REBLOZYL

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 (45.0 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.

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.

• The recommended starting dose is 1 mg/kg once every 3 weeks by subcutaneous injection ( 2.1 , 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 a patient does not experience a decrease in transfusion burden after 9 weeks of treatment (administration of 3 doses) at the maximum dose level or if unacceptable toxicity occurs at any time. 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. If a patient does not achieve a reduction in RBC transfusion burden after at least 2 consecutive doses (6 weeks) at the 1 mg/kg starting dose, increase the REBLOZYL dose to 1.25 mg/kg. Do not increase the dose beyond the maximum dose of 1.25 mg/kg. In the absence of transfusions, 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. Dose level modifications for response are provided 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 at Initiation of Treatment No reduction in RBC transfusion burden after at least 2 consecutive doses (6 weeks) at the 1 mg/kg starting dose • Increase the dose to 1.25 mg/kg every 3 weeks No reduction in RBC transfusion burden after 3 consecutive doses (9 weeks) at 1.25 mg/kg • 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 the absence of transfusions • Interrupt treatment • Restart when the hemoglobin is no more than 11 g/dL Increase in hemoglobin greater than 2 g/dL within 3 weeks in the absence of transfusions 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. REBLOZYL Dosing Recommendation* Grade 3 or 4 hypersensitivity reactions • Discontinue treatment Other Grade 3 or 4 adverse reactions • Interrupt treatment • Restart when the adverse reaction resolves to no more than Grade 1 Extramedullary hematopoietic (EMH) masses causing serious complications • Discontinue treatment 2.2 Recommended Dosage for Myelodysplastic Syndromes Associated Anemia The recommended starting dosage of REBLOZYL is 1 mg/kg once every 3 weeks by subcutaneous injection for the treatment of anemia of MDS. Prior to each REBLOZYL dose, review the patient’s hemoglobin and transfusion record. Titrate the dose based on responses according to Table 3. Interrupt treatment for adverse reactions as described in Table 4. Discontinue REBLOZYL if a patient does not experience a decrease in transfusion burden including no increase from baseline hemoglobin after 9 weeks of treatment (administration of 3 doses) at the maximum dose level (1.75 mg/kg), or if unacceptable toxicity occurs at any time. 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. If a patient is not RBC transfusion-free after at least 2 consecutive doses (6 weeks) at the 1 mg/kg starting dose, increase the REBLOZYL dose to 1.33 mg/kg (Table 3). If a patient is not RBC transfusion-free after at least 2 consecutive doses (6 weeks) at the 1.33 mg /kg dose level, increase the REBLOZYL dose to 1.75 mg/kg. Do not increase the dose more frequently than every 6 weeks (2 doses) or beyond the maximum dose of 1.75 mg/kg. In the absence of transfusions, if hemoglobin increase is greater than 2 g/dL within 3 weeks or if 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 3. If, upon dose reduction, the patient loses response (i.e., requires a transfusion) or hemoglobin concentration drops by 1 g/dL or more in 3 weeks in the absence of transfusion, increase the dose by one dose level. Wait a minimum of 6 weeks between dose increases. Dose modifications for response are provided in Table 3. Table 3: MDS Associated Anemia - REBLOZYL Dose Titration for Response * Do not increase the dose if the patient is experiencing an adverse reaction as described in Table 4. REBLOZYL Dosing Recommendation* Starting Dose • 1 mg/kg every 3 weeks Dose Increases for Insufficient Response at Initiation of Treatment Not RBC transfusion-free after at least 2 consecutive doses (6 weeks) at the 1 mg/kg starting dose • Increase the dose to 1.33 mg/kg every 3 weeks Not RBC transfusion-free after at least 2 consecutive doses (6 weeks) at 1.33 mg/kg • Increase the dose to 1.75 mg/kg every 3 weeks No reduction in RBC transfusion burden including no increase from baseline hemoglobin after at least 3 consecutive doses (9 weeks) at 1.75 mg/kg • 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 the absence of transfusions • Interrupt treatment • Restart when the hemoglobin is no more than 11 g/dL Increase in hemoglobin greater than 2 g/dL within 3 weeks in the absence of transfusions and • current dose is 1.75 mg/kg • current dose is 1.33 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 1.33 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 4. Table 4: MDS Associated Anemia - 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 3 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 > 12 consecutive weeks, discontinue treatment 2.3 Preparation and Administration REBLOZYL should be reconstituted and administered by a healthcare professional. Reconstitute REBLOZYL with Sterile Water for Injection, USP only. Table 5: Reconstitution Volumes Vial Size Amount of Sterile Water for Injection, USP required for reconstitution Final Concentration Deliverable Volume 25 mg vial 0.68 mL 25 mg/0.5 mL (50 mg/mL) 0.5 mL 75 mg vial 1.6 mL 75 mg/1.5 mL 1.5 mL (50 mg/mL) Reconstitute the number of REBLOZYL vials to achieve the appropriate dose based on the patient’s weight. Use a syringe with suitable graduations for reconstitution to ensure accurate dosage. Reconstitution Instructions 1. Reconstitute with Sterile Water for Injection, USP using volumes described in Table 5 (Reconstitution Volumes) with the stream directed onto the lyophilized powder. Allow to stand for one minute. 2. Discard the needle and syringe used for reconstitution. The needle and syringe used for reconstitution should not be used for subcutaneous injections. 3. 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. 4. Inspect the vial for undissolved particles in the solution. If undissolved powder is observed, repeat step 3 until the powder is completely dissolved. 5. 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. 6. Repeat step 5 seven more times to ensure complete reconstitution of material on the sides of the vial. 7. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. REBLOZYL is a colorless to slightly yellow, clear to slightly opalescent solution which is free of foreign particulate matter. Do not use if undissolved product or foreign particulate matter are observed. 8. If the reconstituted solution is not used immediately: • Store at room temperature at 20°C to 25°C (68°F to 77°F) in the original vial for up to 8 hours. Discard if not used within 8 hours of reconstitution. • Alternatively, store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours in the original vial. Remove from refrigerated condition 15-30 minutes prior to injection to allow solution to reach room temperature for a more comfortable injection. Discard if not used within 24 hours of reconstitution. • Do not freeze the reconstituted solution. Discard any unused portion. Do not pool unused portions from the vials. Do not administer more than 1 dose from a vial. Do not mix with other medications. Instructions for Subcutaneous Administration Calculate the exact total dosing volume of 50 mg/mL solution required for the patient. Slowly withdraw the dosing volume of the reconstituted REBLOZYL solution from the single-dose vial(s) into a syringe. Divide doses requiring larger reconstituted volumes (i.e., greater than 1.2 mL) into separate similar volume injections and inject into separate sites. If multiple injections are required, use a new syringe and needle for each subcutaneous injection. Administer the injection subcutaneously into the upper arm, thigh, and/or abdomen.

None. None ( 4 ).

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 (<1%), and headache (<1%). 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. 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 6 summarizes the adverse reactions in BELIEVE. Table 6: 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. 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 Pain b 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 Hypertension c 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) Clinically relevant adverse reactions in <5% of patients include vertigo/vertigo positional, syncope/presyncope, injection site reactions, hypersensitivity, extramedullary hematopoietic masses, and spinal cord compression. Liver function abnormalities in the BELIEVE trial are shown in Table 7. Table 7: Liver Function Laboratory Abnormalities in Patients with Beta Thalassemia in the BELIEVE Trial REBLOZYL N = 223 n (%) Placebo N = 109 n (%) ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal. 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) Treatment of Myelodysplastic Syndromes Associated Anemia in ESA-naïve Patients The safety of REBLOZYL in patients with very low‑ to intermediate‑risk myelodysplastic syndromes was evaluated in the COMMANDS trial in 356 randomized patients [see Clinical Studies ( 14.2 )] . Key eligibility criteria included adult patients who were ESA‑naïve with endogenous sEPO levels of < 500 U/L and who required regular RBC transfusions. The median time on treatment with REBLOZYL was 41.6 weeks (range, 0 – 165 weeks); 71.3% of patients were exposed for 24 weeks and 45.5% completed 48 weeks of treatment. Among the 178 patients treated with REBLOZYL, 17 (9.6%) discontinued due to an adverse reaction, 48 (27%) had a dose interruption due to an adverse reaction, and 5 (2.8%) had a dose reduction due to an adverse reaction. The most common (>10%) all‑grade adverse reactions included diarrhea, fatigue, hypertension, edema peripheral, nausea, and dyspnea. The most common (>2%) Grade > 3 adverse reactions included hypertension and dyspnea. Selected laboratory abnormalities that changed from Grade 0‑2 at baseline to Grade > 2 at any time during the studies in at least 10% of patients were glomerular filtration rate and total bilirubin increased. Table 8 shows the most common adverse reactions for patients treated with REBLOZYL or epoetin alfa in the COMMANDS trial [see Clinical Studies ( 14.2 )] . Table 8: Adverse Reactions (≥5%) in Patients Receiving REBLOZYL in COMMANDS Trial a Reaction includes similar/grouped terms. b Includes asthenic conditions. Body System /Adverse Reaction REBLOZYL (N=178) Epoetin Alfa (N=176) All Grades n (%) Grade ≥3 n (%) All Grades n (%) Grade ≥3 n (%) General disorders and administration site conditions Fatigue a,b 38 (22) 0 (0) 12 (7) 0 (0) Edema peripheral 23 (13) 0 (0) 12 (7) 0 (0) Non-cardiac chest pain 9 (5) 1 (1) 6 (3) 0 (0) Pyrexia 9 (5) 1 (1) 12 (7) 1 (1) Gastrointestinal disorders Diarrhea 26 (15) 0 (0) 20 (11) 0 (0) Nausea 21 (12) 0 (0) 13 (7) 0 (0) Vascular disorders Hypertension a 25 (14) 17 (10) 13 (7) 9 (5) Respiratory, thoracic and mediastinal disorders Dyspnea 21 (12) 7 (4) 13 (7) 2 (1) Dyspnea exertional 9 (5) 0 (0) 1 (1) 0 (0) Nervous system disorders Dizziness 16 (9) 1 (1) 15 (9) 0 (0) Headache 15 (8) 0 (0) 12 (7) 1 (1) Musculoskeletal and connective tissue disorders Back Pain 16 (9) 2 (1) 13 (7) 3 (2) Arthralgia 10 (6) 0 (0) 14 (8) 0 (0) Myalgia 9 (5) 0 (0) 5 (3) 0 (0) Osteoarthritis 9 (5) 1 (1) 4 (2) 0 (0) Infections and infestations COVID-19 19 (11) 6 (3) 17 (10) 2 (1) Urinary tract infection 13 (7) 0 (0) 7 (4) 0 (0) Pneumonia 8 (5) 7 (4) 15 (9) 11 (6) Metabolism and nutrition disorders Hyperuricemia 12 (7) 1 (1) 10 (6) 1 (1) Decreased appetite 8 (5) 0 (0) 11 (6) 0 (0) Blood and lymphatic system disorders Thrombocytopenia 11 (6) 7 (4) 3 (2) 1 (1) Neutropenia 9 (5) 7 (4) 13 (7) 10 (6) Psychiatric disorders Insomnia 9 (5) 0 (0) 6 (3) 0 (0) Other clinically relevant adverse reactions reported in <5% of patients are injection site reactions, including erythema, pruritus, and rash. Shifts from Grades 0‑2 at baseline to Grades 2‑3 abnormalities for selected laboratory tests in the COMMANDS trial are shown in Table 9. Table 9: Selected Treatment‑Emergent Laboratory Abnormalities in COMMANDS Trial that Shift to Grades 2‑3 a Number of patients at Grades 0-1 at baseline. b GFR= glomerular filtration rate (mL/min) Parameter REBLOZYL Epoetin Alfa N a n (%) N a n (%) Total bilirubin 171 38 (22) 165 19 (12) GFR b 171 60 (35) 167 36 (22) Myelodysplastic Syndromes with Ring Sideroblasts or Myelodysplastic / Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis Associated Anemia in ESA-refractory or -intolerant patients The safety of REBLOZYL at the recommended dose and schedule was evaluated in 242 patients with MDS with ring sideroblasts (n=192) or other myeloid neoplasms (n=50) in the MEDALIST trial. The safety population included 63% males and 37% females of median age 72 years (range, 30 – 95 years); of these patients, 81% were White, 0.4% Black, 0.4% Other, and race was not reported in 18.2% of patients. The median time on treatment with REBLOZYL was 50.4 weeks (range, 3 – 221 weeks); 67% of patients were exposed for 6 months or longer and 49% were exposed for greater than one year. Among the 242 patients treated with REBLOZYL, 5 (2.1%) had a fatal adverse reaction, 11 (4.5%) discontinued due to an adverse reaction, and 7 (2.9%) had a dose reduction due to an adverse reaction. The most common (≥10%) all-grade adverse reactions included fatigue, musculoskeletal pain, dizziness, diarrhea, nausea, hypersensitivity reactions, hypertension, headache, upper respiratory tract infection, bronchitis, and urinary tract infection. The most common (≥2%) Grade ≥ 3 adverse reactions included fatigue, hypertension, syncope and musculoskeletal pain. Selected laboratory abnormalities that changed from Grade 0-1 at baseline to Grade ≥ 2 at any time during the studies in at least 10% of patients included creatinine clearance decreased, total bilirubin increased, and alanine aminotransferase increased. Table 10 shows the most common adverse reactions for patients treated with REBLOZYL or placebo through the first 8 cycles in the MEDALIST trial [see Clinical Studies ( 14.3 )] . Table 10: Adverse Reactions (≥5%) in Patients Receiving REBLOZYL with a Difference Between Arms of >2% in MEDALIST Trial Through Cycle 8 Body System /Adverse Reaction REBLOZYL (N=153) Placebo (N=76) All Grades n (%) Grade 3 n (%) All Grades n (%) Grade 3 n (%) a Includes asthenic conditions. b Reaction includes similar/grouped terms. General disorders and administration site conditions Fatigue a, b 63 (41) 11 (7) 17 (22) 2 (3) Musculoskeletal and connective tissue disorders Musculoskeletal pain b 30 (20) 3 (2) 11 (14) 0 (0) Nervous system disorders Dizziness/vertigo 28 (18) 1 (<1) 5 (7) 1 (1) Headache b 21 (14) 0 (0) 5 (7) 0 (0) Syncope / presyncope 8 (5) 5 (3) 0 (0) 0 (0) Gastrointestinal disorders Nausea b 25 (16) 1 (<1) 8 (11) 0 (0) Diarrhea b 25 (16) 0 (0) 7 (9) 0 (0) Respiratory, thoracic and mediastinal disorder Dyspnea b 20 (13) 2 (1) 4 (5) 1 (1) Immune system disorders Hypersensitivity reactions b 15 (10) 1 (<1) 5 (7) 0 (0) Renal and urinary disorders Renal impairment b 12 (8) 3 (2) 3 (4) 0 (0) Cardiac disorders Tachycardia b 12 (8) 0 (0) 1 (1) 0 (0) Injury poisoning and procedural complications Injection site reactions 10 (7) 0 (0) 3 (4) 0 (0) Infections and infestations Upper respiratory tract infection 10 (7) 1 (<1) 2 (3) 0 (0) Influenza / influenza like illness 9 (6) 0 (0) 2 (3) 0 (0) Other clinically relevant adverse reactions reported in <5% of patients include bronchitis, urinary tract infection, and hypertension [see Warnings and Precautions ( 5.2 )] . Shifts from Grades 0-1 to Grades 2-4 abnormalities for selected laboratory tests during the first 8 cycles in the MEDALIST trial are shown in Table 11. Table 11: Selected Grades 2-4 Treatment-Emergent Laboratory Abnormalities Through Cycle 8 in the MEDALIST Trial a Number of patients at Grades 0-1 at baseline. ALT = alanine aminotransferase; AST = aspartate aminotransferase. Parameter REBLOZYL Placebo N a n (%) N a n (%) ALT elevated 151 13 (9) 74 5 (7) AST elevated 152 6 (4) 76 0 (0) Total bilirubin elevated 140 17 (12) 66 3 (5) Creatinine clearance reduced 113 30 (27) 62 13 (21)

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.