Rezurock

REZUROCK- belumosudil tablet
Kadmon Pharmaceuticals, LLC

1 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.

2 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.

Table 1: Recommended Dosage Modifications for REZUROCK for Adverse Reactions
*Based on CTCAE v 4.03

Adverse Reaction

Severity*

REZUROCK Dosage Modifications

Hepatotoxicity [see Adverse Reactions ( 6.1)]

Grade 3 AST or ALT (5x to 20x ULN) or

Grade 2 bilirubin (1.5x to 3x 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 20x ULN) or

Grade ≥ 3 bilirubin (more than 3x 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)].

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.

4 CONTRAINDICATIONS

None.

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

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 2 summarizes the nonlaboratory adverse reactions.

Table 2: Nonlaboratory Adverse Reactions in ≥ 10% Patients with Chronic GVHD Treated with REZUROCK
Adverse Reaction REZUROCK200 mg once daily (N=83)
All Grades (%) Grades 3-4 (%)
a infection with an unspecified pathogen includes acute sinusitis, device related infection, ear infection, folliculitis, gastroenteritis, gastrointestinal infection, hordeolum, infectious colitis, lung infection, skin infection, tooth infection, urinary tract infection, wound infection, upper respiratory tract infection, pneumonia, conjunctivitis, sinusitis, respiratory tract infection, bronchitis, sepsis, septic shock.b includes influenza, rhinovirus infection, gastroenteritis viral, viral upper respiratory tract infection, bronchitis viral, Epstein-Barr viremia, Epstein-Barr virus infection, parainfluenzae virus infection, Varicella zoster virus infection, viral infection.c includes cellulitis, Helicobacter infection, Staphylococcal bacteremia, catheter site cellulitis, Clostridium difficile colitis, Escherichia urinary tract infection, gastroenteritis Escherichia coli, Pseudomonas infection, urinary tract infection bacterial.d includes fatigue, asthenia, malaise.e includes edema peripheral, generalized edema, face edema, localized edema, edema.f includes nausea, vomiting.g includes abdominal pain, abdominal pain upper, abdominal pain lower.h includes dyspnea, dyspnea exertional, apnea, orthopnea, sleep apnea syndrome.i includes cough, productive cough.j includes contusion, hematoma, epistaxis, increased tendency to bruise, conjunctival hemorrhage, hematochezia, mouth hemorrhage, catheter site hemorrhage, hematuria, hemothorax, purpura.k includes pain in extremity, back pain, flank pain, limb discomfort, musculoskeletal chest pain, neck pain, musculoskeletal pain.l includes headache, migraine.m includes rash, rash maculo-papular, rash erythematous, rash generalized, dermatitis exfoliative.n includes pruritus, pruritus generalized.

Infections and infestations

Infection (pathogen not specified)a

53

16

Viral infectionb

19

4

Bacterial infectionc

16

4

General disorders and administration site conditions

Astheniad

46

4

Edemae

27

1

Pyrexia

18

1

Gastrointestinal

Nauseaf

42

4

Diarrhea

35

5

Abdominal paing

22

1

Dysphagia

16

0

Respiratory, thoracic and mediastinal

Dyspneah

33

5

Coughi

30

0

Nasal congestion

12

0

Vascular

Hemorrhagej

23

5

Hypertension

21

7

Musculoskeletal and connective tissue

Musculoskeletal paink

22

4

Muscle spasm

17

0

Arthralgia

15

2

Nervous system

Headachel

21

0

Metabolism and nutrition

Decreased appetite

17

1

Skin and subcutaneous

Rashm

12

0

Pruritusn

11

0

Table 3 summarizes the laboratory abnormalities in REZUROCK.

Table 3: Selected Laboratory Abnormalities in Patients with Chronic GVHD Treated with REZUROCK
REZUROCK 200 mg once daily
Grade 0‐1 Baseline Grade 2‐4 Max Post Grade 3‐4Max 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

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