Version May 2024
Note: Assess Hb and transfusion history prior to each dose. If an RBC transfusion occurred prior to the dose, use pretransfusion Hb for dosing evaluation purposes.
Anemia due to beta thalassemia: Note: Avoid use in patients requiring treatment to control the growth of extramedullary hematopoietic (EMH) masses. Thromboprophylaxis may be considered in patients with beta thalassemia who have elevated risk for thromboembolic events.
SUBQ: Initial: 1 mg/kg once every 3 weeks (Ref).
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Luspatercept Dosing Recommendationa | |
|---|---|
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a Do not increase the dose if patient is experiencing an adverse reaction. | |
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Starting dose |
1 mg/kg once every 3 weeks. |
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Maximum dose |
1.25 mg/kg once every 3 weeks. |
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Dose increases for insufficient response at initiation of treatment | |
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No reduction in RBC transfusion burden after ≥2 consecutive doses (6 weeks) at the 1 mg/kg starting dose |
Increase the dose to 1.25 mg/kg once every 3 weeks (maximum dose). |
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No reduction in RBC transfusion burden after 3 consecutive doses (9 weeks) at 1.25 mg/kg |
Discontinue luspatercept. |
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Dose modifications for predose hemoglobin levels or rapid hemoglobin rise | |
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Predose hemoglobin ≥11.5 g/dL (in the absence of transfusions): Interrupt luspatercept; resume when hemoglobin is ≤11 g/dL. | |
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Increase in hemoglobin >2 g/dL within 3 weeks (in the absence of transfusions) and Current dose is 1.25 mg/kg: Reduce dose to 1 mg/kg once every 3 weeks Current dose is 1 mg/kg: Reduce dose to 0.8 mg/kg once every 3 weeks Current dose is 0.8 mg/kg: Reduce dose to 0.6 mg/kg once every 3 weeks Current dose is 0.6 mg/kg: Discontinue luspatercept | |
Anemia due to myelodysplastic syndromes: Note: The table below contains dose titration for both erythropoiesis-stimulating agent–naive and erythropoiesis-stimulating agent–refractory myelodysplastic syndromes (MDS).
Anemia due to myelodysplastic syndromes , erythropoiesis-stimulating agent–naive: SUBQ: Initial: 1 mg/kg once every 3 weeks (Ref).
Anemia due to myelodysplastic syndromes with ring sideroblasts or myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis, erythropoiesis-stimulating agent–refractory: SUBQ: Initial: 1 mg/kg once every 3 weeks (Ref).
|
Luspatercept Dosing Recommendationa | |
|---|---|
|
a Do not increase the dose if patient is experiencing an adverse reaction. | |
|
Starting dose |
1 mg/kg once every 3 weeks. |
|
Maximum dose |
1.75 mg/kg once every 3 weeks. |
|
Dose increases for insufficient response at initiation of treatment | |
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Not RBC transfusion-free after ≥2 consecutive doses (6 weeks) at the 1 mg/kg starting dose |
Increase the dose to 1.33 mg/kg once every 3 weeks. |
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Not RBC transfusion-free after ≥2 consecutive doses (6 weeks) at 1.33 mg/kg dose |
Increase the dose to 1.75 mg/kg once every 3 weeks (maximum dose). |
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No reduction in RBC transfusion burden (including no increase from baseline hemoglobin) after ≥3 consecutive doses (9 weeks) at 1.75 mg/kg |
Discontinue luspatercept. |
|
Dose modifications for predose hemoglobin levels or rapid hemoglobin rise | |
|
Predose hemoglobin ≥11.5 g/dL (in the absence of transfusions): Interrupt luspatercept; resume when hemoglobin is ≤11 g/dL. | |
|
Increase in hemoglobin >2 g/dL within 3 weeks (in the absence of transfusions) and Current dose is 1.75 mg/kg: Reduce dose to 1.33 mg/kg once every 3 weeks. Current dose is 1.33 mg/kg: Reduce dose to 1 mg/kg once every 3 weeks. Current dose is 1 mg/kg: Reduce dose to 0.8 mg/kg once every 3 weeks. Current dose is 0.8 mg/kg: Reduce dose to 0.6 mg/kg once every 3 weeks. Current dose is 0.6 mg/kg: Discontinue luspatercept. | |
Missed dose: If a dose is delayed or missed, administer as soon as possible and continue the regular dosing schedule (with at least 3 weeks between doses).
eGFR 30 to 89 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling; however, no clinically significant pharmacokinetic differences were observed in patients with mild to moderate kidney impairment.
eGFR <30 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Hepatic impairment prior to treatment initiation:
Total bilirubin ≤ ULN and AST or ALT > ULN or total bilirubin > ULN and any AST or ALT: There are no dosage adjustments provided in the manufacturer's labeling; however, no clinically significant pharmacokinetic differences were observed in patients with hepatic impairment.
AST or ALT >3 times ULN: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2: Utilize patient's actual body weight for calculation of BSA- or weight-based dosing; manage regimen-related toxicities in the same manner as for patients with a BMI <30 kg/m2; if a dose reduction is utilized due to toxicity, may consider resumption of full, weight-based dosing (or previously tolerated dose level) with subsequent cycles only if dose escalations are allowed in the prescribing information, if contributing underlying factors (eg, hepatic or kidney impairment) are sufficiently resolved, AND if performance status has markedly improved or is considered adequate (Ref).
Anemia due to beta thalassemia:
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Adverse reaction |
Severity |
Actions |
|---|---|---|
|
Extramedullary hematopoietic (EMH) masses |
Causing serious complications |
Discontinue luspatercept. Manage according to clinical guidelines. |
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Hypersensitivity reaction |
Grade 3 or 4 |
Discontinue luspatercept. |
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Hypertension |
New-onset or worsening preexisting |
Manage as per clinical guidelines with appropriate antihypertensive therapy. |
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Thromboembolic events |
Any |
Initiate prompt treatment. |
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Other adverse reactions |
Grade 3 or 4 |
Interrupt luspatercept therapy; resume when the adverse reaction resolves to ≤ grade 1. |
Anemia due to myelodysplastic syndromes:
Note: The table below contains dosage modifications for both erythropoiesis-stimulating agent–naive and erythropoiesis-stimulating agent–refractory myelodysplastic syndromes.
|
Adverse reaction |
Severity |
Actions |
|---|---|---|
|
Hypersensitivity reaction |
Grade 3 or 4 |
Discontinue luspatercept. |
|
Hypertension |
New-onset or worsening preexisting |
Manage as per clinical guidelines with appropriate antihypertensive therapy. |
|
Thromboembolic events |
Any |
Initiate prompt treatment. |
|
Other adverse reactions |
Grade 3 or 4 |
Interrupt luspatercept therapy; resume at the next lower dose level when the adverse reaction resolves to ≤ grade 1. If the dose delay is >12 consecutive weeks, discontinue luspatercept. |
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults.
>10%:
Cardiovascular: Hypertension (8% to 14%), peripheral edema (13%)
Gastrointestinal: Abdominal pain (14%), diarrhea (12% to 16%), nausea (9% to 16%)
Hepatic: Increased serum alanine aminotransferase (9% to 12%), increased serum aspartate aminotransferase (4% to 11%), increased serum bilirubin (12% to 64%)
Nervous system: Dizziness (≤18%), fatigue (14% to 41%), headache (8% to 26%), vertigo (≤18%)
Neuromuscular & skeletal: Arthralgia (6% to 19%), musculoskeletal pain (20%), ostealgia (20%)
Renal: Decreased creatinine clearance (27%)
Respiratory: Cough (14%), dyspnea (12% to 13%)
1% to 10%:
Cardiovascular: Presyncope (≤5%), syncope (≤5%), tachycardia (8%), thromboembolism (≤4%; including deep vein thrombosis, ischemic stroke, portal vein thrombosis, pulmonary embolism)
Endocrine & metabolic: Hyperuricemia (7%)
Gastrointestinal: Decreased appetite (5%)
Genitourinary: Urinary tract infection (7%)
Hematologic & oncologic: Neutropenia (5%), thrombocytopenia (6%)
Hepatic: Increased direct serum bilirubin (6%), increased serum alkaline phosphatase (8%)
Hypersensitivity: Hypersensitivity reaction (≤10%)
Immunologic: Antibody development (2% to 6%; neutralizing: ≤4%)
Infection: Influenza (≤9%; flu-like symptoms: ≤6%)
Local: Injection-site reaction (≤7%)
Nervous system: Cerebrovascular accident (1%), insomnia (5%), noncardiac chest pain (5%), spinal cord compression (<5%)
Neuromuscular & skeletal: Back pain (9%), myalgia (5%), osteoarthritis (5%)
Renal: Kidney impairment (8%)
Respiratory: Bronchitis (<5%), dyspnea on exertion (5%), pneumonia (5%), upper respiratory tract infection (7%), viral upper respiratory tract infection (6%)
Miscellaneous: Fever (5%), mass (extramedullary hematopoietic masses: 3% to 6%)
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to luspatercept or any component of the formulation.
Concerns related to adverse effects:
• Extramedullary hematopoietic masses: Extramedullary hematopoietic (EMH) masses were observed in a small percentage of patients with transfusion dependent beta thalassemia receiving luspatercept; symptoms of spinal cord compression due to EMH masses occurred in some patients. EMH masses were also observed in patients with nontransfusion-dependent beta thalassemia (not an approved indication). Risk factors for development of EMH masses may include history of EMH masses, splenectomy, splenomegaly, hepatomegaly, or low baseline hemoglobin (<8.5 g/dL); signs/symptoms may vary based on the anatomical location.
• Hypertension: Hypertension has been reported, including grade 3 and 4 events. Patients with normal baseline BP have developed elevated systolic BP (≥130 mm Hg) and/or elevated diastolic BP (≥80 mm Hg).
• Thromboembolic events: Thromboembolic events, including deep vein thrombosis, pulmonary embolus, portal vein thrombosis, and ischemic strokes, have been reported in a small number of patients with beta thalassemia receiving luspatercept in clinical trials. Patients with known risk factors for thromboembolism such as splenectomy or concomitant use of hormone therapy may be at increased risk of thromboembolic events.
Dosage form specific issues:
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Subcutaneous [preservative free]:
Reblozyl: Luspatercept-aamt 25 mg (1 ea); Luspatercept-aamt 75 mg (1 ea) [contains polysorbate 80]
No
Solution (reconstituted) (Reblozyl Subcutaneous)
25 mg (per each): $4,651.08
75 mg (per each): $13,953.20
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Subcutaneous:
Reblozyl: Luspatercept-aamt 25 mg (1 ea); Luspatercept-aamt 75 mg (1 ea) [contains polysorbate 80]
Luspatercept is available through specialty distributors, specialty pharmacies, and various specialty institutions/accounts. Examples from the manufacturer may be found at https://www.reblozylpro.com/.
SUBQ: Inject SUBQ into the upper arm, thigh, and/or abdomen. Doses requiring larger reconstituted volumes (>1.2 mL) should be divided into separate syringes with similar volumes; inject into separate sites. Use a new syringe and needle for each separate injection. If refrigerated, allow reconstituted solution to come to room temperature for 15 to 30 minutes prior to injection.
Anemia due to beta thalassemia: Treatment of anemia in adults with beta thalassemia who require regular RBC transfusions.
Anemia due to myelodysplastic syndromes, erythropoiesis-stimulating agent–naive: Treatment of anemia in adults without previous erythropoiesis-stimulating agent (ESA) use (ESA-naive) with very low- to intermediate-risk myelodysplastic syndromes (MDS) who may require RBC transfusions.
Anemia due to myelodysplastic syndromes with ring sideroblasts or myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis, erythropoiesis-stimulating agent–refractory: Treatment of anemia failing an erythropoiesis-stimulating agent and requiring 2 or more 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).
Limitations of use: Luspatercept is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.
Luspatercept may be confused with etanercept, lusutrombopag, Lupron.
Reblozyl may be confused with Rebetol, Rebif, Rebinyn.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Androgens: Hypertension-Associated Agents may enhance the hypertensive effect of Androgens. Risk C: Monitor therapy
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Rozanolixizumab: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy
Evaluate pregnancy status prior to use in patients who could become pregnant. Patients who could become pregnant should use effective contraception during luspatercept therapy and for at least 3 months after the last luspatercept dose.
Based on data from animal reproduction studies, in utero exposure to luspatercept may cause fetal harm.
It is not known if luspatercept is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 3 months after the last luspatercept dose.
Assess Hb prior to each luspatercept dose. Evaluate pregnancy status prior to initiation (in patients who could become pregnant). Monitor blood pressure prior to each dose and as clinically necessary. Monitor for signs/symptoms of thromboembolism. Monitor patients with beta thalassemia at therapy initiation and during treatment for signs/symptoms of extramedullary hematopoietic mass and complications that may result.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Luspatercept is a recombinant fusion protein that contains a modified form of the extracellular domain of human activin receptor type IIb and links to the human IgG1 Fc domain. It binds several endogenous transforming growth factor-beta (TGF-β) superfamily ligands, which results in reduced Smad2/3 signaling. Inhibition of TGF-β superfamily results in increased differentiation and proliferation of erythroid precursors and improved hematology parameters.
Onset: Hb increased within 7 days of luspatercept initiation (in patients receiving <4 units of RBCs within 8 weeks prior to dose).
Duration: Hb levels returned to baseline ~6 to 8 weeks from the last dose.
Distribution: Vd: Beta thalassemia: 7.1 L; Myelodysplastic syndromes (MDS): 9.6 L.
Metabolism: Expected to be catabolized into small peptides and amino acids via general protein degradation processes in multiple tissues.
Half-life elimination: Beta thalassemia: ~11 days; MDS: ~14 days.
Time to peak: Median: Beta thalassemia: ~5 days (range: 3 to 8 days); MDS: ~6 days (range: 3 to 7 days).
Excretion: Clearance: Beta thalassemia: 0.44 L/day; MDS: 0.47 L/day.
Weight: The apparent clearance and volume of distribution of luspatercept increased with increasing body weight (34 to 97 kg) in patients with beta thalassemia; 33 to 124 kg in patients with myelodysplastic syndromes.
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