Source: European Medicines Agency (EU) Revision Year: 2020
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
In β-thalassaemia patients, thromboembolic events (TEEs) were reported in 3.6% (8/223) of patients treated with luspatercept in a controlled clinical study. Reported TEEs included deep vein thrombosis (DVT), portal vein thrombosis, pulmonary emboli and ischaemic stroke (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 controlled clinical studies in MDS and β-thalassaemia, patients treated with luspatercept had an average increase in systolic and diastolic blood pressure of 5 mmHg from baseline (see section 4.8). Blood pressure should be monitored prior to each luspatercept administration. In case of persistent hypertension or exacerbations of pre-existing hypertension, patients should be treated for hypertension as per current clinical guidelines.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.
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.
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, asthenia, nausea, dizziness, back pain and headache. The most commonly reported Grade 3 or higher adverse drug reactions (at least 2% of patients) included syncope/presyncope, fatigue, hypertension and asthenia. The most commonly reported serious adverse drug reactions (at least 2% of patients) were urinary tract infection, back pain and syncope.
Asthenia, fatigue, dizziness and headache occurred more frequently during the first 3 months of treatment.
Treatment discontinuation due to an adverse reaction occurred in 2.0% of patients treated with luspatercept. The adverse reactions leading to treatment discontinuation in the luspatercept treatment arm were fatigue and headache.
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 or higher 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 highest frequency for each adverse reaction that was observed and reported in the two pivotal studies in MDS and β-thalassaemia is shown in Table 3 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) and very rare (<1/10,000).
Table 3. Adverse drug reactions (ADRs) in patients treated with Reblozyl for MDS and β-thalassaemia:
| System organ class | Preferred term | Frequency (all grades) for MDS | Frequency (all grades) for β-thalassaemia |
|---|---|---|---|
| Infections and infestations | bronchitis | Very common | Common |
| urinary tract infection | Very common | Common | |
| upper respiratory tract infection | Common | Very common | |
| influenza | Common | Common | |
| Immune system disorders | hypersensitivity* | Common | Common |
| Metabolism and nutrition disorders | hyperuricaemia | Common | Common |
| Nervous system disorders | dizziness | Very common | Very common |
| headache | Very common | Very common | |
| syncope/presyncope | Common | Common | |
| Ear and labyrinth disorders | vertigo/vertigo positional | Common | Common |
| Vascular disorders | hypertension~ | Common | Common |
| thromboembolic events§ | Common | Common | |
| Respiratory, thoracic and mediastinal disorders | dyspnoea | Very common | Common |
| Gastrointestinal disorders | diarrhoea | Very common | Very common |
| nausea | Very common | Common | |
| Musculoskeletal and connective tissue disorders | back pain | Very common | Very common |
| arthralgia | Common | Very common | |
| bone pain | Common | Very common | |
| General disorders and administration site conditions | fatigue | Very common | Very common |
| asthenia | Very common | Common | |
| injection site reactions# | Common | Common |
* Hypersensitivity includes eyelid oedema, drug hypersensitivity, swelling face, periorbital oedema, face oedema, angioedema, lip swelling, drug eruption.
~ Hypertension reaction includes essential hypertension, hypertension and hypertensive crisis.
# Injection site reactions include injection site erythema, injection site pruritus, injection site swelling and injection site rash.
§ Thromboembolic events include deep vein thrombosis, portal vein thrombosis, ischaemic stroke and pulmonary embolism.
Bone pain was reported in 19.7% of β-thalassaemia patients treated with luspatercept (placebo 8.3%) and in 2.6% of MDS patients treated with luspatercept (placebo 3.9%). In β-thalassaemia patients treated with luspatercept, bone pain was most common in the first 3 months (16.6%) compared to months 4-6 (3.7%). Most events (41/44 events) were Grade 1-2, with 3 events Grade 3. One of the 44 events was serious, and 1 event led to treatment discontinuation.
Arthralgia was reported in 19.3% of β-thalassaemia patients treated with luspatercept (placebo 11.9%) and in 5.2% of MDS patients treated with luspatercept (placebo 11.8%). In the β-thalassaemia patients treated with luspatercept, arthralgia led to treatment discontinuation in 2 patients (0.9%).
Patients treated with luspatercept had an average increase in systolic and diastolic blood pressure of 5 mmHg from baseline not observed in patients receiving placebo. Hypertension was reported in 8.5% of MDS patients treated with luspatercept (placebo 9.2%) and in 8.1% of β-thalassaemia patients treated with luspatercept (placebo 2.8%). See section 4.4.
In MDS patients, Grade 3 events were reported for 5 patients (3.3%) treated with luspatercept and in 3 patients (3.9%) receiving placebo. No patient discontinued due to hypertension.
In β-thalassaemia patients, Grade 3 events were reported in 4 patients (1.8%) treated with luspatercept (0.0% placebo). No patient discontinued due to hypertension. See section 4.4.
Hypersensitivity-type reactions (including eyelid oedema, drug hypersensitivity, swelling face, periorbital oedema, face oedema, angioedema, lip swelling, drug eruption) were reported in 4.6% of MDS (2.6% placebo) and 4.5% of β-thalassaemia patients treated with luspatercept (1.8% placebo). In clinical studies, all events were Grade 1/2. In β-thalassaemia patients treated with luspatercept, hypersensitivity led to treatment discontinuation in 1 patient (0.4%).
Injection site reactions (including injection site erythema, injection site pruritus, injection site swelling and injection site rash) were reported in 3.9% of MDS (placebo 0.0%) and in 2.2% of β-thalassaemia patients receiving luspatercept (placebo 1.8%). In clinical studies, all events were Grade 1 and none led to discontinuation.
Thromboembolic events (including deep vein thrombosis, portal vein thrombosis, ischaemic stroke and pulmonary embolism) occurred in 3.6% of β-thalassaemia patients receiving luspatercept (placebo 0.9%). All events were reported in patients who had undergone splenectomy and had at least one other risk factor. No difference in TEEs was observed between luspatercept and placebo arms in MDS patients. See section 4.4.
In clinical studies in MDS, an analysis of 260 MDS patients who were treated with luspatercept and who were evaluable for the presence of anti-luspatercept antibodies showed that 23 (8.8%) MDS patients tested positive for treatment-emergent anti-luspatercept antibodies, including 9 (3.5%) MDS patients who had neutralising antibodies against luspatercept.
In clinical studies in β-thalassaemia, an analysis of 284 β-thalassaemia patients who were treated with luspatercept and who were evaluable for the presence of anti-luspatercept antibodies showed that 4 (1.4%) β-thalassaemia patients tested positive for treatment-emergent anti-luspatercept antibodies, including 2 (0.7%) β-thalassaemia patients who had neutralising antibodies against luspatercept.
Luspatercept serum concentration tended to decrease in the presence of neutralising 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.
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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