Adverse reactions : תופעות לוואי

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  All gradesa (%)    Grade 3-4a (%)
Frequency category
Infections and infestations
Upper respiratory                    Common               7 (3.8%)                 0 tract infectionsb
Lower respiratory                    Common               5 (2.7%)              2 (1.1%) tract infectionsc
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           Common              14 (7.5%)              3 (1.6%) increased
Alanine aminotransferase             Common              13 (7.0%)              2 (1.1%) increased

Adverse Reaction                                                        Rezurock Pooled chronic GVHD
(N=186)
All severity grades         All gradesa (%)              Grade 3-4a (%) Frequency category
Gamma-                                         Common                     9 (4.8%)                   2 (1.1%) glutamyltransferase increased
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                     Common                     7 (3.8%)                       0 increased
Blood creatine phosphokinase                   Common                    4 (2.2%)                    1 (0.5%) increased
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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/