Dosing & Uses
Dosage Forms & Strengths
injection, lyophilized powder for reconstitution
- 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
Initial dose: 1 mg/kg once SC q3Weeks
Do not increase dose if an adverse reaction occurs
Titrate dose based on insufficient response
- No reduction in RBC transfusion burden after at least 2 consecutive doses (6 weeks) at 1 mg/kg: Increase to 1.25 mg/kg q3Weeks
- No reduction in RBC transfusion burden after 3 consecutive doses (9 weeks) at 1.25 mg/kg: Discontinue treatment
Dosage modifications for predose Hgb levels or rapid Hgb rise
- Predose hemoglobin ≥11.5 g/dL in absence of transfusions: Interrupt dose; restart when Hgb ≤11 g/dL
-
Increased hemoglobin >2 g/dL within 3 weeks in absence of transfusions AND
- Current dose is 1.25 mg/kg: Reduce to 1 mg/kg
- Current dose is 1 mg/kg: Reduce to 0.8 mg/kg
- Current dose is 0.8 mg/kg: Reduce to 0.6 mg/kg
- Current dose is 0.6 mg/kg: Discontinue treatment
Anemia-related Myelodysplastic Syndromes
Indications
- Indicated for first-line treatment of anemia without previous erythropoiesis stimulating agent use (ESA-naïve) in adults with very low- to intermediate-risk myelodysplastic syndromes (MDS) who may require regular red blood cell (RBC) transfusions
- Indicated for treatment of anemia failing an ESA and requiring ≥2 RBC units over 8 weeks in adults with very low- to intermediate-risk MDS with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)
Dose
- Initial dose: 1 mg/kg once SC q3Weeks
- Do not increase dose if an adverse reaction occurs
Titrate dose based on insufficient response
- Not RBC transfusion-free after at least 2 consecutive doses (6 weeks) at 1 mg/kg: Increase to 1.33 mg/kg q3Weeks
- Not RBC transfusion-free after at least 2 consecutive doses (6 weeks) at 1.33 mg/kg: Increase to 1.75 mg/kg q3Weeks
- Do not increase dose more frequently than q6Weeks (2 doses) or beyond maximum dose of 1.75 mg/kg
- No reduction in RBC transfusion burden after 3 consecutive doses (9 weeks) at 1.75 mg/kg: Discontinue treatment
Dosage modifications for predose Hgb levels or rapid Hgb rise
- Predose hemoglobin ≥11.5 g/dL in absence of transfusions: Interrupt dose; restart when Hgb ≤11 g/dL
-
Increase in hemoglobin >2 g/dL within 3 weeks in absence of transfusions AND
- Current dose is 1.75 mg/kg: Reduce to 1.33 mg/kg
- Current dose is 1.33 mg/kg: Reduce to 1 mg/kg
- Current dose is 1 mg/kg: Reduce to 0.8 mg/kg
- Current dose is 0.8 mg/kg: Reduce to 0.6 mg/kg
- Current dose is 0.6 mg/kg: Discontinue treatment
Dosage Modifications
Dosage modifications for adverse effects (beta-thalassemia)
- Grade 3 or 4 hypersensitivity reactions: Discontinue treatment
- Other Grade 3 or 4 adverse reactions: Interrupt treatment; restart when adverse reaction resolves to Grade ≤1
- Extramedullary hematopoietic (EMH) masses causing serious complications: Discontinue treatment
Dosage modifications for adverse effects (MDS-associated anemia)
- Grade 3 or 4 hypersensitivity reactions: Discontinue treatment
- Other Grade 3 or 4 adverse reactions: Interrupt treatment; restart when adverse reaction resolves to Grade ≤1
- If dose delay is >12 consecutive weeks, discontinue treatment
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 hemoglobin (Hgb) before each administration
If an RBC transfusion occurred before dosing, use the pretransfusion hemoglobin to evaluate dose
Limitation of use
- Not for use as substitute for RBC transfusions in patients requiring immediate correction of anemia
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (0)
Serious - Use Alternative (0)
Monitor Closely (0)
Minor (0)
Adverse Effects
>10% (Beta Thalassemia)
All grades
- Total bilirubin ≥2x ULN (64%)
- Headache (26%)
- Musculoskeletal
- Bone pain (20%)
- Arthralgia (19%)
- Fatigue (14%)
- Abdominal pain (14%)
- Cough (14%)
- Diarrhea (12%)
- ALT or AST ≥3x ULN (11-12%)
- Dizziness (11%)
>10% (MDS-RS or MDS/MPN-RS-T)
All grades
- Fatigue (41%)
- Reduced creatinine clearance (27%)
- Musculoskeletal pain (20%)
- Dizziness/vertigo (18%)
- Nausea (16%)
- Diarrhea (16%)
- Headache (14%)
- Dyspnea (13%)
- Total bilirubin elevated (12%)
1-10% (Beta Thalassemia)
All grades
- Nausea (9%)
- Hypertension (8%)
- Alkaline phosphatase (ALP) ≥2x ULN (8%)
- Hyperuricemia (7%)
- Direct bilirubin ≥2x ULN (6%)
- Extramedullary hematopoietic masses, and spinal cord compression
Grade 3 or 4
- Hyperuricemia (3%)
- Hypertension (2%)
1-10% (MDS-RS or MDS/MPN-RS-T)
All grades
- Hypersensitivity reactions (10%)
- ALT elevated (9%)
- Renal impairment (8%)
- Tachycardia (8%)
- Injection site reactions (7%)
- Upper respiratory tract infection (7%)
- Influenza/influenza like illness (6%)
- AST elevated (4%)
Grade 3 or 4
- Fatigue (7%)
- Renal impairment (2%)
- Dyspnea (1%)
<1% (Beta Thalassemia)
Grade 3 or 4
- Diarrhea
- Headache
<1% (MDS-RS or MDS/MPN-RS-T)
Grade 3 or 4
- Upper respiratory tract infection
- Hypersensitivity reactions
Warnings
Contraindications
None
Cautions
Hypertension reported; monitor blood pressure before 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
Thrombosis/thromboembolism
- Thromboembolic events (TEE) reported in adults with beta thalassemia
- Reported TEEs included deep vein thromboses, pulmonary embolus, portal vein thrombosis, and ischemic strokes
- Patients with known risk factors (eg, splenectomy or concomitant use of hormone replacement therapy), may be at further increased risk
- Consider thromboprophylaxis in patients at increased risk of TEE
- Monitor for signs and symptoms of thromboembolic events and institute treatment promptly
Extramedullary hematopoietic masses (EMH)
- EMH observed in treated patients with transfusion-dependent beta-thalassemia
- Incidence of EMH was higher in non-transfusion dependent beta-thalassemia compared to placebo
- Spinal cord compression symptoms due to EMH masses reported
- Possible risk factors for developing EMH include history of EMH masses, splenectomy, splenomegaly, hepatomegaly, or low baseline hemoglobin (<8.5 g/dL)
- Monitor at initiation and during treatment for symptoms and signs or complications resulting from EMH masses and treat accordingly
- Discontinue treatment in case of serious complications due to EMH masses
- Avoid use in patients requiring treatment to control the growth of EMH masses
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.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
Administration
SC Preparation
Reconstitute vial with 0.68 mL (25-mg vial) or 1.6 mL (75-mg vial) of Sterile Water for Injection (final concentration of 50 mg/mL); allow reconstituted vial to stand for 1 min
Do use the needle and syringe for reconstitution for SC injections
Gently swirl vial in circular motion for 30 seconds; stop swirling and allow vial to sit in upright position for 30 seconds
Inspect vial for undissolved particles in solution; repeat above step if undissolved powder observed
Invert vial and gently swirl for 30 seconds; bring the vial back to upright position, and let it sit for 30 seconds; repeat 7 more times to ensure complete reconstitution
Discard any unused portion; do not pool unused portions from the vials
Do not administer more than 1 dose from a vial; do not mix with other medications.
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 SC injection into upper arm, thigh, and/or abdomen
Missed or delayed dose: Administer dose as soon as possible and continue dosing as prescribed, with at least 3 weeks between doses
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) for up to 8 hours; discard if not used within 8 hr of reconstitution
- Alternatively, refrigerate at 2-8ºC (36-46ºF) for up to 24 hr; discard if not used within 24 hr of reconstitution
- Do not freeze
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