REBLOZYL Powder for solution for injection / infusion Ref.[10138] Active ingredients: Luspatercept

5.1 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.

5.2 Hypertension

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 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)].

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)]

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 × 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:

* Limited to Grade 3 reactions with the exception of 4 events of Grade 4 hyperuricemia.
^† Grouped term includes abdominal pain and abdominal pain upper.
^‡ Grouped term includes essential hypertension, hypertension, and hypertensive crisis.

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 Trial:

ALP = alkaline phosphatase; ALT = alanine aminotransferase;
AST = aspartate aminotransferase; ULN = upper limit of normal.

Myelodysplastic Syndromes with Ring Sideroblasts or Myelodysplastic / Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis Associated Anemia

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). 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 8 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 (14.2)].

Table 8. Adverse Reactions (≥5%) in Patients Receiving REBLOZYL with a Difference Between Arms of >2% in MEDALIST Trial Through Cycle 8:

* Includes asthenic conditions.
^† Reaction includes similar/grouped terms.

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 9.

Table 9. Selected Grades 2-4 Treatment-Emergent Laboratory Abnormalities Through Cycle 8 in the MEDALIST Trial:

ALT = alanine aminotransferase; AST = aspartate aminotransferase.
* Number of patients at Grades 0-1 at baseline.

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, 4 patients (1.4%) tested positive for treatment-emergent anti-luspatercept-aamt antibodies, including 2 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 9 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.

Risk Summary

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

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

Data

Animal Data

In embryo-fetal development studies, luspatercept-aamt was administered subcutaneously at 5, 15, or 30 mg/kg on gestation days 3 and 10 (rats) or 5, 20, or 40 mg/kg on gestation days 4 and 11 (rabbits). Effects in both species included reductions in numbers of live fetuses and fetal body weights, and increases in resorptions, post-implantation losses, and skeletal variations (such as asymmetric sternal centra in rats and angulated hyoid in rabbits). Effects were observed at exposures (based on AUC) approximately 7-times (rats) and 16-times (rabbits) the MRHD of 1.75 mg/kg.

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

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 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 3 months after the last dose.

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential before starting REBLOZYL treatment.

Contraception

Females

REBLOZYL 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 3 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 a 14-week recovery period.

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 Non-Clinical Toxicology (13.1)].

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.