ADVERSE REACTIONS SECTION.

6 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 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trial Experience. Because clinical trials are conducted under widely variable conditions, adverse reaction rates observed in clinical trials of 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 DiseaseIn 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 2summarizes the nonlaboratory adverse reactions. Table 2: Nonlaboratory Adverse Reactions in >=10% Patients with Chronic GVHD Treated with REZUROCKAdverse ReactionREZUROCK 200 mg once daily (N=83) All Grades (%)Grades 3-4 (%)Infections and infestationsInfection (pathogen not specified) 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. 5316Viral infection 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. 194Bacterial 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. 164General disorders and administration site conditionsAsthenia includes fatigue, asthenia, malaise. 464Edema includes edema peripheral, generalized edema, face edema, localized edema, edema. 271Pyrexia181GastrointestinalNausea includes nausea, vomiting. 424Diarrhea355Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower. 221Dysphagia160Respiratory, thoracic and mediastinalDyspnea includes dyspnea, dyspnea exertional, apnea, orthopnea, sleep apnea syndrome. 335Cough includes cough, productive cough. 300Nasal congestion120VascularHemorrhage includes contusion, hematoma, epistaxis, increased tendency to bruise, conjunctival hemorrhage, hematochezia, mouth hemorrhage, catheter site hemorrhage, hematuria, hemothorax, purpura. 235Hypertension217Musculoskeletal and connective tissueMusculoskeletal pain includes pain in extremity, back pain, flank pain, limb discomfort, musculoskeletal chest pain, neck pain, musculoskeletal pain. 224Muscle spasm170Arthralgia152Nervous systemHeadache includes headache, migraine. 210Metabolism and nutritionDecreased appetite171Skin and subcutaneousRash includes rash, rash maculo-papular, rash erythematous, rash generalized, dermatitis exfoliative. 120Pruritus includes pruritus, pruritus generalized. 110Table 3summarizes the laboratory abnormalities in REZUROCK. Table 3: Selected Laboratory Abnormalities in Patients with Chronic GVHD Treated with REZUROCKREZUROCK 200 mg once daily Grade 0-1 Baseline Grade 2-4 Max Post Grade 3-4 Max Post Parameter(N)(%)(%)ChemistryPhosphate decreased76287Gamma Glutamyl Transferase increased472111Calcium decreased82121Alkaline Phosphatase increased8090Potassium increased8271Alanine Aminotransferase increased8372Creatinine increased8340HematologyLymphocytes decreased622913Hemoglobin decreased79111Platelets decreased82105Neutrophil Count decreased8384.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisCarcinogenicity studies have not been conducted with belumosudil.. MutagenesisBelumosudil was not genotoxic in an in vitrobacterial mutagenicity (Ames) assay, in vitrochromosome aberration assay in human peripheral blood lymphocytes (HPBL) or an in vivorat bone marrow micronucleus assay. Impairment of FertilityIn combined male and female rat fertility 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) included increased pre- or post-implantation loss and decreased number of viable embryos. Administration of belumosudil to male rats at 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 toxicology studies; findings included spermatozoa degeneration at belumosudil dose of 35 mg/kg/day in dogs and decreased follicular development in ovaries at 275 mg/kg/day in rats. Changes were partially or fully reversed during the recovery period. The exposure (AUC) at the doses of 35 mg/kg/day in dogs, and 275 mg/kg/day in rats is 0.5 times and 8-9 times, respectively, the clinical exposure at the recommended dose of 200 mg daily.

CLINICAL PHARMACOLOGY SECTION.

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 IC 50values of approximately 100 nM and uM, respectively. Belumosudil down-regulated proinflammatory responses via regulation of STAT3/STAT5 phosphorylation and shifting Th17/Treg balance in ex-vivo or in vitro-human 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 maxof belumosudil was 22,700 (48%) hng/mL and 2390 (44%) ng/mL, respectively. Belumosudil maxand AUC increased in an approximately proportional manner over dosage range of 200 and 400 mg (1 to times once daily recommended dosage). The accumulation ratio of belumosudil was 1.4. AbsorptionMedian maxof 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 single belumosudil dose in healthy subjects. Effect of foodBelumosudil maxand AUC increased 2.2 times and times, respectively, following administration of single belumosudil dose with 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 maxwas delayed 0.5 hours. DistributionThe geometric mean volume of distribution after single dose of belumosudil in healthy subjects was 184 (geo CV% 67.7%).Belumosudil binding to human serum albumin and human 1-acid glycoprotein was 99.9% and 98.6%, respectively, in vitro. EliminationThe mean (%CV) elimination half-life of belumosudil was 19 hours (39%), and clearance was 9.83 L/hours (46%) in patients.. MetabolismBelumosudil is primarily metabolized by CYP3A4 and to lesser extent by CYP2C8, CYP2D6, and UGT1A9, in vitro.. ExcretionFollowing 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 PopulationsNo 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/1.72m 2to eGFR >=30 and <60 mL/min/1.72m 2). 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 maxby 59% and AUC by 72% in healthy subjects. Moderate CYP3A Inducers: Coadministration of efavirenz is predicted to decrease belumosudil maxby 32% and AUC by 35% in healthy subjects. Proton Pump Inhibitors: Coadministration of rabeprazole decreased belumosudil maxby 87% and AUC by 80%, and omeprazole decreased belumosudil maxby 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) maxand 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).. 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 Vitrostudies Transporter Systems: Belumosudil is substrate of P-gp. Belumosudil inhibits BCRP, P-gp, and OATP1B1 at clinically relevant concentrations. Enzymes Systems: Belumosudil is an inhibitor of CYP1A2, CYP2C19, CYP2D6, UGT1A1 and UGT1A9.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Chronic Graft versus Host Disease. Study KD025-213 (NCT03640481) was randomized, open-label, multicenter study of REZUROCK for treatment of patients with chronic GVHD who had received to prior lines of systemic therapy and required additional treatment. Patients were excluded from the studies if platelets were <50 10 9/L; absolute neutrophil count <1.5 10 9/L; AST or ALT >3 ULN; total bilirubin >1.5 ULN; QTc(F) >480 ms; eGFR <30 mL/min/1.73 2; 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 stable dose for at least 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 4. Table 4: Demographics and Baseline Characteristics of Patients with Chronic GVHDREZUROCK 200 mg once daily (N=65) Age, Median, Years (minimum, maximum)53 (21, 77) Age >=65 Years, (%)17 (26)Male, (%)42 (65)Race, (%) White54 (83) Black6 (9) Other or Not Reported5 (8)Median (range) time (months) from Chronic GVHD Diagnosis25.3 (1.9, 162.4)>=4 Organs Involved, (%)31 (48)Median (range) Number of Prior Lines of Therapy3 (2, 6)Number of Prior Lines of Therapy, (%) 223 (35) 312 (19) 415 (23) >=515 (23)Prior chronic GVHD treatment with ibrutinib, (%)21 (32)Prior chronic GVHD treatment with ruxolitinib, (%)20 (31)Refractory to Last Therapy, (% Denominator excludes patients with unknown status) 43/55 (78)Severe chronic GVHD, (%)46 (71)Median (range) Global Severity Rating7 (2, 9)Median (range) Lee Symptom Scale Score at baseline27 (7, 56)Median (range) Corticosteroid dose at baseline (PE/kg) Prednisone equivalents/kilogram 0.19 (0.03, 0.95)The efficacy of REZUROCK was based on overall response rate (ORR) through Cycle Day where overall response included complete response or partial response according to the 2014 NIH Response Criteria. The ORR results are presented in Table 5. 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 5: Overall Response Rate through Cycle Day for Patients with Chronic GVHD in Study KD025-213REZUROCK 200 mg once daily (N=65) Overall Response Rate (ORR)49 (75%)95% Confidence Interval Estimated using Clopper-Pearson method (63%, 85%) Complete Response4 (6%) Partial Response45 (69%)ORR results were supported by exploratory analyses of patient-reported symptom bother which showed at least 7-point decrease in the Lee Symptom Scale summary score through Cycle Day in 52% (95% CI: 40, 65) of patients.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trial Experience. Because clinical trials are conducted under widely variable conditions, adverse reaction rates observed in clinical trials of 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 DiseaseIn 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 2summarizes the nonlaboratory adverse reactions. Table 2: Nonlaboratory Adverse Reactions in >=10% Patients with Chronic GVHD Treated with REZUROCKAdverse ReactionREZUROCK 200 mg once daily (N=83) All Grades (%)Grades 3-4 (%)Infections and infestationsInfection (pathogen not specified) 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. 5316Viral infection 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. 194Bacterial 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. 164General disorders and administration site conditionsAsthenia includes fatigue, asthenia, malaise. 464Edema includes edema peripheral, generalized edema, face edema, localized edema, edema. 271Pyrexia181GastrointestinalNausea includes nausea, vomiting. 424Diarrhea355Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower. 221Dysphagia160Respiratory, thoracic and mediastinalDyspnea includes dyspnea, dyspnea exertional, apnea, orthopnea, sleep apnea syndrome. 335Cough includes cough, productive cough. 300Nasal congestion120VascularHemorrhage includes contusion, hematoma, epistaxis, increased tendency to bruise, conjunctival hemorrhage, hematochezia, mouth hemorrhage, catheter site hemorrhage, hematuria, hemothorax, purpura. 235Hypertension217Musculoskeletal and connective tissueMusculoskeletal pain includes pain in extremity, back pain, flank pain, limb discomfort, musculoskeletal chest pain, neck pain, musculoskeletal pain. 224Muscle spasm170Arthralgia152Nervous systemHeadache includes headache, migraine. 210Metabolism and nutritionDecreased appetite171Skin and subcutaneousRash includes rash, rash maculo-papular, rash erythematous, rash generalized, dermatitis exfoliative. 120Pruritus includes pruritus, pruritus generalized. 110Table 3summarizes the laboratory abnormalities in REZUROCK. Table 3: Selected Laboratory Abnormalities in Patients with Chronic GVHD Treated with REZUROCKREZUROCK 200 mg once daily Grade 0-1 Baseline Grade 2-4 Max Post Grade 3-4 Max Post Parameter(N)(%)(%)ChemistryPhosphate decreased76287Gamma Glutamyl Transferase increased472111Calcium decreased82121Alkaline Phosphatase increased8090Potassium increased8271Alanine Aminotransferase increased8372Creatinine increased8340HematologyLymphocytes decreased622913Hemoglobin decreased79111Platelets decreased82105Neutrophil Count decreased8384.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended Dosage: 200 mg taken orally once daily with food. 2.1) 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 meal at approximately the same time each day [see Clinical Pharmacology (12.3)] If 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 or hepatic impairment. For patients with pre-existing severe renal or hepatic impairment, consider the risks and potential benefits before initiating treatment with REZUROCK [see Clinical Pharmacology (12.3)] . Swallow REZUROCK tablets whole. Do not cut, crush, or chew tablets.. Take REZUROCK with meal at approximately the same time each day [see Clinical Pharmacology (12.3)] . If dose of REZUROCK is missed, instruct the patient to not take extra doses to make up the missed dose.. 2.2 Dose 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 ReactionsAdverse ReactionSeverity Based on CTCAE 4.03 REZUROCK Dosage ModificationsHepatotoxicity [see Adverse Reactions (6.1)] Grade AST or ALT (5x to 20x ULN) or Grade bilirubin (1.5x to 3x ULN)Hold REZUROCK until recovery of bilirubin, AST and ALT to Grade 0-1, then resume REZUROCK at the recommended dose.Grade AST or ALT (more than 20x ULN) or Grade >=3 bilirubin (more than 3x ULN)Discontinue REZUROCK permanently.Other adverse reactions [see Adverse Reactions (6.1)] Grade 3Hold REZUROCK until recovery to Grade 0-1, then resume REZUROCK at the recommended dose level.Grade 4Discontinue REZUROCK permanently.. 2.3 Dosage Modification Due to Drug Interactions. Strong CYP3A InducersIncrease the dosage of REZUROCK to 200 mg twice daily when coadministered with strong CYP3A inducers [see Drug Interactions (7.1)] . Proton Pump InhibitorsIncrease the dosage of REZUROCK to 200 mg twice daily when coadministered with proton pump inhibitors [see Drug Interactions (7.1)].

INFORMATION FOR PATIENTS SECTION.

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 fetus. Advise females of reproductive potential to inform their healthcare provider of 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 at least 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 at least one week after the last dose [see Use in Specific Populations (8.3)] . Advise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of 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 at least 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 at least one week after the last dose [see Use in Specific Populations (8.3)] . LactationAdvise women not to breastfeed during treatment with REZUROCK and for at least one week after the last dose [see Use in Specific Populations (8.2)] . Advise women not to breastfeed during treatment with REZUROCK and for at least one week after the last dose [see Use in Specific Populations (8.2)] . InfertilityAdvise males and females of reproductive potential that REZUROCK may impair fertility [see Use in Specific Populations (8.3)]. Advise males and females of reproductive potential that REZUROCK may impair fertility [see Use in Specific Populations (8.3)]. AdministrationInform patients to take REZUROCK orally once daily with food according to their physicians instructions and that the oral dosage (tablets) should be swallowed whole with 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 missed daily dose of REZUROCK, it should be taken as soon as possible on the same day with 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)]. Inform patients to take REZUROCK orally once daily with food according to their physicians instructions and that the oral dosage (tablets) should be swallowed whole with 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 missed daily dose of REZUROCK, it should be taken as soon as possible on the same day with 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 InteractionsAdvise 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)] . 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)].

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisCarcinogenicity studies have not been conducted with belumosudil.. MutagenesisBelumosudil was not genotoxic in an in vitrobacterial mutagenicity (Ames) assay, in vitrochromosome aberration assay in human peripheral blood lymphocytes (HPBL) or an in vivorat bone marrow micronucleus assay. Impairment of FertilityIn combined male and female rat fertility 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) included increased pre- or post-implantation loss and decreased number of viable embryos. Administration of belumosudil to male rats at 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 toxicology studies; findings included spermatozoa degeneration at belumosudil dose of 35 mg/kg/day in dogs and decreased follicular development in ovaries at 275 mg/kg/day in rats. Changes were partially or fully reversed during the recovery period. The exposure (AUC) at the doses of 35 mg/kg/day in dogs, and 275 mg/kg/day in rats is 0.5 times and 8-9 times, respectively, the clinical exposure at the recommended dose of 200 mg daily.

PHARMACOKINETICS SECTION.

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 maxof belumosudil was 22,700 (48%) hng/mL and 2390 (44%) ng/mL, respectively. Belumosudil maxand AUC increased in an approximately proportional manner over dosage range of 200 and 400 mg (1 to times once daily recommended dosage). The accumulation ratio of belumosudil was 1.4. AbsorptionMedian maxof 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 single belumosudil dose in healthy subjects. Effect of foodBelumosudil maxand AUC increased 2.2 times and times, respectively, following administration of single belumosudil dose with 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 maxwas delayed 0.5 hours. DistributionThe geometric mean volume of distribution after single dose of belumosudil in healthy subjects was 184 (geo CV% 67.7%).Belumosudil binding to human serum albumin and human 1-acid glycoprotein was 99.9% and 98.6%, respectively, in vitro. EliminationThe mean (%CV) elimination half-life of belumosudil was 19 hours (39%), and clearance was 9.83 L/hours (46%) in patients.. MetabolismBelumosudil is primarily metabolized by CYP3A4 and to lesser extent by CYP2C8, CYP2D6, and UGT1A9, in vitro.. ExcretionFollowing 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 PopulationsNo 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/1.72m 2to eGFR >=30 and <60 mL/min/1.72m 2). 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 maxby 59% and AUC by 72% in healthy subjects. Moderate CYP3A Inducers: Coadministration of efavirenz is predicted to decrease belumosudil maxby 32% and AUC by 35% in healthy subjects. Proton Pump Inhibitors: Coadministration of rabeprazole decreased belumosudil maxby 87% and AUC by 80%, and omeprazole decreased belumosudil maxby 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) maxand 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).. 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 Vitrostudies Transporter Systems: Belumosudil is substrate of P-gp. Belumosudil inhibits BCRP, P-gp, and OATP1B1 at clinically relevant concentrations. Enzymes Systems: Belumosudil is an inhibitor of CYP1A2, CYP2C19, CYP2D6, UGT1A1 and UGT1A9.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased 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 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 >=3- (rat) and >=0.07 (rabbit) times the human exposure (AUC) at the recommended dose (see Animal 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 to 4% and 15 to 20%, respectively.. Data. Animal dataEmbryo-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 pilot study and doses of 15, 50, and 150 mg/kg/day in 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 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 0.07 times the human exposure at the recommended dose of 200 mg.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug AdministrationIssued: July 2022 PATIENT INFORMATION REZUROCK (REZ-ur-ok) (belumosudil) tablets What is REZUROCKREZUROCK is 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 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 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. Femaleswho can become pregnant should use effective birth control during treatment with REZUROCK and for at least week after the last dose. Maleswith female partners who can become pregnant should use effective birth control during treatment with REZUROCK and for at least 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 at least week after the last dose.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. REZUROCK may affect the way other medicines work, and other medicines may affect the way REZUROCK works. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine. How should take REZUROCKTake 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 time day with meal.Take REZUROCK at about the same time each day.Swallow REZUROCK tablets whole with glass of water.Do not cut, crush, or chew REZUROCK tablets.Your healthcare provider will do blood tests to check your liver at least time month during treatment with REZUROCK.If you miss 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 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: infectionstiredness or weaknessnauseadiarrheashortness of breathcoughswellingbleedingstomach (abdominal) painmuscle or bone painheadachehigh blood pressureYour 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 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 store REZUROCKStore REZUROCK at room temperature between 68F to 77F (20C to 25C).Keep REZUROCK in its original container. The REZUROCK bottle contains 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.Keep REZUROCK and all medicines out of the reach of children.General information about the safe and effective use of REZUROCK. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use REZUROCK for 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: microcrystalline cellulose, hypromellose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. Tablet coating: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide and yellow iron oxide. Distributed and marketed by Kadmon Pharmaceuticals, LLC,Bridgewater, NJ 08807, SANOFI COMPANY REZUROCK (R)is registered trademark of Kadmon Pharmaceuticals, LLC (C) 2022 Kadmon Pharmaceuticals, LLC. All rights reserved. For more information, call 1-800-633-1610 or go to www.REZUROCK.com. 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 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. Femaleswho can become pregnant should use effective birth control during treatment with REZUROCK and for at least week after the last dose. Maleswith female partners who can become pregnant should use effective birth control during treatment with REZUROCK and for at least week after the last dose. Femaleswho can become pregnant should use effective birth control during treatment with REZUROCK and for at least week after the last dose. Maleswith female partners who can become pregnant should use effective birth control during treatment with REZUROCK and for at least 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 at least week after the last dose.. 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 time day with meal.. Take REZUROCK at about the same time each day.. Swallow REZUROCK tablets whole with glass of water.. Do not cut, crush, or chew REZUROCK tablets.. Your healthcare provider will do blood tests to check your liver at least time month during treatment with REZUROCK.. If you miss 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 missed dose.. If you take too much REZUROCK, call your healthcare provider or go to the nearest hospital emergency room right away.. infections. tiredness or weakness. nausea. diarrhea. shortness of breath. cough. swelling. bleeding. stomach (abdominal) pain. muscle or bone pain. headache. high blood pressure. Store REZUROCK at room temperature between 68F to 77F (20C to 25C).. Keep REZUROCK in its original container. The REZUROCK bottle contains 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. 8.2) 8.1 Pregnancy. Risk SummaryBased 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 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 >=3- (rat) and >=0.07 (rabbit) times the human exposure (AUC) at the recommended dose (see Animal 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 to 4% and 15 to 20%, respectively.. Data. Animal dataEmbryo-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 pilot study and doses of 15, 50, and 150 mg/kg/day in 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 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 0.07 times the human exposure at the recommended dose of 200 mg.. 8.2 Lactation. Risk SummaryThere 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.. 8.3 Females and Males of Reproductive Potential. REZUROCK can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)] . Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating treatment with REZUROCK.. Contraception. FemalesAdvise 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 fetus.. MalesAdvise 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. FemalesBased on findings from rats, REZUROCK may impair female fertility. The effect on fertility is reversible [see Nonclinical Toxicology (13.1)]. MalesBased on findings from rats and dogs, REZUROCK may impair male fertility. The effects on fertility are reversible [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.