Included as part of the PRECAUTIONS section.
In adult patients with beta thalassemia, thromboembolic
events (TEE) were reported in 8/223 (3.6%) REBLOZYL-treated patients. Reported
TEEs included deep vein thromboses, pulmonary embolus, portal vein thrombosis,
and ischemic strokes. Patients with known risk factors for thromboembolism,
e.g. splenectomy or concomitant use of hormone replacement therapy, may be at
further increased risk of thromboembolic conditions. Consider
thromboprophylaxis in patients with beta thalassemia at increased risk of TEE.
Monitor patients receiving REBLOZYL for signs and symptoms of thromboembolic
events and institute treatment promptly.
Hypertension was reported in 10.7% (61/571) of
REBLOZYL-treated patients. Across clinical studies, the incidence of grade 3-4
hypertension ranged from 1.8% to 8.6%. In adult patients with beta thalassemia
with normal baseline blood pressure, 13 (6.2%) patients developed systolic
blood pressure (SBP) > 130 mm Hg and 33 (16.6%) patients developed diastolic
blood pressure (DBP) > 80 mm Hg. Monitor blood pressure prior to each
administration. Manage new-onset hypertension or exacerbations of preexisting
hypertension using anti-hypertensive agents.
Based on findings from animal reproductive studies,
REBLOZYL may cause fetal harm when administered to a pregnant woman. In animal
reproduction studies, administration of luspatercept-aamt to pregnant rats and
rabbits during organogenesis resulted in adverse developmental outcomes
including increased embryo-fetal mortality, alterations to growth, and
structural abnormalities at exposures (based on area under the curve [AUC])
above those occurring at the maximum recommended human dose (MRHD) of 1.25
Advise pregnant women of the potential risk to a fetus.
Advise females of reproductive potential to use an effective method of
contraception during treatment with REBLOZYL and for at least 3 months after
the final dose [see Use In Specific Populations].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No carcinogenicity or mutagenicity studies have been
conducted with luspatercept-aamt.
In a repeat-dose toxicity study, juvenile rats were
administered luspatercept-aamt subcutaneously at 1, 3, or 10 mg/kg once every 2
weeks from postnatal day 7 to 91. Hematologic malignancies (granulocytic leukemia,
lymphocytic leukemia, malignant lymphoma) were observed at 10 mg/kg resulting
in exposures (based on area under the curve [AUC]) approximately 8 times the
maximum recommended human dose (MRHD) of 1.25 mg/kg.
In a combined male and female fertility and early
embryonic development study in rats, luspatercept-aamt was administered
subcutaneously to animals at doses of 1 to 15 mg/kg. There were significant
reductions in the average numbers of corpora lutea, implantations, and viable
embryos in luspatercept-aamt-treated females. Effects on female fertility were
observed at the highest dose with exposures (based on AUC) approximately 7
times the MRHD of 1.25 mg/kg.
Adverse effects on fertility in female rats were
reversible after a 14-week recovery period. No adverse effects were noted in
Use In Specific Populations
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 or fetal
outcomes. In animal reproduction studies, administration of luspatercept-aamt
to pregnant rats and rabbits during the period of organogenesis resulted in
adverse developmental outcomes including embryo-fetal mortality, alterations to
growth, and structural abnormalities at exposures (based on area under the
curve [AUC]) above those occurring at the maximum recommended human dose (MRHD)
(see Data). 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%,
In embryo-fetal development studies, luspatercept-aamt
was administered subcutaneously at 5, 15, or 30 mg/kg on gestation days 3 and 10
(rats) or 5, 20, or 40 mg/kg on gestation days 4 and 11 (rabbits). Effects in
both species included reductions in numbers of live fetuses and fetal body
weights, and increases in resorptions, post-implantation losses, and skeletal
variations (such as asymmetric sternal centra in rats and angulated hyoid in
rabbits). Effects were observed at exposures (based on AUC) approximately
13-times (rats) and 18-times (rabbits) the MRHD of 1.25 mg/kg.
In a pre- and postnatal development study, pregnant rats
were administered luspatercept-aamt subcutaneously at 3, 10, or 30 mg/kg once
every 2 weeks during organogenesis and through weaning, gestation day 6 through
postnatal day 20. At all dose levels lower F1 pup body weights and adverse
kidney findings (such as membranoproliferative glomerulonephritis, tubular
atrophy/hypoplasia, and vessel ectasia occasionally associated with hemorrhage)
were observed. These effects were observed at exposures (based on AUC)
approximately 1.6-times the MRHD of 1.25 mg/kg.
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.
Females And Males Of Reproductive Potential
Pregnancy testing is recommended for females of
reproductive potential before starting REBLOZYL treatment.
REBLOZYL may cause embryo-fetal harm when administered to
pregnant women [see Use In Specific Populations]. Advise female patients
of reproductive potential to use effective contraception during treatment with
REBLOZYL and for at least 3 months after the last dose.
Based on findings in animals, REBLOZYL may impair female
fertility [see Nonclinical Toxicology]. Adverse effects on fertility in
female rats were reversible after a 14-week recovery period.
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 [see Non-Clinical Toxicology].
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.