Drug Detail:Rezurock (Belumosudil)
Drug Class: Selective immunosuppressants
Highlights of Prescribing Information
(Packaged by Pharma Packaging Solutions, LLC dba Tjoapack LLC)
These highlights do not include all the information needed to use REZUROCK safely and effectively. See full prescribing information for REZUROCK.
Initial U.S. Approval: 2021
Indications and Usage for Rezurock
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)
Rezurock Dosage and Administration
Recommended Dosage: 200 mg taken orally once daily with food. ( 2.1)
Dosage Forms and Strengths
Tablet: 200 mg. ( 3)
Contraindications
None. ( 4)
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)
Adverse Reactions/Side 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. ( 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.
Drug Interactions
Strong CYP3A Inducers: Increase REZUROCK dosage to 200 mg twice daily. ( 7.1)
Proton Pump Inhibitors: Increase REZUROCK dosage to 200 mg twice daily. ( 7.1)
Use In Specific Populations
Lactation: Advise not to breastfeed. ( 8.2)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 4/2023
Full Prescribing Information
1. Indications and Usage for Rezurock
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.
2. Rezurock Dosage and Administration
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 or hepatic impairment. For patients with pre-existing severe renal or hepatic impairment, consider the risks and potential benefits before initiating treatment with REZUROCK [see Clinical Pharmacology (12.3)] .
2.2 Dose 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.
| Adverse Reaction | Severity * | 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. | |
3. Dosage Forms and Strengths
Each 200 mg tablet is a pale yellow film-coated oblong tablet debossed with "KDM" on one side and "200" on the other side.
5. Warnings and Precautions
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 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 at least one week after the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)] .
6. Adverse Reactions/Side Effects
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 2summarizes the nonlaboratory adverse reactions.
| Adverse Reaction | REZUROCK
200 mg once daily (N=83) |
|
|---|---|---|
| All Grades (%) | Grades 3–4 (%) | |
|
||
| Infections and infestations | ||
| Infection (pathogen not specified) * | 53 | 16 |
| Viral infection † | 19 | 4 |
| Bacterial infection ‡ | 16 | 4 |
| General disorders and administration site conditions | ||
| Asthenia § | 46 | 4 |
| Edema ¶ | 27 | 1 |
| Pyrexia | 18 | 1 |
| Gastrointestinal | ||
| Nausea # | 42 | 4 |
| Diarrhea | 35 | 5 |
| Abdominal pain Þ | 22 | 1 |
| Dysphagia | 16 | 0 |
| Respiratory, thoracic and mediastinal | ||
| Dyspnea ß | 33 | 5 |
| Cough à | 30 | 0 |
| Nasal congestion | 12 | 0 |
| Vascular | ||
| Hemorrhage è | 23 | 5 |
| Hypertension | 21 | 7 |
| Musculoskeletal and connective tissue | ||
| Musculoskeletal pain ð | 22 | 4 |
| Muscle spasm | 17 | 0 |
| Arthralgia | 15 | 2 |
| Nervous system | ||
| Headache ø | 21 | 0 |
| Metabolism and nutrition | ||
| Decreased appetite | 17 | 1 |
| Skin and subcutaneous | ||
| Rash ý | 12 | 0 |
| Pruritus £ | 11 | 0 |
Table 3summarizes the laboratory abnormalities in 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. Use In Specific Populations
8.1 Pregnancy
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 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.
8.3 Females and Males of Reproductive Potential
REZUROCK can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)] .
8.4 Pediatric Use
The safety and effectiveness of REZUROCK have been established in pediatric patients 12 years and older. Use of REZUROCK in this age group is supported by evidence from adequate and well-controlled studies of REZUROCK 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 REZUROCK in pediatric patients less than 12 years old have not been established.
11. Rezurock Description
Belumosudil is a kinase inhibitor. The active pharmaceutical ingredient is belumosudil mesylate with the molecular formula C 27H 28N 6O 5S and the molecular weight is 548.62 g/mol. The chemical name for belumosudil mesylate is 2-{3-[4-(1 H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}- N-(propan-2-yl) acetamide methanesulfonate (1:1). The chemical structure is as follows:
Belumosudil mesylate is a yellow powder that is practically insoluble in water, slightly soluble in methanol and DMF and soluble in DMSO.
REZUROCK tablets are for oral administration. Each tablet contains 200 mg of the free base equivalent to 242.5 mg of belumosudil mesylate. The tablet also contains the following inactive ingredients: microcrystalline cellulose, hypromellose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
The tablet film consists of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide and yellow iron oxide.
12. Rezurock - Clinical Pharmacology
12.1 Mechanism of Action
Belumosudil is an inhibitor of rho-associated, coiled-coil containing protein kinase (ROCK) which inhibits ROCK2 and ROCK1 with IC 50values 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.
12.2 Pharmacodynamics
Belumosudil exposure-response relationships and the time course of pharmacodynamic response are not established.
12.3 Pharmacokinetics
The following pharmacokinetic parameters are presented for chronic GVHD patients administered belumosudil 200 mg once daily, unless otherwise specified. The mean (% coefficient of variation, %CV) steady-state AUC and C maxof belumosudil was 22,700 (48%) h∙ng/mL and 2390 (44%) ng/mL, respectively. Belumosudil C maxand AUC increased in an approximately proportional manner over a dosage range of 200 and 400 mg (1 to 2 times once daily recommended dosage). The accumulation ratio of belumosudil was 1.4.
14. Clinical Studies
14.1 Chronic Graft versus Host Disease
Study KD025-213 (NCT03640481) was a randomized, open-label, multicenter study of REZUROCK for treatment of patients with chronic GVHD who had received 2 to 5 prior lines of systemic therapy and required additional treatment. Patients were excluded from the studies if platelets were <50 × 10 9/L; absolute neutrophil count <1.5 × 10 9/L; AST or ALT >3 × ULN; total bilirubin >1.5 × ULN; QTc(F) >480 ms; eGFR <30 mL/min/1.73 m 2; or FEV1 ≤39%. There were 66 patients treated with REZUROCK 200 mg taken orally once daily. Concomitant treatment with supportive care therapies for chronic GVHD was permitted. Concomitant treatment with GVHD prophylaxis and standard care systemic chronic GVHD therapies was permitted as long as the subject has been on a stable dose for at least 2 weeks prior to study. Initiation of new systemic chronic GVHD therapy while on study was not permitted.
Demographics and baseline characteristics are summarized in Table 4.
| REZUROCK
200 mg once daily (N=65) |
|
|---|---|
|
|
| Age, Median, Years (minimum, maximum) | 53 (21, 77) |
| Age ≥65 Years, n (%) | 17 (26) |
| Male, n (%) | 42 (65) |
| Race, n (%) | |
| White | 54 (83) |
| Black | 6 (9) |
| Other or Not Reported | 5 (8) |
| Median (range) time (months) from Chronic GVHD Diagnosis | 25.3 (1.9, 162.4) |
| ≥4 Organs Involved, n (%) | 31 (48) |
| Median (range) Number of Prior Lines of Therapy | 3 (2, 6) |
| Number of Prior Lines of Therapy, n (%) | |
| 2 | 23 (35) |
| 3 | 12 (19) |
| 4 | 15 (23) |
| ≥5 | 15 (23) |
| Prior chronic GVHD treatment with ibrutinib, n (%) | 21 (32) |
| Prior chronic GVHD treatment with ruxolitinib, n (%) | 20 (31) |
| Refractory to Last Therapy, n (% *) | 43/55 (78) |
| Severe chronic GVHD, n (%) | 46 (71) |
| Median (range) Global Severity Rating | 7 (2, 9) |
| Median (range) Lee Symptom Scale Score at baseline | 27 (7, 56) |
| Median (range) Corticosteroid dose at baseline (PE/kg) † | 0.19 (0.03, 0.95) |
The efficacy of REZUROCK was based on overall response rate (ORR) through Cycle 7 Day 1 where overall response included complete response or partial response according to the 2014 NIH Response Criteria. The ORR results are presented in Table 5. The ORR was 75% (95% CI: 63, 85). The median duration of response, calculated from first response to progression, death, or new systemic therapies for chronic GVHD, was 1.9 months (95% CI: 1.2, 2.9). The median time to first response was 1.8 months (95% CI: 1.0, 1.9). In patients who achieved response, no death or new systemic therapy initiation occurred in 62% (95% CI: 46, 74) of patients for at least 12 months since response.
| REZUROCK
200 mg once daily (N=65) |
|
|---|---|
|
|
| Overall Response Rate (ORR) | 49 (75%) |
| 95% Confidence Interval * | (63%, 85%) |
| Complete Response | 4 (6%) |
| Partial Response | 45 (69%) |
ORR results were supported by exploratory analyses of patient-reported symptom bother which showed at least a 7-point decrease in the Lee Symptom Scale summary score through Cycle 7 Day 1 in 52% (95% CI: 40, 65) of patients.
16. How is Rezurock supplied
REZUROCK 200 mg tablets are supplied as pale yellow film-coated oblong tablets containing 200 mg of belumosudil (equivalent to 242.5 mg belumosudil mesylate). Each tablet is debossed with "KDM" on one side and "200" on the other side and is packaged as follows:
- 200 mg tablets in 30 count bottle: NDC 75929-174-03
| REZUROCK
belumosudil tablet |
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| Labeler - Pharma Packaging Solutions, LLC dba Tjoapack LLC (928861723) |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
|---|---|---|---|
| Gregory Pharmaceutical Holdings, Inc., dba UPM Pharmaceuticals | 081301372 | manufacture(75929-174) | |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
|---|---|---|---|
| Pharma Packaging Solutions, LLC dba Tjoapack LLC | 928861723 | pack(75929-174) | |
