Reblozyl

1 

 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 
 



 

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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Reblozyl 25 mg powder for solution for injection 
Reblozyl 75 mg powder for solution for injection 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Reblozyl 25 mg powder for solution for injection 
Each vial contains 25 mg of luspatercept. After reconstitution, each mL of solution contains 50 mg 
luspatercept. 
 
Reblozyl 75 mg powder for solution for injection 
Each vial contains 75 mg of luspatercept. After reconstitution, each mL of solution contains 50 mg 
luspatercept. 
 
Luspatercept is produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for solution for injection (powder for injection). 
 
White to off-white lyophilised powder. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Reblozyl is indicated for the treatment of adult patients with transfusion-dependent anaemia due to 
very low, low and intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts, who 
had an unsatisfactory response to or are ineligible for erythropoietin-based therapy (see section 5.1). 
 
Reblozyl is indicated for the treatment of adult patients with transfusion-dependent anaemia associated 
with beta-thalassaemia (see section 5.1). 
 
4.2 Posology and method of administration 
 
Reblozyl treatment should be initiated by a physician experienced in treatment of haematological 
diseases. 
 
Posology 
Prior to each Reblozyl administration, the haemoglobin (Hb) level of patients should be assessed. In 
case of a red blood cell (RBC) transfusion occurring prior to dosing, the pre-transfusion Hb level must 
be considered for dosing purposes. 
 
Myelodysplastic syndromes 
The recommended starting dose of Reblozyl is 1.0 mg/kg administered once every 3 weeks. 
 



 

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In patients who are not RBC transfusion-free after at least 2 consecutive doses at the 1.0 mg/kg 
starting dose, the dose should be increased to 1.33 mg/kg. If patients are not RBC transfusion-free 
after at least 2 consecutive doses at the 1.33 mg/kg dose level, the dose should be increased to 
1.75 mg/kg. The dose increase should not occur more frequently than every 6 weeks 
(2 administrations) and should not exceed the maximum dose of 1.75 mg/kg every 3 weeks. The dose 
should not be increased immediately after a dose delay. For patients with a pre-dose Hb level of 
> 9 g/dL and who have not yet achieved transfusion independence, a dose increase may be required at 
the physician’s discretion; the risk of Hb increasing above the target threshold with concomitant 
transfusion cannot be excluded. 
 
If a patient loses response (i.e., transfusion independence), the dose should be increased by one dose 
level. 
 
-thalassaemia 
The recommended starting dose of Reblozyl is 1.0 mg/kg administered once every 3 weeks. 
 
In patients who do not achieve a response, defined as a reduction in RBC transfusion burden of at least 
a third after ≥ 2 consecutive doses (6 weeks), at the 1.0 mg/kg starting dose, the dose should be 
increased to 1.25 mg/kg. The dose should not be increased beyond the maximum dose of 1.25 mg/kg 
every 3 weeks. 
 
If a patient loses response (if the RBC transfusion burden increases again after an initial response) the 
dose should be increased by one dose level. 
 
MDS and -thalassaemia 
 
Dose reduction and dose delay  
In case of Hb increase > 2 g/dL within 3 weeks of luspatercept treatment in absence of transfusion, the 
Reblozyl dose should be reduced by one dose level. 
 
If the Hb is ≥ 11.5 g/dL in the absence of transfusion for at least 3 weeks, the dose should be delayed 
until the Hb is ≤ 11.0 g/dL. If there is also a concomitant rapid increase in Hb (> 2 g/dL within 
3 weeks in absence of transfusion), a dose reduction to one step down (minimum 0.8 mg/kg) should be 
considered after the dose delay. 
 
Dose should not be reduced below 0.8 mg/kg. 
 
Dose reductions during treatment with luspatercept are provided below. 
 
Table 1: Dose reductions for MDS 

Current dose Dose reduction 
1.75 mg/kg 1.33 mg/kg
1.33 mg/kg 1 mg/kg

1 mg/kg 0.8 mg/kg
 
Table 2: Dose reductions for -thalassaemia 

Current dose Dose reduction 
1.25 mg/kg 1 mg/kg

1 mg/kg 0.8 mg/kg
 
If patients experience persistent treatment-related Grade 3 or higher adverse reactions (see section 
4.8), the treatment should be delayed until toxicity has improved or returned to baseline. 
 
After a dose delay, patients should be re-started at their previous dose or at reduced dose as per dose 
reduction guidance.  
 



 

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Missed doses 
In case of a missed or delayed scheduled treatment administration, the patient should be administered 
Reblozyl as soon as possible and dosing continued as prescribed with at least 3 weeks between doses. 
 
Patients experiencing a loss of response 
If patients experience a loss of response to Reblozyl, causative factors (e.g. a bleeding event) should 
be assessed. If typical causes for a loss of haematological response are excluded, dose increase should 
be considered as described above for the respective indication being treated. 
 
Discontinuation 
Reblozyl should be discontinued if patients do not experience a reduction in transfusion burden after 
9 weeks of treatment (3 doses) at the maximum dose level if no alternative explanations for response 
failure are found (e.g. bleeding, surgery, other concomitant illnesses) or if unacceptable toxicity occurs 
at any time. 
 
Special populations 
 
Elderly 
No starting dose adjustment is required for Reblozyl (see section 5.2). 
 
Hepatic impairment 
No starting dose adjustment is required for patients with total bilirubin (BIL) > upper limit of normal 
(ULN) and/or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 3 x ULN (see 
section 5.2). No specific dose recommendation can be made for patients with ALT or AST ≥ 3 x ULN 
or liver injury CTCAE Grade ≥ 3 due to lack of data (see section 5.2). 
 
Renal impairment 
No starting dose adjustment is required for patients with mild to moderate renal impairment (estimated 
glomerular filtration rate [eGFR] < 90 and ≥ 30 mL/min/1.73 m2). No specific dose recommendation 
can be made for patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) due to lack of 
clinical data (see section 5.2). Patients with renal impairment at baseline should be closely monitored 
for renal function as per standard of care. 
 
Paediatric population 
There is no relevant use of Reblozyl in the paediatric population for the indication of myelodysplastic 
syndromes, or in paediatric patients less than 6 months of age in -thalassaemia. For non-clinical data, 
see section 5.3. 
 
The safety and efficacy of Reblozyl in the paediatric patients aged from 6 months to less than 18 years 
have not yet been established in -thalassaemia. For non-clinical data, see section 5.3. 
 
Method of administration 
For subcutaneous use. 
 
After reconstitution, Reblozyl solution should be injected subcutaneously into the upper arm, thigh or 
abdomen. The exact total dosing volume of the reconstituted solution required for the patient should 
be calculated and slowly withdrawn from the single-dose vial(s) into a syringe. 
 
The recommended maximum volume of medicinal product per injection site is 1.2 mL. If more than 
1.2 mL is required, the total volume should be divided into separate similar volume injections and 
administered across separate sites. 
 
If multiple injections are required, a new syringe and needle must be used for each subcutaneous 
injection. No more than one dose from a vial should be administered. 
 



 

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If the Reblozyl solution has been refrigerated after reconstitution, it should be removed from the 
refrigerator 15-30 minutes prior to injection to allow it to reach room temperature. This will allow for 
a more comfortable injection. 
 
For instructions on reconstitution of the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications 
 
 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  
 Pregnancy (see section 4.6). 
 
4.4 Special warnings and precautions for use 
 
Traceability 
In order to improve the traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded. 
 
Thromboembolic events 
In -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 -thalassaemia patients with a splenectomy and other 
risk factors for developing TEE. Thromboprophylaxis according to current clinical guidelines should 
be considered in patients with -thalassaemia at higher risk. 
 
Increased blood pressure 
In controlled clinical studies in MDS and -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. 
 
Sodium content 
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 
‘sodium-free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No formal clinical interaction studies have been performed. Concurrent use of iron-chelating agents 
had no effect on luspatercept pharmacokinetics. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential / Contraception in females 
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. 
 
Pregnancy 
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. 
 



 

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Breast-feeding 
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. 
 
Fertility 
The effect of luspatercept on fertility in humans is unknown. Based on findings in animals, 
luspatercept may compromise female fertility (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
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. 
 
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, 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.  
 
-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 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 . 
 
Tabulated list of adverse reactions 
The highest frequency for each adverse reaction that was observed and reported in the two pivotal 
studies in MDS and -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). 
 



 

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Table 3. Adverse drug reactions (ADRs) in patients treated with Reblozyl for MDS and -
thalassaemia 

System organ class Preferred term Frequency  
(all grades) for 
MDS 

Frequency  
(all grades) for 
-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. 
 
Description of selected adverse reactions 
 
Bone pain 
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 
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%). 
 
Hypertension 
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% 



 

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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 
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 
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 
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. 
 
Immunogenicity 
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 -thalassaemia, an analysis of 284 -thalassaemia patients who were treated with 
luspatercept and who were evaluable for the presence of anti-luspatercept antibodies showed that 
4 (1.4%) -thalassaemia patients tested positive for treatment-emergent anti-luspatercept antibodies, 
including 2 (0.7%) -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 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. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Overdose with luspatercept may cause an increase of Hb values above the desired level. In the event of 
an overdose, treatment with luspatercept should be delayed until Hb is ≤ 11 g/dL. 
 
 



 

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5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antianaemic preparations, other antianaemic preparations, ATC code: 
B03XA06.  
 
Mechanism of action 
Luspatercept, an erythroid maturation agent, is a recombinant fusion protein that binds selected 
transforming growth factor-β (TGF-β) superfamily ligands. By binding to specific endogenous ligands 
(e.g. GDF-11, activin B) luspatercept inhibits Smad2/3 signalling, resulting in erythroid maturation 
through differentiation of late-stage erythroid precursors (normoblasts) in the bone marrow. Smad2/3 
signalling is abnormally high in disease models characterised by ineffective erythropoiesis, i.e. MDS 
and β-thalassaemia, and in the bone marrow of MDS patients. 
 
Clinical efficacy and safety 
 
Myelodysplastic syndromes 
The efficacy and safety of luspatercept were evaluated in a Phase 3 multicentre, randomised, 
double-blind, placebo-controlled study MEDALIST (ACE-536-MDS-001) in adult patients with 
anaemia requiring RBC transfusions (≥ 2 units/8 weeks) due to International Prognostic Scoring 
System-Revised (IPSS-R) very low-, low- or intermediate-risk MDS who have ring sideroblasts 
(≥ 15%). Patients were required to have either received prior treatment with an erythropoiesis-
stimulating agent (ESA) with inadequate response, to be ineligible for ESAs (determined to be 
unlikely to respond to ESA treatment with serum erythropoietin (EPO) > 200 U/L), or intolerant to 
ESA treatment. Patients with deletion 5q (del5q) MDS were excluded from the study. 
 
Patients in both arms were treated for 24 weeks, then continued treatment if they had demonstrated 
clinical benefit and absence of disease progression. The study was unblinded for analyses when all 
patients had at least received 48 weeks of treatment or discontinued treatment. 
 
A total of 229 patients were randomised to receive luspatercept 1.0 mg/kg (n=153) or placebo (n=76) 
subcutaneously every 3 weeks. A total of 128 (83.7%) and 68 (89.5%) patients receiving luspatercept 
and placebo respectively completed 24 weeks of treatment. A total of 78 (51%) and 12 (15.8%) 
patients receiving luspatercept and placebo respectively completed 48 weeks of treatment. Dose 
titration up to 1.75 mg/kg was allowed. Dose could be delayed or reduced depending upon Hb level. 
All patients were eligible to receive best supportive care (BSC), which included RBC transfusions, 
iron-chelating agents, use of antibiotic, antiviral and antifungal therapy, and nutritional support, as 
needed. The key baseline disease characteristics in patients with MDS in ACE-536-MDS-001 are 
shown in Table 4. 
 
Table 4. Baseline characteristics in MDS patients with <5% marrow blasts in ACE-536-MDS-
001 

 Luspatercept 
(N=153) 

Placebo 
(N=76) 

Demographics 
Agea (years)  
Median (min, max) 

 
71 (40, 95)

 
72 (26, 91) 

Age categories, n (%) 
<64 years 
65-74 years 
≥75 

 
29 (19.0) 
72 (47.1) 
52 (34.0)

 
16 (21.1) 
29 (38.2) 
31 (40.8) 

Sex, n (%) 
Male 
Female 

 
94 (61.4) 
59 (38.6)

 
50 (65.8) 
26 (34.2) 

Race, n (%) 
Black 

 
1 (0.7)

 
0 (0.0) 



 

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 Luspatercept 
(N=153) 

Placebo 
(N=76) 

White 
Not collected or reported 
Other 

107 (69.9) 
44 (28.8) 
1 (0.7)

51 (67.1) 
24 (31.6) 

1 (1.3) 
Disease characteristics 
Serum EPO (U/L) categories b, n (%) 
< 200 
200 to 500 
> 500 
Missing 

 
88 (57.5) 
43 (28.1) 
21 (13.7) 
1 (0.7)

 
50 (65.8) 
15 (19.7) 
11 (14.5) 

0 
Serum ferritin (µg/L) 
Median (min,max) 

 
1089.2 

(64, 5968)
1122.1 

(165, 5849) 
IPSS-R classification risk category, n (%) 
Very low 
Low 
Intermediate 
Other 

 
18 (11.8) 

109 (71.2) 
25 (16.3) 
1 (0.7)

 
6 (7.9) 

57 (75.0) 
13 (17.1) 

0 
Baseline RBC Transfusion burden/ 8 weeksc, n (%) 
≥ 6 units 

≥ 6 and < 8 units 
≥ 8 and < 12 units 
≥ 12 units 

< 6 units 
≥ 4 and < 6 units 
< 4 units 

 
66 (43.1) 
35 (22.9) 
24 (15.7) 
7 (4.6) 

87 (56.9) 
41 (26.8) 
46 (30.1)

 
33 (43.4) 
15 (20.2) 
17 (22.4) 
1 (1.3) 

43 (56.6) 
23 (30.3) 
20 (26.3) 

Haemoglobind (g/dL) 
Median (min, max) 7.6 (6, 10) 7.6 (5, 9) 
SF3B1, n (%) 
Mutated 
Unmutated 
Missing 

149 (92.2)  
12 (7.8) 

0

65 (85.5) 
10 (13.2) 
1 (1.3) 

EPO=erythropoietin; IPSS-R=International Prognostic Scoring System-Revised 
a Time since original MDS diagnosis was defined as the number of years from the date of original diagnosis to the date of 
informed consent. 
b Baseline EPO was defined as the highest EPO value within 35 days of the first dose of study drug. 
c Collected over 16 weeks prior to randomisation. 
d Baseline haemoglobin was defined as the last value measured on or before the date of the first dose of investigational 

product (IP).After applying the 14/3 day rule, baseline Hb was defined as the lowest Hb value that was within 35 days on 
or prior to the first dose of IP. 

 
The efficacy results are summarised below. 
 
Table 5. Efficacy results in patients with MDS in ACE-536-MDS-001 

Endpoint Luspatercept 
(N=153) 

Placebo 
(N=76) 

Primary endpoint 
 RBC-TI ≥ 8 weeks (Week 1-24) 

Number of responders (response rate %)
 

58 (37.9)
 

10 (13.2)
 Common risk difference on response rate (95% CI) 24.56 (14.48, 34.64) 

Odds ratio (95% CI)a 5.065 (2.278, 11.259) 
p-valuea < 0.0001 



 

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Endpoint Luspatercept 
(N=153) 

Placebo 
(N=76) 

Secondary endpoints 
 RBC-TI ≥ 12 weeks (Weeks 1-24) 

Number of responders (response rate %) 
 

43 (28.1)
 

6 (7.9) 
 Common risk difference on response rate (95% CI) 20.00 (10.92, 29.08) 

Odds ratio (95% CI)a 5.071 (2.002, 12.844) 
p-valuea 0.0002 

 RBC-TI ≥ 12 weeks (Weeks 1-48) 
Number of responders (response rate %)b 

 
51 (33.3)

 
9 (11.8)

 Common risk difference on response rate (95% CI) 21.37 (11.23, 31.51) 
Odds ratio (95% CI)a 4.045 (1.827, 8.956) 
p-valuea 0.0003 

Transfusion event frequencyc 
 Weeks 1-24 
Interval transfusion rate (95% CI) 

 
 

6.26 (5.56, 7.05) 

 
 

9.20 (7.98, 10.60)
Relative risk versus placebo 0.68 (0.58, 0.80) 

 Weeks 25-48 
Interval transfusion rate (95% CI) 

 
6.27 (5.47, 7.19) 

 
8.72 (7.40, 10.28)

Relative risk versus placebo 0.72 (0.60, 0.86) 
RBC Transfusion unitsc 
 Weeks 1-24 

Baseline transfusion burden <6 units/8 weeks 
LS Mean (SE) 
95% CI for LS mean 

 
 
 

7.2 (0.58) 
6.0, 8.3 

 
 
 

12.8 (0.82) 
11.1, 14.4 

LS mean difference (SE) (luspatercept versus placebo) 
95% CI for LS mean difference 

-5.6 (1.01) 
-7.6, -3.6 

Baseline transfusion burden ≥6 units/8 weeks 
LS Mean (SE) 
95% CI for LS mean 

 
18.9(0.93) 
17.1, 20.8

 
23.7(1.32) 
21.1, 26.4

LS mean difference (SE) (luspatercept versus placebo) 
95% CI for LS mean difference 

-4.8 (1.62) 
-8.0, -1.6 

 Weeks 25-48 
Baseline transfusion burden <6 units/8 weeks 

LS Mean (SE) 
95% CI for LS mean 

 
 

7.5 (0.57) 
6.3, 8.6 

 
 

11.8(0.82) 
10.1, 13.4 

LS mean difference (SE) (luspatercept versus placebo) 
95% CI for LS mean difference 

-4.3 (1.00) 
-6.3, -2.3 

Baseline transfusion burden ≥6 units/8 weeks 
LS Mean (SE) 
95% CI for LS mean 

 
19.6(1.13) 
17.4, 21.9

 
22.9(1.60) 
19.7, 26.0

LS mean difference (SE) (luspatercept versus placebo) 
95% CI for LS mean difference 

-3.3(1.96) 
-7.1, 0.6 

RBC-TI: RBC Transfusion Independent; CI: confidence interval 
a Cochran-Mantel-Haenszel test stratified for average baseline transfusion burden (≥ 6 units versus < 6 units per 8 weeks), 
and baseline IPSS-R score (very low or low versus intermediate). 
b After the Week 25 disease assessment visit, patients who were no longer deriving benefit discontinued therapy; few placebo 
patients contributed data for evaluation at the later timepoint compared with luspatercept (n=12 vs. n=78 respectively). 
c Post-hoc analysis using baseline imputation. 
 
A treatment effect in favour of luspatercept over placebo was observed in most subgroups analysed 
using transfusion independence ≥12 weeks (during week 1 to week 24), including patients with high 
baseline endogenous EPO level (200-500 U/L) (23.3% versus 0%, explorative analysis). 
 
Only limited data are available for the group with transfusion burden of ≥ 8 units/8 weeks. Safety and 
efficacy have not been established in patients with a transfusion burden of > 12 units/8 weeks. 



 

12 

 
Exploratory findings 
 
Table 6. Exploratory efficacy results in patients with MDS in ACE-536-MDS-001 

Endpoint Luspatercept 
(N=153)

Placebo 
(N=76)

mHI-Ea 
 Weeks 1-24 

Number of responders (response rate %) 

 
 

81 (52.9) 

 
 

9 (11.8)
(95% CI) (44.72, 61.05) (5.56, 21.29)

RBC transfusion reduction of 4 units/8 weeks, n (%) 52/107 (48.6) 8/56 (14.3)
Mean haemoglobin increase of ≥ 1.5 g/dL for 8 weeks, n 
(%) 

29/46 (63.0) 1/20 (5.0) 

 Weeks 1-48 
Number of responders (response rate %)

 
90 (58.8) 

 
13 (17.1)

(95% CI) (50.59, 66.71) (9.43, 27.47)
RBC transfusion reduction of 4 units/8 weeks, n (%) 58/107 (54.2) 12/56 (21.4)
Mean haemoglobin increase of ≥ 1.5 g/dL for 8 weeks, n 
(%) 

32/46 (69.6) 1/20 (5.0) 

Mean change from baseline in mean serum ferritin with imputation by baseline (ITT 
population) 
Mean change from baseline in mean serum ferritin averaged 
over Weeks 9 through 24 (μg/L)b 
LS Mean (SE) 

 
 

9.9 (47.09) 

 
 

190.0 (60.30)
95% CI for LS Mean -82.9, 102.7 71.2, 308.8
Treatment Comparison (Luspatercept vs Placebo)c

LS Mean Difference (SE) -180.1 (65.81) 
95% CI for LS Mean Difference -309.8, -50.4 

a mHI-E = modified haematological improvement – erythroid. The proportion of patients meeting the HI-E criteria as per 
International Working Group (IWG) 2006 criteria sustained over a consecutive 56-day period during the indicated treatment 
period. For patients with baseline RBC transfusion burden of ≥ 4 units/8 weeks, mHI-E was defined as a reduction in RBC 
transfusion of at least 4 units/8 weeks. For patients with baseline RBC transfusion burden of < 4 units/8 weeks, mHI-E was 
defined as a mean increase in Hb of ≥ 1.5 g/dL for 8 weeks in the absence of RBC transfusions. 
b If a subject did not have a serum ferritin value within the designated postbaseline interval, the serum ferritin is 
imputed from the baseline value. 
c Analysis of covariance was used to compare the treatment difference between groups (including nominal p-value), 
with the change in serum ferritin as the dependent variable, treatment group (2 levels) as a factor, and baseline 
serum ferritin value as covariates, stratified by average baseline RBC transfusion requirement (≥ 6 units versus < 6 
units of RBC per 8 weeks), and baseline IPSS-R (very low or low versus intermediate). 
 
The median duration of the longest RBC Transfusion Independent (RBC-TI) period among responders 
in the luspatercept treatment arm was 30.6 weeks. 
 
62.1% (36/58) of the luspatercept responders who achieved RBC-TI ≥ 8 weeks from Week 1-24 had 2 
or more episodes of RBC-TI at the time of analysis. 
 
-thalassaemia 
The efficacy and safety of luspatercept were evaluated in a Phase 3 multicentre, randomised, 
double-blind, placebo-controlled study BELIEVE (ACE-536-B-THAL-001) in adult patients with 
-thalassaemia–associated anaemia who require RBC transfusions (6-20 RBC units/24 weeks) with no 
transfusion-free period > 35 days during that period. 
 
Patients in both the luspatercept and placebo arms were treated for at least 48 and up to 96 weeks. 
After unblinding, placebo patients were able to cross-over to luspatercept. 
 
A total of 336 adult patients were randomised to receive luspatercept 1.0 mg/kg (n=224) or placebo 
(n=112) subcutaneously every 3 weeks. Dose titration to 1.25 mg/kg was allowed. Dose could be 
delayed or reduced depending upon Hb level. All patients were eligible to receive BSC, which 



 

13 

included RBC transfusions, iron-chelating agents, use of antibiotic, antiviral and antifungal therapy, 
and nutritional support, as needed. The study excluded patients with haemoglobin S/β-thalassaemia or 
alpha (α)-thalassaemia or who had major organ damage (liver disease, heart disease, lung disease, 
renal insufficiency). Patients with recent DVT or stroke or recent use of ESA, immunosuppressant or 
hydroxyurea therapy were also excluded. The key baseline disease characteristics in patients with 
-thalassaemia in ACE-536-B-THAL-001 are shown in Table 7. 
 
Table 7. Baseline characteristics in patients with -thalassaemia in ACE-536-B-THAL-001 

 
Luspatercept 

(N=224) 
Placebo  
(N=112) 

Demographics 
Age (years) 
Median (min, max) 

 
30.0 (18, 66)

 
30.0 (18, 59)

Age categories, n (%) 
≤ 32 
> 32 to ≤ 50 
> 50 

 
129 (57.6) 
78 (34.8) 
17 (7.6)

 
63 (56.3) 
44 (39.3) 

5 (4.5) 
Sex, n (%) 
Male 
Female 

 
92 (41.1) 

132 (58.9)

 
49 (43.8) 
63 (56.3)

Race, n (%) 
Asian 
Black  
White 
Not collected or reported 
Other 

 
81 (36.2) 
1 (0.4) 

122 (54.5) 
5 (2.2) 
15 (6.7)

 
36 (32.1) 

0 
60 (53.6) 

5 (4.5) 
11 (9.8) 

Disease characteristics 
Pretransfusion Hb thresholda, 12 week run-in (g/dL) 
Median (min, max) 9.30 (4.6, 11.4) 

 
9.16 (6.2, 11.5)

Baseline transfusion burden 12 weeks 
Median (min, max) 
(units/12 weeks) (Week -12 to Day 1) 6.12 (3.0, 14.0) 6.27 (3.0, 12.0)
β-thalassaemia gene mutation grouping, n (%) 
β0/β0 
Non-β0/β0 
Missingb 

68 (30.4) 
155 (69.2) 

1 (0.4)

35 (31.3) 
77 (68.8) 

0 
aThe 12-week pretransfusion threshold was defined as the mean of all documented pretransfusions hb values for a subject 
during the 12 weeks prior to Cycle 1 Day 1. 
b "Missing" category includes patients in the population who had no result for the parameter listed. 
 
The study was unblinded for analyses when all patients had at least received 48 weeks of treatment or 
discontinued treatment. 
 
The efficacy results are summarised below. 
 
Table 8. Efficacy results in patients with -thalassaemia in ACE-536-B-THAL-001 

Endpoint Luspatercept 
(N=224)

Placebo 
(N=112) 

≥ 33% reduction from baseline in RBC transfusion 
burden with a reduction of at least 2 units for 
12 consecutive weeks compared to the 12-week 
interval prior to treatment 

 

Primary endpoint – Weeks 13-24 48 (21.4) 5 (4.5) 
Difference in proportions (95% CI)a 17.0 (10.4, 23.6) 
p-valueb < 0.0001 



 

14 

Endpoint Luspatercept 
(N=224)

Placebo 
(N=112) 

Weeks 37-48 44 (19.6) 4 (3.6) 
Difference in proportions (95% CI)a 16.1 (9.8, 22.3) 
p-valueb < 0.0001 

≥ 50% reduction from baseline in RBC transfusion 
burden with a reduction of at least 2 units for 
12 consecutive weeks compared to the 12-week 
interval prior to treatment 

 

Weeks 13-24 17 (7.6) 2 (1.8) 
Difference in proportions (95% CI)a 5.8 (1.6, 10.1) 
p-valueb 0.0303 

Weeks 37-48 23 (10.3) 1 (0.9) 
Difference in proportions (95% CI)a 9.4 (5.0, 13.7) 
p-valueb 0.0017 

CI: confidence interval. 
a Difference in proportions (luspatercept + BSC – placebo + BSC) and 95% CIs estimated from the unconditional exact test. 
b P-value from the Cochran Mantel-Haenszel test stratified by the geographical region.  
Exploratory findings 
 
Table 9. Exploratory efficacy results in patients with -thalassaemia in ACE-536-B-THAL-001 

Endpoint Luspatercept 
(N=224)

Placebo 
(N=112) 

≥ 33% reduction from baseline in RBC transfusion 
burden with a reduction of at least 2 units for 
12 consecutive weeks compared to the 12-week 
interval prior to treatment 

 

Any consecutive 12 weeks* 158 (70.5) 33 (29.5)
Difference in proportions (95% CI)a 41.1 (30.7, 51.4) 

Any consecutive 24 weeks* 92 (41.1) 3 (2.7) 
Difference in proportions (95% CI)a 38.4 (31.3, 45.5) 

≥ 50% reduction from baseline in RBC transfusion 
burden with a reduction of at least 2 units for 
12 consecutive weeks compared to the 12-week 
interval prior to treatment 

 

Any consecutive 12 weeks* 90 (40.2) 7 (6.3) 
Difference in proportions (95% CI)a 33.9 (26.1, 41.8) 

Any consecutive 24 weeks* 37 (16.5) 1 (0.9) 
Difference in proportions (95% CI)a 15.6 (10.5, 20.8) 

Least square (LS) mean change from baseline in transfusion burden (RBC units/48 weeks) 
Weeks 1 to Week 48 

LS mean 
 

-4.67
 

+1.16 
LS mean of difference (luspatercept-placebo)  
(95% CI)b 

-5.83 
(-7.01, -4.6) 

Weeks 49 to Week 96 
LS mean 

 
-5.66

 
+2.19 

LS mean of difference (luspatercept-placebo)  
(95% CI)b 

-7.84  
(-14.44, -1.25) 

CI: confidence interval. 
a Difference in proportions (luspatercept + BSC – placebo + BSC) and 95% CIs estimated from the unconditional exact test. 
b Estimates are based on ANCOVA model with geographical regions and baseline transfusion burden as covariates  
 
A reduction in mean serum ferritin levels was observed from baseline in the luspatercept arm 
compared to an increase in the placebo arm at Week 48 (-233.51 μg/L versus +114.28 μg/L which 
resulted in a least square mean treatment difference of -347.8 µg/L (95% CI: -516.95, -178.65). 
 



 

15 

80.4% (127/158) of luspatercept responders who achieved at least a 33% reduction in transfusion 
burden during any consecutive 12-week interval achieved 2 or more episodes of response at the time 
of analysis. 
 
Paediatric population 
 
Myelodysplastic syndromes 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Reblozyl in all subsets of the paediatric population in myelodysplastic syndromes (see section 4.2 for 
information on paediatric use). 
 
-thalassaemia 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Reblozyl in one or more subsets of paediatric population older than 6 months of age in -thalassaemia 
(see section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
In healthy volunteers and patients, luspatercept is slowly absorbed following subcutaneous 
administration, with the Cmax in serum often observed approximately 7 days post-dose across all dose 
levels. Population pharmacokinetic (PK) analysis suggests that the absorption of luspatercept into the 
circulation is linear over the range of studied doses, and the absorption is not significantly affected by 
the subcutaneous injection location (upper arm, thigh or abdomen). Interindividual variability in AUC 
was approximately 38% in MDS patients and 36% in -thalassaemia patients. 
 
Distribution 
At the recommended doses, the mean apparent volume of distribution was 9.68 L for MDS patients 
and 7.08 L for -thalassaemia patients. The small volume of distribution indicates that luspatercept is 
confined primarily in extracellular fluids, consistent with its large molecular mass. 
 
Biotransformation 
Luspatercept is expected to be catabolised into amino acids by general protein degradation process. 
 
Elimination 
Luspatercept is not expected to be excreted into urine due to its large molecular mass that is above the 
glomerular filtration size exclusion threshold. At the recommended doses, the mean apparent total 
clearance was 0.516 L/day for MDS patients and 0.437 L/day for β-thalassaemia. The mean half-life in 
serum was approximately 13 days for MDS patients and 11 days for -thalassaemia patients. 
 
Linearity/non-linearity 
The increase of luspatercept Cmax and AUC in serum is approximately proportional to increases in dose 
from 0.125 to 1.75 mg/kg. Luspatercept clearance was independent of dose or time. 
 
When administered every three weeks, luspatercept serum concentration reaches the steady state after 
3 doses, with an accumulation ratio of approximately 1.5. 
 
Haemoglobin response 
In patients who received < 4 units of RBC transfusion within 8 weeks prior to the study, Hb increased 
within 7 days of treatment initiation and the increase correlated with the time to reach luspatercept 
Cmax. The greatest mean Hb increase was observed after the first dose, with additional smaller 
increases observed after subsequent doses. Hb levels returned to baseline value approximately 6 to 
8 weeks from the last dose (0.6 to 1.75 mg/kg). Increasing luspatercept serum exposure (AUC) was 
associated with a greater Hb increase in patients with MDS or -thalassaemia. 
 



 

16 

Special populations 
 
Elderly 
Population PK analysis for luspatercept included patients with ages ranging from 18 to 95 years old, 
with a median age of 72 years for MDS patients and of 32 years for -thalassaemia patients. No 
clinically significant difference in AUC or clearance was found across age groups (< 65, 65-74, and 
≥ 75 years for MDS patients; 18-23, 24-31, 32-41, and 42-66 years for -thalassaemia patients). 
 
Hepatic impairment 
Population PK analysis for luspatercept included patients with normal hepatic function (BIL, ALT, 
and AST ≤ ULN; N = 207), mild hepatic impairment (BIL > 1 – 1.5 x ULN, and ALT or AST > ULN; 
N = 160), moderate hepatic impairment (BIL > 1.5 – 3 x ULN, any ALT or AST; N = 138), or severe 
hepatic impairment (BIL > 3 x ULN, any ALT or AST; N = 40) as defined by the National Cancer 
Institute criteria of hepatic dysfunction. Effects of hepatic function categories, elevated liver enzymes 
(ALT or AST, up to 3 x ULN) and elevated total BIL (4 – 246 mol/L) on luspatercept clearance were 
not observed. No clinically significant difference in mean steady state Cmax and AUC was found across 
hepatic function groups. PK data are insufficient for patients with liver enzymes (ALT or AST) 
≥ 3 x ULN. 
 
Renal impairment 
Population PK analysis for luspatercept included patients with normal renal function (eGFR 
≥ 90 mL/min/1.73 m2; N = 315), mild renal impairment (eGFR 60 to 89 mL/min/1.73 m2; N = 171), or 
moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2; N = 59). No clinically significant 
difference in mean steady state Cmax and AUC was found across renal function groups. PK data are not 
available for patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) or end-stage kidney 
disease. 
 
Other intrinsic factors 
The following population characteristics have no clinically significant effect on luspatercept AUC or 
clearance: sex and race (Asian versus White). 
 
The following baseline disease characteristics had no clinically significant effect on luspatercept 
clearance: serum erythropoietin level, RBC transfusion burden, MDS ring sideroblasts, β-thalassaemia 
genotype (β0/β0 versus non-β0/β0) and splenectomy. 
 
The volume of distribution and clearance of luspatercept increased with increase of body weight, 
supporting the body weight-based dosing regimen. 
 
5.3 Preclinical safety data 
 
Single and repeat-dose toxicity 
Following repeated administration of luspatercept in rats, toxicities included: membranoproliferative 
glomerulonephritis; congestion, necrosis and/or mineralisation of the adrenal glands; hepatocellular 
vacuolation and necrosis; mineralisation of the glandular stomach; and decreased heart and lung 
weights with no associated histology findings. A clinical observation of swollen hindlimbs/feet was 
noted in several studies in rats and rabbits (including juvenile and reproductive toxicity studies). In 
one juvenile rat, this correlated histopathologically with new bone formation, fibrosis, and 
inflammation. Membranoproliferative glomerulonephritis was also seen in monkeys. Additional 
toxicities in monkeys included: vascular degeneration and inflammatory infiltrates in the choroid 
plexus. 
 
For the 6-month toxicity study, the longest duration study in monkeys, the no-observed-adverse-effect 
level (NOAEL) was 0.3 mg/kg (0.3-fold of clinical exposure at 1.75 mg/kg every 3 weeks). A NOAEL 
was not identified in rats and the lowest-observed-adverse-effect-level (LOAEL) in the rat 3-month 
study was 1 mg/kg (0.9-fold of clinical exposure at 1.75 mg/kg every 3 weeks). 
 



 

17 

Carcinogenesis and mutagenesis 
Neither carcinogenicity nor mutagenicity studies with luspatercept have been conducted. 
Haematological malignancies were observed in 3 out of 44 rats examined in the highest dose group 
(10 mg/kg) in the definitive juvenile toxicity study. The occurrence of these tumours in young animals 
is unusual and the relationship to luspatercept therapy cannot be ruled out. At the 10 mg/kg dose, at 
which tumours were observed, the exposure represents an exposure multiple of approximately 4 times 
the estimated exposure at a clinical dose of 1.75 mg/kg every three weeks. 
 
No other proliferative or pre-neoplastic lesions, attributable to luspatercept, have been observed in any 
species in other non-clinical safety studies conducted with luspatercept, including the 6-month study in 
monkeys. 
 
Fertility 
In a fertility study in rats, administration of luspatercept to females at doses higher than the currently 
recommended highest human dose reduced the average number of corpora lutea, implantations and 
viable embryos. No such effects were observed when exposure in animals was at 1.5 times the clinical 
exposure. Effects on fertility in female rats were reversible after a 14-week recovery period. 
 
Administration of luspatercept to male rats at doses higher than the currently recommended highest 
human dose had no adverse effect on male reproductive organs or on their ability to mate and produce 
viable embryos. The highest dose tested in male rats yielded an exposure approximately 7 times the 
clinical exposure. 
 
Embryo-foetal development (EFD) 
Embryo-foetal developmental toxicology studies (range-finding and definitive studies) were 
conducted in pregnant rats and rabbits. In the definitive studies, doses of up to 30 mg/kg or 40 mg/kg 
every week were administered twice during the period of organogenesis. Luspatercept was a selective 
developmental toxicant (dam not affected; foetus affected) in the rat and a maternal and foetal 
developmental toxicant (doe and foetus affected) in the rabbit. Embryofoetal effects were seen in both 
species and included reductions in numbers of live foetuses and foetal body weights, increases in 
resorptions, post-implantation loss and skeletal variations and, in rabbit foetuses, malformations of the 
ribs and vertebrae. In both species, effects of luspatercept were observed in the EFD studies at the 
lowest dose tested, 5 mg/kg, which corresponds to an estimated exposure in rats and rabbits of 
approximately 2.7 and 5.5 times greater, respectively, than the estimated clinical exposure.  
 
Pre- and post-natal development 
In a pre- and post-natal development study, with dose levels of 3, 10, or 30 mg/kg administered once 
every 2 weeks from gestational day (GD) 6 through post-natal day (PND) 20, adverse findings at all 
doses consisted of lower F1 pup body weights in both sexes at birth, throughout lactation, and post 
weaning (PND 28); lower body weights during the early premating period (Week 1 and 2) in the F1 
females (adverse only at the 30 mg/kg/dose) and lower body weights in F1 males during the premating, 
pairing and post-mating periods; and microscopic kidney findings in F1 pups. Additionally, 
non-adverse findings included delayed male sexual maturation at the 10 and 30 mg/kg/dose. The delay 
in growth and the adverse kidney findings, in the F1 generation, precluded the determination of a 
NOAEL for F1 general and developmental toxicity. However, there was no effect on behavioural 
indices, fertility or reproductive parameters at any dose level in either sex, therefore the NOAEL for 
behavioural assessments, fertility and reproductive function in the F1 animals was considered to be the 
30 mg/kg/dose. Luspatercept is transferred through the placenta of pregnant rats and rabbits and is 
excreted into the milk of lactating rats. 
 
Juvenile toxicity 
In a study in juvenile rats, luspatercept was administered from postnatal day (PND) 7 to PND 91 at 0, 
1, 3, or 10 mg/kg. Many of the findings seen in repeat-dose toxicity studies in adult rats were repeated 
in the juvenile rats. These findings included glomerulonephritis in the kidney, 
haemorrhage/congestion, necrosis and mineralization of the adrenal gland, mucosal mineralization in 
the stomach, lower heart weights, and swollen hindlimbs/feet. Luspatercept-related findings unique to 
juvenile rats included tubular atrophy/hypoplasia of the kidney inner medulla, delays in the mean age 



 

18 

of sexual maturation in males, effects on reproductive performance (lower mating indices), and non-
adverse decreases in bone mineral density in both male and female rats. The effects on reproductive 
performance were observed after a greater than 3-month recovery period, suggesting a permanent 
effect. Although reversibility of the tubular atrophy/hypoplasia was not examined, these effects are 
also considered to be irreversible. Adverse effects on the kidney and reproductive system were 
observed at clinically relevant exposure levels and seen at the lowest dose tested and, thus, an NOAEL 
was not established. In addition, haematological malignancies were observed in 3 out of 44 rats 
examined in the highest dose group (10 mg/kg). These findings are all considered potential risks in 
paediatric patients. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Citric acid monohydrate (E330) 
Sodium citrate (E331) 
Polysorbate 80 
Sucrose 
Hydrochloric acid (for pH adjustment) 
Sodium hydroxide (for pH adjustment) 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
Unopened vial 
3 years. 
 
After reconstitution 
When stored in the original container, chemical and physical in-use stability of the reconstituted 
medicinal product has been demonstrated for up to 8 hours at room temperature (≤ 25°C) or for up to 
24 hours at 2°C - 8°C. 
 
From a microbiological point of view, the medicinal product should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
should not be longer than 24 hours at 2°C - 8°C. 
 
Do not freeze the reconstituted solution. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C - 8°C). 
 
Do not freeze. 
 
Store in the original carton in order to protect from light. 
 
For storage conditions after reconstitution of the medicinal product, see section 6.3. 
 



 

19 

6.5 Nature and contents of container 
 
Reblozyl 25 mg powder for solution for injection 
3 mL Type I glass vial with a hydrophobic inner coating closed with a bromobutyl rubber stopper and 
aluminium seal with yellow polypropylene flip-off cap. 
 
Reblozyl 75 mg powder for solution for injection 
3 mL Type I glass vial with a hydrophobic inner coating closed with a bromobutyl rubber stopper and 
aluminium seal with orange polypropylene flip-off cap. 
 
Pack size: 1 vial 
 
6.6 Special precautions for disposal and other handling 
 
Reblozyl must be reconstituted gently prior to administration. Aggressive shaking should be avoided. 
 
Reconstitution of the product 
Reblozyl is supplied as a lyophilised powder for reconstitution before use. Only water for injections 
(WFI) should be used when reconstituting Reblozyl. 
 
The appropriate number of Reblozyl vials should be reconstituted to achieve the desired dose. A 
syringe with appropriate graduations must be used for reconstitution to ensure accurate dosage. 
 
The following steps should be followed for reconstitution: 
 
1. Remove the coloured cap from the vial and wipe the top with an alcohol wipe. 
 
2. Reblozyl 25 mg powder for solution for injection 

Add 0.68 mL WFI into the vial by means of a syringe with appropriate graduations with a 
needle directing the flow onto the lyophilised powder. Allow to stand for one minute. Each 
25 mg single-dose vial will deliver at least 0.5 mL of 50 mg/mL luspatercept. 

 
Reblozyl 75 mg powder for solution for injection 
Add 1.6 mL WFI into the vial by means of a syringe with appropriate graduations with a needle 
directing the flow onto the lyophilised powder. Allow to stand for one minute. Each 75 mg 
single-dose vial will deliver at least 1.5 mL of 50 mg/mL luspatercept. 
 

3. Discard the needle and syringe used for reconstitution. Do not use them for subcutaneous 
injection. 

4. Gently swirl the vial in a circular motion for 30 seconds. Stop swirling and let the vial sit in an 
upright position for 30 seconds. 

5. Inspect the vial for undissolved powder in the solution. If undissolved powder is observed, 
repeat step 4 until the powder is completely dissolved. 

6. Invert the vial and gently swirl in an inverted position for 30 seconds. Bring the vial back to the 
upright position and let it sit for 30 seconds. 

7. Repeat step 6 seven more times to ensure complete reconstitution of material on the sides of the 
vial. 

8. Visually inspect the reconstituted solution prior to administration. When properly mixed, 
Reblozyl reconstituted solution is a colourless to slightly yellow, clear to slightly opalescent 
solution which is free of visible foreign particulate matter. Do not use if undissolved product or 
foreign particulate matter is observed. 

9. If the reconstituted solution is not used immediately, see section 6.3 for storage conditions. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 



 

20 

7. MARKETING AUTHORISATION HOLDER 
 
Celgene Europe B.V. 
Winthontlaan 6 N 
3526 KV Utrecht 
Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/20/1452/001 
EU/1/20/1452/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
  



 

21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 



 

22 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Celgene Distribution B.V. 
Winthontlaan 6 N 
3526 KV Utrecht  
Netherlands 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
 Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of 
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 
and any subsequent updates published on the European medicines web-portal. 
 
The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 
6 months following authorisation.  
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 
activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 
marketing authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
An updated RMP shall be submitted by CHMP agreed deadline. 
 
 Additional risk minimisation measures 
 
Prior to launch of Reblozyl in each Member State the Marketing Authorisation Holder (MAH) must 
agree about the content and format of the educational programme, including communication media, 
distribution modalities, and any other aspects of the programme, with the National Competent 
Authority.  
 
The MAH shall ensure that in each member state where Reblozyl is marketed, all HCPs who intend to 
prescribe Reblozyl are provided with an HCP Information Pack, containing the following: 
1. Information on where to find latest SmPC; 
2. HCP Checklist; 



 

23 

3. Patient Card (for WCBP only). 
 
Healthcare Professional Checklist 
The HCP Checklist is to be used before initiating treatment, at each administration, and then at regular 
intervals when performing follow-up. The HCP Checklist shall contain the following key messages: 

• Information on studies in animals showing luspatercept reproductive and embryo-foetal toxicity 
and is therefore contraindicated during pregnancy. 

• Reminder that luspatercept is contraindicated during pregnancy and in WCBP not using 
effective contraception. 

• Need to provide counselling before treatment initiation and regularly thereafter regarding the 
potential teratogenic risk of luspatercept and required actions to minimise this risk. 

• A pregnancy test must be carried out and negative results verified by the prescriber before 
starting treatment. It must be repeated at suitable intervals. 

• Patients must use highly effective contraception during the treatment with luspatercept. 
• While on treatment, women must not become pregnant. If a woman becomes pregnant or wants 

to become pregnant, luspatercept should be discontinued. Women of childbearing potential 
must use highly effective contraception during treatment with luspatercept and for at least 3 
months following discontinuation of treatment with luspatercept. 

• Need to provide counselling in the event of pregnancy and evaluation of the outcome of any 
pregnancy. 

• Should a pregnancy occur during treatment or within 3 months following discontinuation of 
treatment with luspatercept, remind the patient that it should be reported to the HCP, NCA, 
and/or to Celgene by contacting the local e-mail address or visiting the URL provided in the 
material, irrespective of adverse outcomes observed. 
 

Patient Card (for WCBP only) 
The Patient Card is to be handed to WCBP by the HCP at the time of treatment initiation. The HCP is 
to request that the WCBP confirm whether they have the Patient Card prior to each subsequent 
administration and provide them with additional cards as needed. The Patient Card shall contain the 
following key messages: 

• The need for a negative pregnancy test result prior to starting treatment with luspatercept in 
WCBP. 

• The need for WCBP to use at least one highly effective method of contraception during 
treatment with luspatercept and for at least 3 months following discontinuation. 

• The need to report to the doctor any suspected or confirmed pregnancy occurring during and for 
3 months following discontinuation of treatment. 
 

 
  



 

24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



 

25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



 

26 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Reblozyl 25 mg powder for solution for injection 
luspatercept 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 25 mg of luspatercept. After reconstitution, each mL of solution contains 50 mg 
luspatercept. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: citric acid monohydrate (E330), sodium citrate (E331), polysorbate 80, sucrose, 
hydrochloric acid, sodium hydroxide. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for solution for injection. 
 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Subcutaneous use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. Store in the original carton in order to protect from light. 
 
 



 

27 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with the local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Celgene Europe B.V. 
Winthontlaan 6 N 
3526 KV Utrecht 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/20/1452/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
REBLOZYL 25 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
  



 

28 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Reblozyl 25 mg powder for injection 
luspatercept 
SC 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 



 

29 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Reblozyl 75 mg powder for solution for injection 
luspatercept 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 75 mg of luspatercept. After reconstitution, each mL of solution contains 50 mg 
luspatercept. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: citric acid monohydrate (E330), sodium citrate (E331), polysorbate 80, sucrose, 
hydrochloric acid, sodium hydroxide. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for solution for injection. 
 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Subcutaneous use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. Store in the original carton in order to protect from light. 
 
 



 

30 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with the local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Celgene Europe B.V. 
Winthontlaan 6 N 
3526 KV Utrecht 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/20/1452/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
REBLOZYL 75 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
  



 

31 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Reblozyl 75 mg powder for injection 
luspatercept 
SC 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
  



 

32 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 

 



 

33 

Package leaflet: Information for the patient 
 

Reblozyl 25 mg powder for solution for injection 
Reblozyl 75 mg powder for solution for injection 

luspatercept 
 

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or nurse. 
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Reblozyl is and what it is used for 
2. What you need to know before you are given Reblozyl 
3. How Reblozyl is given 
4. Possible side effects 
5. How to store Reblozyl 
6. Contents of the pack and other information 
 
 
1. What Reblozyl is and what it is used for 
 
Reblozyl contains the active substance luspatercept. It is used for:  
 
Myelodysplastic syndromes 
Myelodysplastic syndromes (MDS) are a collection of many different blood and bone marrow 
disorders.  
 Red blood cells become abnormal and do not develop properly.  
 Patients can get a number of signs and symptoms including a low red blood cell count 

(anaemia) and may need red blood cell transfusions. Reblozyl is used in adults with anaemia 
caused by MDS, who need red blood cell transfusions. It is used in adults who have already had 
or are not able to have erythropoietin therapies. 

 
Beta-thalassaemia 
β-thalassaemia is a blood problem that is passed down through genes.  
 It affects the production of haemoglobin.  
 Patients can get a number of signs and symptoms including a low red blood cell count 

(anaemia) and may need red blood cell transfusions. 
 
Reblozyl is used in adults with β-thalassaemia who need red blood cell transfusions. 
 
How Reblozyl works 
Reblozyl improves your body’s ability to make red blood cells. Red blood cells contain haemoglobin, 
which is a protein that carries oxygen throughout your body. As your body makes more red blood 
cells, your haemoglobin level increases. 
 
Having Reblozyl reduces the need for red blood cell transfusions. 
 Regular blood transfusions can cause abnormally high levels of iron in the blood and in 

different organs of the body. This can be harmful over time. 



 

34 

 
 
2. What you need to know before you are given Reblozyl 
 
Do not use Reblozyl 
 if you are allergic to luspatercept or any of the other ingredients of this medicine (listed in 

section 6) 
 if you are pregnant (see section on Pregnancy) 
 
Warnings and precautions 
Talk to your doctor before being given this medicine if: 
 you are a β-thalassaemia patient and you have had your spleen removed. You may have a higher 

risk of getting a blood clot. Your doctor will talk to you about other possible risk factors that 
may increase your risk – these include: 
o hormone replacement therapy or  
o a previous blood clot  
Your doctor may use preventive measures or medicines to reduce the chances of you getting a 
blood clot. 

 you have ever had high blood pressure – this is because Reblozyl may increase it. Your blood 
pressure will be checked before you are given Reblozyl and throughout treatment. 

 
Routine tests 
You will have a blood test before each dose of this medicine. This is because your doctor needs to 
make sure your haemoglobin level is suitable for you to be given treatment. 
 
If you have kidney problems, your doctor may perform additional tests. 
 
Children and adolescents 
This medicine is not recommended for use in children and adolescents under 18 years. 
 
Other medicines and Reblozyl 
Tell your doctor if you are taking, have recently taken or might take any other medicines. 
 
Pregnancy 
 Do not use this medicine during pregnancy and for at least 3 months before getting pregnant. 

Reblozyl may cause harm to your unborn baby. 
 Your doctor will arrange a pregnancy test before starting treatment. 
 If you think you may be pregnant or are planning to have a baby, ask your doctor for advice 

before using this medicine. 
 
Breast-feeding 
 Do not breast-feed when using this medicine and for 3 months after your last dose. It is not 

known if it passes into the mother’s milk. 
 
Contraception 
 You should use an effective method of contraception during treatment with Reblozyl and for at 

least 3 months after your last dose. 
 
Talk to your doctor about contraceptive methods that may be right for you while you are using this 
medicine. 
 
Fertility 
If you are a woman, this medicine may cause fertility problems. This could affect your ability to have 
a baby. Talk to your doctor for advice before using it. 
 



 

35 

Driving and using machines 
You may feel tired, dizzy, or faint, while using Reblozyl. If this happens do not drive or use any tools 
or machines and contact your doctor straight away. 
 
Reblozyl contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 
‘sodium-free’. 
 
 
3. How Reblozyl is given 
 
Before you are given this medicine, your doctor will have carried out blood tests and decided you need 
Reblozyl. 
 
Reblozyl will be given by an injection under your skin (subcutaneously).  
 
How much will you be given 
The dose is based on how much you weigh – in kilograms. The injections will be given by a doctor, 
nurse or other healthcare professional. 
 
 The recommended starting dose is 1.0 mg for each kilogram of body weight. 
 This dose should be given once every three weeks. 
 Your doctor will check your progress and may change your dose if needed. 
 
Your doctor will monitor your blood pressure while you are using Reblozyl. 
 
Myelodysplastic syndromes 
The maximum single dose is 1.75 mg for each kilogram of body weight. 
 
Beta-thalassaemia 
The maximum single dose is 1.25 mg for each kilogram of body weight. 
 
If you miss a dose 
If you miss an injection of Reblozyl, or an appointment is delayed, you will receive a Reblozyl 
injection as soon as possible. Then, your dose will continue as prescribed – with at least 3 weeks 
between doses. 
 
If you have any further questions on the use of this medicine, ask your doctor or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine may cause side effects, although not everybody gets them. 
 
Serious side effects 
Tell your doctor straight away if you notice the following: 
 difficulty in walking or speaking, dizziness, loss of balance and coordination, numbness or 

paralysis in the face, leg or arm (often on one side of your body), blurred vision. They may all 
be symptoms of a stroke. 

 blood clots 
 swelling of the area around the eyes, the face, lips, mouth, tongue or throat 
 allergic reactions 
 rashes 
 



 

36 

Other side effects include: 
 
Very common side effects (may affect more than 1 in 10 people): 
 chest infection 
 difficulty in breathing or shortness of breath 
 urinary tract infection 
 dizziness, headache 
 diarrhoea, feeling sick (nausea) 
 back, joint or bone pain 
 feeling tired or weak 
 
Common side effects (may affect up to 1 in 10 people): 
 flu symptoms  
 fainting, spinning feeling 
 high blood pressure associated with no symptoms or with headache 
 redness, burning and pain at the site of injection (injection site reactions) 
 high level of uric acid in the blood (shown in tests) 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store Reblozyl 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and the vial after EXP. The 
expiry date refers to the last day of that month. 
 
Unopened vials: Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the original carton in order 
to protect from light. 
 
After first opening and reconstitution, Reblozyl should be used immediately. If not used immediately, 
when held in the original carton the reconstituted medicinal product may be stored for up to 8 hours at 
room temperature (≤ 25°C) or for up to 24 hours at 2°C – 8°C. 
 
Do not freeze the reconstituted solution. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
6. Contents of the pack and other information 
 
What Reblozyl contains 
- The active substance is luspatercept. Each vial contains 25 mg or 75 mg of luspatercept. After 

reconstitution, each mL of solution contains 50 mg luspatercept. 
- The other excipients are citric acid monohydrate (E330), sodium citrate (E331), polysorbate 80, 

sucrose, hydrochloric acid (for pH adjustment) and sodium hydroxide (for pH adjustment). 
 
What Reblozyl looks like and contents of the pack 
Reblozyl is a white to off-white powder for solution for injection. Reblozyl is supplied in glass vials 
containing 25 mg or 75 mg of luspatercept. 



 

37 

 
Each pack contains 1 vial. 
 
Marketing Authorisation Holder 
Celgene Europe B.V. 
Winthontlaan 6 N 
3526 KV Utrecht 
Netherlands 
 
Manufacturer 
Celgene Distribution B.V. 
Winthontlaan 6 N 
3526 KV Utrecht 
Netherlands 
 
This leaflet was last revised in  
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 
 
 
------------------------------------------------------------------------------------------------------------------------ 
 
The following information is intended for healthcare professionals only: 
 
Traceability 
In order to improve the traceability of biological medicinal products, the name and batch number of 
the administered medicinal product should be clearly recorded. 
 
Incompatibilities 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6. 
 
Storage of the product 
Unopened vial 
Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the original carton in order to protect from 
light. 
 
Reconstituted solution 
When stored in the original carton, chemical and physical in-use stability of the reconstituted 
medicinal product has been demonstrated for up to 8 hours at room temperature (≤ 25°C) or for up to 
24 hours at 2°C – 8°C. 
 
From a microbiological point of view, the medicinal product should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
should not be longer than 24 hours at 2°C – 8°C. 
 
Do not freeze the reconstituted solution. 
 
Dose calculation 
The total dose, according to the patient’s weight (kg) can be calculated as follow: 
 
Total dose (mg) = Dose (mg) x patient’s weight (kg) every three weeks. 
 



 

38 

Reconstitution instructions 
Reblozyl is supplied as a lyophilised powder to be reconstituted with water for injections (WFI). A 
syringe with appropriate graduations must be used for reconstitution to ensure accurate dosage. See 
Table 1. 
 
Table 1. Reblozyl reconstitution table 

Strength  Amount of WFI required for 
reconstitution 

Post-reconstitution concentration 
(nominal value)

25 mg vial 0.68 mL 50 mg/mL (0.5 mL)
75 mg vial 1.6 mL 50 mg/mL (1.5 mL)

 
1. Remove the coloured cap from the vial and wipe the top with an alcohol wipe.  
2. Add WFI into the vial by means of a syringe with appropriate graduations with a needle 

directing the flow onto the lyophilised powder. Allow to stand for one minute. 
3. Discard the needle and syringe used for reconstitution. Do not use them for subcutaneous 

injection. 
4. Gently swirl the vial in a circular motion for 30 seconds. Stop swirling and let the vial sit in an 

upright position for 30 seconds. 
5. Inspect the vial for undissolved powder in the solution. If undissolved powder is observed, 

repeat step 4 until the powder is completely dissolved. 
6. Invert the vial and gently swirl in an inverted position for 30 seconds. Bring the vial back to the 

upright position and let it sit for 30 seconds. 
7. Repeat step 6 seven more times to ensure complete reconstitution of material on the sides of the 

vial. 
8. Visually inspect the reconstituted solution prior to administration. When properly mixed, 

Reblozyl reconstituted solution is a colourless to slightly yellow, clear to slightly opalescent 
solution which is free of visible foreign particulate matter. Do not use if undissolved product or 
foreign particulate matter is observed. 

9. If the reconstituted solution is not used immediately, see Storage of the product section above. 
 
Method of administration 
If the Reblozyl reconstituted solution has been refrigerated, remove from the refrigerator 
15-30 minutes prior to injection to allow it to reach room temperature. This will allow for a more 
comfortable injection. 
 
The recommended maximum volume of medicinal product per injection site is 1.2 mL. If more than 
1.2 mL is required, the total volume of Reblozyl should be divided into separate similar volume 
injections and administered across separate sites. Reconstitute the appropriate number of Reblozyl 
vials to achieve the desired dose. 
 
Inject Reblozyl subcutaneously into the upper arm, thigh or abdomen. 
 
If multiple injections are required, use a new syringe and needle for each subcutaneous injection. 
Discard any unused portion. Do not administer more than one dose from a vial. 
 
Disposal 
Dispose of any unused medicinal product or waste material in accordance with local requirements. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET