luspatercept (Rx)

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

AdultPediatric

Dosage Forms & Strengths

injection (lyophilized powder)

  • 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

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

Dosing Modifications

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 Hgb results before each administration; if RBC transfusion occurred before dosing, consider pretransfusion Hgb for dosing purposes

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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Adverse Effects

>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%)
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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

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

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) in the original vial for up to 8 hours; discard if not used within 8 hr of reconstitution
  • Alternatively, refrigerate at -8ºC (36-46ºF) for up to 24 hr in original vial; discard if not used within 24 hr of reconstitution
  • Do not freeze reconstituted solution
  • Discard any unused portion; do not pool unused portions from vials or administer more than 1 dose from a vial; do not mix with other medications
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Formulary

FormularyPatient Discounts

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The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

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.
6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
NC NOT COVERED – Drugs that are not covered by the plan.
Code Definition
PA Prior Authorization
Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
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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.