Luspatercept (Reblozyl) is a recombinant fusion protein that improves the hematology parameters in patients with ineffective erythropoiesis. It is indicated in the treatment of patients with beta-thalassemia who require RBC transfusion.

Luspatercept (Reblozyl) Uses:

• Anemia due to beta-thalassemia:

  • It is indicated for the treatment of anemia in adult patients with beta-thalassemia who require regular RBC transfusions.

  • Limitations of use:

    • It is not recommended as a substitute for RBC transfusion in patients who need immediate correction of anemia.

• Off Label Use of Luspatercept in Adults:

  • It is also used as an off-lable drug for patients with anemia due to lower-risk myelodysplastic syndromes with ring sideroblasts.

Luspatercept (Reblozyl) Dose in Adults:

Note:

• Before administering a dose, check hemoglobin levels.
• Patients who have recently received blood transfusion should have pretransfusion Hb considered for dosing purposes.
• Treatment may be delayed if the pretransfusion Hb is equal to or greater than 11.5 gm/dl and is not influenced by recent blood transfusion (until the Hb is less than 11 gm/dl)

Luspatercept (Reblozyl) Dose in the treatment of anemia due to beta-thalassemia:

• Initial: 1 mg/kg administered subQ once every three weeks.

  • Dosage adjustments:

    • If the patient continues to require RBC transfusion at the same frequency and the transfusion burden does not reduce after at least two consecutive doses (a total of 6 weeks), the dose may be increased to 1.25 mg/kg once every three weeks.
    • The maximum dose is 1.25 mg/kg.
    • If a response to luspatercept occurs initially, followed by a lack of response afterward, the patient should be evaluated for other causes of anemia such as blood loss.
    • If other causes of anemia have been adequately investigated and excluded, the dose of luspatercept may be increased to 1.25 mg/kg once every three weeks.
    • The maximum dose is 1.25 mg/kg.
    • If the transfusion burden does not decrease after 9 weeks of the treatment (a total of 3 doses) at maximum doses, or if the patient develops toxicity, the treatment may be discontinued.

Luspatercept (Reblozyl) Dose in the treatment of Anemia due to lower-risk myelodysplastic syndromes with ring sideroblasts (off-label):

• Initial: 1 mg/kg administered subQ once every three weeks.
• The dose may be titrated up to 1.75 mg/kg once every three weeks based on response.
• The treatment may be continued for 24 weeks or more.
• Missed dose:
  • If a dose is missed or delayed, administer the dose as soon as possible and continue the regular dosing schedule with at least three weeks between doses.

Use in Children:

Not indicated.

Pregnancy Risk Category: N

• Based on animal reproduction studies, the drug could cause harm to fetal health.
• Before treatment begins in females with reproductive potential, it is important to determine if you are pregnant.
• Effective contraception should be used during treatment and for the three months following the last dose.

Luspatercept use during breastfeeding:

• It is unknown if the drug will be excreted into breastmilk.
• Because of the potential for serious adverse drug reactions in breastfed infants, the manufacturer suggests that you avoid it while breastfeeding.
• It is not advised to breastfeed during treatment or for the three months after the last dose.

Luspatercept (Reblozyl) Dose in Kidney Disease:

• eGFR 30 to 89 mL/minute/1.73 m²:
  • In mild to moderate renal dysfunction, significant pharmacokinetic differences were not observed. Adjustment in the dose is not required.
• eGFR ≤29 mL/minute/1.73 m²:
  • The drug has not been studied in patients with an eGFR of less than 30 ml/minute. Recommendations regarding dosage adjustment have not been made.

Luspatercept (Reblozyl) Dose in Liver Disease:

• Total bilirubin ≤ ULN and AST or ALT > ULN or total bilirubin > ULN and any AST or ALT:
  • Adjustment in the dose is not required as clinically significant differences in the pharmacokinetics were not observed in patients with hepatic impairment.
• AST or ALT >3 times ULN:
  • The drug has not been studied in patients with moderate to severe hepatic impairment. Dosage recommendations have not been made by the manufacturer.

Common Side Effects of Luspatercept (Reblozyl):

• Cardiovascular:

  • Increased Diastolic Blood Pressure
  • Hypertension

• Central Nervous System:

  • Headache
  • Fatigue
  • Dizziness

• Gastrointestinal:

  • Abdominal Pain
  • Diarrhea

• Hepatic:

  • Increased Serum Bilirubin
  • Increased Serum Aspartate Aminotransferase

• Neuromuscular & Skeletal:

  • Ostealgia
  • Arthralgia

• Respiratory:

  • Cough

Less Common Side Effects of Luspatercept (Reblozyl):

• Cardiovascular:

  • Increased Systolic Blood Pressure
  • Presyncope
  • Syncope
  • Ischemic Stroke
  • Portal Vein Thrombosis
  • Pulmonary Embolism
  • Cerebrovascular Accident
  • Deep Vein Thrombosis

• Central Nervous System:

  • Vertigo

• Endocrine & Metabolic:

  • Hyperuricemia

• Gastrointestinal:

  • Nausea

• Hepatic:

  • Increased Serum Alkaline Phosphatase
  • Increased Direct Serum Bilirubin

• Hypersensitivity:

  • Hypersensitivity Reaction

• Immunologic:

  • Antibody Development

• Infection:

  • Influenza

• Local:

  • Injection Site Reaction

• Respiratory:

  • Viral Upper Respiratory Tract Infection

Side effects of Luspatercept with frequency not defined:

• Hepatic:

  • Increased serum alanine aminotransferase

• Neuromuscular & skeletal:

  • Back pain

Contraindications to Luspatercept (Reblozyl):

The manufacturer's labeling does not contain any contraindications.

Warnings and precautions

• Hypertension:

  • Hypertension can be serious enough to warrant hospitalization and emergency department visits.
  • Patients might develop isolated diastolic or systolic hypertension.
  • Before each dose, monitor blood pressure. If necessary, repeat the process as indicated by a physician.
  • Patients with persistent hypertension should receive the appropriate medications.

• Musculoskeletal adverse effects:

  • Bony pains or arthralgia may occur in some patients. 
  • Clinical trials revealed that 20% of patients experienced musculoskeletal adverse effects.

• Events that are thromboembolic:

  • Thromboembolic events can occur. Patients can develop deep vein embolism, pulmonary embolisms, portal vein thrombosis and stroke.
  • Patients who have other risk factors, such as patients on hormone replacement therapy or those who have had a surgery, are more at risk than those with immobile patients.
  • These patients should be closely monitored for signs and symptoms of thrombosis. Patients at high risk for developing thromboembolic complications may need thromboprophylaxis.

Monitoring parameters:

• The hemoglobin should be monitored before each dose.
• Female patients of reproductive potential should have a pregnancy test done prior to treatment initiation.
• Monitor Blood pressure before administering the drug and as clinically indicated thereafter.
• Monitor for the clinical features of thromboembolism.

How to administer Luspatercept (Reblozyl)?

• It is administered as a subQ injection into the upper arm, thigh, or abdomen.
• When the dose exceeds a volume of 1.2 mL, it should be divided into separate syringes with similar volumes and injected into separate sites.
• For each injection, a new syringe and a separate needle should be used.
• Prior to administering the drug, the injection should be kept at room temperature for 15 - 30 minutes if it is refrigerated.

Mechanism of action of Luspatercept (Reblozyl):

• It is a recombinant protein fusion protein that improves blood-related parameters related to ineffective erythropoiesis.
• It includes a modified version of the extracellular human activin receptor type IIb domain and links to the human IgG1Fc domain.
• This results in decreased Smad2/3 signaling through binding to several TGF-b superfamily ligands.
• Patients with ineffective erythropoiesis may experience increased differentiation and proliferation of erythroid precursors if TGF-b is inhibited.

Onset:

• It takes about 7 days for the hemoglobin to increase after treatment initiation (in patients who have had fewer than 4 units of RBCs within the past 8 weeks prior to dose).

Duration:

• The Hemoglobin levels return to baseline in about 8 weeks from the last dose.

Metabolism:

• The drug is catabolized into amino acids via the protein degradation processes in multiple tissues.

Half-life elimination:

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• About 11 days.

Time to peak:

• About 7 days (ranging from 6 to 8 days).

Excretion:

• Clearance: 0.44 L/day.

International Brand Names of Luspatercept:

• Reblozyl

Luspatercept Brand Names In Pakistan:

No Brands Available in Pakistan.