Reblozyl

Reblozyl was approved by the U.S. Food and Drug Administration (FDA) in November 2019 and April 2020 respectively: (1) for the treatment of anemia in adult patients with beta-thalassemia who require regular red blood cell transfusions; (2) for the treatment of failure of an erythropoiesis stimulating agent and the need for the transfusion of ≥ 2 red blood cells within 8 weeks (RBC) unit, treatment of anemia in adults with very low to intermediate risk myelodysplastic syndrome (MDS-RS) with ringed sideroblasts (RS) on bone marrow smear or myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN-RS-T) with ringed sideroblasts and thrombocythemia on bone marrow smear.

Reblozyl is the first and only FDA-approved red blood cell maturation agent that helps patients reduce the burden of red blood cell transfusion by regulating the late stages of red blood cell maturation.

[Specification]: 25mg/75mg; freeze-dried powder

[Trademark]: Reblozyl

[Common name]: Luspatercept-aamt

[Storage]

Store the vial containing the drug at 2°C to 8°C and do not freeze it. Store in original carton to protect from light. If not used immediately, solutions for reconstitution can be stored (in original vials) at 20°C to 25°C for up to 8 hours, or at 2°C to 8°C for up to 24 hours; if not used within these time frames, discard. Do not freeze solutions for reconstitution.

[Reblozyl indications]

Reblozyl can be used to treat anemia in adult patients with beta-thalassemia who require regular red blood cell transfusions; it can also be used to treat anemia in adult patients who have failed treatment with an erythropoiesis stimulating agent and require the transfusion of ≥ 2 red blood cells within 8 weeks. Treatment of anemia in adults with RBC units, very low to intermediate risk myelodysplastic syndrome (MDS-RS) with ringed sideroblasts (RS) on bone marrow smear, or myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN-RS-T) with ringed sideroblasts and thrombocythemia on bone marrow smear.

[Reblozyl Recommended Dosage and Administration]

Usage and Dosage

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

Recheck hemoglobin (Hgb) results before each dose.

Important Dosing Information

Before using Reblozyl, tell your doctor about any medical conditions or allergies you have, all the drugs you use, and whether you are pregnant or breastfeeding.

Tell your doctor if you have: had spleen removal surgery; had a stroke; have high blood pressure; have high cholesterol; have diabetes; if you smoke; if you use birth control pills or hormone replacement therapy.

If you are pregnant or may become pregnant, tell your doctor, Reblozyl may harm an unborn baby. Use effective birth control to prevent pregnancy while using Reblozyl and for at least 3 months after the last dose. Do not breastfeed while using Reblozyl and for at least 3 months after the last dose.

How to take the drug

Reblozyl is administered by subcutaneous injection, usually once every 3 weeks, by medical staff. Before each injection, a blood test will be needed to check your hemoglobin levels. Be sure to tell your doctor when you had your last blood transfusion. Reblozyl dosage is based on body weight, and your dosage needs may change if you gain or lose weight. Your blood pressure will need to be checked frequently, and you may need other medicines to help control it. Keep using Reblozyl for as long as your doctor prescribes it.

Reconstitution: Reconstitute with 0.68 mL (25 mg specification) or 1.6 mL (75 mg specification) sterile water for injection. The final concentration is 25 mg/0.5 mL or 75 mg/1.5 mL respectively. Add water directly to the lyophilized powder and let sit for 1 minute; discard needle and syringe used for reconstitution. Gently rotate the bottle (in a circular motion) for 30 seconds, then hold the bottle upright for another 30 seconds. If there is still undissolved powder, repeat the above steps until the powder is completely dissolved. Invert the vial and gently rotate (invert it) for 30 seconds, then leave the vial upright for 30 seconds. Repeat the anti-spin step 7 more times to allow for complete reconstitution. The reconstituted solution is colorless to slightly yellow, clear to slightly milky white. If the reconstituted solution is refrigerated, let it sit at room temperature for 15 to 30 minutes before injection. Do not collect unused medication from the vial; do not mix with other medications.

Administration: Inject into the upper arm, thigh, and/or abdomen. Doses requiring larger administration volumes (>1.2 mL) should be divided into separate syringes of similar volume and injected into different sites. Use a new syringe and needle for each individual injection. If refrigerated, allow reconstituted solution to stand at room temperature for 15 to 30 minutes before injection.

Missed dose: If a dose is delayed or missed, administer the dose as soon as possible and continue with your regular dosing schedule (at least 3 weeks between doses).

Because Reblozyl is administered by medical staff in a medical facility, overdose is unlikely.

You should follow your doctor's instructions about food, drink, or activity restrictions while receiving Reblozyl.

[Warnings and Precautions for Reblozyl]

Hypertension: Hypertension, including Grade 3 and 4 adverse reactions, has been reported. Some patients with baseline normal blood pressure develop elevated systolic blood pressure (≥130 mmHg) and/or diastolic blood pressure (≥80 mmHg). Monitor blood pressure before each dose and as clinically necessary. Control new or worsening pre-existing hypertension with appropriate antihypertensive therapy.

Musculoskeletal Adverse Reactions: In clinical trials, approximately 20% of patients treated with Reblozyl reported bone and joint pain, although most events were mild (Grade 1 or 2).

Thromboembolic events: Thromboembolic events, including deep vein thrombosis, pulmonary embolism, portal vein thrombosis, and ischemic stroke, have been reported in a small number of beta-thalassemia patients receiving Reblozyl in clinical trials. Patients with thromboembolic risk factors, such as splenectomy or concomitant use of hormone replacement therapy, may be at increased risk of thromboembolic events. Monitor for signs/symptoms of thrombosis/thromboembolism. Thromboprophylaxis may be considered in patients at increased risk for thromboembolic events.

Polysorbate 80: Some dosage forms may contain polysorbate 80 (also called Tween). Allergic reactions, usually delayed reactions, have been reported in some people after exposure to pharmaceutical products containing polysorbate 80. Thrombocytopenia, ascites, pulmonary exacerbation, renal failure, and hepatic failure have been reported in premature infants receiving parenteral products containing polysorbate 80.

[Reblozyl Monitoring Indicators]

Assess hemoglobin before each dose of Reblozyl; assess pregnancy status (in females of reproductive potential) before initiating dosing; monitor blood pressure before each dose as clinically indicated; monitor for signs/symptoms of thromboembolism.

[Adverse Reactions to Reblozyl]

Although it may be rare, some people may experience serious and sometimes fatal side effects when taking the drug. If you have any of the following signs or symptoms that may be associated with very serious side effects, tell your doctor or get medical help right away:

Signs of an allergic reaction, such as rash; hives; itching; redness, swelling, blistering, or peeling of warm or non-warm skin; wheezing; chest tightness or tightness in the throat; difficulty breathing, swallowing, or speaking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat. Signs of high blood pressure, such as very severe headache or dizziness, fainting, or changes in vision. Weakness on one side of the body, difficulty speaking or thinking, changes in balance, drooping of one side of the face, or blurred vision. Contact your doctor right away if you have signs of a blood clot such as chest pain; cough up blood; have shortness of breath; have swelling, warmth, numbness, discoloration, or pain in your legs or arms; or have trouble speaking or swallowing. High uric acid levels may occur with this drug. If you have joint pain, swelling, or stiffness, contact your doctor immediately.

Other side effects: Many people will not experience the side effects listed below or the side effects will be very small. Contact your doctor or get medical help if these or any other side effects bother you or persist: headache; bone pain; joint pain; feeling dizzy, tired, or weak; cough; stomach pain or diarrhea; upset stomach; flu-like symptoms; signs of the common cold.

These are not all possible side effects. If you have questions about side effects, call your doctor.

[Reblozyl use in special populations]

Reproductive considerations

Assess pregnancy status before using Reblozyl in women of reproductive potential. Females of reproductive potential should use effective contraception during Reblozyl treatment and for ≥3 months after the last Reblozyl dose.

Pregnancy

Based on data from animal reproduction studies, in utero exposure to Reblozyl may cause fetal harm. Animal studies have shown that use of this drug may cause fetal harm; administration during organogenesis can cause adverse developmental outcomes and embryo-fetal mortality, growth changes, and structural abnormalities in excess of the maximum recommended human dose. This drug may impair female fertility; the effects on fertility are reversible after a 14-week recovery period. The background risk of birth defects and miscarriage in a given population is unknown. In the general U.S. population, the risk of major birth defects is estimated to be 2% to 4%, and the risk of miscarriage is 15% to 20%. Inform pregnant women of potential risks to the fetus. Females of reproductive potential should use an effective method of contraception during treatment and for 3 months after the last dose. It is recommended that females of reproductive potential undergo a pregnancy test before treatment with this drug.

Breastfeeding

Breastfeeding is not recommended while using this drug. There is no information available about the presence of this drug in breast milk, the effects on the breastfed infant, or the effects on milk production. Breastfeeding is not recommended while using this drug or for 3 months after the last dose.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Based on findings in young animals, the use of Reblozyl in pediatric patients is not recommended.

Geriatric Use

Clinical studies of Reblozyl for beta thalassemia did not include a sufficient number of subjects aged 65 and older to determine whether they responded differently than younger subjects.

[Drug Interactions]

Sunosi (solriamfetol) may enhance the hypertensive effects of hypertension-related drugs. Other drugs may also affect Reblozyl, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about your current medications and any medications you start or stop using.

[General description of Reblozyl]

Luspatercept-aamt is a erythrocyte maturation agent, a receptor fusion protein, consisting of a modified human activin receptor type IIB extracellular domain, which is connected to the human IgG1 Fc domain, with a calculated molecular weight of approximately 76 kD. Luspatercept is produced in Chinese hamster ovary cells using recombinant DNA technology.

Reblozyl properties and prescription composition

REBLOZYL (luspatercept-aamt) for injection is a sterile, preservative-free white to off-white lyophilized powder in single-dose vials for subcutaneous injection after reconstitution.

Each 25 mg single-dose vial contains 25 mg of Luspatercept-aamt at pH 6.5 and citric acid monohydrate (0.085 mg), polysorbate 80 (0.10 mg), sucrose (45.0 mg), and trisodium citrate dihydrate (1.35 mg). After reconstitution with 0.68 mL of sterile water for injection, the resulting concentration is 25 mg/0.5 mL of drug, and the injection volume is 0.5 mL.

Each 75 mg single-dose vial contains 75 mg of Luspatercept-aamt at pH 6.5 and citric acid monohydrate (0.254 mg), polysorbate 80 (0.30 mg), sucrose (135 mg), and trisodium citrate dihydrate (4.06 mg). After reconstitution with 1.6 mL of sterile water for injection, the resulting concentration of Luspatercept-aamt was 75 mg/1.5 mL (50 mg/mL), with an injection volume of 1.5 mL.

Mechanism of action

Luspatercept-aamt is a recombinant fusion protein that binds several endogenous TGF-β superfamily ligands, thereby downregulating Smad2/3 signaling. Luspatercept-aamt promotes erythroid maturation through differentiation of late erythroid precursor cells in mice. In a beta-thalassemia model, Luspatercept-aamt reduced abnormally elevated Smad2/3 signaling associated with ineffective erythropoiesis in mice and improved hematological parameters.