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Warnings and precautions1

Thrombosis/Thromboembolism

Thromboembolic events (TEE) were reported in 8/223 (3.6%) REBLOZYL-treated patients. TEEs included deep vein thrombosis, pulmonary embolus, portal vein thrombosis, and ischemic stroke. Patients with known risk factors for thromboembolism (splenectomy or concomitant use of hormone replacement therapy) may be at further increased risk of thromboembolic conditions. Consider thromboprophylaxis in patients at increased risk of TEE. Monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly.

Hypertension

Hypertension was reported in 10.7% (61/571) of REBLOZYL-treated patients. Across clinical studies, the incidence of Grade 3 to 4 hypertension ranged from 1.8% to 8.6%. In patients with beta thalassemia with normal baseline blood pressure, 13 (6.2%) patients developed systolic blood pressure (SBP) ≥130 mm Hg and 33 (16.6%) patients developed diastolic blood pressure (DBP) ≥80 mm Hg. Monitor blood pressure prior to each administration. Manage new or exacerbations of preexisting hypertension using anti-hypertensive agents.

Embryo-Fetal Toxicity

REBLOZYL may cause fetal harm when administered to a pregnant woman. REBLOZYL caused increased post-implantation loss, decreased litter size, and an increased incidence of skeletal variations in pregnant rat and rabbit studies. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months after the final dose.

Adverse reactions with REBLOZYL1

  • The data in the Warnings and Precautions reflect exposure to REBLOZYL as a single agent administered across a range of doses (0.125 mg/kg–1.75 mg/kg) in 571 patients in 4 trials
  • The median duration of treatment was similar between the REBLOZYL and placebo arms (63.3 weeks vs 62.1 weeks, respectively)
  • Per protocol, patients in the REBLOZYL and placebo arms were to remain on therapy for at least 48 weeks in the double-blind phase of the trial
  • Among patients receiving REBLOZYL, 94% were exposed for 6 months or longer and 72% were exposed for >1 year
  • Serious adverse reactions occurred in 3.6% of patients on REBLOZYL. Serious adverse reactions reported in 1% of patients were cerebrovascular accident and deep vein thrombosis. A fatal adverse reaction occurred in 1 patient treated with REBLOZYL who died due to an unconfirmed case of acute myeloid leukemia (AML)
  • The most common adverse reactions (at least 10% for REBLOZYL and 1% more than placebo) were headache (26%), bone pain (20%), arthralgia (19%), fatigue (14%), cough (14%), abdominal pain (14%), diarrhea (12%), and dizziness (11%)

Adverse drug reactions (>5%) in patients receiving REBLOZYL with a difference between arms of 1% in the BELIEVE trial1

Adverse reaction REBLOZYL
(n = 223)
Placebo
(n = 109)
All Grades
n (%)
Grades ≥3a
n (%)
All Grades
n (%)
Grades ≥3
n (%)
Musculoskeletal and connective tissue disorders
Bone pain 44 (20) 3 (1) 9 (8) 0 (0)
Arthralgia 43 (19) 0 (0) 13 (12) 0 (0)
Infections and infestation
Influenza 19 (9) 0 (0) 6 (6) 0 (0)
Viral upper respiratory infection 14 (6) 1 (0.4) 2 (2) 0 (0)
Nervous system disorders
Headache 58 (26) 1 (<1) 26 (24) 1 (1)
Dizziness 25 (11) 0 (0) 5 (5) 0 (0)
General disorders and administration site conditions
Fatigue 30 (14) 0 (0) 14 (13) 0 (0)
Gastrointestinal disorders
Abdominal painb 31 (14) 0 (0) 13 (12) 0 (0)
Diarrhea 27 (12) 1 (<1) 11 (10) 0 (0)
Nausea 20 (9) 0 (0) 6 (6) 0 (0)
Vascular disorders
Hypertensionc 18 (8) 4 (2) 3 (3) 0 (0)
Metabolism and nutrition disorders
Hyperuricemia 16 (7) 6 (3) 0 (0) 0 (0)
Respiratory, thoracic, and mediastinal disorders
Cough 32 (14) 0 (0) 12 (11) 0 (0)

aLimited to Grade 3 reactions with the exception of 4 events of Grade 4 hyperuricemia.

bGrouped term includes: Abdominal pain and abdominal pain upper.

cGrouped term includes: Essential hypertension, hypertension, and hypertensive crisis.

  • Clinically relevant adverse reactions in <5% of patients include vertigo/vertigo positional, syncope/presyncope, injection site reactions, and hypersensitivity1

Liver function laboratory abnormalities in the BELIEVE trial1

REBLOZYL
(n = 223)
n (%)
Placebo
(n = 109)
n (%)
ALT ≥3 × ULN 26 (12) 13 (12)
AST ≥3 × ULN 25 (11) 5 (5)
ALP ≥2 × ULN 17 (8) 1 (<1)
Total bilirubin ≥2 × ULN 143 (64) 51 (47)
Direct bilirubin ≥2 × ULN 13 (6) 4 (4)

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.

Immunogenicity1

  • Of 284 patients with β-thalassemia who were treated with REBLOZYL and evaluable for the presence of anti-luspatercept-aamt antibodies, 4 patients (1.4%) tested positive for treatment-emergent anti-luspatercept-aamt antibodies, including 2 patients (0.7%) who had neutralizing antibodies
  • Luspatercept-aamt serum concentration tended to decrease in the presence of neutralizing antibodies
  • There were no severe acute systemic hypersensitivity reactions reported for patients with anti-luspatercept-aamt antibodies in REBLOZYL clinical trials, and there was no association between hypersensitivity type reaction or injection site reaction and presence of anti-luspatercept-aamt antibodies

Lactation1

  • REBLOZYL was detected in milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. There are no data on the presence of REBLOZYL in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with REBLOZYL, and for 3 months after the last dose

REBLOZYL discontinuations, dose reductions, and dose interruptions in β-thalassemia1

Discontinuations due to adverse reactions1

Permanent discontinuation due to an adverse reaction (Grades 1-4) occurred in 5.4% of patients who received REBLOZYL. Most frequent adverse reactions requiring permanent discontinuation in patients who received REBLOZYL included arthralgia (1%), back pain (1%), bone pain (<1%), and headache (<1%).

Dose reductions and interruptions due to adverse reactions1

Dosage reductions due to an adverse reaction occurred in 2.7% of patients who received REBLOZYL. Most frequent adverse reactions requiring dosage reduction in >0.5% of patients who received REBLOZYL included hypertension and headache.

Dosage interruptions due to an adverse reaction occurred in 15.2% of patients who received REBLOZYL. Most frequent adverse reactions requiring dosage interruption in >1% of patients who received REBLOZYL included upper respiratory tract infection, ALT increase, and cough.

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Indication

REBLOZYL is indicated for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions.

REBLOZYL is indicated for the treatment of anemia failing an erythropoiesis stimulating agent and requiring 2 or more red blood cell units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).

REBLOZYL is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Thrombosis/Thromboembolism

In adult patients with beta thalassemia, thromboembolic events (TEE) were reported in 8/223 (3.6%) REBLOZYL-treated patients. TEEs included deep vein thrombosis, pulmonary embolus, portal vein thrombosis, and ischemic stroke. Patients with known risk factors for thromboembolism (splenectomy or concomitant use of hormone replacement therapy) may be at further increased risk of thromboembolic conditions. Consider thromboprophylaxis in patients at increased risk of TEE. Monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly.

Hypertension

Hypertension was reported in 10.7% (61/571) of REBLOZYL-treated patients. Across clinical studies, the incidence of Grade 3 to 4 hypertension ranged from 1.8% to 8.6%. In patients with beta thalassemia with normal baseline blood pressure, 13 (6.2%) patients developed systolic blood pressure (SBP) ≥130 mm Hg and 33 (16.6%) patients developed diastolic blood pressure (DBP) ≥80 mm Hg. In adult patients with MDS with normal baseline blood pressure, 26 (29.9%) patients developed SBP ≥130 mm Hg and 23 (16.4%) patients developed DBP ≥80 mm Hg. Monitor blood pressure prior to each administration. Manage new or exacerbations of preexisting hypertension using anti-hypertensive agents.

Embryo-Fetal Toxicity

REBLOZYL may cause fetal harm when administered to a pregnant woman. REBLOZYL caused increased post-implantation loss, decreased litter size, and an increased incidence of skeletal variations in pregnant rat and rabbit studies. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months after the final dose.

ADVERSE REACTIONS

Beta-Thalassemia

  • Serious adverse reactions occurred in 3.6% of patients on REBLOZYL. Serious adverse reactions occurring in 1% of patients included cerebrovascular accident and deep vein thrombosis. A fatal adverse reaction occurred in 1 patient treated with REBLOZYL who died due to an unconfirmed case of acute myeloid leukemia (AML)
  • Most common adverse reactions (at least 10% for REBLOZYL and 1% more than placebo) were headache (26% vs 24%), bone pain (20% vs 8%), arthralgia (19% vs 12%), fatigue (14% vs 13%), cough (14% vs 11%), abdominal pain (14% vs 12%), diarrhea (12% vs 10%) and dizziness (11% vs 5%)

Myelodysplastic Syndromes

  • Grade ≥3 (≥2%) adverse reactions included fatigue, hypertension, syncope and musculoskeletal pain. A fatal adverse reaction occurred in 5 (2.1%) patients
  • The most common (≥10%) adverse reactions included fatigue, musculoskeletal pain, dizziness, diarrhea, nausea, hypersensitivity reactions, hypertension, headache, upper respiratory tract infection, bronchitis, and urinary tract infection

LACTATION

It is not known whether REBLOZYL is excreted into human milk or absorbed systemically after ingestion by a nursing infant. REBLOZYL was detected in milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because many drugs are excreted in human milk, and because of the unknown effects of REBLOZYL in infants, a decision should be made whether to discontinue nursing or to discontinue treatment. Because of the potential for serious adverse reactions in the breastfed child, breastfeeding is not recommended during treatment and for 3 months after the last dose.

Please click here for full Prescribing Information for REBLOZYL.

Reference: 1. REBLOZYL [Prescribing Information]. Summit, NJ: Celgene Corporation; 2020.