Rezurock

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) ] .

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.1 , 8.1 , 8.3 ) 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) ] .

7 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 ) BCRP Substrates: Avoid concomitant use with drugs that are BCRP substrates where possible. If used together, monitor patients more frequently for adverse reactions and decrease the substrates dosage(s) in accordance with the respective Prescribing Information. ( 7.2 ) OATP1B1 Substrates: If used together, monitor patients more frequently for adverse reactions and decrease the substrates dosage(s) in accordance with the respective Prescribing Information. ( 7.2 ) Certain CYP1A2, CYP3A, P-gp or UGT1A1 Substrates : Avoid concomitant use with these substrates for which minimal concentration changes may lead to serious toxicities. If concomitant use cannot be avoided, decrease the substrates dosage(s) in accordance with the respective Prescribing Information. ( 7.2 ) 7.1 Effect of Other Drugs on REZUROCK Proton Pump Inhibitors Belumosudil exhibits pH-dependent solubility. Concomitant use of REZUROCK with proton pump inhibitors decreases belumosudil exposure [see Clinical Pharmacology (12.3) ] , which may reduce the efficacy of REZUROCK. Increase the dosage of REZUROCK when used concomitantly with proton pump inhibitors [see Dosage and Administration (2.3) ]. Strong CYP3A Inducers Belumosudil is a CYP3A substrate. Concomitant use of REZUROCK with strong CYP3A inducers decreases belumosudil exposure [see Clinical Pharmacology (12.3) ] , which may reduce the efficacy of REZUROCK. Increase the dosage of REZUROCK when used concomitantly with strong CYP3A inducers [see Dosage and Administration (2.3) ]. 7.2 Effect of REZUROCK on Other Drugs BCRP and OATP1B1 Substrates Avoid concomitant use with drugs that are BCRP substrates where possible. If used together, monitor patients more frequently for adverse reactions and decrease the BCRP substrates dosage(s) in accordance with the respective Prescribing Information. Belumosudil is a BCRP inhibitor. Concomitant use of REZUROCK with BCRP substrates increases their plasma concentrations [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates. Belumosudil is an OATP1B1 inhibitor. Concomitant use of REZUROCK with OATP1B1 substrates may increase their plasma concentrations. Monitor patients more frequently for adverse reactions of these substrates and decrease the OATP1B1 substrates dosage(s) in accordance with the respective Prescribing Information [see Clinical Pharmacology (12.3) ] . Certain CYP1A2 Substrates Avoid concomitant use of REZUROCK with drugs that are sensitive CYP1A2 substrates, for which minimal concentration changes may lead to serious toxicities. If concomitant use cannot be avoided, decrease the CYP1A2 substrate dosage(s) in accordance with the respective Prescribing Information. Belumosudil is a CYP1A2 inhibitor. Concomitant use of REZUROCK with sensitive CYP1A2 substrates (e.g., caffeine) is predicted to increase CYP1A2 substrate exposure [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates. Certain CYP3A Substrates Avoid concomitant use of REZUROCK with drugs that are sensitive CYP3A substrates, for which minimal concentration changes may lead to serious toxicities. If concomitant use cannot be avoided, decrease the CYP3A substrate dosage(s) in accordance with the respective Prescribing Information. Belumosudil is a CYP3A inhibitor. Concomitant use of REZUROCK with sensitive CYP3A substrates (e.g., midazolam) is predicted to increase CYP3A substrate exposure [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates. Certain UGT1A1 Substrates Avoid concomitant use of REZUROCK with drugs that are UGT1A1 substrates, for which minimal concentration changes may lead to serious toxicities. If concomitant use cannot be avoided, decrease the UGT1A1 substrates dosage(s) in accordance with the respective Prescribing Information. Belumosudil is a UGT1A1 inhibitor. Concomitant use of REZUROCK with a UGT1A1 substrate decreased plasma concentrations of the glucuronide metabolite of the UGT1A1 substrate [see Clinical Pharmacology (12.3) ]. Concomitant use of belumosudil with other UGT1A1 substrates may increase their plasma concentrations, which may increase the risk of adverse reactions related to these substrates. Certain P-gp Substrates Avoid concomitant use of REZUROCK with drugs that are P-gp substrates, for which minimal concentration changes may lead to serious toxicities. If concomitant use cannot be avoided, decrease the P-gp substrates dosage(s) in accordance with the respective Prescribing Information. Belumosudil is a P-gp inhibitor. Concomitant use of REZUROCK with P-gp substrates increased their plasma concentrations [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates.

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

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.