Reblozyl
(luspatercept-aamt)Dosage & Administration
Reblozyl Prescribing Information
Beta Thalassemia
REBLOZYL is indicated for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions.
1.2 Myelodysplastic Syndromes Associated Anemia
REBLOZYL is indicated for the treatment of anemia without previous erythropoiesis stimulating agent use (ESA-naïve) in adult patients with very low- to intermediate-risk myelodysplastic syndromes (MDS) who may require regular red blood cell (RBC) transfusions.
Myelodysplastic 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 2 or more red blood cell units over 8 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).
Limitations of Use
REBLOZYL is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.
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 a patient does not experience a decrease in transfusion burden after 9 weeks of treatment (administration of 3 doses) at the maximum dose level or if unacceptable toxicity occurs at any time.
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.
If a patient does not achieve a reduction in RBC transfusion burden after at least 2 consecutive doses (6 weeks) at the 1 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 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.
Dose level modifications for response are provided in Table 1.
| * Do not increase the dose if the patient is experiencing an adverse reaction as described in Table 2. | |
| REBLOZYL |
Starting Dose |
|
Dose Increases for Insufficient Response at Initiation of Treatment | |
No reduction in RBC transfusion burden after at least 2 consecutive doses (6 weeks) at the 1 mg/kg starting dose |
|
No reduction in RBC transfusion burden after 3 consecutive doses (9 weeks) at 1.25 mg/kg |
|
Dose Modifications for Predose Hemoglobin Levels or Rapid Hemoglobin Rise | |
Predose hemoglobin is greater than or equal to 11.5 g/dL in the absence of transfusions |
|
Increase in hemoglobin greater than 2 g/dL within 3 weeks in the absence of transfusions and
|
|
Dose Modifications for Toxicity
For patients experiencing Grade 3 or higher adverse reactions, modify treatment as described in Table 2.
| * Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, and Grade 4 is life-threatening. | |
| REBLOZYL |
Grade 3 or 4 hypersensitivity reactions |
|
Other Grade 3 or 4 adverse reactions |
|
Extramedullary hematopoietic (EMH) masses causing serious complications |
|
2.2 Recommended Dosage for Myelodysplastic Syndromes Associated Anemia
The recommended starting dosage of REBLOZYL is 1 mg/kg once every 3 weeks by subcutaneous injection for the treatment of anemia of MDS. Prior to each REBLOZYL dose, review the patient’s 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 a patient does not experience a decrease in transfusion burden including no increase from baseline hemoglobin after 9 weeks of treatment (administration of 3 doses) at the maximum dose level (1.75 mg/kg), or if unacceptable toxicity occurs at any time.
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.
If a patient is not RBC transfusion-free after at least 2 consecutive doses (6 weeks) at the 1 mg/kg starting dose, increase the REBLOZYL dose to 1.33 mg/kg (Table 3). If a patient is not RBC transfusion-free after at least 2 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 6 weeks (2 doses) or beyond the maximum dose of 1.75 mg/kg.
In the absence of transfusions, if hemoglobin increase is greater than 2 g/dL within 3 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 a transfusion) or hemoglobin concentration drops by 1 g/dL or more in 3 weeks in the absence of transfusion, increase the dose by one dose level. Wait a minimum of 6 weeks between dose increases.
Dose modifications for response are provided in Table 3.
| * Do not increase the dose if the patient is experiencing an adverse reaction as described in Table 4. | |
| REBLOZYL |
Starting Dose |
|
Dose Increases for Insufficient Response at Initiation of Treatment | |
Not RBC transfusion-free after at least 2 consecutive doses (6 weeks) at the 1 mg/kg starting dose |
|
Not RBC transfusion-free after at least 2 consecutive doses (6 weeks) at 1.33 mg/kg |
|
No reduction in RBC transfusion burden including no increase from baseline hemoglobin after at least 3 consecutive doses (9 weeks) at 1.75 mg/kg |
|
Dose Modifications for Predose Hemoglobin Levels or Rapid Hemoglobin Rise | |
Predose hemoglobin is greater than or equal to 11.5 g/dL in the absence of transfusions |
|
Increase in hemoglobin greater than 2 g/dL within 3 weeks in the absence of transfusions and
|
|
Dose Modifications for Toxicity
For patients experiencing Grade 3 or higher adverse reactions, modify treatment as described in Table 4.
| * Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, and Grade 4 is life-threatening. **Per Table 3 dose reductions above. | |
| REBLOZYL |
Grade 3 or 4 hypersensitivity reactions |
|
Other Grade 3 or 4 adverse reactions |
|
Preparation and Administration
REBLOZYL should be reconstituted and administered by a healthcare professional.
Reconstitute REBLOZYL with Sterile Water for Injection, USP only.
| Vial Size | Amount of Sterile Water for Injection, USP required for reconstitution | Final Concentration | Deliverable Volume |
|---|---|---|---|
25 mg vial | 0.68 mL | 25 mg/0.5 mL (50 mg/mL) | 0.5 mL |
75 mg vial | 1.6 mL | 75 mg/1.5 mL | 1.5 mL |
(50 mg/mL) |
Reconstitute the number of REBLOZYL vials to achieve the appropriate dose based on the patient’s weight. Use a syringe with suitable graduations for reconstitution to ensure accurate dosage.
Reconstitution Instructions
- 1.
- Reconstitute with Sterile Water for Injection, USP using volumes described in Table 5 (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 a 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 3 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 5 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 a 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:
- •
- Store at room temperature at 20°C to 25°C (68°F to 77°F) in the original vial for up to 8 hours. Discard if not used within 8 hours of reconstitution.
- •
- Alternatively, store refrigerated at 2°C to 8°C (36°F to 46°F) 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 a more comfortable injection. Discard if not used within 24 hours of reconstitution.
- •
- Do not freeze the reconstituted solution.
Discard any unused portion. Do not pool unused portions from the vials. Do not administer more than 1 dose from a vial. Do not mix with other medications.
Instructions for Subcutaneous Administration
Calculate 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 a 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 a new syringe and needle for each subcutaneous injection.
Administer the injection subcutaneously into the upper arm, thigh, and/or abdomen.
- •
- For injection: 25 mg white to off-white lyophilized powder in a single-dose vial for reconstitution.
- •
- For injection: 75 mg white to off-white lyophilized powder in a single-dose vial for reconstitution.
Pregnancy
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.
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 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.
Females and Males of Reproductive Potential
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 ]. 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 ]. 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, REBLOZYL is not recommended for use in pediatric patients [see Non-Clinical Toxicology ].
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 ESA-naïve and ESA-refractory or -intolerant MDS included 347 (82%) patients ≥ 65 years of age and 167 (39%) patients ≥ 75 years of age. No differences in safety or effectiveness were observed between older (≥ 65 years) and younger patients.
None.
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 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 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 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 ].