1 INDICATIONS AND USAGE

1.1 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.

1.3 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).

1.4 Limitations of Use

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

2 DOSAGE AND ADMINISTRATION

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 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.

1 mg/kg every 3 weeks

Increase the dose to 1.25 mg/kg every 3 weeks

Discontinue treatment

Interrupt treatment

Restart when the hemoglobin is no more than 11 g/dL

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.

Discontinue treatment

Interrupt treatment

Restart when the adverse reaction resolves to no more than Grade 1

Discontinue treatment

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.

1 mg/kg every 3 weeks

Increase the dose to 1.33 mg/kg every 3 weeks

Increase the dose to 1.75 mg/kg every 3 weeks

Discontinue treatment

Interrupt treatment

Restart when the hemoglobin is no more than 11 g/dL

current dose is 1.75 mg/kg

current dose is 1.33 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 1.33 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 4.

Discontinue treatment

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 > 12 consecutive weeks, discontinue treatment

2.3 Preparation and Administration

REBLOZYL should be reconstituted and administered by a healthcare professional.

Reconstitute REBLOZYL with Sterile Water for Injection, USP only.

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

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.

Discard the needle and syringe used for reconstitution. The needle and syringe used for reconstitution should not be used for subcutaneous injections.

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.

Inspect the vial for undissolved particles in the solution. If undissolved powder is observed, repeat step 3 until the powder is completely dissolved.

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.

Repeat step 5 seven more times to ensure complete reconstitution of material on the sides of the vial.

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.

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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or mutagenicity studies have been conducted with luspatercept-aamt.

In a repeat-dose toxicity study, juvenile rats were administered luspatercept- aamt subcutaneously at 1, 3, or 10 mg/kg once every 2 weeks from postnatal day 7 to 91. Hematologic malignancies (granulocytic leukemia, lymphocytic leukemia, malignant lymphoma) were observed at 10 mg/kg resulting in exposures (based on area under the curve [AUC]) approximately 4.4 times the maximum recommended human dose (MRHD) of 1.75 mg/kg.

In a combined male and female fertility and early embryonic development study in rats, luspatercept-aamt was administered subcutaneously to animals at doses of 1 to 15 mg/kg. There were significant reductions in the average numbers of corpora lutea, implantations, and viable embryos in luspatercept-aamt-treated females. Effects on female fertility were observed at the highest dose with exposures (based on AUC) approximately 7-times the MRHD of 1.75 mg/kg. Adverse effects on fertility in female rats were reversible after a 14-week recovery period. No adverse effects were noted in male rats.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

REBLOZYL contains luspatercept-aamt, which is not a controlled substance.

9.2 Abuse

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Abuse of REBLOZYL may be seen in athletes for the effects on erythropoiesis to enhance athletic performance. Abuse of drugs that increase erythropoiesis, such as REBLOZYL, by healthy persons may lead to polycythemia, which may be associated with life- threatening cardiovascular complications (e.g., stroke, myocardial infarction, and thromboembolism).

Luspatercept-aamt and its metabolites neither selectively penetrate the central nervous system, nor produce behavioral effects in animals that are consistent with central nervous system activity.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

REBLOZYL (luspatercept-aamt) for injection is a white to off-white lyophilized powder supplied in a single-dose vial. Each carton contains one vial.

REBLOZYL 25 mg/vial (NDC 59572-711-01)
REBLOZYL 75 mg/vial (NDC 59572-775-01)

16.2 Storage

Store vials refrigerated at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze.

17 PATIENT COUNSELING INFORMATION

Discuss the following with patients prior to and during treatment with REBLOZYL.

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) [see Warnings and Precautions (5.1)].

Effects on Blood Pressure

Caution patients that REBLOZYL may cause an increase in blood pressure [see Warnings and Precautions (5.2)].

Extramedullary Hematopoietic Masses

Advise patients with beta thalassemia of the potential risk of extramedullary hematopoietic masses. Review possible risk factors for developing extramedullary hematopoietic masses. Instruct patients to report possible signs and symptoms of EMH masses [see Warnings and Precautions (5.3)].

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 REBLOZYL 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 REBLOZYL [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)].

Lactation

Advise females not to breastfeed during treatment with REBLOZYL and for 3 months after the final dose [see Use in Specific Populations (8.2)].

Manufactured by:
Celgene Corporation, a Bristol-Myers Squibb Company
86 Morris Avenue
Summit, NJ 07901
U.S. License No. 2252

REBLOZYL® is a registered trademark of Celgene Corporation, a Bristol-Myers Squibb Company.

REBPI.006

beta thalassemia who need regular red blood cell (RBC) transfusions.

myelodysplastic syndromes who may need regular RBC transfusions and have never received an erythropoiesis stimulating agent (ESA).

myelodysplastic syndromes with ring sideroblasts (MDS-RS) or myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) who need 2 or more RBC units over 8 weeks and have not responded well to an ESA.

have or have had blood clots 

take hormone replacement therapy or birth control pills (oral contraceptives) 

have had your spleen removed (splenectomy)

smoke

have or have had high blood pressure (hypertension)

have a history of extramedullary hematopoietic (EMH) masses

have or have had enlarged spleen or liver

are pregnant or plan to become pregnant. REBLOZYL may harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with REBLOZYL.  

Your healthcare provider should do a pregnancy test before you start treatment with REBLOZYL.

You should use effective birth control (contraception) during treatment with REBLOZYL and for at least 3 months after the last dose.

are breastfeeding or plan to breastfeed. It is not known if REBLOZYL passes into your breast milk.

Do not breastfeed during treatment with REBLOZYL and for 3 months after the last dose. Talk to your healthcare provider about the best way to feed your baby during this time.

Your healthcare provider will prescribe REBLOZYL in a dose that is right for you. Depending on how you respond to REBLOZYL, your healthcare provider may adjust your dose or stop treatment.

REBLOZYL is given as an injection under your skin (subcutaneous) in the upper arm, thigh, or stomach (abdomen) by your healthcare provider. 

Your healthcare provider will do regular blood tests to check your hemoglobin to monitor if your anemia is getting better before each injection and during your treatment with REBLOZYL.

**Blood clots.** Blood clots in the arteries, veins, brain, and lungs have happened in people with beta thalassemia during treatment with REBLOZYL. The risk of blood clots may be higher in people who have had their spleen removed or who take hormone replacement therapy or birth control (oral contraceptives). Call your healthcare provider or get medical help right away if you get any of these symptoms:

chest pain

trouble breathing or shortness of breath

pain in your leg, with or without swelling

a cold or pale arm or leg

sudden numbness or weakness that are both short-term or continue to happen over a long period of time, especially on one side of the body

severe headache or confusion

sudden problems with vision, speech, or balance (such as trouble speaking, difficulty walking, or dizziness)

**High blood pressure.** REBLOZYL may cause an increase in your blood pressure. Your healthcare provider will check your blood pressure before you receive your REBLOZYL dose. Your healthcare provider may prescribe you medicine to treat high blood pressure or increase the dose of medicine you already take to treat high blood pressure if you develop high blood pressure during treatment with REBLOZYL.

**Extramedullary Hematopoietic (EMH) Masses.** EMH masses have happened in people with beta thalassemia during treatment with REBLOZYL. You may have a higher risk for developing EMH masses if you have a history of EMH masses, have had your spleen removed, have or have had an enlarged spleen or liver, or have low hemoglobin levels. Your healthcare provider will monitor you before you start and during treatment with REBLOZYL. Call your healthcare provider or get medical help right away if you get any of these symptoms:

severe pain in the back

numbness, weakness, or loss of voluntary movement in feet, legs, hands, or arms

loss of bowel and bladder control

tiredness

headache

back, joint, muscle, or bone pain

joint pain

dizziness

nausea

diarrhea

cough

stomach (abdominal) pain

trouble breathing

swelling of your hands, legs, or feet

high blood pressure

allergic reactions

This Patient Information has been approved by the U.S. Food and Drug Administration

Revised: August 2023