Reblozyl Drug Information

• 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 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. 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 8. Table 8: Liver Function Laboratory Abnormalities in Patients with Beta Thalassemia in the BELIEVE Trial 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) 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 9 shows the most common adverse reactions for patients treated with REBLOZYL or epoetin alfa in the COMMANDS trial [see Clinical Studies ( 14.2 )] . Table 9: 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 10. Table 10: 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 ALT increased. Table 11 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 11: 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 12. Table 12: 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. 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)

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 ) 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.

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 .