Luspatercept-aamt is a recombinant fusion protein that functions as an erythroid maturation agent to restore red blood cell (RBC) production and ameliorate anemia. It is indicated for the treatment of anemia in adult patients with beta thalassemia who require regular RBC transfusions. Luspatercept is also indicated for the treatment of anemia due to very low- to intermediate-risk myelodysplastic syndromes (MDS) in adults who are erythropoiesis stimulating agent (ESA)-naive or have failed ESA therapy. Luspatercept is not indicated as a substitute for RBC transfusions in patients who require immediate correction of anemia. Thromboembolism has been reported in luspatercept-treated patients; monitor for signs and symptoms of thromboembolism and initiate prophylaxis in at-risk patients.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Luspatercept is a colorless to slightly yellow, clear to slightly opalescent solution. Do not use if undissolved product or particulate matter is observed.
-Luspatercept should be reconstituted and administered by a healthcare professional.
-If administration is delayed or missed, administer luspatercept as soon as possible and continue dosing as prescribed with at least 3 weeks between doses.
Subcutaneous Administration
Reconstitution
-Reconstitute to a final concentration of 50 mg/mL. Direct stream onto the lyophilized powder. Allow to stand for 1 minute.-For the 25 mg vial: Add 0.68 mL of Sterile Water for Injection (deliverable volume = 0.5 mL).
-For the 75 mg vial: Add 1.6 mL of Sterile Water for Injection (deliverable volume = 1.5 mL).
-Gently swirl the vial in a circular motion for 30 seconds. Stop swirling and let the vial sit in an upright position for 30 seconds.
-Inspect for undissolved particles. If observed, repeat the above step until completely dissolved.
-Invert the vial and gently swirl in this position for 30 seconds. Bring the vial back to the upright position and let sit for 30 seconds. Repeat this step 7 more times to ensure complete reconstitution of materials on the sides of the vial.
-Storage: Store reconstituted solution at room temperature at 20 to 25 degrees C (68 to 77 degrees F) in the original vial for up to 8 hours. Alternatively, store refrigerated at 2 to 8 degrees C (36 to 46 degrees F) in the original vial for up to 24 hours. Do not freeze. Vials are single-dose; do not pool unused portions or administer more than 1 dose from each vial.
Administration
-If refrigerated, allow reconstituted solution to reach room temperature by removing from refrigerated condition 15 to 30 minutes before administration.
-Slowly withdraw the dosing volume into a syringe. Divide doses greater than 1.2 mL into separate similar volume injections and inject into separate sites. Use a new syringe and needle for each injection.
-Administer subcutaneously into the upper arm, thigh, and/or abdomen.
Thromboembolic events (TEE) including deep vein thrombosis (DVT), pulmonary embolism, portal vein thrombosis, and ischemic stroke have been reported in patients with beta thalassemia who received luspatercept therapy. Monitor patients for signs and symptoms of thromboembolism and institute treatment promptly if such events occur. Consider thromboprophylaxis in patients with beta thalassemia who have known risk factors for thromboembolism. TEEs were reported in 3.6% of patients with beta thalassemia who received luspatercept (n = 223) in a randomized trial; DVT and cerebrovascular accident/stroke each were reported in 1% of patients.
Hypertension has been reported in 11.4% of luspatercept-treated patients in clinical trials (n = 571); grade 3 to 4 hypertension occurred in 2% to 9.6% of patients. Evaluate blood pressure before each luspatercept dose. Manage new-onset hypertension or exacerbations of preexisting hypertension with antihypertensive agents. Hypertension (8% vs. 3%; grade 3, 2% vs. 0%) occurred more often in patients with beta thalassemia who received luspatercept (n = 223) compared with placebo (n = 109) in a randomized trial. The hypertension term included essential hypertension and hypertensive crisis. In patients with beta thalassemia and normal baseline blood pressure, 6.2% developed a systolic blood pressure (SBP) of 130 mmHg or more and 16.6% developed a diastolic blood pressure (DBP) of 80 mmHg or more. Sinus tachycardia (8% vs. 1%) occurred more often in erythropoiesis stimulating agent (ESA)-refractory or -intolerant patients with myelodysplastic syndrome (MDS) who received luspatercept (n = 153) compared with placebo (n = 76) in another randomized trial; hypertension was reported in less than 5% of luspatercept-treated patients. In these MDS patients with normal baseline blood pressure, 30% developed a SBP of 130 mmHg or more and 16% developed a DBP of 80 mmHg or more. Additionally, hypertension was reported in 14% (grade 3 or higher, 10%) of ESA-naive patients with MDS who received luspatercept (n = 178) in a comparative randomized trial. In these MDS patients with normal baseline blood pressure, 36% developed a SBP of 140 mmHg or more and 6% developed a DBP of 80 mmHg or more.
Headache (8% to 26%; grade 3, less than 1%), dizziness or dizziness/vertigo (9% to 18%; grade 3, less than 1%), vertigo including positional vertigo (less than 5%), syncope/presyncope (5% or less; grade 3, 3% or less) were reported in patients who received luspatercept in randomized clinical trials.
Musculoskeletal adverse events that were reported more often in patients with beta thalassemia who received luspatercept (n = 223) compared with placebo (n = 109) in a randomized trial included bone pain (20% vs. 8%; grade 3, 1% vs. 0%) and arthralgia (19% vs. 12%). Musculoskeletal pain (20% vs.14 %; grade 3, 2% vs. 0%) occurred more often in erythropoiesis stimulating agent (ESA)-refractory or -intolerant patients with myelodysplastic syndrome (MDS) who received luspatercept (n = 153) compared with placebo (n = 76) in another randomized trial. Additionally, non-cardiac chest pain (5%; grade 3 or higher, 1%), back pain (9%; grade 3 or higher, 1%), arthralgia (6%), myalgia (5%), and osteoarthritis (5%; grade 3 or higher, 1%) were reported in ESA-naive patients with MDS who received luspatercept (n = 178) in a comparative randomized trial.
Infection-related adverse events that were reported more often in patients with beta thalassemia who received luspatercept (n = 223) compared with placebo (n = 109) in a randomized trial included influenza (9% vs. 6%) and viral upper respiratory infection (6% vs. 2%; grade 3, 0.4% vs. 0%). Influenza/influenza like illness (6% vs. 3%) and upper respiratory tract infection (7% vs. 3%; grade 3, less than 1% vs. 0%) occurred more often in erythropoiesis stimulating agent (ESA)-refractory or -intolerant patients with myelodysplastic syndrome (MDS) who received luspatercept (n = 153) compared with placebo (n = 76) in another randomized trial; bronchitis and urinary tract infection were each reported in less than 5% of patients. Additionally, COVID-19 viral infection (11%; grade 3 or higher, 3%), urinary tract infection (7%) and pneumonia (5%; grade 3 or higher, 4%) were reported in ESA-naive patients with MDS who received luspatercept (n = 178) in a comparative randomized trial.
Diarrhea (12% to 16%; grade 3, less than 1%), nausea (9% to 16%; grade 3, less than 1%), abdominal pain (14% or less), and decreased appetite/anorexia (5% or less) were reported in patients who received luspatercept in randomized clinical trials.
Elevated hepatic enzymes and hyperbilirubinemia were reported more often in patients with beta thalassemia who received luspatercept (n = 223) compared with placebo (n = 109) in a randomized trial including AST level 3 times the upper limit of normal (ULN) or more (11% vs. 5%), alkaline phosphatase level 2 times the ULN or more (8% vs. less than 1%), total bilirubin level 2 times the ULN or more (64% vs. 47%), and direct bilirubin level 2 times the ULN or more (6% vs. 4%). Treatment-emergent (shifts from grade 0 or 1 to grade 2 to 4) increased ALT level (9% vs. 7%), increased AST level (4% vs. 0%), and increased total bilirubin level (12% vs. 5%) occurred more often in erythropoiesis stimulating agent (ESA)-refractory or -intolerant patients with myelodysplastic syndrome (MDS) who received luspatercept (n = 153) compared with placebo (n = 76) in another randomized trial. Additionally, treatment-emergent (shifts from grade 0 or 1 to grade 2 or 3) increase in total bilirubin level was reported in 22% of ESA-naive patients with MDS who received luspatercept (n = 178) in a comparative randomized trial.
Hypersensitivity and injection site reaction each were reported in less than 5% of patients with beta thalassemia who received luspatercept (n = 223) in a randomized trial. Hypersensitivity reactions (10% vs. 7%; grade 3, less than 1% vs. 0%) and injection site reaction (7% vs. 4%) occurred more often in erythropoiesis stimulating agent (ESA)-refractory or -intolerant patients with myelodysplastic syndrome (MDS) who received luspatercept (n = 153) compared with placebo (n = 76) in another randomized trial. Additionally, injection site reaction (e.g., erythema, pruritus, and rash) was reported in less than 5% of ESA-naive patients with MDS who received luspatercept (n = 178) in a comparative randomized trial.
Hyperuricemia (7% vs. 0%; grade 3 or 4, 3% vs. 0%) was reported more often in patients with beta thalassemia who received luspatercept (n = 223) compared with placebo (n = 109) in a randomized trial. Hyperuricemia also occurred in 7% (grade 3 or higher, 1%) of erythropoiesis stimulating agent (ESA)-naive patients with myelodysplastic syndrome who received luspatercept (n = 178) in a comparative randomized trial.
Antibody formation occurred in 1.81% of patients with beta thalassemia who received luspatercept (n = 220); 0.9% of patients had neutralizing antibodies. Additionally, antibody formation occurred in 6.3% of patients with myelodysplastic syndrome who received luspatercept (n = 331); 4.2% of patients developed neutralizing antibodies. There was no association between hypersensitivity or injection site reactions and the presence of antibodies.
A fatal adverse reaction occurred in 1 luspatercept-treated patient who died to an unconfirmed case of new primary malignancy, acute myeloid leukemia.
Fatigue was reported in 14% to 41% (grade 3, 7% or less) of patients who received luspatercept in randomized clinical trials. The term fatigue included asthenia/asthenic conditions.
Cough (14% vs. 11%) was reported more often in patients with beta thalassemia who received luspatercept (n = 223) compared with placebo (n = 109) in a randomized trial. Additionally, dyspnea occurred in 13% (grade 3, 1%) of erythropoiesis stimulating agent (ESA)-refractory or -intolerant patients and 12% (grade 3 or higher, 4%) of ESA-naive patients with myelodysplastic syndrome who received luspatercept in randomized trials. Exertional dyspnea was also reported in 5% of ESA-naive patients treated with luspatercept.
Nephrotoxicity, specifically renal impairment (8% vs. 4%; grade 3, 2% vs. 0%) and treatment-emergent (shifts from grade 0 or 1 to grade 2 to 4) reduction in creatinine clearance (27% vs. 21%), occurred more often in erythropoiesis stimulating agent (ESA)-refractory or -intolerant patients with myelodysplastic syndrome (MDS) who received luspatercept (n = 153) compared with placebo (n = 76) in a randomized trial. Additionally, treatment-emergent (shifts from grade 0 or 1 to grade 2 or 3) reduction in glomerular filtration rate was reported in 35% of ESA-naive patients with MDS who received luspatercept (n = 178) in a comparative randomized trial.
In adults with transfusion-dependent beta thalassemia, extramedullary hematopoiesis (EMH) with mass development has been observed in 3.2% of luspatercept-treated patients, with spinal cord compression symptoms due to EMH mass occurring in 1.9% of patients. Monitor patients with beta thalassemia at baseline and during treatment for signs and symptoms of complications resulting from EMH masses and treat according to clinical guidelines. Discontinue treatment if serious complications arise.
Peripheral edema was reported in 13% of erythropoiesis stimulating agent-naive patients with myelodysplastic syndrome who received luspatercept (n = 178) in a comparative randomized trial.
Fever was reported in 5% (grade 3 or higher, 1%) of erythropoiesis stimulating agent-naive patients with myelodysplastic syndrome who received luspatercept (n = 178) in a comparative randomized trial.
Insomnia was reported in 5% of erythropoiesis stimulating agent-naive patients with myelodysplastic syndrome who received luspatercept (n = 178) in a comparative randomized trial.
Thrombocytopenia (6%; grade 3 or higher, 4%) and neutropenia (5%; grade 3 or higher, 4%) were reported in erythropoiesis stimulating agent-naive patients with myelodysplastic syndrome who received luspatercept (n = 178) in a comparative randomized trial.
Monitor patients receiving luspatercept for signs and symptoms of thromboembolic events and institute treatment promptly if such events occur. Consider thromboprophylaxis in patients with beta thalassemia who have known risk factors for thromboembolism (e.g., splenectomy, tobacco smoking, prior thrombosis, concomitant use of hormone replacement therapy).
New or worsening hypertension may occur with luspatercept therapy. Monitor blood pressure prior to each luspatercept dose. Manage new onset hypertension or exacerbations of preexisting hypertension using antihypertensive agents.
Evaluate hemoglobin (Hgb) level prior to each luspatercept dose; use the pretransfusion Hgb level if the patient received a red blood cell (RBC) transfusion prior to dosing. Titrate the dose based on response up to the maximum dose level. Discontinue luspatercept therapy if there is no reduction in RBC transfusion burden (including no increase from baseline hemoglobin) after at least 3 consecutive doses (9 weeks) at the maximum dosage. Therapy interruption, a dosage reduction, or discontinuation may be necessary based on Hgb levels or severe adverse reactions. Do not substitute luspatercept for RBC transfusions in patients who require immediate correction of anemia.
Extramedullary hematopoietic masses (EMH) have been observed in luspatercept-treated patients with transfusion dependent beta thalassemia. Monitor patients with beta thalassemia at baseline and during treatment for signs and symptoms of complications resulting from EMH masses and treat according to clinical guidelines. Discontinue treatment if serious complications due to EMH masses occur. Risk factors for the development of EMH masses in patients with beta thalassemia include history of EMH masses, splenectomy (asplenia), splenomegaly, hepatomegaly, or low baseline hemoglobin (less than 8.5 g/dL). Avoid luspatercept use in patients requiring treatment to control EMH mass growth.
Based on findings in animal reproduction studies, luspatercept may cause fetal harm when administered during human pregnancy. There are no available data on luspatercept use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Advise pregnant women of the potential fetal risk. In animal reproduction studies, luspatercept administration during organogenesis resulted in adverse developmental outcomes including embryo-fetal mortality, growth alterations, and structural abnormalities at exposures above those occurring at the maximum recommended human dose of 1.75 mg/kg.
Be aware of the substance abuse potential of luspatercept. Although luspatercept is not a controlled substance, it has been abused in athletes taking it for its effects on erythropoiesis to enhance athletic performance. Polycythemia may lead to life-threatening cardiovascular complications (e.g., stroke, myocardial infarction, and thromboembolism) in healthy persons who abuse drugs that increase erythropoiesis, such as luspatercept.
Luspatercept is associated with reproductive risk. Pregnancy testing is recommended for females of reproductive potential before luspatercept treatment initiation. Discuss contraception requirements with the patient. Advise females of reproductive potential to use effective contraception during luspatercept treatment and for at least 3 months after the last dose. Also, based on animal studies, luspatercept may cause infertility in females. Impairment of fertility was observed in female rats but was reversible after a 14-week recovery period. No adverse effects were noted in male rats.
Because of the potential for serious adverse reactions in the breast-fed child, breast-feeding is not recommended during luspatercept treatment and for 3 months after the last dose. There are no data on the presence of luspatercept in human milk, the effects on the breast-fed child, or the effects on milk production. Luspatercept was detected in the milk of lactating rats.
For the treatment of anemia in patients with beta thalassemia who require regular red blood cell transfusions:
NOTE: Luspatercept is not indicated as a substitute for RBC transfusions in patients who require immediate correction of anemia.
NOTE: Luspatercept has been designated as an orphan drug for the treatment of beta thalassemia.
Subcutaneous dosage:
Adults: 1 mg/kg/dose subcutaneously once every 3 weeks, initially. Increase the dose to 1.25 mg/kg/dose once every 3 weeks if there is no reduction in red blood cell (RBC) transfusion burden after at least 2 consecutive doses. Max: 1.25 mg/kg/dose. Do not increase the dose if a patient experiences a severe or life-threatening adverse reaction. Therapy interruption, a dosage reduction, or discontinuation may be necessary in patients who develop elevated hemoglobin concentrations or severe adverse reactions. Discontinue therapy if there is no reduction in RBC transfusion burden after at least 3 consecutive doses at 1.25 mg/kg/dose.
For the treatment of myelodysplastic syndrome (MDS):
NOTE: Luspatercept is not indicated as a substitute for RBC transfusions in patients who require immediate correction of anemia.
NOTE: Luspatercept has been designated as an orphan drug for the treatment of MDS.
-for the treatment of anemia in patients with very low- to intermediate-risk MDS with ring sideroblasts or MDS/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis who failed an erythropoiesis stimulating agent and require 2 or more red blood cell (RBC) units over an 8-week period:
Subcutaneous dosage:
Adults: 1 mg/kg subcutaneously once every 3 weeks, initially. Increase the dose to 1.33 mg/kg once every 3 weeks, and then to a maximum of 1.75 mg/kg once every 3 weeks if there is no reduction in RBC transfusion burden after at least 2 consecutive doses at each dose level. Do not increase the dose if a patient experiences a severe or life-threatening adverse reaction. Therapy interruption, a dosage reduction, or discontinuation may be necessary in patients who develop elevated hemoglobin concentrations or severe adverse reactions. Discontinue therapy if there is no reduction in RBC transfusion burden (including no increase from baseline hemoglobin) after at least 3 consecutive doses (9 weeks) at the maximum dose. In patients treated with luspatercept in the randomized trial (n = 153), 22.9%, 18.3%, and 58.8% of patients received a maximum luspatercept dose of 1 mg/kg, 1.33 mg/kg, and 1.75 mg/kg, respectively.
-for the treatment of anemia in patients with very low- to intermediate-risk MDS who may require regular red blood cell (RBC) transfusions and have not previously received an erythropoiesis stimulating agent (ESA-naive):
Subcutaneous dosage:
Adults: 1 mg/kg subcutaneously once every 3 weeks, initially. Increase the dose to 1.33 mg/kg once every 3 weeks, and then to a maximum of 1.75 mg/kg once every 3 weeks if there is no reduction in RBC transfusion burden after at least 2 consecutive doses at each dose level. Do not increase the dose if a patient experiences a severe or life-threatening adverse reaction. Therapy interruption, a dosage reduction, or discontinuation may be necessary in patients who develop elevated hemoglobin concentrations or severe adverse reactions. Discontinue therapy if there is no reduction in RBC transfusion burden (including no increase from baseline hemoglobin) after at least 3 consecutive doses (9 weeks) at the maximum dose. The primary endpoint of RBC transfusion independence for at least 12 weeks with a concurrent mean hemoglobin level increase of at least 1.5 g/dL during weeks 1 to 24 was significantly improved with luspatercept compared with epoetin alfa (59% vs. 31%; odds ratio (OR) = 3.1; 95% CI, 1.9 to 5) in ESA-naive patients with lower risk myelodysplastic syndromes who required RBC transfusions in a prespecified interim analysis (n = 301) of a multinational, randomized, phase 3 (COMMANDS) trial. Additionally, RBC transfusion independence at 24 weeks was significantly improved in the luspatercept arm (48% vs. 29%; OR = 2.3; 95% CI, 1.4 to 3.8). In this trial eligible patients (median age, 74 years) had very low (9%), low (72%), or intermediate (17%) risk myelodysplastic syndromes and a median baseline serum erythropoietin concentration of 84.5 units/L. Supportive care for both treatment arms included transfusions, antibiotics, antivirals, and antifungals as required.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Anemia and Beta Thalassemia
-Elevated Hemoglobin (Hgb) Concentrations (in the absence of transfusions)
Predose Hgb concentration of 11.5 g/dL or more: Interrupt therapy; resume luspatercept when the Hgb concentration is 11 g/dL or less.
Hgb concentration increased by more than 2 g/dL within 3 weeks: Reduce every-3-week luspatercept by 1 dose level as follows: from 1.25 mg/kg to 1 mg/kg, from 1 mg/kg to 0.8 mg/kg, and from 0.8 mg/kg to 0.6 mg/kg; discontinue therapy in patients who require a dose reduction below 0.6 mg/kg.
-Hypersensitivity Reactions
Grade 3 or 4 toxicity: Discontinue luspatercept therapy.
-Other Severe or Life-Threatening Adverse Reactions
Grade 3 or 4 toxicity: Interrupt therapy; resume luspatercept when the toxicity resolves to grade 1 or less.
Extramedullary hematopoietic (EMH) masses causing serious complications: Discontinue luspatercept therapy.
Anemia and Myelodysplastic Syndromes
-Elevated Hgb Concentrations (in the absence of transfusions)
Predose Hgb concentration of 11.5 g/dL or more: Interrupt therapy; resume luspatercept when the Hgb concentration is 11 g/dL or less.
Hgb concentration increased by more than 2 g/dL within 3 weeks: Reduce every-3-week luspatercept by 1 dose level as follows: 1.75 mg/kg to 1.33 mg/kg, from 1.33 mg/kg to 1 mg/kg, from 1 mg/kg to 0.8 mg/kg, and from 0.8 mg/kg to 0.6 mg/kg; discontinue therapy in patients who require a dose reduction below 0.6 mg/kg. If after a dose reduction, a patient loses response (i.e., requires a transfusion) or the Hgb concentration decreases by 1 g/dL or more in 3 weeks in the absence of transfusion, increase luspatercept by 1 dose level; wait a minimum of 6 weeks between dose increases.
-Hypersensitivity Reactions
Grade 3 or 4 toxicity: Discontinue luspatercept therapy.
-Other Severe or Life-Threatening Adverse Reactions
Grade 3 or 4 toxicity: Interrupt therapy; resume luspatercept when the toxicity resolves to grade 1 or less at a reduced every-3-week dose as follows: from 1.75 mg/kg to 1.33 mg/kg, from 1.33 mg/kg to 1 mg/kg, from 1 mg/kg to 0.8 mg/kg, and from 0.8 mg/kg to 0.6 mg/kg. Discontinue therapy in patients who require a dose reduction below 0.6 mg/kg or if the dose delay is longer than 12 consecutive weeks.
Maximum Dosage Limits:
-Adults
1.75 mg/kg subcutaneously every 3 weeks.
-Geriatric
1.75 mg/kg subcutaneously every 3 weeks.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Luspatercept products.
Luspatercept-aamt is a receptor fusion protein consisting of 2 parts, a modified extracellular domain of the human activin receptor type IIB linked to a human immunoglobulin G1 Fc domain. It is produced in Chinese hamster ovary cells by recombinant DNA technology. Luspatercept works by binding several endogenous transforming growth factor (TGF)-beta superfamily ligands which causes decreased Smad2/3 signaling. In mice with beta thalassemia and myelodysplastic syndromes, luspatercept decreased abnormally elevated Smad2/3 signaling and improved hematology parameters associated with ineffective erythropoiesis; it also promoted erythroid maturation through differentiation and increasing the percentage of late-stage erythroid precursors (normoblasts) in the bone marrow. Additionally, increased erythroid precursors/erythropoiesis was demonstrated in human patients who received luspatercept.
Luspatercept is administered subcutaneously. In patients with beta thalassemia, the geometric mean apparent Vd of luspatercept was 7.1 L (coefficient of variation (CV), 26.7%), the geometric mean half-life was about 11 days (CV, 25.7%), and geometric mean apparent total clearance was 0.44 L/day (CV, 38.5%). In patients with myelodysplastic syndrome, the geometric mean apparent Vd of luspatercept was 9.6 L (CV, 26.7%), the geometric mean half-life was about 14 days (CV, 31.7%), and geometric mean apparent total clearance was 0.47 L/day (CV, 42.9%). It appears that luspatercept is metabolized via catabolism into amino acids by general protein degradation processes in multiple tissues.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Subcutaneous Route
Absorption of luspatercept is not significantly affected by injection sites (upper arm, thigh, or abdomen). Linear pharmacokinetics are observed over the dosage range 0.2 to 1.25 mg/kg in patients with beta thalassemia and over the dosage range 0.125 to 1.75 mg/kg in patients with myelodysplastic syndrome (MDS). At the starting dose of 1 mg/kg, the geometric mean steady-state AUC values were 126 mcg x day/mL (coefficient of variation (CV), 35.9%) and 154 mcg x day/mL (CV, 37.4%) in patients with beta thalassemia and MDS, respectively. The Tmax occurs at about 5 (range, 3 to 8) days post-dose in patients with beta thalassemia and 6 (range, 3 to 7) days post-dose in patients with MDS. Steady-state concentrations are achieved after 3 doses when administered every 3 weeks. The accumulation ratio is approximately 1.5.
During clinical trials, hemoglobin increased within 7 days of luspatercept initiation and correlated with Tmax in patients who had received less than 4 units of red blood cell transfusion within 8 weeks prior to the study. Hemoglobin increased the greatest after the first dose with additional smaller increases observed after subsequent doses. Hemoglobin concentrations returned to baseline approximately 6 to 8 weeks after the last dose. Increasing luspatercept exposure was associated with greater increases in hemoglobin.
-Special Populations
Hepatic Impairment
No clinically significant differences in luspatercept pharmacokinetic (PK) parameters were observed based on baseline albumin level (range, 30 to 56 g/L) or mild to severe hepatic impairment (AST or ALT levels above the upper limit of normal (ULN) without an elevated total bilirubin level or any AST or ALT levels with a total bilirubin level above the ULN). The effect of AST or ALT levels more than 3 times the ULN on the PK parameters of luspatercept is unknown.
Renal Impairment
No clinically significant differences in luspatercept pharmacokinetic (PK) parameters were observed based on mild to moderate renal impairment (estimated glomerular filtration rate (eGFR) of 30 to 89 mL/minute). The effect of severe renal impairment (eGFR less than 29 mL/minute) on the PK parameters of luspatercept is unknown.
Geriatric
No clinically significant differences in luspatercept pharmacokinetic parameters were observed based on age (18 to 95 years).
Gender Differences
No clinically significant differences in luspatercept pharmacokinetic parameters were observed based on gender.
Ethnic Differences
No clinically significant differences in luspatercept pharmacokinetic parameters were observed based on ethnicity (Asian, White).
Obesity
Increased body weight (range, 34 to 97 kg in patients with beta thalassemia; range, 33 to 124 kg in patients with myelodysplastic syndrome) resulted in increased apparent Vd and clearance of luspatercept.
Other
No clinically significant differences in luspatercept pharmacokinetic parameters were observed based on baseline serum erythropoietin level (range, 2.4 to 2,920 units/L), red blood cell transfusion burden (range, 0 to 43 units per 24 weeks), splenectomy status, beta thalassemia genotype (in patients with beta thalassemia), or ring sideroblasts status (in patients with myelodysplastic syndrome).