belumosudil 200 MG Oral Tablet [Rezurock]

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 )

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) ] .

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) ] .

CONTRAINDICATIONS None. None. ( 4 )

Mechanism of Action Belumosudil is an inhibitor of rho-associated, coiled-coil containing protein kinase (ROCK) which inhibits ROCK2 and ROCK1 with IC 50 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.