Source: European Medicines Agency (EU) Revision Year: 2026 Publisher: Sanofi Winthrop Industrie, 82 Avenue Raspail, 94250 Gentilly, France
Pregnancy and breast-feeding (see section 4.6).
Patients with severe hepatic impairment (Child-Pugh C) without liver GVHD (see section 5.2).
Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.
Women of childbearing potential must have their pregnancy status verified prior to initiating treatment with belumosudil and must use highly effective 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 section 4.6). Patient must be informed of the potential hazard to the foetus.
While taking belumosudil, male patients with female partners of childbearing potential must be advised that their female partners should avoid becoming pregnant and of the potential risks to a foetus.
Male patients with female partners of childbearing potential must use highly effective contraception during treatment with belumosudil and for one week after the last dose of belumosudil (see section 4.6).
Breast-feeding should be discontinued during treatment and for at least one week after the last dose of belumosudil (see section 4.6).
Based on testicular findings and effects on sperm observed in animal studies from rats and dogs, belumosudil may impair male fertility (see section 4.6).
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 must be performed prior to the initiation of treatment and monitored at least monthly during treatment, and the dose must be adjusted for Grade ≥2 toxicities (see section 4.2).
Belumosudil is an inhibitor of both CYP3A4 and P-gp. Co-administration of belumosudil with medicinal products that are substrates of both CYP3A4 and P-gp (e.g., tacrolimus, sirolimus) may result in an increase in their concentrations (see section 4.5). As a result, dose adjustments may be required in accordance with the respective prescribing information. Close therapeutic drug monitoring until steady state is achieved is recommended.
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.
The co-administration of multiple doses of rifampicin (a strong CYP3A4 inducer) decreased belumosudil Cmax by 59% and AUC by 72%. The co-administration of strong CYP3A4 inducers (e.g. carbamazepine, phenytoin, rifampin [rifampicin], St. John's wort [Hypericum perforatum]) with belumosudil may decrease belumosudil exposure, which may reduce the efficacy. Co-administration of strong CYP3A4 inducers is not recommended. However, if co-administration is required, the dose of belumosudil should be increased to 200 mg twice daily. It is recommended to resume the belumosudil 200 mg once daily dose within 1 day after the last administration of the strong CYP3A inducer.
The co-administration of moderate CYP3A4 inducers e.g. efavirenz is expected 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.
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, which may reduce the efficacy. Therefore, the dose of belumosudil should be increased to 200 mg twice daily.
The co-administration of belumosudil with gastric acid reducing agents (e.g. H2 antagonist and antacids) other than proton pump inhibitors may decrease belumosudil exposure. No dose adjustment is recommended. It is recommended to take belumosudil 2 hours before or 12 hours after the gastric acid reducing agent.
Belumosudil is an inhibitor of OATP1B1 and BCRP. Co-administration of belumosudil (200 mg once daily) increased the AUC and Cmax of rosuvastatin (substrate of OATP1B1 and BCRP) by 4.4-fold and 3.6-fold, respectively. Co-administration of belumosudil with substrates of OATP1B1 and BCRP, for which concentration changes may lead to serious toxicities, is not recommended. If co-administration cannot be avoided, the OATP1B1 and BCRP substrate dose(s) should be decreased in accordance with the respective product information.
Belumosudil is an inhibitor of P-gp. Co-administration of belumosudil (200 mg once daily) increased the AUC and Cmax of dabigatran (substrate of P-gp) by 2.1-fold and 2.4-fold, respectively. Co-administration of belumosudil with substrates of P-gp, for which small concentration changes may lead to serious toxicities, is not recommended. If co-administration cannot be avoided, the P-gp substrate dose(s) should be decreased in accordance with the respective product information.
Belumosudil is an inhibitor of UGT1A1. Co-administration of belumosudil (200 mg once daily) with raltegravir (substrate of UGT1A1) decreased exposure to raltegravir glucuronide by 40%. Co-administration of belumosudil with sensitive substrates of UGT1A1, for which small concentration changes may lead to serious toxicities, is not recommended. If co-administration cannot be avoided, the UGT1A1 substrate dose(s) should be decreased in accordance with the respective product information.
In vitro findings have demonstrated that belumosudil is a reversible and time-dependent inhibitor of CYP1A2 and CYP3A4/5 and a time-dependent inhibitor of CYP2C19.
Clinical inhibition of these CYP enzymes in presence of belumosudil cannot be excluded at the recommended dose of 200 mg once daily. Co-administration of belumosudil with sensitive substrates of these enzymes, for which small concentration changes may lead to serious toxicities, is not recommended. If co-administration cannot be avoided, the substrate dose(s) should be decreased in accordance with the respective product information.
Belumosudil is an inhibitor of both CYP3A4 and P-gp. Co-administration of belumosudil with medicinal products that are substrates of both CYP3A4 and P-gp (e.g., tacrolimus, sirolimus) may result in a significant increase in their concentrations. Close therapeutic drug monitoring until steady state is achieved is recommended (see section 4.4).
Interaction studies have only been performed in adults.
Women of childbearing potential should use highly effective contraception during treatment with belumosudil and for at least one week after the last dose of belumosudil (see sections 4.4 and 5.3).
Male patients with female partners of childbearing potential must use highly effective contraception during treatment with belumosudil and for one week after the last dose of belumosudil (see section 4.4).
There are no data from the use of belumosudil in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3). REZUROCK is contraindicated during pregnancy (see section 4.3). REZUROCK is not recommended in women of childbearing potential not using highly effective contraception.
It is unknown whether belumosudil/metabolites are secreted in animal or human milk. A risk to the suckling child cannot be excluded. Breast-feeding is contraindicated (see section 4.3) during treatment with REZUROCK and for at least one week after the last dose (see section 4.4).
No human data are available to determine potential effects of belumosudil on fertility in females and males.
Belumosudil repeat dose toxicity studies in rats demonstrated adverse effects of general toxicity manifesting in low body weight that may lead to impairment of female fertility (see section 5.3).
Based on testicular findings and effects on sperm observed in animal studies, belumosudil may impair male fertility (see section 5.3).
REZUROCK has a minor influence on the ability to drive and use machines. It may cause fatigue or dizziness (see section 4.8). If patients experience related symptoms, driving or operating machines is not recommended.
The most common adverse reactions were fatigue (20.2%), diarrhoea (12.8%), nausea (11.7%), headache (10.6%), vomiting (8.5%), and aspartate aminotransferase (AST) increased (7.4%), alanine aminotransferase (ALT) increased (5.3%), and gamma-glutamyltransferase (GGT) increased (4.3%).
The most common Grade 3 or 4 adverse reaction was pneumonia, hypoxia and diarrhoea (2.1% each).
Serious adverse reactions were pneumonia (2.1%) and cellulitis, large intestine infection, periorbital cellulitis, staphylococcal bacteraemia, upper respiratory tract infection, hypoxia, pulmonary embolism, diarrhoea, nausea, tongue dysplasia, vomiting, and multiple organ dysfunction syndrome (1.1% each).
The most common adverse reaction leading to discontinuation of treatment was nausea (2.1%).
Adverse reactions leading to dose interruption occurred in 14.9% of patients and were nausea (2.1%) and gastroenteritis, large intestine infection, periorbital cellulitis, pneumonia, ALT increased, blood creatine phosphokinase increased, GGT increased, procalcitonin increased, diarrhoea, vomiting, fatigue, pulmonary embolism, neutropenia, arthralgia, neuropathy peripheral, and dermatitis bullous (1.1% each).
Long-term safety data beyond 12 months demonstrated that 13.8% of patients in the 200 mg once daily group experienced at least one related adverse reaction. The most frequent observed related adverse reactions were diarrhoea (4.3%), upper respiratory infections (2.1%), nausea (2.1%) and weight decreased (2.1%).
Table 2 presents the frequency category for adverse reactions reported in all open-label clinical trials with belumosudil 200 mg once daily in 94 patients. The median duration of treatment was 9.18 months (range 0.46 to 83.75 months).
Their frequency is defined using the following conventions: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000), not known (cannot be estimated from the available data). Within each system organ class, adverse reactions are presented in order of decreasing seriousness.
Table 2. Adverse reactions:
| Adverse reactions | All severity grades frequency category | All grades (%) | Grade 3-4 (%) |
| Infections and infestations | |||
| Upper respiratory tract infection | Common | 4 (4.3) | 0 |
| Pneumonia | Common | 2 (2.1) | 2 (2.1) |
| Cellulitis | Common | 2 (2.1) | 1 (1.1) |
| Gastroenteritis | Common | 1 (1.1) | 0 |
| Large intestine infection | Common | 1 (1.1) | 0 |
| Nasopharyngitis | Common | 1 (1.1) | 0 |
| Periorbital cellulitis | Common | 1 (1.1) | 0 |
| Sinusitis | Common | 1 (1.1) | 1 (1.1) |
| Staphylococcal bacteremia | Common | 1 (1.1) | 0 |
| Blood and lymphatic system disorders | |||
| Anaemia | Common | 3 (3.2) | 0 |
| Neutropenia | Common | 1 (1.1) | 1 (1.1) |
| Endocrine disorders | |||
| Hypothyroidism | Common | 2 (2.1) | 0 |
| Metabolism and nutrition disorders | |||
| Decreased appetite | Common | 6 (6.4) | 1 (1.1) |
| Hyperglycaemia | Common | 4 (4.3) | 0 |
| Hypophosphataemia | Common | 2 (2.1) | 0 |
| Hyperlipidaemia | Common | 2 (2.1) | 0 |
| Nervous system disorders | |||
| Headache | Very common | 10 (10.6) | 0 |
| Neuropathy peripheral | Common | 4 (4.3) | 0 |
| Dizziness | Common | 2 (2.1) | 0 |
| Paraesthesia | Common | 2 (2.1) | 0 |
| Migraine | Common | 1 (1.1) | 0 |
| Vascular disorders | |||
| Hypertension | Common | 2 (2.1) | 1 (1.1) |
| Hypotension | Common | 1 (1.1) | 1 (1.1) |
| Respiratory, thoracic and mediastinal disorders | |||
| Dyspnoea | Common | 6 (6.4) | 1 (1.1) |
| Cough | Common | 2 (2.1) | 0 |
| Hypoxia | Common | 2 (2.1) | 2 (2.1) |
| Pulmonary embolism | Common | 2 (2.1) | 1 (1.1) |
| Gastrointestinal disorders | |||
| Nausea | Very common | 11 (11.7) | 1 (1.1) |
| Diarrhoea | Very common | 12 (12.8) | 2 (2.1) |
| Vomiting | Common | 8 (8.5) | 1 (1.1) |
| Constipation | Common | 5 (5.3) | 1 (1.1) |
| Abdominal pain | Common | 2 (2.1) | 0 |
| Abdominal distension | Common | 2 (2.1) | 0 |
| Abdominal discomfort | Common | 2 (2.1) | 0 |
| Tongue dysplasia | Common | 1 (1.1) | 0 |
| Skin and subcutaneous tissue disorders | |||
| Pruritus | Common | 1 (1.1) | 0 |
| Rash | Common | 1 (1.1) | 0 |
| Dermatitis bullous | Common | 1 (1.1) | 0 |
| Musculoskeletal and connective tissue disorders | |||
| Back pain | Common | 3 (3.2) | 0 |
| Muscle spasms | Common | 2 (2.1) | 0 |
| Arthralgia | Common | 2 (2.1) | 0 |
| General disorders and administration site conditions | |||
| Fatigue | Very common | 19 (20.2) | 1 (1.1) |
| Oedema peripheral | Common | 3 (3.2) | 0 |
| Pyrexia | Common | 2 (2.1) | 0 |
| Malaise | Common | 1 (1.1) | 0 |
| Localized oedema | Common | 1 (1.1) | 0 |
| Multiorgan dysfunction syndrome | Common | 1 (1.1) | 1 (1.1) |
| Swelling | Common | 1 (1.1) | 0 |
| Investigations | |||
| Aspartate aminotransferase increased | Common | 7 (7.4) | 1 (1.1) |
| Alanine aminotransferase increased | Common | 5 (5.3) | 1 (1.1) |
| Gamma-glutamyltransferase increased | Common | 4 (4.3) | 1 (1.1) |
| Weight decreased | Common | 3 (3.2) | 0 |
| Blood alkaline phosphatase increased | Common | 3 (3.2) | 0 |
| Blood creatine phosphokinase increased | Common | 3 (3.2) | 1 (1.1) |
| Platelet count decreased | Common | 2 (2.1) | 0 |
| Blood creatinine increased | Common | 2 (2.1) | 0 |
| Lymphocyte count decreased | Common | 2 (2.1) | 0 |
| White blood cell count decreased | Common | 2 (2.1) | 1 (1.1) |
| Bilirubin conjugated increased | Common | 1 (1.1) | 0 |
| Procalcitonin increase | Common | 1 (1.1) | 0 |
AST, ALT and GGT increased within the first month of belumosudil treatment with the incidence decreasing thereafter. For recommended dose modifications following elevations of liver enzymes, see section 4.2. For recommended monitoring of liver enzymes, see section 4.4.
Anaemia (all severity grade) occurred in 12.5% of patients and grade ≥3 anaemia occurred in 4.2% of patients. There were no consistent differences in the time to first occurrence of anaemia across dose groups in the pooled analysis. The highest incidence of anaemia was between 3 and <6 months. The single event of severe neutropenia occurred on day 253, i.e. approximately 8 months after initiating treatment with belumosudil. See modifications in case of adverse reactions, section 4.2.
There were no differences in adverse reaction frequency for mild and moderate cGVHD patients when evaluated based on normal renal function, mild and moderate renal impairment. For severe cGVHD patients, a higher frequency of adverse reactions was observed in patients with moderate renal impairment compared to mild impairment and normal renal function.
There is limited experience in adolescents. A total of three adolescent patients (2 in the 200 mg once daily group and 1 in the 200 mg twice daily group) received belumosudil in study KD025-213. From the post-marketing setting and compassionate use 112 adolescents have received treatment with belumosudil and reported safety information. The most frequently reported adverse reactions were nausea (4.6%) and headache (2.8%). The safety profile of belumosudil in paediatric patients (aged ≥12 years) with cGVHD was consistent in type, nature, and severity with the known safety profile in adult patients.
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 adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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