZUROCK
belumosudil tabletProduct Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:79802-200 Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BELUMOSUDIL (UNII: 834YJF89WO) (BELUMOSUDIL - UNII:834YJF89WO) BELUMOSUDIL 200 mg Inactive Ingredients Ingredient Name Strength MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) MAGNESIUM STEARATE (UNII: 70097M6I30) POLYVINYL ALCOHOL, UNSPECIFIED (UNII: 532B59J990) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A) TALC (UNII: 7SEV7J4R1U) FERRIC OXIDE YELLOW (UNII: EX438O2MRT) Product Characteristics Color yellow (Pale Yellow to Yellow) Score no score Shape OVAL Size 14mm Flavor Imprint Code KDM;200 Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:79802-200-30 1 in 1 CARTON 07/16/2021 1 30 in 1 BOTTLE; Type 0: Not a Combination Product Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA214783 07/16/2021 Labeler - Kadmon Pharmaceuticals, LLC (117510981) Establishment Name Address ID/FEI Business Operations Dr. Reddy's Laboratories Limited, CTO Unit-V1 650443430 api manufacture(79802-200) , pack(79802-200) , analysis(79802-200) Establishment Name Address ID/FEI Business Operations Catalent Micron 015966157 analysis(79802-200) Establishment Name Address ID/FEI Business Operations Gregory Pharmaceutical Holdings, Inc., dba UPM Pharmaceuticals 081301372 analysis(79802-200) , manufacture(79802-200) , pack(79802-200) , label(79802-200) Establishment Name Address ID/FEI Business Operations Daicel Chiral Technologies (I) Pvt. Ltd. 650645067 analysis(79802-200) Establishment Name Address ID/FEI Business Operations Carton Service Inc. (dba Pharma Packaging Solutions) 928861723 label(79802-200) , pack(79802-200)
