Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Bristol-Myers Squibb Pharma EEIG, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland
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In β-thalassaemia patients, thromboembolic events (TEEs) were reported in 3.6% (8/223) of patients treated with luspatercept in the double-blind phase of the pivotal study in transfusion-dependent patients and in 0.7% (1/134) of patients during the open-label phase of the pivotal study in non-transfusion-dependent patients. Reported TEEs included deep vein thrombosis (DVT), portal vein thrombosis, pulmonary emboli, ischaemic stroke and superficial thrombophlebitis (see section 4.8). All patients with TEEs were splenectomised and had at least one other risk factor for developing TEE (e.g. history of thrombocytosis or concomitant use of hormone replacement therapy). The occurrence of TEE was not correlated with elevated Hb levels. The potential benefit of treatment with luspatercept should be weighed against the potential risk of TEEs in β-thalassaemia patients with a splenectomy and other risk factors for developing TEE. Thromboprophylaxis according to current clinical guidelines should be considered in patients with β-thalassaemia at higher risk.
In MDS patients, TEEs were reported in 3.9% (13/335) of patients treated with luspatercept. Reported TEEs included cerebral ischemia and cerebrovascular accident in 1.2% (4/335) 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.
In transfusion-dependent β-thalassaemia patients, extramedullary haemopoiesis (EMH) masses were observed in 3.2% (10/315) of patients treated with luspatercept in the pivotal study and in the long-term follow-up study. Spinal cord compression symptoms due to EMH masses occurred in 1.9% (6/315) of patients treated with luspatercept (see section 4.8).
In non-transfusion-dependent β-thalassaemia patients, EMH masses were observed in 6.3% (6/96) of patients treated with luspatercept in the pivotal study. Spinal cord compression due to EMH masses occurred in 1.0% (1/96) of patients treated with luspatercept. 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 (see section 4.8).
Patients with EMH masses may experience worsening of these masses and complications during treatment. Signs and symptoms may vary depending on anatomical location. Patients should be monitored at initiation and during treatment for symptoms and signs or complications resulting from the EMH masses, and be treated according to clinical guidelines. Treatment with luspatercept must be discontinued in case of serious complications due to EMH masses.
In MDS and β-thalassaemia pivotal studies, patients treated with luspatercept had an average increase in systolic and diastolic blood pressure of up to 5 mmHg from baseline (see section 4.8).
An increased incidence of hypertension was observed in the first 12 months of treatment in non-transfusion-dependent β-thalassaemia patients treated with luspatercept (see section 4.8).
The treatment must be started only if the blood pressure is adequately controlled. Blood pressure should be monitored prior to each luspatercept administration. Luspatercept dose may require adjustment or may be delayed, and patients should be treated for hypertension as per current clinical guidelines (see Table 6 in section 4.2). The potential benefit of treatment with Reblozyl should be re-evaluated in case of persistent hypertension or exacerbations of pre-existing hypertension.
In transfusion-dependent β-thalassaemia patients, traumatic fractures were observed in 0.4% (1/223) of patients treated with luspatercept.
In non-transfusion-dependent β-thalassaemia patients, traumatic fractures were observed in 8.3% (8/96) of patients treated with luspatercept. Patients should be informed of the risk of traumatic fracture.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.
This medicinal product contains 0.1 mg of polysorbate 80 in each 25 mg vial or 0.3 mg of polysorbate 80 in each 75 mg vial which is equivalent to 0.2 mg/mL. Polysorbates may cause allergic reactions.
No formal clinical interaction studies have been performed. Concurrent use of iron-chelating agents had no effect on luspatercept pharmacokinetics.
Women of childbearing potential have to use effective contraception during treatment with Reblozyl and for at least 3 months after the last dose. Prior to starting treatment with Reblozyl, a pregnancy test has to be performed for women of childbearing potential and the patient card has to be provided.
Treatment with Reblozyl should not be started if the woman is pregnant (see section 4.3). There are no data from the use of Reblozyl in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Reblozyl is contraindicated during pregnancy (see section 4.3). If a patient becomes pregnant, Reblozyl should be discontinued.
It is unknown whether luspatercept or its metabolites are excreted in human milk. Luspatercept was detected in the milk of lactating rats (see section 5.3). Because of the unknown adverse effects of luspatercept in newborns/infants, a decision must be made whether to discontinue breast-feeding during therapy with Reblozyl and for 3 months after the last dose or to discontinue Reblozyl therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
The effect of luspatercept on fertility in humans is unknown. Based on findings in animals, luspatercept may compromise female fertility (see section 5.3).
Reblozyl may have a minor influence on the ability to drive and use machines. The ability to react when performing these tasks may be impaired due to risks of fatigue, vertigo, dizziness or syncope (see section 4.8). Therefore, patients should be advised to exercise caution until they know of any impact on their ability to drive and use machines.
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 g/dL occurred in 24.3% of luspatercept treated patients.
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.
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.
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 (all grades) for MDS | Frequency (all grades) for β-thalassaemia |
|---|---|---|---|
| Infections and infestations | bronchitis | Common | Commona |
| urinary tract infection | Very common | Commona | |
| respiratory tract infection | Common | ||
| upper respiratory tract infection | Common | Very commona | |
| influenza | Common | Very common | |
| Blood and lymphatic system disorders | extramedullary haemopoiesisVI | Not knownVII | Common |
| thrombocytopenia | Common | ||
| Immune system disorders | hypersensitivityI,VI | Common | Common |
| Metabolism and nutrition disorders | hyperuricaemia | Common | Common |
| dehydration | Common | ||
| decreased appetite | Common | ||
| electrolyte imbalanceIX | Very common | ||
| 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 compressionVI | Common | ||
| syncope/presyncope | Common | Commona | |
| Ear and labyrinth disorders | vertigo/vertigo positional | Common | Commona |
| Cardiac disorders | atrial fibrillation | Common | |
| cardiac failure | Common | ||
| Vascular disorders | prehypertension | Very commonb | |
| hypertensionII,VI | Very common | Very common | |
| tachycardia | Common | ||
| thromboembolic eventsIV,VI | Common | Common | |
| Respiratory, thoracic and mediastinal disorders | cough | Very common | |
| epistaxis | Common | Commonb | |
| dyspnoeaVIII | Very common | Common | |
| Gastrointestinal disorders | abdominal pain | Common | Very commonb |
| abdominal discomfort | Common | ||
| diarrhoea | Very common | Very commona | |
| nausea | Very common | Very common | |
| Skin and subcutaneous tissue disorders | hyperhidrosis | Common | |
| Musculoskeletal and connective tissue disorders | back pain | Very common | Very common |
| 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 administration site conditions | non-cardiac chest pain | Common | |
| influenza-like illness | Common | ||
| fatigue | Very common | Very commona | |
| asthenia | Very common | Very common | |
| injection site reactionsIII,VI | Common | Common | |
| oedema peripheral | Very common | ||
| Investigations | alanine aminotransferase increased | Common | CommonV |
| aspartate aminotransferase increased | Common | Very commonV | |
| blood bilirubin increased | Common | Very commonV | |
| gamma- glutamyltransferase increased | Common | ||
| Injury, poisoning and procedural complications | traumatic fractureVI | Commonb |
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.
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 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%).
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-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 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.
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.
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 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 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.
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.
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.
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 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.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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