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					        Take IV iron therapy to a proven place:

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Formulary
    Monograph


  Leading anemia management.™
                                       Millions prescribed. Millions treated. ™
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Table of contents:
          I. Key points about Venofer ® (iron sucrose injection, USP)..............................................................................1
        II. Iron deficiency anemia in chronic kidney disease.....................................................................5
       III. Options for effective protocol development ........................................................................................7
                    • Optimization of anemia management in NDD-CKD without ESA therapy

                    • Optimization of erythropoietin therapy

                    • Guidelines for anemia treatment

      IV. Comparison chart .................................................................................................................................................................11
                    • Overview of parenteral iron preparations

        V. Venofer ® prescribing information ...................................................................................................................13
      VI. Clinical efficacy and safety......................................................................................................................................19
                    • Review of clinical trials

     VII. Pharmacy specifications............................................................................................................................................25
    VIII. Reimbursement information...................................................................................................................................27
                    • HCPCS: J-Code

                    • Reimbursement hotline

                    • Patient assistance program

      IX. Requests for additional information about Venofer ® ............................................................31
        X. References....................................................................................................................................................................................33
      XI. Venofer ® fact sheet...........................................................................................................................................................39
Enclosure:
Venofer ® full prescribing information




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                                                                                                            1

I. Key points about Venofer                             ®
                                                            (iron sucrose injection, USP)

Venofer ® (iron sucrose injection, USP) is a brown, sterile, aqueous complex of polynuclear iron (III)-
hydroxide in sucrose for intravenous use. It contains no preservatives or dextran polysaccharides.
Venofer ® is indicated in the treatment of iron deficiency anemia in non-dialysis dependent-chronic
kidney disease (CKD) patients receiving or not receiving an erythropoietin and in hemodialysis or
peritoneal dialysis dependent-chronic kidney disease patients receiving an erythropoietin.1

Proven worldwide clinical experience 2
Venofer ® is used to replenish body iron stores in patients with iron deficiency anemia. Clinical trials,
and the long history of the use of iron sucrose injection worldwide, have established the efficacy
and safety of this drug in patients with iron deficiency anemia from chronic renal failure. Since 1992,
over 9 million patients worldwide have received over 180 million units (100 mg equivalents) of
Venofer ®.2 In the United States, over 2.25 million patients have received over 45 million vials
(100 mg equivalents) of Venofer ®.2

The clinical evaluation of Venofer ® is based on results from more than 100 studies 3-124 involving more
than 7,000 subjects. More than 5,000 patients were treated with Venofer ®. These studies demonstrate
the effectiveness of Venofer ® in the treatment of iron deficiency anemia alone and in combination
with an erythropoietin.

A first-line IV iron therapy for the treatment of anemia in non-dialysis and
dialysis dependent CKD patients
Venofer ® is indicated in the treatment of iron deficiency anemia in the following patients:
      • Non-dialysis dependent-chronic kidney disease (NDD-CKD) patients not receiving
        an erythropoietin
      • Non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving
        an erythropoietin
      • Hemodialysis dependent-chronic kidney disease (HDD-CKD) patients receiving
        an erythropoietin
      • Peritoneal dialysis dependent-chronic kidney disease (PDD-CKD) patients receiving
        an erythropoietin

Venofer ® increases Hb levels in NDD-CKD patients, with or without
erythropoiesis stimulating agent (ESA) usage
Maintaining iron stores with Venofer ® may allow avoidance or discontinuation of ESA therapy.

Clinical trials have shown that, in up to one-third of non-dialysis dependent-CKD patients with iron
deficiency anemia, treatment with Venofer ® corrected anemia without an ESA.89,125




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2
    Van Wyck, et al studied 91 NDD-CKD patients who received treatment with
    Venofer ® (iron sucrose injection, USP) without an ESA. A total of 38.3% of these patients
    had a clinically significant response ( ≥1 g/dL Hb increase).123

    Greater tolerability than oral iron
    Venofer ® does not have the same incidence of adverse gastrointestinal symptoms as does oral iron.
    It has been estimated that more than 25% of patients taking oral iron experience gastrointestinal
    distress or constipation. Noncompliance with oral iron supplementation may be as high as 32%
    within 2 months after initiation of therapy.92

    Large safety database
    A large safety database for Venofer ® is available from clinical trial reports, publications, and
    postmarketing surveillance.

    Data on the safety of Venofer ® have been collected since its introduction to the European market
    (Switzerland) in 1950 and during a modern clinical development program begun in 1992. These data,
    and the data observed in worldwide post-marketing surveillance, suggest that most adverse events
    are mild to moderate and similar to those seen in patients with chronic renal failure not receiving
    intravenous iron.2

    Safely administered to hemodialysis patients intolerant to other
    IV iron products
    In 4 US Clinical trials in hemodialysis dependent-CKD patients, a total of 130 patients who were
    intolerant to other IV iron products (109 intolerant to iron dextran alone, 6 intolerant to ferric gluconate
    alone, 15 intolerant to both) were successfully treated with Venofer ®. There were no discontinuations
    or serious adverse drug reactions. A total of 8 patients experienced one or more non-serious related
    adverse events. The most common were taste disturbance (4) and nausea (3).1

    Serious adverse reactions related to Venofer ® are uncommon
    The incidence of serious adverse reactions is low. Serious hypersensitivity reactions have been
    reported in patients receiving Venofer ®. No life-threatening hypersensitivity reactions were observed
    in the clinical studies. Several cases of mild or moderate hypersensitivity reactions were observed in
    these studies.1

    Administered by slow injection or by infusion
    Venofer ® is simple to administer. Venofer ® may be administered either by undiluted IV push injection
    or by IV infusion.1 This option gives healthcare providers the flexibility to deliver iron therapy in the
    most convenient way for the patient.

    Convenient single dose vials, preservative free
    Because it is in vials, Venofer ® does not cause the difficulties associated with glass ampules, such as
    breakage and splintering. One 5 mL vial of Venofer ® provides 100 mg (20 mg/mL) of iron as iron
    sucrose. One 10 mL vial of Venofer® provides 200 mg (20 mg/mL) of iron as iron sucrose. Venofer ®
    contains no preservatives such as benzyl alcohol. Each Venofer ® vial is bar coded with its National
    Drug Code to help prevent medication errors.

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Contains no dextran polysaccharides
Venofer ® (iron sucrose injection, USP) contains no dextran, modified dextran, or reduced dextran.
Dextran polysaccharides are associated with antibody-induced anaphylaxis.

No black box warning
Unlike IV iron products that contain dextran, Venofer ® does not have a black box warning, which
appears on the package insert for prescription drugs that may cause serious or life threatening adverse
effects. Dextran-containing preparations carry this warning due to the risk of serious anaphylactic
reactions, which may cause death. A test dose is required prior to use of iron dextran. Because
Venofer ® does not contain dextran, modified dextran, or reduced dextran, a test dose is not required.




IMPORTANT SAFETY INFORMATION: Venofer ® (iron sucrose injection, USP) is contraindicated in
patients with evidence of iron overload, in patients with known hypersensitivity to Venofer ® or any of
its inactive components, and in patients with anemia not caused by iron deficiency. Hypersensitivity
reactions have been reported with IV iron products. Hypotension has been reported frequently in
hemodialysis dependent-CKD patients receiving IV iron, and has also been reported in non-dialysis and
peritoneal dialysis dependent-CKD patients receiving IV iron. Hypotension following administration of
Venofer ® may be related to rate of administration and total dose delivered.
In multi-dose efficacy studies in hemodialysis dependent-CKD patients (N=231), the most frequent
adverse events (>5%), whether or not related to Venofer ® administration, were hypotension, muscle
cramps, nausea, headache, graft complications, vomiting, dizziness, hypertension, chest pain, and
diarrhea. In post-marketing safety studies in hemodialysis dependent-CKD patients (N=1,051),
the most frequent adverse events reported (>1%) were congestive heart failure, sepsis, and taste
disturbance. In multi-dose efficacy studies in non-dialysis dependent-CKD patients (N=91), the most
frequent adverse events ( 5%) whether or not related to Venofer ® administration, were taste
disturbance, peripheral edema, diarrhea, constipation, nausea, dizziness, and hypertension. In the
study of peritoneal dialysis dependent-CKD patients (N=75), the most frequent adverse events,
whether or not related to Venofer®, reported by 5% of these patients were diarrhea, peritoneal
infection, vomiting, hypertension, pharyngitis, peripheral edema, and nausea.




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                                                                                                                     5

II. Iron deficiency anemia in chronic kidney disease
CKD is a progressive disease that gradually impairs kidney function, usually over a period of years.
According to the National Kidney Foundation (NKF), approximately 8 million people in the US are living
with moderate (stage 3) or severe (stage 4) CKD and are not yet receiving dialysis.126 CKD often
progresses to end stage renal disease (ESRD), where the kidneys fail and renal replacement therapy
such as dialysis or transplantation is required to sustain life. The primary goal of treatment for CKD is
to slow the progression of the disease, mainly by controlling the underlying cause: commonly hypertension
or diabetes. Patients with CKD suffer from a myriad of complications, which may also effect CKD
progression. These include malnutrition, bone disease and iron deficiency anemia.

Iron deficiency anemia is a significant complication of CKD, developing early in the course of the disease
and progressing with loss of renal function.127-128 Published data indicate that approximately 44% of
patients with CKD stage 3 or 4 are anemic (defined as Hb <13.5 g/dL for men and Hb <12.0 g/dL for
women), and the prevalence of anemia increases to 75% in patients reaching CKD stage 5 (ESRD).126
The cause of this anemia is multifactorial, and includes the inability of the failing kidney to produce
enough erythropoietin to stimulate adequate hematopoiesis, iron deficiency, and shortened red blood cell
survival. Iron deficiency is a common cause of anemia in CKD patients. Iron deficiency and iron deficiency
anemia can be due to both poor nutrition and blood loss, and can be exacerbated by the use of erythropoietic
stimulating agents (ESAs). ESA therapy depletes iron stores as iron needs are increased in order to
produce iron containing red blood cells (RBCs).

Left untreated, anemia can have adverse effects on cardiac function, CKD progression, and survival 126-128,131-132
Anemia has also been shown to be an independent predictor and risk multiplier for increased mortality in
CKD patients who have not progressed to ESRD. Patients diagnosed with CKD and anemia have a risk
of death that is equivalent to that in patients diagnosed with both diabetes and congestive heart failure
combined.133-136 Treatment of iron deficiency anemia in CKD stages 1 through 4 may be critical to
reducing this cardiovascular morbidity and mortality, since anemia-associated left ventricular hypertrophy
may be irreversible if therapy is delayed until the beginning of dialysis.137 Evidence suggests that
aggressive treatment of iron deficiency anemia early in the course of CKD can improve quality of life
(QOL) as well as disease outcome, and may possibly slow the progression of renal failure.138-139




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III. Options for effective protocol development
Iron deficiency commonly complicates anemia in patients with non-dialysis dependent-chronic kidney
disease (NDD-CKD). Up to 40% of males and 85% of females with anemia and NDD-CKD show
evidence of iron deficiency.140 With the recent safety controversy surrounding ESA therapy,141
the use of IV iron without ESAs may present an attractive and cost effective alternative for treating
anemia. IV iron therapy can provide effective anemia management, even in the absence of an
erythropoietin, in a substantial portion of these patients.

A stepwise approach to anemia management, with a trial of IV iron as primary therapy, followed
by the addition of an ESA, if necessary, provides a practical option for anemia protocols, providing
individualized, effective treatment and the lowest possible ESA dose. Efforts to develop and implement
this type of protocol can have both significant clinical outcomes as well as economic benefits.142

In addition, The NKF-Kidney Disease Outcomes Quality Initiative (KDOQI) Clinical Practice Guidelines
and Clinical Practice Recommendations for Anemia in CKD (discussed in more detail below) state that
iron agents may serve as primary therapy for selected patients (particularly those with NDD-CKD) or as
adjuvant therapy for those also undergoing treatment with an ESA. Administered as adjuvants to
ESAs, iron agents prevent iron deficiency and serve to minimize the dose of ESA needed to achieve
target-range Hb levels.126

Optimization of anemia management in NDD-CKD without ESA therapy
The efficacy of IV iron as primary therapy in anemic patients with non-dialysis dependent-CKD has
been studied in 5 clinical trials.36, 89, 125, 143, 144 Maintaining iron stores with Venofer ® (iron sucrose injection,
USP) may allow avoidance or discontinuation of ESA therapy. Clinical trials have shown that in up to
one-third of non-dialysis dependent-CKD patients with iron deficiency anemia, treatment with
Venofer ® corrected anemia without an ESA.89,125 Results from all five clinical studies indicate a hematopoietic
response, defined as a rise in Hb of >1 g/dL, in patients treated with IV iron alone. Approximately 1/3 to
1/2 of treated patients were able to reach the target Hb/hematocrit (HCT) defined during the studies.

Optimization of erythropoietin therapy
Aggressive intravenous iron therapy with products such as Venofer ® is increasingly recognized as a
means of optimizing the response to erythropoietin. Evidence from numerous studies 5-7,145-152 conducted
since 1992, totaling more than 450 patients, shows that intensive intravenous iron supplementation
(iron dextran, iron sucrose, or sodium ferric gluconate in sucrose complex) allows a reduction in
erythropoietin dose of 19% to 70%.




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    Intravenous Iron Therapy Decreases ESA Doses
         MacDougall 148

               Ahsan 151

               Nyvad 6

               Taylor 150

             Sepandj 149

            Fishbane 147

            Schaefer 146

          Silverberg 7

    Sunder-Plassman 145
                            0     10         20          30          40          50          60          70           80

                                                               Percent (%)



    Guidelines for anemia treatment 126
    The NKF-KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in CKD
    represent the standard of care for anemia in CKD patients. These guidelines provide a roadmap for the
    development of anemia management protocols.
         2006/2007 KDOQI Anemia and Iron Indices Targets
         Diagnosis of Anemia           Hemoglobin
         General Population            Hb <13.5 g/dL males
                                       Hb <12.0 g/dL females

         CKD                           Hb should generally be in the range of 11-12 g/dL
                                       Hb target should not be greater than 13 g/dL

         CKD Target Iron Status        TSAT >20%

                                       Ferritin (ng/mL)
                                       • HDD-CKD: >200 ng/mL
                                       • NDD-CKD & PDD-CKD: >100 ng/mL
                                       • When serum ferritin is >500 ng/mL, decisions regarding IV iron administration should weigh ESA
                                         responsiveness, Hb, TSAT, and patient’s clinical status.




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Monitoring iron status
Transferrin saturation (TSAT), content of hemoglobin in reticulocytes (CHr), and serum ferritin are the
best indicators of iron available for erythropoiesis and iron stores but do not provide absolute criteria
of either iron deficiency or iron overload.

Results of iron status tests, Hb, and ESA dose should be interpreted together to guide iron therapy.
      • In the patient initiating ESA therapy, monitor iron indices monthly.
      • In patients who have achieved target range Hb or are receiving IV iron therapy, monitor
         iron status (including TSAT and ferritin levels) every 3 months.
      • Clinical settings in which more frequent iron testing may be necessary
              – Initiation of ESA therapy
              – Correction of a less-than-target Hb level during ongoing ESA therapy
              – Recent bleeding
              – After surgery or hospitalization
              – Monitoring response after a course of IV iron
              – Evaluation for ESA hyporesponsiveness

Recommendations for ESA use
These general recommendations include dosing that is based on Hb concentration, rate of Hb rise,
non-responsiveness, and clinical circumstances.

Recommendations for iron therapy
The NKF-KDOQI guidelines have general recommendations for iron therapy. The recommendations
state that
       • Supplemental iron should be given to prevent iron deficiency and maintain target Hb.
         Maintaining target Hb can improve patient survival, reduce hospitalizations, and enhance QOL.
       • Intravenous (IV) iron is the preferred route of administration in patients with HDD-CKD or
         when ESA therapy is administered, since the GI tract is bypassed, allowing for iron to become
         immediately available for erythropoiesis.22
              – Most HDD patients will require repeated IV iron administration due to HDD-associated
                blood loss that results in a negative iron balance.
       • For patients with non-dialysis dependent-CKD not receiving ESA therapy or for those patients
         receiving peritoneal dialysis, the route of iron administration can be IV or oral.126


Oral iron
        • Daily dose of elemental iron in oral iron therapy is approximately 200 mg.
        • Oral iron is unlikely to maintain target iron indices in ESA-treated patients.
        • If oral iron is initiated on trial basis but fails to maintain target iron levels, discontinue oral
          iron and administer a course of IV iron.




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     Intravenous iron
     There are 2 widely used and effective approaches to IV iron treatment. These are outlined in the
     KDOQI guidelines as follows:

     Periodic iron repletion: A series of IV iron doses administered episodically to replenish iron
     stores whenever iron status tests decrease.
           • To correct iron deficiency, administer 1 gram IV iron in divided doses (e.g., 100 mg doses of
             Venofer ® (iron sucrose injection, USP) on 10 consecutive dialysis sessions). Reassess iron
             status and repeat if necessary.

     Please refer to page 17 for complete Venofer ® dosing.

     Continuous maintenance treatment: Smaller doses administered at regular intervals to maintain
     iron status within target. The average IV iron dose needed to maintain a stable ferritin level appears
     to be in the range of 22 to 65 mg/week.
            • To maintain target iron levels, administer IV iron weekly, monthly, or at each dialysis session,
               in doses sufficient to maintain TSAT >20% and ferritin >200 ng/mL (HDD-CKD) or >100 ng/mL
               (PDD or NDD-CKD).

     Successful anemia therapy in patients with CKD requires appropriate targets of therapy, testing of
     iron status, and the safe and effective use of iron agents. The goal of iron therapy is to achieve and
     maintain target Hb levels, to avoid iron storage depletion, and prevent iron-deficient erythropoiesis.153




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IV. Comparison Chart
  Overview of parenteral iron preparations
                                                       Venofer ®                    Dexferrum® or INFeD®                    Ferrlecit®
                                                   (iron sucrose1)                   (iron dextran154-155)            (ferric gluconate156)
  FDA Approved Indication
                                                                                    Yes (second line, when
             NDD-CKD Anemia                       Yes (first line) Adult              oral iron therapy is             Not FDA approved
                                                                                  unsatisfactory or impossible)

                                                                                    Yes (second line, when
             HDD-CKD Anemia                       Yes (first line) Adult              oral iron therapy is          Yes (first line) Adult and
                                                                                  unsatisfactory or impossible)         Pediatric >6 yr

                                                                                    Yes (second line, when
             PDD-CKD Anemia                       Yes (first line) Adult              oral iron therapy is             Not FDA approved
                                                                                  unsatisfactory or impossible)

  Safety

            “Black Box” Warning                            No                                 Yes                              No

            Test Dose Required                             No                                 Yes                              No

  Administration
                                                 100 mg over 2-5 min
                                                   (20-50 mg/min)
                                                                                      100 mg over 2 min               125 mg over 10 min
                                                     (HDD-CKD)
                  IV Push                                                                (50 mg/min)                    (12.5 mg/min)
                                                                                     1 hour after test dose               (HDD-CKD)
                                                 200 mg over 2-5 min
                                                   (40-100 mg/min)                                                          (Adult)
                                                      (NDD-CKD)
                                                100 mg/100 mL 0.9%
                                                  NaCl over 15 min
                                                     (HDD-CKD)                                                     125 mg/100 mL 0.9% NaCl
             IV Infusion in 0.9%                                                                                           over 1 hr
               Sodium Chloride                  300 mg/250 mL 0.9%                     Not FDA approved                   (HDD-CKD)
                                                  NaCl over 1.5 hr                                                          (Adult)
                                                400 mg/250 mL 0.9%
                                                  NaCl over 2.5 hr
                                                     (PDD-CKD)

                                                                                        Dexferrum® No
                     IM                                    No                                                                  No
                                                                                         INFeD® Yes

  Pharmacy Specifications

        Filter Needle Recommended                          No                                  No                             Yes*

                                                                                   Dexferrum® - 72 hr room
                                              48 hr room temperature or           temperature or refrigerated              Unavailable;
                                              refrigerated (in 0.9% NaCl              (in 0.9% NaCl at a               If diluted in saline,
           Stability in 0.9% NaCl                                                       concentration of
                                                 at a concentration of                                                   use immediately
               After Dilution                                                        1 mg/mL-5 mg/mL)†
                                                0.5 mg/mL-2 mg/mL)†                                                        after dilution
                                                                                     INFeD® - unavailable


                Preservative                              None                               None                        Benzyl alcohol

                                                                                    50 mg/mL Dexferrum®
               How Supplied                        100 mg/5 mL vial                   1 mL & 2 mL vials
                                                  200 mg/10 mL vial                                                  62.5 mg/5 mL ampule
                                                                                       INFeD® 2 mL vial

*American Society of Health System. ASHP guidelines on quality assurance for pharmacy-prepared sterile products.
  Am J Health-Syst Pharm. 2000:57:1150-1695.
†Data on file.
Note: INFeD® is a registered trademark of Watson Pharma, Inc. & Ferrlecit® is a registered
trademark of A. Nattermann & CIE. GMbH.


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V. Venofer               ®
                             (iron sucrose injection, USP)    prescribing information
Clinical pharmacology 1
Physical description and chemical formula
Venofer ® (iron sucrose injection, USP) is a brown, sterile, aqueous complex of polynuclear iron (III)
hydroxide in sucrose, containing 20 mg elemental iron per mL. The sterile solution has an osmolarity
of 1250 mOsmol/L. The product does not contain preservatives.

          Molecular Formula ................[Na 2Fe5O8 (OH) · 3(H2O)]n· m(C12H22O11)
          Molecular Weight .................Approximately 34,000 – 60,000 daltons
          Description ............................Iron sucrose is a brown, aqueous solution with a pH of 10.5–11.1

Mechanism of action
Venofer ® is used to replenish body iron stores in patients with iron deficiency anemia in non-dialysis
dependent-CKD patients receiving or not receiving an erythropoietin, and in hemodialysis and peritoneal
dialysis dependent-CKD patients receiving an erythropoietin. Iron is essential to the formation of
hemoglobin and to the function and formation of other heme and nonheme compounds. Untreated
depletion of iron stores leads to iron-deficient erythropoiesis and, in turn, to iron deficiency anemia.
Administration of Venofer ® replenishes tissue iron stores, reverses iron depletion and iron-deficient
erythropoiesis, and corrects or prevents iron deficiency anemia.

Following intravenous administration, Venofer ® is dissociated into iron and sucrose by the reticuloen-
dothelial system, and iron is transferred from the blood to a pool of iron in the liver and bone marrow.
Ferritin, an iron storage protein, binds and sequesters iron in a nontoxic form, from which iron is easily
available. Iron binds to plasma transferrin, which carries iron within the plasma and the extracellular
fluid to supply the tissues. The transferrin receptor, located in the cell membrane, binds the transferrin
iron complex, which is then internalized in vesicles. Iron is released within the cell, and the transferrin
-receptor complex is returned to the cell membrane. Transferrin without iron (apotransferrin) is then
released to the plasma. The intracellular iron becomes (mostly) hemoglobin in circulating red blood
cells (RBCs). Transferrin synthesis is increased and ferritin production reduced in iron deficiency.
The converse is true when iron is plentiful.

The stability of Venofer ® allows a competitive exchange of iron between iron sucrose and selective
iron-binding proteins such as transferrin and ferritin. Pharmacokinetic parameters show that the
administered iron disappears very rapidly from the serum, insuring a rapid correction of iron deficiency
anemia.157




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     Pharmacokinetics157-162
     In healthy adults treated with intravenous doses of Venofer ® (iron sucrose injection, USP) , its iron
     component exhibits first-order kinetics:

           – Elimination T1/2 ..........................................................................6 hours
           – Total clearance.............................................................................1.2 Liters per hour
           – Non–steady–state apparent volume of distribution...................10.0 Liters
           – Steady–state apparent volume of distribution ...........................7.9 Liters

     Since iron disappearance from the serum depends on the need for iron in the iron stores and iron-
     utilizing tissues of the body, serum clearance of iron is expected to be more rapid in iron-deficient
     patients treated with Venofer ® as compared with healthy individuals.

           Distribution
           In healthy adults, the iron component of Venofer ® appears to distribute mainly in the blood and
           to some extent in extravascular fluid.

           Metabolism
           Iron sucrose is dissociated into iron and sucrose by the reticuloendothelial system.

           Elimination
           The sucrose component is eliminated mainly by urinary excretion. Some iron is also eliminated
           in the urine (approximately 5%).

     Ferrokinetics159
     Following a single dose of 100 mg iron, iron uptake in bone marrow, liver, and spleen is rapid,
     followed by emergence of injected iron in circulating RBCs. Total RBC uptake accounts for 68%
     to 97% of injected iron within 2–4 weeks.

     Adverse reactions1
     The safety of Venofer ® has been documented in 6 randomized clinical trials involving 231 hemodialysis
     dependent; 139 non-dialysis dependent; 75 peritoneal dialysis dependent patients; and two post-
     marketing safety studies in 1,051 hemodialysis patients for a total of 1,496 patients. Please refer
     to the Venofer ® product package insert for a complete list of adverse events.




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Adverse event by dose group
The frequency of adverse events associated with the use of Venofer ® (iron sucrose injection, USP)
has been documented in five randomized clinical trials involving 231 hemodialysis dependent and 139
non-dialysis dependent patients.


      Drug Related Adverse Events Reported in >2% of Patients by Dose Group1

                                                                  HDD-CKD              NDD-CKD*                                  PDD-CKD**

      Adverse Events                                               100 mg               200 mg                 500 mg            300 mg for
      (Preferred Term)                                             (N=231)              (N=109)                (N=30)              2 doses
                                                                                                                                 followed by
                                                                                                                                 400 mg for
                                                                                                                                    1 dose
                                                                                                                                    (N=75)

      Subjects With Any Adverse Event                                14.7%                23.9%                 20.0%               10.7%

      Gastrointestinal Disorders
       Diarrhea NOS                                                   0.9                  0                     0                   2.7
       Dysgeusia                                                      0.9                  7.3                   3.3                 0
       Nausea                                                         1.7                  2.8                   0                   1.3

      General Disorders and
      Administration Site Conditions
       Infusion site burning                                          0                    3.7                   0                  0
       Injection site pain                                            0                    2.8                   0                  0
       Peripheral edema                                               0                    1.8                   6.7                0

      Nervous Systems Disorders
       Dizziness                                                      0                    2.8                   6.7                0
       Headache                                                       0                    2.8                   0                  0

      Vascular Disorders
       Hypotension NOS                                                5.2                  0                     6.7                0

*In non-dialysis dependent-CKD patients, there is limited experience with administration of an infusion of 500 mg of Venofer® in 250 mL 0.9% NaCl
 over 3.5-4 hours; hypotension occurred in 2 of 30 patients treated.
**Peritoneal dialysis dependent-CKD patients total cumulative dose of 1,000 mg over a 28-day period.


Non-dialysis dependent-chronic kidney disease studies 92,123
Adverse reactions, whether or not related to Venofer ® administration, reported by >5% of treated
patients from a total of 139 patients in two clinical studies are as follows: taste disturbance, peripheral
edema, diarrhea, constipation, nausea, dizziness, hypertension, vomiting, arthralgia, back pain,
headache, extremity pain, and injection site burning.

Hemodialysis studies11-13
In three clinical safety and efficacy trials (231 patients), several patients experienced pruritus and one
patient experienced a facial rash. No patients experienced generalized rashes or urticaria. None of
these reactions led to treatment discontinuation. No serious or life-threatening anaphylactoid reaction
was observed in the three clinical efficacy trials11-13. Adverse reactions, whether or not related to
Venofer ® administration, reported by >5% of the 231 treated patients in the above three hemodialysis
studies are as follows: hypotension, muscle cramps, nausea, headache, graft complications, vomiting,
dizziness, hypertension, chest pain, and diarrhea. Some of these symptoms may be seen in hemodialysis
patients not receiving intravenous iron.


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16
     Peritoneal dialysis dependent-chronic kidney disease study 1,124
     Adverse reactions, whether or not related to Venofer ® (iron sucrose injection, USP) administration, reported
     by >5% of treated patients from a total of 121 patients (75 Venofer ® treated patients) are as follows:
     diarrhea, peritoneal infection, vomiting, hypertension, pharyngitis, peripheral edema, and nausea.

     Post marketing safety studies
     In the two post-marketing safety studies, 665 patients received multiple doses of Venofer ®, and 386
     patients received a single dose of Venofer ®. In the multiple dose study, only serious adverse events
     and drug related non-serious events were reported. Adverse events reported in >1% of 1,051 patients
     were congestive heart failure (CHF), sepsis, and taste disturbance.23,24

     Drug interactions 1
     As with all parenteral iron preparations, Venofer® should not be administered concomitantly with oral
     iron preparations since the absorption of oral iron may be reduced. In patients previously receiving
     oral iron therapy, administration of Venofer ® should prompt discontinuation of oral iron agents.

     Pregnancy category B 1
     Teratology studies have been performed in rats and have revealed no evidence of impaired fertility or
     harm to the fetus due to Venofer ®. There are, however, no adequate and well controlled studies in
     pregnant women. Because animal reproduction studies are not always predictive of human response,
     this drug should be used during pregnancy only if clearly needed.

     Pediatric use1
     Safety and effectiveness of Venofer ® (iron sucrose injection, USP) in pediatric patients have not
     been established. In a country where Venofer ® is available for use in children, at a single site, five
     premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five
     expired during or following a period when they received Venofer ®, several other medications, and
     erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth
     weight infants. No causal relationship to Venofer ® or any other drugs could be established.

     Geriatric use1
     The clinical efficacy studies of Venofer ® did not include sufficient numbers of subjects aged 65 and
     over to determine whether they respond differently from younger subjects. Of the 1,051 patients in
     two post-marketing safety studies of Venofer ®, 40% were age 65 or older. No overall differences in
     safety were observed between these subjects and younger subjects. Other reported clinical experience
     has not identified differences in response between elderly and younger patients. However, greater
     sensitivity of some older individuals cannot be ruled out.




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               Leading anemia management.™
                                                                                                          17
Indications and dosage               1

Venofer ® is indicated in the treatment of iron deficiency anemia in the following patients:
      • Non-dialysis dependent-chronic kidney disease (NDD-CKD) patients not receiving
        an erythropoietin
      • Non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving
        an erythropoietin
      • Hemodialysis dependent-chronic kidney disease (HDD-CKD) patients receiving
        an erythropoietin
      • Peritoneal dialysis dependent-chronic kidney disease (PDD-CKD) patients receiving
        an erythropoietin
Venofer is contraindicated in:
        ®


      • Patients with evidence of iron overload.
      • Patients with known hypersensitivity to iron sucrose or any of its inactive components.
      • Patients with anemia not caused by iron deficiency.


Usual dosage 1
Most CKD patients will require a minimum cumulative repletion dose of 1,000 mg of elemental iron
to achieve a favorable hemoglobin response and to replenish iron stores (ferritin, TSAT). Patients
may continue to require therapy with Venofer ® (iron sucrose injection, USP) at the lowest dose
necessary to maintain target levels of hemoglobin and laboratory parameters of iron storage
within acceptable limits.
      • Non-Dialysis Dependent-Chronic Kidney Disease Patients (NDD-CKD):
         Venofer ® is administered as a total cumulative dose of 1,000 mg over a 14 day period as a
         200 mg slow IV injection undiluted over 2 to 5 minutes on 5 different occasions within a 14
         day period. There is limited experience with administration of an infusion of 500 mg of
         Venofer ®, diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5-4 hours on day
         1 and day 14; hypotension occurred in 2 of 30 patients treated.
      • Hemodialysis Dependent-Chronic Kidney Disease Patients (HDD-CKD):
         Venofer ® may be administered undiluted as a 100 mg slow intravenous injection over 2 to 5
         minutes or as an infusion of 100 mg, diluted in a maximum of 100 mL of 0.9% NaCl over a
         period of at least 15 minutes per consecutive hemodialysis session for a total cumulative dose
         of 1,000 mg.
      • Peritoneal Dialysis Dependent-Chronic Kidney Disease Patients (PDD-CKD):
         Venofer ® is administered as a total cumulative dose of 1,000 mg in 3 divided doses, given by
         slow intravenous infusion, within a 28 day period: 2 infusions of 300 mg over 1.5 hours 14
         days apart followed by one 400 mg infusion over 2.5 hours 14 days later. The Venofer ® dose
         should be diluted in a maximum of 250 mL of 0.9% NaCl.




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18
     Monitoring parameters1
           • Patients receiving regular parenteral iron therapy require monitoring of hematologic
             parameters and iron indices (Hb, Hct, TSAT, and ferritin).
           • Since transferrin saturation values increase rapidly after IV administration of iron sucrose,
             serum iron values may be reliably obtained 48 hours after IV iron sucrose dosing.




     IMPORTANT SAFETY INFORMATION: Venofer ® (iron sucrose injection, USP) is contraindicated in
     patients with evidence of iron overload, in patients with known hypersensitivity to Venofer ® or any of
     its inactive components, and in patients with anemia not caused by iron deficiency. Hypersensitivity
     reactions have been reported with IV iron products. Hypotension has been reported frequently in
     hemodialysis dependent-CKD patients receiving IV iron, and has also been reported in non-dialysis and
     peritoneal dialysis dependent-CKD patients receiving IV iron. Hypotension following administration of
     Venofer ® may be related to rate of administration and total dose delivered.
     In multi-dose efficacy studies in hemodialysis dependent-CKD patients (N=231), the most frequent
     adverse events (>5%), whether or not related to Venofer ® administration, were hypotension, muscle
     cramps, nausea, headache, graft complications, vomiting, dizziness, hypertension, chest pain, and
     diarrhea. In post-marketing safety studies in hemodialysis dependent-CKD patients (N=1,051),
     the most frequent adverse events reported (>1%) were congestive heart failure, sepsis, and taste
     disturbance. In multi-dose efficacy studies in non-dialysis dependent-CKD patients (N=91), the most
     frequent adverse events ( 5%) whether or not related to Venofer ® administration, were taste
     disturbance, peripheral edema, diarrhea, constipation, nausea, dizziness, and hypertension. In the
     study of peritoneal dialysis dependent-CKD patients (N=75), the most frequent adverse events,
     whether or not related to Venofer®, reported by 5% of these patients were diarrhea, peritoneal
     infection, vomiting, hypertension, pharyngitis, peripheral edema, and nausea.




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              Leading anemia management.™
                                                                                                                  19

VI. Clinical efficacy and safety
Since Venofer ® (iron sucrose injection, USP) was first approved in Switzerland in 1950, a large body
of evidence in the form of study reports and publications has been produced that demonstrates the
safety and efficacy of intravenous iron sucrose. The evaluation of clinical safety and efficacy of
Venofer® is based on results from more than 100 studies 3 -124 involving more than 7,000 subjects.
More than 5,000 patients were treated with Venofer ®. These studies demonstrate the effectiveness of
Venofer ® in the treatment of iron deficiency anemia, alone and in combination with an erythropoietin.
Venofer ® is well tolerated in the vast majority of patients, including those with a history of hypersen-
sitivity reactions to iron dextran and other parenteral iron preparations. Venofer ® is easy to administer
as either a slow injection or as an infusion. A test dose is not required, however, some physicians
used a test dose at their discretion in two U.S. pivotal trials in HDD-CKD patients.

Review of selected clinical trials in CKD
Study A-Hemodialysis patients (Charytan et al,12 Van Wyck et al 163)
Study A was a multicenter, open-label, historically controlled study in 101 hemodialysis patients (77
patients with Venofer ® treatment and 24 in the historical control group) with iron deficiency anemia.
Eligibility for Venofer ® treatment included patients undergoing chronic hemodialysis three times week-
ly, receiving erythropoietin, hemoglobin concentration greater than 8.0 and less than 11.0 g/dL for at
least two consecutive weeks, transferrin saturation <20%, and serum ferritin <300 ng/mL. The erythro-
poietin dose was to be held constant throughout the study. The protocol did not require administration
of a test dose; however, some patients received a test dose at the physician’s discretion. Exclusion
criteria included significant underlying disease, asthma, active inflammatory disease, or serious bacterial
or viral infection. Venofer ® 5 mL (one vial) containing 100 mg of elemental iron was administered through
the dialysis line at each dialysis session either as a slow injection or a saline-diluted slow infusion for a
total of 10 dialysis sessions with a cumulative dose of 1000 mg elemental iron. A maximum of 15 mL
(300 mg of elemental iron) of Venofer ® was administered per week. No additional iron preparations
were allowed until after the day 57 evaluation. The mean change in hemoglobin from baseline to day
24 (end of treatment), day 36, and day 57 was assessed.
        • Four of the 77 patients (5%) had six adverse events believed to be related to Venofer ®,
           including diarrhea (2 patients), abdominal pain, nausea, constipation, and taste disturbance.
        • No hypersensitivity reactions were seen, including in any of 10 patients who had shown
           previous intolerance/allergy to iron dextran injection, USP.
The historical control population consisted of 24 patients similar to patients treated with Venofer ®
who were off intravenous iron for at least 2 weeks and who had received erythropoietin therapy with
hematocrit averaging 31% to 36% for at least two months prior to study entry.51 Patient age and
serum ferritin level were similar between treatment and historical control patients. The mean baseline
hemoglobin and hematocrit were higher, and the erythropoietin dose was lower in the historical control
population than in the Venofer ®-treated population.
        • Patients in the Venofer ®-treated population showed a statistically significantly greater
           increase in hemoglobin and hematocrit than did patients in the historical control population.
                – At the 2-week follow-up, patients in the Venofer ® -treated population showed a significantly
                  (p<0.01) greater increase in hemoglobin (1.3 g/dL) and hematocrit (3.6%) than did
                  patients in the historical control population (Hb, -0.6 g/dL, Hct, -1.2%).

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20
                 – At the 5-week follow-up, Venofer ® (iron sucrose injection, USP)-treated patients
                    showed a significantly (p<0.05) greater increase in hemoglobin (1.2 g/dL) than did
                    patients in the historical control group (-0.1 g/dL).
                 – At the end of treatment, patients in the Venofer ®-treated population showed a significantly
                    (p<0.01) greater increase in hemoglobin (1.0 g/dL) and hematocrit (3.1%) than did
                    patients in the historical control group (Hb, -0.5 g/dL, Hct, -0.8%).
           • Serum ferritin increased significantly (p=0.001) at endpoint of study from baseline in the
             Venofer ®-treated population (165.3 ng/mL) compared with the historical control population
             (-27.6 ng/mL). Transferrin saturation also increased significantly (p=0.0016) at endpoint of
             study from baseline in the Venofer ® treated population (8.8%) compared with the historical
             control population (-5.1%).

     The authors concluded that doses of 100 mg Venofer ® given IV in 10 consecutive dialysis
     sessions for a total dose of 1,000 mg were effective and safe in hemodialysis patients
     with iron deficiency anemia receiving supplemental erythropoietin therapy and can be
     administered without a test dose.

     Study B-Hemodialysis patients (Van Wyck et al 13)
     The safety and efficacy of Venofer ® in hemodialysis patients who had experienced intolerance to iron
     dextran were also examined in a single-arm, two-period, open-label, multicenter study by Van Wyck
     et al. Sixteen patients with Hb <11g/dL and a history of mild reactions and 7 patients with a history
     of severe anaphylactoid reactions to iron dextran were included. Following an observation period,
     patients received 100 mg Venofer ® either by intravenous injection or infusion for 10 consecutive
     dialysis sessions over 3-4 weeks. A test dose was not required; however, some patients received
     a test dose at the physician’s discretion. Since the study was primarily a safety study, efficacy
     assessments were limited to changes from baseline to day 24 (end of treatment evaluation).
            • There were no serious hypersensitivity reactions, no serious adverse drug reactions,
               and no patients discontinued from the study due to adverse drug reactions.
            • Three mild adverse events considered related or possibly related to Venofer ® were
               reported in 2 patients:
                   – Taste disturbance (metallic taste, 1 patient twice)
                   – Pruritus (1 patient)
            • Concomitant use of ACE inhibitors was present in 12 of 23 patients (52%).
            • Mean hemoglobin increased from 10.4 g/dL to 11.5 g/dL at day 24 (p<0.05, increase 11.0%).
            • Mean hematocrit increased from 32.8% to 36.4% at day 24 (p<0.05, increase of 11.0%).
            • MCV, MCHC, serum iron, TSAT, and serum ferritin also increased significantly, and total iron
               binding capacity (TIBC) decreased significantly.

     The authors concluded that Venofer ® is safe and effective in the management of anemia in
     hemodialysis patients receiving supplemental erythropoietin sensitive to iron dextran and
     can be administered without a test dose by IV push or infusion.




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              Leading anemia management.™
                                                                                                                21
Study C-Hemodialysis patients (Van Zyl-Smit et al )                  11

A safety and efficacy study of Venofer ® (iron sucrose injection, USP) or the combination of Venofer ®
and erythropoietin was performed in an open, single-arm, two-period, multicenter study by Van Zyl-Smit
et al in South Africa. One hundred thirty-one patients were enrolled. All suffered from hemodialysis-
associated anemia, were undergoing maintenance hemodialysis (2 to 3 sessions per week), had an Hb
<10.0 g/dL, serum transferrin saturation <20%, and serum ferritin <200 ng/mL. A first dose of 50 mg
of Venofer ® was administered at the first hemodialysis session, followed by doses of 100 mg of iron
during dialysis 3 times weekly until an individually calculated dose, based upon baseline hemoglobin,
and body weight, was administered. Patients were then followed for an additional 4 weeks, in a no-
treatment observation period. The modified intent-to-treat population consisted of 130 patients. Mean
hematologic and iron parameters at baseline and following treatment with Venofer ® are given below:
        • Mean hemoglobin increased from 7.2 g/dL to 9.0 g/dL at observation week two and 9.2 g/dL
          at observation week four (p<0.0001, maximum increase of 28%).
        • Mean hematocrit increased from 22.5% to 27.9% at observation week two and 28.5% at
          observation week four (p<0.0001, maximum increase of 27%).
        • Mean serum ferritin increased from 65.1 ng/mL to 512.7 ng/mL at observation week two and
          440.2 ng/mL at observation week four (p<0.0001, maximum increase of 687%).
        • Mean serum transferrin saturation increased from 11.4% to 27.7% at observation week two
          and 27.6% at observation week four (p<0.0001, maximum increase of 143%).
Adverse events (>1%) that were reported to be possibly related to Venofer ® were hypotension (13%),
nausea (3%), increased liver function test (2%), pneumonia (2%), and vomiting (2%). Hypotension was
also associated with hemodialysis itself and occurred with similar frequency during the treatment
period and during the observation period when no iron was given.

The authors concluded that Venofer ® was safe and effective in the treatment of patients
with hemodialysis-associated anemia.

Study D-Non-dialysis dependent CKD patients (VanWyck et al) 123
The safety and efficacy of Venofer ® in non-dialysis CKD patients was examined in a randomized, open-label
multicenter, active-controlled study by Van Wyck et al. 182 patients were treated with oral iron (N=91) or
Venofer ® (N=91) with or without an erythropoietin. Erythropoietin therapy was stable for 8 weeks prior to
randomization. Patients with an average baseline Hg <11 g/dL, TSAT <25%, and ferritin <300 ng/mL were
randomized to receive either oral iron (325 mg ferrous sulfate TID for 56 days) or Venofer ® (200 mg IV over
2-5 minutes 5 times within 14 days or 500 mg IV infusion over 3.5-4 hours on Day 1 and Day 14). Sixty-one
patients received 280 doses of 200 mg iron sucrose, and 30 patients received 58 doses of iron sucrose 500 mg.
       • A statistically greater proportion of Venofer ® treated patients (44.3%) compared to oral iron
          patients (28%) had a clinically significant response as defined as an increase in hemoglobin
          >1 g/dL at any time during the study. (p=0.03)
       • The mean increase in hemoglobin at Day 42 was greater in the Venofer ® treated patients (0.7
          g/dL) compared to oral iron patients. (0.4 g/dL) (p=0.0298)
       • A greater proportion of Venofer ® treated patients (39.2%) compared to oral iron patients
          (1.2%) had a clinically significant response defined as an increase in hemoglobin >1 g/dL, and
          ferritin >160 ng/mL at any time during the study. (p<0.0001)


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22
           • Patients in the oral iron group, but not the Venofer ® (iron sucrose injection, USP) group,
             showed a statistically significant rise in serum creatinine at study day 56/end of study.
             (0.2 mg/dL, p<0.0013)
           • Non-compliance was more common in the oral iron treatment group.
           • No serious adverse drug events were seen in patients administered Venofer ® 200 mg IV over
             2-5 minutes, but drug related hypotension, including one event considered serious, occurred
             in 2 females weighing less than 65 kg after 500 mg doses were given over 4 hours.
           • Among non-serious ADEs reported, GI complaints were seen most frequently in both treatment
             groups, but the nature of GI complaints differed between groups. Transient taste disturbance
             was the most prominent GI complaint associated with Venofer ® administration. Constipation,
             diarrhea, nausea, vomiting and dyspepsia were associated with oral iron therapy. Headache,
             myalgia, and hypotension were also associated with Venofer ® administration.

     The authors concluded that Venofer ® administration of 1,000 mg in divided doses is superior to
     oral iron therapy in the management of NDD-CKD patients with anemia and low iron indices.
     Venofer® therapy was safe, well tolerated and more effective than oral iron treatment.

     Study E-Peritoneal dialysis dependent CKD patients (Singh et al) 1,124
     The safety and efficacy of Venofer ® in peritoneal dialysis dependent-CKD patients receiving an
     erythropoietin was examined in a multicenter, randomized, controlled trial by Singh et al. 126 patients
     were treated with an erythropoietin and Venofer ® (N=75), or an erythropoietin alone without iron
     supplementation. Erythropoietic therapy was unchanged for 8 weeks prior to randomization and during
     the study period. Patients with Hg <11.5 g/dL, TSAT <25%, and ferritin <500 ng/mL were randomized
     to receive either no iron (n=46) or Venofer ® (300 mg diluted in 250 mL 0.9% NaCl over 1.5 hours on
     Days 1 and 15 and 400 mg diluted in 250 mL 0.9% NaCl over 2.5 hours on Day 29) (n=75).
            • Patients in the Venofer ®/erythropoietin group had a greater mean hemoglobin change from
              baseline to the highest hemoglobin value. (1.3 g/dL) (p<0.01)
            • A greater proportion of patients treated with Venofer ®/erythropoietin (59.1%) had an
              increase in hemoglobin of >1 g/dL at any time during the study compared to patients who
              received erythropoietin alone. (33.3%) (p < 0.05)
            • There were no serious adverse events after Venofer ® administration at either dose level.
              8 patients experienced at least 1 non-serious adverse event thought to be related to study
              drug with GI complaints seen most frequently.

     The authors concluded that Venofer ® is an effective adjunct to erythropoietic therapy in
     anemic patients with PDD-CKD. Administration of Venofer ® as an IV infusion of 300 mg over
     1.5 hours or 400 mg over 2.5 hours is well tolerated and provides a practical approach to
     correcting iron deficiency anemia and replenishing iron stores.




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              Leading anemia management.™
                                                                                                           23
Post-marketing safety study 1                  23

665 chronic hemodialysis patients on an erythropoietin were treated with 100 mg Venofer ® (iron
sucrose injection, USP) at each dialysis session for up to 10 consecutive sessions for iron deficiency,
or on a weekly basis for 10 weeks for maintenance of iron stores. Some patients received as many as
5 cycles (50 doses). A total of 8,583 doses of iron were administered. 80 patients with previous
intolerance to other IV iron products (63 iron dextran, 5 ferric gluconate, 12 both) were included.
There were no drug related deaths, serious adverse drug reactions, or withdrawals due to serious
adverse reactions. There were 2 non-serious adverse reactions reported (constipation 1, pruritus 1).
History of intolerance to other IV iron products had no impact on the occurrence of adverse events.

Post-marketing safety study II 24
386 chronic hemodialysis patients on an erythropoietin were exposed to a single dose of Venofer ®
100 mg IV by slow injection or 200 mg IV by slow injection over 5 minutes [200 mg dose not FDA
approved for this indication]. Only serious and non-serious events considered by the investigation
to be drug related were collected. No study drug related serious adverse events were reported.
Three patients experienced unrelated serious adverse events during the study. Two patients experienced
adverse reactions that lead to premature discontinuation from the study. No hypersensitivity reactions
were observed during the study. Only one patient with a history of iron intolerance reported a transient
taste disturbance. History of intolerance to other IV iron products had no impact on the occurrence of
adverse events.




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24




                                   Please see full prescribing information at back page.
     Leading anemia management.™
                                                                                                           25

VII. Pharmacy specifications
Dosage form
Venofer ® (iron sucrose injection, USP) is available in 5 mL and 10 mL single dose vials. Each 5 mL vial
contains 100 mg (20 mg/mL) and each 10 mL vial contains 200 mg (20 mg/mL) of elemental iron as
iron sucrose in water for injection. Venofer ® contains no preservatives.1

Syringe stability
Venofer ® when diluted with 0.9% Sodium Chloride for Injection, USP at concentrations ranging from
2 mg to 10 mg of elemental iron per mL, or undiluted (20 mg elemental iron per mL) and stored in a
plastic syringe, was found to be physically and chemically stable for 48 hours at controlled room
temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).2

IV admixture stability
Venofer ®, when added to IV infusion bags (PVC) containing 0.9% Sodium Chloride Injection, USP at
concentrations ranging from 0.5 mg to 2 mg of elemental iron per mL, has been found to be physically
and chemically stable for 48 hours at controlled room temperature (25°C ± 2°C) and under refrigeration
(4°C ± 2°C).2

Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to infusion.




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26




                                   Please see full prescribing information at back page.
     Leading anemia management.™
                                                                                                            27

VIII. Reimbursement information
American Regent, Inc. is committed to helping the renal community understand reimbursement issues. This
section provides general coverage, coding, and reimbursement information that will help you understand
the policies of the Medicare program and other payers for Venofer ® (iron sucrose injection, USP).

COVERAGE FOR Venofer ®
Medicare is likely to cover Venofer ® when used for its approved indications and when provided to
Medicare-eligible beneficiaries.

Insurers of CKD patients, including Medicaid and leading private insurers, may also cover Venofer ®.
Medicaid coverage policies can vary from state to state. Private payer coverage policies can vary
considerably from one insurer to another and from patient to patient based on specific policy benefits.

CODING FOR Venofer ®
Proper coding of services provided is critical to ensuring appropriate reimbursement.

Venofer ® has been assigned a specific HCPCS Code: J1756.
     HCPCS Code                                 Short Descriptor             Long Descriptor

     J1756                                      Iron sucrose injection       Injection, iron sucrose, 1mg




Billing for administration
96365* IV infusion for therapy, prophylaxis, or diagnosis; up to 1 hour
96366* IV infusion for therapy, prophylaxis, or diagnosis; each additional hour
       (List separately in addition to code for primary procedure)
96374* Therapeutic, prophylactic or diagnostic injection; IV push single or initial
       substance/drug

*2008 Current Procedural Terminology (CPT) codes. 2008 American Medical Association. All rights reserved.


Diagnosis
Venofer ® is indicated for the treatment of iron deficiency anemia in non-dialysis dependent-chronic
kidney disease (CKD) patients receiving or not receiving erythropoietin, and in hemodialysis and
peritoneal dialysis dependent-chronic kidney disease patients receiving erythropoietin.




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28

     Examples of primary or secondary diagnosis codes that may support the use of Venofer ® (iron sucrose
     injection, USP) in an appropriate case include the following:

     280.0 .................Iron deficiency anemia secondary to blood loss (chronic)
     280.1 .................Iron deficiency anemia secondary to inadequate dietary iron intake
     280.8 .................Other specified iron deficiency anemia
     280.9 .................Unspecified iron deficiency anemia
     585.1 .................Chronic kidney disease, Stage I
     585.2 .................Chronic kidney disease, Stage II (mild)
     585.3 .................Chronic kidney disease, Stage III (moderate)
     585.4 .................Chronic kidney disease, Stage IV (severe)
     585.5 .................Chronic kidney disease, Stage V
     585.6 .................End stage renal disease (ESRD)
     585.9 .................Chronic kidney disease, unspecified

     Please note that only a physician is qualified to make a diagnosis, and the diagnosis must be
     documented in the patient’s medical record. American Regent, Inc. does not recommend the
     use of any specific diagnosis code in any particular situation.

     Please see complete prescribing information enclosed.

     Venofer ® (iron sucrose injection, USP), is available as 100 mg/5 mL single dose, preservative-free vials
     and 200 mg/10 mL single dose, preservative-free vials.

     NDC# 0517-2340-10 ...................5 mL Single Dose Vial (100 mg) (10 Pack)
     NDC# 0517-2340-25 ...................5 mL Single Dose Vial (100 mg) (25 Pack)
     NDC# 0517-2310-05 ..................10 mL Single Dose Vial (200 mg) (5 Pack)

     Each 1 mg of Venofer ® (iron sucrose injection, USP) equals one (1) service unit.
     For example:

     100 mg (5 mL) equals 100 service Units
     200 mg (10 mL) equals 200 service Units
     300 mg (15 mL) equals 300 service Units

     Please Note: Venofer ® is supplied in 100 mg/5 mL and 200 mg/10 mL single-dose vials. When billing,
     indicate the total amount of drug used as a multiple of service units (1 mg = 1 service unit).




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               Leading anemia management.™
                                                                                                          29
Venofer (iron sucrose injection, USP) PATIENT ASSISTANCE PROGRAM and
             ®

REIMBURSEMENT HOTLINE
American Regent, Inc. has created the Venofer ® Patient Assistance Program (PAP) to help improve
access to Venofer ® for patients who lack health insurance and cannot afford therapy. To be eligible
for the program, patients must completely lack health insurance, be ineligible for public insurance or
financing, and must meet income and other criteria established by American Regent. American Regent
will replace the Venofer ® provided free of charge while the patient is enrolled in the program.

In addition, American Regent has created a toll-free hotline to help physicians and other providers
understand payers’ coverage and reimbursement policies for Venofer ® and, when necessary, address
reimbursement issues. American Regent’s Venofer ® Reimbursement Hotline is available to provide
expert assistance with all types of insurance claims.

This service can be reached at 800-282-7712 between 9 am and 5 pm, ET.

Specifically, hotline program associates assist with the following:

Insurance verifications-Help callers verify payer coverage and reimbursement policies for Venofer ®
for specific patients. Program associates will determine patients’ benefits level and discuss potential
billing options.

Billing assistance-Assist callers with filing claims and understanding the reimbursement policies
for Venofer ® including researching state-specific local codes.

Claims appeals-Support callers in appealing denied claims or inadequate reimbursement for Venofer ®.

Patient assistance-Screen individuals with no health insurance who are ineligible for public assistance
for enrollment in a free product replacement program. After-hours callers may leave a message, and
the call will be returned the following business day.




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30




                                   Please see full prescribing information at back page.
     Leading anemia management.™
                                                                                                         31

IX. Requests for additional information
    about Venofer (iron sucrose injection, USP)
                                        ®




Additional information about Venofer ® (iron sucrose injection, USP) is available.

The Professional Services Department at American Regent, Inc. is available to answer questions or
requests for information. Office hours are 9 am–5 pm, ET, Monday through Friday. Please contact us at:

American Regent, Inc.
Professional Services Department
One Luitpold Drive
P.O. Box 9001
Shirley, New York 11967

Phone....................800-645-1706
Fax ........................631-924-1731
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32




                                   Please see full prescribing information at back page.
     Leading anemia management.™
                               .
                                                                                                                                                         33

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     apy for iron deficiency anemia: safety and efficacy. Blood.                  death among patients with congestive heart failure admitted to
     2004;104(11):abs #3681.                                                      community hospitals: a population-based study. J Am Soc
121. Erichsen K, et al. Oral versus intravenous iron therapy in patients          Nephrol. 2002;13:1928-1936.
     with inflammatory bowel disease Gut. 2004;53(suppl V):A220.             136. Al-Ahmad A, Rand WM, Manjunath G, et al. Reduced kidney func-
122. Biesenbach G, et al. Erythropoietin requirement in patients with             tion and anemia as risk factors for mortality in patients with left
     type 2 diabetes mellitus on maintenance haemodialysis therapy.               ventricular dysfunction. J Am Coll Cardiol. 2001;38(4):955-962.
     Wein Klin Wochenschr. 2004;116(24):844-848.                             137. Tarng D. Cardio renal anemia syndrome in chronic kidney disease.
123. Van Wyck DB, Roppolo M, Martinez CO, Mazey RM, McMurray S,                   J Chin Med Assoc. 2007;70(10):424–429.
     for the United States Iron Sucrose (Venofer®) Clinical Trials Group.    138. Fink JC, Blahut SA, Reddy M, Weir MR. Use of erythropoietin
     A randomized controlled trial comparing IV iron sucrose to oral              before the initiation of dialysis and its impact on mortality. Am J
     iron in anemic patients with non-dialysis dependent CKD. Kidney              Kidney Dis. 2001;37:348–355.
     Int. 2005;68:2846-2856.                                                 139. Gouva C, Nikolopoulos P, Ioannidis JP, Siamopoulos KC. Treating
124. Singh H, Reed J, Noble S. Effect of iron therapy in peritoneal dial-         anemia early in renal failure patients slows the decline of renal
     ysis patients receiving erythropoiesis stimulating agents for ane-           function: a randomized controlled trial. Kidney Int.
     mia: a randomized, controlled trial. Clin J Am Soc Nephrol.                  2004;66:753–760.
     2006;1(3):475-482.                                                      140. Hsu CY, McCulloch CE, Curhan GC. Iron status and hemoglobin
125. Mircescu G,                              Ursea N. Intravenous iron           level in chronic renal insufficiency. J Am Soc Nephrol.
     supplementation for the treatment of anaemia in pre-dialyzed                 2002;13(11):2783-2786.
     chronic renal failure patients. Nephrol Dial Transplant. 2006;21;120-   141. Federal Drug Administration. FDA strengthens safety information
     124.                                                                         for erythropoiesis-stimulating agents (ESAs). FDA News.
126. National Kidney Foundation. KDOQI clinical practice guidelines               Available at: http://www.fda.gov/bbs/topics/NEWS/2007
     and clinical practice recommendations for anemia in chronic kidney           /NEW01582.html. Accessed February 4, 2009.
     disease. Am J Kidney Dis. 2006;47(suppl 3):S1-S146.                     142. Kimura T, Arai M, Masuda H, et al. Impact of a pharmacist-imple-
127. Astor BC, Muntner P, Levin A, Eustace JA, Coresh J. Association of           mented anemia management in outpatients with end-stage renal
     kidney function with anemia. Arch Intern Med. 2002;162:1401-1408.            disease in Japan. Biol Pharm Bull. 2004; 27:1831–1833.
128. Kazmi WH, Kausz AT, Khans, et al. Anemia: an early complication         143. Gotloib L, Silverberg D, Fudin R, Shostak A. Iron deficiency is a
     of chronic renal insufficiency. Am J Kidney Dis. 2001;38(4):                 common cause of anemia in chronic kidney disease and can often
     803-812.                                                                     be corrected with intravenous iron. J Nephrol. 2006;19(2):161-167.



Please see full prescribing information at back page.
38
     144. Agarwal R, Rizkala A, Bastani B Kaskas M, Leehey D, Besarab A.        154. Dexferrum® [package insert]. Shirley, NY: American Regent, Inc.; 2005.
          A randomized controlled trial of oral versus intravenous iron in      155. INFed® [package insert]. Corona, CA: Watson Laboratories, Inc; 2006.
          chronic kidney disease. Am J Nephrol. 2006;26:445-454.
                                                                                156. Ferrlecit® [package insert]. Corona, CA: Watson Laboratories, Inc;
     145. Sunder-Plassman G, Horl WH. Importance of iron supply for                  2006.
          erythropoietin therapy. Nephrol Dial Transplant. 1995;10:2070-2076.
                                                                                157. Danielson BG, Salmonson T, Derendorf H, Geisser P.
     146. Schaefer RM, Schaefer L. Management of iron substitution                   Pharmacokinetics of iron (III)-hydroxide sucrose complex after a
          during r-HuEPO therapy in chronic renal failure patients.                  single dose in healthy volunteers. Arzn-Forsch/Drug Res.
          Erythropoiesis. 1992;3:71-75.                                              1996;46:615-621.
     147. Fishbane S, Frei GL, Maesaka J. Reduction in recombinant human        158. Beshara S, Lundqvist H, Sundin J, et al. Kinetic analysis of 52Fe
          erythropoietin doses by the use of chronic intravenous iron                labeled iron (III)-hydroxide sucrose complex following bolus
          administration. Am J Kidney Dis. 1995;26:41-46.                            administration using positron emission tomography.
     148. Macdougall IC, Tucker B, Thompson J, et al. A randomized                   Br J Haematol. 1999;104:288-295.
          controlled study of iron supplementation in patients treated with     159. Beshara S, Lundqvist H, Sundin J, et al. Kinetic analysis of 52Fe
          erythropoietin. Kidney Int. 1996;50:1694-1699.                             labeled iron (III)-hydroxide sucrose complex following bolus
     149. Sepandj F, Jindall K, West M, Hirsch D. Economic appraisal of              administration using positron emission tomography. Clinical
          maintenance parenteral iron administration in the treatment of             study report, 1997 and data on file, American Regent, Inc.,
          anemia in chronic hemodialysis patients. Nephrol Dial Transplant.          Shirley, NY.
          1996;11: 319-322.                                                     160. Krysko K, Bokowski W, Wichlinski LM. Pharmacokinetics of
     150. Taylor, JE, Peat N, Porter C, Morgan AG. Regular low-dose                  serum iron in humans. ZBL Pharm. 1984;123: 598-599.
          intravenous iron therapy improves response to erythropoietin in       161. Anatkov A, Gekova K. The use of large intravenous doses of iron
          hemodialysis patients. Nephrol Dial Transplant. 1996;11:                   in the treatment of iron-deficiency anemia. Problems Hematol
          1079-1083.                                                                 Blood Transfusions Med Physioculture. 1970;13:295- 298.
     151. Ahsan N, Groff JA, Waybill MA. Efficacy of bolus intravenous iron     162. Major A, Mathez-Loic F, Rohling R, Gautschi K, Brugnara C. The
          dextran treatment in peritoneal dialysis patients receiving recom-         effect of intravenous iron on the reticulocyte response to recom-
          binant human erythropoietin. Adv Perit Dial. 1996;12:161-166.              binant human erythropoietin. Br J Haematol. 1997;98:292-294.
     152. Macdougall I. Meeting the challenges of a new millennium:             163. Van Wyck DB. The natural history of iron deficiency in patients
          optimizing the use of recombinant human erythropoietin.                    with dialysis-associated anemia: Analysis of the first 10 weeks
          Nephrol Dial Transplant. 1998;13(suppl 2):23-27.                           without iron and comparison to LU98001. Clinical study report,
     153. Van Wyck DB. Lessons from NKF-DOQI: iron management.                       2000 and data on file: American Regent, Inc., Shirley, NY.
          Seminars Nephrol. 2000; 20:330-334.




                                                                                         Please see full prescribing information at back page.
                   Leading anemia management.™
                                                                                                      39

XI. Venofer                  ®
                                 (iron sucrose injection, USP)        fact sheet
NDA # ........................................21-135

Initial FDA Approval Date ..........November 6, 2000

Strength ......................................20 mg Elemental Iron per mL

Vial Size ......................................5 mL Single Dose Vial (100 mg) (Preservative Free)
NDC#...........................................0517-2340-10 (10 Pack)
NDC#...........................................0517-2340-25 (25 Pack)

Vial Size ......................................10 mL Single Dose Vial (200 mg) (Preservative Free)
NDC#...........................................0517-2310-05 (5 Pack)

For more information concerning Venofer ® (iron sucrose injection, USP) please call our
Customer Service Department at 800-645-1706.




Please see full prescribing information at back page.
                                       Millions prescribed. Millions treated. ™


     Venofer® is manufactured under license from Vifor (International) Inc., Switzerland. © 2009 American Regent, Inc.
Reimbursement and Patient Assistance Program Hotline: 800-282-7712 • Orders or information: 800-645-1706 • venofer.com



                                                                                                                       2340FM09
                                                                                                                      Rev. 7/2009
         Leading anemia management.™                                                                               Printed in USA
          Venofer®                                                                 Venofer®                                                    Venofer®                                                                     Venofer®
   (iron sucrose injection, USP)                                           (iron sucrose injection, USP)                               (iron sucrose injection, USP)                                               (iron sucrose injection, USP)

                  Rx Only                                                                  Rx Only                                                    Rx Only                                                                       Rx Only



DESCRIPTION                                                                                                                       Study E: Peritoneal DialysisDopendent-Chronic Kidney Disease (PDD-CKD)
Venofer<> (ironsucrose injeclion, USP)is a brown, sterile, aqueous, complex of polynuclear iron(1I1)-hydroxide in sucrose for     StUdy Ewasa randomized [2:1 treatment: contrail, open-label, multicenter studycomparing PDD-CKD patients receiving an
inlravenous use. Ironsucrose injection hasa molecular weight of approximately 34,000 - 60,000 daltons enda proposed               erythropoietin and IV iron to PDD-CKD patients receiving an erythropoietin alone ~thout iron supplementation. 126
structural formula:                                                                                                               patients ~th PDD-CKD, stableerythropoietin for 8 weeks,TSATs 25%, Ferritins 500ng/mL andan average baseline
                                        [Na2FesOa(OH) • 3(H~)ln • m(C12H22011)                                                    hemoglobin of s 11.5g/dLwererandomized to receive eitherno iron or Venofer<> (ironsucrose injection, USP)(300mg in
                                                                                                                                  250mL0.9%NaCI over1.5 hours on Day1 and 15and 400mgin 250mL 0.9%NaCI over2.5 hours on Day29). 121 of
where: n is the degree of iron polymerization and m is the number of sucrose molecules associated ~th the iron (111)­             the 126randomized patients weretreated andfollowed for up to 71days~th a totalof 88patients whocompleted thestudy.
hydroxide.                                                                                                                        Efficacy assessments were measured on days 15, 29, 43, 57 and 71. Patient demographic characteristics were not
EachmLcontains 20 mgelemental ironas ironsucrose in waterfor injeclion. Venofer<> is available in 5 mLsingle dosevials            significantly different between thegroups. Themean ageof the75 treated patients in theVenofer<> I erythropoietin group was
(100mgeiemental ironper5 mL)and10mLsingle dosevials(200mgelemental ironper10mL), Thedrugproducl contains                          51,9years(range 21 to 81 years) vs. 52.8years(range 23 to 77 years) for 46 patients in the erythropoietin alonegroup,
apprOXimately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5-11.1. The product contains no preservatives. The                   Ethnicity breakdown ofthepetients in theVenofer<>1 erythropoietin Group wasas follows: Caucasian (36%); Hispanic (32%);
osmolarity of the injection is 1,250mOsmoVL.                                                                                      Black(21.3%); Other(10.7%). Ethnicity breakdown for the erythropoietin alonegroup was: Hispanic (43,5%); Caucasian
Therapeutic class: Hematinic                                                                                                      (30.4%); Biack (15.2%); Ofher(10,9%). Patients in theVenofer<> 1 erythropoietin group hadstatistically significantly greater
                                                                                                                                  mean change frombaseline to the highest hemoglobin value (1.3g/dL), compared to subjects who received erythropoietin
CLINICAL PHARMACOLOGY                                                                                                             alone (0.6g/dL)(p < 0.01). A statistically significantly greater proportion of subjects treated ~th Venofer<> 1 erythropoietin
Phannacodynamics: FolI~ng intravenous administration ofVenafer<>, ironsucrose is dissociated bythereticuloendothelial             (59.1 %) had an inaease in hemoglobin of 2 1 g/dLat any time during the stUdy compared to the subjecls who received
system into iron and sucrose. In 22 hemodialysis patients on erythropoietin (recombinant human erythropoietin) therapy            erythropoietin only(33,3%) (p < 0,05),
treated ~th ironsucrose containing 100mg of iron,threetimesweekly for three weeks, significant increases in serum iron
and serum ferritin and significant decreases in total iron binding capacity occurred four weeks fromthe initiation of iron        CUNICALINDICATIONS ANDUSAGE

sucrose treatment.                                                                                                                Venofer<> is indicated in thetreatment of irondeficiency anemia in thefollowing patients:

                                                                                                                                  • non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving an erythropoietin
Phannacokinetics: In healthy adults treated ~th intravenous dosesof Venofer<>, its iron component exhibits first order

                                                                                                                                  • non-dialysis dependent-chronic kidney disease (NDD-CKD) patients notreceiving anerythropoietin
kinetics ~th an elimination half-life of 6 h, totalclearance of 1.2 Uh, non-steady state apparent volume of distribution of

10,0Landsteady state apparent volume of distribution of7,9 L.Since irondisappearance fromserum depends ontheneed
                 • hemodialysis dependent-chronic kidney disease (HDD-CKD) patients receiving anerythropoielin
for ironin the ironstores andiron utilizing tissues of the body, serum clearance of ironis expected to bemore rapid in iron
      • peritoneal dialysis dependent-chronic kidney disease (PDD-CKD) patients receiving anerythropoietin.
deficient patients treated ~th Venofer<> as compared to healthy individuals, The effects of age and gender on the
                CONTRAINDICATIONS

phannacokinetics of Venofer<> havenotbeen studied.
                                                                               Theuseof Venofer<> is contraindicated in patients withevidence of ironoverload, in patients ~lh known hypersensitivity to

Venofer<> is not dialyzable through CA210 (Baxter) HighEfficiency or Fresenius F80AHighFluxdialysis membranes. In in
             Venofer<> or anyof its inactive components, andin patients ~th anemia not caused by irondeficiency.

vitrostudies, theamount of ironsucrose in thedialysate fluidwasbelowthelevels of detection oftheassay (iessthan2 parts
           WARNINGS

permillion),
                                                                                                                     Hypersensitivity reactions have been reported      ~th    injectable iron products,     See PRECAUTIONS and ADVERSE

                                                                                                                                  REACTIONS,

Distribution: In heallhy adullsreceiving intravenous doses of Venofer<>, its iron component appears to distribute mainly in

bloodandto someexlentin extravascular fluid, A studyevaluating Venofer<> containing 100mgof ironlabeled with52FelS        9Fe
    PRECAUTIONS

in patients with iron deficiency shows thata significant amount of the administered iron distributes in the liver, spleen and
    General:

bonemanrow andthatthe bonemarrow is an irontrapping compartment andnot a reversible volume of distribution,
                      Because bodyironexcretion is limited andexcess tissueironcanbehazardous, caution should be exercised to ~thhold iron

                                                                                                                                  administration in the presence of evidence of tissue ironoverload. Palients receiVing Venofer<> require periodic monitoring of

Metabolismand Elimination: FolI~ng intravenous administration of Venofer<>, iron sucrose is dissociated into ironand
             hematologic and hematinic parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Iron therapy

sucrose by the reticuloendothelial system. The sucrose component is eliminated mainly by urinary excretion, In a study
           should be ~thheld in patienls ~th evidence of iron overload. Transferrin saturation values increase rapidly after IV

evaiuating a singleintravenous doseof Venofer<> containing 1,510mg of sucrose and 100mg of ironin 12 healthy adults
              administration of ironsucrose; thus,serum iron values maybe reliably obtained 48 hours afterIV dosing, (SeeDOSAGE

(9female, 3 male: agerange 32-52), 68.3% ofthesucrose waseliminated in urine in 4 hand 75.4% in 24 h, Some ironalso
              ANDADMINISTRATION andOVERDOSAGE),

is eliminated intheurine, Neither transferrin nortransferrin receptor levelschanged immediately afterthedoseadministration

[1].In thisstudyandanother studyevaluating a single intravenous doseof ironsucrose containing 500-700 mg of ironin 26
            HypersensitivityReaelions:

anemic patients onerythropoietin therapy (23female, 3 male; agerange 16-60), approximately 5%oftheironwaseliminated
              Serious hypersensitivity reactions havebeen reported in patients receiving Venofer<>. No life-threatening hypersensitivity

in urinein 24 h at eachdoselevel[2].
                                                                                             reactions were observed inthecJinical studies. Several cases ofmild ormoderate hypersensitivity reactions mrs observed

                                                                                                                                  in thesestudies. Thereare post-marl<eting spontaneous reports of life-threatening hypersensitivity reactions in patients

Drug-drugInteraelions: Drug-drug interactions involving Venofer<> havenot been studied. However, like otherparenteral
            receiving Venofer<>. SeeADVERSE REACTIONS.

ironpreparations, Venofer<> maybe expected to reduce theabsorption of concomitantly administered oralironpreparations.

                                                                                                                                  Hypotension:

CLINICAL TRIALS
                                                                                                                  Hypotension hasbeen reported frequently in hemodialysis dependent-chronic kidney disease patients receiving intravenous

Venofer<> is used to replenish body iron stores in non-dialysis dependent-chronic kidney disease (NDD-CKD) patients
              iron. Hypotension also has been reporled in non-dialysis dependent and peritoneal dialysis dependent-chronic kidney

receiving erythropoietin and in NDD-CKD patients not receiving erythropoietin, and in hemodialysis dependent-chronic
             disease patients receiving intravenous iron. Hypotension foll~ng administration of Venofer<> may be related to rate of

kidney disease (HDD-CKD) and peritoneal dialysis dependent-chronic kidney disease (PDD-CKD) patients receiving
                   administration and totaidoseadministered, Caution should be taken to administer Venofer<> according to recommended

erythropoietin. Iron deficiency may be caused by blood loss during dialysis, increased erythropoiesis secondary to
               guidelines. SeeDOSAGE ANDADMINISTRATION.

erythropoietin use, and insufficient absorption of iron from the gastrointestinal tract. Iron is essential to the synthesis of

hemoglobin to maintain oxygen transport andto thefunction andformaton of otherphysiologically important heme andnon­
             Carcinogenesis, Mutagenesis, and Impairmentof Fertility:

heme compounds. Mostdialysis patients require intravenous ironto maintain sufficient ironstores,
                                 Nolong-tenn studies in animals havebeenperfonned to evaiuate thecarcinogenic potential of Venofer<>.

Sixclinical trialswereconducted to assess the safety andefficacy of Venofer<>. Fivestudies wereconducted in the United
           Venofer<> was not genotoxic in theAmestest,the mouse lymphoma cell (L5178YfTK+I-) forward mutation test, the human

States (516patients) andonewasconducled in South Africa (131 patients).
                                                          lymphocyte chromosome aberration test, orthemouse micronucleus test.
StudyA: Hemodialysis Dopendent-Chronic Kidney Disease (HDD-CKD)
                                                                  Venofer<> at IV doses up to 15 mgiron/kg/day (about 1.2timesthe recommended maximum human doseon a bodysurface

StUdy A wasa mullicenter, open-label, historically-controlled stUdy in 101 hemodialysis patients \T7 patients ~th Venofer<>
      areabasis) wasfound to haveno effectonfertility andreproduclive perfonnance of maleandfemale rats.

treatment and24 in the historical control group) ~th iron deficiency anemia. Eligibility for Venofer<> treatment included
        Pregnancy CategoryB:

patients undergoing chronichemodialysis threelimesweekly, receiving erythropoietin, hemoglobin concentration greater
             Teratology studies havebeen perfonned in ratsat IV dosesup to 13 mg iron/kg/day (about 0.5 times the recommended

than8.0andlessthan11.0g/dLfor at leasttwo consecutive weeks, transferrin saturation < 20%,andserum ferritin < 300
                maximum human doseon a bodysurface areabasis) and rabbits at IV doses up to 13 mg iron/kg/day (about 1 timesthe

ng/mL. Themean ageof the patients in thetreatment groupwas65 years~th theagerange being31 to 85yearsof age.
                      recommended maximum human doseon a bodysurface areabasis) andhevereveaied no evidence of impaired fertility or

 The erythropoietin dosewas to be held constant throughoul the study, The protocol did not require administration of a
           harmto the fetus due to Venofer<>, There are, however, no adequate and well controlled studies in pregnant women.

testdose;however, some patients received a testdoseat the physician'S discretion. Exclusion criteria included significant
        Because animal reproduclion studies are not always predictive of human response, this drug should be used during

underlying disease, asthma, activeinflammatory disease, or serious bacterial or viralinfection. Venofer<> 5 mLcontaining
         pregnancy onlyif ciearly needed.

100mg of elemental ironwas administered through the dialysisline at eachdialysis session eitheras slowinjection or a
             NursingMothers:

saline diluted slowinfusion for a totalof 10dialysis sessions ~th a cumulative doseof 1,000 mgelemental iron, A maximum
          Venofer<> is excreted in milkof rats, It is not known whether thisdrugis excreted in human milk.Because manydrugs are

of 15 mLs(300mg of elemental iron)of Venofer<> wasadministered perweek,
                                                          exaeted inhuman milk, caution should beexercised lNhen venofer«> isadministered toa nursing woman.
Noadditional ironpreparations wereallowed untilaftertheDay57evaluation. Themean change in hemoglobin frombaseline
                PediatricUse:
to Day24 (endof treatment), Day36, andDay57 wasassessed, Thehistorical control population consisted of 24 patients
               Safety andeffectiveness ofVenofer<> in pediatric patients havenotbeen established. In a country where Venafer<> is available
~th similarferritin levels as patients treated ~th Venofer<>, whowereoff intravenous ironfor at leasl2 weeks andwhohad
           for usein children, at a single site,fivepremature infants (weight lessthan1,250g) developed necrotizing enterocolitis and
received erythropoietin therapy ~Ih hematocrit averaging 31-36for at leasttwo rnomhs priorto stUdy entry. Themean age
            two of the five expired during or follo~ng a period when they received Venofer<>, several other medications and
of patients in the historical control groupwas56years, ~th an agerange of 29 to 80 years. Patient ageandserum ferritin
           erythropoietin. Necrotizing enterocolitis may be a complication of prematurity In verylow birth weight infants, No causal
levelweresimilar between treatment andhistorical control patients. Ofthe77patients in thetreatment group, 44(57%) were
           relationship toVenofer<> oranyother drugs could be established,
maleand33 (43%) werefemale. The mean baseline hemoglobin andhematocrit, werehigheranderythropoietin dosewas

lowerin the historical control population thantheVenofer<> treated population.
                                                   Geriatric Use:
                                                                                                                                  Studies A through E did not include sufficient numbers of subjects aged 65 years and older to detennine whether they
Patients in theVenofer<> treated population showed a statistically significantly greater increase in hemoglobin andhematocrit
    respond differently fromyounger subjects. Ofthe 1,051 patients in two post-marl<eting safetystudies of Vena
                                                                                                                                                                                                                                            fer<>, 40%were
thandid patients in the historical control population. SeeTable 1.
                                                               65years andolder, Nooverall differences in safety wereobserved between these SUbjects andyounger SUbjects, andother
Table1. Changesfrom Baselinein Hemoglobin and Hematocrit
                                                                         reported clinical experience hasnotidentified differences in responses between theelderly andyounger patients, butgreater
                                                                                                                                  sensitivity of some olderindividuals cannot be ruledout.
                               End of Treatment                 2 Week follow-up                   5 week follow-up
                                                                                                                                  ADVERSE REACTIONS
       Efficacy                             Historical                       Historical                        Historical         AdverseEventsobservedin atl treated populations
      parameters            Venofer0                         Venofer'>                         Venofer0                           Thefrequency ofadverse events associated ~th the useofVenofer<> hasbeen documented in sixrandomized clinical trials
                             (n=69)          Control          (n=73)          Control           (n=71)          Control
                                             (n=18)                           (n=18)                            (n=15)            involving 231hemodialysis dependent, 139non-dialysis dependent and75 peritoneal dialysis dependent-CKD patients; and
                                                                                                                                  in two post-marketing sefetystudies involving 1,051 hemodialysis dependent-CKD patients for a totalof 1,496patients. In
 Hemoglobin (g/dL)         1,O±O.12~         0.O±O.21        1.3±O.14~        -{).6±O.24       1.2±O.17"        -{),1±O,23        addition, over2,000 patients treated ~th Venofer<> havebeen reported in the medical literature.
                                                                                                                                  Treatment-emergent adverse events reported by 2 2% of treated patients in the randomized clinical trials, whether or not
 Hematocrit (%)            3,1±O.37~        -{).3±O.65       3.6±O,44~        -1.2±O.76        3,3±O.54         0.2±O,86          related to Venofer<> administration, arelistedby indication in Table 2.
                                                                                                                                  Table 2. Most CommonTreatment-Emergent Adve.... Events Reported in 2 2% of Patients By Clinical Indication
~p<0.01  and ·p<0,05compared to historical control fromANCOVA analysis          ~th   baseline hemoglobin, serum ferritin and     (MultidoseSafetyPopulation)
erythropoietin doseas covariates.
                                                                                                                                  "NOS= Nototherwise specified
Serum ferritin increased significantly (p=0.0001) at endpoint of study from baseline in the Venofer<>-treated population
(165.3±24,2 ng/mL) compared to the historical control population (-27.6±9.5 ng/mL). Transferrin saluration also increesed                                                            HDD-CKD                   NDD-CKD                      PDD-CKD
significantly (p=0,0016) at endpoint of stUdy frombaseline in theVenofer<>-treated population (8.8±1.6%) compared to this
                                                                                                                                                Adverse Events
historical control population (-5.1±4.3%) [3J.                                                                                                 (Preferred Tenm)                      Venofer0          Venofer'>        Oral Iron    Venofer0    EPOOnly
                                                                                                                                                                                     (N=231)           (N=139)          (N=139)       (N=75)      (N=46)
StudyB: HemodialysisDopendent-Chronic Kidney Disease (HDD-CKD)                                                                                                                          %                 %                %            %           %
StUdy B was a multicenter, open label studyof Venofer<> (iron sucrose injection, USP) in 23 iron deficient hemodialysis
patients whohadbeendiscontinued fromirondexlran dueto intolerance, Eligibility criteria andVenofer<> administration were          Subjects with any adverse event                                         76.3            73.4         72.0          65.2
                                                                                                                                                                                        78.8
otherwise idenlical to Study A. Themean ageof thepatients in thisstUdy was53years, withagesranging from21-79years,
Ofthe23 patients enrolled in thestudy, 10(44%) weremaleand13(56%) werefemale. Theethnicity breakdown of patients                  Ear and Labyrinth Disorders
enrolled in thisstudywasas follows: Caucasian (35%); Black (35%); Hispanic (26%); Asian (4%), Themean change from                  Ear Pain                                                0              2.2              0.7          0              0
baseline to the endof treatment (Day24) in hemoglobin, hematocrit, andserum ironparameters wasassessed.
                                                                                                                                  Eye Disorders
All 23 enrolled patients wereevaluated for efficacy. Statistically significant increases in mean hemoglobin (1.1±O.2 g/dL),
                                                                                                                                   Conjunctivitis                                          0.4             0                0          2,7             0
hematocrit (3.6±O.6%), serum ferritin (286.3±30.3 ng/mL) andtransferrin saturation (8.7±2.0%) wereobserved frombaseline
to endof treatment [4J.
                                                                                                                                  Gastrointestinal Disorders
Study C: HemodialysisDopendent-Chronic Kidney Disease (HDD-CKD)                                                                    Abdominal pain NOS"                                  3.5               1.4             2.9          4.0            6.5
Study C was a multicenter, open-label, two period (treatment foilowed by observation period) study in iron deficient               Constipation                                          1.3              4.3             12.9         4.0            6.5
hemodialysis patients. Eligibility for this studyincluded chronic hemodialysis patients ~th a hemoglobin lessthanor equai          Diarrhea NOS                                         5,2               7,2             10.1         8.0            4.3
to 10 g/dL, a serum transferrin saturation lessthanor equal to 20%,anda serum ferritin lessthanor equal to 200ng/mL,               Dysgeusia                                            0.9               7.9              0            0              0
whowereundergoing maintenance hemodialysis 2 to 3 timesweekly. Themean age of the patients enrolled in this study                  Nausea                                               14.7              8,6             12,2         5.3            4.3
was41years, ~th agesranging from 16-70 years. Of 130patients evaluated for efficacy in thisstudy, 68 (52%) weremale                Vomiting NOS                                         9.1               5.0             8,6          8.0            2.2
and62 (48%) werefemale. The ethnicity breakdown of patients enrolled in this stUdy wasas follows: Caucasian (23%);
Black (23%); Asian (5%); Other(mixed ethnicity) (49%). Forty-eight percent of thepatients hadpreviously beentreated ~th           General Disorders and
oraliron.Exclusion criteria weresimilar to those in Studies A andB. Venofer<> wasadministered in doses of 100mg during            Administration Site Conditions
sequential dialysis sessions untila pre-detennined (celcelateo) totaldoseof ironwasadministered,                                   Asthenia                                                2.2            0.7              2.2         2.7            0
                                                                                                                                   Chest pain                                              6.1            1.4               0          2.7            0
Patients received Venofer<> at eachdialysis session, twoto threetimesweekly. Onehourafterthestartof eachsession,S                                                                          0.4            6,5              6.5          0            2.2
                                                                                                                                   Edema NOS
mLironsucrose (100mgiron)in 100mL 0.9%NaCI wasadministered intothe hemodialysis line. A 50 mgdose(2.5mL)                                                                                   1.7            3,6              5.8          0            4.3
wasgivento patients ~thin two weeksof studyentry. Patients weretreated untiltheyreached anindividually calculated totai            Fatigue
                                                                                                                                   Feeling abnormal                                        3.0             0                0           0             0
irondosebased on baseline hemoglobin levelandbodyweight. Twenty-seven patients (20%) werereceiving erythropoietin                                                                           0             3.6               0           0             0
                                                                                                                                   Infusion site buming
treatment at studyentryandtheycontinued to receive the same erythropoietin dosefor the duration of thestUdy.                                                                                0             2.2               0           0             0
                                                                                                                                   Injection site extravasation
Changes frombaseline to observation week2 andobservation week4 (endof study) wereanalyzed,                                         Injection site pain                                      0             2,2               0           0             0
Themodified intention-to-treat populaton consisted of 131 patients. Significant (p<0.0001) increases frombaseline in mean          Peripheral edema                                        2.6            7.2              5,0         5.3           10,9
hemoglobin (1.7g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), andserum transferrin saturation (14%) wereobserved            Pyrexia                                                 3.0            0.7              0.7         1.3            0
at week 2 of the observalion period and these values remained significantly increased (p<0,0001) at week 4 of the
observalion period.                                                                                                                Infections and Infestations
                                                                                                                                     Catheter site infection                                0              0                0          4.0           8.7
Study 0: Non-DialysisDopendent-Chronic Kidney Disease (NDD-CKD)                                                                                                                                                                        2.7
                                                                                                                                     Nasopharyngitis                                       0.9            0.7              2.2                       2.2
StUdy D was a randomized, open-label, multicenter, active-controlled studyof the safety and efficacy of oral iron versus
                                                                                                                                     Peritoneal infection                                   0              0                0          8.0           10.9
intravenous ironsucrose (Venofer<» in NDD-CKD patients ~th or ~thout erythropoietin therapy. Erythropoietin therapy was
                                                                                                                                     Sinusitis NOS                                          0             0.7              0.7         4.0            0
stabiefor 8 weeks priorto randomization. In the study188patients ~th NDD-CKD, transferrin saturation s 25%,ferritin
                                                                                                                                     Upper respiratory tract infection NOS                 1.3            0.7              1.4         2.7           2.2
s 300ng/mLandanaverage baseline hemoglobin ofs 11.0g/dLwererandomized to receive oraliron(325mgferrous sulfate                                                                                                             5,0
                                                                                                                                     Urinary tract infection NOS                           0.4            0.7                          1.3           2,2
threetimes dailyfor 56 days); or Venofer<> (either200mg over2-5 minutes 5 times ~thin 14 daysor two 500mginfusions
on Day1 and Day14,administered over3,5-4hours). Of the 188randomized patients, 182weretreated andfollowed for                      Injury, Poisoning and
up to 56 days. Efficacy assessments weremeasured on days14,28, 42 and56. The mean ageof the 91treated patients                     Procedural Complications
in theVenofer<> groupwas61.6years(range 25 to 86years) and64 years(range 21to 86years) for the91 patients in the                     Graft complication                                    9.5             1.4              0           0              0
oralirongroup, Ethnicity breakdown ofthepatients in theVenofer<> group wasasfollows: Caucasian (60.4%), Black(34,1%),
Hispanic (3.3%), Other(2,2%). Ethnicity breakdown fortheoralirongroup was:Caucasian (50.5%), Black(44.0%), Hispanic                Investigations
(4.4%), Other(1,1%), Patient demographic characteristics werenotsignificantly different between thegroups. Astatistically            Cardiac murmur NOS                                    0.4             2.2             2,2          0              0
significantly greater proportion of Venofer<> subjects (35179; 44.3%) compared to oral iron SUbjects (23/82; 28%) had an             Fecal occult blood positive                            0              1.4             3,6         2.7            4,3
increase in hemoglobin 2 1 g/dLat anytime during the study(p= 0,03). In patients 2 65 yearsof age,the proportion of
subjecls achieving 2 1.0g/dLincrease in hemoglobin frombaseline was53%(20/38) in theVenofer<> group compared to                   Table 2 continued on reverse side.
23%(10/43) in theoralirongroup. In patients < 65yearsof age,the proportion of subjects achieving 21.0 g/dLinaeasein
hemoglobin from baseline was 37% (15/41) in the Venofer<> group compared to 33% (13/39) in the oral iron group, A
statisticaily significantly greater proportion ofVenofer<> treated patients (31179; 39.2%) compared to oraiirontreated patients
(1/82; 1.2%) hadan increase in hemoglobin 21 g/dLandferritin 2160 ng/mL at anytime during thestudy(p<0.OOO1).
         venoeer»                                                               Venofer®                                          venofer®                                                                 Venofer®

 (iron sucrose injection, USP)                                           (iron sucrose injection, USP)                    (iron sucrose injection, USP)                                            (iron sucrose injection, USP)

                Rx Only                                                                 Rx Only                                          Rx Only                                                                  Rx Only


Table2. Most CommonTreatment-Emergent Adverse Events Reported in ;, 2% of Patients By Clinical Indication            Table 4. Most Common Adverse Events Related to Study Drug Reported in ;, 2% of Patients by Dose Group
(MultidoseSafety Population)- CONTINUED                                                                              (MultidoseSafetyPopulation) - CONTINUED

                                                HDD-CKD                 NDD-CKD                     PDD-CKD                                                   HDD-CKD                        NDD-CKD                        PDD-CKD
              Adverse Events
             (Preferred Term)                   Venofer®       Venofer®        Oral Iron     Venofer®     EPOOnly              Adverse Events                  100mg               200mg               SOOmg          300 mg for 2 doses
                                                (N=231)        (N=139)         (N=139)        (N=75)       (N=46)                                              (N=231)             (N=109)             (N=30)             followed by
                                                   %              %               %             %            %                 (Preferred Term)
                                                                                                                                                                  %                   %                  %            400 mg for 1 dose
 Metabolism and Nutrition Disorders                                                                                                                                                                                         (N=75)
  Fluid overload                                   3.0             1.4            0.7          1.3             a                                                                                                               %
  Gout                                              a              2.9            1.4           a              a     General Disorders and
  HyperglycemiaNOS                                  a              2.9            a             a              2.2   Administration Site
  HypoglycemiaNOS                                  0.4             0.7            0.7          4.0             a     Conditions
 Musculoskeletal and Connec1ive
                                                                                                                      Infusion site burning                        a                  3.7                 a                      a
 Tissue Disorders
                                                                                                                      Injeelion site pain                          a                  2.8                 a                      a
   Arthralgia
                                                                                                                      Peripheraledema                              a                  1.8                6.7                     a
                                                   3.5             1.4            2.2          4.0             4.3
   Arthritis NOS                                    a               a             a             a              4.3    Nervous System Disorders
   Sack pain                                        2.2            2.2            3.6          1.3             4.3     Dizziness                                   a                  2.8                6.7                     a
   Muscle cramp                                    29.4            0.7            0.7          2.7             a       Headache                                    a                  2.8                 a                      a
   Myalgia                                          a              3.6            a            1.3             a
   Pain in extremity                               5.6             4.3            a            2.7             6.5   Vascular Disorders

 Nervous System Disorders
                                                                                                                      HypotensionNOS                              5.2                  a                 6.7                     a
  Dizziness                                        6.5             6.5            1.4          1.3             4.3   'NOS = Notofherwise specified
  Headache                                         12.6            2.9            0.7          4.0             a     AdverseEventsObserved in Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) Patients
  Hypoesthesia                                      a              0.7            0.7           a              4.3   Adverse reaelions, whether or not related to Venofe'" (ironsucrose injeelion. USP) administration. reported by > 5% of
                                                                                                                     treated patients froma totalof231 patients in HDD-CKD Studies A, B,andC wereas follows: hypotension (39.4%), muscle
 Respiratory, Thoracic and
                                                                                                                     cramps (29.4%), nausea (14.7%), headache (12.6%), graft complications (9.5%), vomiting (9.1%), dizziness (6.5%),
 Mediastinal Disorders                                                                                               hypertension (6.5%), chest pain(6.1%), anddiarrhea (5.2%).
  Cough                                            3.0             2.2           0.7           1.3             a     In the firstpost-marKeting safety study, 665chronic hemodialysis patients weretreated with Venofe'"doses of 100mg at
  Dyspnea                                          3.5             3.6           0.7           1.3             2.2
                                                                                                                     eachdialysis session for up to 10 consecutive dialysis sessions for theiriron deficiency or on a weekly basis for 10weeks
  Dyspnea exacerbated                               a              2.2           0.7            a              a     for maintenance of iron stores. In this study, 72%of the patients received up to 10 doses, 27%received between 11-30
  Nasal congestion                                  a              1.4           2.2           1.3             a     doses, and1% received 40 to SO doses ofVenofe"'. Serious adverse events anddrug-related non-serious adverse events
  Pharyngitis                                      0.4              a             a            6.7             a     were colleeled. In the seoond post-marKeting safety study, 386 hemodiaiysis patients wereexposed to a single dose of
  Rhinitis allergic NOS                             a              0.7           2.2            a              a     Venofe'"(100mg IV by slowinjeelion over2 minutes or 200 mg IV by slowinjeelion over5 minutes). The mean ageof
 Skin and Subcutaneous lissue                                                                                        patients enrolled intothe twopost-marKeting safetystudies was59 years, witha range of 2()'93years. Malesmade up60%
 Disorders                                                                                                           of the population. The ethnicity of the patients enrolled in the two studies included Blacks (44%), Caucasians (41 %),
   Pruritus                                        3.9             2.2           4.3           2.7             a     Hispanics (11%), Asians (3%), andothers (1%). Adverse events reported by > 1%of 1,051 treated patients were: cardiac
   Rash NOS                                        0.4             1.4           2.2            a              2.2   failure congestive, sepsis NOSanddysgeusia.
                                                                                                                     AdverseEventsObserved in Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) Patients
 Vascular Disorders
                                                                                                                     In Study D of 162treated NDD-CKD patients, 91 were exposed to Venofe"'. Adverse events, whether or not related to
   Hypertension NOS                                6.5             6.5           4.3           8.0             6.5   Venofe"', reported by;, 5%oftheVenofe'" exposed patients wereas follows: dysgeusia (7.7%), peripheral edema (7.7%),
   Hypotension NOS                                 39.4            2.2           0.7           2.7             2.2   diarrhea (5.5%), oonstipation (5.5%), nausea (5.5%), dizziness (5.5%), and hypertension (5.5%). One serious related
 NOS= Nototherwise specified
                                                                                        adverse reaelion wasreported (hypotension andshortness of breath notrequiring hospitalization in a Venofe'"patient). Two
                                                                                                                     patients experienced possibie hypersensitivity/allergic reaelions (local edema/hypotension) during the study. Of the 5
Treatment-emergent adverse events reported in ;, 2% of patients by dosegroupareshown in Table 3.

                                                                                                                     patients who prematurely discontinued the treatment phase of the studydueto adverse events (2 oral iron groupand 3
Table3. Most CommonTreatment-Emergent AdverseEventsReported in ;,2% of Patientsby DoseGroup(Multidose
               Venofe'"group), threeVenofe'"patients hadevents thatwereconsidered drug-reiated (hypotension, dyspnea andnausea).
Safety Population)
                                                                                                  In an additional study of Venofe.., with varying erythropoietin doses in 96 treated NDD-CKD patients, adverse events,
                                                                                                                     whether or notrelated toVenofe'"reported by 2 5%of Venofe'"exposed patients areas follows: diarrhea (16.5%), edema
                                                   HDD-CKD                   NDD-CKD                 PDD-CKD         (16.5%), nausea (13.2%), vomiting' (12.1%), arthralgia (1.7%), backpain (1.7%), headache (7.7%), hypertension (7.7%),
                                                                                                                     dysgeusia (1.7%), dizziness (6.6%), extremity pain (5.5%), and injeelion site buming (5.5%). No patient experienced a
               Adverse Events                        100mg         200mg          500mg        300 mg for 2 doses    hypersensitivity/allergic reaction during the stUdy. Of thepatients whoprematurely discontinued thetreatment phase of the
               (Preferred Term)                      (N=231)       (N=109)        (N=30)          followed by        studydueto adverse events (2.1% oralirongroupand12.5% Venofe'"group), onlyonepatient (Venofe'"group) hadevents
                                                       %             %              %          400 mg for 1 dose     thatwereconsidered drug-related (anxiety, headache, andnausea). Ninety-one (91)patients in thisstudywereexposed to
                                                                                                     (N=75)          Venofe'"eitherduring thetreatment or extended follow-up phase.
                                                                                                       %             AdverseEventsObserved in Peritoneal DialysisDependent-Chronic Kidney Disease (PDD-CKD) Patients
 Subjects with any adverse event                                                                                     in StUdy E of 121 treated PDD-CKD patients, 75patients wereexposed to Venofe"'. Adverse events, whether or notrelated
                                                        78.8         75.2           80.0                72.0
                                                                                                                     to Venofe'" reported by z 5% of these patients are as follows: diarrhea, peritoneal infection, vomiting, hypertension,
 Ear and Labyrinth Disorders                                                                                         pharyngitis, peripheral edema andnausea.
  Ear Pain                                                a             0.9           6.7                a           In these 75 patients exposed to Venofe"', 9 patients experienced serious adverse events as follows: peritoneal infeelion (2
                                                                                                                     patients) and 1 patient eachwith cardiopulmonary arrest, myocardiai infarelion, upperrespiratory infeelion NOS, anemia,
 Eye Disorders                                                                                                       gangrene, hypovolemia and tuberculosis. None of these events were considered drug-related. TwoVenofe'" patients
  Conjunctivitis                                         0.4             a              a               2.7          experienced a moderate hypersensitivity/allergic reaction (rashor sweliinglitching) during thestudy.
 Gastrointestinal Disorders                                                                                          Theonlydrugrelated adverse reaction to Venofe'"administration reported by 2 2% of patients wasdiarrhea.
  Abdominal pain NOS·                                   3.5             1.8             a               4.0          Three patients in the Venofe,., studygroupdiscontinued study treatment due to adverse events (cardiopuimonary arrest,
  Constipation                                          1.3             3.7           6.7               4.0          peritonitis andmyocardial infarelion, hypertension) which wereconsidered to benotdrug-reiated.
  DiamheaNOS                                            5.2             6.4           10.0              8.0          HypersensitivityReactions: SeeWARNINGS andPRECAUTIONS.
  Dysgeusia                                             0.9             9.2           3.3                a           In clinical studies, several patients experienced hypersensitivity reactions presenting withwheezing, dyspnea, hypotension,
  Nausea                                                14.7            9.2           6.7               5.3          rashes, or pruritus. Serious episodes of hypotension occurred in 2 patients treated withVenofe'"at a dose of 500mg.
  Vomiting NOS                                          9.1             5.5           3.3               8.0
                                                                                                                     Thepost-marKeting spontaneous reporting system inciudes reports of patients who experienced serious or life-threatening
General Disorders and                                                                                                reaelions (anaphylaelic shock, lossof consciousness or collapse, bronchospasm withdyspnea, or convulsion) associated
Administration Site Conditions                                                                                       withVenofe'"administration.
 Asthenia                                                2.2            0.9             a               2.7          Onehundred thirty(11%) of the 1,151 patients evaluated in the 4 U.S. trialsin HDD-CKD patients (studies A, B andthe two
 Chest pain                                              6.1            0.9           3.3               2.7          postmarketing studies) hadpriorotherintravenous irontherapy andwerereported to be intolerant (defined as precluding
 Edema NOS                                               0.4            7.3           3.3                a           further use of that iron produel). When these patients were treated with Venofe'"therewereno occurrences of adverse
 Fatigue                                                 1.7            4.6          a                   a           events thatprecluded further useof Venofe"'.
 Feeling abnormal                                        3.0             a           a                   a           OVERDOSAGE
 Infusion site burning                                    a             3.7           3.3                a           Dosages ofVenofe'"(ironsucrose injeelion, USP) in excess of ironneeds mayleadto accumulation of ironin storage sites
 Injection site pain                                      a             2.8          a                   a           leading tohemosiderosis. Periodic monitoring ofiron parameters such asserum fanilin and transferrin saturation may assist
 Peripheral edema                                        2.6            5.5         13.3                5.3
                                                                                                                     in recognizing iron accumulation. Venofe'" should not be administered to patients with iron overload and should be
   Pyrexia                                               3.0            0.9          a                  1.3
                                                                                                                     discontinued whenserum ferritin levelsequal or exceed established guidelines [5). Particular caution should beexercised to
Infections and Infestations                                                                                          avoid iron overload where anemia unresponsive totreatment has been incorrectly diagnosed asiron deficiency anemia.
  Catheter site infection                                 a              a              a               4.0          Symptoms associated withoverdosage or infusing Venofe'"toorapidly included hypotension, dyspnea, headache, vomiting,

  Nasopharyngitis                                        0.9            0.9             a               2.7          nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. Most

  Perrtoneal infection                                    a              a              a               8.0          symptoms havebeen successfully treated with IV fluids, hydrocortisone, and/orantihistamines. Infusing the solution as

  Sinusitis NOS                                           a              a            3.3                4           recommended or at a slower ratemayalsoalleviate symptoms.

  Upper respiratory trael infeelion                      1.3            0.9             a               2.7          PreclinicalData:

Injury, Poisoning and                                                                                                Single IV doses of Venofe'"at lSOmgiron/kg in mice (about 3 timesthe recommended maximum human doseon a body

                                                                                                                     surface areabasis) and 100mgiron/kg in rats(about 6 timesthe recommended maximum human dose on a body surface

Procedural Complications                                                                                             areabasis) werelethal.

  Graft complication                                     9.5            1.8             a                a
                                                                                                                     Thesymptoms of acute toxicjty weresedation, hypoaelivity, paleeyes, andbleeding in thegastrointestinal tractandiungs.

Investigations                                                                                                       DOSAGE ANDADMINISTRATION

  Cardiac mumnur NOS                                     0.4            2.8             a                a           Thedosage ofVenofe'"is expressed in terms of mgof elemental iron. Each mLcontains 20 mgof elemental iron.

  Fecal occult blood positive                             a             1.8             a               2.7
                                                                                                                     Most CKD patients will require a minimum cumulative repletion dose of 1,000 mg of elemental iron, administered over

 Metabolism and Nutrition Disorders                                                                                  sequential sessions, to achieve a favorable hemoglobin response andto replenish ironstores (ferritin, TSAl). Hemodialysis

                                                         3.0            1.8             a               1.3          patients maycontinue to require therapy withVenofe'"or otherintravenous ironpreparations at thelowest dosenecessary

  Fluid overload
                                                          a             1.8           6.7                a           to maintain target ievelsof hemoglobin, andlaboratory parameters of ironstorage within acceptable limits.

  Gout
  Hyperglycemia NOS                                       a             3.7             a                a           Administration:Venofe'"mustonlybe administered intravenously eltharby slowinjection or by infusion.

  Hypoglycemia NOS                                       0.4            0.9             a               4.0          Recommended Adult Dosage:

                                                                                                                     Hemodialysis Dependent-Chronic Kidney Disease Patients (HDD-CKD): Venofe'"maybe administered undiluted as a

Musculoskeletal and Connective
                                                                                                                     100mgslowintravenous injection over2 to 5 minutes or as an infusion of 100mg,diluted in a maximum of 100mLof 0.9%

lissue Disorders
                                                                                                                     NaCi overa period of at least15 minutes per oonsecutive hemodialysis session for a totalcumulative doseof 1,000 mg.

  Arthralgia                                            3.5             0.9           3.3               4.0
   Sack pain                                             2.2            1.8           3.3               1.3          Non-Dialysis Dependent-Chronic Kidney Disease Patients(NDD-CKD): Venofe'"is administered as a totalcumulative

  Muscle cramp                                          29.4             a            3.3               2.7          doseof 1,000mg overa 14dayperiod as a 200mg slowIV injeelion undiluted over2 to 5 minutes on5 different occasions

  Myalgia                                                 a             2.8           6.7               1.3          within the 14day period. There is limited experience withadministration of an infusion of SOO mg of Venofe"', diluted in a

   Pain in extremity                                     5.6            4.6           3.3               2.7          maximum of250mLofO.9% NaCI, overa period of3.5-4hours onday1 andday14;hypotension occurred in 2 of30patients

                                                                                                                     treated. (SeeCLINICAL TRIALS, Study 0: Non-Dialysis Dependenl-Chronic Kidney Disease (NDD-CKD) Patientsand

 Nervous System Disorders                                                                                            ADVERSE REACTIONS, Adverse EventsObserved in Non-Dialysis Dependent Chronic Kidney Disease (NDD-CKD)

  Dizziness                                             6.5             5.5         10.0                1.3          Patientssections.)

  Headacihe                                             12.6            3.7             a               4.0          Peritoneal Dialysis Dependenl-Chronic Kidney Disease Patients (PDD-CKD): Venofe'" is administered as a total

 Respiratory, Thoracic and                                                                                           cumulative dose of 1,000 mg in 3 divided doses, givenby slowintravenous infusion, wrthin a 28 dayperiod: 2 infusions of

 Mediastinal Disorders                                                                                               300mgover1.5hours 14daysapart followed byone400mgInfusion over2.5hours 14dayslater. TheVenofe'"doseshould

                                                                                                                     be diluted in a maximum of 250mLof 0.9%NaCI.

  Cough                                                  3.0            0.9           6.7               1.3
  Dyspnea                                                3.5            1.8           10.0              1.3          HOWSUPPLIED

  Pharyngitis                                            0.4             a              a               6.7          Venofe'"is supplied in 5 mLand 10 mLsingle dosevials. Each 5 mLvialcontains 100mgelemental iron(20mg/mL) and

                                                                                                                     each 10 mL vial contains 200 mg elemental iron(20 mg/mL). Contains no preservatives. Store in original carton at 25'C

 Skin and Subcutaneous lissue Disorders                                                                              (77'F). Excursions permitted to 15'-30'C (59'-86'F).[Seethe USPoontrolled room temperature]. Donot freeze.

  Pruritus                                               3.9            0.9           6.7               2.7
                                                                                                                     Sterile
 Vascular Disorders                                                                                                  NDC-0517-234()'01             100mg/5mLSingle Dose Vial                Individually Boxed
  Hypertension NOS                                      6.5             6.4           6.7               8.0          NDC-0517-234()'10             100mg/5mLSingle Dose Vial                Packages of 10
  Hypotension NOS                                       39.4            0.9           6.7               2.7          NDC0517-234()'25              100mg/5mLSingle Dose Vial                Packages of 25
'NOS = Nototherwise specified                                                                                        NDC-0517-231()'01            200mg/l0 mLSingle Dose Vial               Individually Boxed
Drug related adverse events reported by;, 2%ofVenofe'"treated patients areshown by dose group in Table 4.            NDC-0517-231()'05            200mg/10 mLSingle Dose Vial               Packages of 5
                                                                                                                     NDC-0517-231()'10            200mg/l0 mLSingle Dose Vial               Packages of 10
Table 4. Most Common Adverse Events Related to Study Drug Reported in ;, 2% of Patients by Dose Group
(MultidoseSafetyPopulation)                                                                                          RxOnly
                                                   HDD-CKD                   NDD-CKD                 PDD-CKD         REFERENCES:
                                                                                                                     [1] Danielson, et al.; Drug Research 46:615-621,1996.
               Adverse Events                       100 mg         200 mg         500 mg       300 mg for 2 doses    [2]Anatkov andGekova; Problems of Hem. Bid.Transfsns., MedPhysiocu/ture, 13:295-298, 1970.

               (Preferred Term)                     (N=231)        (N=109)        (N=30)           followed by       [3J Charylan, et al.; Am J Kidney Dis37:30()'307, 2001.

                                                       %             %              %          400 mg for 1 dose     [4] Ven Wyck, et al.; Am J Kidney Dis 36:68-97, 2000.

                                                                                                      (N=75)         [5] National Kidney Foundation. KlDOQI Clinical Praelice Guidelines forAnemia of Chronic Kidney Disease, 2000. Am J

                                                                                                        %            Kidney Dis37:S182-8238, (suppI1)2001.

 Subjects with any adverse event                        14.7         23.9           20.0                10.7
 Gastrointestinal Disorders
                                                                                                                     IN2340ADV
                                                                                                                     Rev. 11/07
                                                                                                                                                                                                                 AMERICAN
   DiamheaNOS'                                           0.9             a              a               2.7                                                                                                      REGENT, INC.
   Dysgeusia                                             0.9            7.3           3.3                a                                                                                                       SHIRLEY, NY 11967
   Nausea                                                1.7            2.8             a               1.3          Venofer4l' is manufaelured underlicense fromWar (Intemational) Inc.,Switzerland.
'NOS = Nototherwise specified

				
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