4.1. Therapeutic indications

Rezurock is indicated for the treatment of patients aged 12 years and older with chronic graft-versus-host disease (chronic GVHD) who have received at least two prior lines of systemic therapy.

4.2. Posology and method of administration

Rezurock treatment should be initiated and supervised by physicians experienced in the management of chronic GVHD.

Posology

The recommended dose of Rezurock is 200 mg administered orally once daily at approximately the same time with a meal.

Treatment should continue until disease progression or unacceptable toxicity.

A complete blood cell count and liver function test must be performed before initiating therapy with Rezurock.

Dose modification due to adverse reactions

Perform liver function tests at least monthly throughout treatment (see section 4.4).

The recommended Rezurock dose modifications for hepatotoxicity and other adverse reactions are provided in Table 1.

Table 1: Dose modifications for adverse reactions

Criteria*

Rezurock Dosage Modifications

Grade 3 ALT or AST (>5 to 20 × ULN) or

Grade 2 bilirubin (>1.5 to 3 × ULN)

Hold Rezurock until recovery to ≤ Grade 1, then resume Rezurock at the recommended dose at physician's discretion.

Grade 4 ALT or AST (>20 × ULN) or

Grade ≥3 bilirubin (>3 × ULN)

Permanently discontinue Rezurock.

Other Grade 3 adverse reactions

Hold Rezurock until recovery to ≤ Grade 1, then resume Rezurock at the recommended dose at physician's discretion.

Other Grade 4 adverse reactions

Permanently discontinue Rezurock.

ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal.

*Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening. Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.3 (NCI-CTCAE v4.3). See section 4.8.

Dose modification due to drug interactions

Strong CYP3A4 inducers and Proton Pump Inhibitors decrease the exposure of belumosudil (see section 4.5).

Strong CYP3A Inducers

Increase the dosage of Rezurock to 200 mg twice daily when co-administered with strong CYP3A inducers.

Proton Pump Inhibitors

Increase the dosage of Rezurock to 200 mg twice daily when co-administered with proton pump inhibitors.

Delayed or missed dose

If a dose is missed or delayed for less than 12 hours after the scheduled dose, the dose should be taken as soon as possible on the same day with a return to the normal schedule the following day.

If a dose is missed or delayed for more than 12 hours after the scheduled dose, the dose should be taken at the usual time the following day.

If a patient vomits following the intake of a dose, the next dose should be taken at the usual time the following day.

Patients should not take extra doses to make up the missed dose.

Special populations

Hepatic impairment

Use in patients with moderate hepatic impairment (Child-Pugh B) or severe hepatic impairment (Child-Pugh C) without liver GVHD is not recommended (see section 5.2). Dose modification is not recommended when administering belumosudil to patients with mild hepatic impairment (Child-Pugh A).

Monitor patients frequently for adverse reactions.

Renal impairment

No dose modification of Rezurock is required in patients with mild or moderate renal impairment (creatinine clearance ≥ 30 mL/min).

No data are available for patients with severe renal impairment (creatinine clearance < 30 mL/min) or for patients with end-stage renal disease on dialysis (see sections 5.1 and 5.2). Use with caution.

Elderly patients (≥65 years)

No additional dose adjustments are recommended for elderly patients (see sections 5.1 and 5.2).

Paediatric population

The posology is the same in adults and adolescents aged 12 to 18 years.

The safety and efficacy of Rezurock in children and adolescents aged below 12 years of age have not been established. No data are available (see section 5.1).

Method of administration

For oral use.

Rezurock should be taken at approximately the same time each day with a meal (see section 5.2).

The film-coated tablet should not be broken, crushed or chewed.

4.3. Contraindications

Pregnancy.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Women of childbearing potential

Women of childbearing potential should be advised to avoid becoming pregnant while taking belumosudil and of the potential risk to a foetus, and to have a pregnancy test prior to starting treatment with belumosudil.

Women of childbearing potential must use a highly effective method of contraception during treatment with belumosudil and for at least one week after the last dose of belumosudil (see sections 4.6 and 5.3).

Male patients

Male patients with female partners of childbearing potential should be advised that their female partners should avoid becoming pregnant while taking belumosudil and of the potential risk to a foetus.

Males with female partners of childbearing potential must use a highly effective method of contraception during treatment with belumosudil and for at least a week after the last dose of belumosudil (see sections 4.6 and 5.3).

Breast-feeding

Breast-feeding is not recommended during treatment with belumosudil and for at least one week after the last dose (see section 4.6).

Hepatotoxicity

Increases in liver function tests were observed in clinical studies with belumosudil and generally occurred early during treatment with the incidence decreasing thereafter (see section 4.8). Liver function tests should be performed prior to the initiation of treatment with belumosudil and monitored at least monthly during treatment with belumosudil and the dose should be adjusted for ≥ Grade 2 toxicities (see section 4.2)

4.5. Interaction with other medicinal products and other forms of interaction

Effect of CYP3A inhibitors on belumosudil

The co-administration of multiple doses of itraconazole (a strong CYP3A inhibitor) did not alter exposure to belumosudil to any clinically relevant extent.

Effect of CYP3A inducers on belumosudil

The co-administration of multiple doses of rifampin (a strong CYP3A4 inducer) decreased belumosudil Cmax by 59% and AUC by 72%. The co-administration of strong CYP3A4 inducers with belumosudil may decrease belumosudil exposure. Increase the dose of belumosudil to 200 mg twice daily (see section 4.2).

The co-administration of moderate CYP3A4 inducers e.g., efavirenz is predicted to have a reduced effect on belumosudil as compared to strong CYP3A4 inducers. The co-administration of moderate CYP3A4 inducers with belumosudil may decrease belumosudil exposure. No dose adjustment is recommended.

Effect of proton pump inhibitors on belumosudil

The co-administration of multiple doses of rabeprazole decreased belumosudil Cmax by 87% and AUC by 80%. The co-administration of multiple doses of omeprazole decreased belumosudil Cmax by 68% and AUC by 47%. The co-administration of proton pump inhibitors with belumosudil may decrease belumosudil exposure. Increase the dose of belumosudil to 200 mg twice daily (see section 4.2).

Effect of other gastric acid reducing agents on belumosudil

The co-administration of belumosudil with gastric acid reducing agents other than proton pump inhibitors may decrease belumosudil exposure. No dose adjustment is recommended, however belumosudil and the gastric acid reducing agent should be taken 12 hours apart.

In vitro studies

Effect of belumosudil on CYP3A substrates

The co-administration of belumosudil is predicted to increase midazolam (a sensitive CYP3A substrate) Cmax and AUC approximately 1.30- and 1.65-fold, respectively. No dose adjustment is recommended.

The co-administration of belumosudil may increase exposure of sensitive CYP3A4 substrates with a narrow therapeutic index such as ciclosporin and tacrolimus. No dose adjustment is recommended.

Effect of belumosudil on CYP2C9 substrates

The co-administration of belumosudil is not expected to have clinically meaningful effect on the exposure of CYP2C9 substrates (such as warfarin).

Effect of belumosudil on CYP2C8 substrates

The co-administration of belumosudil is not expected to have clinically meaningful effect on the exposure of CYP2C8 substrates that are not an OATP1B1 substrate.

Effect of belumosudil on UGT1A1 substrates

Belumosudil is a weak inhibitor of UGT1A1, the clinical consequences are not known.

Transporters

Avoid coadministration of belumosudil with P-gp (e.g. dabigatran), OATP1B1, and BCRP substrates (e.g. rosuvastatin), for which minimal concentration changes may lead to serious toxicities. If coadministration cannot be avoided, decrease the P-gp, OATP1B1, and BCRP substrates dosage(s) in accordance with the respective Prescribing Information.

Belumosudil is an inhibitor of P-gp, OATP1B1, and BCRP. Coadministration of belumosudil with P- gp, OATP1B1, and BCRP substrates increased their plasma concentrations (see section 5.2), which may increase the risk of adverse reactions related to these substrates.

Certain CYP1A2 substrates

Caution should be advised when co-administering belumosudil with sensitive CYP1A2 substrates, for which minimal concentration changes may lead to serious toxicities (for examples of sensitive CYP1A2 substrates see Section 5.2 Pharmacokinetic properties).

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data on the use of belumosudil in pregnant women.

Belumosudil can cause foetal harm based on findings from animal studies (see section 5.3) and its mechanism of action. In pregnant rats and rabbits, oral administration of belumosudil resulted in maternal and/or foetal toxicity at doses below the recommended human dose. As a precautionary measure, belumosudil is contraindicated in pregnancy (see section 4.3).

Women of childbearing potential/Contraception in males and females

Women of childbearing potential should be informed that animal studies show belumosudil to be harmful to the developing foetus. Women of childbearing potential must have their pregnancy status verified prior to initiating treatment with belumosudil, and must use a reliable and highly effective method of contraception during treatment with belumosudil and for at least one week after the last dose of belumosudil. In case pregnancy should occur during treatment with belumosudil, a risk/benefit evaluation must be carried out on an individual basis with careful counselling regarding potential risks to the foetus (see sections 4.4 and 5.3).

Male patients with female partners of childbearing potential should be advised that their female partners should avoid becoming pregnant while taking belumosudil and of the potential risks to a foetus.

Male patients with female partners of childbearing potential must use a highly effective method of contraception during treatment and for at least one week after the last dose of belumosudil (see section 4.4).

Breast-feeding

It is unknown whether belumosudil or its metabolites are excreted in human milk. No data are available regarding the presence of belumosudil or its metabolites in animal or human milk or its effects on the breast-fed child, or on milk production. A risk to the infant cannot be excluded. Because of the potential for serious adverse reactions in a breast-fed child, breast-feeding should be discontinued during treatment with belumosudil and for at least one week after the last dose (see section 4.4).

Fertility

There are no human data on the effect of belumosudil on fertility.

Belumosudil repeat dose toxicity studies in rats demonstrated effects of general toxicity manifesting low body weight that may lead to impairment of female fertility (see section 5.3).

Based on testicular findings from rats and dogs, belumosudil may impair male fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

Belumosudil may cause fatigue and dizziness (see section 4.8). Patients should be advised not to drive or operate machines if they experience these symptoms.

4.8. Undesirable effects

Summary of safety profile

The overall safety profile of belumosudil in chronic graft-versus-host-disease is based on data from 186 patients from two clinical trials, KD025-208 and KD025-213.

The most common adverse reactions (≥5%) were asthenia (21.0%), nausea (12.4%), liver function test abnormalities of elevation of AST (7.5%), elevation of ALT (7.0%) and elevation of GGT (4.8%), headache (8.6%), diarrhoea (7.0%) and musculoskeletal pain (5.9%). The most common Grade 3 or 4 adverse reaction (≥ 2%) was asthenia (2.7%). Serious adverse reactions were pneumonia (1.1%), cellulitis, infectious colitis, staphylococcal bacteraemia, diarrhoea, nausea, vomiting, microangiopathic haemolytic anaemia, multiple organ dysfunction syndrome and cGVHD (0.5% each).

The most common adverse reactions leading to discontinuation were nausea (2.4%) and headache (2.4%). Adverse reactions leading to dose interruption occurred in 9.6% of patients and were mainly investigations (3.6%), including ALT increased, GGT increased and blood creatine phosphokinase increased (1.2% each), and infections (2.4%).

Tabulated list of adverse reactions

Table 2 presents the frequency category for adverse reactions reported in the open-label clinical trials (studies KD025-208 and KD025-213) with belumosudil. A total of 186 adult patients with chronic GVHD were treated with belumosudil 200 mg once daily (N=83), 200 mg twice daily (N=82), or 400 mg once daily (N=21) (see section 5.1). The median duration of treatment of the 83 patients with 200 mg once daily belumosudil was 9.2 months (range 0.5 to 44.7 months) and in the 186 patients across the three dosing cohorts was 9.89 months (range 0.39 to 44.71 months).

The frequency of adverse reactions are defined as follows:

Very common: (≥1/10)

Common: (≥1/100 to <1/10)

Uncommon: (≥1/1000 to <1/100)

Rare: (≥1/10,000 to <1/1000)

Very rare: (<1/10,000)

Not known: (cannot be estimated from the available data)

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 2: Adverse reactions (≥2%) in patients with chronic GVHD who received belumosudil

Adverse Reaction

Rezurock

Pooled chronic GVHD

(N=186)

All severity grades

Frequency category

All gradesa (%)

Grade 3-4a (%)

Infections and infestations

Upper respiratory tract infectionsb

Common

7 (3.8%)

0

Lower respiratory tract infectionsc

Common

5 (2.7%)

2 (1.1%)

Blood and lymphatic system disorders

Anaemia*

Common

6 (3.2%)

1 (0.5%)

Leukopeniad*

Common

9 (4.8%)

3 (1.6%)

Platelet count decreased

Common

5 (2.7%)

0

Metabolism and nutrition disorders

Decreased appetite

Common

7 (3.8%)

1 (0.5%)

Hyperglycaemia

Common

7 (3.8%)

0

Nervous system disorders

Headache

Common

16 (8.6%)

1 (0.5%)

Neuropathy peripheral

Common

6 (3.2%)

0

Dizziness

Common

4 (2.2%)

0

Vascular disorders

Hypertension

Common

6 (3.2%)

3 (1.6%)

Respiratory, thoracic and mediastinal disorders

Dyspneae

Common

7 (3.8%)

0

Coughf

Common

7 (3.8%)

0

Gastrointestinal disorders

Nausea

Very common

23 (12.4%)

2 (1.1%)

Diarrhoea

Common

13 (7.0%)

2 (1.1%)

Vomiting

Common

9 (4.8%)

1 (0.5%)

Abdominal paing

Common

5 (2.7%)

0

Constipation

Common

5 (2.7%)

1 (0.5%)

Hepatobiliary disorders

Aspartate aminotransferase increased

Common

14 (7.5%)

3 (1.6%)

Alanine aminotransferase increased

Common

13 (7.0%)

2 (1.1%)

Gamma-glutamyltransferase increased

Common

9 (4.8%)

2 (1.1%)

Skin and subcutaneous tissue disorders

Pruritus

Common

5 (2.7%)

0

Musculoskeletal and connective tissue disorders

Musculoskeletal painh

Common

11 (5.9%)

0

Muscle spasms

Common

8 (4.3%)

0

Blood alkaline phosphatase increased

Common

7 (3.8%)

0

Blood creatine phosphokinase increased

Common

4 (2.2%)

1 (0.5%)

Renal and urinary disorders

Blood creatinine increased

Common

4 (2.2%)

0

General disorders and administration site conditions

Astheniai

Very common

39 (21.0%)

5 (2.7%)

Oedemaj

Common

9 (4.8%)

0

Pyrexia

Common

3 (1.6%)

0

Investigations

Weight decreased

Common

6 (3.2%)

0

a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 and version 4.03 for studies KD025-208 and KD025-213, respectively

b includes upper respiratory tract infection, sinusitis.

c includes pneumonia, bronchitis, bronchitis viral.

d includes leukopenia, neutropenia, neutrophil count decreased, white blood cell count decreased, lymphocyte count decreased.

e includes dyspnea, dyspnea exertional.

f includes cough, productive cough.

g includes abdominal pain, abdominal pain upper.

h includes arthralgia, pain in extremity, back pain, neck pain.

i includes fatigue, asthenia, malaise.

j includes oedema peripheral, face oedema, localized oedema, swelling.

* See description of selected adverse reactions.

Description of selected adverse reactions

Hepatobiliary disorders

Elevations of liver enzymes were reported in patients treated with belumosudil in clinical trials. In two randomised, open label, multi-centre clinical trials in patients with cGVHD (studies KD025-208 and KD025-213), any grade laboratory abnormalities of increased AST, increased ALT and increased GGT occurred in 7.5%, 7.0% and 4.8%, respectively, of patients receiving belumosudil. Grade ≥ 3 laboratory abnormalities of increased AST, increased ALT and increased GGT occurred in 1.6%, 1.1% and 1.1%, respectively, of patients receiving belumosudil. Events resolved with few drug discontinuations, drug interruptions or dose reductions. The events generally occurred early during belumosudil treatment with the incidence decreasing thereafter. For recommended dosage modifications following elevations of liver enzymes see section 4.2. For recommended monitoring of liver enzymes see section 4.4.

Blood and lymphatic disorders

In the randomised, open label, multi-centre clinical trials in patients with cGVHD (studies KD025-208 and KD025-213), any grade anaemia and leukopenia occurred in 3.2% and 4.8%, respectively, of patients receiving belumosudil. Grade ≥ 3 events of anaemia and leukopenia occurred in 0.5% and 1.6%, respectively, of patients receiving belumosudil. Grade 3 cytopenias were often associated with relapse of the underlying malignancy.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected new or serious adverse reactions via the Yellow Card Scheme. You can find information on this at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No cases of overdose have been reported.

There is no specific experience in the management of belumosudil overdose in patients. There is no known antidote for overdoses with belumosudil. Single doses up to 1000 mg have been given with acceptable tolerability in healthy volunteers. Appropriate supportive treatment should be given.