Luspatercept

Indications

Luspatercept is used for: Anemia Related Beta-Thalassemia

Adult Dose

Anemia Related Beta-Thalassemia Erythroid maturation agent indicated for anemia in adults with beta thalassemia who require regular red blood cell (RBC) transfusions 1 mg/kg once SC q3weeks initially Increase to 1.25 mg/kg maximum if patient does not achieve reduction in RBC transfusion burden after at least 2 consecutive doses (6 weeks) at starting dose of 1 mg/kg If predose hemoglobin (Hgb) ?11.5 g/dL and Hgb level not influenced by recent transfusion, delay dosing until Hgb is ?11 g/dL If patient loses response to drug after initial response, search for causative factors (eg, bleeding event); if typical causes for lack of loss of response excluded, follow dosing recommendations for management of patients with insufficient response to therapy Discontinue therapy if no decrease in transfusion burden after 9 weeks of treatment (3 doses) at maximum dose level or if unacceptable toxicity occurs at any time 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

Child Dose

Renal Dose

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

Administration

Reconstitution Reconstitute with sterile water for injection only 25-mg vial: Add 0.68 mL of sterile water for final concentration of 50 mg/mL for deliverable volume of 0.5 mL 75-mg vial: Add 1.6 mL of sterile water for final concentration of 50 mg/mL for deliverable volume of 1.5 mL Allow reconstitution to stand for 1 min Discard needle and syringe used for reconstitution; do not use for SC administration Gently swirl vial in circular motion for 30 sec; stop swirling and let vial sit in upright position for 30 sec Inspect for undissolved particles in solution; if undissolved powder is observed, repeat step above until powder completely dissolved Invert vial and gently swirl in an inverted position for 30 seconds; bring vial back to upright position, and let it sit for 30 sec; repeat 7 more times to ensure complete reconstitution of the vial Visually inspect for particulate matter and discoloration prior to administration whenever possible; drug is a colorless to slightly yellow, clear to slightly opalescent solution that is free of foreign particulate matter; discard if foreign particulate matter observed 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 injection subcutaneously into upper arm, thigh, and/or abdomen

Contra Indications

Precautions

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

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

Interactions

Adverse Effects

Side effects of Luspatercept : >10% All grades Total bilirubin ≥2x ULN (64%) Headache (26%) Arthralgia (19%) Fatigue (14%) Abdominal pain (14%) Cough (14%) Diarrhea (12%) ALT >3x ULN (12%) Dizziness (11%) AST >3x ULN (11%) 1-10% All grades Nausea (9%) Influenza (9%) Alkaline phosphatase ≥2x ULN (8%) Hypertension (8%) Hyperuricemia (7%) Direct bilirubin >2x ULN (6%) Viral upper respiratory tract infection (6%) Grade >3 Hyperuricemia (3%) Hypertension (2%) <1% Grade ≥3 Diarrhea (<1%) Headache (<1%) Viral upper respiratory tract infection (0.4%)

Mechanism of Action

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