Reblozyl

Dosage and Administration, Recommended Dosage for Beta Thalassemia ( 2.1 ) 2/2026 Dosage and Administration, Recommended Dosage for Myelodysplastic Syndromes Associated Anemia ( 2.2 ) 2/2026

1 INDICATIONS AND USAGE REBLOZYL is an erythroid maturation agent indicated for the treatment of: • Anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions ( 1.1 ). • Anemia without previous erythropoiesis stimulating agent use (ESA-naïve) in adult patients with very low- to intermediate-risk myelodysplastic syndromes (MDS) who may require regular red blood cell (RBC) transfusions ( 1.2 ). • Anemia failing an erythropoiesis stimulating agent and requiring 2 or more RBC 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) ( 1.3 ). • Limitations of Use: REBLOZYL is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia ( 1.4 ). 1.1 Beta Thalassemia REBLOZYL is indicated for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions. 1.2 Myelodysplastic Syndromes Associated Anemia REBLOZYL is indicated for the treatment of anemia without previous erythropoiesis stimulating agent use (ESA-naïve) in adult patients with very low- to intermediate-risk myelodysplastic syndromes (MDS) who may require regular red blood cell (RBC) transfusions. 1.3 Myelodysplastic Syndromes with Ring Sideroblasts or Myelodysplastic/ Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis Associated Anemia 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). 1.4 Limitations of Use REBLOZYL is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.

2 DOSAGE AND ADMINISTRATION • Beta thalassemia: The recommended starting dose is 1 mg/kg once every 3 weeks by subcutaneous injection. Increase dose if patient has no reduction in RBC transfusion burden to a maximum of 1.25 mg/kg ( 2.1 ). • Myelodysplastic Syndromes: The recommended starting dose is 1 mg/kg once every 3 weeks by subcutaneous injection. o For ESA-naïve MDS, increase dose to maintain patient’s hemoglobin concentrations within the target range of 10 g/dL to 12 g/dL to a maximum of 1.75 mg/kg ( 2.2 ). o For ESA-refractory or intolerant MDS, increase dose if patient is not RBC transfusion-free to a maximum of 1.75 mg/kg ( 2.2 ). • Review hemoglobin (Hgb) results prior to each administration ( 2.1 , 2.2 ). • See full prescribing information for preparation and administration instructions ( 2.3 ). 2.1 Recommended Dosage for Beta Thalassemia The recommended starting dose of REBLOZYL is 1 mg/kg once every 3 weeks by subcutaneous injection for patients with beta thalassemia. Prior to each REBLOZYL dose, review the patient’s hemoglobin and transfusion record. Titrate the dose based on responses according to Table 1. Interrupt treatment for adverse reactions as described in Table 2. Discontinue REBLOZYL if no response as described in Table 1 , or if unacceptable toxicity occurs at any time as described in Table 2 . If a planned administration of REBLOZYL is delayed or missed, administer REBLOZYL as soon as possible and continue dosing as prescribed, with at least 3 weeks between doses. Dose Modifications for Response Assess and review hemoglobin results prior to each administration of REBLOZYL. If an RBC transfusion occurred prior to dosing, use the pretransfusion hemoglobin for dose evaluation. Dose modifications for response are provided in Table 1. Do not increase the dose beyond the maximum dose of 1.25 mg/kg. In absence of transfusion, if hemoglobin increase is greater than 2 g/dL within 3 weeks or the predose hemoglobin is greater than or equal to 11.5 g/dL, reduce the dose or interrupt treatment with REBLOZYL as described in Table 1. Table 1: Beta Thalassemia - REBLOZYL Dose Titration for Response * Do not increase the dose if the patient is experiencing an adverse reaction as described in Table 2. REBLOZYL Dosing Recommendation* Starting Dose • 1 mg/kg every 3 weeks Dose Increases for Insufficient Response If after at least 2 consecutive doses (6 weeks) at 1 mg/kg, a patient: • Has no reduction in RBC transfusion burden • Increase the dose to 1.25 mg/kg every 3 weeks If after 3 consecutive doses (9 weeks) at 1.25 mg/kg, a patient: • Has no reduction in RBC transfusion burden • Discontinue treatment Dose Modifications for Predose Hemoglobin Levels or Rapid Hemoglobin Rise Predose hemoglobin is greater than or equal to 11.5 g/dL in absence of transfusion • Interrupt treatment • Restart at same dose when the hemoglobin is no more than 11 g/dL Increase in hemoglobin greater than 2 g/dL within 3 weeks in absence of transfusion and • current dose is 1.25 mg/kg • current dose is 1 mg/kg • current dose is 0.8 mg/kg • current dose is 0.6 mg/kg • Reduce dose to 1 mg/kg • Reduce dose to 0.8 mg/kg • Reduce dose to 0.6 mg/kg • Discontinue treatment Dose Modifications for Toxicity For patients experiencing Grade 3 or higher adverse reactions, modify treatment as described in Table 2. Table 2: Beta Thalassemia - REBLOZYL Dosing Modifications for Adverse Reactions * Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, and Grade 4 is life-threatening. **Per Table 1 dose reductions above. REBLOZYL Dosing Recommendation* Grade 3 or 4 hypersensitivity reactions • Discontinue treatment Other Grade 3 or 4 adverse reactions • Interrupt treatment • When the adverse reaction resolves to no more than Grade 1, restart treatment at the next lower dose level** • If the dose delay is greater than 15 consecutive weeks, discontinue treatment Extramedullary hematopoietic (EMH) masses causing serious complications • Discontinue treatment 2.2 R …

3 DOSAGE FORMS AND STRENGTHS • For injection: 25 mg white to off-white lyophilized powder in a single-dose vial for reconstitution. • For injection: 75 mg white to off-white lyophilized powder in a single-dose vial for reconstitution. • For injection: 25 mg lyophilized powder in a single-dose vial for reconstitution ( 3 ). • For injection: 75 mg lyophilized powder in a single-dose vial for reconstitution ( 3 ).

4 CONTRAINDICATIONS None. None ( 4 ).

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Thrombosis/Thromboembolism [see Warnings and Precautions ( 5.1 )] • Hypertension [see Warnings and Precautions ( 5.2 )] • Extramedullary Hematopoietic Masses [see Warnings and Precautions ( 5.3 )] The most common (>10%) adverse reactions were fatigue, headache, musculoskeletal pain, arthralgia, dizziness/vertigo, nausea, diarrhea, cough, abdominal pain, dyspnea, COVID-19, edema peripheral, hypertension, and hypersensitivity ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-888-423-5436 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 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 to 1.75 mg/kg) in 571 patients in 4 trials. Beta Thalassemia The safety of REBLOZYL in patients with beta thalassemia was evaluated in the BELIEVE trial [see Clinical Studies ( 14.1 )] . Key eligibility criteria included adult patients with beta thalassemia (with the exception of patients with hemoglobin S or alpha-thalassemia disease) without major organ damage or recent DVT stroke and platelet counts less than or equal to 1000 x 10 9 /L. Patients received a starting dose of REBLOZYL 1 mg/kg subcutaneous injection every 3 weeks. Overall, 53% of patients had their dose increased to 1.25 mg/kg (46% REBLOZYL, n = 223) or placebo (66%, n = 109). 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 greater than one year. The median age of patients who received REBLOZYL was 30 years (range: 18, 66); 59% female; 54% White and 36% Asian. 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 one patient treated with REBLOZYL who died due to an unconfirmed case of AML (M6). 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 (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. 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%). Table 7 summarizes the adverse reactions in BELIEVE. Table 7: Adverse Drug Reactions (>5%) in Patients with Beta Thalassemia Receiving REBLOZYL with a Difference Between Arms of 1% in BELIEVE Trial Body System REBLOZYL (N=223) Placebo (N=109) Adverse Reaction All Grades n (%) Grades ≥3 a n (%) All Grades n (%) Grades ≥3 n (%) a Limited to Grade 3 reactions with the exception of 4 events of Grade 4 hyperuricemia. b Grouped term includes abdominal pain and abdominal pain upper. c Grouped term includes essential hypertension, hypertension, and hypertensive crisis. …

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed ( 8.2 ). 8.1 Pregnancy Risk Summary Based on findings in animal reproduction studies, REBLOZYL may cause fetal harm when administered to a pregnant woman . There are no available data on REBLOZYL use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, administration of luspatercept-aamt to pregnant rats and rabbits during the period of organogenesis resulted in adverse developmental outcomes including embryo-fetal mortality, alterations to growth, and structural abnormalities at exposures (based on area under the curve [AUC]) above those occurring at the maximum recommended human dose (MRHD) ( see Data ). Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In embryo-fetal development studies, luspatercept-aamt was administered subcutaneously at 5, 15, or 30 mg/kg on gestation days 3 and 10 (rats) or 5, 20, or 40 mg/kg on gestation days 4 and 11 (rabbits). Effects in both species included reductions in numbers of live fetuses and fetal body weights, and increases in resorptions, post-implantation losses, and skeletal variations (such as asymmetric sternal centra in rats and angulated hyoid in rabbits). Effects were observed at exposures (based on AUC) approximately 7-times (rats) and 16-times (rabbits) the MRHD of 1.75 mg/kg. In a pre- and postnatal development study, pregnant rats were administered luspatercept-aamt subcutaneously at 3, 10, or 30 mg/kg once every 2 weeks during organogenesis and through weaning, gestation day 6 through postnatal day 20. At all dose levels lower F 1 pup body weights and adverse kidney findings (such as membranoproliferative glomerulonephritis, tubular atrophy/hypoplasia, and vessel ectasia occasionally associated with hemorrhage) were observed. These effects were observed at exposures (based on AUC) approximately 1.6-times the MRHD of 1.75 mg/kg. 8.2 Lactation Risk Summary Luspatercept-aamt 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 . 8.3 Females and Males of Reproductive Potential Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential before starting REBLOZYL treatment. Contraception Females REBLOZYL may cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations ( 8.1 )] . Advise female patients of reproductive potential to use effective contraception during treatment with REBLOZYL and for at least 3 months after the last dose. Infertility Females Based on findings in animals, REBLOZYL may impair female fertility [see Nonclinical Toxicology ( 13.1 )] . Adverse effects on fertility in female rats were reversible after a 14-week recovery period. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Based on findings in juvenile animals, REBLOZYL is not recommended for use in pediatric patients [see Nonclinical Toxicology ( 13.1 )] . 8.5 Geriatric Use Clinical studies of REBLOZYL in beta thalassemia did not include sufficient numbers of patients age 65 years and older to determine whether they respond different …

12.1 Mechanism of Action Luspatercept-aamt is a recombinant fusion protein that binds several endogenous TGF-β superfamily ligands, thereby diminishing Smad2/3 signaling. In models of β-thalassemia and MDS, luspatercept-aamt decreased abnormally elevated Smad2/3 signaling and improved hematology parameters associated with ineffective erythropoiesis in mice. Luspatercept-aamt promoted erythroid maturation through differentiation and increasing the percentage of late-stage erythroid precursors (normoblasts) in the bone marrow of mice and increased erythroid precursors in humans, thereby increasing erythropoiesis.

11 DESCRIPTION Luspatercept-aamt is an erythroid maturation agent. Luspatercept-aamt is a receptor fusion protein consisting of a modified extracellular domain of the human activin receptor type IIB linked to a human IgG1 Fc domain with a calculated molecular mass of approximately 76 kD. Luspatercept is produced in Chinese hamster ovary cells by recombinant DNA technology. REBLOZYL (luspatercept-aamt) for injection is a sterile, preservative-free, white to off-white, lyophilized powder in single-dose vials for subcutaneous use after reconstitution. Each 25 mg single-dose vial provides nominal 25 mg of luspatercept-aamt and citric acid monohydrate (0.085 mg), polysorbate 80 (0.10 mg), sucrose (45 mg), and tri-sodium citrate dihydrate (1.35 mg) at pH 6.5. After reconstitution with 0.68 mL Sterile Water for Injection USP, the resulting concentration is 25 mg/0.5 mL of luspatercept-aamt and the nominal deliverable volume is 0.5 mL. Each 75 mg single-dose vial provides nominal 75 mg of luspatercept-aamt and citric acid monohydrate (0.254 mg), polysorbate 80 (0.30 mg), sucrose (135 mg), and tri-sodium citrate dihydrate (4.06 mg) at pH 6.5. After reconstitution with 1.6 mL Sterile Water for Injection USP, the resulting concentration is 75 mg/1.5 mL (50 mg/mL) of luspatercept-aamt and the nominal deliverable volume is 1.5 mL.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied REBLOZYL (luspatercept-aamt) for injection is a white to off-white lyophilized powder supplied in a single-dose vial. Each carton contains one vial. REBLOZYL 25 mg/vial (NDC 59572-711-01) REBLOZYL 75 mg/vial (NDC 59572-775-01) 16.2 Storage Store vials refrigerated at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze.