LACTATION SECTION.

8.2 Lactation. Risk SummaryLuspatercept-aamt was detected in milk of lactating rats. When 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 months after the last dose.

MECHANISM OF ACTION SECTION.

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

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Luspatercept-aamt is recombinant fusion protein that binds several endogenous TGF- superfamily ligands, thereby diminishing Smad2/3 signaling. Luspatercept-aamt promoted erythroid maturation through differentiation of late-stage erythroid precursors (normoblasts) in mice. In models of -thalassemia and MDS, luspatercept-aamt decreased abnormally elevated Smad2/3 signaling and improved hematology parameters associated with ineffective erythropoiesis in mice.. 12.2 Pharmacodynamics. Increases in Hemoglobin in Patients with Low RBC Transfusion BurdenIn patients having received 4 units of RBC transfusion within weeks prior to study, hemoglobin increased within days of initiating REBLOZYL and correlated with the time to luspatercept-aamt maximum serum concentration (Cmax). The greatest Hgb increase occurred after the first dose; approximately 0.75 g/dL at dose of 0.6 to 1.25 times the recommended starting dose for beta thalassemia, or approximately g/dL at dose of 0.75 to 1.75 times the recommended starting dose for MDS. Additional smaller increases were observed after subsequent doses. Hemoglobin levels returned to baseline approximately to weeks from the last dose following administration of luspatercept-aamt (0.6 to 1.75 mg/kg). Increasing luspatercept-aamt serum exposure (AUC) was associated with greater Hgb increase in patients with beta thalassemia or MDS who had baseline transfusion burden 4 units/8 weeks. Increasing luspatercept-aamt serum exposure (time-averaged AUC) was associated with greater probability of achieving transfusion independence for at least consecutive weeks in patients with MDS requiring transfusions (>= units of RBC transfusion within weeks). 12.3 Pharmacokinetics. Luspatercept-aamt exhibited linear pharmacokinetics (PK) over the dose range of 0.2 to 1.25 mg/kg (0.2 to 1.25 times the recommended starting dosage) in patients with beta thalassemia, and from 0.125 mg/kg to 1.75 mg/kg in patients with MDS. The mean (% coefficient of variation [%CV]) steady-state AUC at the starting dose of mg/kg was 126 (35.9%) dayug/mL for patients with beta thalassemia and 145 (38.3%) dayug/mL for patients with MDS. Luspatercept-aamt serum concentration reached steady state after doses when administered every weeks. The accumulation ratio of luspatercept-aamt was approximately 1.5.. AbsorptionThe median (range) time to maximum concentration (Tmax) of luspatercept-aamt was observed at approximately [6 to 10] days post-dose in adult patients with beta thalassemia or [5 to 21] days post-dose in adult patients with MDS. The absorption of luspatercept-aamt was not significantly affected by the subcutaneous injection sites (upper arm, thigh, or abdomen). DistributionThe mean (%CV) apparent volume of distribution (Vd/F) of luspatercept-aamt was 7.1 (26.7%) for patients with beta thalassemia, and 9.7 (26.5%) for patients with MDS. EliminationThe mean (%CV) half-life (t1/2) of luspatercept-aamt was approximately 11 (25.7%) days and the mean (%CV) apparent total clearance (CL/F) was 0.44 (38.5%) L/day in patients with beta thalassemia. The mean (%CV) t1/2 of luspatercept-aamt was approximately 13 (31.6%) days and the mean (%CV) CL/F was 0.52 (41.2%) L/day in patients with MDS.. MetabolismLuspatercept-aamt is expected to be catabolized into amino acids by general protein degradation processes in multiple tissues.. Specific PopulationsNo clinically significant differences in the luspatercept-aamt PK was observed based on age (18 to 95 years), sex, race/ethnicity (Asian, White), mild to severe hepatic impairment (total bilirubin <= upper limit of normal [ULN] and aspartate aminotransaminase [AST] or alanine transaminase [ALT] ULN, or total bilirubin ULN and any AST or ALT), mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] 30 to 89 mL/min/1.73 m2), baseline albumin (30 to 56 g/L), baseline serum erythropoietin (2.4 to 2450 U/L), red blood cell (RBC) transfusion burden (0 to 43 units/24 weeks), beta thalassemia genotype (0/0 vs. non-0/0), splenectomy, and ring sideroblasts status in MDS (negative vs. positive). The effect of AST or ALT >3 ULN and the effect of severe renal impairment (eGFR <30 mL/min/1.73 m2) on luspatercept-aamt PK is unknown. Body WeightThe apparent CL/F and Vd/F of luspatercept-aamt increased with increasing body weight in patients with beta thalassemia (34 to 97 kg) and in patients with MDS (46 to 124 kg). Drug Interaction Studies. Effect of Iron-chelating Agents on Luspatercept-aamtNo clinically significant differences in luspatercept-aamt PK were observed when used concomitantly with iron-chelating agents.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Beta Thalassemia. The efficacy of REBLOZYL was evaluated in adult patients with beta thalassemia in the BELIEVE trial (NCT02604433). BELIEVE was multicenter, randomized, double-blind, placebo-controlled trial in which (n=336) patients with beta thalassemia requiring regular red blood cell transfusions (6-20 RBC units per 24 weeks) with no transfusion-free period greater than 35 days during that period were randomized 2:1 to REBLOZYL (n=224) or placebo (n=112). In BELIEVE, REBLOZYL was administered subcutaneously once every weeks as long as reduction in transfusion requirement was observed or until unacceptable toxicity. All patients were eligible to receive best supportive care, which included RBC transfusions; iron-chelating agents; use of antibiotic, antiviral, and antifungal therapy; and/or nutritional support, as needed.The BELIEVE trial excluded patients with diagnosis of Hemoglobin S/-thalassemia or isolated alpha ()-thalassemia (e.g., Hemoglobin H) or who had major organ damage (liver disease, heart disease, lung disease, renal insufficiency). Patients with recent deep vein thrombosis or stroke or recent use of ESA, immunosuppressant, or hydroxyurea therapy were also excluded. The median age was 30 years (range: 18-66). The trial was comprised of patients who were 42% male, 54.2% White, 34.8% Asian, and 0.3% Black or African American. The percent of patients reporting their race as other was 7.7%, and race was not collected or reported for 3% of patients. Table 10 summarizes the baseline disease-related characteristics in the BELIEVE study.Table 10: Baseline Disease Characteristics of Patients with Beta Thalassemia in BELIEVEHbE=hemoglobin E. Missing category includes patients in the population who had no result for the parameter listed.Disease CharacteristicREBLOZYL(N=224)Placebo(N=112)Beta thalassemia diagnosis, (%) Beta-thalassemia174 (77.7)83 (74.1) HbE/beta thalassemia31 (13.8)21 (18.8) Beta thalassemia combined with alpha-thalassemia18 (8)8 (7.1) Missing 1 (0.4)0Baseline transfusion burden 12 weeks prior to randomization Median (min, max) (Units/12 weeks)6.12 (3, 14)6.27 (3, 12)Beta thalassemia gene mutation grouping, (%) 0/068 (30.4)35 (31.3) Non-0/0155 (69.2)77 (68.8) Missing 1 (0.4)0Baseline serum ferritin level (ug/L) N220111 Median (min, max)1441.25 (88, 6400)1301.50 (136, 6400)Splenectomy, (%) Yes129 (57.6)65 (58) No95 (42.4)47 (42)Age patient started regular transfusions (years) N16985 Median (min, max)2 (0, 52)2 (0, 51)The efficacy of REBLOZYL in adult patients with beta thalassemia was established based upon the proportion of patients achieving RBC transfusion burden reduction (>=33% reduction from baseline) with reduction of at least units from Week 13 to Week 24.Efficacy results are shown in Table 11.Table 11: Efficacy Results in Beta Thalassemia BELIEVEEndpointREBLOZYL(N=224)Placebo(N=112)Risk Difference(95% CI)p-value>=33% Reduction from baseline in RBC transfusion burden with reduction of at least units for 12 consecutive weeks Primary endpoint Week 13 to Week 2448 (21.4)5 (4.5)17.0(10.4, 23.6)<0.0001 Week 37 to Week 4844 (19.6)4 (3.6)16.1(9.8, 22.4)<0.0001>=50% Reduction from baseline in RBC transfusion burden with reduction of at least units for 12 consecutive weeks Week 13 to Week 2417 (7.6)2 (1.8)5.8(1.6, 10.1)0.0303 Week 37 to Week 4823 (10.3)1 (0.9)9.4(5, 13.7)0.0017. 14.2 Myelodysplastic Syndromes with Ring Sideroblasts or Myelodysplastic Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis Associated Anemia. The efficacy of REBLOZYL was evaluated in the MEDALIST trial (NCT02631070), multi-center, randomized, double-blind, placebo-controlled trial in patients with IPSS-R very low, low, or intermediate-risk myelodysplastic syndromes who have ring sideroblasts and require red blood cell transfusions (2 or more RBC units over weeks). For eligibility, patients were required to have had an inadequate response to prior treatment with an erythropoiesis-stimulating agent (ESA), be intolerant of ESAs, or have serum erythropoietin 200 U/L. The MEDALIST trial excluded patients with deletion 5q (del 5q), white blood cell count 13 Gi/L, neutrophils 0.5 Gi/L, platelets 50 Gi/L, or with prior use of disease modifying agent for treatment of MDS. The MEDALIST trial included 229 patients randomized 2:1 to REBLOZYL (n=153) or placebo (n=76). Randomization was stratified by baseline RBC transfusion burden and baseline IPSS-R. Treatment was started at mg/kg subcutaneously every weeks; the dose could be increased after completion of the first cycles if the patient had at least one RBC transfusion in the prior weeks. Two dose level increases were allowed (to 1.33 mg/kg and to 1.75 mg/kg). Doses were held and subsequently reduced for adverse reactions, reduced if the hemoglobin increased by >= g/dL from the prior cycle, and held if the predose hemoglobin was >= 11.5 g/dL. All patients received best supportive care, which included RBC transfusions as needed. The primary efficacy assessment was conducted after completion of 24 weeks on study drug. Patients with decrease in transfusion requirement or increase in hemoglobin could continue on blinded study drug thereafter until unacceptable toxicity, loss of efficacy, or disease progression.The median age of the 229 study participants was 71 years (range: 26, 95 years). The trial population was 63% male and 69% White. Table 12 summarizes the baseline disease-related characteristics in the MEDALIST study.Table 12: Baseline Disease Characteristics of Patients in MEDALISTEPO=erythropoietin; IPSS R=International Prognostic Scoring System-Revised; ITT=intent-to-treat; MDS=myelodysplastic syndromes; RARS=refractory anemia with ring sideroblasts; RBC=red blood cell; RCMD=refractory cytopenia with multilineage dysplasia; SD=standard deviation; WHO=World Health Organization. Time since original MDS diagnosis was defined as the number of years from the date of original diagnosis to the date of informed consent. Baseline EPO was defined as the highest EPO value within 35 days of the first dose of study drug. Includes MDS-RS-MLD and MDS-RS-SLD. Includes MDS-EB-1, MDS-EB-2, and MDS-U.Disease CharacteristicREBLOZYL(N=153)Placebo(N=76)Time Since Original MDS Diagnosis (months)Median (range)44.0 (3, 421)36.1 (4, 193)Serum EPO (U/L) Categories b, (%) 20088 (57.5)50 (65.8) 200 to 50043 (28.1)15 (19.7) 50021 (13.7)11 (14.5) Missing1 (0.7)0Diagnosis per WHO Criteria, (%) MDS-RS 135 (88.2)65 (85.5) MDS/MPN-RS-T14 (9.2)9 (11.8) Other 4 (2.6)2 (2.6)IPSS-R Classification Risk Category, (%) Very low18 (11.8)6 (7.9) Low109 (71.2)57 (75) Intermediate25 (16.3)13 (17.1) High1 (0.7)0RBC Transfusions/8 Weeks Over 16 Weeks Categories, (%) 4 units46 (30.1)20 (26.3) >= and 6 units41 (26.8)23 (30.3) >= units66 (43.1)33 (43.4)The efficacy of REBLOZYL in adult patients with MDS-RS and MDS-RS-T was established based upon the proportion of patients who were red blood cell transfusion independent (RBC-TI), defined as the absence of any RBC transfusion during any consecutive 8-week period occurring entirely within Weeks through 24.The efficacy results are shown in Tables 13 and 14.Table 13: Efficacy Results in MEDALIST The median (range) duration of treatment was 49 weeks (6 to 114 weeks) on the REBLOZYL arm and 24 weeks (7 to 89 weeks) on the placebo arm.EndpointREBLOZYL(N=153)n, %(95% CI)Placebo(N=76)n, %(95% CI)Common Risk Difference(95% CI)p-valueRBC-TI >= weeks during Weeks 1-2458 (37.9)(30.2, 46.1)10 (13.2)(6.5, 22.9)24.6(14.5, 34.6)<0.0001RBC-TI >= 12 weeks during Weeks 1-2443 (28.1)(21.1, 35.9)6 (7.9)(3.0, 16.4)20.0(10.9, 29.1)0.0002RBC-TI >= 12 weeks during Weeks 1-4851 (33.3)(25.9, 41.4)9 (11.8)(5.6, 21.3)21.4(11.2, 31.5)0.0003Table 14 shows the proportion of patients who achieved RBC-TI >= weeks during Weeks 1-24 by diagnosis and baseline transfusion requirement.Table 14: RBC-TI >= weeks during Weeks 1-24 By Diagnosis and Baseline Transfusion Burden in MEDALISTa Includes MDS-EB-1, MDS-EB-2, and MDS-U. Includes patients who received 3.5 units. Includes patients who received 5.5 units.Responders N% Response (95% CI)REBLOZYLPlaceboREBLOZYLPlaceboWHO 2016 DiagnosisMDS-RS46 1358 6534.1 (26.1, 42.7)12.3 (5.5, 22.8)MDS/MPN-RS-T9 142 964.3 (35.1, 87.2)22.2 (2.8, 60.0)Other 3 40 275.0 (19.4, 99.4)0.0 (0.0, 84.2)Baseline RBC Transfusion Burden2 3 units/8 weeks 37 468 2080.4 (66.1, 90.6)40.0 (19.1, 63.9)4 5 units/8 weeks 15 411 2336.6 (22.1, 53.1)4.3 (0.1, 21.9)>= units/8 weeks6 661 339.1 (3.4, 18.7)3.0 (0.1, 15.8).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None (4).

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:oThrombosis/Thromboembolism [see Warnings and Precautions (5.1)]oHypertension [see Warnings and Precautions (5.2)]. oThrombosis/Thromboembolism [see Warnings and Precautions (5.1)]. oHypertension [see Warnings and Precautions (5.2)]. The most common (>10%) adverse reactions were fatigue, headache, musculoskeletal pain, arthralgia, dizziness/vertigo, nausea, diarrhea, cough, abdominal pain, dyspnea, 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 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 single agent administered across range of doses (0.125 mg/kg to 1.75 mg/kg) in 571 patients in trials.. Beta ThalassemiaThe 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 or alpha-thalassemia disease) without major organ damage or recent DVT stroke and platelet counts less than or equal to 1000 109/L.Patients received starting dose of REBLOZYL mg/kg subcutaneous injection every weeks. Overall, 53% of patients had their dose increased to 1.25 mg/kg (46% REBLOZYL, = 223) or placebo (66%, = 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 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. 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 summarizes the adverse reactions in BELIEVE.Table 6: Adverse Drug Reactions (>5%) in Patients with Beta Thalassemia Receiving REBLOZYL with Difference Between Arms of 1% in BELIEVE TrialBody SystemREBLOZYL(N=223)Placebo(N=109) Adverse ReactionAll Gradesn (%)Grades >=3a (%)All Gradesn (%)Grades >=3n (%)a Limited to Grade reactions with the exception of events of Grade hyperuricemia. Grouped term includes abdominal pain and abdominal pain upper. Grouped term includes essential hypertension, hypertension, and hypertensive crisis.Musculoskeletal and connective tissue disorders Bone Pain44 (20)3 (1)9 (8)0 (0) Arthralgia43 (19)0 (0)13 (12)0 (0)Infections and infestation Influenza19 (9)0 (0)6 (6)0 (0) Viral Upper Respiratory Infection14 (6)1 (0.4)2 (2)0 (0)Nervous system disorders Headache58 (26)1 (<1)26 (24)1 (1) Dizziness25 (11)0 (0)5 (5)0 (0)General disorders and administration site conditions Fatigue30 (14)0 (0)14 (13)0 (0)Gastrointestinal disorders Abdominal Pain 31 (14)0 (0)13 (12)0 (0) Diarrhea27 (12)1 (<1)11 (10)0 (0) Nausea20 (9)0 (0)6 (6)0 (0)Vascular disorders Hypertension 18 (8)4 (2)3 (3)0 (0)Metabolism and nutrition disorders Hyperuricemia16 (7)6 (3)0 (0)0 (0)Respiratory, thoracic and mediastinal disorders Cough32 (14)0 (0)12 (11)0 (0)Clinically relevant adverse reactions in <5% of patients include vertigo/vertigo positional, syncope/presyncope, injection site reactions and hypersensitivity.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 TrialREBLOZYLN 223n (%)PlaceboN 109n (%)ALP alkaline phosphatase; ALT alanine aminotransferase;AST aspartate aminotransferase; ULN upper limit of normal.ALT >= x ULN26 (12)13 (12)AST >= x ULN25 (11)5 (5)ALP >= x ULN17 (8)1 (<1)Total bilirubin >= x ULN143 (64)51 (47)Direct bilirubin >= x ULN13 (6)4 (4). Myelodysplastic Syndromes with Ring Sideroblasts or Myelodysplastic Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis Associated AnemiaThe 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). 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, - 221 weeks); 67% of patients were exposed for months or longer and 49% were exposed for greater than one year. Among the 242 patients treated with REBLOZYL, (2.1%) had fatal adverse reaction, 11 (4.5%) discontinued due to an adverse reaction, and (2.9%) had 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 >= adverse reactions included fatigue, hypertension, syncope and musculoskeletal pain. Selected laboratory abnormalities that changed from Grade 0-1 at baseline to Grade >= at any time during the studies in at least 10% of patients included creatinine clearance decreased, total bilirubin increased, and alanine aminotransferase increased.Table shows the most common adverse reactions for patients treated with REBLOZYL or placebo through the first cycles in the MEDALIST trial [see Clinical Studies (14.2)]. Table 8: Adverse Reactions (>=5%) in Patients Receiving REBLOZYL with Difference Between Arms of >2% in MEDALIST Trial Through Cycle 8Body System /Adverse ReactionREBLOZYL(N=153)Placebo (N=76)All Gradesn (%)Grade 3n (%)All Gradesn (%)Grade 3n (%)a Includes asthenic conditions. Reaction includes similar/grouped terms.General disorders and administration site conditionsFatigue a, 63 (41)11 (7)17 (22)2 (3)Musculoskeletal and connective tissue disordersMusculoskeletal pain 30 (20)3 (2)11 (14)0 (0)Nervous system disordersDizziness/vertigo28 (18)1 (<1)5 (7)1 (1)Headache 21 (14)0 (0)5 (7)0 (0)Syncope presyncope8 (5)5 (3)0 (0)0 (0)Gastrointestinal disordersNausea 25 (16)1 (<1)8 (11)0 (0)Diarrhea 25 (16)0 (0)7 (9)0 (0)Respiratory, thoracic and mediastinal disordersDyspnea 20 (13)2 (1)4 (5)1 (1)Immune system disordersHypersensitivity reactions 15 (10)1 (<1)5 (7)0 (0)Renal and urinary disordersRenal impairment 12 (8)3 (2)3 (4)0 (0)Cardiac disordersTachycardia 12 (8)0 (0)1 (1)0 (0)Injury poisoning and procedural complicationsInjection site reactions 10 (7)0 (0)3 (4)0 (0)Infections and infestationsUpper respiratory tract infection10 (7)1 (<1)2 (3)0 (0)Influenza influenza like illness9 (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 cycles in the MEDALIST trial are shown in Table 9.Table 9: Selected Grades 2-4 Treatment-Emergent Laboratory Abnormalities Through Cycle in the MEDALIST Triala Number of patients at Grades 0-1 at baseline.ALT alanine aminotransferase; AST aspartate aminotransferase.ParameterREBLOZYLPlaceboNa (%)Na (%)ALT elevated15113 (9)745 (7)AST elevated1526 (4)760 (0)Total bilirubin elevated14017 (12)663 (5)Creatinine clearance reduced11330 (27)6213 (21). 6.2 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to luspatercept in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.Of 284 patients with beta thalassemia who were treated with REBLOZYL and evaluable for the presence of anti-luspatercept-aamt antibodies, patients (1.4%) tested positive for treatment-emergent anti-luspatercept-aamt antibodies, including patients (0.7%) who had neutralizing antibodies.Of 260 patients with MDS who were treated with REBLOZYL and evaluable for the presence of anti-luspatercept-aamt antibodies, 23 patients (8.9%) tested positive for treatment-emergent anti-luspatercept-aamt antibodies, including patients (3.5%) 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No carcinogenicity or mutagenicity studies have been conducted with luspatercept-aamt.In repeat-dose toxicity study, juvenile rats were administered luspatercept-aamt subcutaneously at 1, 3, or 10 mg/kg once every weeks from postnatal day to 91. Hematologic malignancies (granulocytic leukemia, lymphocytic leukemia, malignant lymphoma) were observed at 10 mg/kg resulting in exposures (based on area under the curve [AUC]) approximately 4.4 times the maximum recommended human dose (MRHD) of 1.75 mg/kg.In combined male and female fertility and early embryonic development study in rats, luspatercept-aamt was administered subcutaneously to animals at doses of to 15 mg/kg. There were significant reductions in the average numbers of corpora lutea, implantations, and viable embryos in luspatercept-aamt-treated females. Effects on female fertility were observed at the highest dose with exposures (based on AUC) approximately 7-times the MRHD of 1.75 mg/kg. Adverse effects on fertility in female rats were reversible after 14-week recovery period. No adverse effects were noted in male rats.

DESCRIPTION SECTION.

11 DESCRIPTION. Luspatercept-aamt is an erythroid maturation agent. Luspatercept-aamt is receptor fusion protein consisting of modified extracellular domain of the human activin receptor type IIB linked to human IgG1 Fc domain with 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 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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oThe recommended starting dose is mg/kg once every weeks by subcutaneous injection (2.1, 2.2). oReview hemoglobin (Hgb) results prior to each administration (2.1, 2.2).oSee full prescribing information for preparation and administration instructions (2.3).. oThe recommended starting dose is mg/kg once every weeks by subcutaneous injection (2.1, 2.2). oReview hemoglobin (Hgb) results prior to each administration (2.1, 2.2).. oSee full prescribing information for preparation and administration instructions (2.3).. 2.1Recommended Dosage in Beta Thalassemia. The recommended starting dose of REBLOZYL is mg/kg once every weeks by subcutaneous injection for patients with beta thalassemia. Prior to each REBLOZYL dose, review the patients 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 patient does not experience decrease in transfusion burden after weeks of treatment (administration of doses) at the maximum dose level or if unacceptable toxicity occurs at any time.If planned administration of REBLOZYL is delayed or missed, administer REBLOZYL as soon as possible and continue dosing as prescribed, with at least weeks between doses.. Dose Modifications for ResponseAssess 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 patient does not achieve reduction in RBC transfusion burden after at least consecutive doses (6 weeks) at the 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 g/dL within 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. REBLOZYLDosing RecommendationStarting Doseo1 mg/kg every weeksDose Increases for Insufficient Response at Initiation of TreatmentNo reduction in RBC transfusion burden after at least consecutive doses (6 weeks) at the mg/kg starting doseoIncrease the dose to 1.25 mg/kg every weeksNo reduction in RBC transfusion burden after consecutive doses (9 weeks) at 1.25 mg/kgoDiscontinue treatmentDose Modifications for Predose Hemoglobin Levels or Rapid Hemoglobin RisePredose hemoglobin is greater than or equal to 11.5 g/dL in the absence of transfusionsoInterrupt treatmentoRestart when the hemoglobin is no more than 11 g/dLIncrease in hemoglobin greater than g/dL within weeks in the absence of transfusions andocurrent dose is 1.25 mg/kgocurrent dose is mg/kgocurrent dose is 0.8 mg/kgocurrent dose is 0.6 mg/kgoReduce dose to mg/kg oReduce dose to 0.8 mg/kgoReduce dose to 0.6 mg/kgoDiscontinue treatment. o1 mg/kg every weeks. oIncrease the dose to 1.25 mg/kg every weeks. oDiscontinue treatment. oInterrupt treatment. oRestart when the hemoglobin is no more than 11 g/dL. ocurrent dose is 1.25 mg/kg. ocurrent dose is mg/kg. ocurrent dose is 0.8 mg/kg. ocurrent dose is 0.6 mg/kg. oReduce dose to mg/kg oReduce dose to 0.8 mg/kg. oReduce dose to 0.6 mg/kg. oDiscontinue treatment. Dose Modifications for ToxicityFor patients experiencing Grade or higher adverse reactions, modify treatment as described in Table 2.Table 2: Beta Thalassemia REBLOZYL Dosing Modifications for Adverse Reactions Grade is mild, Grade is moderate, Grade is severe, and Grade is life-threatening. REBLOZYLDosing RecommendationGrade or hypersensitivity reactionsoDiscontinue treatmentOther Grade or adverse reactionsoInterrupt treatmentoRestart when the adverse reaction resolves to no more than Grade 1. oDiscontinue treatment. oInterrupt treatment. oRestart when the adverse reaction resolves to no more than Grade 1. 2.2Recommended Dosage for Myelodysplastic Syndromes with Ring Sideroblasts (MDS-RS) or Myelodysplastic/ Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T) Associated Anemia. The recommended starting dose of REBLOZYL is mg/kg once every weeks by subcutaneous injection for patients with anemia of MDS-RS or MDS/MPN-RS-T. Prior to each REBLOZYL dose, review the patients 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 patient does not experience decrease in transfusion burden after weeks of treatment (administration of doses) at the maximum dose level or if unacceptable toxicity occurs at any time.If planned administration of REBLOZYL is delayed or missed, administer REBLOZYL as soon as possible and continue dosing as prescribed, with at least weeks between doses.. Dose Modifications for ResponseAssess 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 patient is not RBC transfusion-free after at least consecutive doses (6 weeks) at the mg/kg starting dose, increase the REBLOZYL dose to 1.33 mg/kg (Table 3). If patient is not RBC transfusion-free after at least 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 weeks (2 doses) or beyond the maximum dose of 1.75 mg/kg.In the absence of transfusions, if hemoglobin increase is greater than g/dL within 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 transfusion) or hemoglobin concentration drops by g/dL or more in weeks in the absence of transfusion, increase the dose by one dose level. Wait minimum of weeks between dose increases.Dose modifications for response are provided in Table 3.Table 3: MDS-RS and MDS/MPN-RS-T 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. REBLOZYLDosing RecommendationStarting Doseo1 mg/kg every weeksDose Increases for Insufficient Response at Initiation of TreatmentNot RBC transfusion-free after at least consecutive doses (6 weeks) at the mg/kg starting doseoIncrease the dose to 1.33 mg/kg every weeksNot RBC transfusion-free after at least consecutive doses (6 weeks) at 1.33 mg/kgoIncrease the dose to 1.75 mg/kg every weeksNo reduction in RBC transfusion burden after at least consecutive doses (9 weeks) at 1.75 mg/kgoDiscontinue treatmentDose Modifications for Predose Hemoglobin Levels or Rapid Hemoglobin RisePredose hemoglobin is greater than or equal to 11.5 g/dL in the absence of transfusionsoInterrupt treatmentoRestart when the hemoglobin is no more than 11 g/dLIncrease in hemoglobin greater than g/dL within weeks in the absence of transfusions andocurrent dose is 1.75 mg/kgocurrent dose is 1.33 mg/kgocurrent dose is mg/kgocurrent dose is 0.8 mg/kgocurrent dose is 0.6 mg/kgoReduce dose to 1.33 mg/kgoReduce dose to mg/kgoReduce dose to 0.8 mg/kgoReduce dose to 0.6 mg/kgoDiscontinue treatment. o1 mg/kg every weeks. oIncrease the dose to 1.33 mg/kg every weeks. oIncrease the dose to 1.75 mg/kg every weeks. oDiscontinue treatment. oInterrupt treatment. oRestart when the hemoglobin is no more than 11 g/dL. ocurrent dose is 1.75 mg/kg. ocurrent dose is 1.33 mg/kg. ocurrent dose is mg/kg. ocurrent dose is 0.8 mg/kg. ocurrent dose is 0.6 mg/kg. oReduce dose to 1.33 mg/kg. oReduce dose to mg/kg. oReduce dose to 0.8 mg/kg. oReduce dose to 0.6 mg/kg. oDiscontinue treatment. Dose Modifications for ToxicityFor patients experiencing Grade or higher adverse reactions, modify treatment as described in Table 4.Table 4: MDS-RS and MDS/MPN-RS-T Associated Anemia REBLOZYL Dosing Modifications for Adverse Reactions Grade is mild, Grade is moderate, Grade is severe, and Grade is life-threatening. Per Table dose reductions above. REBLOZYLDosing RecommendationGrade or hypersensitivity reactionsoDiscontinue treatmentOther Grade or adverse reactionsoInterrupt treatmentoWhen the adverse reaction resolves to no more than Grade 1, restart treatment at the next lower dose leveloIf the dose delay is 12 consecutive weeks, discontinue treatment. oDiscontinue treatment. oInterrupt treatment. oWhen the adverse reaction resolves to no more than Grade 1, restart treatment at the next lower dose level. oIf the dose delay is 12 consecutive weeks, discontinue treatment. 2.3 Preparation and Administration. REBLOZYL should be reconstituted and administered by healthcare professional.Reconstitute REBLOZYL with Sterile Water for Injection, USP only.Table 5: Reconstitution VolumesVial SizeAmount of Sterile Water for Injection, USP required for reconstitutionFinal ConcentrationDeliverable Volume25 mg vial0.68 mL25 mg/0.5 mL0.5 mL75 mg vial1.6 mL75 mg/1.5 mL1.5 mL(50 mg/mL)Reconstitute the number of REBLOZYL vials to achieve the appropriate dose based on the patients weight. Use syringe with suitable graduations for reconstitution to ensure accurate dosage.. Reconstitution Instructions1.Reconstitute with Sterile Water for Injection, USP using volumes described in Table (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 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 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 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 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:oStore at room temperature at 20C to 25C (68F to 77F) in the original vial for up to hours. Discard if not used within hours of reconstitution.oAlternatively, store refrigerated at 2C to 8C (36F to 46F) 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 more comfortable injection. Discard if not used within 24 hours of reconstitution.oDo not freeze the reconstituted solution.Discard any unused portion. Do not pool unused portions from the vials. Do not administer more than dose from vial. Do not mix with other medications.. 1.Reconstitute with Sterile Water for Injection, USP using volumes described in Table (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 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 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 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 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:oStore at room temperature at 20C to 25C (68F to 77F) in the original vial for up to hours. Discard if not used within hours of reconstitution.oAlternatively, store refrigerated at 2C to 8C (36F to 46F) 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 more comfortable injection. Discard if not used within 24 hours of reconstitution.oDo not freeze the reconstituted solution.. oStore at room temperature at 20C to 25C (68F to 77F) in the original vial for up to hours. Discard if not used within hours of reconstitution.. oAlternatively, store refrigerated at 2C to 8C (36F to 46F) 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 more comfortable injection. Discard if not used within 24 hours of reconstitution.. oDo not freeze the reconstituted solution.. Instructions for Subcutaneous AdministrationCalculate 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 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 new syringe and needle for each subcutaneous injection.Administer the injection subcutaneously into the upper arm, thigh, and/or abdomen.

DOSAGE FORMS & STRENGTHS SECTION.

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

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Pregnancy TestingPregnancy testing is recommended for females of reproductive potential before starting REBLOZYL treatment.. Contraception. FemalesREBLOZYL 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 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 14-week recovery period.

GERIATRIC USE SECTION.

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 differently from younger patients.Clinical studies of REBLOZYL for treatment of anemia in MDS-RS and MDS/MPN-RS-T included 206 (79%) patients >= 65 years of age and 93 (36%) patients >= 75 years of age. No differences in safety or effectiveness were observed between older (>= 65 years) and younger patients.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1How Supplied. REBLOZYL (luspatercept-aamt) for injection is white to off-white lyophilized powder supplied in 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 2C to 8C (36F to 46F) in original carton to protect from light. Do not freeze.

IMMUNOGENICITY.

6.2 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to luspatercept in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.Of 284 patients with beta thalassemia who were treated with REBLOZYL and evaluable for the presence of anti-luspatercept-aamt antibodies, patients (1.4%) tested positive for treatment-emergent anti-luspatercept-aamt antibodies, including patients (0.7%) who had neutralizing antibodies.Of 260 patients with MDS who were treated with REBLOZYL and evaluable for the presence of anti-luspatercept-aamt antibodies, 23 patients (8.9%) tested positive for treatment-emergent anti-luspatercept-aamt antibodies, including patients (3.5%) 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.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. REBLOZYL is an erythroid maturation agent indicated for the treatment of:oAnemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions (1.1).oAnemia failing an erythropoiesis stimulating agent and requiring or more RBC units over 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) (1.2).oLimitations of Use: REBLOZYL is not indicated for use as substitute for RBC transfusions in patients who require immediate correction of anemia (1.3).. oAnemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions (1.1).. oAnemia failing an erythropoiesis stimulating agent and requiring or more RBC units over 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) (1.2).. oLimitations of Use: REBLOZYL is not indicated for use as substitute for RBC transfusions in patients who require immediate correction of anemia (1.3).. 1.1Beta Thalassemia. REBLOZYL is indicated for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions. 1.2Myelodysplastic 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 or more red blood cell units over 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 substitute for RBC transfusions in patients who require immediate correction of anemia.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Discuss the following with patients prior to and during treatment with REBLOZYL.. Thromboembolic EventsAdvise beta thalassemia patients of the potential risk of thromboembolic events. Review known risk factors for developing thromboembolic events and advise patients to reduce modifiable risk factors (e.g., smoking, use of oral contraceptives) [see Warnings and Precautions (5.1)]. Effects on Blood PressureCaution patients that REBLOZYL may cause an increase in blood pressure [see Warnings and Precautions (5.2)]. Embryo-Fetal ToxicityAdvise females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to use effective contraception while receiving REBLOZYL and for at least months after the final dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with REBLOZYL [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)]. LactationAdvise females not to breastfeed during treatment with REBLOZYL and for months after the final dose [see Use in Specific Populations (8.2)].

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No carcinogenicity or mutagenicity studies have been conducted with luspatercept-aamt.In repeat-dose toxicity study, juvenile rats were administered luspatercept-aamt subcutaneously at 1, 3, or 10 mg/kg once every weeks from postnatal day to 91. Hematologic malignancies (granulocytic leukemia, lymphocytic leukemia, malignant lymphoma) were observed at 10 mg/kg resulting in exposures (based on area under the curve [AUC]) approximately 4.4 times the maximum recommended human dose (MRHD) of 1.75 mg/kg.In combined male and female fertility and early embryonic development study in rats, luspatercept-aamt was administered subcutaneously to animals at doses of to 15 mg/kg. There were significant reductions in the average numbers of corpora lutea, implantations, and viable embryos in luspatercept-aamt-treated females. Effects on female fertility were observed at the highest dose with exposures (based on AUC) approximately 7-times the MRHD of 1.75 mg/kg. Adverse effects on fertility in female rats were reversible after 14-week recovery period. No adverse effects were noted in male rats.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 25 mg Vial Label. NDC 59572-711-01 Reblozyl(R)(luspatercept-aamt)for Injection25 mg/vial For Subcutaneous Use OnlyReconstitute priorto administration LOTEXP. Reblozyl(R)(luspatercept-aamt)for Injection. For Subcutaneous Use OnlyReconstitute priorto administration. LOTEXP. PRINCIPAL DISPLAY PANEL 75 mg Vial Carton Singapore.

PEDIATRIC USE SECTION.

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)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Increases in Hemoglobin in Patients with Low RBC Transfusion BurdenIn patients having received 4 units of RBC transfusion within weeks prior to study, hemoglobin increased within days of initiating REBLOZYL and correlated with the time to luspatercept-aamt maximum serum concentration (Cmax). The greatest Hgb increase occurred after the first dose; approximately 0.75 g/dL at dose of 0.6 to 1.25 times the recommended starting dose for beta thalassemia, or approximately g/dL at dose of 0.75 to 1.75 times the recommended starting dose for MDS. Additional smaller increases were observed after subsequent doses. Hemoglobin levels returned to baseline approximately to weeks from the last dose following administration of luspatercept-aamt (0.6 to 1.75 mg/kg). Increasing luspatercept-aamt serum exposure (AUC) was associated with greater Hgb increase in patients with beta thalassemia or MDS who had baseline transfusion burden 4 units/8 weeks. Increasing luspatercept-aamt serum exposure (time-averaged AUC) was associated with greater probability of achieving transfusion independence for at least consecutive weeks in patients with MDS requiring transfusions (>= units of RBC transfusion within weeks).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Luspatercept-aamt exhibited linear pharmacokinetics (PK) over the dose range of 0.2 to 1.25 mg/kg (0.2 to 1.25 times the recommended starting dosage) in patients with beta thalassemia, and from 0.125 mg/kg to 1.75 mg/kg in patients with MDS. The mean (% coefficient of variation [%CV]) steady-state AUC at the starting dose of mg/kg was 126 (35.9%) dayug/mL for patients with beta thalassemia and 145 (38.3%) dayug/mL for patients with MDS. Luspatercept-aamt serum concentration reached steady state after doses when administered every weeks. The accumulation ratio of luspatercept-aamt was approximately 1.5.. AbsorptionThe median (range) time to maximum concentration (Tmax) of luspatercept-aamt was observed at approximately [6 to 10] days post-dose in adult patients with beta thalassemia or [5 to 21] days post-dose in adult patients with MDS. The absorption of luspatercept-aamt was not significantly affected by the subcutaneous injection sites (upper arm, thigh, or abdomen). DistributionThe mean (%CV) apparent volume of distribution (Vd/F) of luspatercept-aamt was 7.1 (26.7%) for patients with beta thalassemia, and 9.7 (26.5%) for patients with MDS. EliminationThe mean (%CV) half-life (t1/2) of luspatercept-aamt was approximately 11 (25.7%) days and the mean (%CV) apparent total clearance (CL/F) was 0.44 (38.5%) L/day in patients with beta thalassemia. The mean (%CV) t1/2 of luspatercept-aamt was approximately 13 (31.6%) days and the mean (%CV) CL/F was 0.52 (41.2%) L/day in patients with MDS.. MetabolismLuspatercept-aamt is expected to be catabolized into amino acids by general protein degradation processes in multiple tissues.. Specific PopulationsNo clinically significant differences in the luspatercept-aamt PK was observed based on age (18 to 95 years), sex, race/ethnicity (Asian, White), mild to severe hepatic impairment (total bilirubin <= upper limit of normal [ULN] and aspartate aminotransaminase [AST] or alanine transaminase [ALT] ULN, or total bilirubin ULN and any AST or ALT), mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] 30 to 89 mL/min/1.73 m2), baseline albumin (30 to 56 g/L), baseline serum erythropoietin (2.4 to 2450 U/L), red blood cell (RBC) transfusion burden (0 to 43 units/24 weeks), beta thalassemia genotype (0/0 vs. non-0/0), splenectomy, and ring sideroblasts status in MDS (negative vs. positive). The effect of AST or ALT >3 ULN and the effect of severe renal impairment (eGFR <30 mL/min/1.73 m2) on luspatercept-aamt PK is unknown. Body WeightThe apparent CL/F and Vd/F of luspatercept-aamt increased with increasing body weight in patients with beta thalassemia (34 to 97 kg) and in patients with MDS (46 to 124 kg). Drug Interaction Studies. Effect of Iron-chelating Agents on Luspatercept-aamtNo clinically significant differences in luspatercept-aamt PK were observed when used concomitantly with iron-chelating agents.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on findings in animal reproduction studies, REBLOZYL may cause fetal harm when administered to pregnant woman. There are no available data on REBLOZYL use in pregnant women to inform 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 fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 DataIn embryo-fetal development studies, luspatercept-aamt was administered subcutaneously at 5, 15, or 30 mg/kg on gestation days and 10 (rats) or 5, 20, or 40 mg/kg on gestation days 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 pre- and postnatal development study, pregnant rats were administered luspatercept-aamt subcutaneously at 3, 10, or 30 mg/kg once every weeks during organogenesis and through weaning, gestation day through postnatal day 20. At all dose levels lower F1 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.

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationREBLOZYL(R) (REB-low-zil)(luspatercept-aamt)for injection, for subcutaneous useWhat is REBLOZYLREBLOZYL is prescription medicine used to treat anemia (low red blood cells) in adults with:obeta thalassemia who need regular red blood cell (RBC) transfusions.omyelodysplastic syndromes with ring sideroblasts (MDS-RS) or myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) who need regular RBC transfusion and have not responded well to or cannot receive an erythropoiesis stimulating agent (ESA).REBLOZYL is not for use as substitute for RBC transfusions in people who need immediate treatment for anemia. It is not known if REBLOZYL is safe or effective in children.Before receiving REBLOZYL, tell your healthcare provider about all of your medical conditions, including if you:ohave or have had blood clots ohave or have had high blood pressure (hypertension)otake hormone replacement therapy or birth control pills (oral contraceptives) ohave had your spleen removed (splenectomy)osmokeoare pregnant or plan to become pregnant. REBLOZYL may harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with REBLOZYL.Females who are able to become pregnant:oYour healthcare provider should do pregnancy test before you start treatment with REBLOZYL.oYou should use effective birth control (contraception) during treatment with REBLOZYL and for at least months after the last dose.oare breastfeeding or plan to breastfeed. It is not known if REBLOZYL passes into your breast milk.oDo not breastfeed during treatment with REBLOZYL and for months after the last dose. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements How will receive REBLOZYLoYour healthcare provider will prescribe REBLOZYL in dose that is right for you.oREBLOZYL is given as an injection under your skin (subcutaneous) in the upper arm, thigh or stomach (abdomen) by your healthcare provider. oYour healthcare provider will do regular blood tests to check your hemoglobin to monitor if your anemia is getting better before each injection and during your treatment with REBLOZYL.oYour healthcare provider may adjust your dose or stop treatment depending on how you respond to REBLOZYL.oIf your scheduled REBLOZYL dose is delayed or missed, your healthcare provider will give your dose of REBLOZYL as soon as possible and continue your treatment as prescribed with at least weeks between doses. What are the possible side effects of REBLOZYLREBLOZYL may cause serious side effects, including:oBlood clots. Blood clots in the arteries, veins, brain, and lungs have happened in people with beta thalassemia during treatment with REBLOZYL. The risk of blood clots may be higher in people who have had their spleen removed or who take hormone replacement therapy or birth control (oral contraceptives). Call your healthcare provider or get medical help right away if you have any of these symptoms:ochest painotrouble breathing or shortness of breathopain in your leg, with or without swelling oa cold or pale arm or legosudden numbness or weakness that are both short-term or continue to happen over long period of time, especially on one side of the body osevere headache or confusion osudden problems with vision, speech, or balance (such as trouble speaking, difficulty walking, or dizziness) oHigh blood pressure. REBLOZYL may cause an increase in your blood pressure. Your healthcare provider will check your blood pressure before you receive your REBLOZYL dose. Your healthcare provider may prescribe you medicine to treat high blood pressure or increase the dose of medicine you already take to treat high blood pressure, if you develop high blood pressure during treatment with REBLOZYL.The most common side effects of REBLOZYL include:otirednessomuscle or bone painodizzinessodiarrheaostomach (abdominal) painoallergic reactionsoheadacheojoint pain (arthralgia)onauseaocoughotrouble breathingREBLOZYL may cause fertility problems in females. This could affect your ability to become pregnant. Talk to your healthcare provider if this is concern for you.These are not all of the possible side effects of REBLOZYL.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of REBLOZYL.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. You can ask your healthcare provider or pharmacist for information about REBLOZYL that is written for healthcare professionals.What are the ingredients in REBLOZYLActive ingredient: luspatercept-aamt Inactive ingredients: citric acid monohydrate, polysorbate 80, sucrose, and tri-sodium citrate dihydrate.For more information, go to www.REBLOZYL.com or call 1-888-423-5436.Manufactured by: Celgene Corporation, Bristol-Myers Squibb Company, 86 Morris Avenue, Summit, NJ 07901Jointly Marketed by: Acceleron Pharma, Inc. Cambridge, MA 02139REBLOZYL(R) is registered trademark of Celgene Corporation, Bristol-Myers Squibb Company.(C) 2021 Celgene Corporation, Bristol-Myers Squibb Company. All rights reserved. REBPPI V2 10/2021This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: October 2021. obeta thalassemia who need regular red blood cell (RBC) transfusions.. omyelodysplastic syndromes with ring sideroblasts (MDS-RS) or myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) who need regular RBC transfusion and have not responded well to or cannot receive an erythropoiesis stimulating agent (ESA).. ohave or have had blood clots ohave or have had high blood pressure (hypertension). otake hormone replacement therapy or birth control pills (oral contraceptives) ohave had your spleen removed (splenectomy). osmoke. oare pregnant or plan to become pregnant. REBLOZYL may harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with REBLOZYL.Females who are able to become pregnant:oYour healthcare provider should do pregnancy test before you start treatment with REBLOZYL.oYou should use effective birth control (contraception) during treatment with REBLOZYL and for at least months after the last dose.. oYour healthcare provider should do pregnancy test before you start treatment with REBLOZYL.. oYou should use effective birth control (contraception) during treatment with REBLOZYL and for at least months after the last dose.. oare breastfeeding or plan to breastfeed. It is not known if REBLOZYL passes into your breast milk.oDo not breastfeed during treatment with REBLOZYL and for months after the last dose. Talk to your healthcare provider about the best way to feed your baby during this time. oDo not breastfeed during treatment with REBLOZYL and for months after the last dose. Talk to your healthcare provider about the best way to feed your baby during this time. oYour healthcare provider will prescribe REBLOZYL in dose that is right for you.. oREBLOZYL is given as an injection under your skin (subcutaneous) in the upper arm, thigh or stomach (abdomen) by your healthcare provider. oYour healthcare provider will do regular blood tests to check your hemoglobin to monitor if your anemia is getting better before each injection and during your treatment with REBLOZYL.. oYour healthcare provider may adjust your dose or stop treatment depending on how you respond to REBLOZYL.. oIf your scheduled REBLOZYL dose is delayed or missed, your healthcare provider will give your dose of REBLOZYL as soon as possible and continue your treatment as prescribed with at least weeks between doses. oBlood clots. Blood clots in the arteries, veins, brain, and lungs have happened in people with beta thalassemia during treatment with REBLOZYL. The risk of blood clots may be higher in people who have had their spleen removed or who take hormone replacement therapy or birth control (oral contraceptives). Call your healthcare provider or get medical help right away if you have any of these symptoms:ochest painotrouble breathing or shortness of breathopain in your leg, with or without swelling oa cold or pale arm or legosudden numbness or weakness that are both short-term or continue to happen over long period of time, especially on one side of the body osevere headache or confusion osudden problems with vision, speech, or balance (such as trouble speaking, difficulty walking, or dizziness) ochest pain. otrouble breathing or shortness of breath. opain in your leg, with or without swelling oa cold or pale arm or leg. osudden numbness or weakness that are both short-term or continue to happen over long period of time, especially on one side of the body osevere headache or confusion osudden problems with vision, speech, or balance (such as trouble speaking, difficulty walking, or dizziness). oHigh blood pressure. REBLOZYL may cause an increase in your blood pressure. Your healthcare provider will check your blood pressure before you receive your REBLOZYL dose. Your healthcare provider may prescribe you medicine to treat high blood pressure or increase the dose of medicine you already take to treat high blood pressure, if you develop high blood pressure during treatment with REBLOZYL.. otiredness. omuscle or bone pain. odizziness. odiarrhea. ostomach (abdominal) pain. oallergic reactions. oheadache. ojoint pain (arthralgia). onausea. ocough. otrouble breathing.

SPL UNCLASSIFIED SECTION.

1.1Beta Thalassemia. REBLOZYL is indicated for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions.

STORAGE AND HANDLING SECTION.

16.2 Storage. Store vials refrigerated at 2C to 8C (36F to 46F) in original carton to protect from light. Do not freeze.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed (8.2).. 8.1 Pregnancy. Risk SummaryBased on findings in animal reproduction studies, REBLOZYL may cause fetal harm when administered to pregnant woman. There are no available data on REBLOZYL use in pregnant women to inform 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 fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 DataIn embryo-fetal development studies, luspatercept-aamt was administered subcutaneously at 5, 15, or 30 mg/kg on gestation days and 10 (rats) or 5, 20, or 40 mg/kg on gestation days 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 pre- and postnatal development study, pregnant rats were administered luspatercept-aamt subcutaneously at 3, 10, or 30 mg/kg once every weeks during organogenesis and through weaning, gestation day through postnatal day 20. At all dose levels lower F1 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 SummaryLuspatercept-aamt was detected in milk of lactating rats. When 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 months after the last dose. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingPregnancy testing is recommended for females of reproductive potential before starting REBLOZYL treatment.. Contraception. FemalesREBLOZYL 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 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 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 differently from younger patients.Clinical studies of REBLOZYL for treatment of anemia in MDS-RS and MDS/MPN-RS-T included 206 (79%) patients >= 65 years of age and 93 (36%) patients >= 75 years of age. No differences in safety or effectiveness were observed between older (>= 65 years) and younger patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oThrombosis/Thromboembolism: Increased risk in patients with beta thalassemia. Monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly (5.1).oHypertension: Monitor blood pressure (BP) during treatment. Initiate anti-hypertensive treatment if necessary (5.2). oEmbryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and use of effective contraception (5.3, 8.1, 8.3).. oThrombosis/Thromboembolism: Increased risk in patients with beta thalassemia. Monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly (5.1).. oHypertension: Monitor blood pressure (BP) during treatment. Initiate anti-hypertensive treatment if necessary (5.2). oEmbryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and use of effective contraception (5.3, 8.1, 8.3).. 5.1Thrombosis/Thromboembolism. In adult patients with beta thalassemia, thromboembolic events (TEE) were reported in 8/223 (3.6%) REBLOZYL-treated patients. Reported TEEs included deep vein thromboses, pulmonary embolus, portal vein thrombosis, and ischemic strokes. Patients with known risk factors for thromboembolism, e.g. splenectomy or concomitant use of hormone replacement therapy, may be at further increased risk of thromboembolic conditions. Consider thromboprophylaxis in patients with beta thalassemia at increased risk of TEE. Monitor patients receiving REBLOZYL for signs and symptoms of thromboembolic events and institute treatment promptly.. 5.2Hypertension. Hypertension was reported in 10.7% (61/571) of REBLOZYL-treated patients. Across clinical studies, the incidence of grade 3-4 hypertension ranged from 1.8% to 8.6%. In adult 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-onset hypertension or exacerbations of preexisting hypertension using anti-hypertensive agents.. 5.3 Embryo-Fetal Toxicity. Based on findings from animal reproductive studies, REBLOZYL may cause fetal harm when administered to pregnant woman. In animal reproduction studies, administration of luspatercept-aamt to pregnant rats and rabbits during organogenesis resulted in adverse developmental outcomes including increased 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) of 1.75 mg/kg.Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with REBLOZYL and for at least months after the final dose [see Use in Specific Populations (8.1, 8.3)].

RECENT MAJOR CHANGES SECTION.

Dosage and Administration, Beta Thalassemia (2.1) 7/2022Warnings and Precautions, Extramedullary Hematopoietic Masses (5.3) 7/2022.