Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The safety of belzutifan was evaluated in an open-label Phase 2 clinical study (Study-004), in 61 patients with VHL disease-associated RCC and who did not require immediate nephrectomy or partial nephrectomy. Patients were treated with 120 mg belzutifan once daily. The median duration of exposure to belzutifan was 28.9 months (range: 1.9 to 37.5).

The most common adverse reactions with belzutifan were anaemia (90%), fatigue (71%), dizziness (44%) and nausea (36%).

The most common Grade 3 or 4 adverse reactions were anaemia (10%), and fatigue (5%).

Serious adverse reactions occurred in 5% of patients who received belzutifan, including anaemia, dyspnoea and hypoxia (1 patient each).

Dose interruption of belzutifan due to adverse reactions occurred in about 23% of patients. The most common adverse reactions resulting in dose interruption of belzutifan were fatigue (13.1%), nausea (8.2%), and anaemia (4.9%).
Dose reduction of belzutifan due to adverse reactions occurred in about 11.5% of patients. The adverse reactions resulting in dose reduction of belzutifan were fatigue (8.2%), anaemia, and hypoxia (one patient each 1.6%).

Tabulated list of adverse reactions.
Adverse reactions reported in clinical studies of belzutifan are listed in the table below by MedDRA system organ class and by frequency. Frequencies are defined as 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), and very rare (< 1/10,000).

Table 2: Adverse drug reactions for Welireg 120 mg Once Daily

Adverse Drug Reaction                 All Grades                      Grade 3 – 4 Blood and lymphatic disorders
Anaemia                           Very common                     Common Nervous system disorders
Dizziness                         Very common                     Very rare Respiratory, thoracic and mediastinal disorders
Dyspnoea                         Very common                   Common Hypoxia                          Common                        Common Gastrointestinal disorders
Nausea                           Very common                   Very rare General disorders and administration site disorders
Fatigue                          Very common                   Common Investigations
Weight Increased                     Very common                   Common 
The safety of belzutifan was also evaluated in a Phase 1 clinical study (Study-001), in 58 patients with non-VHL disease-associated advanced solid tumours, treated with belzutifan 120 mg once daily.
Study-001 patients differed from VHL-associated RCC patients (Study-004). Study-001 patients were older (median: 62.5 years old; range: 39 to 75 vs. 41.0; range: 19 to 66), had worse ECOG PS (scale 1: 63.8% in study-001 vs. 16.4% in study-004), had metastatic disease, had prior systemic therapies, had more comorbidities, and had lower baseline haemoglobin levels at treatment initiation (median: 119; range: 89 to 173 vs. 140; range 91 to 171). Study-001 had a median duration of exposure to belzutifan of 25.4 weeks (range: 1.1 to 145.9 weeks). The adverse reactions with belzutifan in Study-001 were anaemia (76%), fatigue (71%), dyspnoea (47%), nausea (35%), hypoxia (29%), dizziness (22%) and weight increased (10%). The adverse reactions resulting in dose interruption of belzutifan were hypoxia (10.3%), anaemia (8.6%), dyspnoea (5.2%), fatigue (1.7%) and nausea (1.7%). The adverse reactions resulting in dose reduction of belzutifan were hypoxia (3.4%), nausea (1.7%) and fatigue (1.7%). The adverse reactions resulting in discontinuation were hypoxia (3.4%) and fatigue (1.7%).

Description of selected adverse reactions

Anaemia due to decreased erythropoietin (see section 5.1)
In Study-004 anaemia was reported in 90.2% of all patients with Grade 3 anaemia occurring in 9.8%.
Median time to onset of all Grade anaemia events was 31 days (range: 1 day to 8.38 months). Most of the anaemia occurred in the first 3 months of treatment initiation and was not progressive. Three (4.9%) participants had anaemia events leading to study drug interruption and 1 participant (1.6%) had a dose reduction due to anaemia. No participant discontinued treatment due to anaemia. Of the 13 patients that were treated with an ESA, 4 received treatment with both an ESA and blood transfusions, while 9 received treatment with an ESA alone. Patients received an ESA based on haemoglobin levels and physician discretion. Anaemia was reported as resolved in 13 (21.3%) of participants and resolving or not yet resolved in 40 (65.6%) participants.

In another clinical study (Study-001) for the treatment of non-VHL disease-associated advanced solid tumours using the same dose of belzutifan, anaemia was reported in 44 patients (75.9%) with Grade 3 anaemia occurring in 16 patients (27.6%).

Hypoxia (see section 5.2)
In Study-004 Grade 3 hypoxia occurred in 1 patient (1.6%). This case of hypoxia occurred within 2 months of treatment initiation in a patient with previously undiagnosed restrictive lung disease and was asymptomatic. This patient did not receive supplemental oxygen and was managed with dose reduction to 80 mg once daily with no recurrence of hypoxia. In another clinical study (Study-001) for the treatment of non-VHL disease-associated advanced solid tumours using the same dose of belzutifan, hypoxia occurred in 17 patients (29.3%), with Grade 3 hypoxia occurring in 9 patients (15.5%).
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 Regulations by using an online form: https://sideeffects.health.gov.il