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Luspatercept: Drug information

Luspatercept: Drug information
(For additional information see "Luspatercept: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Reblozyl
Brand Names: Canada
  • Reblozyl
Pharmacologic Category
  • Activin Receptor Ligand Trap;
  • Hematopoietic Agent
Dosing: Adult

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

Anemia due to beta thalassemia: Note: Avoid use in patients requiring treatment to control the growth of extramedullary hematopoietic 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 (Cappellini 2020).

Luspatercept Dose Titration for Response in the Treatment of Anemia Due to Beta Thalassemia

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

1.25 mg/kg once every 3 weeks

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

Increase the dose to 1.25 mg/kg once every 3 weeks (maximum dose)

No reduction in RBC transfusion burden after 3 consecutive doses (9 weeks) at 1.25 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 1.25 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

Dose modification for adverse reactionsa

Hypersensitivity reaction, grade 3 or 4

Discontinue luspatercept

Other grade 3 or 4 adverse reactions

Interrupt luspatercept therapy; resume when the adverse reaction resolves to ≤ grade 1.

Extramedullary hematopoietic masses (causing serious complications)

Discontinue luspatercept. Manage according to clinical guidelines.

New-onset or worsened preexisting hypertension

Manage as per clinical guidelines with appropriate antihypertensive therapy.

Thromboembolic events

Initiate prompt treatment.

Anemia due to myelodysplastic syndromes with ring sideroblasts or myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis

Anemia due to myelodysplastic syndromes with ring sideroblasts or myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis: SUBQ: Initial: 1 mg/kg once every 3 weeks (Fenaux 2020).

Luspatercept Dose Titration for Response in the Treatment of Anemia Due to Myelodysplastic Syndromes with Ring Sideroblasts or Myelodysplastic/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis

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

Not RBC transfusion-free after at least 2 consecutive doses (6 weeks) at the 1 mg/kg starting dose

Increase the dose to 1.33 mg/kg once every 3 weeks

Not RBC transfusion-free after at least 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)

No reduction in RBC transfusion burden 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

Dose modification for adverse reactionsa

Hypersensitivity reaction, grade 3 or 4

Discontinue luspatercept.

Other grade 3 or 4 adverse reactions

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.

New-onset or worsened preexisting hypertension

Manage as per clinical guidelines with appropriate antihypertensive therapy.

Thromboembolic events

Initiate prompt treatment.

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).

Dosing: Kidney Impairment: Adult

eGFR 30 to 89 mL/minute/1.73 m2: No clinically significant pharmacokinetic differences were observed in patients with mild to moderate renal impairment; dosage adjustment is likely not necessary.

eGFR <30 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment: Adult

Total bilirubin ≤ ULN and AST or ALT > ULN or total bilirubin > ULN and any AST or ALT: No clinically significant pharmacokinetic differences were observed in patients with hepatic impairment; dosage adjustment is likely not necessary.

AST or ALT >3 times ULN: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Older Adult

Refer to adult dosing.

Dosage Forms: US

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]

Generic Equivalent Available: US

No

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Subcutaneous:

Reblozyl: 25 mg (1 ea); 75 mg (1 ea) [contains polysorbate 80]

Prescribing and Access Restrictions

Luspatercept is available only through authorized distributors. For further information on patient assistance, product availability, and prescribing instructions, please refer to the following website: https://www.reblozylpro.com/.

Administration: Adult

SUBQ: Inject 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.

Use: Labeled Indications

Anemia due to beta thalassemia: Treatment of anemia in adults with beta thalassemia who require regular RBC transfusions.

Anemia due to myelodysplastic syndromes with ring sideroblasts or myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis: 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.

Medication Safety Issues
Sound-alike/look-alike issues:

Luspatercept may be confused with etanercept, lusutrombopag, Lupron.

Reblozyl may be confused with Rebetol, Rebif, Rebinyn.

Adverse Reactions

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 11%)

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 (14% to 26%), vertigo (≤18%)

Neuromuscular & skeletal: Arthralgia (19%), musculoskeletal pain (20%), ostealgia (20%)

Renal: Decreased creatinine clearance (27%)

Respiratory: Cough (14%), dyspnea (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%)

Genitourinary: Urinary tract infection (<5%)

Hepatic: Increased direct serum bilirubin (6%), increased serum alkaline phosphatase (8%)

Hypersensitivity: Hypersensitivity reaction (≤10%)

Immunologic: Antibody development (1% to 9%; neutralizing: ≤4%)

Infection: Influenza (≤9%; flu-like symptoms: ≤6%)

Local: Injection-site reaction (≤7%)

Nervous system: Cerebrovascular accident (1%), spinal cord compression (<5%)

Renal: Renal insufficiency (8%)

Respiratory: Bronchitis (<5%), upper respiratory tract infection (7%), viral upper respiratory tract infection (6%)

Miscellaneous: Mass (extramedullary hematopoietic [EMH] masses: 3% to 6%)

Frequency not defined: Neuromuscular & skeletal: Back pain

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to luspatercept or any component of the formulation.

Warnings/Precautions

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 occurred in some patients. EMH masses were also observed in patients with non-transfusion 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. Some patients with normal baseline BP 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 risk factors for thromboembolism such as splenectomy or concomitant use of hormone replacement therapy may be at increased risk of thromboembolic events. Thromboprophylaxis may be considered in patients with elevated risk for 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.

Metabolism/Transport Effects

None known.

Drug Interactions

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

Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy

Reproductive Considerations

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.

Pregnancy Considerations

Based on data from animal reproduction studies, in utero exposure to luspatercept may cause fetal harm.

Breastfeeding Considerations

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.

Monitoring Parameters

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.

Mechanism of Action

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 improves hematology parameters associated with ineffective erythropoiesis.

Pharmacokinetics

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): 9.7 L.

Metabolism: Expected to be catabolized into amino acids via general protein degradation processes in multiple tissues.

Half-life elimination: Beta thalassemia: ~11 days; MDS: ~13 days.

Time to peak: Median: Beta thalassemia: ~7 days (range: 6 to 10 days); MDS: ~7 days (range: 5 to 21 days).

Excretion: Clearance: Beta thalassemia: 0.44 L/day; MDS: 0.52 L/day.

Pharmacokinetics: Additional Considerations

Weight: The apparent clearance and volume of distribution of luspatercept increased with increasing body weight (34 to 97 kg) in patients with beta thalassemia; 46 to 124 kg in patients with myelodysplastic syndromes.

Pricing: US

Solution (reconstituted) (Reblozyl Subcutaneous)

25 mg (per each): $4,382.81

75 mg (per each): $13,148.42

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.

Brand Names: International
  • Reblozyl (AT, AU, CZ, DE, DK, EE, HR, HU, LT, LV, NO, PT, SK)


For country code abbreviations (show table)
  1. Alade SL, Brown RE, Paquet A Jr. Polysorbate 80 and E-Ferol toxicity. Pediatrics. 1986;77(4):593-597. [PubMed 3960626]
  2. Cappellini MD, Viprakasit V, Taher AT, et al; BELIEVE Investigators. A phase 3 trial of luspatercept in patients with transfusion-dependent β-thalassemia. N Engl J Med. 2020;382(13):1219‐1231. doi:10.1056/NEJMoa1910182 [PubMed 32212518]
  3. Centers for Disease Control and Prevention (CDC). Unusual syndrome with fatalities among premature infants: association with a new intravenous vitamin E product. MMWR Morb Mortal Wkly Rep. 1984;33(14):198-199. http://www.cdc.gov/mmwr/preview/mmwrhtml/00000319.htm. [PubMed 6423951]
  4. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020;382(2):140-151. doi: 10.1056/NEJMoa1908892. [PubMed 31914241]
  5. Isaksson M, Jansson L. Contact allergy to Tween 80 in an inhalation suspension. Contact Dermatitis. 2002;47(5):312-313. doi: 10.1034/j.1600-0536.2002.4705104.x. [PubMed 12534540]
  6. Lucente P, Iorizzo M, Pazzaglia M. Contact sensitivity to Tween 80 in a child. Contact Dermatitis. 2000;43(3):172. [PubMed 10985636]
  7. Piga A, Perrotta S, Gamberini MR, et al. Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with β-thalassemia. Blood. 2019;133(12):1279-1289. doi: 10.1182/blood-2018-10-879247. [PubMed 30617198]
  8. Reblozyl (luspatercept) [prescribing information]. Summit, NJ: Celgene Corporation; September 2022.
  9. Reblozyl (luspatercept) [product monograph]. Saint-Laurent, Quebec, Canada: Celgene Inc; February 2021.
  10. Shelley WB, Talanin N, Shelley ED. Polysorbate 80 hypersensitivity. Lancet. 1995;345(8980):1312-1313. doi: 10.1016/s0140-6736(95)90963-x. [PubMed 7746084]
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