Luspatercept

B03X - Other antianemic preparations ATC B03XA06 Protein approved 2019 Parenteral First-in-class Orphan

JFDA label: REBLOZYL 75mg Powder for solution for Injection for Subcutaneous Use

Mechanism of Action

Inhibitor of Transforming growth factor beta — Transforming growth factor beta inhibitor

Target	Action	Gene / class
Transforming growth factor beta efficacy	INHIBITOR

Indications

Approved

Anemia — anemia (phenotype)
Myelodysplastic Syndromes — myelodysplastic syndrome
beta-Thalassemia — Beta-thalassemia

Off-label

Anemia, Aplastic
Myeloproliferative Disorders
Thalassemia

Contraindications

Source: openFDA

None. None ( 4 ). Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Nervous system disorders (2)

Very Common And Dizziness · Were Headache

Gastrointestinal disorders (2)

Very Common Abdominal Pain · Diarrhea

Musculoskeletal and connective tissue disorders (4)

Very Common Arthralgia · Bone Pain

Common Back Pain · Patients Who Received Reblozyl Included Arthralgia

General disorders and administration site conditions (1)

Very Common Fatigue

Respiratory, thoracic and mediastinal disorders (1)

Very Common Cough

Dosing

Source: openFDA

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

Warnings & Precautions

Source: openFDA

Warnings & Precautions

• Thrombosis/Thromboembolism: Increased risk in patients with beta thalassemia. Monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly ( 5.1 ). • Hypertension: Monitor blood pressure (BP) during treatment. Initiate anti-hypertensive treatment if necessary ( 5.2 ). • Extramedullary Hematopoietic (EMH) Masses: Increased risk in patients with beta thalassemia. Monitor patients for symptoms and signs or complications resulting from the EMH masses. Treat according to clinical guidelines and discontinue treatment in case of serious complications due to EMH masses ( 5.3 ). • Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception ( 5.4 , 8.1 , 8.3 ).

Thrombosis/Thromboembolism In adult patients with beta thalassemia, th

Thrombosis/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.

Hypertension Hypertension was reported in 63/554 (11.4%) of REBLOZYL-t

Hypertension Hypertension was reported in 63/554 (11.4%) of REBLOZYL-treated patients. Across clinical studies, the incidence of Grade 3-4 hypertension ranged from 2% to 9.6%. 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 ESA-refractory or -intolerant adult patients with MDS with normal baseline blood pressure, 26 (30%) patients developed SBP ≥130 mm Hg and 23 (16%) patients developed DBP ≥80 mm Hg. In ESA-naïve adult patients with MDS with normal baseline blood pressure, 23 (36%) patients developed SBP ≥140 mm Hg and 11 (6%) 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.

Extramedullary Hematopoietic Masses In adult patients with transfusion

Extramedullary Hematopoietic Masses In adult patients with transfusion dependent beta thalassemia, EMH masses were observed in 3.2% of REBLOZYL-treated patients, with spinal cord compression symptoms due to EMH masses occurring in 1.9% of patients (BELIEVE and REBLOZYL long-term follow-up study). In a study of adult patients with non-transfusion dependent beta thalassemia, a higher incidence of EMH masses was observed in 6.3% of REBLOZYL-treated patients vs. 2% of placebo-treated patients in the double-blind phase of the study, with spinal cord compression due to EMH masses occurring in 1 patient with a prior history of EMH. REBLOZYL is not indicated for use in patients with non-transfusion dependent beta-thalassemia. Possible risk factors for the development of EMH masses in patients with beta thalassemia include history of EMH masses, splenectomy, splenomegaly, hepatomegaly, or low baseline hemoglobin (<8.5 g/dL). Signs and symptoms may vary depending on the anatomical location. Monitor patients with beta thalassemia at initiation and during treatment for symptoms and signs or complications resulting from the EMH masses and treat according to clinical guidelines. Discontinue treatment with REBLOZYL in case of serious complications due to EMH masses. Avoid use of REBLOZYL in patients requiring treatment to control the growth of EMH masses.

Embryo-Fetal Toxicity Based on findings from animal reproductive studi

Embryo-Fetal Toxicity Based on findings from animal reproductive studies, REBLOZYL may cause fetal harm when administered to a 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 a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with REBLOZYL and for at least 3 months after the final dose [see Use in Specific Populations ( 8.1 , 8.3 )] .

Pregnancy & Lactation

Lactation

Probably Unsafe Hale L4

Until more data become available, the manufacturer recommends that breastfeeding be discontinued during luspatercept therapy and for 3 months after the last dose.

Registered Products (2)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
REBLOZYL 25mg Powder for solution for Injection for Subcutaneous Use	Powder for Injection 25 mg	1 vial	Petra Drug Store	—
REBLOZYL 75mg Powder for solution for Injection for Subcutaneous Use	Powder for Injection 75 mg	1 vial	Petra Drug Store	—