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Discover the differences in
IV iron therapies
Dextran/Modified Dextran
Non-Dextran
Pharmacy Specifications
Administration
Dosing
Indications/
Contraindications
Injectafer®
Indications
Venofer®
2
1
(ferric carboxymaltose injection)
(iron sucrose injection, USP)
Treatment of iron deficiency
anemia (IDA) in adult patients who
have intolerance to oral iron or
have had unsatisfactory response
to oral iron, and in adult patients
with non-dialysis dependent
chronic kidney disease
Treatment of IDA in patients
with chronic kidney disease
Ferrlecit®3/
Generic available
INFeD®4
Feraheme®5
(sodium ferric gluconate
complex injection)
(iron dextran injection, USP)
(ferumoxytol injection)
Treatment of IDA in patients age 6 years
and older with chronic kidney disease
receiving hemodialysis who are receiving
supplemental epoetin therapy
Treatment of patients with
documented iron deficiency
in whom oral administration is
unsatisfactory or impossible
Treatment of IDA in adult patients
with chronic kidney disease
Hypersensitivity to the product
Known hypersensitivity to Feraheme
or any of its components
Contraindications
Hypersensitivity to Injectafer® or
any of its inactive components
Known hypersensitivity to Venofer®
Known hypersensitivity to sodium ferric
gluconate or any of its inactive components
Single dose
750 mg
(2 doses separated
by at least 7 days)
100 mg to 400 mg,
depending upon the indication
The maximum dosage should
not exceed 125 mg per dose
Individual doses of 100 mg or less may
be given on a daily basis
Initial 510 mg dose followed by a
second 510 mg dose 3 to 8 days later
Recommended
cumulative dose
Total cumulative dose not to
exceed 1500 mg of iron per course
Usual total treatment course is 1000 mg
Most patients may require a
cumulative dose of 1000 mg
Ranges based on the calculated
iron requirement for each patient*
1020 mg
Number of administrations
for recommended
cumulative dose
(maximum dose)
(for non-dialysis CKD IDA)
IV Push
Yes
Yes
All anemias not associated
with iron deficiency
History of allergic reaction to any
intravenous iron product
to
Yes
Yes
to
IV Infusion
No
Not indicated
Yes, over at least 15 minutes
Yes, over 15 minutes to 2.5 hours,
depending on dose
Yes, over 1 hour
Test Dose Required
No
No
No
Yes
No
MRI Interference
No
No
No
No
Yes (for up to 3 months)
Stability when mixed with
0.9% NaCl
Stable for 72 hrs at
room temperature at
concentrations of 2 mg to
4 mg of iron per mL
Stable for 7 days
• Admixture: concentrations of 1 mg to
2 mg of iron per mL at controlled
room temperature
• Syringe: concentrations of 2 mg to 10 mg
of iron per mL (or undiluted) at controlled
room temperature or under refrigeration
Not listed in package insert
Not listed in package insert
Stable for 4 hours at room temperature
in either 0.9% sodium chloride or
5% dextrose at concentrations
of 2 mg to 8 mg of iron per mL
Preservative
None
None
Benzyl alcohol
None
None
How Supplied
750 mg/15 mL single-use vial
50 mg/2.5 mL single-use vial
100 mg/5 mL single-use vial
200 mg/10 mL single-use vial
62.5 mg/5 mL single-use vial
100 mg/2 mL single-use vial
510 mg/17 mL
single-use vial
Please see attached Full Prescribing Information for Injectafer ® and Venofer ® and Important safety Information on next page.
Yes, over at least 15 minutes
Important Safety Information on next page.
*The total amount of INFeD® required for the treatment of iron deficiency anemia is
determined based on the table and formula in the INFeD® Full Prescribing Information.
INJECTAFER® (ferric carboxymaltose injection)
INDICATIONS
Injectafer® is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients who have intolerance to
oral iron or have had unsatisfactory response to oral iron, and in adult patients with non-dialysis dependent chronic kidney disease.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
Injectafer® is contraindicated in patients with hypersensitivity to Injectafer® or any of its inactive components.
WARNINGS AND PRECAUTIONS
Serious hypersensitivity reactions, including anaphylactic-type 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 were not limited to, pruritus, rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these subjects.
In clinical studies, hypertension was reported in 3.8% (67/1775) of subjects. Transient elevations in systolic blood pressure, sometimes
occurring with facial flushing, dizziness, or nausea were observed in 6% (106/1775) of subjects. These elevations generally occurred
immediately after dosing and resolved within 30 minutes. Monitor patients for signs and symptoms of hypertension following each
Injectafer® administration.
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
In two randomized clinical studies, a total of 1775 patients were exposed to Injectafer®, 15 mg/kg of body weight, up to a single
maximum 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 ≥2% of Injectafer®-treated patients were nausea (7.2%); hypertension (3.8%); flushing/hot flush (3.6%); blood
phosphorus decrease (2.1%); and dizziness (2.0%).
The following serious adverse reactions have been most commonly reported from the post-marketing spontaneous reports: urticaria,
dyspnea, pruritus, tachycardia, erythema, pyrexia, chest discomfort, chills, angioedema, back pain, arthralgia, and syncope.
Please see attached Full Prescribing Information for Injectafer®.
VENOFER® (iron sucrose injection, USP)
INDICATION
Venofer® is indicated for the treatment of iron deficiency anemia in patients with chronic kidney disease.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
Venofer® is contraindicated in patients with known hypersensitivity to Venofer®.
WARNINGS AND PRECAUTIONS
Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening
and fatal, have been reported in patients receiving Venofer®. Patients may present with shock, clinically significant
hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during
administration, stop Venofer® immediately. Monitor patients for signs and symptoms of hypersensitivity during and
after Venofer® administration for at least 30 minutes and until clinically stable following completion of the infusion.
Only administer Venofer® when personnel and therapies are immediately available for the treatment of serious
hypersensitivity reactions. Most reactions associated with intravenous iron preparations occur within 30 minutes of the completion
of the infusion.
Venofer® may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration
of Venofer®. Hypotension following administration of Venofer® may be related to rate of administration and/or total dose delivered.
Excessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. All adult and
pediatric patients receiving Venofer® require periodic monitoring of hematologic and iron parameters (hemoglobin, hematocrit, serum
ferritin and transferrin saturation). Do not administer Venofer® to patients with evidence of iron overload. Transferrin saturation (TSAT)
values increase rapidly after intravenous administration of iron sucrose; do not perform serum iron measurements for at least 48 hours
after intravenous dosing.
ADVERSE REACTIONS
The most common adverse reactions (≥2%) following the administration of Venofer® are diarrhea, nausea, vomiting, headache,
dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain and
peripheral edema. Additional adverse reactions include infusion site pain or burning, graft complications, and nasopharyngitis, sinusitis,
upper respiratory tract infections and pharyngitis.
In pediatric patients, more than 50% of the patients experienced at least one treatment-emergent reaction. The most common adverse
reactions (≥2%) were headache, respiratory tract viral infection, peritonitis, vomiting, pyrexia, dizziness, cough, renal transplant,
nausea, arteriovenous fistula thrombosis, hypotension and hypertension.
In post-marketing safety studies of Venofer® in 1,051 patients with HDD-CKD, adverse reactions reported by >1% were cardiac failure
congestive, sepsis and dysgeusia.
Because adverse reactions from post-marketing experience are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In addition to potential serious
hypersensitivity reactions, the following adverse reactions have been identified during post-approval use of Venofer®: bronchospasm,
dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, bradycardia and chromaturia.
Symptoms associated with Venofer® total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea,
dizziness, joint aches, paresthesia, abdominal and muscle pain, edema and cardiovascular collapse. These adverse reactions have
occurred up to 30 minutes after the administration of Venofer® injections. Reactions have occurred following the first dose or subsequent
doses of Venofer®. Slowing the infusion rate may alleviate symptoms.
Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.
Please see attached Full Prescribing Information for Venofer®.
References: 1. Injectafer® (ferric carboxymaltose injection) [package insert]. Shirley, NY: American Regent, Inc.; 2013. 2. Venofer® (iron sucrose injection, USP)
[package insert]. Shirley, NY: American Regent, Inc.; 2013. 3. Ferrlecit® (sodium ferric gluconate complex injection) [package insert]. Bridgewater, NJ: sanofiaventis US LLC, 2011. 4. INFeD® (iron dextran injection, USP) [package insert]. Morristown, NJ: Watson Pharma, Inc; 2009. 5. Feraheme® (ferumoxytol injection)
[package insert]. Waltham, MA: AMAG Pharmaceuticals, Inc; 2015.
American Regent® is a registered trademark of Luitpold Pharmaceuticals, Inc.
Venofer®, Injectafer® and the Injectafer® logo are trademarks of Vifor (International), Inc., Switzerland.
Venofer® and Injectafer® are manufactured under license from Vifor (International), Inc., Switzerland.
Trademarks not owned by Luitpold Pharmaceuticals, Inc. or Vifor (International) are the property of their
respective owners.
©2015 American Regent, Inc.
FCM192EM
Iss. 07/2015
®
r
INJECTAFER®
(ferric carboxymaltose injection)
--------------------------DOSAGE FORMS AND STRENGTHS----------------------750 mg iron / 15 mL single-use vial. (3)
-------------------------------CONTRAINDICATIONS--------------------------------Hypersensitivity to Injectafer or any of its inactive components. (4)
------------------------WARNINGS AND PRECAUTIONS---------------------------• Hypersensitivity reactions: Observe for signs and symptoms of
hypersensitivity during and after Injectafer administration for at least
30 minutes and until clinically stable following completion of each
administration. (5.1)
• Hypertension: Monitor patients closely for signs and symptoms of
hypertension following each Injectafer administration. (5.2)
------------------------------ADVERSE REACTIONS---------------------------------The most common adverse reactions (≥ 2%) are nausea, hypertension,
flushing, hypophosphatemia, and dizziness (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact American Regent at
1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------USE IN SPECIFIC POPULATIONS---------------------------• Nursing Mothers: Exercise caution when administered to a nursing
woman. (8.3)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved
patient labeling.
Revised: July 2013
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICALRQ105200
STUDIES
14.1 Trial 1: Iron Deficiency Anemia in Patients Who are Intolerant to
Oral Iron or Have Had Unsatisfactory Response to Oral Iron
14.2 Trial 2: Iron Deficiency Anemia in Patients with Non-Dialysis
Dependent Chronic Kidney Disease
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
RQ105200
*Sections or subsections omitted from the full prescribing information
are not listed.
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.
5.2 Hypertension
In clinical studies, hypertension was reported in 3.8% (67/1,775) 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% (106/1,775) 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 [see Dosage and Administration (2)].
5.3 Laboratory Test Alterations
--------------------------DOSAGE
FORMS AND STRENGTHS----------------------In the 24 hours following administration of Injectafer, laboratory assays may
750 mg iron / 15 mL single-use vial. (3)
overestimate serum iron and transferrin bound iron by also measuring the
-------------------------------CONTRAINDICATIONS--------------------------------iron
in Injectafer.
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
Injectafer is indicated for the treatment of iron deficiency anemia in adult
patients:
• who have intolerance to oral iron or have had unsatisfactory response to
oral iron;
• who have non-dialysis dependent chronic kidney disease.
2
DOSAGE AND ADMINISTRATION
For patients weighing 50 kg (110lb) 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 (110lb): 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.
The dosage of Injectafer is expressed in mg of elemental iron. Each mL of
Injectafer contains 50 mg of elemental iron. 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.
When added to an infusion bag containing 0.9% sodium chloride injection,
USP, at concentrations ranging from 2 mg to 4 mg of iron per mL, Injectafer
solution is physically and chemically stable for 72 hours when stored at room
temperature. To maintain stability, do not dilute to concentrations less than
2 mg iron/mL.
Inspect parenteral drug products visually for the absence of particulate
matter and discoloration prior to administration. The product contains no
preservatives. Each vial of Injectafer is intended for single-use only. Any
unused drug remaining after injection must be discarded.
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.
3
*Sections or subsections omitted from the full prescribing information
are not listed.
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.
5.2 Hypertension
In clinical studies, hypertension was reported in 3.8% (67/1,775) 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% (106/1,775) 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 [see Dosage and Administration (2)].
5.3 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.
6
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other
sections of the labeling:
• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
• Hypertension [see Warnings and Precautions (5.2)]
• Laboratory Test Alterations [see Warnings and Precautions (5.3)]
6.1 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 rates observed in clinical practice.
In two randomized clinical studies [Studies 1 and 2, See Clinical Studies (14)],
a total of 1,775 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
Term
DOSAGE FORMS AND STRENGTHS
750 mg iron / 15 mL single-use vial
4
CONTRAINDICATIONS
Nausea
Hypertension
Flushing/Hot Flush
Blood Phosphorus Decrease
Dizziness
Vomiting
Injection Site Discoloration
Headache
Alanine Aminotransferase
Increase
Dysgeusia
Hypotension
Constipation
Hypersensitivity to Injectafer or any of its components [see Warnings and
Precautions (5.1)].
5
WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions
Serious hypersensitivity reactions, including anaphylactic-type 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. [see Adverse Reactions (6.1 and 6.2)].
DRUG INTERACTIONS
7
8
a
INJECTAFER®
(ferric carboxymaltose injection)
Other adverse reactions reported by ≥ 0.5% of treated patients include
abdominal pain, diarrhea, gamma glutamyl transferase increased, injection
site pain/irritation, rash, paraesthesia, sneezing. Transient decreases in
laboratory blood phosphorus levels (< 2 mg/dL) have been observed in 27%
(440/1638) patients in clinical trials.
6.2 Post-marketing Experience
Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure. The following serious adverse reactions
have been most commonly reported from the post-marketing spontaneous
reports with Injectafer: urticaria, dyspnea, pruritis, 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.
Other adverse reactions reported by ≥ 0.5% of treated patients include
abdominal pain, diarrhea, gamma glutamyl transferase increased, injection
site pain/irritation, rash, paraesthesia, sneezing. Transient decreases in
laboratory blood phosphorus levels (< 2 mg/dL) have been observed in 27%
(440/1638) patients in clinical trials.
6.2 Post-marketing Experience
Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure. The following serious adverse reactions
have been most commonly reported from the post-marketing spontaneous
reports with Injectafer: urticaria, dyspnea, pruritis, 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.
6
INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions
5.2 Hypertension
5.3 Laboratory Test Alterations
ADVERSE REACTIONS
6.1 Adverse Reactions in Clinical Trials
6.2 Post-marketing Experience
DRUG INTERACTIONS
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
USE IN SPECIFIC POPULATIONS
1
2
3
4
5
7
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Trial 1: Iron Deficiency Anemia in Patients Who are Intolerant to
Oral Iron or Have Had Unsatisfactory Response to Oral Iron
14.2 Trial 2: Iron Deficiency Anemia in Patients with Non-Dialysis
Dependent Chronic Kidney Disease
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
Formal drug interaction studies have not been performed with Injectafer.
FULL PRESCRIBING INFORMATION: CONTENTS*
8
--------------------------DOSAGE FORMS AND STRENGTHS----------------------750 mg iron / 15 mL single-use vial. (3)
-------------------------------CONTRAINDICATIONS--------------------------------Hypersensitivity to Injectafer or any of its inactive components. (4)
------------------------WARNINGS AND PRECAUTIONS---------------------------• Hypersensitivity reactions: Observe for signs and symptoms of
hypersensitivity during and after Injectafer administration for at least
30 minutes and until clinically stable following completion of each
administration. (5.1)
• Hypertension: Monitor patients closely for signs and symptoms of
hypertension following each Injectafer administration. (5.2)
------------------------------ADVERSE REACTIONS---------------------------------The most common adverse reactions (≥ 2%) are nausea, hypertension,
flushing, hypophosphatemia, and dizziness (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact American Regent at
1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------USE IN SPECIFIC POPULATIONS---------------------------• Nursing Mothers: Exercise caution when administered to a nursing
woman. (8.3)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved
patient labeling.
Revised: July 2013
8.1 Pregnancy
Pregnancy Category C
Risk Summary
Adequate and well controlled studies in pregnant women have not been
conducted. However, animal reproduction studies have been conducted with
ferric carboxymaltose. In these studies, administration of ferric carboxymaltose
to rabbits during the period of organogenesis caused fetal malformations and
increased implantation loss at maternally toxic doses of approximately 12%
to 23% of the human weekly dose of 750 mg (based on body surface area).
The incidence of major malformations in human pregnancies has not been
established for Injectafer. However, all pregnancies, regardless of exposure to
any drug, has a background rate of 2 to 4% for major malformations, and 15
to 20% for pregnancy loss. Injectafer should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus.
Animal Data
Administration of ferric carboxymaltose to rats as a one-hour intravenous
infusion up to 30 mg/kg/day iron on gestation days 6 to 17 did not result in
adverse embryofetal findings. This daily dose in rats is approximately 40%
of the human weekly dose of 750 mg based on body surface area. In rabbits,
ferric carboxymaltose was administered as a one-hour infusion on gestation
days 6 to 19 at iron doses of 4.5, 9, 13.5, and 18 mg/kg/day. Malformations
were seen starting at the daily dose of 9 mg/kg (23% of the human weekly
dose of 750 mg). Spontaneous abortions occurred starting at the daily iron
dose of 4.5 mg/kg (12% of the human weekly dose based on body surface
area). Pre-implantation loss was at the highest dose. Adverse embryofetal
effects were observed in the presence of maternal toxicity.
A pre- and post-natal development study was conducted in rats at intravenous
doses up to 18 mg/kg/day of iron (approximately 23% of the weekly human
dose of 750 mg on a body surface area basis). There were no adverse effects
on survival of offspring, their behavior, sexual maturation or reproductive
parameters.
8.3 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.
Other adverse reactions reported by ≥ 0.5% of treated patients include
8.4 Pediatric Use
abdominal pain, diarrhea, gamma glutamyl transferase increased, injection
Safety and effectiveness have not been established in pediatric patients.
site pain/irritation, rash, paraesthesia, sneezing. Transient decreases in
8.5
Geriatric
laboratory
bloodUse
phosphorus levels (< 2 mg/dL) have been observed in 27%
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
Injectafer safely and effectively. See full prescribing information for
Injectafer.
INJECTAFER® (ferric carboxymaltose injection)
For intravenous use
Initial U.S. Approval: 2013
------------------------------INDICATIONS AND USAGE-----------------------------Injectafer is an iron replacement product indicated for the treatment of iron
deficiency anemia in adult patients:
• who have intolerance to oral iron or have had unsatisfactory response to
oral iron;
• who have non-dialysis dependent chronic kidney disease.
-------------------------DOSAGE AND ADMINISTRATION--------------------------For patients weighing 50 kg (110lb) or more: Give Injectafer in two
doses separated by at least 7 days. Give each dose as 750 mg for a total
cumulative dose of 1500 mg of iron per course.
For patients weighing less than 50 kg (110lb): Give Injectafer in two doses
separated by at least 7 days and give each dose as 15 mg/kg body weight.
Injectafer treatment may be repeated if iron deficiency anemia reoccurs. (2)
RQ105200
-------iron
nse to
--------
tal
oses
ght.
s. (2)
n adult
nse to
doses
mulative
doses
ht for a
r
mL of
may be
INJECTAFER®
(ferric carboxymaltose injection)
Injectafer
Pooled
Comparatorsa
Oral
iron
(N=1775)
%
7.2
3.8
3.6
2.1
2.0
1.7
1.4
1.2
(N=1783)
%
1.8
1.9
0.2
0.1
1.2
0.5
0.3
0.9
(N=253)
%
1.2
0.4
0.0
0.0
0.0
0.4
0.0
0.0
1.1
0.2
0.0
1.1
1.0
0.5
2.1
1.9
0.9
0.0
0.0
3.2
Includes oral iron and all formulations of IV iron other than Injectafer
7
DRUG INTERACTIONS
Formal drug interaction studies have not been performed with Injectafer.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
Risk Summary
Adequate and well controlled studies in pregnant women have not been
conducted. However, animal reproduction studies have been conducted with
ferric carboxymaltose. In these studies, administration of ferric carboxymaltose
to rabbits during the period of organogenesis caused fetal malformations and
increased implantation loss at maternally toxic doses of approximately 12%
to 23% of the human weekly dose of 750 mg (based on body surface area).
The incidence of major malformations in human pregnancies has not been
established for Injectafer. However, all pregnancies, regardless of exposure to
any drug, has a background rate of 2 to 4% for major malformations, and 15
to 20% for pregnancy loss. Injectafer should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus.
Animal Data
Administration of ferric carboxymaltose to rats as a one-hour intravenous
infusion up to 30 mg/kg/day iron on gestation days 6 to 17 did not result in
adverse embryofetal findings. This daily dose in rats is approximately 40%
of the human weekly dose of 750 mg based on body surface area. In rabbits,
ferric carboxymaltose was administered as a one-hour infusion on gestation
days 6 to 19 at iron doses of 4.5, 9, 13.5, and 18 mg/kg/day. Malformations
were seen starting at the daily dose of 9 mg/kg (23% of the human weekly
dose of 750 mg). Spontaneous abortions occurred starting at the daily iron
dose of 4.5 mg/kg (12% of the human weekly dose based on body surface
area). Pre-implantation loss was at the highest dose. Adverse embryofetal
effects were observed in the presence of maternal toxicity.
A pre- and post-natal development study was conducted in rats at intravenous
doses up to 18 mg/kg/day of iron (approximately 23% of the weekly human
dose of 750 mg on a body surface area basis). There were no adverse effects
on survival of offspring, their behavior, sexual maturation or reproductive
parameters.
8.3 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.
8.4 Pediatric Use
Safety and effectiveness have not been established in pediatric patients.
8.5 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.
10 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. [see Post-marketing
Experience (6.2)].
11
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-a-D-glucopyranosyl)-oxy-2(R),3(S),5(R),6tetrahydroxy-hexanoate. It has a relative molecular weight of approximately
150,000 Da corresponding to the following empirical formula:
[FeOx(OH)y(H2O)z]n [{(C6H10O5)m (C6H12O7)}l]k,
where n ≈ 103, m ≈ 8, l≈ 11, and k ≈ 4
(l represents the mean branching degree of the ligand).
The chemical structure is presented below:
RQ105200
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 trials, Injectafer was administered at a 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.
14.1 Trial 1: Iron Deficiency Anemia in Patients Who Are Intolerant to Oral
Iron or Have Had Unsatisfactory Response to Oral Iron
Trial 1 was a randomized, open-label, controlled clinical study in patients
with iron deficiency anemia who had an unsatisfactory response to oral iron
(Cohort 1) or who were intolerant to oral iron (Cohort 2) during the 14 day
oral iron run-in period. Inclusion criteria prior to randomization included
hemoglobin (Hb) <12 g/dL, ferritin ≤ 100 ng/mL or ferritin ≤ 300 ng/mL when
transferrin saturation (TSAT) ≤ 30%. Cohort 1 subjects were randomized to
Injectafer or oral iron for 14 more days. Cohort 2 subjects were randomized
to Injectafer or another IV iron per standard of care [90% of subjects received
iron sucrose]. The mean age of study patients was 43 years (range, 18 to
94); 94% were female; 42% were Caucasian, 32% were African American,
24% were Hispanic, and 2% were other races. The primary etiologies of iron
deficiency anemia were heavy uterine bleeding (47%) and gastrointestinal
disorders (17%).
Table 2 shows the baseline and the change in hemoglobin from baseline to
highest value between baseline and Day 35 or time of intervention.
Table 2. Mean Change in Hemoglobin From Baseline to the Highest
Value Between Day 35 or Time of Intervention (Modified Intent‑to‑Treat
Population)
Hemoglobin (g/dL)
Mean (SD)
Cohort 1
Injectafer Oral Iron
(N=244)
(N=251)
Cohort 2
Injectafer
IV SCa
(N=245)
(N=237)
Baseline
10.6 (1.0) 10.6 (1.0)
9.1 (1.6)
9.0 (1.5)
Highest Value
12.2 (1.1) 11.4 (1.2)
12.0 (1.2)
11.2 (1.3)
Change (from baseline to
highest value)
1.6 (1.2)
2.9 (1.6)
2.2 (1.3)
0.8 (0.8)
p-value
0.001
0.001
SD=standard deviation; a: Intravenous iron per standard of care
Increases from baseline in mean ferritin (264.2 ± 224.2 ng/mL in Cohort 1
and 218.2 ± 211.4 ng/mL in Cohort 2), and transferrin saturation (13 ± 16%
in Cohort 1 and 20 ± 15% in Cohort 2) were observed at Day 35 in Injectafertreated patients.
14.2 Trial 2: Iron Deficiency Anemia in Patients with Non‑Dialysis
Dependent Chronic Kidney Disease
Trial 2 was a randomized, open-label, controlled clinical study in patients with
non-dialysis dependent chronic kidney disease. Inclusion criteria included
hemoglobin (Hb) ≤ 11.5 g/dL, ferritin ≤ 100 ng/mL or ferritin ≤ 300 ng/mL
when transferrin saturation (TSAT) ≤ 30%. Study patients were randomized
to either Injectafer or Venofer. The mean age of study patients was 67 years
(range, 19 to 96); 64% were female; 54% were Caucasian, 26% were African
American, 18% Hispanics, and 2% were other races.
Table 3 shows the baseline and the change in hemoglobin from baseline to
highest value between baseline and Day 56 or time of intervention.
1.1 (1.0)
0.9 (0.92)
0.21 (0.13, 0.28)
HOW SUPPLIED/STORAGE AND HANDLING
NDC 0517-0650-01 750 mg iron/15 mL Single-Use Vial Individually boxed
NDC 0517-0650-02 750 mg iron/15 mL Single-Use Vial Packages of 2
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C
(59°F to 86°F). [See the USP controlled room temperature]. Do not freeze.
17
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 [see Warnings and Precautions (5)]
Injectafer is manufactured under license from Vifor (International) Inc,
Switzerland.
AMERICAN
REGENT, INC.
SHIRLEY, NY 11967
IN0650ADV
Iss. 7/2013
RQ105200
14
10.3 (0.8)
11.3 (1.1)
DRUG INTERACTIONS
13.1 Carcinogenesis, Mutagenesis, 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.
10.3 (0.8)
11.4 (1.2)
INJECTAFER®
(ferric carboxymaltose injection)
Patient Information
INJECTAFER (ferric carboxymaltose injection)
Please read this information carefully before taking this
medication. This summary does not tell you everything
about INJECTAFER. Speak with your doctor or healthcare
professional if there is something you do not understand or if
you would like to learn more about INJECTAFER. Your doctor
or healthcare professional is your best source of information
about this medicine.
What is INJECTAFER?
Iron is a mineral that the body needs to produce red blood
cells. When the body does not get enough iron, it cannot
produce the number of normal red blood cells needed to keep
you in good health. This condition is called iron deficiency
(iron shortage) or iron deficiency anemia.
INJECTAFER is used to treat iron deficiency anemia. Iron
deficiency anemia may be caused by several medical
conditions including heavy menstrual bleeding, pregnancy,
childbirth, inflammatory bowel disease, other malabsorption
diseases, bariatric surgery, or chronic kidney disease.
General information about using INJECTAFER safely and
effectively
Injectable iron is administered only by or under the supervision
of your health care professional.
Serious or life threatening allergic reactions have been
reported with intravenous iron products. Tell your health
care professional if you have ever had any unusual or allergic
reaction to any IV iron.
Patients should report to their healthcare professional any
signs and symptoms of an allergic reaction to INJECTAFER, in
particular rashes, shortness of breath and wheezing.
Iron is not easily eliminated from the body, and its build up
may be lead to a condition called iron overload which may be
harmful. Certain medical conditions such as liver disease may
also make you more likely to develop iron overload. Ask your
doctor or healthcare professional.
Who should not take INJECTAFER?
You should not be given INJECTAFER if you have anemia that
is not caused by iron deficiency, or if you have iron overload.
If you are pregnant or plan to become pregnant please notify
your doctor or healthcare professional. They will decide
whether it is safe for you to receive INJECTAFER.
How should I take INJECTAFER?
INJECTAFER is administered intravenously (into your vein) by
your doctor or healthcare professional in two doses.
What should I avoid while taking INJECTAFER?
You should not take iron supplements by mouth if you
are receiving iron injections. Tell your doctor about all
the medicines you take, including prescription and nonprescription medicines, vitamins and herbal supplements.
Other adverse reactions reported by ≥ 0.5% of treated patients include
abdominal pain, diarrhea, gamma glutamyl transferase increased, injection
site pain/irritation, rash, paraesthesia, sneezing. Transient decreases in
laboratory blood phosphorus levels (< 2 mg/dL) have been observed in 27%
(440/1638) patients in clinical trials.
6.2 Post-marketing Experience
Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure. The following serious adverse reactions
have been most commonly reported from the post-marketing spontaneous
reports with Injectafer: urticaria, dyspnea, pruritis, 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.
NONCLINICAL TOXICOLOGY
Venofer
(N=1244)
7
13
Injectafer
(N=1249)
Increases from baseline in mean ferritin (734.7 ± 337.8 ng/mL), and transferrin
saturation (30 ± 17%) were observed at Day 56 in Injectafer-treated patients.
USE IN SPECIFIC POPULATIONS
12.3 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.
Formal drug interaction studies have not been performed with Injectafer.
Baseline
Highest Value
Change (from baseline to highest
value)
Treatment Difference (95% CI)
16
r
Hemoglobin (g/dL)
Mean (SD)
8
12.2 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% at 24 days after Injectafer dose. In patients with renal anemia red cell
uptake of radio-labeled iron ranged from 61% to 84% after 24 days Injectafer
dose.
-------iron
Table 3.
Mean Change in Hemoglobin From Baseline to the
Highest Value Between Baseline and Day 56 or Time of Intervention
(Modified Intent‑to‑Treat Population)
8.1 Pregnancy
Pregnancy Category C
Risk Summary
Adequate and well controlled studies in pregnant women have not been
conducted. However, animal reproduction studies have been conducted with
ferric carboxymaltose. In these studies, administration of ferric carboxymaltose
to rabbits during the period of organogenesis caused fetal malformations and
increased implantation loss at maternally toxic doses of approximately 12%
to 23% of the human weekly dose of 750 mg (based on body surface area).
The incidence of major malformations in human pregnancies has not been
established for Injectafer. However, all pregnancies, regardless of exposure to
any drug, has a background rate of 2 to 4% for major malformations, and 15
to 20% for pregnancy loss. Injectafer should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus.
Animal Data
Administration of ferric carboxymaltose to rats as a one-hour intravenous
infusion up to 30 mg/kg/day iron on gestation days 6 to 17 did not result in
adverse embryofetal findings. This daily dose in rats is approximately 40%
of the human weekly dose of 750 mg based on body surface area. In rabbits,
ferric carboxymaltose was administered as a one-hour infusion on gestation
days 6 to 19 at iron doses of 4.5, 9, 13.5, and 18 mg/kg/day. Malformations
were seen starting at the daily dose of 9 mg/kg (23% of the human weekly
dose of 750 mg). Spontaneous abortions occurred starting at the daily iron
dose of 4.5 mg/kg (12% of the human weekly dose based on body surface
area). Pre-implantation loss was at the highest dose. Adverse embryofetal
effects were observed in the presence of maternal toxicity.
A pre- and post-natal development study was conducted in rats at intravenous
doses up to 18 mg/kg/day of iron (approximately 23% of the weekly human
dose of 750 mg on a body surface area basis). There were no adverse effects
on survival of offspring, their behavior, sexual maturation or reproductive
parameters.
8.3 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.
Other adverse reactions reported by ≥ 0.5% of treated patients include
8.4 Pediatric Use
abdominal pain, diarrhea, gamma glutamyl transferase increased, injection
Safety and effectiveness have not been established in pediatric patients.
site pain/irritation, rash, paraesthesia, sneezing. Transient decreases in
8.5
Geriatric
laboratory
bloodUse
phosphorus levels (< 2 mg/dL) have been observed in 27%
12.1 Mechanism of Action
Ferric carboxymaltose is a colloidal iron (III) hydroxide in complex with
carboxymaltose, a carbohydrate polymer that releases iron.
nse to
CLINICAL PHARMACOLOGY
--------
12
--------------------------DOSAGE FORMS AND STRENGTHS----------------------750 mg iron / 15 mL single-use vial. (3)
-------------------------------CONTRAINDICATIONS--------------------------------Hypersensitivity to Injectafer or any of its inactive components. (4)
------------------------WARNINGS AND PRECAUTIONS---------------------------• Hypersensitivity reactions: Observe for signs and symptoms of
hypersensitivity during and after Injectafer administration for at least
30 minutes and until clinically stable following completion of each
administration. (5.1)
• Hypertension: Monitor patients closely for signs and symptoms of
hypertension following each Injectafer administration. (5.2)
------------------------------ADVERSE REACTIONS---------------------------------The most common adverse reactions (≥ 2%) are nausea, hypertension,
flushing, hypophosphatemia, and dizziness (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact American Regent at
1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------USE IN SPECIFIC POPULATIONS---------------------------• Nursing Mothers: Exercise caution when administered to a nursing
woman. (8.3)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved
patient labeling.
Revised: July 2013
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Trial 1: Iron Deficiency Anemia in Patients Who are Intolerant to
Oral Iron or Have Had Unsatisfactory Response to Oral Iron
14.2 Trial 2: Iron Deficiency Anemia in Patients with Non-Dialysis
Dependent Chronic Kidney Disease
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information
are not listed.
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.
5.2 Hypertension
In clinical studies, hypertension was reported in 3.8% (67/1,775) 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% (106/1,775) 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 [see Dosage and Administration (2)].
5.3 Laboratory Test Alterations
--------------------------DOSAGE
FORMS AND STRENGTHS----------------------In the 24 hours following administration of Injectafer, laboratory assays may
750 mg iron / 15 mL single-use vial. (3)
overestimate serum iron and transferrin bound iron by also measuring the
-------------------------------CONTRAINDICATIONS--------------------------------iron
in Injectafer.
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. Injectafer is available in
15 mL single-use vials. Sodium hydroxide and/or hydrochloric acid may have
been added to adjust the pH to 5.0-7.0.
Vial closure is not made with natural rubber latex.
tal
oses
ght.
s. (2)
n adult
nse to
doses
mulative
doses
ht for a
r
mL of
may be
INJECTAFER®
(ferric carboxymaltose injection)
What are the possible side effects of INJECTAFER?
The side effects of INJECTAFER are infrequent, usually
mild and generally do not cause patients to stop treatment.
The most common side effects are nausea, injection site
reactions (including pain or bruising at the injection site),
asymptomatic reductions in blood phosphorus, flushing,
headache, hypertension, dizziness, and increased alanine
aminotransferase. Potentially long lasting brown staining of
skin near injection site may occur.
These are not all the possible side effects of INJECTAFER. For
more information ask your doctor or healthcare professional.
Talk to your doctor if you think you have side effects from
taking INJECTAFER.
®®
®®
(iron
(ironsucrose
sucroseinjection,
injection,USP)
USP)
(iron
(ironsucrose
sucroseinjection,
injection,USP)
USP)
Rx
RxOnly
Only
Rx
RxOnly
Only
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use VENOFER safely and effectively. See full
prescribing information for VENOFER.
Venofer ® (iron sucrose injection, USP)
Initial U.S. Approval: 2000
----------------------------------------------------INDICATIONS AND USAGE --------------------------------------------------Venofer is an iron replacement product indicated for the treatment of iron deficiency anemia in patients with chronic
kidney disease (CKD). (1)
------------------------------------------------DOSAGE AND ADMINISTRATION-----------------------------------------------Population
Adult patients
Pediatric patients
Dose
Hemodialysis DependentChronic Kidney Disease
(HDD-CKD) (2.1)
100 mg slow intravenous
injection or infusion
Non-Dialysis DependentChronic Kidney Disease
(NDD-CKD) (2.2)
200 mg slow intravenous
injection or infusion
Peritoneal Dialysis
Dependent-Chronic Kidney
Disease (PDD-CKD) (2.3)
300 mg or 400 mg
intravenous infusion
HDD-CKD (2.4), PDDCKD or NDD-CKD (2.5)
0.5 mg/kg slow
intravenous injection or
infusion
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATION
2
2.1
Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)
2.2
Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD)
Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD)
2.3
2.4
Pediatric Patients (2 years of age and older) with HDD-CKD for iron maintenance treatment
2.5
Pediatric Patients (2 years of age and older) with NDD-CKD or PDD-CKD who are on erythropoietin therapy for iron maintenance treatment
3
DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS
4
5
WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions
5.1
5.2
Hypotension
5.3
Iron Overload
6
ADVERSE REACTIONS
6.1
Adverse Reactions in Clinical Trials
Adverse Reactions from Post-Marketing Experience
6.2
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Nursing Mothers
8.3
8.4
Pediatric Use
8.5
Geriatric Use
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
Venofer is indicated for the treatment of iron deficiency anemia in patients with chronic kidney disease (CKD).
2
DOSAGE AND ADMINISTRATION
Venofer must only be administered intravenously either by slow injection or by infusion. The dosage of Venofer is expressed in mg of elemental iron. Each
mL contains 20 mg of elemental iron.
2.1
Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)
Administer Venofer 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of
0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. Venofer should be administered early during the dialysis session.
The usual total treatment course of Venofer is 1000 mg. Venofer treatment may be repeated if iron deficiency reoccurs.
2.2
Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD)
Administer Venofer 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9%
NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion
of 500 mg of Venofer, diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. Venofer treatment may be repeated
if iron deficiency reoccurs.
2.3
Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD)
Administer Venofer in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart
followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Venofer in a maximum of 250 mL of 0.9% NaCl. Venofer treatment may be repeated
if iron deficiency reoccurs.
2.4
Pediatric Patients (2 years of age and older) with HDD-CKD for iron maintenance treatment
The dosing for iron replacement treatment in pediatric patients with HDD-CKD has not been established.
For iron maintenance treatment: Administer Venofer at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted
by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Venofer treatment may be repeated
if necessary.
2.5
Pediatric Patients (2 years of age and older) with NDD-CKD or PDD-CKD who are on erythropoietin therapy for iron maintenance treatment
The dosing for iron replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.
For iron maintenance treatment: Administer Venofer at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted
by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Venofer treatment may be repeated
if necessary.
3
DOSAGE FORMS AND STRENGTHS
•
10 mL single-use vial / 200 mg elemental iron (20 mg/mL)
•
5 mL single-use vial / 100 mg elemental iron (20 mg/mL)
•
2.5 mL single-use vial / 50 mg elemental iron (20 mg/mL)
4
CONTRAINDICATIONS
•
Known hypersensitivity to Venofer
5
WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Reactions
Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in
patients receiving Venofer. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If
hypersensitivity reactions or signs of intolerance occur during administration, stop Venofer immediately. Monitor patients for signs and symptoms
of hypersensitivity during and after Venofer administration for at least 30 minutes and until clinically stable following completion of the infusion. Only
administer Venofer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions
associated with intravenous iron preparations occur within 30 minutes of the completion of the infusion [see Adverse Reactions (6.1 and 6.2)].
5.2
Hypotension
Venofer may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Venofer. Hypotension
following administration of Venofer may be related to the rate of administration and/or total dose administered [See Dosage and Administration (2),
Warnings and Precautions (5.1), and Adverse Reactions (6.2)].
5.3
Iron Overload
Excessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients
receiving Venofer require periodic monitoring of hematologic and iron parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do
not administer Venofer to patients with evidence of iron overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration
of iron sucrose; do not perform serum iron measurements for at least 48 hours after intravenous dosing [See Dosage and Administration (2) and Overdosage
(10)].
6
ADVERSE REACTIONS
The following serious adverse reactions associated with Venofer are described in other sections [See Warnings and Precautions (5.1, 5.2 and 5.3)].
6.1
Adverse Reactions in Clinical Trials
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates
observed in practice.
Adverse Reactions in Adult Patients with CKD
The frequency of adverse reactions associated with the use of Venofer has been documented in six clinical trials involving 231 patients with HDD-CKD,
139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse reactions reported by ³ 2% of treated patients in the six clinical
trials for which the rate for Venofer exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at
10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over
2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a
period of 4 weeks.
----------------------------------------------DOSAGE FORMS AND STRENGTHS ---------------------------------------------• 10 mL single-use vial / 200 mg elemental iron (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental iron (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental iron (20 mg/mL) (3)
------------------------------------------------------CONTRAINDICATIONS -----------------------------------------------------• Known hypersensitivity to Venofer (4)
------------------------------------------------WARNINGS AND PRECAUTIONS -----------------------------------------------• Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Venofer
administration for at least 30 minutes and until clinically stable following completion of each administration. Only
administer Venofer when personnel and therapies are immediately available for the treatment of serious
hypersensitivity reactions. (5.1)
• Hypotension: Venofer may cause hypotension. Monitor for signs and symptoms of hypotension during and
following each administration of Venofer. (5.2)
• Iron Overload: Regularly monitor hematologic responses during Venofer therapy. Do not administer Venofer to
patients with iron overload. (5.3)
------------------------------------------------------ADVERSE REACTIONS -----------------------------------------------------• The most common adverse reactions (³2%) following the administration of Venofer are diarrhea, nausea, vomiting,
headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site
reactions, chest pain, and peripheral edema. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at
1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION
Revised: 1/2014
10
11
12
13
14
16
17
OVERDOSAGE
DESCRIPTION
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
CLINICAL STUDIES
14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)
14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)
14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)
14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD)
14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD)
14.6 Study F: Iron Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease
HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Stability and Storage
PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are not listed.
Table 1. Treatment-Emergent Adverse Reactions Reported in ³ 2% of Study Populations and for which the Rate for Venofer Exceeds the Rate for
Comparator
Adverse Reactions
(Preferred Term)
Subjects with any adverse reaction
Ear and Labyrinth Disorders
Ear Pain
Eye Disorders
Conjunctivitis
Gastrointestinal Disorders
Abdominal pain
Diarrhea
Dysgeusia
Nausea
Vomiting
General Disorders and
Administration Site Conditions
Asthenia
Chest pain
Feeling abnormal
Infusion site pain or burning
Injection site extravasation
Peripheral edema
Pyrexia
Infections and Infestations
Nasopharyngitis, Sinusitis, Upper
respiratory tract infections, Pharyngitis
Injury, Poisoning and Procedural
Complications
Graft complication
Metabolism and Nutrition Disorders
Fluid overload
Gout
Hyperglycemia
Hypoglycemia
Musculoskeletal and Connective
Tissue Disorders
Arthralgia
Back pain
Muscle cramp
Myalgia
Pain in extremity
Nervous System Disorders
Dizziness
Headache
Respiratory, Thoracic and
Mediastinal Disorders
Cough
Dyspnea
Nasal congestion
Skin and Subcutaneous
Tissue Disorders
Pruritus
Vascular Disorders
Hypertension
Hypotension
HDD-CKD
Venofer
(N=231)
%
78.8
Venofer
(N=139)
%
76.3
NDD-CKD
Oral Iron
(N=139)
%
73.4
Venofer
(N=75)
%
72.0
PDD-CKD
EPO* Only
(N=46)
%
65.2
0
2.2
0.7
0
0
0.4
0
0
2.7
0
3.5
5.2
0.9
14.7
9.1
1.4
7.2
7.9
8.6
5.0
2.9
10.1
0
12.2
8.6
4.0
8.0
0
5.3
8.0
6.5
4.3
0
4.3
2.2
2.2
6.1
3.0
0
0
2.6
3.0
0.7
1.4
0
5.8
2.2
7.2
0.7
2.2
0
0
0
0
5.0
0.7
2.7
2.7
0
0
0
5.3
1.3
0
0
0
0
0
10.9
0
2.6
2.2
4.3
16.0
4.3
9.5
1.4
0
0
0
3.0
0
0
0.4
1.4
2.9
2.9
0.7
0.7
1.4
0
0.7
1.3
0
0
4.0
0
0
2.2
0
3.5
2.2
29.4
0
5.6
1.4
2.2
0.7
3.6
4.3
2.2
3.6
0.7
0
0
4.0
1.3
2.7
1.3
2.7
4.3
4.3
0
0
6.5
6.5
12.6
6.5
2.9
1.4
0.7
1.3
4.0
4.3
0
3.0
3.5
0
2.2
5.8
1.4
0.7
1.4
2.2
1.3
1.3
1.3
0
2.2
0
3.9
2.2
4.3
2.7
0
6.5
39.4
6.5
2.2
4.3
0.7
8.0
2.7
6.5
2.2
* EPO=Erythropoietin
One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had
prior other intravenous iron therapy and were reported to be intolerant (defined as precluding further use of that iron product). When these patients were
treated with Venofer there were no occurrences of adverse reactions that precluded further use of Venofer [See Warning and Precautions (5)].
®®
®®
(iron
(ironsucrose
sucroseinjection,
injection,USP)
USP)
(iron
(ironsucrose
sucroseinjection,
injection,USP)
USP)
Rx
RxOnly
Only
Rx
RxOnly
Only
Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)
In a randomized, open-label, dose-ranging trial for iron maintenance treatment with Venofer in pediatric patients with CKD on stable erythropoietin therapy
[see Clinical Studies (14.6)], at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving Venofer 0.5 mg/kg,
53% (25/47) of the patients receiving Venofer 1.0 mg/kg, and 55% (26/47) of the patients receiving Venofer 2.0 mg/kg.
A total of 5 (11%) subjects in the Venofer 0.5 mg/kg group, 10 (21%) patients in the Venofer 1.0 mg/kg group, and 10 (21%) patients in the Venofer
2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of
patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%),
renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).
6.2
Adverse Reactions from Post-Marketing Experience
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish
a causal relationship to drug exposure.
In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis
and dysgeusia.
The following adverse reactions have been identified during post-approval use of Venofer. Because these reactions are reported voluntarily from a population
of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions,
shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints,
hyperhidrosis, back pain, bradycardia, and chromaturia.
Symptoms associated with Venofer total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches,
paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the
administration of Venofer injection. Reactions have occurred following the first dose or subsequent doses of Venofer. Symptoms may respond to intravenous
fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.
Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.
7
DRUG INTERACTIONS
Drug interactions involving Venofer have not been studied. However, Venofer may reduce the absorption of concomitantly administered oral iron preparations.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B
There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, iron sucrose was administered intravenously to rats
and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental iron (half or equivalent to the maximum recommended human
dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to iron sucrose. Because animal reproductive studies
are not always predictive of human response, Venofer should be used during pregnancy only if clearly needed.
8.3
Nursing Mothers
It is not known whether iron sucrose is excreted in human milk. Iron sucrose is secreted into the milk of lactating rats. Because many drugs are excreted
in human milk, caution should be exercised when Venofer is administered to a nursing woman.
8.4
Pediatric Use
Safety and effectiveness of Venofer for iron replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not
been established.
Safety and effectiveness of Venofer for iron maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysisdependent CKD receiving erythropoietin therapy were studied. Venofer at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three doses
maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing. [See Clinical
Studies (14.6)]
Venofer has not been studied in patients younger than 2 years of age.
In a country where Venofer is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis
and two of the five died during or following a period when they received Venofer, several other medications and erythropoietin. Necrotizing enterocolitis
may be a complication of prematurity in very low birth weight infants. No causal relationship to Venofer or any other drugs could be established.
8.5
Geriatric Use
Clinical studies of Venofer did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from
younger subjects. Of the 1,051 patients in two post-marketing safety studies of Venofer, 40% were 65 years and older. No overall differences in safety
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. In general, dose administration to an elderly patient
should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
10
OVERDOSAGE
No data are available regarding overdosage of Venofer in humans. Excessive dosages of Venofer may lead to accumulation of iron in storage sites potentially
leading to hemosiderosis. Do not administer Venofer to patients with iron overload. [See Contraindications (4)]
Toxicities in single-dose studies in mice and rats, at intravenous iron sucrose doses up to 8 times the maximum recommended human dose based on body
surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.
11
DESCRIPTION
Venofer (iron sucrose injection, USP), an iron replacement product, is a brown, sterile, aqueous, complex of polynuclear iron (III)-hydroxide in sucrose for
intravenous use. Iron sucrose injection has a molecular weight of approximately 34,000 to 60,000 daltons and a proposed structural formula:
[Na2Fe5O8(OH) ×3(H2O)]n ×m(C12H22O11)
where: n is the degree of iron polymerization and m is the number of sucrose molecules associated with the iron (III)-hydroxide.
Each mL contains 20 mg elemental iron as iron sucrose in water for injection. Venofer is available in 10 mL single-use vials (200 mg elemental iron per
10 mL), 5 mL single-use vials (100 mg elemental iron per 5 mL), and 2.5 mL single-use vials (50 mg elemental iron per 2.5 mL). The drug product contains
approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is
1,250 mOsmol/L.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Venofer is an aqueous complex of poly-nuclear iron (III)-hydroxide in sucrose. Following intravenous administration, Venofer is dissociated into iron and
sucrose and the iron is transported as a complex with transferrin to target cells including erythroid precursor cells. The iron in the precursor cells is
incorporated into hemoglobin as the cells mature into red blood cells.
12.2 Pharmacodynamics
Following intravenous administration, Venofer is dissociated into iron and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin
(recombinant human erythropoietin) therapy treated with iron sucrose containing 100 mg of iron, three times weekly for three weeks, significant increases
in serum iron and serum ferritin and significant decreases in total iron binding capacity occurred four weeks from the initiation of iron sucrose treatment.
12.3 Pharmacokinetics
In healthy adults administered intravenous doses of Venofer, its iron component exhibited first order kinetics with an elimination half-life of 6 h, total
clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The iron component appeared to distribute mainly in blood and to some
extent in extravascular fluid. A study evaluating Venofer containing 100 mg of iron labeled with 52Fe/59Fe in patients with iron deficiency showed that a
significant amount of the administered iron is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible iron trapping
compartment.
Following intravenous administration of Venofer, iron sucrose is dissociated into iron and sucrose. The sucrose component is eliminated mainly by urinary
excretion. In a study evaluating a single intravenous dose of Venofer containing 1,510 mg of sucrose and 100 mg of iron in 12 healthy adults (9 female,
3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some iron was also eliminated in the urine. Neither
transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous
dose of iron sucrose containing 500 to 700 mg of iron in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60),
approximately 5% of the iron was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Venofer have
not been studied.
Pharmacokinetics in Pediatric Patients
In a single-dose PK study of Venofer, patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Venofer at 7 mg/kg (maximum
200 mg) administered over 5 minutes. Following single dose Venofer, the half-life of total serum iron was 8 hours. The mean Cmax and AUC values were
8545 µg/dL and 31305 hr•µg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.
Venofer is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of iron
sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been performed with iron sucrose.
Iron sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Iron sucrose was not clastogenic
in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.
Iron sucrose at intravenous doses up to 15 mg/kg/day of elemental iron (1.2 times the maximum recommended human dose based on body surface area)
had no effect on fertility and reproductive function of male and female rats.
14
CLINICAL STUDIES
Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Venofer.
14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)
Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Venofer treatment and 24 in the historical
control group) with iron deficiency anemia. Eligibility criteria for Venofer treatment included patients undergoing chronic hemodialysis, receiving
erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients
was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.
Venofer 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted
of 24 patients with similar ferritin levels as patients treated with Venofer, who were off intravenous iron for at least 2 weeks and who had received
erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control
group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.
Patients in the Venofer treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population.
See Table 2.
Table 2. Changes from Baseline in Hemoglobin and Hematocrit
End of treatment
Efficacy
parameters
2 week follow-up
5 week follow-up
Venofer
(n=69)
Historical
Control
(n=18)
Venofer
(n=73)
Historical
Control
(n=18)
Venofer
(n=71)
Historical
Control
(n=15)
Hemoglobin (g/dL)
1.0 ± 0.12**
0.0 ± 0.21
1.3 ± 0.14**
-0.6 ± 0.24
1.2 ± 0.17*
-0.1 ± 0.23
Hematocrit (%)
3.1 ± 0.37**
-0.3 ± 0.65
3.6 ± 0.44**
-1.2 ± 0.76
3.3 ± 0.54
0.2 ± 0.86
**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose as
covariates.
Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control
population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%)
compared to this historical control population (-5.1 ± 4.3%).
14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)
Study B was a multicenter, open label study of Venofer in 23 patients with iron deficiency and HDD-CKD who had been discontinued from iron dextran due
to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from
21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.
All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin
(266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.
14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)
Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin  10 g/dL, a serum transferrin
saturation  20%, and a serum ferritin  200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients
enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and
62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral iron. Exclusion criteria were similar to those in studies A
and B. Venofer was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of iron was
administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving
erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.
The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum
ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at
week 4 of the observation period.
14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD)
Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral iron versus Venofer in patients with NDD-CKD
with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD,
hemoglobin of  11.0 g/dL, transferrin saturation  25%, ferritin  300 ng/mL were randomized to receive oral iron (325 mg ferrous sulfate three times
daily for 56 days); or Venofer (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over
3.5 to 4 hours). The mean age of the 91 treated patients in the Venofer group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years)
for the 91 patients in the oral iron group.
A statistically significantly greater proportion of Venofer subjects (35/79; 44.3%) compared to oral iron subjects (23/82; 28%) had an increase in hemoglobin
³ 1 g/dL at anytime during the study (p = 0.03).
14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD)
Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous iron to patients
with PDD-CKD receiving an erythropoietin alone without iron supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of
 11.5 g/dL, TSAT  25%, ferritin  500 ng/mL were randomized to receive either no iron or Venofer (300 mg in 250 mL 0.9% NaCl over 1.5 hours on
Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the Venofer / erythropoietin group
was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients in the erythropoietin alone group.
Patients in the Venofer / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL),
compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with Venofer / erythropoietin
(59.1 %) had an increase in hemoglobin of ³ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).
14.6 Study F: Iron Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease
Study F was a randomized, open-label, dose-ranging study for iron maintenance treatment in pediatric patients with dialysis-dependent or non-dialysisdependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of Venofer (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg).
The mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females.
About 60% of patients underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was
12 g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received Venofer once every other week for 6 doses.
Patients with PDD-CKD or NDD-CKD received Venofer once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing,
the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL during the 12-week treatment period was 58.7%, 46.7%, and 45.0%
in the Venofer 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
Venofer is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental iron, each 5 mL vial contains 100 mg
elemental iron, and each 2.5 mL vial contains 50 mg elemental iron (20 mg/mL).
NDC-0517-2310-05
200 mg/10 mL Single-Use Vial
Packages of 5
NDC-0517-2310-10
200 mg/10 mL Single-Use Vial
Packages of 10
NDC-0517-2340-01
NDC-0517-2340-10
NDC-0517-2340-25
100 mg/5 mL Single-Use Vial
100 mg/5 mL Single-Use Vial
100 mg/5 mL Single-Use Vial
Individually Boxed
Packages of 10
Packages of 25
NDC-0517-2340-99
100 mg/5 mL Single-Use Vial
Packages of 10
NDC-0517-2325-10
NDC-0517-2325-25
50 mg/2.5 mL Single-Use Vial
50 mg/2.5 mL Single-Use Vial
Packages of 10
Packages of 25
16.2 Stability and Storage
Contains no preservatives. Store in original carton at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled
Room Temperature]. Do not freeze.
Syringe Stability: Venofer, when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental iron per mL, or undiluted (20 mg
elemental iron per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature
(25°C ± 2°C) and under refrigeration (4°C ± 2°C).
Intravenous Admixture Stability: Venofer, when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging
from 1 mg to 2 mg of elemental iron per mL, has been found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C).
Do not dilute to concentrations below 1 mg/mL.
Do not mix Venofer with other medications or add to parenteral nutrition solutions for intravenous infusion.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.
17
PATIENT COUNSELING INFORMATION
Prior to Venofer administration:
•
Question patients regarding any prior history of reactions to parenteral iron products
•
Advise patients of the risks associated with Venofer
•
Advise patients to report any symptoms of hypersensitivity that may develop during and following Venofer administration, such as rash, itching,
dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]
AMERICAN
REGENT, INC.
IN2340ADV
MG #15727
Venofer is manufactured under license from Vifor (International) Inc., Switzerland.
PREMIERProTMRx is a trademark of Premier, Inc., used under license.
SHIRLEY, NY 11967