Written in Blood
Next-generation sequencing of DNA isolated from the bone marrow of
trial participants revealed one or more somatic mutations in 71 percent
of MDS patients (Group A), 62 percent of patients with ICUS and some
dysplasia (and only rare dysplastic morphology; Group B), and 20 percent of ICUS patients with no evidence of dysplasia (Group C; p<0.0001).
“Combining Groups B and C, 33 out of 120 of these ICUS patients
(28%) carried at least one somatic mutation indicative of clonal hematopoiesis,” the authors reported, and another nine ICUS patients without a
detected somatic mutation harbored a clonal chromosomal abnormality.
“We also learned that 33 percent of ICUS patients will have an acquired
gene mutation or chromosomal abnormality, indicating the presence of
clonal hematopoiesis [also referred to as clonal ICUS],” Dr. Bejar said.
“Many of the mutated genes we identified in clonal ICUS patients are the
same genes mutated in patients with MDS and other myeloid malignancies
and are particularly common in patients with some evidence of dysplasia.”
The retrospective study analyzed bone marrow samples that had been
submitted to a commercial laboratory between January and June 2014
for the evaluation of persistent unexplained cytopenias. The analysis
identified 249 patients with ICUS and 91 patients with lower-risk MDS.
Patients were required to have a comprehensive bone marrow evaluation
with a morphology review, flow cytometry, karyotype analysis, fluorescence in situ hybridization, and myeloid gene sequencing, then classified
into one of three cohorts:
• MDS
• ICUS with mild dysplasia
Brief Summary of Full Prescribing Information
InjectaFer® (ferric carboxymaltose injection)
rx Only
InDIcatIOnS anD USaGe: Injectafer® (ferric carboxymaltose injection) is an iron replacement
product indicated for the treatment of iron deficiency anemia in adult patients:
• who have intolerance to oral iron or who have had unsatisfactory response to oral iron,
• who have non-dialysis dependent chronic kidney disease.
DOSaGe anD aDMInIStratIOn: For patients weighing 50 kg (110 lb) or more: Give
Injectafer® in two doses separated by at least 7 days. Give each dose as 750 mg for a total
cumulative dose not to exceed 1500 mg of iron per course.
For patients weighing less than 50 kg (110 lb): Give Injectafer® in two doses separated by
at least 7 days. Give each dose as 15 mg/kg body weight for a total cumulative dose not to
exceed 1500 mg of iron per course.
Injectafer® treatment may be repeated if iron deficiency anemia reoccurs.
Administer Injectafer® intravenously, either as an undiluted slow intravenous push or by
infusion. When administering as a slow intravenous push, give at the rate of approximately
100 mg (2 mL) per minute. When administered via infusion, dilute up to 750 mg of iron in no
more than 250 mL of sterile 0.9% sodium chloride injection, USP, such that the concentration
of the infusion is not less than 2 mg of iron per mL and administer over at least 15 minutes.
Inspect parenteral drug products visually for the absence of particulate matter and
discoloration prior to administration. The product contains no preservatives. Injectafer® is a
single-use vial. Discard unused portion.
Avoid extravasation of Injectafer® since brown discoloration of the extravasation site may be
long lasting. Monitor for extravasation. If extravasation occurs, discontinue the Injectafer®
administration at that site.
DOSaGe FOrMS anD StrenGtHS: Single-use vials containing 50 mg elemental iron
per mL in the following presentation: 750 mg iron/15 mL
cOntraInDIcatIOnS: Hypersensitivity to Injectafer® or any of its inactive components.
WarnInGS anD PrecaUtIOnS
Hypersensitivity reactions: Serious hypersensitivity reactions, including anaphylactictype reactions, some of which have been life-threatening and fatal, have been reported
in patients receiving Injectafer®. Patients may present with shock, clinically significant
hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and
symptoms of hypersensitivity during and after Injectafer® administration for at least 30
minutes and until clinically stable following completion of the infusion. Only administer
Injectafer® when personnel and therapies are immediately available for the treatment of
serious hypersensitivity reactions. In clinical trials, serious anaphylactic/anaphylactoid reactions
were reported in 0.1% (2/1775) of subjects receiving Injectafer®. Other serious or severe adverse
reactions potentially associated with hypersensitivity which included, but not limited to, pruritus,
rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these subjects.
Hypertension: In clinical studies, hypertension was reported in 3.8% (67/1775) of subjects
in clinical trials 1 and 2. Transient elevations in systolic blood pressure, sometimes occurring
with facial flushing, dizziness, or nausea were observed in 6% (106/1775) of subjects in these
two clinical trials. These elevations generally occurred immediately after dosing and resolved
within 30 minutes. Monitor patients for signs and symptoms of hypertension following each
Injectafer® administration.
Laboratory test alterations: In the 24 hours following administration of Injectafer®,
laboratory assays may overestimate serum iron and transferrin bound iron by also measuring
the iron in Injectafer®.
aDVerSe reactIOnS
adverse reactions in clinical trials: Because clinical trials are conducted under widely
varying conditions, the adverse reaction rates observed cannot be directly compared to rates
in other clinical trials and may not reflect the rate s observed in clinical practice.
In two randomized clinical studies, a total of 1775 patients were exposed to Injectafer®
15 mg/kg body weight up to a maximum single dose of 750 mg of iron on two occasions
separated by at least 7 days up to a cumulative dose of 1500 mg of iron.
Adverse reactions reported by ≥ 1% of treated patients are shown in the following table.
Table 1. Adverse reactions reported in ≥ 1% of Study Patients in Clinical Trials 1 and 2
Injectafer® Pooled Comparatorsa
(N=1775)
(N=1783)
%
%
Nausea
7.2
1.8
Hypertension
3.8
1.9
Flushing/Hot Flush
3.6
0.2
Blood Phosphorus Decrease
2.1
0.1
Dizziness
2.0
1.2
Vomiting
1.7
0.5
Injection Site Discoloration
1.4
0.3
Headache
1.2
0.9
Alanine Aminotransferase Increase
1.1
0.2
Dysgeusia
1.1
2.1
Hypotension
1.0
1.9
Constipation
0.5
0.9
a
Includes oral iron and all formulations of IV iron other than Injectafer®
Term
Oral iron
(N=253)
%
1.2
0.4
0.0
0.0
0.0
0.4
0.0
0.0
0.0
0.0
0.0
3.2
Transient decreases in laboratory blood phosphorus levels (< 2 mg/dL) have been observed in
27% (440/1638) of patients in clinical trials.
adverse reactions from Post-marketing experience: The following serious adverse
reactions have been most commonly reported from the post-marketing spontaneous reports
with Injectafer®: urticaria, dyspnea, pruritus, tachycardia, erythema, pyrexia, chest discomfort,
chills, angioedema, back pain, arthralgia, and syncope. One case of hypophosphatemic
osteomalacia was reported in a subject who received 500 mg of Injectafer® every 2 weeks for
a total of 16 weeks. Partial recovery followed discontinuation of Injectafer®.
DrUG InteractIOnS: Formal drug interaction studies have not been performed
with Injectafer®.
USe In SPecIFIc POPULatIOnS
Pregnancy Pregnancy Category C: Adequate and well controlled studies in pregnant women
have not been conducted. Injectafer® should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
nursing Mothers: A study to determine iron concentrations in breast milk after administration
of Injectafer® (n=11) or oral ferrous sulfate (n=14) was conducted in 25 lactating women with
postpartum iron deficiency anemia. Mean breast milk iron levels were higher in lactating
women receiving Injectafer® than in lactating women receiving oral ferrous sulfate.
Pediatric Use: Safety and effectiveness has not been established in pediatric patients.
Geriatric Use: Of the 1775 subjects in clinical studies of Injectafer®, 50% were 65 years and
over, while 25% were 75 years and over. No overall differences in safety or effectiveness were
observed between these subjects and younger subjects, and other reported clinical experience
has not identified differences in responses between the elderly and younger patients, but
greater sensitivity of some older individuals cannot be ruled out.
OVerDOSaGe: Excessive dosages of Injectafer® may lead to accumulation of iron in storage
sites potentially leading to hemosiderosis. A patient who received Injectafer® 18,000 mg
over 6 months developed hemosiderosis with multiple joint disorder, walking disability and
asthenia. Hypophosphatemic osteomalacia was reported in a patient who received Injectafer®
4000 mg over 4 months. Partial recovery followed discontinuation of Injectafer®.
DeScrIPtIOn: Ferric carboxymaltose, an iron replacement product, is an iron
carbohydrate complex with the chemical name of polynuclear iron (III) hydroxide
4(R)-(poly-(1→4)-O-α-D-glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate.
It has a relative molecular weight of approximately 150,000 Da.
Injectafer® (ferric carboxymaltose injection) is a dark brown, sterile, aqueous, isotonic colloidal
solution for intravenous injection. Each mL contains 50 mg iron as ferric carboxymaltose in
water for injection. Sodium hydroxide and/or hydrochloric acid may have been added to adjust
the pH to 5.0-7.0. The vial closure is not made with natural rubber latex.
cLInIcaL PHarMacOLOGY
Mechanism of action: Ferric carboxymaltose is a colloidal iron (III) hydroxide in complex
with carboxymaltose, a carbohydrate polymer that releases iron.
Pharmacodynamics: Using positron emission tomography (PET) it was demonstrated that
red cell uptake of 59Fe and 52Fe from Injectafer® ranged from 61% to 99%. In patients with
iron deficiency, red cell uptake of radio-labeled iron ranged from 91% to 99% after 24 days
Injectafer® dose. In patients with renal anemia red cell uptake of radio-labeled iron ranged
from 61% to 84% after 24 days Injectafer® dose.
Pharmacokinetics: After administration of a single dose of Injectafer® of 100 to 1000 mg
of iron in iron deficient patients, maximum iron levels of 37 µg/mL to 333 µg/mL were
obtained respectively after 15 minutes to 1.21 hours post dose. The volume of distribution
was estimated to be 3 L. The iron injected or infused was rapidly cleared from the plasma, the
terminal half life ranged from 7 to 12 hours. Renal elimination of iron was negligible.
nOncLInIcaL tOXIcOLOGY
carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenicity studies have
not been performed with ferric carboxymaltose.
Ferric carboxymaltose was not genotoxic in the following genetic toxicology studies:
in vitro microbial mutagenesis (Ames) assay, in vitro chromosome aberration test in human
lymphocytes, in vitro mammalian cell mutation assay in mouse lymphoma L5178Y/TK+/- cells,
in vivo mouse micronucleus test at single intravenous doses up to 500 mg/kg.
In a combined male and female fertility study, ferric carboxymaltose was administered
intravenously over one hour to male and female rats at iron doses of up to 30 mg/kg. Animals
were dosed 3 times per week (on Days 0, 3, and 7). There was no effect on mating function,
fertility or early embryonic development. The dose of 30 mg/kg in animals is approximately
40% of the human dose of 750 mg based on body surface area.
cLInIcaL StUDIeS: The safety and efficacy of Injectafer® for treatment of iron deficiency
anemia were evaluated in two randomized, open-label, controlled clinical trials (Trial 1 and
Trial 2). In these two tr ials, Injectafer® was administered at dose of 15 mg/kg body weight up
to a maximum single dose of 750 mg of iron on two occasions separated by at least 7 days up
to a cumulative dose of 1500 mg of iron.
PatIent cOUnSeLInG InFOrMatIOn
• Question patients regarding any prior history of reactions to parenteral iron products.
• Advise patients of the risks associated with Injectafer®.
• Advise patients to report any signs and symptoms of hypersensitivity that may develop
during and following Injectafer® administration, such as rash, itching, dizziness,
lightheadedness, swelling and breathing problems.
Injectafer® is manufactured under license from Vifor (International) Inc, Switzerland.
• ICUS with no dysplasia
In this cohort, the researchers identified
mutations in 79 percent of patients with
MDS, 45 percent of patients with ICUS with
mild dysplasia, and 17 percent of patients
with ICUS with no dysplasia. The spectrum
of mutated genes was similar, with the exception of SF3B1, which was rarely mutated
in patients without dysplasia.
Many of the
mutated genes
identified in
clonal ICUS patients were also
found in MDS.
It should be noted, however, that identifying a genomic abnormality in a patient
with cytopenias does not necessarily produce an MDS diagnosis. “We do not have
a clear understanding of what happens to
clonal ICUS patients over time,” Dr. Bejar
cautioned. “The presence of an MDS-like
gene mutation in a patient who does not
meet the standard diagnostic criteria
for MDS cannot be used as presumptive
evidence of the disease.”
He added: “These mutations should
not be used to justify treatment with
MDS-specific drugs like the hypomethylating agents. Clonal ICUS patients will
have to be followed over time to determine their risk of clinical progression,
and eventually, teach us how to interpret
mutations in cytopenic patients.”
Due to the limited patient follow-up,
additional clinical trials are needed to
determine the significance of somatic
mutations in ICUS patients, the authors
concluded. ●
REFERENCE
IN0650BS
Iss. 7/2013
Kwok B, Hall JM, Witte JS, et al. MDS-associated somatic mutations
and clonal hematopoiesis are common in idiopathic cytopenias of
undetermined significance. Blood. 2015 October 1. [Epub ahead of print]
November 2015