6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

•: Thrombosis/Thromboembolism [see Warnings and Precautions (5.1)]
•: Hypertension [see Warnings and Precautions (5.2)]
•: Extramedullary Hematopoietic Masses [see Warnings and Precautions (5.3)]

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 109/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 ≥3a 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)
Body System /Adverse Reaction	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)
Body System /Adverse Reaction	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
	Na	n (%)	Na	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)