important safety information …€¦ · injectafer®1 venofer® (ferric carboxymaltose injection)...

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. FCM192 Iss. 7/2015

®

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: sano�-aventis 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.

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Discover the differences in

IV iron therapies

INDICATIONVenofer® is indicated for the treatment of iron de�ciency anemia in patients with chronic kidney disease.

IMPORTANT SAFETY INFORMATIONCONTRAINDICATIONSVenofer® is contraindicated in patients with known hypersensitivity to Venofer®.

WARNINGS AND PRECAUTIONSSerious 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 signi�cant 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 signi�cant 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 REACTIONSThe 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 �stula 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 identi�ed 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 �rst 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.

INDICATIONSInjectafer® is an iron replacement product indicated for the treatment of iron de�ciency 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

CONTRAINDICATIONSInjectafer® is contraindicated in patients with hypersensitivity to Injectafer® or any of its inactive components.

WARNINGS AND PRECAUTIONSSerious 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 signi�cant 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 �ushing, 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 REACTIONSIn 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%); �ushing/hot �ush (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 Full Prescribing Information for Injectafer® inside pocket. Please see Full Prescribing Information for Venofer® inside pocket.

INJECTAFER® (ferric carboxymaltose injection) VENOFER® (iron sucrose injection, USP)

Injectafer®1 (ferric carboxymaltose injection)

Venofer®2 (iron sucrose injection, USP)

Indications

Treatment of iron de�ciency 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

Contraindications Hypersensitivity to Injectafer® or any of its inactive components

Known hypersensitivity to Venofer®

Single dose750 mg

(2 doses separated by at least 7 days)

100 mg to 400 mg, depending upon the indication

Recommended cumulative dose

Total cumulative dose not to exceed 1500 mg of iron per course

Usual total treatment course is 1000 mg

Number of administrations for recommended cumulative dose

IV Push Yes Yes

IV Infusion

Yes, over at least 15 minutesYes, over 15 minutes to 2.5 hours,

depending on dose

Test Dose Required No No

MRI Interference No No

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

Preservative None None

How Supplied 750 mg/15 mL single-use vial50 mg/2.5 mL single-use vial 100 mg/5 mL single-use vial

200 mg/10 mL single-use vial

Non-Dextran

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to

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Important Safety Information on next page.

Ferrlecit®3/ Generic available (sodium ferric gluconate

complex injection)

INFeD®4

(iron dextran injection, USP)Feraheme®5

(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 de�ciency

in whom oral administration is unsatisfactory or impossible

Treatment of IDA in adult patients with chronic kidney disease

Known hypersensitivity to sodium ferric gluconate or any of its inactive components

Hypersensitivity to the product

All anemias not associated with iron de�ciency

Known hypersensitivity to Feraheme or any of its components

History of allergic reaction to any intravenous iron product

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

Most patients may require a cumulative dose of 1000 mg

Ranges based on the calculated iron requirement for each patient*

1020 mg

Yes Yes No

Yes, over 1 hour

Not indicated

Yes, over at least 15 minutes

No Yes No

No No Yes (for up to 3 months)

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

Benzyl alcohol None None

62.5 mg/5 mL single-use vial 100 mg/2 mL single-use vial510 mg/17 mL single-use vial

Dextran/Modi�ed Dextran

to

*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.Please see Full Prescribing Information for Injectafer® and Venofer® enclosed in the pocket of this guide, and the Important Safety Information on next page.

Injectafer®1 (ferric carboxymaltose injection)

Venofer®2 (iron sucrose injection, USP)

Indications

Treatment of iron de�ciency 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

Contraindications Hypersensitivity to Injectafer® or any of its inactive components

Known hypersensitivity to Venofer®

Single dose750 mg

(2 doses separated by at least 7 days)

100 mg to 400 mg, depending upon the indication

Recommended cumulative dose

Total cumulative dose not to exceed 1500 mg of iron per course

Usual total treatment course is 1000 mg

Number of administrations for recommended cumulative dose

IV Push Yes Yes

IV Infusion

Yes, over at least 15 minutesYes, over 15 minutes to 2.5 hours,

depending on dose

Test Dose Required No No

MRI Interference No No

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

Preservative None None

How Supplied 750 mg/15 mL single-use vial50 mg/2.5 mL single-use vial 100 mg/5 mL single-use vial

200 mg/10 mL single-use vial

Non-Dextran

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(for non-dialysis CKD IDA)

to

(maximum dose)

Please see Full Prescribing Information for Injectafer® and Venofer® enclosed in the pocket of this guide, and the Important Safety Information on next page.

Ferrlecit®3/ Generic available (sodium ferric gluconate

complex injection)

INFeD®4

(iron dextran injection, USP)Feraheme®5

(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 de�ciency

in whom oral administration is unsatisfactory or impossible

Treatment of IDA in adult patients with chronic kidney disease

Known hypersensitivity to sodium ferric gluconate or any of its inactive components

Hypersensitivity to the product

All anemias not associated with iron de�ciency

Known hypersensitivity to Feraheme or any of its components

History of allergic reaction to any intravenous iron product

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

Most patients may require a cumulative dose of 1000 mg

Ranges based on the calculated iron requirement for each patient*

1020 mg

Yes Yes No

Yes, over 1 hour

Not indicated

Yes, over at least 15 minutes

No Yes No

No No Yes (for up to 3 months)

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

Benzyl alcohol None None

62.5 mg/5 mL single-use vial 100 mg/2 mL single-use vial510 mg/17 mL single-use vial

Dextran/Modi�ed Dextran

to

*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.Important Safety Information on next page.

Please see attached Full Prescribing Information for Injectafer and Venofer and Important safety Information on next page.® ®






®


®


IV iron therapies













Please see attached Full Prescribing Information for Injectafer®. Please see Full Prescribing Information for Venofer® inside pocket.







®


®


IV iron therapies













Please see Full Prescribing Information for Injectafer® inside pocket. Please see attached Full Prescribing Information for Venofer®.






©2015 American Regent, Inc. FCM192EM Iss. 07/2015

®


®


IV iron therapies













Please see Full Prescribing Information for Injectafer® inside pocket. Please see Full Prescribing Information for Venofer® inside pocket.


651 S ML King Jr Ave • Waukegan, IL 60085 • Phone 847.336.4200 • Fax 847.360.4924complete packaging | individual solutionsSM

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258024LUITPOLD PHARMACEUTICALS INC

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FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Injectafer is indicated for the treatment of iron deficiency anemia in adultpatients:• 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 ADMINISTRATIONFor patients weighing 50 kg (110lb) or more: Give Injectafer in two dosesseparated by at least 7 days. Give each dose as 750 mg for a total cumulativedose not to exceed 1500 mg of iron per course.For patients weighing less than 50 kg (110lb): Give Injectafer in two dosesseparated by at least 7 days. Give each dose as 15 mg/kg body weight for atotal cumulative dose not to exceed 1500 mg of iron per course.The dosage of Injectafer is expressed in mg of elemental iron. Each mL ofInjectafer contains 50 mg of elemental iron. Injectafer treatment may berepeated if iron deficiency anemia reoccurs.Administer Injectafer intravenously, either as an undiluted slow intravenouspush or by infusion. When administering as a slow intravenous push, give atthe rate of approximately 100 mg (2 mL) per minute. When administered viainfusion, 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 isnot 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, Injectafersolution is physically and chemically stable for 72 hours when stored at roomtemperature. To maintain stability, do not dilute to concentrations less than2 mg iron/mL.Inspect parenteral drug products visually for the absence of particulatematter and discoloration prior to administration. The product contains nopreservatives. Each vial of Injectafer is intended for single-use only. Anyunused drug remaining after injection must be discarded.Avoid extravasation of Injectafer since brown discoloration of the extravasationsite may be long lasting. Monitor for extravasation. If extravasation occurs,discontinue the Injectafer administration at that site.

3 DOSAGE FORMS AND STRENGTHS

750 mg iron / 15 mL single-use vial

4 CONTRAINDICATIONS

Hypersensitivity to Injectafer or any of its components [see Warnings andPrecautions (5.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity ReactionsSerious hypersensitivity reactions, including anaphylactic-type reactions,some of which have been life-threatening and fatal, have been reported inpatients receiving Injectafer. Patients may present with shock, clinicallysignificant hypotension, loss of consciousness, and/or collapse. Monitorpatients for signs and symptoms of hypersensitivity during and afterInjectafer administration for at least 30 minutes and until clinically stablefollowing completion of the infusion. Only administer Injectafer whenpersonnel and therapies are immediately available for the treatment ofserious hypersensitivity reactions. [see Adverse Reactions (6.1 and 6.2)].

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to useInjectafer safely and effectively. See full prescribing information forInjectafer.INJECTAFER® (ferric carboxymaltose injection)For intravenous useInitial U.S. Approval: 2013------------------------------INDICATIONS AND USAGE------------------------------Injectafer is an iron replacement product indicated for the treatment of irondeficiency 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 twodoses separated by at least 7 days. Give each dose as 750 mg for a totalcumulative dose of 1500 mg of iron per course.For patients weighing less than 50 kg (110lb): Give Injectafer in two dosesseparated 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)

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE2 DOSAGE AND ADMINISTRATION3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions5.2 Hypertension5.3 Laboratory Test Alterations

6 ADVERSE REACTIONS6.1 Adverse Reactions in Clinical Trials6.2 Post-marketing Experience

7 DRUG INTERACTIONS8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use

--------------------------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 least30 minutes and until clinically stable following completion of eachadministration. (5.1)

• Hypertension: Monitor patients closely for signs and symptoms ofhypertension 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 at1-800-734-9236 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-approvedpatient labeling.

Revised: July 2013

10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

14 CLINICAL STUDIES14.1 Trial 1: Iron Deficiency Anemia in Patients Who are Intolerant to

Oral Iron or Have Had Unsatisfactory Response to Oral Iron14.2 Trial 2: Iron Deficiency Anemia in Patients with Non-Dialysis

Dependent Chronic Kidney Disease16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing informationare not listed.

In clinical trials, serious anaphylactic/anaphylactoid reactions were reportedin 0.1% (2/1775) of subjects receiving Injectafer. Other serious or severeadverse reactions potentially associated with hypersensitivity which included,but not limited to, pruritus, rash, urticaria, wheezing, or hypotension werereported in 1.5% (26/1775) of these subjects.5.2 HypertensionIn clinical studies, hypertension was reported in 3.8% (67/1,775) of subjectsin clinical trials 1 and 2. Transient elevations in systolic blood pressure,sometimes occurring with facial flushing, dizziness, or nausea were observedin 6% (106/1,775) of subjects in these two clinical trials. These elevationsgenerally occurred immediately after dosing and resolved within 30 minutes.Monitor patients for signs and symptoms of hypertension following eachInjectafer administration [see Dosage and Administration (2)].5.3 Laboratory Test AlterationsIn the 24 hours following administration of Injectafer, laboratory assays mayoverestimate serum iron and transferrin bound iron by also measuring theiron in Injectafer.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in othersections 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 TrialsBecause clinical trials are conducted under widely varying conditions, theadverse reaction rates observed cannot be directly compared to rates in otherclinical 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 upto a maximum single dose of 750 mg of iron on two occasions separated byat least 7 days up to a cumulative dose of 1500 mg of iron.Adverse reactions reported by ≥ 1% of treated patients are shown in thefollowing table.Table 1. Adverse reactions reported in ≥ 1% of Study Patients in Clinical Trials1 and 2

Term Injectafer

(N=1775)%

PooledComparatorsa

(N=1783)%

Oraliron

(N=253)%

Nausea 7.2 1.8 1.2Hypertension 3.8 1.9 0.4Flushing/Hot Flush 3.6 0.2 0.0Blood Phosphorus Decrease 2.1 0.1 0.0Dizziness 2.0 1.2 0.0Vomiting 1.7 0.5 0.4Injection Site Discoloration 1.4 0.3 0.0Headache 1.2 0.9 0.0Alanine AminotransferaseIncrease 1.1 0.2 0.0

Dysgeusia 1.1 2.1 0.0Hypotension 1.0 1.9 0.0Constipation 0.5 0.9 3.2

a Includes oral iron and all formulations of IV iron other than Injectafer

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Other adverse reactions reported by ≥ 0.5% of treated patients includeabdominal pain, diarrhea, gamma glutamyl transferase increased, injectionsite pain/irritation, rash, paraesthesia, sneezing. Transient decreases inlaboratory blood phosphorus levels (< 2 mg/dL) have been observed in 27%(440/1638) patients in clinical trials.6.2 Post-marketing ExperienceBecause these reactions are reported voluntarily from a population of uncertainsize, it is not always possible to reliably estimate their frequency or establish acausal relationship to drug exposure. The following serious adverse reactionshave been most commonly reported from the post-marketing spontaneousreports with Injectafer: urticaria, dyspnea, pruritis, tachycardia, erythema,pyrexia, chest discomfort, chills, angioedema, back pain, arthralgia, andsyncope. One case of hypophosphatemic osteomalacia was reported ina subject who received 500 mg of Injectafer every 2 weeks for a total of16 weeks. Partial recovery followed discontinuation of Injectafer.

7 DRUG INTERACTIONS

Formal drug interaction studies have not been performed with Injectafer.

8 USE IN SPECIFIC POPULATIONS

8.1 PregnancyPregnancy Category CRisk SummaryAdequate and well controlled studies in pregnant women have not beenconducted. However, animal reproduction studies have been conducted withferric carboxymaltose. In these studies, administration of ferric carboxymaltoseto rabbits during the period of organogenesis caused fetal malformations andincreased 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 beenestablished for Injectafer. However, all pregnancies, regardless of exposure toany drug, has a background rate of 2 to 4% for major malformations, and 15to 20% for pregnancy loss. Injectafer should be used during pregnancy only ifthe potential benefit justifies the potential risk to the fetus.Animal DataAdministration of ferric carboxymaltose to rats as a one-hour intravenousinfusion up to 30 mg/kg/day iron on gestation days 6 to 17 did not result inadverse 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 gestationdays 6 to 19 at iron doses of 4.5, 9, 13.5, and 18 mg/kg/day. Malformationswere seen starting at the daily dose of 9 mg/kg (23% of the human weeklydose of 750 mg). Spontaneous abortions occurred starting at the daily irondose of 4.5 mg/kg (12% of the human weekly dose based on body surfacearea). Pre-implantation loss was at the highest dose. Adverse embryofetaleffects were observed in the presence of maternal toxicity.A pre- and post-natal development study was conducted in rats at intravenousdoses up to 18 mg/kg/day of iron (approximately 23% of the weekly humandose of 750 mg on a body surface area basis). There were no adverse effectson survival of offspring, their behavior, sexual maturation or reproductiveparameters.8.3 Nursing MothersA study to determine iron concentrations in breast milk after administration ofInjectafer (n=11) or oral ferrous sulfate (n=14) was conducted in 25 lactatingwomen with postpartum iron deficiency anemia. Mean breast milk iron levelswere higher in lactating women receiving Injectafer than in lactating womenreceiving oral ferrous sulfate.8.4 Pediatric UseSafety and effectiveness have not been established in pediatric patients.8.5 Geriatric UseOf the 1775 subjects in clinical studies of Injectafer, 50% were 65 years andover, while 25% were 75 years and over. No overall differences in safety oreffectiveness were observed between these subjects and younger subjects,and other reported clinical experience has not identified differences inresponses between the elderly and younger patients, but greater sensitivity ofsome older individuals cannot be ruled out.

10 OVERDOSAGEExcessive dosages of Injectafer may lead to accumulation of iron in storagesites potentially leading to hemosiderosis. A patient who received Injectafer18,000 mg over 6 months developed hemosiderosis with multiple jointdisorder, walking disability and asthenia . Hypophosphatemic osteomalaciawas reported in a patient who received Injectafer 4000 mg over 4 months.Partial recovery followed discontinuation of Injectafer. [see Post-marketingExperience (6.2)].

11 DESCRIPTION

Ferric carboxymaltose, an iron replacement product, is an iron carbohydratecomplex with the chemical name of polynuclear iron (III) hydroxide4(R)-(poly-(1→4)-O-a-D-glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate. It has a relative molecular weight of approximately150,000 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:

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258024LU

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Cyan

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1INDICATIONS AND USAGE

Injectaferis

indicatedfor

thetreatm

entof

irondeficiency

anemia

inadult

patients:•

who

haveintolerance

tooraliron

orhavehad

unsatisfactoryresponse

tooral iron;

•who

havenon-dialysis

dependentchronickidney

disease.2

DOSAGE AND ADMINISTRATION

Forpatients

weighing

50kg

(110lb)or

more:

GiveInjectafer

intwodoses

separatedby

atleast7days.

Giveeach

doseas

750mgfora

totalcumulative

dosenotto

exceed1500

mgofiron

percourse.For

patientsweighing

lessthan

50kg

(110lb):Give

Injectaferin

twodoses

separatedby

atleast7days.Give

eachdose

as15

mg/kg

bodyweightfor

atotalcum

ulativedose

nottoexceed

1500mgofiron

percourse.The

dosageof

Injectaferis

expressedin

mgof

elementaliron.Each

mLof

Injectafercontains

50mgof

elemental

iron.Injectafer

treatment

may

berepeated

ifirondeficiency

anemiareoccurs.

Administer

Injectaferintravenously,either

asan

undilutedslow

intravenouspush

orbyinfusion.W

henadm

inisteringas

aslow

intravenouspush,give

atthe

rateofapproxim

ately100

mg(2

mL)perm

inute.When

administered

viainfusion,dilute

upto

750mgofiron

inno

more

than250

mLofsterile

0.9%sodium

chlorideinjection,USP,such

thattheconcentration

oftheinfusion

isnotless

than2mgofiron

permLand

administeroveratleast15

minutes.

When

addedto

aninfusion

bagcontaining

0.9%sodium

chlorideinjection,

USP,atconcentrationsranging

from2mgto

4mgofiron

permL,Injectafer

solutionisphysically

andchem

icallystable

for72hours

when

storedatroom

temperature.To

maintain

stability,donot

diluteto

concentrationsless

than2mgiron/m

L.Inspect

parenteraldrug

productsvisually

forthe

absenceof

particulatematter

anddiscoloration

priorto

administration.

Theproduct

containsno

preservatives.Each

vialof

Injectaferis

intendedfor

single-useonly.

Anyunused

drugrem

ainingafterinjection

mustbe

discarded.Avoid

extravasationofInjectafersince

browndiscoloration

oftheextravasation

sitemay

belong

lasting.Monitor

forextravasation.Ifextravasation

occurs,discontinue

theInjectaferadm

inistrationatthatsite.

3DOSAGE FORM

S AND STRENGTHS

750mgiron

/15mLsingle-use

vial

4CONTRAINDICATIONS

Hypersensitivityto

Injectaferor

anyof

itscom

ponents[see

Warnings

andPrecautions (5.1)].

5W

ARNINGS AND PRECAUTIONS

5.1Hypersensitivity Reactions

Serioushypersensitivity

reactions,including

anaphylactic-typereactions,

some

ofwhich

havebeen

life-threateningand

fatal,havebeen

reportedin

patientsreceiving

Injectafer.Patients

may

presentw

ithshock,

clinicallysignificant

hypotension,loss

ofconsciousness,

and/orcollapse.

Monitor

patientsfor

signsand

symptom

sof

hypersensitivityduring

andafter

Injectaferadministration

foratleast30m

inutesand

untilclinicallystable

following

completion

ofthe

infusion.Only

administer

Injectaferw

henpersonnel

andtherapies

areim

mediately

availablefor

thetreatm

entof

serioushypersensitivity

reactions.[see

AdverseReactions

(6.1and

6.2)].

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 useInitial U.S. Approval: 2013------------------------------INDICATIONS

ANDUSAGE------------------------------

Injectafer is an iron replacement product indicated for the treatm

ent of irondeficiency anem

ia in adult patients:•

who

haveintolerance

tooraliron

orhavehad


tooral iron;

•who

havenon-dialysis


disease.-------------------------DOSAGE AND ADM

INISTRATION---------------------------Forpatients

weighing

50kg

(110lb)ormore:

GiveInjectaferin

two

dosesseparated

byatleast7

days.Give

eachdose

as750

mgfora

totalcum

ulativedose

of1500mgofiron

percourse.Forpatients

weighing

lessthan

50kg

(110lb):Give

Injectaferintwodoses

separatedby

atleast7days

andgive

eachdose

as15

mg/kg

bodyweight.

Injectafertreatmentm

aybe

repeatedifiron

deficiencyanem

iareoccurs.(2)



2DOSAGE AND ADM

INISTRATION3

DOSAGE FORMS AND STRENGTHS

4CONTRAINDICATIONS

5W

ARNINGS AND PRECAUTIONS5.1

HypersensitivityReactions

5.2Hypertension

5.3Laboratory

TestAlterations6

ADVERSE REACTIONS6.1

AdverseReactions

inClinicalTrials

6.2Post-m

arketingExperience

7DRUG INTERACTIONS

8USE IN SPECIFIC POPULATIONS8.1

Pregnancy8.3

NursingMothers

8.4Pediatric

Use8.5

GeriatricUse

--------------------------DOSAGEFORM

SAND

STRENGTHS-----------------------750

mgiron

/15mLsingle-use

vial.(3)-------------------------------CONTRAINDICATIONS---------------------------------Hypersensitivity

toInjectaferorany

ofitsinactive

components.(4)

------------------------WARNINGS AND PRECAUTIONS----------------------------

•Hypersensitivity reactions:Observe

forsignsand

symptom

sof


andafterInjectaferadm

inistrationforatleast

30minutes

anduntilclinically

stablefollow

ingcom

pletionofeach

administration.(5.1)

•Hypertension:M

onitorpatientsclosely

forsignsand

symptom

sof

hypertensionfollow

ingeach

Injectaferadministration.(5.2)

------------------------------ADVERSE REACTIONS----------------------------------The

mostcom

mon

adversereactions

(≥2%

)arenausea,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 orwww.fda.gov/m

edwatch.

------------------------USE IN SPECIFIC POPULATIONS----------------------------•

NursingMothers:Exercise

cautionwhen

administered

toanursing

wom

an.(8.3)See 17 for PATIENT COUNSELING INFORM

ATION and FDA-approvedpatient labeling.

Revised: July 2013

10OVERDOSAGE

11DESCRIPTION

12CLINICAL PHARM

ACOLOGY12.1

Mechanism

ofAction12.2

Pharmacodynam

ics12.3

Pharmacokinetics

13NONCLINICAL TOXICOLOGY13.1

Carcinogenesis,Mutagenesis,and

Impairm

entofFertility14

CLINICAL STUDIES14.1

Trial1:IronDeficiency

AnemiainPatients

Who

areIntolerantto

OralIronorHave

HadUnsatisfactory

Responseto

OralIron14.2


AnemiainPatients

with

Non-DialysisDependentChronic

KidneyDisease

16HOW

SUPPLIED/STORAGE AND HANDLING17

PATIENT COUNSELING INFORMATION

*Sectionsorsubsections

omitted

fromthe

fullprescribinginform

ationare

notlisted.

Inclinicaltrials,serious

anaphylactic/anaphylactoidreactions

were

reportedin

0.1%(2/1775)

ofsubjects

receivingInjectafer.

Otherserious

orsevere

adversereactions

potentiallyassociated

with

hypersensitivitywhich

included,but

notlim

itedto,

pruritus,rash,

urticaria,wheezing,

orhypotension

were

reportedin1.5%

(26/1775)ofthesesubjects.

5.2Hypertension

Inclinicalstudies,hypertension

was

reportedin3.8%

(67/1,775)ofsubjectsin

clinicaltrials

1and

2.Transient

elevationsin

systolicblood

pressure,som

etimes

occurringwith

facialflushing,dizziness,ornauseawere

observedin

6%(106/1,775)

ofsubjects

inthese

twoclinicaltrials.

Theseelevations

generallyoccurred

immediately

afterdosingand

resolvedwithin

30minutes.

Monitor

patientsfor

signsand

symptom

sof

hypertensionfollow

ingeach


[seeDosage and Adm

inistration(2)].

5.3Laboratory Test Alterations

Inthe

24hours

following

administration

ofInjectafer,laboratoryassays

may

overestimate

serumiron

andtransferrin

boundiron

byalso

measuring

theiron

inInjectafer.

6ADVERSE REACTIONS

Thefollow

ingadverse

reactionsare

discussedin

greaterdetail

inother

sectionsofthe

labeling:•


[seeW

arnings and Precautions(5.1)]

•Hypertension

[seeW


•Laboratory

TestAlterations[see

Warnings and Precautions

(5.3)]6.1

Adverse Reactions in Clinical TrialsBecause

clinicaltrials

areconducted

underwidely

varyingconditions,

theadverse

reactionrates

observedcannotbe

directlycom

paredto

ratesinother

clinicaltrialsand

may

notreflecttherates

observedinclinicalpractice.

Intworandom

izedclinicalstudies

[Studies1and

2,SeeClinicalStudies

(14)],atotalof1,775

patientswere

exposedto

Injectafer15mg/kg

bodyweightup

toamaxim

umsingle

doseof750

mgofiron

ontwooccasions

separatedby

atleast7days

upto

acum

ulativedose

of1500mgofiron.

Adversereactions

reportedby

≥1%

oftreated

patientsare

shownin

thefollow

ingtable.

Table1.

Adversereactions

reportedin

≥1%

ofStudyPatients

inClinicalTrials

1 and 2

TermInjectafer

(N=1775)%

PooledCom

paratorsa

(N=1783)%

Oraliron

(N=253)%

Nausea7.2

1.81.2

Hypertension3.8

1.90.4

Flushing/HotFlush3.6

0.20.0

BloodPhosphorus

Decrease2.1

0.10.0

Dizziness2.0

1.20.0

Vomiting

1.70.5

0.4Injection

SiteDiscoloration

1.40.3

0.0Headache

1.20.9

0.0Alanine Am

inotransferaseIncrease

1.10.2

0.0

Dysgeusia1.1

2.10.0

Hypotension1.0

1.90.0

Constipation0.5

0.93.2


INJECTAFER®

(ferric carboxymaltose injection)

RQ105200

Otheradverse

reactionsreported

by≥

0.5%of

treatedpatients

includeabdom

inalpain,

diarrhea,gam

maglutam

yltransferase

increased,injection

sitepain/irritation,

rash,paraesthesia,

sneezing.Transient

decreasesin

laboratoryblood

phosphoruslevels

(<2mg/dL)have

beenobserved

in27%

(440/1638)patientsinclinicaltrials.

6.2Post-m

arketing ExperienceBecause

thesereactions

arereported

voluntarilyfrom

apopulation

ofuncertainsize,itis

notalways

possibletoreliably

estimate

theirfrequencyorestablish

acausalrelationship

todrug

exposure.Thefollow

ingserious

adversereactions

havebeen

most

commonly

reportedfrom

thepost-m

arketingspontaneous

reportswith

Injectafer:urticaria,

dyspnea,pruritis,

tachycardia,erythem

a,pyrexia,

chestdiscom

fort,chills,

angioedema,

backpain,

arthralgia,and

syncope.One

caseof

hypophosphatemic

osteomalacia

was

reportedin

asubject

who

received500

mgof

Injectaferevery

2weeks

foratotal

of16

weeks.Partialrecovery

followed

discontinuationofInjectafer.

7DRUG INTERACTIONS

Formaldrug

interactionstudies

havenotbeen

performed

with

Injectafer.

8USE IN SPECIFIC POPULATIONS

8.1Pregnancy

PregnancyCategory

CRisk

Summ

aryAdequate

andwell

controlledstudies

inpregnant

wom

enhave

notbeen

conducted.However,anim

alreproductionstudies

havebeen

conductedwith

ferriccarboxymaltose.In

thesestudies,administration

offerriccarboxymaltose

torabbits

duringthe

periodoforganogenesis

causedfetalm

alformations

andincreased

implantation

lossatm

aternallytoxic

dosesofapproxim

ately12%

to23%

ofthehum

anweekly

doseof750

mg(based

onbody

surfacearea).

Theincidence

ofmajor

malform

ationsin

human

pregnancieshas

notbeen

establishedforInjectafer.How

ever,allpregnancies,regardlessofexposure

toany

drug,hasabackground

rateof2

to4%

formajorm

alformations,and

15to

20%forpregnancy

loss.Injectafershouldbe

usedduring

pregnancyonly

ifthe

potentialbenefitjustifiesthe

potentialriskto

thefetus.

Animal Data

Administration

offerric

carboxymaltose

torats

asaone-hour

intravenousinfusion

upto

30mg/kg/day

ironon

gestationdays

6to

17did

notresultinadverse

embryofetalfindings.This

dailydose

inrats

isapproxim

ately40%

ofthehum

anweekly

doseof750

mgbased

onbody

surfacearea.In

rabbits,ferric

carboxymaltose

was

administered

asaone-hour

infusionon

gestationdays

6to

19atiron

dosesof4.5,9,13.5,and

18mg/kg/day.M

alformations

were

seenstarting

atthedaily

doseof9

mg/kg

(23%ofthe

human

weekly

doseof750

mg).Spontaneous

abortionsoccurred

startingatthe

dailyiron

doseof4.5

mg/kg

(12%ofthe

human

weekly

dosebased

onbody

surfacearea).

Pre-implantation

losswas

atthe

highestdose.

Adverseem

bryofetaleffects

were

observedinthe

presenceofm

aternaltoxicity.Apre-and

post-nataldevelopmentstudy

was

conductedinrats

atintravenousdoses

upto

18mg/kg/day

ofiron(approxim

ately23%

oftheweekly

human

doseof750

mgon

abody

surfacearea

basis).Therewere

noadverse

effectson

survivalof

offspring,their

behavior,sexual

maturation

orreproductive

parameters.

8.3Nursing M

othersAstudy

todeterm

ineiron

concentrationsinbreastm

ilkafteradm

inistrationof

Injectafer(n=11)ororalferroussulfate

(n=14)was

conductedin25

lactatingwom

enwith

postpartumiron

deficiencyanem

ia.Mean

breastmilk

ironlevels

were

higherin

lactatingwom

enreceiving

Injectaferthan

inlactating

wom

enreceiving

oralferroussulfate.

8.4Pediatric Use

Safetyand

effectivenesshave

notbeenestablished

inpediatric

patients.8.5

Geriatric UseOfthe

1775subjects

inclinicalstudies

ofInjectafer,50%were

65years

andover,w

hile25%

were

75years

andover.No

overalldifferencesin

safetyor

effectivenesswere

observedbetw

eenthese

subjectsand

youngersubjects,

andother

reportedclinical

experiencehas

notidentified

differencesin

responsesbetw

eenthe

elderlyand

youngerpatients,butgreatersensitivityof

someolderindividuals

cannotberuled

out.

10OVERDOSAGE

Excessivedosages

ofInjectafermay

leadto

accumulation

ofironin

storagesites

potentiallyleading

tohem

osiderosis.Apatientw

horeceived

Injectafer18,000

mg

over6

months

developedhem

osiderosiswith

multiple

jointdisorder,

walking

disabilityand

asthenia.Hypophosphatem

icosteom

alaciawas

reportedin

apatient

who

receivedInjectafer

4000mgover

4months.

Partialrecoveryfollow

eddiscontinuation

ofInjectafer.

[seePost-m

arketingExperience (6.2)].

11DESCRIPTION

Ferriccarboxym

altose,aniron

replacementproduct,is

aniron

carbohydratecom

plexwith

thechem

icalnam

eof

polynucleariron

(III)hydroxide

4(R)-(poly-(1→

4)-O-a

-D-glucopyranosyl)-oxy-2(R

),3(S),5(R

),6-tetrahydroxy-hexanoate.It

hasarelative

molecular

weight

ofapproxim

ately150,000

Dacorresponding

tothe

following

empiricalform

ula:[FeO

x (OH)y (H2 O)z ]n [{(C

6 H10 O

5 )m(C

6 H12 O

7 )}l ]k ,

where

n≈10

3,m≈8,l≈

11,andk≈4

(lrepresentsthe

mean

branchingdegree

oftheligand).

Thechem

icalstructureispresented

below:

651 S M

L King Jr A


hone 847.336.4200 • Fax 847.360.4924co

mp

lete packag

ing

| ind

ividu

al solu

tion

sS

M

Pro

du

ct Info

rmatio

nS

pecified

Co

lors

P/N: J/N:C

ust:Size:

Pro

of A

7/26/2013A

pp

roved

By

Nam

e

DateO

K to PrintN

ew Proof R

equired



ill be matched on


n_Dem

and Solutions FourC

olor Book, On _D



olor Standards.

258024LU

ITPOLD

PHAR

MAC

EUTIC

ALS INC

Cyan

Magenta

Yellow

Black



Injectaferis

indicatedfor

thetreatm

entof

irondeficiency

anemia

inadult

patients:•

who

haveintolerance

tooraliron

orhavehad


tooral iron;

•who

havenon-dialysis


disease.2


Forpatients

weighing

50kg

(110lb)or

more:

GiveInjectafer

intwodoses

separatedby

atleast7days.

Giveeach

doseas

750mgfora

totalcumulative

dosenotto

exceed1500

mgofiron

percourse.For

patientsweighing

lessthan

50kg

(110lb):Give

Injectaferin

twodoses

separatedby

atleast7days.Give

eachdose

as15

mg/kg

bodyweightfor

atotalcum

ulativedose

nottoexceed

1500mgofiron

percourse.The

dosageof

Injectaferis

expressedin

mgof

elementaliron.Each

mLof

Injectafercontains

50mgof

elemental

iron.Injectafer

treatment

may

berepeated

ifirondeficiency

anemiareoccurs.

Administer


asan

undilutedslow

intravenouspush

orbyinfusion.W

henadm

inisteringas

aslow


atthe

rateofapproxim

ately100

mg(2

mL)perm

inute.When

administered

viainfusion,dilute

upto

750mgofiron

inno

more

than250

mLofsterile

0.9%sodium



oftheinfusion

isnotless

than2mgofiron

permLand


minutes.

When

addedto

aninfusion

bagcontaining

0.9%sodium

chlorideinjection,


from2mgto

4mgofiron

permL,Injectafer


andchem

icallystable

for72hours

when

storedatroom

temperature.To

maintain

stability,donot

diluteto

concentrationsless

than2mgiron/m

L.Inspect

parenteraldrug

productsvisually

forthe

absenceof

particulatematter

anddiscoloration

priorto

administration.

Theproduct

containsno

preservatives.Each

vialof

Injectaferis

intendedfor

single-useonly.

Anyunused

drugrem


mustbe

discarded.Avoid


browndiscoloration

oftheextravasation

sitemay

belong

lasting.Monitor


occurs,discontinue

theInjectaferadm


3DOSAGE FORM

S AND STRENGTHS

750mgiron

/15mLsingle-use

vial

4CONTRAINDICATIONS

Hypersensitivityto

Injectaferor

anyof

itscom

ponents[see

Warnings


5W




reactions,including


some

ofwhich

havebeen

life-threateningand

fatal,havebeen

reportedin

patientsreceiving

Injectafer.Patients

may

presentw

ithshock,


hypotension,loss

ofconsciousness,

and/orcollapse.

Monitor

patientsfor

signsand

symptom

sof


andafter


foratleast30m

inutesand


following

completion

ofthe

infusion.Only

administer

Injectaferw

henpersonnel

andtherapies

areim

mediately

availablefor

thetreatm

entof


reactions.[see

AdverseReactions

(6.1and

6.2)].







ANDUSAGE------------------------------




who

haveintolerance

tooraliron

orhavehad


tooral iron;

•who

havenon-dialysis




weighing

50kg

(110lb)ormore:

GiveInjectaferin

two

dosesseparated

byatleast7

days.Give

eachdose

as750

mgfora

totalcum

ulativedose

of1500mgofiron


weighing

lessthan

50kg

(110lb):Give


separatedby

atleast7days

andgive

eachdose

as15

mg/kg

bodyweight.


aybe

repeatedifiron

deficiencyanem

iareoccurs.(2)



2DOSAGE AND ADM

INISTRATION3


4CONTRAINDICATIONS

5W



5.2Hypertension

5.3Laboratory

TestAlterations6


AdverseReactions

inClinicalTrials

6.2Post-m

arketingExperience

7DRUG INTERACTIONS


Pregnancy8.3

NursingMothers

8.4Pediatric

Use8.5

GeriatricUse

--------------------------DOSAGEFORM

SAND

STRENGTHS-----------------------750

mgiron

/15mLsingle-use


toInjectaferorany

ofitsinactive

components.(4)



forsignsand

symptom

sof




30minutes

anduntilclinically

stablefollow

ingcom

pletionofeach


•Hypertension:M


forsignsand

symptom

sof

hypertensionfollow

ingeach



mostcom

mon

adversereactions

(≥2%



dizziness(6.1)



edwatch.



cautionwhen

administered

toanursing

wom



Revised: July 2013

10OVERDOSAGE

11DESCRIPTION

12CLINICAL PHARM

ACOLOGY12.1

Mechanism

ofAction12.2

Pharmacodynam

ics12.3

Pharmacokinetics



Impairm

entofFertility14



AnemiainPatients

Who

areIntolerantto

OralIronorHave

HadUnsatisfactory

Responseto

OralIron14.2


AnemiainPatients

with


KidneyDisease

16HOW




omitted

fromthe


ationare

notlisted.



were

reportedin

0.1%(2/1775)

ofsubjects


Otherserious

orsevere

adversereactions


with


included,but

notlim

itedto,

pruritus,rash,

urticaria,wheezing,

orhypotension

were

reportedin1.5%


5.2Hypertension


was

reportedin3.8%


clinicaltrials

1and

2.Transient

elevationsin

systolicblood

pressure,som

etimes

occurringwith


observedin

6%(106/1,775)

ofsubjects

inthese

twoclinicaltrials.

Theseelevations

generallyoccurred

immediately

afterdosingand

resolvedwithin

30minutes.

Monitor

patientsfor

signsand

symptom

sof

hypertensionfollow

ingeach


[seeDosage and Adm

inistration(2)].


Inthe

24hours

following

administration


may

overestimate

serumiron

andtransferrin

boundiron

byalso

measuring

theiron

inInjectafer.

6ADVERSE REACTIONS

Thefollow

ingadverse

reactionsare

discussedin

greaterdetail

inother

sectionsofthe

labeling:•


[seeW


•Hypertension

[seeW


•Laboratory

TestAlterations[see


(5.3)]6.1


clinicaltrials

areconducted

underwidely

varyingconditions,

theadverse

reactionrates

observedcannotbe

directlycom

paredto

ratesinother

clinicaltrialsand

may

notreflecttherates


Intworandom

izedclinicalstudies

[Studies1and


(14)],atotalof1,775

patientswere

exposedto

Injectafer15mg/kg

bodyweightup

toamaxim

umsingle

doseof750

mgofiron

ontwooccasions

separatedby

atleast7days

upto

acum

ulativedose

of1500mgofiron.

Adversereactions

reportedby

≥1%

oftreated

patientsare

shownin

thefollow

ingtable.

Table1.

Adversereactions

reportedin

≥1%

ofStudyPatients

inClinicalTrials

1 and 2

TermInjectafer

(N=1775)%

PooledCom

paratorsa

(N=1783)%

Oraliron

(N=253)%

Nausea7.2

1.81.2

Hypertension3.8

1.90.4


0.20.0

BloodPhosphorus

Decrease2.1

0.10.0

Dizziness2.0

1.20.0

Vomiting

1.70.5

0.4Injection

SiteDiscoloration

1.40.3

0.0Headache

1.20.9

0.0Alanine Am


1.10.2

0.0

Dysgeusia1.1

2.10.0

Hypotension1.0

1.90.0

Constipation0.5

0.93.2


INJECTAFER®


RQ105200

Otheradverse

reactionsreported

by≥

0.5%of

treatedpatients

includeabdom

inalpain,

diarrhea,gam

maglutam

yltransferase

increased,injection


rash,paraesthesia,

sneezing.Transient

decreasesin

laboratoryblood

phosphoruslevels

(<2mg/dL)have

beenobserved

in27%


6.2Post-m


thesereactions

arereported

voluntarilyfrom

apopulation


notalways

possibletoreliably

estimate


acausalrelationship

todrug

exposure.Thefollow

ingserious

adversereactions

havebeen

most

commonly

reportedfrom

thepost-m

arketingspontaneous

reportswith


dyspnea,pruritis,

tachycardia,erythem

a,pyrexia,

chestdiscom

fort,chills,

angioedema,

backpain,

arthralgia,and

syncope.One

caseof

hypophosphatemic

osteomalacia

was

reportedin

asubject

who

received500

mgof

Injectaferevery

2weeks

foratotal

of16


followed


7DRUG INTERACTIONS

Formaldrug

interactionstudies

havenotbeen

performed

with

Injectafer.


8.1Pregnancy

PregnancyCategory

CRisk

Summ

aryAdequate

andwell

controlledstudies

inpregnant

wom

enhave

notbeen



havebeen

conductedwith




torabbits

duringthe


causedfetalm

alformations

andincreased

implantation

lossatm

aternallytoxic

dosesofapproxim

ately12%

to23%

ofthehum

anweekly

doseof750

mg(based

onbody

surfacearea).

Theincidence

ofmajor

malform

ationsin

human

pregnancieshas

notbeen



toany

drug,hasabackground

rateof2

to4%

formajorm

alformations,and

15to

20%forpregnancy


usedduring

pregnancyonly

ifthe


potentialriskto

thefetus.

Animal Data

Administration

offerric

carboxymaltose

torats

asaone-hour

intravenousinfusion

upto

30mg/kg/day

ironon

gestationdays

6to

17did

notresultinadverse


dailydose

inrats

isapproxim

ately40%

ofthehum

anweekly

doseof750

mgbased

onbody

surfacearea.In

rabbits,ferric

carboxymaltose

was

administered

asaone-hour

infusionon

gestationdays

6to

19atiron


18mg/kg/day.M

alformations

were

seenstarting

atthedaily

doseof9

mg/kg

(23%ofthe

human

weekly

doseof750

mg).Spontaneous

abortionsoccurred

startingatthe

dailyiron

doseof4.5

mg/kg

(12%ofthe

human

weekly

dosebased

onbody

surfacearea).

Pre-implantation

losswas

atthe

highestdose.

Adverseem

bryofetaleffects

were

observedinthe

presenceofm



was

conductedinrats

atintravenousdoses

upto

18mg/kg/day

ofiron(approxim

ately23%

oftheweekly

human

doseof750

mgon

abody

surfacearea

basis).Therewere

noadverse

effectson

survivalof

offspring,their

behavior,sexual

maturation

orreproductive

parameters.

8.3Nursing M

othersAstudy

todeterm

ineiron


ilkafteradm

inistrationof


(n=14)was

conductedin25

lactatingwom

enwith

postpartumiron

deficiencyanem

ia.Mean

breastmilk

ironlevels

were

higherin

lactatingwom

enreceiving

Injectaferthan

inlactating

wom

enreceiving

oralferroussulfate.

8.4Pediatric Use

Safetyand

effectivenesshave

notbeenestablished

inpediatric

patients.8.5

Geriatric UseOfthe

1775subjects

inclinicalstudies


65years

andover,w

hile25%

were

75years

andover.No


safetyor

effectivenesswere

observedbetw

eenthese

subjectsand

youngersubjects,

andother

reportedclinical

experiencehas

notidentified

differencesin

responsesbetw

eenthe

elderlyand



cannotberuled

out.

10OVERDOSAGE

Excessivedosages

ofInjectafermay

leadto

accumulation

ofironin

storagesites

potentiallyleading

tohem


horeceived

Injectafer18,000

mg

over6

months

developedhem

osiderosiswith

multiple

jointdisorder,

walking

disabilityand


icosteom

alaciawas

reportedin

apatient

who

receivedInjectafer

4000mgover

4months.


eddiscontinuation

ofInjectafer.

[seePost-m


11DESCRIPTION

Ferriccarboxym

altose,aniron


aniron

carbohydratecom

plexwith

thechem

icalnam

eof

polynucleariron

(III)hydroxide

4(R)-(poly-(1→

4)-O-a


),3(S),5(R


hasarelative

molecular

weight

ofapproxim

ately150,000

Dacorresponding

tothe

following

empiricalform

ula:[FeO

x (OH)y (H2 O)z ]n [{(C

6 H10 O

5 )m(C

6 H12 O

7 )}l ]k ,

where

n≈10

3,m≈8,l≈

11,andk≈4

(lrepresentsthe

mean

branchingdegree

oftheligand).

Thechem


below:

1100 Venture Court • Suite 100 • Carrollton, Texas 75006 • Phone 972.478.6400 • Fax 972.478.6401651 S ML King Jr Ave • Waukegan, IL 60085 • Phone 847.336.4200 • Fax 847.360.4924

complete packaging | individual solutionsSM

Product Information Specified Colors

P/N: J/N:Cust:Size:

Proof A7/26/2013

Approved By

Name

Date

We must have signed proof before we can begin production.

OK to Print New Proof Required

This proof is to show size, copy placement andcolor break. Actual colors will be matched onpress to: PMS Book, On_Demand Solutions FourColor Book, On _Demand Solutions IndichromePlus Book and/or approved Color Standards.

258024LUITPOLD PHARMACEUTICALS INC

Black

Injectafer (ferric carboxymaltose injection) is a dark brown, sterile, aqueous,isotonic colloidal solution for intravenous injection. Each mL contains 50 mgiron as ferric carboxymaltose in water for injection. Injectafer is available in15 mL single-use vials. Sodium hydroxide and/or hydrochloric acid may havebeen added to adjust the pH to 5.0-7.0.Vial closure is not made with natural rubber latex.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of ActionFerric carboxymaltose is a colloidal iron (III) hydroxide in complex withcarboxymaltose, a carbohydrate polymer that releases iron.

12.2 PharmacodynamicsUsing positron emission tomography (PET) it was demonstrated that red celluptake of 59Fe and 52Fe from Injectafer ranged from 61% to 99%. In patientswith iron deficiency, red cell uptake of radio-labeled iron ranged from 91% to99% at 24 days after Injectafer dose. In patients with renal anemia red celluptake of radio-labeled iron ranged from 61% to 84% after 24 days Injectaferdose.

12.3 PharmacokineticsAfter administration of a single dose of Injectafer of 100 to 1000 mg of iron iniron deficient patients, maximum iron levels of 37 μg/mL to 333 μg/mL wereobtained respectively after 15 minutes to 1.21 hours post dose. The volume ofdistribution was estimated to be 3 L.The iron injected or infused was rapidly cleared from the plasma, the terminalhalf-life ranged from 7 to 12 hours. Renal elimination of iron was negligible.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenicity studies have not been performed with ferric carboxymaltose.Ferric carboxymaltose was not genotoxic in the following genetic toxicologystudies: in vitro microbial mutagenesis (Ames) assay, in vitro chromosomeaberration test in human lymphocytes, in vitro mammalian cell mutation assayin mouse lymphoma L5178Y/TK+/- cells, in vivo mouse micronucleus test atsingle intravenous doses up to 500 mg/kg.In a combined male and female fertility study, ferric carboxymaltose wasadministered intravenously over one hour to male and female rats at irondoses 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 embryonicdevelopment. The dose of 30 mg/kg in animals is approximately 40% of thehuman dose of 750 mg based on body surface area.

14 CLINICAL STUDIES

The safety and efficacy of Injectafer for treatment of iron deficiency anemiawere evaluated in two randomized, open-label, controlled clinical trials (Trial1 and Trial 2). In these two trials, Injectafer was administered at a dose of15 mg/kg body weight up to a maximum single dose of 750 mg of ironon two occasions separated by at least 7 days up to a cumulative dose of1500 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 IronTrial 1 was a randomized, open-label, controlled clinical study in patientswith 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 dayoral iron run-in period. Inclusion criteria prior to randomization includedhemoglobin (Hb) <12 g/dL, ferritin ≤ 100 ng/mL or ferritin ≤ 300 ng/mL whentransferrin saturation (TSAT) ≤ 30%. Cohort 1 subjects were randomized toInjectafer or oral iron for 14 more days. Cohort 2 subjects were randomizedto Injectafer or another IV iron per standard of care [90% of subjects receivediron sucrose]. The mean age of study patients was 43 years (range, 18 to94); 94% were female; 42% were Caucasian, 32% were African American,24% were Hispanic, and 2% were other races. The primary etiologies of irondeficiency anemia were heavy uterine bleeding (47%) and gastrointestinaldisorders (17%).Table 2 shows the baseline and the change in hemoglobin from baseline tohighest value between baseline and Day 35 or time of intervention.Table 2. Mean Change in Hemoglobin From Baseline to the HighestValue Between Day 35 or Time of Intervention (Modified Intent‑to‑TreatPopulation)

Hemoglobin (g/dL)Mean (SD)

Cohort 1 Cohort 2Injectafer(N=244)

Oral Iron(N=251)

Injectafer(N=245)

IV SCa

(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 tohighest value) 1.6 (1.2) 0.8 (0.8) 2.9 (1.6) 2.2 (1.3)

p-value 0.001 0.001SD=standard deviation; a: Intravenous iron per standard of careIncreases from baseline in mean ferritin (264.2 ± 224.2 ng/mL in Cohort 1and 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 Injectafer-treated patients.14.2 Trial 2: Iron Deficiency Anemia in Patients with Non‑DialysisDependent Chronic Kidney DiseaseTrial 2 was a randomized, open-label, controlled clinical study in patients withnon-dialysis dependent chronic kidney disease. Inclusion criteria includedhemoglobin (Hb) ≤ 11.5 g/dL, ferritin ≤ 100 ng/mL or ferritin ≤ 300 ng/mLwhen transferrin saturation (TSAT) ≤ 30%. Study patients were randomizedto 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 AfricanAmerican, 18% Hispanics, and 2% were other races.Table 3 shows the baseline and the change in hemoglobin from baseline tohighest value between baseline and Day 56 or time of intervention.

Table 3. Mean Change in Hemoglobin From Baseline to theHighest Value Between Baseline and Day 56 or Time of Intervention(Modified Intent‑to‑Treat Population)

Hemoglobin (g/dL)Mean (SD)

Injectafer(N=1249)

Venofer(N=1244)

Baseline 10.3 (0.8) 10.3 (0.8)Highest Value 11.4 (1.2) 11.3 (1.1)Change (from baseline to highestvalue) 1.1 (1.0) 0.9 (0.92)

Treatment Difference (95% CI) 0.21 (0.13, 0.28)

Increases from baseline in mean ferritin (734.7 ± 337.8 ng/mL), and transferrinsaturation (30 ± 17%) were observed at Day 56 in Injectafer-treated patients.

16 HOW SUPPLIED/STORAGE AND HANDLING

NDC 0517-0650-01 750 mg iron/15 mL Single-Use Vial Individually boxedNDC 0517-0650-02 750 mg iron/15 mL Single-Use Vial Packages of 2Store 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 toparenteral 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 andbreathing problems [see Warnings and Precautions (5)]

Injectafer is manufactured under license from Vifor (International) Inc,Switzerland.

AMERICANREGENT, INC.SHIRLEY, NY 11967

Patient InformationINJECTAFER (ferric carboxymaltose injection)

Please read this information carefully before taking thismedication. This summary does not tell you everythingabout INJECTAFER. Speak with your doctor or healthcareprofessional if there is something you do not understand or ifyou would like to learn more about INJECTAFER. Your doctoror healthcare professional is your best source of informationabout this medicine.What is INJECTAFER?Iron is a mineral that the body needs to produce red bloodcells. When the body does not get enough iron, it cannotproduce the number of normal red blood cells needed to keepyou in good health. This condition is called iron deficiency(iron shortage) or iron deficiency anemia.INJECTAFER is used to treat iron deficiency anemia. Irondeficiency anemia may be caused by several medicalconditions including heavy menstrual bleeding, pregnancy,childbirth, inflammatory bowel disease, other malabsorptiondiseases, bariatric surgery, or chronic kidney disease.General information about using INJECTAFER safely andeffectivelyInjectable iron is administered only by or under the supervisionof your health care professional.Serious or life threatening allergic reactions have beenreported with intravenous iron products. Tell your healthcare professional if you have ever had any unusual or allergicreaction to any IV iron.Patients should report to their healthcare professional anysigns and symptoms of an allergic reaction to INJECTAFER, inparticular rashes, shortness of breath and wheezing.Iron is not easily eliminated from the body, and its build upmay be lead to a condition called iron overload which may beharmful. Certain medical conditions such as liver disease mayalso make you more likely to develop iron overload. Ask yourdoctor or healthcare professional.Who should not take INJECTAFER?You should not be given INJECTAFER if you have anemia thatis not caused by iron deficiency, or if you have iron overload.If you are pregnant or plan to become pregnant please notifyyour doctor or healthcare professional. They will decidewhether it is safe for you to receive INJECTAFER.How should I take INJECTAFER?INJECTAFER is administered intravenously (into your vein) byyour doctor or healthcare professional in two doses.What should I avoid while taking INJECTAFER?You should not take iron supplements by mouth if youare receiving iron injections. Tell your doctor about allthe medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.

What are the possible side effects of INJECTAFER?The side effects of INJECTAFER are infrequent, usuallymild and generally do not cause patients to stop treatment.The most common side effects are nausea, injection sitereactions (including pain or bruising at the injection site),asymptomatic reductions in blood phosphorus, flushing,headache, hypertension, dizziness, and increased alanineaminotransferase. Potentially long lasting brown staining ofskin near injection site may occur.These are not all the possible side effects of INJECTAFER. Formore information ask your doctor or healthcare professional.Talk to your doctor if you think you have side effects fromtaking INJECTAFER.

651 S M

L King Jr A


hone 847.336.4200 • Fax 847.360.4924co

mp

lete packag

ing

| ind

ividu

al solu

tion

sS

M

Pro

du

ct Info

rmatio

nS

pecified

Co

lors

P/N: J/N:C

ust:Size:

Pro

of A

7/26/2013A

pp

roved

By

Nam

e

DateO

K to PrintN

ew Proof R

equired



ill be matched on


n_Dem

and Solutions FourC

olor Book, On _D



olor Standards.

258024LU

ITPOLD

PHAR

MAC

EUTIC

ALS INC

Cyan

Magenta

Yellow

Black



Injectaferis

indicatedfor

thetreatm

entof

irondeficiency

anemia

inadult

patients:•

who

haveintolerance

tooraliron

orhavehad


tooral iron;

•who

havenon-dialysis


disease.2


Forpatients

weighing

50kg

(110lb)or

more:

GiveInjectafer

intwodoses

separatedby

atleast7days.

Giveeach

doseas

750mgfora

totalcumulative

dosenotto

exceed1500

mgofiron

percourse.For

patientsweighing

lessthan

50kg

(110lb):Give

Injectaferin

twodoses

separatedby

atleast7days.Give

eachdose

as15

mg/kg

bodyweightfor

atotalcum

ulativedose

nottoexceed

1500mgofiron

percourse.The

dosageof

Injectaferis

expressedin

mgof

elementaliron.Each

mLof

Injectafercontains

50mgof

elemental

iron.Injectafer

treatment

may

berepeated

ifirondeficiency

anemiareoccurs.

Administer


asan

undilutedslow

intravenouspush

orbyinfusion.W

henadm

inisteringas

aslow


atthe

rateofapproxim

ately100

mg(2

mL)perm

inute.When

administered

viainfusion,dilute

upto

750mgofiron

inno

more

than250

mLofsterile

0.9%sodium



oftheinfusion

isnotless

than2mgofiron

permLand


minutes.

When

addedto

aninfusion

bagcontaining

0.9%sodium

chlorideinjection,


from2mgto

4mgofiron

permL,Injectafer


andchem

icallystable

for72hours

when

storedatroom

temperature.To

maintain

stability,donot

diluteto

concentrationsless

than2mgiron/m

L.Inspect

parenteraldrug

productsvisually

forthe

absenceof

particulatematter

anddiscoloration

priorto

administration.

Theproduct

containsno

preservatives.Each

vialof

Injectaferis

intendedfor

single-useonly.

Anyunused

drugrem


mustbe

discarded.Avoid


browndiscoloration

oftheextravasation

sitemay

belong

lasting.Monitor


occurs,discontinue

theInjectaferadm


3DOSAGE FORM

S AND STRENGTHS

750mgiron

/15mLsingle-use

vial

4CONTRAINDICATIONS

Hypersensitivityto

Injectaferor

anyof

itscom

ponents[see

Warnings


5W




reactions,including


some

ofwhich

havebeen

life-threateningand

fatal,havebeen

reportedin

patientsreceiving

Injectafer.Patients

may

presentw

ithshock,


hypotension,loss

ofconsciousness,

and/orcollapse.

Monitor

patientsfor

signsand

symptom

sof


andafter


foratleast30m

inutesand


following

completion

ofthe

infusion.Only

administer

Injectaferw

henpersonnel

andtherapies

areim

mediately

availablefor

thetreatm

entof


reactions.[see

AdverseReactions

(6.1and

6.2)].







ANDUSAGE------------------------------




who

haveintolerance

tooraliron

orhavehad


tooral iron;

•who

havenon-dialysis




weighing

50kg

(110lb)ormore:

GiveInjectaferin

two

dosesseparated

byatleast7

days.Give

eachdose

as750

mgfora

totalcum

ulativedose

of1500mgofiron


weighing

lessthan

50kg

(110lb):Give


separatedby

atleast7days

andgive

eachdose

as15

mg/kg

bodyweight.


aybe

repeatedifiron

deficiencyanem

iareoccurs.(2)



2DOSAGE AND ADM

INISTRATION3


4CONTRAINDICATIONS

5W



5.2Hypertension

5.3Laboratory

TestAlterations6


AdverseReactions

inClinicalTrials

6.2Post-m

arketingExperience

7DRUG INTERACTIONS


Pregnancy8.3

NursingMothers

8.4Pediatric

Use8.5

GeriatricUse

--------------------------DOSAGEFORM

SAND

STRENGTHS-----------------------750

mgiron

/15mLsingle-use


toInjectaferorany

ofitsinactive

components.(4)



forsignsand

symptom

sof




30minutes

anduntilclinically

stablefollow

ingcom

pletionofeach


•Hypertension:M


forsignsand

symptom

sof

hypertensionfollow

ingeach



mostcom

mon

adversereactions

(≥2%



dizziness(6.1)



edwatch.



cautionwhen

administered

toanursing

wom



Revised: July 2013

10OVERDOSAGE

11DESCRIPTION

12CLINICAL PHARM

ACOLOGY12.1

Mechanism

ofAction12.2

Pharmacodynam

ics12.3

Pharmacokinetics



Impairm

entofFertility14



AnemiainPatients

Who

areIntolerantto

OralIronorHave

HadUnsatisfactory

Responseto

OralIron14.2


AnemiainPatients

with


KidneyDisease

16HOW




omitted

fromthe


ationare

notlisted.



were

reportedin

0.1%(2/1775)

ofsubjects


Otherserious

orsevere

adversereactions


with


included,but

notlim

itedto,

pruritus,rash,

urticaria,wheezing,

orhypotension

were

reportedin1.5%


5.2Hypertension


was

reportedin3.8%


clinicaltrials

1and

2.Transient

elevationsin

systolicblood

pressure,som

etimes

occurringwith


observedin

6%(106/1,775)

ofsubjects

inthese

twoclinicaltrials.

Theseelevations

generallyoccurred

immediately

afterdosingand

resolvedwithin

30minutes.

Monitor

patientsfor

signsand

symptom

sof

hypertensionfollow

ingeach


[seeDosage and Adm

inistration(2)].


Inthe

24hours

following

administration


may

overestimate

serumiron

andtransferrin

boundiron

byalso

measuring

theiron

inInjectafer.

6ADVERSE REACTIONS

Thefollow

ingadverse

reactionsare

discussedin

greaterdetail

inother

sectionsofthe

labeling:•


[seeW


•Hypertension

[seeW


•Laboratory

TestAlterations[see


(5.3)]6.1


clinicaltrials

areconducted

underwidely

varyingconditions,

theadverse

reactionrates

observedcannotbe

directlycom

paredto

ratesinother

clinicaltrialsand

may

notreflecttherates


Intworandom

izedclinicalstudies

[Studies1and


(14)],atotalof1,775

patientswere

exposedto

Injectafer15mg/kg

bodyweightup

toamaxim

umsingle

doseof750

mgofiron

ontwooccasions

separatedby

atleast7days

upto

acum

ulativedose

of1500mgofiron.

Adversereactions

reportedby

≥1%

oftreated

patientsare

shownin

thefollow

ingtable.

Table1.

Adversereactions

reportedin

≥1%

ofStudyPatients

inClinicalTrials

1 and 2

TermInjectafer

(N=1775)%

PooledCom

paratorsa

(N=1783)%

Oraliron

(N=253)%

Nausea7.2

1.81.2

Hypertension3.8

1.90.4


0.20.0

BloodPhosphorus

Decrease2.1

0.10.0

Dizziness2.0

1.20.0

Vomiting

1.70.5

0.4Injection

SiteDiscoloration

1.40.3

0.0Headache

1.20.9

0.0Alanine Am


1.10.2

0.0

Dysgeusia1.1

2.10.0

Hypotension1.0

1.90.0

Constipation0.5

0.93.2


INJECTAFER®


RQ105200

Otheradverse

reactionsreported

by≥

0.5%of

treatedpatients

includeabdom

inalpain,

diarrhea,gam

maglutam

yltransferase

increased,injection


rash,paraesthesia,

sneezing.Transient

decreasesin

laboratoryblood

phosphoruslevels

(<2mg/dL)have

beenobserved

in27%


6.2Post-m


thesereactions

arereported

voluntarilyfrom

apopulation


notalways

possibletoreliably

estimate


acausalrelationship

todrug

exposure.Thefollow

ingserious

adversereactions

havebeen

most

commonly

reportedfrom

thepost-m

arketingspontaneous

reportswith


dyspnea,pruritis,

tachycardia,erythem

a,pyrexia,

chestdiscom

fort,chills,

angioedema,

backpain,

arthralgia,and

syncope.One

caseof

hypophosphatemic

osteomalacia

was

reportedin

asubject

who

received500

mgof

Injectaferevery

2weeks

foratotal

of16


followed


7DRUG INTERACTIONS

Formaldrug

interactionstudies

havenotbeen

performed

with

Injectafer.


8.1Pregnancy

PregnancyCategory

CRisk

Summ

aryAdequate

andwell

controlledstudies

inpregnant

wom

enhave

notbeen



havebeen

conductedwith




torabbits

duringthe


causedfetalm

alformations

andincreased

implantation

lossatm

aternallytoxic

dosesofapproxim

ately12%

to23%

ofthehum

anweekly

doseof750

mg(based

onbody

surfacearea).

Theincidence

ofmajor

malform

ationsin

human

pregnancieshas

notbeen



toany

drug,hasabackground

rateof2

to4%

formajorm

alformations,and

15to

20%forpregnancy


usedduring

pregnancyonly

ifthe


potentialriskto

thefetus.

Animal Data

Administration

offerric

carboxymaltose

torats

asaone-hour

intravenousinfusion

upto

30mg/kg/day

ironon

gestationdays

6to

17did

notresultinadverse


dailydose

inrats

isapproxim

ately40%

ofthehum

anweekly

doseof750

mgbased

onbody

surfacearea.In

rabbits,ferric

carboxymaltose

was

administered

asaone-hour

infusionon

gestationdays

6to

19atiron


18mg/kg/day.M

alformations

were

seenstarting

atthedaily

doseof9

mg/kg

(23%ofthe

human

weekly

doseof750

mg).Spontaneous

abortionsoccurred

startingatthe

dailyiron

doseof4.5

mg/kg

(12%ofthe

human

weekly

dosebased

onbody

surfacearea).

Pre-implantation

losswas

atthe

highestdose.

Adverseem

bryofetaleffects

were

observedinthe

presenceofm



was

conductedinrats

atintravenousdoses

upto

18mg/kg/day

ofiron(approxim

ately23%

oftheweekly

human

doseof750

mgon

abody

surfacearea

basis).Therewere

noadverse

effectson

survivalof

offspring,their

behavior,sexual

maturation

orreproductive

parameters.

8.3Nursing M

othersAstudy

todeterm

ineiron


ilkafteradm

inistrationof


(n=14)was

conductedin25

lactatingwom

enwith

postpartumiron

deficiencyanem

ia.Mean

breastmilk

ironlevels

were

higherin

lactatingwom

enreceiving

Injectaferthan

inlactating

wom

enreceiving

oralferroussulfate.

8.4Pediatric Use

Safetyand

effectivenesshave

notbeenestablished

inpediatric

patients.8.5

Geriatric UseOfthe

1775subjects

inclinicalstudies


65years

andover,w

hile25%

were

75years

andover.No


safetyor

effectivenesswere

observedbetw

eenthese

subjectsand

youngersubjects,

andother

reportedclinical

experiencehas

notidentified

differencesin

responsesbetw

eenthe

elderlyand



cannotberuled

out.

10OVERDOSAGE

Excessivedosages

ofInjectafermay

leadto

accumulation

ofironin

storagesites

potentiallyleading

tohem


horeceived

Injectafer18,000

mg

over6

months

developedhem

osiderosiswith

multiple

jointdisorder,

walking

disabilityand


icosteom

alaciawas

reportedin

apatient

who

receivedInjectafer

4000mgover

4months.


eddiscontinuation

ofInjectafer.

[seePost-m


11DESCRIPTION

Ferriccarboxym

altose,aniron


aniron

carbohydratecom

plexwith

thechem

icalnam

eof

polynucleariron

(III)hydroxide

4(R)-(poly-(1→

4)-O-a


),3(S),5(R


hasarelative

molecular

weight

ofapproxim

ately150,000

Dacorresponding

tothe

following

empiricalform

ula:[FeO

x (OH)y (H2 O)z ]n [{(C

6 H10 O

5 )m(C

6 H12 O

7 )}l ]k ,

where

n≈10

3,m≈8,l≈

11,andk≈4

(lrepresentsthe

mean

branchingdegree

oftheligand).

Thechem


below:

651 S M

L King Jr A


hone 847.336.4200 • Fax 847.360.4924co

mp

lete packag

ing

| ind

ividu

al solu

tion

sS

M

Pro

du

ct Info

rmatio

nS

pecified

Co

lors

P/N: J/N:C

ust:Size:

Pro

of A

7/26/2013A

pp

roved

By

Nam

e

DateO

K to PrintN

ew Proof R

equired



ill be matched on


n_Dem

and Solutions FourC

olor Book, On _D



olor Standards.

258024LU

ITPOLD

PHAR

MAC

EUTIC

ALS INC

Cyan

Magenta

Yellow

Black



Injectaferis

indicatedfor

thetreatm

entof

irondeficiency

anemia

inadult

patients:•

who

haveintolerance

tooraliron

orhavehad


tooral iron;

•who

havenon-dialysis


disease.2


Forpatients

weighing

50kg

(110lb)or

more:

GiveInjectafer

intwodoses

separatedby

atleast7days.

Giveeach

doseas

750mgfora

totalcumulative

dosenotto

exceed1500

mgofiron

percourse.For

patientsweighing

lessthan

50kg

(110lb):Give

Injectaferin

twodoses

separatedby

atleast7days.Give

eachdose

as15

mg/kg

bodyweightfor

atotalcum

ulativedose

nottoexceed

1500mgofiron

percourse.The

dosageof

Injectaferis

expressedin

mgof

elementaliron.Each

mLof

Injectafercontains

50mgof

elemental

iron.Injectafer

treatment

may

berepeated

ifirondeficiency

anemiareoccurs.

Administer


asan

undilutedslow

intravenouspush

orbyinfusion.W

henadm

inisteringas

aslow


atthe

rateofapproxim

ately100

mg(2

mL)perm

inute.When

administered

viainfusion,dilute

upto

750mgofiron

inno

more

than250

mLofsterile

0.9%sodium



oftheinfusion

isnotless

than2mgofiron

permLand


minutes.

When

addedto

aninfusion

bagcontaining

0.9%sodium

chlorideinjection,


from2mgto

4mgofiron

permL,Injectafer


andchem

icallystable

for72hours

when

storedatroom

temperature.To

maintain

stability,donot

diluteto

concentrationsless

than2mgiron/m

L.Inspect

parenteraldrug

productsvisually

forthe

absenceof

particulatematter

anddiscoloration

priorto

administration.

Theproduct

containsno

preservatives.Each

vialof

Injectaferis

intendedfor

single-useonly.

Anyunused

drugrem


mustbe

discarded.Avoid


browndiscoloration

oftheextravasation

sitemay

belong

lasting.Monitor


occurs,discontinue

theInjectaferadm


3DOSAGE FORM

S AND STRENGTHS

750mgiron

/15mLsingle-use

vial

4CONTRAINDICATIONS

Hypersensitivityto

Injectaferor

anyof

itscom

ponents[see

Warnings


5W




reactions,including


some

ofwhich

havebeen

life-threateningand

fatal,havebeen

reportedin

patientsreceiving

Injectafer.Patients

may

presentw

ithshock,


hypotension,loss

ofconsciousness,

and/orcollapse.

Monitor

patientsfor

signsand

symptom

sof


andafter


foratleast30m

inutesand


following

completion

ofthe

infusion.Only

administer

Injectaferw

henpersonnel

andtherapies

areim

mediately

availablefor

thetreatm

entof


reactions.[see

AdverseReactions

(6.1and

6.2)].







ANDUSAGE------------------------------




who

haveintolerance

tooraliron

orhavehad


tooral iron;

•who

havenon-dialysis




weighing

50kg

(110lb)ormore:

GiveInjectaferin

two

dosesseparated

byatleast7

days.Give

eachdose

as750

mgfora

totalcum

ulativedose

of1500mgofiron


weighing

lessthan

50kg

(110lb):Give


separatedby

atleast7days

andgive

eachdose

as15

mg/kg

bodyweight.


aybe

repeatedifiron

deficiencyanem

iareoccurs.(2)



2DOSAGE AND ADM

INISTRATION3


4CONTRAINDICATIONS

5W



5.2Hypertension

5.3Laboratory

TestAlterations6


AdverseReactions

inClinicalTrials

6.2Post-m

arketingExperience

7DRUG INTERACTIONS


Pregnancy8.3

NursingMothers

8.4Pediatric

Use8.5

GeriatricUse

--------------------------DOSAGEFORM

SAND

STRENGTHS-----------------------750

mgiron

/15mLsingle-use


toInjectaferorany

ofitsinactive

components.(4)



forsignsand

symptom

sof




30minutes

anduntilclinically

stablefollow

ingcom

pletionofeach


•Hypertension:M


forsignsand

symptom

sof

hypertensionfollow

ingeach



mostcom

mon

adversereactions

(≥2%



dizziness(6.1)



edwatch.



cautionwhen

administered

toanursing

wom



Revised: July 2013

10OVERDOSAGE

11DESCRIPTION

12CLINICAL PHARM

ACOLOGY12.1

Mechanism

ofAction12.2

Pharmacodynam

ics12.3

Pharmacokinetics



Impairm

entofFertility14



AnemiainPatients

Who

areIntolerantto

OralIronorHave

HadUnsatisfactory

Responseto

OralIron14.2


AnemiainPatients

with


KidneyDisease

16HOW




omitted

fromthe


ationare

notlisted.



were

reportedin

0.1%(2/1775)

ofsubjects


Otherserious

orsevere

adversereactions


with


included,but

notlim

itedto,

pruritus,rash,

urticaria,wheezing,

orhypotension

were

reportedin1.5%


5.2Hypertension


was

reportedin3.8%


clinicaltrials

1and

2.Transient

elevationsin

systolicblood

pressure,som

etimes

occurringwith


observedin

6%(106/1,775)

ofsubjects

inthese

twoclinicaltrials.

Theseelevations

generallyoccurred

immediately

afterdosingand

resolvedwithin

30minutes.

Monitor

patientsfor

signsand

symptom

sof

hypertensionfollow

ingeach


[seeDosage and Adm

inistration(2)].


Inthe

24hours

following

administration


may

overestimate

serumiron

andtransferrin

boundiron

byalso

measuring

theiron

inInjectafer.

6ADVERSE REACTIONS

Thefollow

ingadverse

reactionsare

discussedin

greaterdetail

inother

sectionsofthe

labeling:•


[seeW


•Hypertension

[seeW


•Laboratory

TestAlterations[see


(5.3)]6.1


clinicaltrials

areconducted

underwidely

varyingconditions,

theadverse

reactionrates

observedcannotbe

directlycom

paredto

ratesinother

clinicaltrialsand

may

notreflecttherates


Intworandom

izedclinicalstudies

[Studies1and


(14)],atotalof1,775

patientswere

exposedto

Injectafer15mg/kg

bodyweightup

toamaxim

umsingle

doseof750

mgofiron

ontwooccasions

separatedby

atleast7days

upto

acum

ulativedose

of1500mgofiron.

Adversereactions

reportedby

≥1%

oftreated

patientsare

shownin

thefollow

ingtable.

Table1.

Adversereactions

reportedin

≥1%

ofStudyPatients

inClinicalTrials

1 and 2

TermInjectafer

(N=1775)%

PooledCom

paratorsa

(N=1783)%

Oraliron

(N=253)%

Nausea7.2

1.81.2

Hypertension3.8

1.90.4


0.20.0

BloodPhosphorus

Decrease2.1

0.10.0

Dizziness2.0

1.20.0

Vomiting

1.70.5

0.4Injection

SiteDiscoloration

1.40.3

0.0Headache

1.20.9

0.0Alanine Am


1.10.2

0.0

Dysgeusia1.1

2.10.0

Hypotension1.0

1.90.0

Constipation0.5

0.93.2


INJECTAFER®


RQ105200

Otheradverse

reactionsreported

by≥

0.5%of

treatedpatients

includeabdom

inalpain,

diarrhea,gam

maglutam

yltransferase

increased,injection


rash,paraesthesia,

sneezing.Transient

decreasesin

laboratoryblood

phosphoruslevels

(<2mg/dL)have

beenobserved

in27%


6.2Post-m


thesereactions

arereported

voluntarilyfrom

apopulation


notalways

possibletoreliably

estimate


acausalrelationship

todrug

exposure.Thefollow

ingserious

adversereactions

havebeen

most

commonly

reportedfrom

thepost-m

arketingspontaneous

reportswith


dyspnea,pruritis,

tachycardia,erythem

a,pyrexia,

chestdiscom

fort,chills,

angioedema,

backpain,

arthralgia,and

syncope.One

caseof

hypophosphatemic

osteomalacia

was

reportedin

asubject

who

received500

mgof

Injectaferevery

2weeks

foratotal

of16


followed


7DRUG INTERACTIONS

Formaldrug

interactionstudies

havenotbeen

performed

with

Injectafer.


8.1Pregnancy

PregnancyCategory

CRisk

Summ

aryAdequate

andwell

controlledstudies

inpregnant

wom

enhave

notbeen



havebeen

conductedwith




torabbits

duringthe


causedfetalm

alformations

andincreased

implantation

lossatm

aternallytoxic

dosesofapproxim

ately12%

to23%

ofthehum

anweekly

doseof750

mg(based

onbody

surfacearea).

Theincidence

ofmajor

malform

ationsin

human

pregnancieshas

notbeen



toany

drug,hasabackground

rateof2

to4%

formajorm

alformations,and

15to

20%forpregnancy


usedduring

pregnancyonly

ifthe


potentialriskto

thefetus.

Animal Data

Administration

offerric

carboxymaltose

torats

asaone-hour

intravenousinfusion

upto

30mg/kg/day

ironon

gestationdays

6to

17did

notresultinadverse


dailydose

inrats

isapproxim

ately40%

ofthehum

anweekly

doseof750

mgbased

onbody

surfacearea.In

rabbits,ferric

carboxymaltose

was

administered

asaone-hour

infusionon

gestationdays

6to

19atiron


18mg/kg/day.M

alformations

were

seenstarting

atthedaily

doseof9

mg/kg

(23%ofthe

human

weekly

doseof750

mg).Spontaneous

abortionsoccurred

startingatthe

dailyiron

doseof4.5

mg/kg

(12%ofthe

human

weekly

dosebased

onbody

surfacearea).

Pre-implantation

losswas

atthe

highestdose.

Adverseem

bryofetaleffects

were

observedinthe

presenceofm



was

conductedinrats

atintravenousdoses

upto

18mg/kg/day

ofiron(approxim

ately23%

oftheweekly

human

doseof750

mgon

abody

surfacearea

basis).Therewere

noadverse

effectson

survivalof

offspring,their

behavior,sexual

maturation

orreproductive

parameters.

8.3Nursing M

othersAstudy

todeterm

ineiron


ilkafteradm

inistrationof


(n=14)was

conductedin25

lactatingwom

enwith

postpartumiron

deficiencyanem

ia.Mean

breastmilk

ironlevels

were

higherin

lactatingwom

enreceiving

Injectaferthan

inlactating

wom

enreceiving

oralferroussulfate.

8.4Pediatric Use

Safetyand

effectivenesshave

notbeenestablished

inpediatric

patients.8.5

Geriatric UseOfthe

1775subjects

inclinicalstudies


65years

andover,w

hile25%

were

75years

andover.No


safetyor

effectivenesswere

observedbetw

eenthese

subjectsand

youngersubjects,

andother

reportedclinical

experiencehas

notidentified

differencesin

responsesbetw

eenthe

elderlyand



cannotberuled

out.

10OVERDOSAGE

Excessivedosages

ofInjectafermay

leadto

accumulation

ofironin

storagesites

potentiallyleading

tohem


horeceived

Injectafer18,000

mg

over6

months

developedhem

osiderosiswith

multiple

jointdisorder,

walking

disabilityand


icosteom

alaciawas

reportedin

apatient

who

receivedInjectafer

4000mgover

4months.


eddiscontinuation

ofInjectafer.

[seePost-m


11DESCRIPTION

Ferriccarboxym

altose,aniron


aniron

carbohydratecom

plexwith

thechem

icalnam

eof

polynucleariron

(III)hydroxide

4(R)-(poly-(1→

4)-O-a


),3(S),5(R


hasarelative

molecular

weight

ofapproxim

ately150,000

Dacorresponding

tothe

following

empiricalform

ula:[FeO

x (OH)y (H2 O)z ]n [{(C

6 H10 O

5 )m(C

6 H12 O

7 )}l ]k ,

where

n≈10

3,m≈8,l≈

11,andk≈4

(lrepresentsthe

mean

branchingdegree

oftheligand).

Thechem


below:

IN0650ADVIss. 7/2013

FULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGEVenofer is indicated for the treatment of iron deficiency anemia in patients with chronic kidney disease (CKD).2 DOSAGE AND ADMINISTRATIONVenofer must only be administered intravenously either by slow injection or by infusion. The dosage of Venofer is expressed in mg of elemental iron. EachmL 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 of0.9% 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 infusionof 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 repeatedif 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 apartfollowed 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 repeatedif iron deficiency reoccurs. 2.4 Pediatric Patients (2 years of age and older) with HDD-CKD for iron maintenance treatmentThe 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 undilutedby 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 repeatedif 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 treatmentThe 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 undilutedby 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 repeatedif 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 PRECAUTIONS5.1 Hypersensitivity ReactionsSerious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported inpatients receiving Venofer. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Ifhypersensitivity reactions or signs of intolerance occur during administration, stop Venofer immediately. Monitor patients for signs and symptomsof hypersensitivity during and after Venofer administration for at least 30 minutes and until clinically stable following completion of the infusion. Onlyadminister Venofer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactionsassociated with intravenous iron preparations occur within 30 minutes of the completion of the infusion [see Adverse Reactions (6.1 and 6.2)]. 5.2 HypotensionVenofer may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Venofer. Hypotensionfollowing 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 OverloadExcessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. All adult and pediatric patientsreceiving Venofer require periodic monitoring of hematologic and iron parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Donot administer Venofer to patients with evidence of iron overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administrationof 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 REACTIONSThe 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 TrialsBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the ratesobserved in practice.Adverse Reactions in Adult Patients with CKDThe 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 clinicaltrials 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 at10 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 aperiod of 4 weeks.

Table 1. Treatment-Emergent Adverse Reactions Reported in ³ 2% of Study Populations and for which the Rate for Venofer Exceeds the Rate forComparator

* EPO=ErythropoietinOne 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) hadprior other intravenous iron therapy and were reported to be intolerant (defined as precluding further use of that iron product). When these patients weretreated with Venofer there were no occurrences of adverse reactions that precluded further use of Venofer [See Warning and Precautions (5)].

Adverse Reactions(Preferred Term)

HDD-CKD NDD-CKD PDD-CKDVenofer Venofer Oral Iron Venofer EPO* Only(N=231) (N=139) (N=139) (N=75) (N=46)% % % % %

Subjects with any adverse reaction 78.8 76.3 73.4 72.0 65.2Ear and Labyrinth DisordersEar Pain 0 2.2 0.7 0 0

Eye DisordersConjunctivitis 0.4 0 0 2.7 0

Gastrointestinal DisordersAbdominal pain 3.5 1.4 2.9 4.0 6.5Diarrhea 5.2 7.2 10.1 8.0 4.3Dysgeusia 0.9 7.9 0 0 0Nausea 14.7 8.6 12.2 5.3 4.3Vomiting 9.1 5.0 8.6 8.0 2.2

General Disorders andAdministration Site ConditionsAsthenia 2.2 0.7 2.2 2.7 0Chest pain 6.1 1.4 0 2.7 0Feeling abnormal 3.0 0 0 0 0Infusion site pain or burning 0 5.8 0 0 0Injection site extravasation 0 2.2 0 0 0Peripheral edema 2.6 7.2 5.0 5.3 10.9Pyrexia 3.0 0.7 0.7 1.3 0

Infections and InfestationsNasopharyngitis, Sinusitis, Upper respiratory tract infections, Pharyngitis 2.6 2.2 4.3 16.0 4.3

Injury, Poisoning and ProceduralComplicationsGraft complication 9.5 1.4 0 0 0

Metabolism and Nutrition DisordersFluid overload 3.0 1.4 0.7 1.3 0Gout 0 2.9 1.4 0 0Hyperglycemia 0 2.9 0 0 2.2Hypoglycemia 0.4 0.7 0.7 4.0 0

Musculoskeletal and ConnectiveTissue DisordersArthralgia 3.5 1.4 2.2 4.0 4.3Back pain 2.2 2.2 3.6 1.3 4.3Muscle cramp 29.4 0.7 0.7 2.7 0Myalgia 0 3.6 0 1.3 0Pain in extremity 5.6 4.3 0 2.7 6.5

Nervous System DisordersDizziness 6.5 6.5 1.4 1.3 4.3Headache 12.6 2.9 0.7 4.0 0

Respiratory, Thoracic andMediastinal DisordersCough 3.0 2.2 0.7 1.3 0Dyspnea 3.5 5.8 1.4 1.3 2.2Nasal congestion 0 1.4 2.2 1.3 0

Skin and SubcutaneousTissue DisordersPruritus 3.9 2.2 4.3 2.7 0

Vascular DisordersHypertension 6.5 6.5 4.3 8.0 6.5Hypotension 39.4 2.2 0.7 2.7 2.2

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use VENOFER safely and effectively. See fullprescribing 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 chronickidney disease (CKD). (1)------------------------------------------------DOSAGE AND ADMINISTRATION------------------------------------------------

----------------------------------------------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 Venoferadministration for at least 30 minutes and until clinically stable following completion of each administration. Onlyadminister Venofer when personnel and therapies are immediately available for the treatment of serioushypersensitivity reactions. (5.1)

• Hypotension: Venofer may cause hypotension. Monitor for signs and symptoms of hypotension during andfollowing each administration of Venofer. (5.2)

• Iron Overload: Regularly monitor hematologic responses during Venofer therapy. Do not administer Venofer topatients 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 sitereactions, 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

Population DoseAdult patients Hemodialysis Dependent-

Chronic Kidney Disease (HDD-CKD) (2.1)

100 mg slow intravenous injection or infusion

Non-Dialysis Dependent-Chronic 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

Pediatric patients HDD-CKD (2.4), PDD-CKD or NDD-CKD (2.5)

0.5 mg/kg slow intravenous injection or infusion

FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION

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)2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD)2.4 Pediatric Patients (2 years of age and older) with HDD-CKD for iron maintenance treatment2.5 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 STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions5.2 Hypotension5.3 Iron Overload

6 ADVERSE REACTIONS6.1 Adverse Reactions in Clinical Trials6.2 Adverse Reactions from Post-Marketing Experience

7 DRUG INTERACTIONS8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use

10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES14.1 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

16 HOW SUPPLIED/STORAGE AND HANDLING16.1 How Supplied16.2 Stability and Storage

17 PATIENT COUNSELING INFORMATION* Sections or subsections omitted from the full prescribing information are not listed.

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(iron sucrose injection, USP)

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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% ofpatients) 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 ExperienceBecause these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establisha 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, sepsisand dysgeusia.The following adverse reactions have been identified during post-approval use of Venofer. Because these reactions are reported voluntarily from a populationof 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 theadministration of Venofer injection. Reactions have occurred following the first dose or subsequent doses of Venofer. Symptoms may respond to intravenousfluids, 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 INTERACTIONSDrug interactions involving Venofer have not been studied. However, Venofer may reduce the absorption of concomitantly administered oral iron preparations.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category BThere are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, iron sucrose was administered intravenously to ratsand rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental iron (half or equivalent to the maximum recommended humandose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to iron sucrose. Because animal reproductive studiesare not always predictive of human response, Venofer should be used during pregnancy only if clearly needed.8.3 Nursing MothersIt 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 excretedin 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 notbeen established.Safety and effectiveness of Venofer for iron maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent 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 dosesmaintained 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 ClinicalStudies (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 enterocolitisand two of the five died during or following a period when they received Venofer, several other medications and erythropoietin. Necrotizing enterocolitismay 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 fromyounger subjects. Of the 1,051 patients in two post-marketing safety studies of Venofer, 40% were 65 years and older. No overall differences in safetywere observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses betweenthe elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patientshould be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 10 OVERDOSAGENo data are available regarding overdosage of Venofer in humans. Excessive dosages of Venofer may lead to accumulation of iron in storage sites potentiallyleading 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 bodysurface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.11 DESCRIPTIONVenofer (iron sucrose injection, USP), an iron replacement product, is a brown, sterile, aqueous, complex of polynuclear iron (III)-hydroxide in sucrose forintravenous 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 containsapproximately 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 PHARMACOLOGY12.1 Mechanism of ActionVenofer is an aqueous complex of poly-nuclear iron (III)-hydroxide in sucrose. Following intravenous administration, Venofer is dissociated into iron andsucrose and the iron is transported as a complex with transferrin to target cells including erythroid precursor cells. The iron in the precursor cells isincorporated into hemoglobin as the cells mature into red blood cells.12.2 PharmacodynamicsFollowing 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 increasesin 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 PharmacokineticsIn healthy adults administered intravenous doses of Venofer, its iron component exhibited first order kinetics with an elimination half-life of 6 h, totalclearance 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 someextent in extravascular fluid. A study evaluating Venofer containing 100 mg of iron labeled with 52Fe/59Fe in patients with iron deficiency showed that asignificant amount of the administered iron is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible iron trappingcompartment.Following intravenous administration of Venofer, iron sucrose is dissociated into iron and sucrose. The sucrose component is eliminated mainly by urinaryexcretion. 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. Neithertransferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenousdose 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 havenot been studied.Pharmacokinetics in Pediatric PatientsIn 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 were8545 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 ironsucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenicity 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 clastogenicin 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 STUDIESFive 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 historicalcontrol group) with iron deficiency anemia. Eligibility criteria for Venofer treatment included patients undergoing chronic hemodialysis, receivingerythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patientswas 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 consistedof 24 patients with similar ferritin levels as patients treated with Venofer, who were off intravenous iron for at least 2 weeks and who had receivederythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical controlgroup 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

Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical controlpopulation (-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 dueto 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 transferrinsaturation 20%, and a serum ferritin 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patientsenrolled 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 and62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral iron. Exclusion criteria were similar to those in studies Aand B. Venofer was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of iron wasadministered. 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 receivingerythropoietin 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%), serumferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased atweek 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-CKDwith 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 timesdaily 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 over3.5 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 hemoglobin³ 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 patientswith 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 onDay 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 groupwas 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 DiseaseStudy F was a randomized, open-label, dose-ranging study for iron maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent 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 HANDLING16.1 How SuppliedVenofer 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 mgelemental 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 5NDC-0517-2310-10 200 mg/10 mL Single-Use Vial Packages of 10NDC-0517-2340-01 100 mg/5 mL Single-Use Vial Individually BoxedNDC-0517-2340-10 100 mg/5 mL Single-Use Vial Packages of 10NDC-0517-2340-25 100 mg/5 mL Single-Use Vial Packages of 25NDC-0517-2340-99 100 mg/5 mL Single-Use Vial Packages of 10NDC-0517-2325-10 50 mg/2.5 mL Single-Use Vial Packages of 10 NDC-0517-2325-25 50 mg/2.5 mL Single-Use Vial Packages of 2516.2 Stability and StorageContains 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 ControlledRoom 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 mgelemental 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 rangingfrom 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 INFORMATIONPrior 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)]

IN2340ADVMG #15727

Venofer is manufactured under license from Vifor (International) Inc., Switzerland.

PREMIERProTMRx is a trademark of Premier, Inc., used under license.

Efficacyparameters

End of treatment 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)

HistoricalControl(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 ascovariates.

AMERICAN REGENT, INC.SHIRLEY, NY 11967

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important safety information …€¦ · injectafer®1 venofer® (ferric carboxymaltose injection)...

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