Luspatercept-aamt (Monograph)

Brand name: Reblozyl
Drug class: Hematopoietic Agents
Chemical name: Activin receptor type IIB (synthetic human extracellular domain 107-amino acid fragment) fusion protein with glycylglycylglycine fusion protein with immunoglobulin G1 (synthetic human Fc region 225-amino acid C-terminal fragment), dimer
Molecular formula: C₃₃₅₀H₅₀₇₀N₉₀₆O₁₀₄₄S₃₈
CAS number: 1373715-00-4

Introduction

Luspatercept-aamt is a hematopoietic agent.

Uses for Luspatercept-aamt

Luspatercept-aamt has the following uses:

Luspatercept-aamt is an erythroid maturation agent indicated for the treatment of anemia in adults with beta thalassemia who require regular red blood cell (RBC) transfusions.

Luspatercept-aamt has the following limitations of use:

Luspatercept-aamt is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.

Luspatercept-aamt Dosage and Administration

General

Luspatercept-aamt is available in the following dosage form(s) and strength(s):

• For injection: 25 mg as lyophilized powder in a single-dose vial for reconstitution.

• For injection: 75 mg as lyophilized powder in a single-dose vial for reconstitution.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• The recommended starting dose is 1 mg/kg once every 3 weeks by subcutaneous injection.

• Review hemoglobin (Hgb) results prior to each administration.

• See full prescribing information for preparation and administration instructions.

Related/similar drugs

pyridoxine, Revlimid, lenalidomide, ferrous gluconate, epoetin alfa, Zynteglo, Reblozyl

Cautions for Luspatercept-aamt

Contraindications

None.

Warnings/Precautions

Thrombosis/Thromboembolism

In adult patients with beta thalassemia, thromboembolic events (TEE) were reported in 8/223 (3.6%) luspatercept-aamt-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 luspatercept-aamt for signs and symptoms of thromboembolic events and institute treatment promptly.

Hypertension

Hypertension was reported in 10.7% (61/571) of luspatercept-aamt-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) greater than 130 mm Hg and 33 (16.6%) patients developed diastolic blood pressure (DBP) greater than 80 mm Hg.

Monitor blood pressure prior to each administration. Manage new-onset hypertension or exacerbations of preexisting hypertension using anti-hypertensive agents.

Embryo-fetal Toxicity

Based on findings from animal reproductive studies, luspatercept-aamt 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 1.25 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 luspatercept-aamt and for at least 3 months after the final dose.

Specific Populations

Pregnancy

Risk Summary: Based on findings in animal reproduction studies, luspatercept-aamt may cause fetal harm when administered to a pregnant woman. There are no available data on luspatercept-aamt use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, administration of luspatercept-aamt to pregnant rats and rabbits during the period of organogenesis resulted in adverse developmental outcomes including embryo-fetal mortality, alterations to growth, and structural abnormalities at exposures (based on AUC) above those occurring at the MRHD. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Animal Data: In embryo-fetal development studies, luspatercept-aamt was administered subcutaneously at 5, 15, or 30 mg/kg on gestation days 3 and 10 (rats) or 5, 20, or 40 mg/kg on gestation days 4 and 11 (rabbits). Effects in both species included reductions in numbers of live fetuses and fetal body weights, and increases in resorptions, post-implantation losses, and skeletal variations (such as asymmetric sternal centra in rats and angulated hyoid in rabbits). Effects were observed at exposures (based on AUC) approximately 13-times (rats) and 18-times (rabbits) the MRHD of 1.25 mg/kg.

In a pre- and postnatal development study, pregnant rats were administered luspatercept-aamt subcutaneously at 3, 10, or 30 mg/kg once every 2 weeks during organogenesis and through weaning, gestation day 6 through postnatal day 20. At all dose levels lower 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 1.25 mg/kg.

Lactation

Risk Summary: Luspatercept-aamt was detected in milk of lactating rats. When a 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 luspatercept-aamt 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 luspatercept-aamt, and for 3 months after the last dose.

Females and Males of Reproductive Potential

Pregnancy testing is recommended for females of reproductive potential before starting luspatercept-aamt treatment.

Luspatercept-aamt may cause embryo-fetal harm when administered to pregnant women. Advise female patients of reproductive potential to use effective contraception during treatment with luspatercept-aamt and for at least 3 months after the last dose.

Based on findings in animals, luspatercept-aamt may impair female fertility. Adverse effects on fertility in female rats were reversible after a 14-week recovery period.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Based on findings in juvenile animals, luspatercept-aamt is not recommended for use in pediatric patients.

Geriatric Use

Clinical studies of luspatercept-aamt in beta thalassemia did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects.

Common Adverse Effects

The most common adverse reactions (>10%) in patients with beta thalassemia were headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, and dizziness.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

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

Advice to Patients

Discuss the following with patients prior to and during treatment with luspatercept-aamt.

Thromboembolic Events

Advise 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).

Effects on Blood Pressure

Caution patients that luspatercept-aamt may cause an increase in blood pressure.

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception while receiving luspatercept-aamt and for at least 3 months after the final dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with luspatercept-aamt.

Lactation

Advise females not to breastfeed during treatment with luspatercept-aamt and for 3 months after the final dose.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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