Belumosudil

1 INDICATIONS AND USAGE REZUROCK is 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. 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 )

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 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 Based on CTCAE v 4.03 REZUROCK Dosage Modifications 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) ] .

6 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. 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 (%) Infections and infestations Infection (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. 53 16 Viral 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. 19 4 Bacterial 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. 16 4 General disorders and administration site conditions Asthenia includes fatigue, asthenia, malaise. 46 4 Edema includes edema peripheral, generalized edema, face edema, localized edema, edema. 27 1 Pyrexia 18 1 Gastrointestinal Nausea includes nausea, vomiting. 42 4 Diarrhea 35 5 Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower. 22 1 Dysphagia 16 0 Respiratory, thoracic and mediastinal Dyspnea includes dyspnea, dyspnea exertional, apnea, orthopnea, sleep apnea syndrome. 33 5 Cough includes cough, productive cough. 30 0 Nasal congestion 12 0 Vascular Hemorrhage includes contusion, hematoma, epistaxis, increased tendency to bruise, conjunctival hemorrhage, hematochezia, mouth hemorrhage, catheter site hemorrhage, hematuria, hemothorax, purpura. 23 5 Hypertension 21 7 Musculoskeletal and connective tissue Musculoskeletal pain includes pain in extremity, back pain, flank pain, limb discomfort, musculoskeletal chest pain, neck pain, musculoskeletal pain. 22 4 Muscle spasm 17 0 Arthralgia 15 2 Nervous system Headache includes headache, migraine. 21 0 Metabolism and nutrition Decreased appetite 17 1 Skin and subcutaneous Rash includes rash, rash maculo-papular, rash erythematous, rash generalized, dermatitis exfoliative. 12 0 Pruritus includes pruritus, pruritus generalized. 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 daily Grade 0–1 Baseline Grade 2–4 Max Post Grade 3–4 Max Post Parameter (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

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 C max of belumosudil was 22,700 (48%) h∙ng/mL and 2390 (44%) ng/mL, respectively. Belumosudil C max 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 T max 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 C max 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 T max 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 α 1 -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 CYP3A 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/1.72m 2 to eGFR ≥30 and <60 mL/min/1.72m 2 ). 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 C max AUC C max 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 Proton Pump Inhibitors : Concomitant use of rabeprazole decreased belumosudil C max by 87% and AUC by 80%, and omeprazole decreased belumosudil C max by 68% and AUC by 47% in healthy subjects. Strong Cytochrome P450 (CYP) 3A Inhibitors : There was no clinically meaningful effect on belumosudil exposure when used concomitantly with itraconazole (strong CYP3A inhibitor) in healthy subjects. Strong CYP3A Inducers : Concomitant use of rifampin (strong CYP3A inducer) decreased belumosudil C max by 59% and AUC by 72% in healthy subjects. Moderate CYP3A Inducers : Concomitant use of efavirenz (moderate CYP3A inducer) is predicted to decrease belumosudil C max by 19% and AUC by 35% in healthy subjects. CYP1A2 Substrates: Concomitant use of belumosudil is predicted to increase caffeine (sensitive CYP1A2 substrate) C max and AUC approximately 1.1- and 1.6-fold, respectively. CYP3A Substrates: Concomitant use of belumosudil is predicted to increase midazolam (sensitive CYP3A substrate) C max and AUC approximately 1.3- and 1.7-fold, respectively. UGT1A1 Substrates: Concomitant use of belumosudil did not have clinically significant effect on the exposure of raltegravir (UGT1A1 substrate), but decreased raltegravir glucuronide (metabolite formed via the UGT1A1 pathway) C max by 42% and AUC by 40%. BCRP/OATP1B1 Substrates : Concomitant use of belumosudil increased rosuvastatin (BCRP and OATP1B1 substrate) C max and AUC by 3.6- and 4.6-fold, respectively . P-glycoprotein (P-gp) Substrates: Concomitant use of belumosudil increased dabigatran (P-gp substrate) C max and AUC by 2-fold. Other drugs : Concomitant use of belumosudil is not predicted to have clinically significant effects on the exposure of ( S )-warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), and CYP2C8 substrates that are not an OATP1B1 substrate. In Vitro Studies UDP-Glucuronosyltransferase (UGT) : Belumosudil is an inhibitor of UGT1A9. Transporter Systems : Belumosudil is a substrate of P-gp.