SAFETY

Safety Profile

The safety evaluation of Reblozyl in MDS is based on the double-blind, randomized, placebo-controlled, phase 3 MEDALIST trial (with 153 patients treated with Reblozyl and 76 patients receiving placebo).1

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.1

Most frequently reported adverse drug reactions
in at least 15% of patients receiving Reblozyl1

Fatigue

Diarrhea

Asthenia

Nausea

Dizziness

Back pain

Headache

Asthenia, fatigue, dizziness, and headache occurred more frequently during the first 3 months of treatment1

The frequency for each adverse reaction observed in the MEDALIST trial is shown in the center table.

ADVERSE DRUG REACTIONS IN PATIENTS TREATED
WITH REBLOZYL FOR MDS1
SYSTEM ORGAN CLASS PREFERRED TERM FREQUENCY (ALL GRADES)a
Infections and infestations Bronchitis Very common
Urinary tract infection Very common
Upper respiratory
tract infection
Common
Influenza Common
Immune system disorders Hypersensitivityb Common
Metabolism and
nutrition disorders
Hyperuricemia Common
Nervous system disorders Dizziness Very common
Headache Very common
Syncope/presyncope Common
Ear and labyrinth disorders Vertigo/vertigo positional Common
Vascular disorders Hypertensionc Common
Thromboembolic eventsd Common
Respiratory, thoracic
and mediastinal disorders
Dyspnea Very common
Gastrointestinal disorders Diarrhea Very common
Nausea Very common
Musculoskeletal and
connective tissue
disorders
Back pain Very common
Arthralgia Common
Bone pain Common
General disorders and
administration site
conditions
Fatigue Very common
Asthenia Very common
Injection site reactionse Common

aFrequencies 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).

bHypersensitivity includes eyelid edema, drug hypersensitivity, swelling face, periorbital edema, face edema, angioedema, lip swelling, and drug eruption.

cHypertension reaction includes essential hypertension, hypertension, and hypertensive crisis.

dThromboembolic events include deep vein thrombosis, portal vein thrombosis, ischemic stroke, and pulmonary embolism.

eInjection site reactions include injection site erythema, injection site pruritus, injection site swelling, and injection site rash.

Safety Profile

The safety evaluation of Reblozyl in MDS is based on the double-blind, randomized, placebo-controlled, Phase 3 MEDALIST trial (with 153 patients treated with Reblozyl and 76 patients receiving placebo).1

Fatigue

Dizziness

Diarrhea

Back pain

Asthenia

Headache

Nausea

Asthenia, fatigue, dizziness, and headache occurred less frequently during the first 3 months of treatment1  

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.1

Adverse drug reactions observed

ADVERSE DRUG REACTIONSOBSERVED AND REPORTED IN PATIENTS TREATED WITH REBLOZYL FOR MDS1
SYSTEM ORGAN CLASS
PREFERRED TERM
FREQUENCY (ALL GRADES)a
Infections and infestations
Bronchitis Very common
Urinary tract infection Very common
Upper respiratory tract infection Common
Influenza Common
Immune system disorders
Hypersensitivityb Common
Metabolism and nutrition disorders
Hyperuricemia Common
Nervous system disorders
Dizziness Very common
Headache Very common
Syncope/presyncope Common
Ear and labyrinth disorders
Vertigo/vertigo positional Common
Vascular disorders
Hypertensionc Common
Thromboembolic eventsd Common
Respiratory, thoracic and mediastinal disorders
Dyspnea Very common
Gastrointestinal disorders
Diarrhea Very common
Nausea Very common
Musculoskeletal and connective tissue disorders
Back pain Very common
Arthralgia Common
Bone pain Common
General disorders and administration site conditions
Fatigue Very common
Asthenia Very common
Injection site reactionse Common

a 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). [Reblozyl Draft SPC/p7/para4/lns3-5]

b Hypersensitivity includes eyelid edema, drug hypersensitivity, swelling face, periorbital edema, face edema, angioedema, lip swelling, and drug eruption.

c Hypertension reaction includes essential hypertension, hypertension, and hypertensive crisis.

d Thromboembolic events include deep vein thrombosis, portal vein thrombosis, ischemic stroke, and pulmonary embolism.

e Injection site reactions include injection site erythema, injection site pruritus, injection site swelling, and injection site rash.

Reference:

1. Reblozyl® (luspatercept) Summary of Product Characteristics (SmPC). Celgene 2020.

Selected adverse reactions

Selected adverse reactions across MEDALIST and BELIEVE trials1
  • Hypersensitivity: Hypersensitivity-type reactions (including eyelid edema, drug hypersensitivity, swelling face, periorbital edema, face edema, angioedema, lip swelling, drug eruption) were reported in 4.6% of patients with MDS (2.6% placebo) and 4.5% of patients with β-thalassemia treated with Reblozyl (1.8% placebo). In clinical studies, all events were Grade 1/2. In patients with β-thalassemia treated with Reblozyl, 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 patients with MDS (placebo 0.0%) and in 2.2% of patients with β-thalassemia receiving Reblozyl (placebo 1.8%). In clinical studies, all events were Grade 1 and none led to discontinuation.
  • Immunogenicity: In an analysis of 260 patients with MDS who were treated with Reblozyl and who were evaluable for the presence of anti-luspatercept antibodies, 8.8% of MDS patients tested positive for treatment‑emergent anti-luspatercept antibodies, including 3.5% of MDS patients who had neutralizing antibodies against Reblozyl

    In an analysis of 284 patients with β-thalassemia who were treated with Reblozyl and who were evaluable for the presence of anti-luspatercept antibodies, 4 (1.4%) patients tested positive for treatment-emergent anti-luspatercept antibodies, including 2 (0.7%) patients who had neutralizing antibodies against Reblozyl
  • 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
  • Thromboembolic events (TEEs): Thromboembolic events (including deep vein thrombosis, portal vein thrombosis, ischemic stroke and pulmonary embolism) occurred in 3.6% of patients with β-thalassemia receiving Reblozyl (placebo 0.9%). All events were reported in patients who had undergone splenectomy and had at least 1 other risk factor. No difference in TEEs was observed between Reblozyl and placebo arms in patients with MDS
  • Hypertension: Patients treated with Reblozyl had an average increase in systolic and diastolic blood pressure of 5 mm Hg from baseline not observed in patients receiving placebo. Hypertension was reported in 8.5% of patients with MDS (placebo 9.2%) and in 8.1% of patients with β-thalassemia (placebo 2.8%).
    • In patients with MDS, Grade 3 events were reported for 5 patients (3.3%) treated with Reblozyl and in 3 patients (3.9%) receiving placebo. No patient discontinued due to hypertension.
    • In patients with β-thalassemia, Grade 3 events were reported in 4 patients (1.8%) treated with Reblozyl (0.0% placebo). No patient discontinued due to hypertension
  • Arthralgia: Arthralgia was reported in 19.3% of patients with β-thalassemia treated with Reblozyl (placebo 11.9%) and in 5.2% of patients with MDS treated with Reblozyl (placebo 11.8%). In the patients with β-thalassemia treated with Reblozyl, arthralgia led to treatment discontinuation in 2 patients (0.9%).
  • Bone pain: Bone pain was reported in 19.7% of patients with β-thalassemia treated with Reblozyl (placebo 8.3%) and in 2.6% of patients with MDS treated with Reblozyl (placebo 3.9%). In patients with β-thalassemia treated with Reblozyl, bone pain was most common in the first 3 months (16.6%) compared with 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.

Selected adverse reactions in patients with MDS1

Higher instance of adverse reactions with Reblozyl vs placebo in the MEDALIST trial
Hypersensitivity Was Reported In 4.6% Of Patients Receiving Reblozyl (2.6% Placebo)

Hypersensitivity

4.6% Reblozyl

2.6% Placebo

All events were Grade 1 or 2

Injection Site Reactions Were Reported In 3.9% Of Patients Receiving Reblozyl (0% Placebo)

Injection site reactions

3.9% Reblozyl

0% Placebo

All were Grade 1 and did not lead to treatment discontinuation


Other adverse reactions in MDS

8.8% Of Patients Receiving Reblozyl Tested Positive For Treatment-Emergent Anti-Reblozyl Antibodies

Immunogenicity

8.8% of Reblozyl patients tested positive for
treatment-emergent anti-luspatercept antibodies

No Difference in Thromboembolic Events Was Observed Between Reblozyl and Placebo

Thromboembolic events

No difference between Reblozyl and Placebo

Hypertension Was Reported in 8.5% Patients Receiving Reblozyl (9.2% Placebo)

Hypertension

8.5% Reblozyl

9.2% Placebo

Grade 3 events were reported in 5 patients receiving Reblozyl (3.3%);
none led to treatment discontinuation

Arthralgia Was Reported In 5.2% Patients Receiving Reblozyl (11.8% Placebo)

Arthralgia

5.2% Reblozyl

11.8% Placebo

Bone Pain Was Reported in 2.6% Patients Receiving Reblozyl (3.9% Placebo)

Bone pain

2.6% Reblozyl

3.9% Placebo

Selected adverse reactions

Selected adverse reactions in patients with MDS1

Higher instance of adverse reactions with Reblozyl vs placebo in the MEDALIST trial1
No Difference in Thromboembolic Events Was Observed Between Reblozyl and Placebo

Hypersensitivity

4.6% Reblozyl

2.6% Placebo

Hypersensitivity-type reactions (including eyelid edema, drug hypersensitivity, swelling face, periorbital edema, face edema, angioedema, lip swelling, drug eruption) were reported in 4.6% of patients with MDS (2.6% placebo) and 4.5% of patients with β-thalassemia treated with Reblozyl (1.8% placebo).In clinical studies, all events were Grade 1/2. In patients with β-thalassemia treated with Reblozyl, hypersensitivity led to treatment discontinuation in 1 patient (0.4%).1

Injection Site Reactions Were Reported In 3.9% Of Patients Receiving Reblozyl (0% Placebo)

Injection site reactions

3.9% Reblozyl

0% Placebo

Injection site reactions (including injection site erythema, injection site pruritus, injection site swelling and injection site rash) were reported in 3.9% of patients with MDS (placebo 0.0%) and in 2.2% of patients with β-thalassemia receiving Reblozyl (placebo 1.8%). In clinical studies, all events were Grade 1 and none led to discontinuation.1


Other adverse reactions in MDS

8.8% Of Patients Receiving Reblozyl Tested Positive For Treatment-Emergent Anti-Reblozyl Antibodies

Immunogenicity

8.8% of Reblozyl patients tested positive for treatment-emergent anti-Reblozyl antibodies

In an analysis of 260 patients with MDS who were treated with Reblozyl and who were evaluable for the presence of anti-Reblozyl antibodies, 8.8% of patients tested positive for treatment‑emergent anti-Reblozyl antibodies, including 3.5% of patients who had neutralizing antibodies against Reblozyl1

In an analysis of 284 patients with ß-thalassemia who were treated with Reblozyl and who were evaluable for the presence of anti-luspatercept antibodies, 4 (1.4%) patients tested positive for treatment-emergent anti-luspatercept antibodies, including 2 (0.7%) patients who had neutralizing antibodies against Reblozyl1

  • There were no severe systemic hypersensitivity reactions reported for patients with anti-luspatercept antibodies1
  • There was no association between hypersensitivity type reactions or injection site reactions and presence of anti-luspatercept antibodies1
No Difference in Thromboembolic Events Was Observed Between Reblozyl and Placebo

Thromboembolic Events

No difference between Reblozyl and placebo

Thromboembolic events (including deep vein thrombosis, portal vein thrombosis, ischemic stroke and pulmonary embolism) occurred in 3.6% of patients with β-thalassemia receiving Reblozyl (placebo 0.9%). All events were reported in patients who had undergone splenectomy and had at least 1 other risk factor. No difference in TEEs was observed between Reblozyl and placebo arms in MDS patients1

Hypertension Was Reported in 8.5% Patients Receiving Reblozyl (9.2% Placebo)

Hypertension

8.5% Reblozyl

9.2% Placebo

Patients treated with Reblozyl had an average increase in systolic and diastolic blood pressure of 5 mm Hg from baseline not observed in patients receiving placebo. Hypertension was reported in 8.5% of patients with MDS (placebo 9.2%) and in 8.1% of patients with ß-thalassemia (placebo 2.8%).1

  • In patients with MDS, Grade 3 events were reported for 5 patients (3.3%) treated with Reblozyl and in 3 patients (3.9%) receiving placebo. No patient discontinued due to hypertension.1
  • In patients with β-thalassemia, Grade 3 events were reported in 4 patients (1.8%) treated with Reblozyl (0.0% placebo). No patient discontinued due to hypertension1
Arthralgia Was Reported In 5.2% Patients Receiving Reblozyl (11.8% Placebo)

Arthralgia

5.2% Reblozyl

11.8% Placebo

Arthralgia was reported in 19.3% of patients with ß-thalassemia treated with Reblozyl (placebo 11.9%) and in 5.2% of patients with MDS treated with Reblozyl (placebo 11.8%). In the patients with β-thalassemia treated with Reblozyl, arthralgia led to treatment discontinuation in 2 patients (0.9%).1

Bone Pain Was Reported in 2.6% Patients Receiving Reblozyl (3.9% Placebo)

Bone Pain

2.6% Reblozyl

3.9% Placebo

Bone pain was reported in 19.7% of patients with β-thalassemia treated with Reblozyl (placebo 8.3%) and in 2.6% of patients with MDS treated with Reblozyl (placebo 3.9%). In patients with β-thalassemia treated with Reblozyl, bone pain was most common in the first 3 months (16.6%) compared with 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.1

Reference:

1. Reblozyl® (luspatercept) Summary of Product Characteristics (SmPC). Celgene 2020.

Discontinuations

Treatment discontinuation due to an adverse reaction occurred in 2.0% of patients with MDS. The adverse reactions leading to treatment discontinuation in the Reblozyl arm were fatigue and headache.1

Only 2% Of Patients With MDS Receiving Reblozyl Discontinued Treatment Due To An Adverse Event

Discontinuations

Only 2% Of Patients With MDS Receiving Reblozyl Discontinued Treatment Due To An Adverse Event
of MDS patients receiving Reblozyl discontinued treatment due to an adverse reaction1

The adverse reactions leading to treatment discontinuation in the Reblozyl arm were fatigue and headache.1

Reference:

1. Reblozyl® (luspatercept) Summary of Product Characteristics (SmPC). Celgene 2020.

 

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EU Summary of Product Characteristics.