35/19. Luspatercept-aamt-@- (REBLOZYL)- (Nov 2019- Treatment of Anemia
Drug Name:35/19. Luspatercept-aamt-@- (REBLOZYL)- (Nov 2019- Treatment of Anemia
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
Drug Interaction Studies
Effect of Iron-chelating Agents on Luspatercept-aamt. No clinically significant differences in luspatercept-aamt PK were observed when used concomitantly with iron-chelating agents.
Indication:
WARNINGS-
• Thrombosis/Thromboembolism: Increased risk in patients with beta thalassemia. Monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly
• Hypertension: Monitor blood pressure (BP) during treatment. Initiate anti-hypertensive treatment if necessary
Advise beta thalassemia patients of the potential risk of thromboembolic events. Review known risk factors for developing thromboembolic events and advise patients to reduce modifiable risk factors (e.g., smoking, use of oral contraceptives)
Effects on Blood Pressure
Caution patients that REBLOZYL may cause an increase in blood pressure
Adverse Reaction:
ADVERSE REACTIONS
The most common adverse reactions (>10%) in patients with beta thalassemia were headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, and dizziness
Contra-Indications:
WARNINGS AND PRECAUTIONS
• Thrombosis/Thromboembolism: Increased risk in patients with beta thalassemia. Monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly
• Hypertension: Monitor blood pressure (BP) during treatment. Initiate anti-hypertensive treatment if necessary
• Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception.
Dosages/ Overdosage Etc:
Patient Information:
PATIENT COUNSELING INFORMATION
Discuss the following with patients prior to and during treatment with REBLOZYL.
Thromboembolic Events
Advise beta thalassemia patients of the potential risk of thromboembolic events. Review known risk factors for developing thromboembolic events and advise patients to reduce modifiable risk factors (e.g., smoking, use of oral contraceptives)
Effects on Blood Pressure
Caution patients that REBLOZYL may cause an increase in blood pressure [
Embryo-Fetal Toxicity
Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception while receiving REBLOZYL and for at least 3 months after the final dose.
Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with REBLOZYL
Advise females not to breastfeed during treatment with REBLOZYL and for 3 months after the final dose
Manufactured by: Celgene Corporation 86 Morris Avenue Summit, NJ 07901 U.S. License No. 2114
Jointly Marketed by: Acceleron Pharma, Inc. Cambridge, MA 02139 REBLOZYL® is a registered trademark of Celgene Corporation. Patent: www.celgene.com/therapies © 2016-2019 Celgene Corporation. All Rights Reserved. REBPI
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action
Luspatercept-aamt is a recombinant fusion protein that binds several endogenous TGF-ß superfamily ligands, thereby diminishing Smad2/3 signaling. Luspatercept-aamt promoted erythroid maturation through differentiation of late-stage erythroid precursors (normoblasts) in mice.
2. Pharmacodynamics
Increases in Hemoglobin in Patients with Low RBC Transfusion Burden
In patients having received < 4 units of RBC transfusion within 8 weeks prior to study, hemoglobin increased within 7 days of initiating REBLOZYL and correlated with the time to luspatercept-aamt maximum serum concentration (Cmax).
3. Pharmacokinetics
Luspatercept-aamt exhibited linear pharmacokinetics (PK) over the dose range of 0.2 to 1.25 mg/kg (0.2 to 1.25 times the recommended starting dosage) in patients with beta thalassemia.
The mean (%CV) steady-state Cmax was 8.17 (29.9%) µg/mL at 1 mg/kg and 10.2 (29.9%) µg/mL at 1.25 mg/kg in patients with beta thalassemia.
Absorption
The median (range) time to maximum concentration (Tmax) of luspatercept-aamt was observed at approximately 7 [6 to 8] days post-dose in adult healthy volunteers and patients with beta thalassemia.
The absorption of luspatercept-aamt was not significantly affected by the subcutaneous injection sites (upper arm, thigh, or abdomen).
Distribution
The mean (%CV) apparent volume of distribution (Vd/F) of luspatercept-aamt was 7.1 (26.7%) L for patients with beta thalassemia.
Elimination
The mean (%CV) half-life (t1/2) of luspatercept-aamt was approximately 11 (25.7%) days and the mean (%CV) apparent total clearance (CL/F) was 0.44 (38.5%) L/day in patients with beta thalassemia.
Metabolism
Luspatercept-aamt is expected to be catabolized into amino acids by general protein degradation processes in multiple tissues.
Specific Populations
No clinically significant differences in the luspatercept-aamt PK was observed based on age (18 to 66 years), sex, race/ethnicity (Asian, White),
Mild to severe hepatic impairment (total bilirubin = upper limit of normal [ULN] and aspartate aminotransaminase [AST] or alanine transaminase [ALT] > ULN, or total bilirubin > ULN and any AST or ALT)
Mild to moderate renal impairment estimated lomerular filtration rate [eGFR] 30 to 89 mL/min/1.73 m2 ), baseline albumin (30 to 56 g/L), baseline serum erythropoietin (2.4 to 972 U/L), red blood cell (RBC) transfusion burden (0 to 34 units/24 weeks), beta thalassemia genotype (ß0/ß0 vs. non-ß0/ß0) and splenectomy.
Body Weight The apparent CL/F and Vd/F of luspatercept-aamt increased with increasing body weight (34 to 97 kg).
Drug Interaction Studies
Effect of Iron-chelating Agents on Luspatercept-aamt. No clinically significant differences in luspatercept-aamt PK were observed when used concomitantly with iron-chelating agents.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy Risk Summary
Based on findings in animal reproduction studies, REBLOZYL may cause fetal harm when administered to a pregnant woman.
There are no available data on REBLOZYL use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal 9 or fetal outcomes.
Advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
2. Lactation Risk Summary
Luspatercept-aamt was detected in milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk.
There are no data on the presence of REBLOZYL in human milk, the effects on the breastfed child, or the effects on milk production.
Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with REBLOZYL, and for 3 months after the last dose.
3. Females and Males of Reproductive Potential Pregnancy Testing
Pregnancy testing is recommended for females of reproductive potential before starting REBLOZYL treatment.
Contraception
Females REBLOZYL may cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].
Advise female patients of reproductive potential to use effective contraception during treatment with REBLOZYL and for at least 3 months after the last dose.
Infertility Females
Based on findings in animals, REBLOZYL may impair female fertility . Adverse effects on fertility in female rats were reversible after a 14-week recovery period.
4. Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Based on findings in juvenile animals, REBLOZYL is not recommended for use in pediatric patients.
5. Geriatric Use
Clinical studies of REBLOZYL in beta thalassemia did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects.