Belumosudil (Monograph)

Brand name: Rezurock
Drug class: Other Miscellaneous Therapeutic Agents

Medically reviewed by Drugs.com on Feb 10, 2024. Written by ASHP.

Introduction

Kinase inhibitor.

Uses for Belumosudil

Chronic graft-versus-host disease

Treatment of adult and pediatric patients ≥12 years of age with chronic graft-versus-host disease (GVHD) after failure of ≥2 prior lines of systemic therapy. Designated an orphan drug by FDA for this use. Some experts consider belumosudil for patients with chronic GVHD who have not responded to front-line systemic treatment with corticosteroids or second-line treatment with ibrutinib or ruxolitinib.

Belumosudil Dosage and Administration

General

Pretreatment Screening

Verify pregnancy status in females of reproductive potential before initiating therapy.

Patient Monitoring

Monitor total bilirubin, AST, and ALT at least once monthly in patients receiving belumosudil.

Administration

Oral Administration

Swallow tablets whole; do not cut, crush, or chew. Take at the same time every day with a meal.

If a dose is missed, take the missed dose as soon as possible on the same day and resume normal schedule the following day. Do not take extra doses to make up for the missed dose.

Dosage

Dosage of belumosudil besylate is expressed in terms of belumosudil.

Pediatric Patients

Chronic GVHD

Oral

≥12 years of age: 200 mg once daily. Continue until progression of chronic GVHD requires new systemic treatment.

Adults

Chronic GVHD

Oral

200 mg once daily. Continue until progression of chronic GVHD requires new systemic treatment.

Dosage Modification for Toxicity

Modify belumosudil dosage for adverse reactions as instructed in Table 1.

Table 1. Recommended Dosage Modifications for Adverse Reactions1
Adverse Reaction	Severity^a	Dosage Modification
Hepatotoxicity	Grade 3 AST or ALT elevation (5–20 times the ULN) or grade 2 bilirubin elevation (1.5–3 times the ULN)	Hold until bilirubin, AST, and ALT recover to grade 0–1, then resume at recommended dosage
	Grade 4 AST or ALT elevation (>20 times the ULN) or grade 3 or 4 bilirubin elevation (>3 times the ULN)	Permanently discontinue
Other adverse reactions	Grade 3	Hold until recovery to grade 0–1, then resume at recommended dosage
	Grade 4	Permanently discontinue

Based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Dosage Modifications for Drug Interactions

Concomitant use with a strong CYP3A inducer: Increase belumosudil dosage to 200 mg twice daily.

Concomitant use with proton pump inhibitor: Increase belumosudil dosage to 200 mg twice daily.

Special Populations

Hepatic Impairment

Avoid use in moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment without liver GVHD. Dosage adjustment not recommended in mild (Child-Pugh A) hepatic impairment.

Renal Impairment

Not studied in patients with pre-existing severe renal impairment. In pharmacokinetic studies, mild to moderate renal impairment (eGFR ≥30 mL/min/1.72m²) did not significantly impact pharmacokinetics. Consider risks and benefits of treatment initiation in pre-existing severe renal impairment.

Geriatric Use

No specific dosage recommendations.

Cautions for Belumosudil

Contraindications

None.

Warnings/Precautions

Embryo-fetal Toxicity

Based on animal data and its mechanism of action, belumosudil can cause fetal harm when administered during pregnancy. In animal reproduction studies, administration during organogenesis caused adverse developmental outcomes including embryo-fetal mortality and malformations at maternal exposures less than those in patients at the recommended dose.

Verify pregnancy status of females of reproductive potential prior to initiating belumosudil. Inform patients of the potential fetal risk. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for ≥1 week after the last dose of belumosudil.

Specific Populations

Pregnancy

Based on animal data and its mechanism of action, belumosudil can cause fetal harm. There are no human data on use in pregnancy to evaluate for a drug-associated risk.

Advise patients of potential fetal risk. Verify pregnancy status of females of reproductive potential prior to initiating belumosudil.

Lactation

Not known if present in human milk. Effects on the breastfed infant or on milk production not known. Because of the potential for serious adverse effects on the breastfed child, avoid breastfeeding during treatment and for ≥1 week from the last dose.

Females and Males of Reproductive Potential

Can cause fetal harm. Verify pregnancy status of females of reproductive potential prior to initiation of treatment.

Advise females of reproductive potential to use effective contraception during treatment and for ≥1 week after the last dose of belumosudil. If used during pregnancy or if the patient becomes pregnant, inform patient of the potential fetal hazard.

Advise males with female partners of reproductive potential to use effective contraception during treatment and for ≥1 week after the last dose of belumosudil.

Based on findings in animal studies, belumosudil may impair female and male fertility. Effect on fertility is reversible.

Pediatric Use

Safety and efficacy established in pediatric patients ≥12 years of age. Use in this age group is supported by adequate and well-controlled studies in adults with additional population pharmacokinetic analyses in pediatric patients ≥12 years of age.

Safety and efficacy not established in pediatric patients <12 years of age.

Geriatric Use

Out of the 186 patients with chronic GVHD in studies, 26% were ≥65 years of age. No clinically meaningful differences in safety or efficacy observed in comparison to younger patients.

Hepatic Impairment

Avoid use in patients without liver GVHD and moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. No dosage adjustment recommended in mild (Child-Pugh A) hepatic impairment.

Renal Impairment

Pharmacokinetic exposure not affected by mild (eGFR ≥60 and <90 mL/minute/1.72m²) or moderate (eGFR ≥30 and <60 mL/minute/1.72m²) renal impairment. Effect of severe renal impairment (eGFR <30 mL/minute/1.72m²) on pharmacokinetics not known.

Common Adverse Effects

Most common (≥20%) adverse reactions: infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, decreased phosphate and lymphocytes, increased gamma glutamyl transferase, hypertension.

Drug Interactions

Metabolized principally by CYP3A4 and, to a lesser extent, CYP2C8, CYP2D6, and UGT1A9. In vitro, belumosudil inhibits CYP1A2, CYP2C19, CYP2D6, UGT1A1, and UGT1A9. In vitro studies indicate that belumosudil is a substrate and inhibitor of P-glycoprotein (P-gp). Belumosudil is also an inhibitor of breast cancer resistance protein (BRCP) and organic anion transporter polypeptide (OATP) 1B1.

Drugs Affecting Hepatic Microsomal Enzymes

Inducers of CYP3A: Concomitant use of belumosudil decreases belumosudil exposure and potentially efficacy. Increase belumosudil dosage to 200 mg twice daily when used concomitantly with strong CYP3A inducers.

Inhibitors of CYP3A: When itraconazole (a strong CYP3A inhibitor) was used concomitantly with belumosudil, no clinically meaningful effects on belumosudil exposure were observed in healthy subjects.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Possible increased exposure to the CYP3A substrate when used concomitantly with belumosudil.

Substrates of CYP2C9: Concomitant use of belumosudil not expected to have clinically meaningful effects on CYP2C9 substrate exposure.

Substrates of CYP2C8: Concomitant use of belumosudil with CYP2C8 substrates that are not OATP1B1 substrates not expected to have clinically meaningful effects on the exposure of the CYP2C8 substrate.

Specific Drugs

Drug	Interaction	Comments
Efavirenz	Concomitant use predicted to decrease belumosudil AUC and maximum serum concentrations by 35% and 32%, respectively
Itraconazole	No clinically meaningful effects on belumosudil exposure expected
Midazolam	Concomitant use expected to increase midazolam maximum serum concentrations and AUC 1.3- and 1.5-fold, respectively
Proton pump inhibitors (e.g., omeprazole, rabeprazole)	Concomitant use of omeprazole and rabeprazole decreased belumosudil AUC by 47% and 80%, respectively, and decreased maximum serum concentrations of belumosudil by 68% and 87%, respectively	If used concomitantly, increase belumosudil dosage to 200 mg twice daily
Rifampin	Concomitant use of rifampin decreased AUC and maximum serum concentrations of belumosudil by 72% and 59%, respectively	If used concomitantly, increase belumosudil dosage to 200 mg twice daily
Warfarin	No clinically meaningful effects on warfarin exposure expected

Belumosudil Pharmacokinetics

Absorption

Peak plasma concentrations and AUC approximately dose proportional over a dosage range of 200–400 mg.

Accumulation ratio is approximately 1.4.

At steady state, maximum belumosudil concentrations achieved at a median of 1.26–2.53 hours after administration of 200 mg once or twice daily.

Bioavailability

64%.

Food

Peak plasma concentrations and AUC of belumosudil increased 2.2 and 2 times, respectively, following administration with a high-fat, high-calorie meal (800–1000 calories with approximately 50% of caloric content from fat) when compared to the fasted state. Time to maximum serum concentration delayed by 30 minutes when administered with a high-fat, high-calorie meal.

Distribution

Extent

Not known if present in human milk.

Plasma Protein Binding

99.9% bound to human serum albumin.

Elimination

Metabolism

Primarily metabolized by CYP3A4, and to a lesser extent, CYP2C8, CYP2D6, and UGT1A9.

Elimination Route

Following oral administration of a single radiolabeled dose, 85% of radioactivity was recovered in feces (30% of the dose as unchanged drug); <5% recovered in urine.

Half-life

19 hours.

Special Populations

Pharmacokinetic exposure not affected by age (18–77 years), sex, weight (38.6–143 kg), or mild (eGFR ≥60 and <90 mL/minute/1.72m²) or moderate (eGFR ≥30 and <60 mL/minute/1.72m²) renal impairment. Effects of severe renal impairment (eGFR <30 mL/minute/1.72m²) on belumosudil pharmacokinetics not known.

Stability

Storage

Oral

Tablets

20–25ºC; excursions permitted between 15–30ºC. Store in original container; do not discard desiccant.

Actions

Belumosudil inhibits rho-associated, coiled-coil containing protein kinase (ROCK), which inhibits ROCK2 and ROCK1 with half-maximal inhibitory concentration (IC₅₀) values of approximately 100 nM and 3 mcM, respectively.
In ex-vivo or in vitro-human T cell assays, causes down-regulation of proinflammatory responses via regulation of signal transducer and activator of transcription (STAT) 3/STAT5 phosphorylation and shifting Th17/Treg balance.
In vitro, also inhibits aberrant pro-fibrotic signaling.

Advice to Patients

Instruct patients to take belumosudil orally once daily with food according to their physician's instructions; advise patients that the tablets should be swallowed whole with a glass of water without cutting, crushing or chewing the tablets approximately the same time each day.
Advise patients that in the event of a missed daily dose of belumosudil, 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.
Advise pregnant females 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.
Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for ≥1 week after the last dose.
Advise patients not to breastfeed during treatment and for ≥1 week after the last dose.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.
Advise patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Belumosudil is obtained through designated specialty pharmacies. Contact the manufacturer or consult the Rezurock website at [Web] for specific availability information.