Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
Myelodysplastic syndromes
The most frequently reported adverse drug reactions in patients receiving Reblozyl (at least 15% of patients) were fatigue, diarrhoea, nausea, asthenia, dizziness, oedema peripheral and back pain. The most commonly reported Grade ≥ 3 adverse drug reactions (at least 2% of patients) included hypertension events (12.5%), syncope (3.6%), dyspnoea (2.7%), fatigue (2.4%) and thrombocytopenia (2.4%). The most commonly reported serious adverse drug reactions (at least 1% of patients) were urinary tract infection (1.8%), dyspnoea (1.5%) and back pain (1.2%).

Asthenia, fatigue, nausea, diarrhoea, hypertension, dyspnoea, dizziness and headache occurred more frequently during the first 3 months of treatment.

Treatment discontinuation due to an adverse event occurred in 10.1% of patients treated with luspatercept. The most common reason for discontinuation in the luspatercept treatment arm was progression of underlying MDS.

Dose delays due to pre-dose Hb ≥12.0 g/dL occurred in 24.3% of luspatercept treated patients.

Transfusion-dependentβ-thalassaemia
The most frequently reported adverse drug reactions in patients receiving Reblozyl (at least 15% of patients) were headache, bone pain and arthralgia. The most commonly reported Grade ≥ 3 adverse drug reaction was hyperuricaemia. The most serious adverse reactions reported included thromboembolic events of deep vein thrombosis, ischaemic stroke portal vein thrombosis and pulmonary embolism (see section 4.4).

Bone pain, asthenia, fatigue, dizziness and headache occurred more frequently during the first 3 months of treatment.



Treatment discontinuation due to an adverse reaction occurred in 2.6% of patients treated with luspatercept. The adverse reactions leading to treatment discontinuation in the luspatercept treatment arm were arthralgia, back pain, bone pain and headache.

Non-transfusion-dependent β-thalassaemia
The most frequently reported adverse drug reactions in patients receiving Reblozyl (at least 15% of patients) were bone pain, headache, arthralgia, back pain, prehypertension and hypertension. The most commonly reported Grade ≥ 3 and most serious adverse reaction (at least 2% of patients) reported was traumatic fracture. Spinal cord compression due to EMH masses occurred in 1% of patients.

Bone pain, back pain, upper respiratory tract infection, arthralgia, headache and prehypertension occurred more frequently during the first 3 months of treatment.

The majority of adverse drug reactions were non-serious and did not require discontinuation.
Treatment discontinuation due to an adverse reaction occurred in 3.1% of patients treated with luspatercept. Adverse reactions leading to treatment discontinuation were spinal cord compression, extramedullary haemopoiesis and arthralgia.

Tabulated list of adverse reactions
The highest frequency for each adverse reaction that was observed and reported in patients in the pivotal studies in MDS, β-thalassaemia and the long-term follow-up study is shown in Table 7 below.
The adverse reactions are listed below by body system organ class and preferred term. 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), very rare (< 1/10,000) and not known (frequency cannot be estimated from the available data).

Table 7: Adverse drug reactions (ADRs) in patients treated with Reblozyl for MDS and / or β- thalassaemia in the four pivotal studies
System organ class                   Preferred term         Frequency        Frequency (all grades) for (all grades) for
MDS              β-thalassaemia
Infections and infestations          bronchitis             Common           Commona urinary tract          Very common Commona infection respiratory tract      Common infection upper respiratory      Common           Very commona tract infection influenza              Common           Very common
Blood and lymphatic system           extramedullary         Not known VII    Common disorders                            haemopoiesis VI thrombocytopenia       Common
Immune system disorders              hypersensitivity I, VI Common           Common Metabolism and nutrition             hyperuricaemia         Common           Common disorders                            dehydration            Common decreased appetite     Common electrolyte            Very common imbalanceIX
Psychiatric disorders                insomnia               Common           Very commonb anxiety                Common           Common irritability                            Common confusional state      Common
Nervous system disorders             dizziness              Very common Very common headache               Very common Very common migraine                                Commonb spinal cord                             Common
System organ class            Preferred term        Frequency        Frequency (all grades) for (all grades) for
MDS              β-thalassaemia compressionVI syncope/presyncope    Common           Commona
Ear and labyrinth disorders   vertigo/vertigo       Common           Commona positional
Cardiac disorders             atrial fibrillation   Common cardiac failure       Common
Vascular disorders            prehypertension                        Very commonb hypertensionII, VI    Very common      Very common tachycardia           Common thromboembolic        Common           Common eventsIV, VI
Respiratory, thoracic and     cough                 Very common mediastinal disorders         epistaxis             Common           Commonb dyspnoeaVIII          Very common      Common
Gastrointestinal disorders    abdominal pain        Common           Very commonb abdominal             Common discomfort diarrhoea             Very common      Very commona



System organ class                                 Preferred term                Frequency               Frequency (all grades) for        (all grades) for
MDS                     β-thalassaemia nausea                        Very common             Very common
Skin and subcutaneous tissue                       hyperhidrosis                 Common disorders
Musculoskeletal and connective                     back pain                     Very common             Very common tissue disorders                                   arthralgiaVI                  Common                  Very common bone painVI                   Common                  Very common myalgia                       Common muscular weakness             Common
Renal and urinary disorders                        proteinuria                                           Commonb albuminuria                                           Commonb kidney injuryX                Common
General disorders and                              non-cardiac chest      Common administration site conditions                     pain influenza-like illness Common fatigue                       Very common             Very commona asthenia                      Very common             Very common injection site                Common                  Common reactionsIII, VI oedema peripheral             Very common
Investigations                                     alanine                       Common                  CommonV aminotransferase increased aspartate                     Common                  Very commonV aminotransferase increased blood bilirubin               Common                  Very commonV increased gamma-                        Common glutamyltransferase increased
Injury, poisoning and procedural                   traumatic fractureVI                                  Commonb complications

The four pivotal studies are ACE-536-MDS-001(ESA-refractory or -intolerant MDS), ACE-536-MDS-002 (MDS), ACE- 536-B-THAL-001 (transfusion-dependent β-thalassaemia) and ACE-536-B-THAL-002 (non-transfusion-dependent β- thalassaemia).
I Hypersensitivity includes eyelid oedema, drug hypersensitivity, swelling face, periorbital oedema, face oedema,  angioedema, lip swelling, drug eruption.
II Hypertension includes essential hypertension, hypertension and hypertensive crisis.
III
Injection site reactions include injection site erythema, injection site pruritus, injection site swelling and injection site rash.
IV
TEEs include deep vein thrombosis, portal vein thrombosis, ischaemic stroke and pulmonary embolism.
V Frequency is based on laboratory values of any grade.
VI See section 4.8 Description of selected adverse reactions.
VII Reported only in post-marketing.
VIII
Dyspnoea includes dyspnoea exertional for ACE-536-MDS-002.
IX
Electrolyte imbalance includes bone, calcium, magnesium and phosphorus metabolism disorders and electrolyte and fluid balance conditions.
X ADR includes similar/grouped terms.
a ADRs observed in transfusion-dependent β-thalassaemia study ACE-536-B-THAL-001.
b ADRs observed in non-transfusion-dependent β-thalassaemia study ACE-536-B-THAL-002.



Description of selected adverse reactions

Bone pain
Bone pain was reported in 2.4% of MDS patients treated with luspatercept with all events being Grade 1-2.

Bone pain was reported in 19.7% of transfusion-dependent β-thalassaemia patients treated with luspatercept (placebo 8.3%) with most events (41/44) being Grade 1-2, and 3 events Grade 3. One of the 44 events was serious, and 1 event led to treatment discontinuation. Bone pain was most common in the first 3 months (16.6%) compared to months 4-6 (3.7%).

Bone pain was reported in 36.5% of non-transfusion-dependent β-thalassaemia patients treated with luspatercept (placebo 6.1%) with most events (32/35) being Grade 1-2, and 3 events Grade 3. No patient discontinued due to bone pain.

Arthralgia
Arthralgia was reported in 7.2% of MDS patients treated with luspatercept with 0.6% being ≥ Grade 3.

Arthralgia was reported in 19.3% of transfusion-dependent β-thalassaemia patients treated with luspatercept (placebo 11.9%) and led to treatment discontinuation in 2 patients (0.9%).

Arthralgia was reported in 29.2% of non-transfusion-dependent β-thalassaemia patients treated with luspatercept (placebo 14.3%) with most events (26/28) being Grade 1-2, and 2 events Grade 3.
Arthralgia led to treatment discontinuation in 1 patient (1.0%).

Hypertension
MDS and β-thalassaemia patients treated with luspatercept had an average increase in systolic and diastolic blood pressure of up to 5 mmHg from baseline not observed in patients receiving placebo.

Hypertension events were reported in 12.5% of MDS patients treated with luspatercept (placebo 9.2%). Grade 3 hypertension events were reported in 25/335 patients (7.5%) treated with luspatercept (placebo 3.9%).

Hypertension was reported in 19.8% of non-transfusion-dependent β-thalassaemia patients treated with luspatercept (placebo 2.0%). Most events (16/19) were Grade 1-2 with 3 events Grade 3 (3.1%) in patients treated with luspatercept (placebo 0.0%). An increased incidence of hypertension was observed over time in the first 8-12 months in non-transfusion-dependent β-thalassaemia patients treated with luspatercept. See section 4.4.

Hypertension was reported in 8.1% of transfusion-dependent β-thalassaemia patients treated with luspatercept (placebo 2 .8%). See section 4.4. Grade 3 events were reported in 4 patients (1.8%) treated with luspatercept (placebo 0.0%).

Hypersensitivity
Hypersensitivity-type reactions included eyelid oedema, drug hypersensitivity, swelling face, periorbital oedema, face oedema, angioedema, lip swelling, drug eruption.

Hypersensitivity-type reactions were reported in 4.6% of MDS patients (placebo 2.6%) with all events being Grade 1-2 in patients treated with luspatercept.

Face oedema occurred in 3.1% of non-transfusion-dependent β-thalassaemia patients (placebo 0.0%).

Hypersensitivity-type reactions were reported in 4.5% of transfusion-dependent β-thalassaemia patients treated with luspatercept (placebo 1.8%) with all events being Grade 1-2. Hypersensitivity led to treatment discontinuation in 1 patient (0.4%).


Injection site reactions
Injection site reactions included injection site erythema, injection site pruritus, injection site swelling and injection site rash.

Injection site reactions were reported in 3.6% of MDS patients .

Injection site reactions were reported in 2.2% of transfusion-dependent β-thalassaemia patients (placebo 1.8%) with all events Grade 1 and none leading to discontinuation.

Injection site reactions were reported in 5.2% of non-transfusion-dependent β-thalassaemia patients (placebo 0.0%) with all events Grade 1 and none leading to discontinuation.

Thromboembolic events
TEEs included deep vein thrombosis, portal vein thrombosis, ischaemic stroke and pulmonary embolism.

TEEs were reported in 3.9% of MDS patients (placebo 3.9%). Reported TEEs included cerebral ischemia and cerebrovascular accident in 1.2% of patients. All TEEs occurred in patients with significant risk factors (atrial fibrillation, stroke or heart failure and peripheral vascular disease) and were not correlated with elevated Hb, platelet levels or hypertension. See section 4.4.

TEEs occurred in 3.6% of transfusion-dependent β-thalassaemia patients receiving luspatercept (placebo 0.9%).

TEE (superficial thrombophlebitis) occurred in 0.7% of patients in the open-label phase of the pivotal study in non-transfusion-dependent β-thalassaemia.

All TEEs events were reported in patients who had undergone splenectomy and had at least one other risk factor. See section 4.4.

Extramedullary haemopoiesis masses
EMH masses occurred in 10/315 (3.2%) transfusion-dependent β-thalassaemia patients receiving luspatercept (placebo 0.0%). Five events were Grade 1-2, 4 events were Grade 3, and 1 event was Grade 4. Three patients discontinued due to EMH masses. See section 4.4.

EMH masses occurred in 6/96 (6.3%) non-transfusion-dependent β-thalassaemia patients receiving luspatercept (placebo 2.0%). Most (5/6) were Grade 2 and 1 was Grade 1. One patient discontinued due to EMH masses. During the open-label portion of the study, EMH masses were observed in 2 additional patients for a total of 8/134 (6.0%) of patients. Most (7/8) were Grade 1-2 and manageable with standard clinical practice. In 6/8 patients, luspatercept was continued after onset of event. See section 4.4.

EMH masses may also occur after extended treatment with luspatercept (i.e. after 96 weeks).

Spinal cord compression
Spinal cord compression or symptoms due to EMH masses occurred in 6/315 (1.9%) transfusion-dependent β-thalassaemia patients receiving luspatercept (placebo 0.0%). Four patients discontinued treatment due to Grade ≥ 3 symptoms of spinal cord compression.

Spinal cord compression due to EMH masses occurred in 1/96 (1.0%) non-transfusion-dependent β-thalassaemia patient with a history of EMH masses receiving luspatercept (placebo 0.0%). This patient discontinued treatment due to Grade 4 spinal cord compression. See section 4.4.

Traumatic fracture
Traumatic fracture occurred in 1 (0.4%) transfusion-dependent β-thalassaemia patient receiving luspatercept (placebo 0.0%).

Traumatic fracture occurred in 8 (8.3%) non-transfusion-dependent β-thalassaemia patients receiving luspatercept (placebo 2.0%) with Grade ≥ 3 events reported for 4 patients (4.2%) treated with luspatercept and in 1 patient (2.0%) receiving placebo.

Immunogenicity
In clinical studies in MDS, an analysis of 395 MDS patients who were treated with luspatercept and who were evaluable for the presence of anti-luspatercept antibodies showed that 36 (9.1%) patients tested positive for treatment -emergent anti-luspatercept antibodies, including 18 (4.6%) patients who had neutralising antibodies against luspatercept.

In clinical studies in transfusion-dependent and non-transfusion-dependentβ-thalassaemia, an analysis of 380 β-thalassaemia patients who were treated with luspatercept and who were evaluable for the presence of anti-luspatercept antibodies showed that 7 (1.84%) patients tested positive for treatment emergent anti-luspatercept antibodies, including 5 (1.3%) patients who had neutralising antibodies against luspatercept.

Luspatercept serum concentration tended to decrease in the presence of anti-luspatercept antibodies.
There were no severe systemic hypersensitivity reactions reported for patients with anti-luspatercept antibodies. There was no association between hypersensitivity type reactions or injection site reactions and presence of anti-luspatercept antibodies. Patients with treatment -emergent anti-luspatercept antibodies were more likely to report a serious treatment -emergent adverse event (69.4% [25/36] for anti-luspatercept antibodies -positive patients vs. 45.7% [164/359] for anti-luspatercept antibodies -negative patients) or a Grade 3 or 4 treatment -emergent adverse event (77.8% [28/36] for anti-luspatercept antibodies -positive patients vs. 56.8% [204/359] for anti-luspatercept antibodies -negative patients) compared to patients without anti-luspatercept antibodies in the TD MDS pool.

Other special population

MDS patients without ring sideroblast (RS-)
RS- patients are more likely to experience serious adverse events, Grade 5 treatment -emergent adverse events, adverse events leading to drug discontinuation or dose reduction compared to patients with ring sideroblasts (RS+). In ACE-536-MDS-002 study, RS- patients showed higher incidence of some adverse reactions compared to RS+ patients in both treatment arms. When comparing RS subgroups in the luspatercept arm, asthenia, nausea, vomiting, dyspnoea, cough, thromboembolic events, alanine aminotransferase increased, aspartate aminotransferase increased, and thrombocytopenia occurred more frequently in the RS- subgroup.

MDS patients with mutational status SF3B1 non-mutated
Patients with mutational status SF3B1 non-mutated are more likely to experience Grade 3 or 4 treatment -emergent adverse events, serious adverse events, Grade 5 treatment -emergent adverse events, adverse events leading to drug discontinuation, dose reduction as well as dose interruption compared to patients with mutational status SF3B1 mutated. Known luspatercept adverse reactions with a frequency ≥ 3% higher in the non-mutated SF3B1 luspatercept arm subgroup included vomiting, dyspnoea, and hypertension.


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 event should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il.