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Belumosudil (Monograph)

Brand name: Rezurock
Drug class: Other Miscellaneous Therapeutic Agents
Chemical name: 2-[3-[4-(1H-indazol-5-ylamino)quinazolin-2-yl]phenoxy]-N-propan-2-ylacetamide
Molecular formula: C26H24N6O2
CAS number: 911417-87-3

Medically reviewed by Drugs.com on Jul 31, 2023. Written by ASHP.

Introduction

Belumosudil mesylate is a kinase inhibitor.

Uses for Belumosudil

Belumosudil mesylate has the following uses:

Belumosudil mesylate 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.

Belumosudil Dosage and Administration

General

Belumosudil mesylate is available in the following dosage form(s) and strength(s):

Tablet: 200 mg (as belumosudil).

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Pediatric Patients

Dosage and Administration

The recommended dosage in pediatric patients ≥12 years of age is 200 mg taken orally once daily with food.

Adults

Dosage and Administration

The recommended dosage in adults is 200 mg taken orally once daily with food.

Cautions for Belumosudil

Contraindications

None.

Warnings/Precautions

Embryo-fetal Toxicity

Based on findings in animals and its mechanism of action, belumosudil mesylate 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 belumosudil mesylate and for at least one week after the last dose.

Specific Populations

Pregnancy

Risk Summary: Based on findings from animal studies and the mechanism of action, belumosudil mesylate can cause fetal harm when administered to pregnant women. There are no available human data on belumosudil mesylate 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 ≥ 3 (rat) and ≥ 0.07 (rabbit) times the human exposure (AUC) at the recommended dose. 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.

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 3 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.

Lactation

There 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 belumosudil mesylate and for at least one week after the last dose.

Females and Males of Reproductive Potential

Belumosudil mesylate can cause fetal harm when administered to a pregnant woman.

Verify the pregnancy status of females of reproductive potential prior to initiating treatment with belumosudil mesylate.

Advise females of reproductive potential to use effective contraception during treatment with belumosudil mesylate and for at least one week after the last dose of belumosudil mesylate. 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 a fetus.

Advise males with female partners of reproductive potential to use effective contraception during treatment with belumosudil mesylate and for at least one week after the last dose of belumosudil mesylate.

Based on findings from rats, belumosudil mesylate may impair female fertility. The effect on fertility is reversible.

Based on findings from rats and dogs, belumosudil mesylate may impair male fertility. The effects on fertility are reversible.

Pediatric Use

The safety and effectiveness of belumosudil mesylate have been established in pediatric patients 12 years and older. Use of belumosudil mesylate in this age group is supported by evidence from adequate and well-controlled studies of belumosudil mesylate 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 belumosudil mesylate in pediatric patients less than 12 years old have not been established.

Geriatric Use

Of the 186 patients with chronic GVHD in clinical studies of belumosudil mesylate, 26% were 65 years and older. No clinically meaningful differences in safety or effectiveness of belumosudil mesylate were observed in comparison to younger patients.

Common Adverse Effects

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.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Strong CYP3A Inducers: Increase belumosudil dosage to 200 mg twice daily.

Proton Pump Inhibitors: Increase belumosudil dosage to 200 mg twice daily.

Actions

Mechanism of Action

Belumosudil is an inhibitor of rho-associated, coiled-coil containing protein kinase (ROCK) which inhibits ROCK2 and ROCK1 with IC50 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.

Advice to Patients

  • Advise the patient to read the FDA-approved patient labeling (Patient Information).

  • Advise pregnant women 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 to use effective contraceptive during treatment with belumosudil mesylate and for at least one week after the last dose.

  • Advise males with female partners of reproductive potential to use effective contraceptive during treatment with belumosudil mesylate and for at least one week after the last dose.

  • Advise women not to breastfeed during treatment with belumosudil mesylate and for at least one week after the last dose.

  • Advise males and females of reproductive potential that belumosudil mesylate may impair fertility.

  • Inform patients to take belumosudil mesylate orally once daily with food according to their physician's instructions and that the oral dosage (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 mesylate, 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 patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products.

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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 Mesylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

200 mg (of belumosudil)

Rezurock

Kadmon Pharmaceuticals LLC

AHFS Drug Information. © Copyright 2023, Selected Revisions August 9, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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