luspatercept (Rx)

Brand and Other Names:Reblozyl, luspatercept-aamt
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injection, lyophilized powder for reconstitution

  • 25mg/vial (single-dose)
  • 75mg/vial (single-dose)

Anemia Related Beta-Thalassemia

Erythroid maturation agent indicated for anemia in adults with beta thalassemia who require regular red blood cell (RBC) transfusions

Initial dose: 1 mg/kg once SC q3Weeks

Do not increase dose if an adverse reaction occurs

Titrate dose based on insufficient response

  • No reduction in RBC transfusion burden after at least 2 consecutive doses (6 weeks) at 1 mg/kg: Increase to 1.25 mg/kg q3Weeks
  • No reduction in RBC transfusion burden after 3 consecutive doses (9 weeks) at 1.25 mg/kg: Discontinue treatment

Dosage modifications for predose Hgb levels or rapid Hgb rise

  • Predose hemoglobin ≥11.5 g/dL in absence of transfusions: Interrupt dose; restart when Hgb ≤11 g/dL
  • Increased hemoglobin >2 g/dL within 3 weeks in absence of transfusions AND
    • Current dose is 1.25 mg/kg: Reduce to 1 mg/kg
    • Current dose is 1 mg/kg: Reduce to 0.8 mg/kg
    • Current dose is 0.8 mg/kg: Reduce to 0.6 mg/kg
    • Current dose is 0.6 mg/kg: Discontinue treatment

Anemia-related Myelodysplastic Syndromes

Indicated for treatment of anemia failing an erythropoiesis stimulating agent and requiring ≥2 RBC units over 8 weeks in adults 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)

Initial dose: 1 mg/kg once SC q3Weeks

Do not increase dose if an adverse reaction occurs

Titrate dose based on insufficient response

  • No reduction in RBC transfusion-free after at least 2 consecutive doses (6 weeks) at 1 mg/kg: Increase to 1.33 mg/kg q3Weeks
  • No reduction in RBC transfusion-free after at least 2 consecutive doses (6 weeks) at 1.33 mg/kg: Increase to 1.75 mg/kg q3Weeks
  • No reduction in RBC transfusion burden after 3 consecutive doses (9 weeks) at 1.75 mg/kg: Discontinue treatment

Dosage modifications for predose Hgb levels or rapid Hgb rise

  • Predose hemoglobin ≥11.5 g/dL in absence of transfusions: Interrupt dose; restart when Hgb ≤11 g/dL
  • Increase in hemoglobin >2 g/dL within 3 weeks in absence of transfusions AND
    • Current dose is 1.75 mg/kg: Reduce to 1.33 mg/kg
    • Current dose is 1.33 mg/kg: Reduce to 1 mg/kg
    • Current dose is 1 mg/kg: Reduce to 0.8 mg/kg
    • Current dose is 0.8 mg/kg: Reduce to 0.6 mg/kg
    • Current dose is 0.6 mg/kg: Discontinue treatment

Dosage Modifications

Dosage modifications for adverse reactions

  • Grade 3 or 4 hypersensitivity reactions: Discontinue treatment
  • Other Grade 3 or 4 adverse reactions: Interrupt treatment; restart when adverse reaction resolves to Grade ≤1
  • For MDS-RS or MDS/MPN-RS-T
    • If dose delay is >12 consecutive weeks, discontinue treatment

Hepatic impairment

  • Mild-to-severe (total bilirubin ≤ULN and AST or ALT >ULN, or total bilirubin >ULN and any AST or ALT): No clinically significant differences observed in pharmacokinetics of luspatercept
  • AST or ALT>3x ULN: Pharmacokinetics are unknown

Renal impairment

  • Mild-to-moderate (eGFR 30-89 mL/min/1.73m2): No clinically significant differences observed in pharmacokinetics of luspatercept
  • Severe (eGFR <30 mL/min/1.73m2): Pharmacokinetics are unknown

Dosing Considerations

Assess and review hemoglobin (Hgb) before each administration

If an RBC transfusion occurred before dosing, use the pretransfusion hemoglobin to evaluate dose

Limitation of use

  • Not for use as substitute for RBC transfusions in patients requiring immediate correction of anemia

Safety and efficacy not established

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Interactions

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            Adverse Effects

            >10% (Beta Thalassemia)

            All grades

            • Total bilirubin ≥2x ULN (64%)
            • Headache (26%)
            • Musculoskeletal
            • Bone pain (20%)
            • Arthralgia (19%)
            • Fatigue (14%)
            • Abdominal pain (14%)
            • Cough (14%)
            • Diarrhea (12%)
            • ALT or AST ≥3x ULN (11-12%)
            • Dizziness (11%)

            >10% (MDS-RS or MDS/MPN-RS-T)

            All grades

            • Fatigue (41%)
            • Reduced creatinine clearance (27%)
            • Musculoskeletal pain (20%)
            • Dizziness/vertigo (18%)
            • Nausea (16%)
            • Diarrhea (16%)
            • Headache (14%)
            • Dyspnea (13%)
            • Total bilirubin elevated (12%)

            1-10% (Beta Thalassemia)

            All grades

            • Nausea (9%)
            • Hypertension (8%)
            • Alkaline phosphatase (ALP) ≥2x ULN (8%)
            • Hyperuricemia (7%)
            • Direct bilirubin ≥2x ULN (6%)

            Grade 3 or 4

            • Hyperuricemia (3%)
            • Hypertension (2%)

            1-10% (MDS-RS or MDS/MPN-RS-T)

            All grades

            • Hypersensitivity reactions (10%)
            • ALT elevated (9%)
            • Renal impairment (8%)
            • Tachycardia (8%)
            • Injection site reactions (7%)
            • Upper respiratory tract infection (7%)
            • Influenza/influenza like illness (6%)
            • AST elevated (4%)

            Grade 3 or 4

            • Fatigue (7%)
            • Renal impairment (2%)
            • Dyspnea (1%)

            <1% (Beta Thalassemia)

            Grade 3 or 4

            • Diarrhea
            • Headache

            <1% (MDS-RS or MDS/MPN-RS-T)

            Grade 3 or 4

            • Upper respiratory tract infection
            • Hypersensitivity reactions
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            Warnings

            Contraindications

            None

            Cautions

            Increased risk of thrombosis/thromboembolism in patients with beta thalassemia; patients with known risk factors for thromboembolism, eg, splenectomy or concomitant use of hormone replacement therapy, may be at further increased risk; consider thromboprophylaxis in patients with beta thalassemia at increased risk;.monitor for signs and symptoms of and institute treatment promptly

            Monitor for hypertension; monitor blood pressure prior to each administration; manage new-onset hypertension or exacerbations of preexisting hypertension using anti-hypertensive agents

            May cause fetal harm; advise females of reproductive potential of potential risk to fetus and use of effective contraception

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            Pregnancy & Lactation

            Pregnancy

            There are no available data on drug use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes

            Pregnancy testing recommended for females of reproductive potential before starting treatment

            Animal data

            • Based on findings in animal reproduction studies, therapy may cause fetal harm when administered to a pregnant woman; in animal reproduction studies, administration to pregnant rats and rabbits during the period of organogenesis resulted in adverse developmental outcomes, including embryofetal mortality, alterations to growth, and structural abnormalities at exposures 13 times (rats) and 18 times (rabbits) of maximum recommended human dose (MRHD); advise pregnant women of potential risk to a fetus

            Contraception

            • Females of reproductive potential: Use effective contraception during treatment and for at least 3 months after last dose; may cause embryofetal harm when administered to pregnant women

            Infertility

            • Females: Based on findings in animals, therapy may impair female fertility; adverse effects on fertility in female rats were reversible after a 14-week recovery period

            Lactation

            Luspatercept-aamt was detected in milk of lactating rats

            When a drug is present in animal milk, it is likely the drug will be present in human milk

            There are no data on the presence of luspatercept in human milk, the effects on the breastfed child, or the effects on milk production

            Owing to the potential for serious adverse reactions in the breastfed child, advise that breastfeeding is not recommended during treatment and for 3 months after the last dose

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Drug is a recombinant fusion protein that diminishes Smad2/3 signaling by binding several endogenous TGF-β superfamily ligands

            In a model of beta thalassemia, drug decreased abnormally elevated Smad2/3 signaling and improved hematology parameters associated with ineffective erythropoiesis in mice

            Treatment promoted erythroid maturation through differentiation of late-stage erythroid precursors (normoblasts) in mice

            Absorption

            AUC in patients with beta thalassemia: 126 day·mcg/mL (1 mg/kg); 157 day·mcg/mL (1.25 mg/kg)

            Peak plasma concentration at steady-state in patients with beta thalassemia: 8.17 mcg/mL (1 mg/kg); 10.2 mcg/mL (1.25 mg/kg)

            Peak plasma time: 7 days post dose in healthy patients and patients with beta thalassemia

            Steady-state was achieved after 3 doses when administered every 3 weeks

            Absorption of luspatercept-aamt was not significantly affected by SC injection sites (eg, upper arm, thigh, abdomen)

            Distribution

            Vd: 7.1 L

            Metabolism

            Catabolized into amino acids by general protein degradation processes in multiple tissues

            Elimination

            Half-life: ~11 days

            Clearance: 0.44 L/day

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            Administration

            SC Preparation

            Reconstitute vial with 0.68 mL (25-mg vial) or 1.6 mL (75-mg vial) of Sterile Water for Injection (final concentration of 50 mg/mL); allow reconstituted vial to stand for 1 min

            Do use the needle and syringe for reconstitution for SC injections

            Gently swirl vial in circular motion for 30 seconds; stop swirling and allow vial to sit in upright position for 30 seconds

            Inspect vial for undissolved particles in solution; repeat above step if undissolved powder observed

            Invert vial and gently swirl for 30 seconds; bring the vial back to upright position, and let it sit for 30 seconds; repeat 7 more times to ensure complete reconstitution

            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.

            SC Administration

            Calculate exact total dosing volume of 50 mg/mL solution required for patient

            If reconstituted vial was refrigerated, remove from refrigeration 15-30 min prior to injection to allow solution to reach room temperature for a more comfortable injection

            Slowly withdraw dosing volume of reconstituted solution from single-dose vial(s) into a syringe

            Divide doses requiring larger reconstituted volumes (ie, >1.2 mL) into separate similar volume injections and inject into separate sites; if multiple injections required, use a new syringe and needle for each SC injection

            Administer SC injection into upper arm, thigh, and/or abdomen

            Missed or delayed dose: Administer dose as soon as possible and continue dosing as prescribed, with at least 3 weeks between doses

            Storage

            Unused vials: Refrigerate at 2-8ºC (36-46ºF) in original carton to protect from light; do not freeze

            Reconstituted solution

            • Store at room temperature at 20-25ºC (68-77ºF) for up to 8 hours; discard if not used within 8 hr of reconstitution
            • Alternatively, refrigerate at 2-8ºC (36-46ºF) for up to 24 hr; discard if not used within 24 hr of reconstitution
            • Do not freeze
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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.