Belumosudil

Belumosudil
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tejasvi Aryaputra

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Overview

Belumosudil is a kinase inhibitor that is FDA approved for the treatment of chronic graft-versus-host disease after failure of at least two prior lines of systemic therapy. Common adverse reactions include dyspnea, asthenia, phosphate decrease, hypertension, cough, nausea, lymphocytes decreased, edema, diarrhea, glutamyl transferase increased,, hemorrhage, headache, abdominal pain, and musculoskeletal pain.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Recommended Dosage

• 200 mg given once daily is the recommended dosage of Belumosudil.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Belumosudil in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Belumosudil in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Belumosudil FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Belumosudil in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Belumosudil in pediatric patients.

Contraindications

There are no contraindications associated with Belumosudil.

Warnings

Embryo-Fetal Toxicity

• Fetal harm may occur in pregnant women when taking Belumosudil based on animal studies.
• Embryo-fetal mortality and malformations were seen in animal studies conducted on pregnant rabbits and rats when taking Belumosudil during the period organogenesis.
• Advise females of reproductive potential to use effective contraception during treatment with Belumosudil and for at least 1 week after the last dose.
• Advise males with female partners of reproductive potential to use effective contraception during treatment with Belumosudil and for at least 1 week after the last dose.

Adverse Reactions

Clinical Trials Experience

Clinical Trial Experience

• Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Chronic Graft versus Host Disease

• 83 adult patients with chronic GVHD were part of 2 clinical trials that looked into adverse reactions caused by Belumosudil.
• 200 mg of Belumosudil was given to each patient part of the clinical trial.
• 9.2 months was the median duration of Belumosudil treatment.
• 1 patient in the trials reported fatal adverse reactions such as diarrhea, multi-organ failure, nausea, and vomiting.
• 18% of patients had to permanently stop Belumosudil treatment as a result of adverse reactions.
• 29% of patients had to interrupt Belumosudil treatment as a result of adverse reactions.
• Hemorrhage, renal failure, infection, liver function test abnormal, asthenia, dyspnea, nausea, pyrexia, edema, and diarrhea were common adverse reactions reported by patients that dosage interruptions in clinical studies.

Table 2 summarizes the Non-laboratory Adverse Reactions.

This image is provided by the National Library of Medicine.

This image is provided by the National Library of Medicine.

Table 3 summarizes the Laboratory Abnormalities in Belumosudil.

This image is provided by the National Library of Medicine.

Postmarketing Experience

There is limited information regarding Belumosudil Postmarketing Experience in the drug label.

Drug Interactions

Strong CYP3A Inducers

• Belumosudil exposure is decreased with the co-administration of strong CYP3A inducers and Belumosudil.
• Advise patients that co-administration of strong CYP3A inducers and Belumosudil should result in an increase in Belumosudil dosage.

Proton Pump Inhibitors

• Belumosudil exposure is decreased with the co-administration of proton pump inhibitors and Belumosudil.
• Advise patients that co-administration of proton pump inhibitors and Belumosudil should result in an increase in Belumosudil dosage.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): Fetal harm is associated with Belumosudil treatment in pregnant women based on animal studies. Embryo-fetal mortality, alterations to growth, and embryo-fetal malformations were seen in pregnant rabbits and rats given Belumosudil during the period of organogenesis. Pregnant rats part of embryo-fetal development studies were given oral doses of 25, 50, 150, and 300 mg/kg/day in a pilot study. Pregnant rats were also given dose of 15, 50, and 150 mg/kg/day in a pivotal study. At doses of 150 and 300 mg/kg/day, pregnant rats experienced maternal toxicity. At doses of 50 and 300 mg/kg/day, pregnant rats experienced an increase in post-implantation loss. At doses greater than 50 mg/kg/day, fetal malformations were seen in pregnant rats. Pregnant rabbits part of embryo-fetal developmental studies were given oral doses of 50, 125, and 225 mg/kg/day. At doses ≥125 mg/kg/day, pregnant rabbits experienced maternal toxicity such as body weight loss and mortality. At doses ≥50 mg/kg/day, pregnant rabbits experienced embryo-fetal effects such as increased post-implantation loss, decreased fetal body weight, spontaneous abortion, malformations, and decreased percentage of live fetuses.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Belumosudil in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Belumosudil during labor and delivery.

Nursing Mothers

No data is present on the effects done on the breastfed child and the effects on milk production when treated with Belumosudil. Advise female patients not to nurse during treatment with Belumosudil and for at least 1 week after the last dose based on the potential for serious adverse reactions.

Pediatric Use

Pediatric patients 12 years and older were part of studies to look into the safety and effectiveness of Belumosudil. The exposure of Belumosudil between adults and pediatric patients age 12 years and older should be similar. Studies have not been conducted on pediatric patients less than 12 years of age that looks into the safety and effectiveness of Belumosudil.

Geriatic Use

Based on clinical studies, the differences in safety and effectiveness of Belumosudil is not clinically meaningful between older and younger patients.

Gender

There is no FDA guidance on the use of Belumosudil with respect to specific gender populations.

Race

There is no FDA guidance on the use of Belumosudil with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Belumosudil in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Belumosudil in patients with hepatic impairment.

Females of Reproductive Potential and Males

Fetal harm is associated with Belumosudil treatment in pregnant women. Before starting Belumosudil treatment, verify pregnancy status of females with reproductive potential. Advise females of reproductive potential to use effective contraception during treatment with Belumosudil and for at least 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Belumosudil and for at least 1 week after the last dose. Fertility may be impaired in females and males taking Belumosudil based on rat studies. Fertility effects caused by Belumosudil can be reversed in males and females.

Immunocompromised Patients

There is no FDA guidance one the use of Belumosudil in patients who are immunocompromised.

Administration and Monitoring

Administration

Administration

• Advise patients to swallow Belumosudil tablets whole.
• Advise patients to take Belumosudil at the same time each day with a meal.
• Advise patients to not take extra doses if a dosage is missed.

Monitoring

Dose Modifications for Adverse Reactions

• Monitor patients AST, ALT, and total bilirubin levels monthly.'

Table 1 summarizes the Dosage Changes in Belumosudil depending on Adverse Reactions.

This image is provided by the National Library of Medicine.

Dosage Modification Due to Drug Interactions

Strong CYP3A Inducers:

• If taking a strong CYP3A inducer, increase Belumosudil dosage to 200 mg twice daily.

Proton Pump Inhibitors:

• If taking a proton pump inhibitor, increase Belumosudil dosage to 200 mg twice daily.

IV Compatibility

There is limited information regarding the compatibility of Belumosudil and IV administrations.

Overdosage

There is limited information regarding Belumosudil overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

Mechanism of Action

• Belumosudil is an inhibitor of rho-associated, coiled-coil containing protein kinase.
• STAT3/STAT5 phosphorylation and shifting Th17/Treg balance is regulated by Belumosudil.

Structure

• Belumosudil is a kinase inhibitor. It has an empirical formula of C27H28N6O5S.
• The molecular weight is 548.62 g/mol.

This image is provided by the National Library of Medicine.

Pharmacodynamics

• Pharmacodynamic studies on Belumosudil when looking into exposure-response relationships have not been conducted.

Pharmacokinetics

• 22,700 h∙ng/mL is the mean steady-state AUC of Belumosudil in chronic GVHD patients.
• 2390 ng/mL is the Cmax of Belumosudil in chronic GVHD patients.
• 1.4 is the accumulation ratio of Belumosudil.

Absorption

• 1.26 to 2.53 hours is the range of time for the Median T-max at steady state of Belumosudil.
• 64% is the mean bioavailability of a single dose of Belumosudil.

Effect of Food

• When given a high-fat and high-calorie meal, a 2.2 times increase in Cmax was observed of Belumosudil in patients.
• When given a high-fat and high-calorie meal, a 2 times increase in AUC was observed of Belumosudil in patients.
• 0.5 hours is the time that the Median Tmax was delayed of Belumosudil after patients were given a high-fat and high-calorie meal.

Distribution

• 184 L is the geometric mean volume of distribution of a singe dose of Belumosudil.
• In vitro, 99.9% is the binding percentage of Belumosudil to human serum albumin.
• In vitro, 98.6% is the binding percentage of Belumosudil to human α1-acid glycoprotein.

Elimination

• 19 hours is the mean elimination half-life of Belumosudil.
• 9.83 L/hours is the clearance of Belumosudil.

Metabolism

• In vitro, CYP3A4 is the primary metabolizer of Belumosudil.
• In vitro, CYP2D6, CYP2C8, and UGT1A9 metabolizes Belumosudil to a lesser extent.

Excretion

• 85% of Belumosudil was recovered in feces in which 30% was found unchanged after patients were given a single oral dose of radiolabeled Belumosudil.
• Less than 5% of Belumosudil was recovered in urine after patients were given a single oral dose of radiolabeled Belumosudil.

Specific Populations

• Weight, age, mild to moderate renal impairment, or sex had no clinically significant effects on the pharmacokinetics of Belumosudil.

Drug Interaction Studies

Effects of other drugs on Belumosudil:

• When co-administrating Belumosudil and Itraconazole, there were no clinically meaningful effects on the exposure of Belumosudil.
• A 59% decrease of Belumosudil Cmax was observed with the co-administration of Belumosudil and Rifampin.
• A 72% decrease of Belumosudil AUC was observed with the co-administration of Belumosudil and Rifampin.
• A 32% decrease of Belumosudil Cmax was predicted with the co-administration of Belumosudil and Efavirenz.
• A 35% decrease of Belumosudil AUC was predicted with the co-administration of Belumosudil and Efavirenz.
• A 87% decrease of Belumosudil Cmax was observed with the co-administration of Belumosudil and Rabeprazole.
• A 80% decrease of Belumosudil AUC was observed with the co-administration of Belumosudil and Rabeprazole.
• A 68% decrease of Belumosudil Cmax was observed with the co-administration of Belumosudil and Omeprazole.
• A 47% decrease of Belumosudil AUC was observed with the co-administration of Belumosudil and Omeprazole.

Effects of Belumosudil on other drugs:

• 1.3 fold increase of Midazolam Cmax was observed with the co-administration of Belumosudil and Midazolam.
• 1.5 fold increase of Midazolam AUC was observed with the co-administration of Belumosudil and Midazolam.
• The exposure of CYP2C9 substrates is not effected clinically with the co-administration of Belumosudil and CYP2C9 substrates.
• The exposure of CYP2C8 substrates is not effected clinically, excluding OATP1B1 substrate, with the co-administration of Belumosudil and CYP2C8 substrates.

In Vitro studies

• A substrate of P-gp is Belumosudil.
• P-gp, BCRP, and OATP1B1 are inhibited by Belumosudil.
• Belumosudil is an inhibitor of CYP2C19, CYP2D6, UGT1A1, CYP1A2, and UGT1A9.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis:

• Studies on carcinogenicity have not been done on Belumosudil.

Mutagenesis:

• In human peripheral blood lymphocytes, vitro chromosome aberration assay, vivo rat bone marrow micronucleus assay, or in vitro bacterial mutagenicity assay, Belumosudil was not genotoxic.

Impairment of Fertility:

• 70 days prior to mating period for male rats, doses of 50, 150 or 275 mg/kg/day of Belumosudil were given to male rats.
• 14 days prior to mating for female rats, doses of 50, 150 or 275 mg/kg/day of Belumosudil were given to female rats.
• Decreased number of viable embryos and increased pre- or post-implantation loss was seen in female rats that were given 275 mg/kg/day of Belumosudil.
• Testes/epididymis organ changes and abnormal sperm findings were seen in male rats that were given 275 mg/kg/day of Belumosudil.
• When both male and female rats were given 275 mg/kg/day of Belumosudil, a reduction of fertility was seen.
• In general toxicology studies, there were adverse changes in both male and female reproductive organs.

Clinical Studies

Chronic Graft versus Host Disease

• Study KD025-213 is a a randomized, open-label, multicenter study.
• The study looked at the effects of Belumosudil on chronic GVHD patients who had received 2 to 5 prior lines of systemic therapy.
• A total of 66 patients receiving 200 mg of Belumosudil once daily made up the study.

Table 4 shows the Demographics and Baseline Characteristics of the Patient Pool.

This image is provided by the National Library of Medicine.

Table 5 shows the Overall Response Rate through Cycle 7 Day 1 for Patients with Chronic GVHD in Study KD025-213.

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How Supplied

• 200 mg pale yellow film-coated oblong tablets of Belumosudil in a 30 count bottle.

Storage

• Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
• To prevent moisture, store in original container.
• Advise patients to seal cap securely each time bottle is opened.

Images

Drug Images

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Package and Label Display Panel

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This image is provided by the National Library of Medicine.

This image is provided by the National Library of Medicine.

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Patient Counseling Information

Embryo-fetal Toxicity

• Advise patients about the harms of the fetus that may occur when taking Belumosudil.
• Verify pregnancy status of females with reproductive potential.
• Advise females of reproductive potential to use effective contraception during treatment with Belumosudil and for at least 1 week after the last dose.
• Advise males with female partners of reproductive potential to use effective contraception during treatment with Belumosudil and for at least 1 week after the last dose.

Lactation

• Advise female patients not to nurse during treatment with Belumosudil and for at least 1 week after the last dose.

Infertility

• Advise patients that fertility may be impaired in both females and males taking Belumosudil.

Administration

• Advise patients to take Belumosudil orally once daily with a meal.
• Advise patients to swallow tablet whole with water.
• Advise patients to not crush, chew, or cut Belumosudil tablets.
• Advise patients to not take extra doses if a dosage is missed.
• Advise patients to take a dosage immediately the same day if missed.

Drug Interactions

• Advise patients about the effects of concomitant medications when taking Belumosudil.

Belumosudil Package Insert:

This image is provided by the National Library of Medicine.

This image is provided by the National Library of Medicine.

Precautions with Alcohol

Alcohol-Belumosudil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• Rezurock

Look-Alike Drug Names

There is limited information regarding Belumosudil Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.