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					        Take IV iron therapy to a proven place:

Responsewith toleration!


Formulary
    Monograph


  Leading anemia management.™
                                                                             ™
                                        Millions prescribed. Millions treated.
Table of contents:
         I. Key points about Venofer ® (iron sucrose injection, USP)..............................................................................1
       II. Iron deficiency anemia in chronic kidney disease.....................................................................4
      III. Options for effective protocol development ........................................................................................6
                   • 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




Please see Important Safety Information on page 3
and full prescribing information at back page.
                              Please see Important Safety Information on page 3
Leading anemia management.™        and full prescribing information at back page.
                                                                                                              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 adult non-dialysis dependent-
chronic kidney disease (CKD) patients receiving or not receiving an erythropoietin and in adult
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 12 million patients worldwide have received over 240 million units (100 mg equivalents) of
Venofer ®.2 In the United States, over 3 million patients have received over 60 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:
      • Adult non-dialysis dependent-chronic kidney disease (NDD-CKD) patients not receiving
        an erythropoietin
      • Adult non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving
        an erythropoietin
      • Adult hemodialysis dependent-chronic kidney disease (HDD-CKD) patients receiving
        an erythropoietin
      • Adult peritoneal dialysis dependent-chronic kidney disease (PDD-CKD) patients receiving
        an erythropoietin

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. Serious hypersensitivity reactions have been reported in
patients receiving Venofer®.
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

Please see Important Safety Information on page 3
and full prescribing information at back page.
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 Serious hypersensitivity reactions have been reported with Venofer®.
    See Important Safety Information on page 3.

    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

    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.




                                                                          Please see Important Safety Information on page 3
              Leading anemia management.™                                      and full prescribing information at back page.
                                                                                                            3
Contains no dextran polysaccharides
Venofer ® (iron sucrose injection, USP) contains no dextran, modified dextran, or reduced dextran.


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. Serious
hypersensitivity reactions have been reported in patients receiving Venofer®. In clinical
studies, several patients experienced hypersensitivity reactions presenting with wheezing, dyspnea,
hypotension, rashes, or pruritus. The post-marketing spontaneous reporting system includes reports of
patients who experienced serious or life-threatening reactions (anaphylactic shock, loss of consciousness
or collapse, bronchospasm with dyspnea, or convulsion) associated with Venofer® administration.
Hypotension has been reported frequently in non-dialysis dependent-chronic kidney disease (NND-
CKD) patients receiving IV iron. Hypotension following administration of Venofer® may be related to
rate of administration and total dose delivered.
In a multi-dose efficacy study in NDD-CKD patients (N=91), the most frequent adverse events (≥5%)
whether or not related to Venofer® administration, were taste disturbance (7.7%), peripheral edema
(7.7%), diarrhea (5.5%), constipation (5.5%), nausea (5.5%), dizziness (5.5%), and hypertension (5.5%).
In an additional study of Venofer® with varying erythropoietin doses in 96 treated NDD-CKD patients,
adverse events, whether or not related to Venofer® reported by ≥5% of Venofer® exposed patients are
as follows: diarrhea (16.5%), edema (16.5%), nausea (13.2%), vomiting (12.1%), arthralgia (7.7%),
back pain (7.7%), headache (7.7%), hypertension (7.7%), taste disturbance (7.7%), dizziness (6.6%),
extremity pain (5.5%), and injection site burning (5.5%).
In multi-dose efficacy studies in hemodialysis dependent (HDD)-CKD patients (N=231), the most
frequent adverse events (>5%) whether or not related to Venofer® administration, were hypotension
(39.4%), muscle cramps (29.4%), nausea (14.7%), headache (12.6%), graft complications (9.5%),
vomiting (9.1%), dizziness (6.5%), hypertension (6.5%), chest pain (6.1%), and diarrhea (5.2%).
In post-marketing safety studies in HDD-CKD patients (N=1051), the most frequent adverse events
reported (>1%), whether or not related to Venofer® administration, were congestive heart failure,
sepsis, and taste disturbance. 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 (8.0%), peritoneal infection (8.0%), vomiting (8.0%), hypertension (8.0%), pharyngitis
(6.7%), peripheral edema (5.3%), and nausea (5.3%).




Please see Important Safety Information on page 3
and full prescribing information at back page.
4

    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




                                                                              Please see Important Safety Information on page 3
              Leading anemia management.™                                          and full prescribing information at back page.
                                                    5




Please see Important Safety Information on page 3
and full prescribing information at back page.
6

    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 may provide effective anemia management, even in the absence of an
    erythropoietin.

    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%.




                                                                                 Please see Important Safety Information on page 3
               Leading anemia management.™                                            and full prescribing information at back page.
                                                    7




Please see Important Safety Information on page 3
and full prescribing information at back page.
8
    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.




                                                                                                  Please see Important Safety Information on page 3
               Leading anemia management.™                                                             and full prescribing information at back page.
                                                                                                               9
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.126
       • 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.




Please see Important Safety Information on page 3
and full prescribing information at back page.
10
     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




                                                                           Please see Important Safety Information on page 3
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                                                                                                                                                    11
IV. Comparison Chart
Non-Dextran
                                                              Venofer®                                       Ferrlecit®
                                                      (iron sucrose injection, USP)1    (sodium ferric gluconate complex in sucrose injection)156
       Molecular Weight
          Molecular Weight                           34,000 - 60,000 daltons1                      350,000 daltons ± 23,000164
       FDA Approved Indication
          a
            NDD-CKD Anemia                             Yes (first line) Adult                        Not FDA Approved
          b
            HDD-CKD Anemia                   Yes (first line) Adult on erythropoietin    Adult and Pediatric > 6 yrs on erythropoietin
          c
            PDD-CKD Anemia                   Yes (first line) Adult on erythropoietin                Not FDA Approved
       Safety
          “Black Box” Warning                                     No                                              No
          Test Dose Required                                      No                                              No
       Administration
                                                      100 mg over 2 - 5 minutes
                                                     (20 - 50 mg/min) (HDD-CKD)                       125 mg over 10 minutes
           IV Push
                                                      200 mg over 2 - 5 minutes                      (12.5 mg/min) (HDD-CKD)
                                                    (40 - 100 mg/min) (NDD-CKD)                               (Adult)

                                                    100 mg/100 mL 0.9% NaCI
                                                     over 15 mins (HDD-CKD)
                                                                                                 125 mg/100 mL 0.9% NaCI over
           IV Infusion                              300 mg/250 mL 0.9% NaCI
                                                                                                       1 hour (HDD-CKD)
                                                      over 1.5 hrs (PDD-CKD)
                                                                                                            (Adult)
                                                    400 mg/250 mL 0.9% NaCI
                                                      over 2.5 hrs (PDD-CKD)
           IM Injection                                           No                                              No

       Pharmacy Specifications
           Filter Needle                                                                                        Yes165
                                                                  No
           Recommended
                                             7 days at room temperature (25°C ±2°C)
                                               or refrigerated (4°C ±2°C): undiluted,        Unavailable. If diluted in 0.9% NaCl,
           Syringe Stability
                                               or 2-10 mg/mL diluted in 0.9% NaCl              use immediately after dilution
                                                         in plastic syringe*
                                             7 days at room temperature (25°C ±2°C)
                                                     or refrigerated (4°C ±2°C):
          IV Admixture Stability                                                                             Unavailable
                                                     1-2 mg/mL diluted in 0.9%
                                               NaCl in PVC or non-PVC containers*
           Preservative                                          None                                      Benzyl alcohol
                                                          100 mg/5 mL vial
           How Supplied                                                                                62.5 mg/5 mL ampule
                                                         200 mg/10 mL vial




Please see Important Safety Information on page 3
and full prescribing information at back page.
12

     IV. Comparison Chart (cont’d)
     Dextran Derivatives
                                                                                                  UNMODIFIED                                                    MODIFIED166

                                                                         INFeD®                                         Dexferrum®                              Feraheme®
                                                               (iron dextran injection, USP)155                  (iron dextran injection, USP)154           (ferumoxytol) Injection167
                                                                                                                                                        no detectable unmodified dextran
           Molecular Weight
              Molecular Weight                                    165,000 daltons155                                265,000 daltons168                       750,000 daltons167
           FDA Approved Indication
                a
                    NDD-CKD Anemia                             Yes (second line, when oral                      Yes (second line, when oral
                                                             iron therapy is unsatisfactory                    iron therapy is unsatisfactory               Yes (first line) Adult
                                                                     or impossible)                                    or impossible)
                b
                    HDD-CKD Anemia                             Yes (second line, when oral                      Yes (second line, when oral
                                                             iron therapy is unsatisfactory                    iron therapy is unsatisfactory               Yes (first line) Adult
                                                                     or impossible)                                    or impossible)
                c
                    PDD-CKD Anemia                             Yes (second line, when oral                      Yes (second line, when oral
                                                             iron therapy is unsatisfactory                    iron therapy is unsatisfactory               Yes (first line) Adult
                                                                     or impossible)                                    or impossible)
           Safety
                “Black Box” Warning                                       Yes                                               Yes                                      No
                                                                 Yes, prior to receiving                           Yes, prior to receiving
               Test Dose Required                                                                                                                                    No
                                                                 first therapeutic dose                            first therapeutic dose
            Administration
                                                                 100 mg over 2 minutes                             100 mg over 2 minutes             510 mg over 17 seconds, followed
                                                                      (50 mg/min)                                       (50 mg/min)                  by 2nd 510 mg dose 3-8 days later
                    IV Push                                 Observe patients for at least                    Observe patients for at least               Observe patients for at least
                                                         one hour after test dose for signs &             one hour after test dose for signs &        30 minutes after administration for
                                                             symptoms of anaphylaxis                          symptoms of anaphylaxis               signs & symptoms of hypersensitivity
                    IV Infusion                                    Not FDA Approved                                  Not FDA Approved                        Not FDA Approved

                                                                          Yes,
                                                              Adult: Not to exceed 100 mg
                                                                  by Z-Track Method
                    IM Injection                                                                                               No                                     No
                                                            Observe patients for at least
                                                         one hour after test dose for signs &
                                                             symptoms of anaphylaxis
            Pharmacy Specifications
                    Filter Needle                                            No                                                No                                     No
                    Recommended
                                                                                                               72 hrs room or refrigerated
                    Syringe Stability                                   Unavailable                       (in 0.9% NaCI at a concentration of                    Unavailable
                                                                                                                  1 mg/mL - 5 mg/mL)*
                    Preservative                                            None                                              None                                  None

                    How Supplied                                                                                       50 mg/1 mL vial                       510 mg/17 mL vial
                                                                    100 mg/2 mL vial
                                                                                                                      100 mg/2 mL vial

                                                                    a
     *Data on file: American Regent, Inc., (Shirley , NY).            NDD-CKD = Non-Dialysis Dependent-Chronic Kidney Disease
                                                                    b
                                                                      HDD-CKD = Hemodialysis Dependent-Chronic Kidney Disease
                                                                    c
                                                                      PDD-CKD = Peritoneal Dialysis Dependent-Chronic Kidney Disease

      Note: All registered trademarks are the property of their respective owners.




                                                                                                                             Please see Important Safety Information on page 3
                       Leading anemia management.™                                                                                and full prescribing information at back page.
                                                                                                                    13

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 adult 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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14
     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.

     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. There are post-marketing spontaneous
     reports of life-threatening hypersensitivity reactions in patients receiving Venofer®. See Important
     Safety Information on page 3 and the Venofer® full prescribing information at back page for more
     information on adverse events.




                                                                                              Please see Important Safety Information on page 3
               Leading anemia management.™                                                         and full prescribing information at back page.
                                                                                                                                                    15
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 (7.7%),
peripheral edema (7.7%), diarrhea (5.5%), constipation (5.5%), nausea (5.5%), dizziness (5.5%),
hypertension (5.5%), vomiting (12.1%), arthralgia (7.7%), back pain (7.7%), headache (7.7%),
extremity pain (5.5%), and injection site burning (5.5%).

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 trials.11-13 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 (39.4%), muscle cramps (29.4%), nausea (14.7%), headache
(12.6%), graft complications (9.5%), vomiting (9.1%), dizziness (6.5%) hypertension (6.5%), chest pain
(6.1%), and diarrhea (5.2%). Some of these symptoms may be seen in hemodialysis patients not
receiving intravenous iron.

Please see Important Safety Information on page 3
and full prescribing information at back page.
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 (8.0%), peritoneal infection (8.0%) vomiting (8.0%), hypertension (8.0%), pharyngitis (6.7%),
     peripheral edema (5.3%), and nausea (5.3%).

     Post marketing safety studies
     In a post-marketing safety study of 665 adult hemodialysis patients who received multiple doses of
     Venofer®, the most frequent adverse events (>1%), whether or not related to Venofer® administration,
     were congestive heart failure (1.8%), sepsis (1.7%), myocardial infarction (1.2%), chest pain (1.1%),
     pneumonia (1.1%), pulmonary edema (1.1%), and cerebrovascular accident (1.1%).

     In an additional post-marketing safety study of 386 adult hemodialysis patients, 192 patients received
     Venofer® 100 mg and 194 patients received Venofer® 200 mg. The primary difference between the two
     treatment groups was the increased incidence of taste disturbance experienced by patients in the
     Venofer® 200 mg group (4.6%) compared to the Venofer® 100 mg group (1%).

     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.




                                                                            Please see Important Safety Information on page 3
               Leading anemia management.™                                       and full prescribing information at back page.
                                                                                                          17
Indications and dosage             1

Venofer ® is indicated in the treatment of iron deficiency anemia in the following patients:
      • Adult non-dialysis dependent-chronic kidney disease (NDD-CKD) patients not receiving
        an erythropoietin
      • Adult non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving
        an erythropoietin
      • Adult hemodialysis dependent-chronic kidney disease (HDD-CKD) patients receiving
        an erythropoietin
      • Adult 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 adult 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.




Please see Important Safety Information on page 3
and full prescribing information at back page.
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. Serious
     hypersensitivity reactions have been reported in patients receiving Venofer®. In clinical
     studies, several patients experienced hypersensitivity reactions presenting with wheezing, dyspnea,
     hypotension, rashes, or pruritus. The post-marketing spontaneous reporting system includes reports of
     patients who experienced serious or life-threatening reactions (anaphylactic shock, loss of consciousness
     or collapse, bronchospasm with dyspnea, or convulsion) associated with Venofer® administration.
     Hypotension has been reported frequently in non-dialysis dependent-chronic kidney disease (NND-
     CKD) patients receiving IV iron. Hypotension following administration of Venofer® may be related to
     rate of administration and total dose delivered.
     In a multi-dose efficacy study in NDD-CKD patients (N=91), the most frequent adverse events (≥5%)
     whether or not related to Venofer® administration, were taste disturbance (7.7%), peripheral edema
     (7.7%), diarrhea (5.5%), constipation (5.5%), nausea (5.5%), dizziness (5.5%), and hypertension (5.5%).
     In an additional study of Venofer® with varying erythropoietin doses in 96 treated NDD-CKD patients,
     adverse events, whether or not related to Venofer® reported by ≥5% of Venofer® exposed patients are
     as follows: diarrhea (16.5%), edema (16.5%), nausea (13.2%), vomiting (12.1%), arthralgia (7.7%),
     back pain (7.7%), headache (7.7%), hypertension (7.7%), taste disturbance (7.7%), dizziness (6.6%),
     extremity pain (5.5%), and injection site burning (5.5%).
     In multi-dose efficacy studies in hemodialysis dependent (HDD)-CKD patients (N=231), the most
     frequent adverse events (>5%) whether or not related to Venofer® administration, were hypotension
     (39.4%), muscle cramps (29.4%), nausea (14.7%), headache (12.6%), graft complications (9.5%),
     vomiting (9.1%), dizziness (6.5%), hypertension (6.5%), chest pain (6.1%), and diarrhea (5.2%).
     In post-marketing safety studies in HDD-CKD patients (N=1051), the most frequent adverse events
     reported (>1%), whether or not related to Venofer® administration, were congestive heart failure,
     sepsis, and taste disturbance. 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 (8.0%), peritoneal infection (8.0%), vomiting (8.0%), hypertension (8.0%), pharyngitis
     (6.7%), peripheral edema (5.3%), and nausea (5.3%).




                                                                         Please see Important Safety Information on page 3
              Leading anemia management.™                                     and full prescribing information at back page.
                                                                                                                  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. See Important Safety
Information on page 18. 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-Adult 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 perversion.
        • 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%).


Please see Important Safety Information on page 3
and full prescribing information at back page.
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-Adult 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 perversion (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.




                                                                          Please see Important Safety Information on page 3
              Leading anemia management.™                                      and full prescribing information at back page.
                                                                                                                21
Study C-Adult 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-Adult 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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and full prescribing information at back page.
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-Adult 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.




                                                                        Please see Important Safety Information on page 3
              Leading anemia management.™                                    and full prescribing information at back page.
                                                                                                          23
Post-marketing safety study 1                23

665 adult chronic hemodialysis patients on 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 adult hemodialysis patients on erythropoietin were exposed to a single dose of Venofer ® 100 mg
IV by slow injection or 200 mg by slow injection over 5 minutes [200 mg dose not FDA approved for
this indication]. At least one drug-related treatment-emergent adverse event was experienced by 6.7%
(13/194) of the patients in the Venofer® 200 mg group and 3.6% (7/192) of the patients in the Venofer ®
100 mg group. No study-drug related serious adverse events were reported in either Venofer ® treatment
group. History of iron intolerance (iron dextran or iron gluconate) had no impact on the occurrence of
adverse events. Seventeen (4.4%) patients with a history of prior iron intolerance were included in
this study. Only one patient (Venofer ® 100 mg group) with a history of iron intolerance reported any
drug-related treatment-emergent adverse events. This patient developed a transient taste disturbance.




Please see Important Safety Information on page 3
and full prescribing information at back page.
24




                                   Please see Important Safety Information on page 3
     Leading anemia management.™        and full prescribing information at back page.
                                                                                                          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 7 days 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 and non-PVC) containing 0.9% Sodium Chloride
Injection, USP at concentrations ranging from 1 mg to 2 mg of elemental iron per mL, has been found
to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and
under refrigeration (4°C ± 2°C).2
Do not dilute at concentrations below 1 mg/mL.
Do not mix Venofer ® with other medications or add to parenteral nutrition solutions for intravenous
infusion.

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




Please see Important Safety Information on page 3
and full prescribing information at back page.
26




                                   Please see Important Safety Information on page 3
     Leading anemia management.™        and full prescribing information at back page.
                                                                                                             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 adult 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 adult non-dialysis dependent-
chronic kidney disease (CKD) patients receiving or not receiving erythropoietin, and in adult hemodialysis
and peritoneal dialysis dependent-chronic kidney disease patients receiving erythropoietin.




Please see Important Safety Information on page 3
and full prescribing information at back page.
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

     *Some Medicare contractors require use of both a 280 code and a 585 code to obtain reimbursement
      for Venofer ®. Note Venofer ® is only approved for treatment of adult CKD patients with iron deficiency
      anemia (and in HD and PD patients only if on an ESA). No representation is made by American
      Regent that Venofer ® is safe and effective for non-CKD iron deficiency anemia or that reimbursement
      for non-CKD anemia is permissible or legal. Please check your local coverage decision for specific
      ICD-9-CM codes to be used.

     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).



                                                                         Please see Important Safety Information on page 3
              Leading anemia management.™                                     and full prescribing information at back page.
                                                                                                             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 adult 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.




Please see Important Safety Information on page 3
and full prescribing information at back page.
30




                                   Please see Important Safety Information on page 3
     Leading anemia management.™        and full prescribing information at back page.
                                                                                                         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
E-mail....................inquiry@americanregent.com

For emergency drug information after normal business hours, please call 877-845-6371.
One of our drug information specialists will return your call promptly.

Please visit us at www.venofer.com.




American Regent, Inc. (www.americanregent.com) is a subsidiary of
Luitpold Pharmaceuticals, Inc. (www.luitpold.com).

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


Please see Important Safety Information on page 3
and full prescribing information at back page.
32




                                   Please see Important Safety Information on page 3
     Leading anemia management.™        and full prescribing information at back page.
                                                                                                                                                         33

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                                                                                 effects of adopting an aggressive intravenous iron policy in a
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                                                                             18. Andrade LJ, Garica MI, Acuna GD, et al. I.V. iron sacharate, five
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                                                                             20. Baskin E, Besbas S, Ozdemir S, et al. Effect of intravenous iron sac-
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    Clinical study report, 1997 and data on file: American Regent, Inc.,         administered to hemodialysis patients. Data on file: American
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12. Charytan C, Levin N, Al-Saloum M, et al. Efficacy and safety of iron     25. McKane W, Green C, Farrington K. Porphyria cutanea tarda precip-
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    2001;37(2):300-307.                                                      26. Tarif N, Mitwalli AH, AlWakeel JS, et al. Safety of intravenous fer-
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14. Kosch M, Bahner U, Bettger H, Matzkies F, Teschner M, Schaefer           27. Jamil B, Hussain HH, Nasir H, Kumar H, Naqvi SAJ. Parenteral iron
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    Transplant. 2001;16:1239-1244.                                               2001.




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34
     28. Sikole A, Spasovski G, Zafirov D, Polenakovic M. Epoetin omega          41. Aaronson ML, Cornell LD, Tolerability of high dose [500 mg]
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         Trans. 2001;16:115-119.                                                     immediate puerperium, and of other ferropenic conditions with
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                                                                                 54. Frappier J, Delaporte-Cerceau S, deVaumas C et al. Prise en
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         2001;16:967-974.




                                                                                                   Please see Important Safety Information on page 3
                   Leading anemia management.™                                                          and full prescribing information at back page.
                                                                                                                                                         35
55. Breymann C, Vesca E, Huch R, Huch A, Efficacy and safety of intra-        70. Gasché C, Dejaco C, Waldhoer T, et al. Intravenous iron and erythro-
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    anemia. Israel Med Assoc J. 2008;10:335-338.                              83. Breymann C, Buhner M, Lex B, Tulusan A. Recombinantes
69. Jasper A, Adams A, Smith PA, Lewis NJA. Successful strategies for             erythropoietin [40 000 E] und eisensaccharatkomplex zur
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    management in chronic renal impairment. Ann Dial Conf. Feb. 2001.             communication. February 2003.


Please see Important Safety Information on page 3
and full prescribing information at back page.
36
     84. Silverberg DS, Wexler D, Blum M, et al. The use of subcutaneous         99. Bodemar G. Treatent of anaemia in inflammatory bowel disease
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                                                                                                          Please see Important Safety Information on page 3
                    Leading anemia management.™                                                                and full prescribing information at back page.
                                                                                                      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 Important Safety Information on page 3
and full prescribing information at back page.
     Venofer® is manufactured under license from Vifor (International) Inc., Switzerland. © 2010 American Regent, Inc.
Reimbursement and Patient Assistance Program Hotline: 800-282-7712 • Orders or information: 800-645-1706 • venofer.com



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         Leading anemia management.™                                                                               Printed in USA

				
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