The four topics that were included in the guide were:
1. Getting enough dialysis to stay healthy for patients on Hemodialysis
(Adequacy of Hemodialysis).
2. Getting enough dialysis to stay healthy for Peritoneal Dialysis patients
(Adequacy of Peritoneal Dialysis).
3. The best ways to provide you with a blood access for dialysis (fistula, graft, or
catheter) and how to care for that access (Vascular Access).
4. The best ways to use an ESA (erythropoietin stimulating agent) and iron to
keep your blood count high and prevent anemia (Anemia Management).
The NKF-DOQI™ guide helped make patient care better. Because of this, the NKF
decided to update their original guides and to print new guides for other special
problems of patients with kidney disease. They changed the name from the NKF
Dialysis Outcomes Quality Initiative (NKF-DOQI™) to the NKF-Kidney Disease
Outcomes Quality Initiative (NKF-KDOQI™).
This pamphlet you are about to read tells only one small story. It explains the
importance of:
How iron prevents anemia in patients with kidney disease (like you).
National Kidney
Foundation Kidney
Disease Outcomes
Quality Initiative
2
When your doctor tells you that your blood count is low, it
means you do not have enough red blood cells (RBCs)
in your blood. Red blood cells are responsible for
delivering oxygen throughout the body. Anemia is a sign
of disease, and not a disease itself. This is very common
in chronic kidney disease. Anemia can also be caused by hemodialysis alone. There is
always some blood that remains in the dialyzer and blood lines after each treatment.
When you lose blood, you are losing RBCs, and when you lose RBCs, you lose
hemoglobin and iron.
Possible Symptoms of anemia
• Often, no symptoms
• Paleness
• Feeling tired
• Unusual shortness of breath
• Fast heartbeat
• Colder hands and feet than usual
• Headaches
Anemia, over a long period of time, can cause you to have problems with your heart.
If you already have heart problems, it can make those problems worse.
The Kidneys, Iron and Anemia.
The healthy kidney produces a hormone called erythropoietin
(commonly known as EPO). A hormone is a chemical substance
that acts as a messenger delivering material from one part of the
body to another. RBCs are formed in the bone marrow with the
help of this hormone. The bone marrow is also supplied with a
small amount of iron, which helps to build healthy new RBCs.
Then the RBCs carry oxygen to all parts of the body. Every living human cell needs
oxygen to live. Muscles are made up of millions of cells. An important muscle is the
heart. This is why heart conditions can develop or worsen if there are not enough
RBCs to deliver oxygen to the cells of the heart. Oxygen is the fuel for cell survival.
What is
Anemia?
3
There are two common causes of anemia in chronic kidney disease patients:
1. Too few red blood cells. This is because the kidney is no longer making the
hormone erythropoietin.
2. Too little iron.
Too little iron may be caused by the following:
• Diet restrictions
• The body is not able to absorb enough iron
• Some blood is lost during hemodialysis. It’s almost impossible to return all
your blood after hemodialysis. Some blood remains in the dialyzer and tubing
• Other blood loss: GI (gastrointestinal) bleeding, catheter lines, bleeding from
the access site after hemodialysis, surgery, clotted dialyzers and blood lines
• Erythropoietic stimulating agents (ESA) such as EPO speed up the making of
RBCs and quickly use a lot of the iron in your body to make RBCs
How your doctor knows when to give you iron.
The blood tests that are taken each month will give your doctor a picture of how
healthy your red blood cells are. It will show if they are receiving enough iron. (These
tests may be taken less often if your red blood count remains good.)
There are blood tests that show how
your red blood cells are doing and there
are blood tests that show where the iron
is in your body and how it is being used.
What happens when the kidneys don’t work properly?
4
1. Hemoglobin: This is the part of the red blood cell which contains iron and
carries oxygen.
2. Hematocrit: a percentage of red blood cells (RBCs) within a sample of blood.
1. Ferritin: This is a protein that reflects stored
iron. Think of ferritin as gas in the tank. You need
to have enough gas to keep a car running. This
is why it is important to measure and track these
values regularly. Remember, when you lose blood
you lose iron and RBCs. Losing iron is like losing
gas from your car.
When you have a serious infection, it is possible that your body will hold onto the iron
in storage. In this case, your ferritin levels will be high but you don’t have enough iron
in your red blood cells. The infection should be treated before continuing your iron
therapy.
2. Transferrin Saturation (TSAT): Transferrin is a protein that takes the iron from
the storage protein (ferritin), or the iron that you’re being treated with, and
brings it to the bone marrow where it may be used to build healthy red blood
cells. This lab value is a percentage. Think of it as the tube that brings the
gas to the engine. It’s the transportation vehicle for iron. A TSAT of <20%
means that you do not have enough iron for your RBCs.
Reticulocyte Hemoglobin Content (CHr): This test measures the amount of
iron in the youngest red blood cells, known as reticulocytes. This lets you see
iron status earlier in the newest RBCs and is a more sensitive test when you
have an infection or inflammation. During infection or inflammation,
your ferritin levels can be higher even if you do not have enough iron. The
CHr level is not affected in this way, and can help show if you need iron
therapy. This new test has been added to the NKF-KDOQI guidelines for 2006.
Your most important red blood cell tests are:
The two iron blood tests you should know about are:
Other:
5
Lab Values Hemodialysis
Dependent CKD
Non-Dependent Dialysis
CKD & Peritoneal Dialysis
Hemoglobin
Ferritin
Transferrin Saturation
CHr
>11 g/dL
200 - 500 ng/mL
>20%
>29 pg/cell
>11 g/dL
100 - 500 ng/mL
>20%
None Recommended
Reading this booklet is one of the first
steps to preventing and controlling
anemia. It’s very important to find the
reason for a low iron level. Talk to your
doctor or nurse if you think you might
have anemia. A blood test will probably
be done to diagnose anemia. GI
bleeding many times is undetected. If you develop dark tarry stools, report it
immediately to your doctor or nurse. Other tests may be needed to find out what’s
causing the anemia. Early and controlled treatment can reduce some of the symptoms
of anemia.
Taking an erythropoietin stimulating agent (ESA). Since as a patient with chronic
kidney disease you may not be making enough erythropoietin, you will receive a manmade
form of erythropoietin. An ESA may be given during your hemodialysis treatment
through the blood lines or by an intravenous (IV) injection. It may also be given by a
very small injection under your skin. This is a subcutaneous or S.C. injection.
Taking Iron. Taking iron by mouth (oral iron) may be enough if you are not receiving
an ESA. However, some patients with chronic kidney disease and almost all patients
on hemodialysis who are taking an ESA will need to receive injectable iron. Oral iron is
not fast enough to replace the iron that’s needed once the ESA begins to make new
red blood cells.
What can be
done to prevent or
control anemia?
National Kidney Foundation (NKF) KDOQI Guidelines
Based on recent recommendations the target range is between 11.0 g/dL to 12.0 g/dL. Each patient should discuss how
best to treat their anemia with their doctor and such treatment should be based on their individual healthcare needs.
*
6
*
Stored iron will be used when needed but eventually will need to be replaced for future
use. Without enough iron, an ESA cannot completely correct anemia.
If you are on an ESA and you are not getting enough iron, your doctor may
treat you with intravenous (IV) iron. You will receive intravenous iron during your
hemodialysis treatment or when you come to your doctor’s office or clinic visit.
There are two ways of receiving iron if diet alone is not enough. Your doctor may
prescribe oral iron (pills that you may buy without a prescription). Oral iron is usually
given three times a day between meals. How and when you take oral iron is very
important:
• Take iron one hour before or two hours after a meal
• Do not take with antacids
• Do not take phosphate binders at the same time
• Avoid alcohol
If you begin to get constipated, have nausea, or a feeling of fullness, consult your
doctor. You may take stool softeners to help avoid constipation, and let your doctor
know if you begin to have this problem. If you are not able to obtain a good blood
count with oral iron, your doctor may prescribe intravenous iron. This is the iron
injected into your bloodstream.
An ESA and iron work together to help your body make healthy new red blood cells.
Your doctor will decide how to give you these drugs based on the procedures in your
dialysis unit and the suggestions from the NKF-KDOQI™ guidelines.
The Food and Drug Administration (FDA) has approved four types of intravenous
iron injectable products for use in the United States. These are iron sucrose, iron
dextran, iron gluconate* and ferumoxytol. All of these will help to increase the amount
of iron you have in your body. There are some differences among them, however.
*Iron gluconate: also known as sodium ferric gluconate in sucrose injection.
What type of iron may my doctor prescribe?
7
These differences have to do with the approved uses, how quickly they work, whether
or not a test dose is required, the types of side effects you may see, and the size of
your dose. Your doctor will decide which is best for you. Like many other treatments,
IV iron may be partially covered through your medical insurance.
A person can experience an allergic reaction to intravenous iron just as they do to
other medications. It is important for you to notify your doctor or a member of the
dialysis staff immediately if you experience:
• Flushing
• Difficulty breathing
• Itching
• Rash
• Any unusual symptoms during or just after the drug was given
If you have had an allergic reaction to intravenous iron in the past, you need to
discuss with your doctor whether a different type of intravenous iron may be better
for you.
Conclusion
We hope this booklet has helped you understand the importance of iron in your
body to help correct the problem of anemia. If you still have questions about iron or
anemia, talk to your doctor. We salute you for taking the time to learn about your
health, and hope you will continue to take steps to be an active participant in your
care.
8
Anemia: A decrease in the amount of red blood cells that are needed
to carry enough oxygen to meet the body’s needs.
CHr: Reticulocyte Hemoglobin Content. This lab value measures
the iron status of a young red blood cell usually 24
hours before it becomes a mature red blood cell.
CKD: Chronic Kidney Disease (reduced kidney function).
EPO: (Erythropoietin). A hormone produced by the kidney. It
stimulates the bone marrow to produce red blood cells.
ESA: Erythropoietin stimulating agent. Drugs that replace the hormone
erythropoietin when the kidneys fail to produce it.
Ferritin: A form of storage iron.
Hematocrit: Measures the amount of red blood cells within a specific
amount of blood.
Hemoglobin: The part of the red blood cells that carries oxygen from
the lungs to the tissues.
RBC: Red blood cell.
Transferrin: A protein in the blood that carries iron.
Transferrin Saturation:
(TSAT) measures the amount of iron that is immediately
available to produce RBCs.
Glossary
9
10
Aronoff G, Van Wyck D. Iron sucrose in hemodialysis patients: Safety of replacement and maintenance regimens.
Kidney International 2004;66:1-6.
Bailie GR, Clark JA, Lane CE, Lane PL. Hypersensitivity reactions and deaths associated with intravenous iron
preparations. Nephrology Dialysis Transplantation (2005); Advance Access Publication.
Bailie G, Johnson C, Mason N. Parenteral Iron Use in the Management of Anemia in End-Stage Renal Disease
Patients. Am J Kidney Dis 35:1, pp. 1-12, January 2000.
Bailie G, Johnson C, Mason N. Parenteral iron products for anemia in end-stage renal disease: Comparative
considerations. Formulary 35:6, June 2000.
Blaustein D, Schwenk M, Chattopadhyay J, Singh H, Daoui R, Gadh R, Avram M. The safety and efficacy of an
accelerated iron sucrose dosing regimen in patients with chronic kidney disease. Kidney International 2003;64(S
87);S72-S77.
Charytan C. Comparison of intravenous iron sucrose to oral iron in the treatment of anemic patients with chronic
kidney disease not on dialysis. Nephron Clinical Practice 2005;100:c55-c62.
Charytan C, Levin N, Al-Saloum M, Hafeez T, Gagnon S, Van Wyck D. Efficacy and safety of iron sucrose for
iron deficiency in patients with dialysis-associated anemia: North American clinical trial. Am J Kidney Dis
2001;37:300-307.
Charytan C, Schwenk M, Al-Saloum M, Spinowitz B. Safety of iron sucrose in hemodialysis patients intolerant to
other parenteral iron products. Nephron Clinical Practice 2004;96:c63-c66.
Macdougall IC, Roche A. Administration of intravenous iron sucrose as a 2-minute push to CKD patients: A
prospective evaluation of 2,297 injections. Am J Kidney Dis 2005;46(2):283-289
NKF - K/DOQI: Clinical practice guidelines for Anemia of Chronic Kidney Disease: Update 2006. American Journal
of Kidney Diseases, Vol 47, No 5, Suppl 3(May), 2006: pp S58-S70.
Schiesser D, Binet I, Tsinalis D, Dickenmann M, Keusch G, Schmidli M, Ambuhl PM, Luthi L, Wuthrich RP.
Weekly low-dose treatment with intravenous iron sucrose maintains iron status and decreases epoetin requirement
in iron-replete haemodialysis patients. Nephrology Dialysis Transplantation 2006.
Singh H, Reed J, Noble S, Cangiano JL, Van Wyck D. Effect of intravenous iron sucrose in peritoneal dialysis
patients who receive erythropoiesis-stimulating agents for anemia: A randomized, controlled trial. Clin J Am Soc
Nephrol 2006.
Van Wyck D, Cavallo G, Spinowitz B, Adhikaria R, Gagnon S, Charytan C, Levin N. Safety and Efficacy of Iron
Sucrose in Patients Sensitive to Iron Dextran: North American Clinical Trial. Am J Kidney Dis 36:1, pp. 88-97, July
2000.
Van Wyck D, Roppolo M, Martinez CO, Mazey RM, McMurray S. A randomized, controlled trial comparing IV iron
sucrose to oral iron in anemic patients with nondialysisdependent CKD. Kidney International 2005;68:2846-2856.
Yee J, Besarab A. Iron sucrose: the oldest iron therapy becomes new. Am J Kidney Dis, 2002;40(6):1111-21.
Bibliography For Further Reading
11
Resources
American Association of Kidney Patients (AAKP): www.aakp.org
Dialysis Patient Citizens: www.dialysispatients.org
National Anemia Action Council: www.anemia.org
Renal Support Network: www.rsnhope.org
Society for the Advancement of Blood Management: www.sabm.org
TISEV2
Rev. 1/2010
One Luitpold Drive, PO Box 9001
Shirley, NY 11967
1-800-645-1706
www.americanregent.com
www.venofer.com
Copyright © 2010 American Regent, Inc.
Leading anemia management.™
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
Venofer<> (ironsucrose injeclion, USP)is a brown, sterile, aqueous, complex of polynuclear iron(1I1)-hydroxide in sucrose for
inlravenous use. Ironsucrose injection hasa molecular weight of approximately 34,000 - 60,000 daltons enda proposed
structural formula:
[Na2FesOa(OH) • 3(H~)ln • m(C12H22011)
where: n is the degree of iron polymerization and m is the number of sucrose molecules associated ~th the iron (111)hydroxide.
EachmLcontains 20mgelemental ironas ironsucrose in waterfor injeclion. Venofer<> is available in5 mLsingle dosevials
(100mgeiemental ironper5 mL)and10mLsingle dosevials(200mgelemental ironper10mL), Thedrugproducl contains
apprOXimately 30% sucrose w/v (300mg/mL) and has a pH of 10.5-11.1. The product contains no preservatives. The
osmolarity of the injection is 1,250mOsmoVL.
Therapeutic class: Hematinic
CLINICAL PHARMACOLOGY
Phannacodynamics: FolI~ng intravenous administration ofVenafer<>, ironsucrose is dissociated bythereticuloendothelial
system into iron and sucrose. In 22 hemodialysis patients on erythropoietin (recombinant human erythropoietin) therapy
treated ~th ironsucrose containing 100mgof 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
sucrose treatment.
Phannacokinetics: In healthy adults treated ~th intravenous dosesof Venofer<>, its ironcomponent exhibits first order
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
for ironin the ironstores andironutilizing tissues of the body, serum clearance of ironis expected to bemore rapid in iron
deficient patients treated ~th Venofer<> as compared to healthy individuals, The effects of age and gender on the
phannacokinetics of Venofer<> havenotbeen studied.
Venofer<> is notdialyzable through CA210 (Baxter) HighEfficiency or Fresenius F80AHighFluxdialysis membranes. Inin
vitrostudies, theamount of ironsucrose in thedialysate fluidwasbelowthelevels of detection oftheassay (iessthan2 parts
permillion),
Distribution: In heallhy adullsreceiving intravenous doses of Venofer<>, its ironcomponent appears to distribute mainly in
bloodandtosomeexlentin extravascular fluid, Astudyevaluating Venofer<> containing 100mgof ironlabeled with52FelS9Fe
in patients with iron deficiency shows thata significant amount of the administered iron distributes in the liver, spleen and
bonemanrow andthatthebonemarrow isan irontrapping compartment andnota reversible volume of distribution,
Metabolismand Elimination: FolI~ng intravenous administration of Venofer<>, ironsucrose is dissociated into ironand
sucrose by the reticuloendothelial system. The sucrose component is eliminated mainly by urinary excretion, In a study
evaiuating a singleintravenous doseof Venofer<> containing 1,510mgof sucrose and 100mgof ironin 12healthy adults
(9female, 3 male: agerange 32-52), 68.3% ofthesucrose waseliminated in urine in 4 hand 75.4% in24h, Some ironalso
is eliminated intheurine, Neither transferrin nortransferrin receptor levelschanged immediately afterthedoseadministration
[1].In thisstudyandanother studyevaluating a single intravenous doseof ironsucrose containing 500-700 mgof ironin 26
anemic patients onerythropoietin therapy (23female, 3 male; agerange 16-60), approximately 5%oftheironwaseliminated
in urinein 24 h at eachdoselevel[2].
Drug-drugInteraelions: Drug-drug interactions involving Venofer<> havenot been studied. However, like otherparenteral
ironpreparations, Venofer<> maybe expected to reduce theabsorption of concomitantly administered oralironpreparations.
CLINICAL TRIALS
Venofer<> is used to replenish body iron stores in non-dialysis dependent-chronic kidney disease (NDD-CKD) patients
receiving erythropoietin and in NDD-CKD patients not receiving erythropoietin, and in hemodialysis dependent-chronic
kidney disease (HDD-CKD) and peritoneal dialysis dependent-chronic kidney disease (PDD-CKD) patients receiving
erythropoietin. Iron deficiency may be caused by blood loss during dialysis, increased erythropoiesis secondary to
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 andnonheme
compounds. Mostdialysis patients require intravenous ironto maintain sufficient ironstores,
Sixclinical trialswereconducted to assess the safety andefficacy of Venofer<>. Fivestudies wereconducted in the United
States (516patients) andonewasconducled in South Africa (131 patients).
StudyA: Hemodialysis Dopendent-Chronic KidneyDisease (HDD-CKD)
StUdyAwasa mullicenter, open-label, historically-controlled stUdy in 101 hemodialysis patients \T7 patients ~th Venofer<>
treatment and24 in the historical control group) ~th iron deficiency anemia. Eligibility for Venofer<> treatment included
patients undergoing chronichemodialysis threelimesweekly, receiving erythropoietin, hemoglobin concentration greater
than8.0andlessthan11.0g/dLfor at leasttwoconsecutive weeks, transferrin saturation < 20%,andserum ferritin <300
ng/mL. Themean ageof the patients in thetreatment groupwas65 years~th theagerange being31 to 85yearsof age.
The erythropoietin dosewasto be held constant throughoul the study, The protocol did not require administration of a
testdose;however, some patients received a testdoseat the physician'S discretion. Exclusion criteria included significant
underlying disease, asthma, activeinflammatory disease, or serious bacterial or viralinfection. Venofer<> 5 mLcontaining
100mg of elemental ironwas administered through the dialysisline at eachdialysis session eitheras slowinjection or a
saline diluted slowinfusion foratotalof10dialysis sessions ~th acumulative doseof 1,000 mgelemental iron, A maximum
of 15mLs(300mgof elemental iron)of Venofer<> wasadministered perweek,
Noadditional ironpreparations wereallowed untilaftertheDay57evaluation. Themean change inhemoglobin frombaseline
to Day24 (endof treatment), Day36, andDay57 wasassessed, Thehistorical control population consisted of 24 patients
~th similarferritin levels as patients treated ~th Venofer<>, whowereoff intravenous ironfor at leasl2weeks andwhohad
received erythropoietin therapy ~Ih hematocrit averaging 31-36for at leasttwo rnomhs priorto stUdy entry. Themean age
of patients in the historical control groupwas56years, ~th anagerange of 29to 80years. Patient ageandserum ferritin
levelweresimilar between treatment andhistorical control patients. Ofthe77patients in thetreatment group, 44(57%) were
maleand33 (43%) werefemale. Themean baseline hemoglobin andhematocrit, werehigheranderythropoietin dosewas
lowerin the historical control population thantheVenofer<> treated population.
Patients in theVenofer<> treated population showed a statistically significantly greater increase in hemoglobin andhematocrit
thandidpatients in the historical control population. SeeTable 1.
Table1. Changesfrom Baselinein Hemoglobin and Hematocrit
Efficacy
parameters
End of Treatment 2 Week follow-up 5 week follow-up
Venofer0
(n=69)
Historical
Control
(n=18)
Venofer'>
(n=73)
Historical
Control
(n=18)
Venofer0
(n=71)
Historical
Control
(n=15)
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
Hematocrit (%) 3,1±O.37~ -{).3±O.65 3.6±O,44~ -1.2±O.76 3,3±O.54 0.2±O,86
~p<0.01 and·p<0,05compared to historical control fromANCOVA analysis ~th baseline hemoglobin, serum ferritin and
erythropoietin doseascovariates.
Serum ferritin increased significantly (p=0.0001) at endpoint of studyfrom 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
significantly (p=0,0016) at endpoint of stUdy frombaseline in theVenofer<>-treated population (8.8±1.6%) compared to this
historical control population (-5.1±4.3%) [3J.
StudyB: HemodialysisDopendent-Chronic KidneyDisease (HDD-CKD)
StUdy B was a multicenter, openlabelstudyof Venofer<> (iron sucrose injection, USP)in 23 iron deficient hemodialysis
patients whohadbeendiscontinued fromirondexlran dueto intolerance, Eligibility criteria andVenofer<> administration were
otherwise idenlical to Study A.Themean ageof thepatients in thisstUdy was53years, withagesranging from21-79years,
Ofthe23patients enrolled in thestudy, 10(44%) weremaleand13(56%) werefemale. Theethnicity breakdown of patients
enrolled in thisstudywasas follows: Caucasian (35%); Black (35%); Hispanic (26%); Asian (4%), Themean change from
baseline to theendof treatment (Day24)in hemoglobin, hematocrit, andserum ironparameters wasassessed.
All 23 enrolled patients wereevaluated for efficacy. Statistically significant increases in mean hemoglobin (1.1±O.2 g/dL),
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.
Study C: HemodialysisDopendent-Chronic KidneyDisease (HDD-CKD)
Study C was a multicenter, open-label, two period (treatment foilowed by observation period) study in iron deficient
hemodialysis patients. Eligibility for this studyincluded chronic hemodialysis patients ~th a hemoglobin lessthanor equai
to 10g/dL, a serum transferrin saturation lessthanor equal to 20%,anda serum ferritin lessthanor equal to 200ng/mL,
whowereundergoing maintenance hemodialysis 2 to 3 timesweekly. Themean age of the patients enrolled in this study
was41years, ~th agesranging from16-70 years. Of 130patients evaluated for efficacy in thisstudy, 68 (52%) weremale
and62 (48%) werefemale. Theethnicity 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
oraliron.Exclusion criteria weresimilar to those in Studies A andB. Venofer<> wasadministered in doses of 100mgduring
sequential dialysis sessions untila pre-detennined (celcelateo) totaldoseof ironwasadministered,
Patients received Venofer<> at eachdialysis session, twoto threetimesweekly. Onehourafterthestartof eachsession,S
mLironsucrose (100mgiron)in 100mL0.9%NaCI wasadministered intothe hemodialysis line. A 50mgdose(2.5mL)
wasgivento patients ~thin two weeksof studyentry. Patients weretreated untiltheyreached anindividually calculated totai
irondosebased on baseline hemoglobin levelandbodyweight. Twenty-seven patients (20%) werereceiving erythropoietin
treatment at studyentryandtheycontinued to receive thesame erythropoietin doseforthe duration of thestUdy.
Changes frombaseline to observation week2 andobservation week4 (endof study) wereanalyzed,
Themodified intention-to-treat populaton consisted of 131 patients. Significant (p<0.0001) increases frombaseline in mean
hemoglobin (1.7g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), andserum transferrin saturation (14%) wereobserved
at week 2 of the observalion period and these values remained significantly increased (p<0,0001) at week 4 of the
observalion period.
Study 0: Non-DialysisDopendent-Chronic KidneyDisease (NDD-CKD)
StUdy D wasa randomized, open-label, multicenter, active-controlled studyof the safety andefficacy of oral iron versus
intravenous ironsucrose (Venofer<» in NDD-CKD patients ~th or ~thout erythropoietin therapy. Erythropoietin therapy was
stabiefor 8 weeks priorto randomization. In the study188patients ~th NDD-CKD, transferrin saturation s 25%,ferritin
s 300ng/mLandanaverage baseline hemoglobin ofs 11.0g/dLwererandomized to receive oraliron(325mgferrous sulfate
threetimes dailyfor 56 days); or Venofer<> (either200mgover2-5minutes 5 times ~thin 14daysor two 500mginfusions
on Day1 andDay14,administered over3,5-4hours). Ofthe 188randomized patients, 182weretreated andfollowed for
upto 56 days. Efficacy assessments weremeasured ondays14,28,42 and56. Themean ageof the91treated patients
in theVenofer<> groupwas61.6years(range 25to 86years) and64 years(range 21to 86years) forthe91 patients in the
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
(4.4%), Other(1,1%), Patient demographic characteristics werenotsignificantly different between thegroups. Astatistically
significantly greater proportion of Venofer<> subjects (35179; 44.3%) compared to oral iron SUbjects (23/82; 28%)had an
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
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%) hadanincrease in hemoglobin 21g/dLandferritin 2160 ng/mL at anytime during thestudy(p<0.OOO1).
Study E: Peritoneal DialysisDopendent-Chronic KidneyDisease (PDD-CKD)
StUdy Ewasa randomized [2:1 treatment: contrail, open-label, multicenter studycomparing PDD-CKD patients receiving an
erythropoietin and IV iron to PDD-CKD patients receiving an erythropoietin alone ~thout iron supplementation. 126
patients~th PDD-CKD, stableerythropoietin for 8 weeks,TSATs 25%,Ferritins 500ng/mL andanaverage baseline
hemoglobin of s 11.5g/dLwererandomized to receive eithernoiron or Venofer<> (ironsucrose injection, USP)(300mgin
250mL0.9%NaCI over1.5hours on Day1 and15and400mgin 250mL0.9%NaCI over2.5 hours on Day29). 121 of
the126randomized patients weretreated andfollowed forupto71days~th a totalof 88patients whocompleted thestudy.
Efficacy assessments were measured on days 15, 29, 43, 57 and 71. Patient demographic characteristics were not
significantly different between thegroups. Themean ageof the75 treated patients in theVenofer<> I erythropoietin group was
51,9years(range 21 to 81 years) vs. 52.8years(range 23 to 77 years) for 46 patients in the erythropoietin alonegroup,
Ethnicity breakdown ofthepetients in theVenofer<>1 erythropoietin Group wasasfollows: Caucasian (36%); Hispanic (32%);
Black(21.3%); Other(10.7%). Ethnicity breakdown for the erythropoietin alonegroup was: Hispanic (43,5%); Caucasian
(30.4%); Biack (15.2%); Ofher(10,9%). Patients in theVenofer<> 1erythropoietin group hadstatistically significantly greater
mean change frombaseline to the highest hemoglobin value (1.3g/dL), compared to subjects whoreceived erythropoietin
alone (0.6g/dL)(p < 0.01). A statistically significantly greater proportion of subjects treated ~th Venofer<> 1erythropoietin
(59.1 %) hadan inaeasein hemoglobin of 2 1 g/dLat anytimeduring the stUdy compared to the subjecls who received
erythropoietin only(33,3%) (p < 0,05),
CUNICALINDICATIONS ANDUSAGE
Venofer<> is indicated in thetreatment of irondeficiency anemia in thefollowing patients:
• non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving an erythropoietin
• non-dialysis dependent-chronic kidney disease (NDD-CKD) patients notreceiving anerythropoietin
• hemodialysis dependent-chronic kidney disease (HDD-CKD) patients receiving anerythropoielin
• peritoneal dialysis dependent-chronic kidney disease (PDD-CKD) patients receiving anerythropoietin.
CONTRAINDICATIONS
Theuseof Venofer<> is contraindicated in patients withevidence of ironoverload, in patients ~lh known hypersensitivity to
Venofer<> or anyof its inactive components, andin patients ~th anemia notcaused by irondeficiency.
WARNINGS
Hypersensitivity reactions have been reported ~th injectable iron products, See PRECAUTIONS and ADVERSE
REACTIONS,
PRECAUTIONS
General:
Because bodyironexcretion is limited andexcess tissueironcanbehazardous, caution should beexercised to ~thhold iron
administration in the presence of evidence of tissue ironoverload. Palients receiVing Venofer<> require periodic monitoring of
hematologic and hematinic parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Iron therapy
should be ~thheld in patienls ~th evidence of iron overload. Transferrin saturation values increase rapidly after IV
administration of ironsucrose; thus,serum iron values maybe reliably obtained 48 hours afterIV dosing, (SeeDOSAGE
ANDADMINISTRATION andOVERDOSAGE),
HypersensitivityReaelions:
Serious hypersensitivity reactions havebeenreported in patients receiving Venofer<>. No life-threatening hypersensitivity
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
receiving Venofer<>. SeeADVERSE REACTIONS.
Hypotension:
Hypotension hasbeen reported frequently in hemodialysis dependent-chronic kidney disease patients receiving intravenous
iron. Hypotension also has been reporled in non-dialysis dependent and peritoneal dialysis dependent-chronic kidney
disease patients receiving intravenous iron. Hypotension foll~ng administration of Venofer<> maybe related to rate of
administration andtotaidoseadministered, Caution should be taken to administer Venofer<> according to recommended
guidelines. SeeDOSAGE ANDADMINISTRATION.
Carcinogenesis, Mutagenesis, and Impairmentof Fertility:
Nolong-tenn studies in animals havebeenperfonned to evaiuate thecarcinogenic potential of Venofer<>.
Venofer<> wasnotgenotoxic in theAmestest,themouse lymphoma cell(L5178YfTK+I-) forward mutation test, thehuman
lymphocyte chromosome aberration test, orthemouse micronucleus test.
Venofer<> atIVdoses upto 15mgiron/kg/day (about 1.2timestherecommended maximum human doseona bodysurface
areabasis) wasfound to havenoeffectonfertility andreproduclive perfonnance of maleandfemale rats.
Pregnancy CategoryB:
Teratology studies havebeen perfonned in ratsat IV dosesup to 13 mg iron/kg/day (about 0.5 times the recommended
maximum human doseon a bodysurface areabasis) andrabbits at IV doses up to 13 mg iron/kg/day (about 1 timesthe
recommended maximum human doseona bodysurface areabasis) andhevereveaied noevidence of impaired fertility or
harmto the fetusdue to Venofer<>, There are, however, no adequate and well controlled studies in pregnant women.
Because animal reproduclion studies are not always predictive of human response, this drug should be usedduring
pregnancy onlyif ciearly needed.
NursingMothers:
Venofer<> is excreted in milkof rats, It is not known whether thisdrugis excreted in human milk.Because manydrugs are
exaeted inhuman milk, caution should beexercised lNhen venofer«> isadministered toa nursing woman.
PediatricUse:
Safety andeffectiveness ofVenofer<> in pediatric patients havenotbeen established. In acountry where Venafer<> is available
for usein children, at a single site,fivepremature infants (weight lessthan1,250g) developed necrotizing enterocolitis and
two of the five expired during or follo~ng a period when they received Venofer<>, several other medications and
erythropoietin. Necrotizing enterocolitis may be a complication of prematurity In verylowbirth weight infants, Nocausal
relationship toVenofer<> oranyother drugs could be established,
GeriatricUse:
Studies A through E did not include sufficient numbers of subjects aged65 yearsandolderto detennine whether they
respond differently fromyounger subjects. Ofthe1,051 patients in two post-marl<eting safetystudies of Venafer<>, 40%were
65years andolder, Nooverall differences in safety wereobserved between these SUbjects andyounger SUbjects, andother
reported clinical experience hasnotidentified differences in responses between theelderly andyounger patients, butgreater
sensitivity of some olderindividuals cannot beruledout.
ADVERSE REACTIONS
AdverseEventsobservedin atl treated populations
Thefrequency ofadverse events associated ~th theuseofVenofer<> hasbeen documented in sixrandomized clinical trials
involving 231hemodialysis dependent, 139non-dialysis dependent and75peritoneal dialysis dependent-CKD patients; and
in twopost-marketing sefetystudies involving 1,051 hemodialysis dependent-CKD patients for a totalof 1,496patients. In
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
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
(MultidoseSafetyPopulation)
"NOS= Nototherwise specified
Adverse Events
(Preferred Tenm)
HDD-CKD NDD-CKD PDD-CKD
Venofer0
(N=231)
%
Venofer'>
(N=139)
%
Oral Iron
(N=139)
%
Venofer0
(N=75)
%
EPOOnly
(N=46)
%
Subjects with any adverse event 78.8 76.3 73.4 72.0 65.2
Ear and Labyrinth Disorders
Ear Pain 0 2.2 0.7 0 0
Eye Disorders
Conjunctivitis 0.4 0 0 2,7 0
Gastrointestinal Disorders
Abdominal pain NOS" 3.5 1.4 2.9 4.0 6.5
Constipation 1.3 4.3 12.9 4.0 6.5
Diarrhea NOS 5,2 7,2 10.1 8.0 4.3
Dysgeusia 0.9 7.9 0 0 0
Nausea 14.7 8,6 12,2 5.3 4.3
Vomiting NOS 9.1 5.0 8,6 8.0 2.2
General Disorders and
Administration Site Conditions
Asthenia 2.2 0.7 2.2 2.7 0
Chest pain 6.1 1.4 0 2.7 0
Edema NOS 0.4 6,5 6.5 0 2.2
Fatigue 1.7 3,6 5.8 0 4.3
Feeling abnormal 3.0 0 0 0 0
Infusion site buming 0 3.6 0 0 0
Injection site extravasation 0 2.2 0 0 0
Injection site pain 0 2,2 0 0 0
Peripheral edema 2.6 7.2 5,0 5.3 10,9
Pyrexia 3.0 0.7 0.7 1.3 0
Infections and Infestations
Catheter site infection 0 0 0 4.0 8.7
Nasopharyngitis 0.9 0.7 2.2 2.7 2.2
Peritoneal infection 0 0 0 8.0 10.9
Sinusitis NOS 0 0.7 0.7 4.0 0
Upper respiratory tract infection NOS 1.3 0.7 1.4 2.7 2.2
Urinary tract infection NOS 0.4 0.7 5,0 1.3 2,2
Injury, Poisoning and
Procedural Complications
Graft complication 9.5 1.4 0 0 0
Investigations
Cardiac murmur NOS
Fecal occult blood positive
0.4
0
2.2
1.4
2,2
3,6
0
2.7
0
4,3
Table 2 continued on reverse side.
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 CommonAdverse Events Related to Study Drug Reported in ;, 2% of Patients by Dose Group
(MultidoseSafetyPopulation)- CONTINUED (MultidoseSafetyPopulation) - CONTINUED
Adverse Events
(Preferred Term)
HDD-CKD NDD-CKD PDD-CKD
Venofer®
(N=231)
Venofer®
(N=139)
Oral Iron
(N=139)
Venofer®
(N=75)
EPOOnly
(N=46)
% % % % %
Metabolism and Nutrition Disorders
Fluid overload 3.0 1.4 0.7 1.3 a
Gout a 2.9 1.4 a a
HyperglycemiaNOS a 2.9 a a 2.2
HypoglycemiaNOS 0.4 0.7 0.7 4.0 a
Musculoskeletal and Connec1ive
Tissue Disorders
Arthralgia 3.5 1.4 2.2 4.0 4.3
Arthritis NOS a a a a 4.3
Sack pain 2.2 2.2 3.6 1.3 4.3
Muscle cramp 29.4 0.7 0.7 2.7 a
Myalgia a 3.6 a 1.3 a
Pain in extremity 5.6 4.3 a 2.7 6.5
Nervous System Disorders
Dizziness 6.5 6.5 1.4 1.3 4.3
Headache 12.6 2.9 0.7 4.0 a
Hypoesthesia a 0.7 0.7 a 4.3
Respiratory,Thoracic and
Mediastinal Disorders
Cough 3.0 2.2 0.7 1.3 a
Dyspnea 3.5 3.6 0.7 1.3 2.2
Dyspnea exacerbated a 2.2 0.7 a a
Nasal congestion a 1.4 2.2 1.3 a
Pharyngitis 0.4 a a 6.7 a
Rhinitis allergic NOS a 0.7 2.2 a a
Skin and Subcutaneous lissue
Disorders
Pruritus 3.9 2.2 4.3 2.7 a
Rash NOS 0.4 1.4 2.2 a 2.2
Vascular Disorders
HypertensionNOS 6.5 6.5 4.3 8.0 6.5
HypotensionNOS 39.4 2.2 0.7 2.7 2.2
Adverse Events
(Preferred Term)
HDD-CKD NDD-CKD PDD-CKD
100mg
(N=231)
%
200mg
(N=109)
%
SOOmg
(N=30)
%
300 mg for 2 doses
followed by
400 mg for 1 dose
(N=75)
%
General Disorders and
Administration Site
Conditions
Infusion site burning a 3.7 a a
Injeelion site pain a 2.8 a a
Peripheraledema a 1.8 6.7 a
Nervous System Disorders
Dizziness a 2.8 6.7 a
Headache a 2.8 a a
Vascular Disorders
HypotensionNOS 5.2 a 6.7 a
NOS= Nototherwise specified
Treatment-emergent adverse events reported in ;,2%of patients bydosegroupareshown in Table 3.
Table3.MostCommonTreatment-Emergent AdverseEventsReported in ;,2% of Patientsby DoseGroup(Multidose
SafetyPopulation)
Adverse Events
(Preferred Term)
HDD-CKD NDD-CKD PDD-CKD
100mg
(N=231)
%
200mg
(N=109)
%
500mg
(N=30)
%
300 mg for 2 doses
followed by
400 mg for 1 dose
(N=75)
%
Subjects with any adverse event 78.8 75.2 80.0 72.0
Ear and Labyrinth Disorders
Ear Pain a 0.9 6.7 a
Eye Disorders
Conjunctivitis 0.4 a a 2.7
Gastrointestinal Disorders
Abdominal pain NOS· 3.5 1.8 a 4.0
Constipation 1.3 3.7 6.7 4.0
DiamheaNOS 5.2 6.4 10.0 8.0
Dysgeusia 0.9 9.2 3.3 a
Nausea 14.7 9.2 6.7 5.3
Vomiting NOS 9.1 5.5 3.3 8.0
General Disorders and
Administration Site Conditions
Asthenia 2.2 0.9 a 2.7
Chest pain 6.1 0.9 3.3 2.7
Edema NOS 0.4 7.3 3.3 a
Fatigue 1.7 4.6 a a
Feeling abnormal 3.0 a a a
Infusion site burning a 3.7 3.3 a
Injection site pain a 2.8 a a
Peripheraledema 2.6 5.5 13.3 5.3
Pyrexia 3.0 0.9 a 1.3
Infections and Infestations
Catheter site infection a a a 4.0
Nasopharyngitis 0.9 0.9 a 2.7
Perrtoneal infection a a a 8.0
Sinusitis NOS a a 3.3 4
Upper respiratory trael infeelion 1.3 0.9 a 2.7
Injury, Poisoning and
Procedural Complications
Graft complication 9.5 1.8 a a
Investigations
Cardiac mumnur NOS
Fecal occult blood positive
0.4
a
2.8
1.8
a
a
a
2.7
Metabolism and Nutrition Disorders
Fluid overload 3.0 1.8 a 1.3
Gout a 1.8 6.7 a
HyperglycemiaNOS a 3.7 a a
HypoglycemiaNOS 0.4 0.9 a 4.0
Musculoskeletal and Connective
lissue Disorders
Arthralgia 3.5 0.9 3.3 4.0
Sack pain 2.2 1.8 3.3 1.3
Muscle cramp 29.4 a 3.3 2.7
Myalgia a 2.8 6.7 1.3
Pain in extremity 5.6 4.6 3.3 2.7
Nervous System Disorders
Dizziness 6.5 5.5 10.0 1.3
Headacihe 12.6 3.7 a 4.0
Respiratory, Thoracic and
Mediastinal Disorders
Cough 3.0 0.9 6.7 1.3
Dyspnea 3.5 1.8 10.0 1.3
Pharyngitis 0.4 a a 6.7
Skin and Subcutaneous lissue Disorders
Pruritus 3.9 0.9 6.7 2.7
Vascular Disorders
HypertensionNOS 6.5 6.4 6.7 8.0
HypotensionNOS 39.4 0.9 6.7 2.7
'NOS= Nototherwise specified
Drug related adverse events reported by;, 2%ofVenofe'"treated patients areshown bydose group in Table 4.
Table 4. Most Common Adverse Events Related to Study Drug Reported in ;, 2% of Patients by Dose Group
(MultidoseSafetyPopulation)
Adverse Events
(Preferred Term)
HDD-CKD NDD-CKD PDD-CKD
100 mg
(N=231)
%
200 mg
(N=109)
%
500 mg
(N=30)
%
300 mg for 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
DiamheaNOS'
Dysgeusia
Nausea
0.9
0.9
1.7
a
7.3
2.8
a
3.3
a
2.7
a
1.3
'NOS = Notofherwise specified
AdverseEventsObserved in Hemodialysis Dependent-Chronic KidneyDisease (HDD-CKD) Patients
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,andCwereasfollows: 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%), anddiarrhea (5.2%).
In the firstpost-marKeting safety study, 665chronic hemodialysis patients weretreated withVenofe'"doses of 100mgat
eachdialysis session forupto 10consecutive dialysis sessions for theiriron deficiency or on a weekly basis for 10weeks
for maintenance of iron stores. In this study, 72%of the patients received up to 10 doses, 27%received between 11-30
doses, and1% received 40to SO doses ofVenofe"'. Serious adverse events anddrug-related non-serious adverse events
werecolleeled. In the seoond post-marKeting safety study, 386hemodiaiysis patients wereexposed to a single dose of
Venofe'"(100mgIV by slowinjeelion over2 minutes or 200mgIV by slowinjeelion over5 minutes). Themean ageof
patients enrolled intothetwopost-marKeting safetystudies was59 years, witha range of 2()'93years. Malesmade up60%
of the population. The ethnicity of the patients enrolled in the two studies included Blacks (44%), Caucasians (41 %),
Hispanics (11%), Asians (3%), andothers (1%). Adverse events reported by> 1%of 1,051 treated patients were: cardiac
failure congestive, sepsis NOSanddysgeusia.
AdverseEventsObserved in Non-Dialysis Dependent-Chronic KidneyDisease (NDD-CKD) Patients
In Study D of 162treated NDD-CKD patients, 91 were exposed to Venofe"'. Adverse events, whether or not related to
Venofe"', reported by;,5%oftheVenofe'" exposed patients wereasfollows: dysgeusia (7.7%), peripheral edema (7.7%),
diarrhea (5.5%), oonstipation (5.5%), nausea (5.5%), dizziness (5.5%), and hypertension (5.5%). One serious related
adverse reaelion wasreported (hypotension andshortness of breath notrequiring hospitalization in aVenofe'"patient). Two
patients experienced possibie hypersensitivity/allergic reaelions (local edema/hypotension) during the study. Of the 5
patients whoprematurely discontinued the treatment phase of the studydueto adverse events (2 oral irongroupand3
Venofe'"group), threeVenofe'"patients hadevents thatwereconsidered drug-reiated (hypotension, dyspnea andnausea).
In an additional study of Venofe.., with varying erythropoietin doses in 96 treated NDD-CKD patients, adverse events,
whether or notrelated toVenofe'"reported by25%of Venofe'"exposed patients areasfollows: diarrhea (16.5%), edema
(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
hypersensitivity/allergic reaction during the stUdy. Of thepatients whoprematurely discontinued thetreatment phase of the
studydueto adverse events (2.1% oralirongroupand12.5% Venofe'"group), onlyonepatient (Venofe'"group) hadevents
thatwereconsidered drug-related (anxiety, headache, andnausea). Ninety-one (91)patients in thisstudywereexposed to
Venofe'"eitherduring thetreatment or extended follow-up phase.
AdverseEventsObserved in Peritoneal DialysisDependent-Chronic KidneyDisease (PDD-CKD) Patients
in StUdy Eof 121 treated PDD-CKD patients, 75patients wereexposed to Venofe"'. Adverse events, whether ornotrelated
to Venofe'" reported by z 5% of these patients are as follows: diarrhea, peritoneal infection, vomiting, hypertension,
pharyngitis, peripheral edema andnausea.
In these 75patients exposed to Venofe"', 9 patients experienced serious adverse events asfollows: peritoneal infeelion (2
patients) and 1 patient eachwith cardiopulmonary arrest, myocardiai infarelion, upperrespiratory infeelion NOS, anemia,
gangrene, hypovolemia andtuberculosis. None of these events were considered drug-related. TwoVenofe'" patients
experienced a moderate hypersensitivity/allergic reaction (rashor sweliinglitching) during thestudy.
Theonlydrugrelated adverse reaction to Venofe'"administration reported by22%of patients wasdiarrhea.
Three patients in the Venofe,., studygroupdiscontinued study treatment due to adverse events (cardiopuimonary arrest,
peritonitis andmyocardial infarelion, hypertension) which wereconsidered to benotdrug-reiated.
HypersensitivityReactions: SeeWARNINGS andPRECAUTIONS.
In clinical studies, several patients experienced hypersensitivity reactions presenting withwheezing, dyspnea, hypotension,
rashes, or pruritus. Serious episodes of hypotension occurred in 2 patients treated withVenofe'"at a dose of500mg.
Thepost-marKeting spontaneous reporting system inciudes reports of patients whoexperienced serious or life-threatening
reaelions (anaphylaelic shock, lossof consciousness or collapse, bronchospasm withdyspnea, or convulsion) associated
withVenofe'"administration.
Onehundred thirty(11%) of the 1,151 patients evaluated in the 4 U.S. trialsin HDD-CKD patients (studies A, B andthetwo
postmarketing studies) hadpriorotherintravenous irontherapy andwerereported to beintolerant (defined as precluding
further useof that iron produel). When these patients weretreated withVenofe'"therewereno occurrences of adverse
events thatprecluded further useof Venofe"'.
OVERDOSAGE
Dosages ofVenofe'"(ironsucrose injeelion, USP) in excess of ironneeds mayleadto accumulation of ironin storage sites
leading tohemosiderosis. Periodic monitoring ofiron parameters such asserum fanilin and transferrin saturation may assist
in recognizing iron accumulation. Venofe'" should not be administered to patients with iron overload and should be
discontinued whenserum ferritin levelsequal orexceed established guidelines [5). Particular caution should beexercised to
avoid iron overload where anemia unresponsive totreatment has been incorrectly diagnosed asiron deficiency anemia.
Symptoms associated withoverdosage orinfusing Venofe'"toorapidly included hypotension, dyspnea, headache, vomiting,
nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. Most
symptoms havebeen successfully treated with IV fluids, hydrocortisone, and/orantihistamines. Infusing the solution as
recommended or at a slower ratemayalsoalleviate symptoms.
PreclinicalData:
Single IV doses of Venofe'"at lSOmgiron/kg in mice (about 3 timesthe recommended maximum human doseon a body
surface areabasis) and100mgiron/kg in rats(about 6 timestherecommended maximum human dose on a body surface
areabasis) werelethal.
Thesymptoms of acute toxicjty weresedation, hypoaelivity, paleeyes, andbleeding in thegastrointestinal tractandiungs.
DOSAGE ANDADMINISTRATION
Thedosage ofVenofe'"is expressed in terms ofmgof elemental iron. Each mLcontains 20mgof elemental iron.
MostCKDpatients will require a minimum cumulative repletion dose of 1,000 mg of elemental iron, administered over
sequential sessions, to achieve a favorable hemoglobin response andto replenish ironstores (ferritin, TSAl). Hemodialysis
patients maycontinue to require therapy withVenofe'"or otherintravenous ironpreparations at thelowest dosenecessary
to maintain target ievelsof hemoglobin, andlaboratory parameters of ironstorage within acceptable limits.
Administration:Venofe'"mustonlybeadministered intravenously eltharbyslowinjection or by infusion.
Recommended Adult Dosage:
Hemodialysis Dependent-Chronic Kidney Disease Patients (HDD-CKD): Venofe'"maybeadministered undiluted as a
100mgslowintravenous injection over2 to 5 minutes orasaninfusion of 100mg,diluted in a maximum of 100mLof 0.9%
NaCi overa period of at least15minutes per oonsecutive hemodialysis session fora totalcumulative doseof 1,000 mg.
Non-Dialysis Dependent-Chronic Kidney Disease Patients(NDD-CKD): Venofe'"is administered as a totalcumulative
doseof 1,000mgovera 14dayperiod asa 200mgslowIV injeelion undiluted over2 to 5 minutes on5 different occasions
within the 14dayperiod. There is limited experience withadministration of aninfusion of SOO mgof Venofe"', diluted in a
maximum of250mLofO.9% NaCI, overa period of3.5-4hours onday1andday14;hypotension occurred in2 of30patients
treated. (SeeCLINICAL TRIALS, Study0: Non-Dialysis Dependenl-Chronic KidneyDisease (NDD-CKD) Patientsand
ADVERSE REACTIONS, AdverseEventsObserved in Non-Dialysis Dependent Chronic Kidney Disease (NDD-CKD)
Patientssections.)
Peritoneal Dialysis Dependenl-Chronic Kidney Disease Patients (PDD-CKD): Venofe'" is administered as a total
cumulative dose of 1,000 mg in 3 divided doses, givenby slowintravenous infusion, wrthin a 28 dayperiod: 2 infusions of
300mgover1.5hours 14daysapart followed byone400mgInfusion over2.5hours 14dayslater. TheVenofe'"doseshould
bediluted in a maximum of250mLof 0.9%NaCI.
HOWSUPPLIED
Venofe'"is supplied in 5 mLand10mLsingle dosevials. Each 5 mLvialcontains 100mgelemental iron(20mg/mL) and
each 10 mLvial contains 200mg elemental iron(20 mg/mL). Contains no preservatives. Store in original carton at 25'C
(77'F). Excursions permitted to 15'-30'C (59'-86'F).[SeetheUSPoontrolled room temperature]. Donotfreeze.
Sterile
100mg/5mLSingle Dose Vial
100mg/5mLSingle Dose Vial
100mg/5mLSingle Dose Vial
NDC-0517-234()'01
NDC-0517-234()'10
NDC0517-234()'25
Individually Boxed
Packages of 10
Packages of 25
200mg/l0 mLSingle Dose Vial
200mg/10 mLSingle Dose Vial
200mg/l0 mLSingle Dose Vial
NDC-0517-231()'01
NDC-0517-231()'05
NDC-0517-231()'10
Individually Boxed
Packages of 5
Packages of 10
RxOnly
1. Getting enough dialysis to stay healthy for patients on Hemodialysis
(Adequacy of Hemodialysis).
2. Getting enough dialysis to stay healthy for Peritoneal Dialysis patients
(Adequacy of Peritoneal Dialysis).
3. The best ways to provide you with a blood access for dialysis (fistula, graft, or
catheter) and how to care for that access (Vascular Access).
4. The best ways to use an ESA (erythropoietin stimulating agent) and iron to
keep your blood count high and prevent anemia (Anemia Management).
The NKF-DOQI™ guide helped make patient care better. Because of this, the NKF
decided to update their original guides and to print new guides for other special
problems of patients with kidney disease. They changed the name from the NKF
Dialysis Outcomes Quality Initiative (NKF-DOQI™) to the NKF-Kidney Disease
Outcomes Quality Initiative (NKF-KDOQI™).
This pamphlet you are about to read tells only one small story. It explains the
importance of:
How iron prevents anemia in patients with kidney disease (like you).
National Kidney
Foundation Kidney
Disease Outcomes
Quality Initiative
2
When your doctor tells you that your blood count is low, it
means you do not have enough red blood cells (RBCs)
in your blood. Red blood cells are responsible for
delivering oxygen throughout the body. Anemia is a sign
of disease, and not a disease itself. This is very common
in chronic kidney disease. Anemia can also be caused by hemodialysis alone. There is
always some blood that remains in the dialyzer and blood lines after each treatment.
When you lose blood, you are losing RBCs, and when you lose RBCs, you lose
hemoglobin and iron.
Possible Symptoms of anemia
• Often, no symptoms
• Paleness
• Feeling tired
• Unusual shortness of breath
• Fast heartbeat
• Colder hands and feet than usual
• Headaches
Anemia, over a long period of time, can cause you to have problems with your heart.
If you already have heart problems, it can make those problems worse.
The Kidneys, Iron and Anemia.
The healthy kidney produces a hormone called erythropoietin
(commonly known as EPO). A hormone is a chemical substance
that acts as a messenger delivering material from one part of the
body to another. RBCs are formed in the bone marrow with the
help of this hormone. The bone marrow is also supplied with a
small amount of iron, which helps to build healthy new RBCs.
Then the RBCs carry oxygen to all parts of the body. Every living human cell needs
oxygen to live. Muscles are made up of millions of cells. An important muscle is the
heart. This is why heart conditions can develop or worsen if there are not enough
RBCs to deliver oxygen to the cells of the heart. Oxygen is the fuel for cell survival.
What is
Anemia?
3
There are two common causes of anemia in chronic kidney disease patients:
1. Too few red blood cells. This is because the kidney is no longer making the
hormone erythropoietin.
2. Too little iron.
Too little iron may be caused by the following:
• Diet restrictions
• The body is not able to absorb enough iron
• Some blood is lost during hemodialysis. It’s almost impossible to return all
your blood after hemodialysis. Some blood remains in the dialyzer and tubing
• Other blood loss: GI (gastrointestinal) bleeding, catheter lines, bleeding from
the access site after hemodialysis, surgery, clotted dialyzers and blood lines
• Erythropoietic stimulating agents (ESA) such as EPO speed up the making of
RBCs and quickly use a lot of the iron in your body to make RBCs
How your doctor knows when to give you iron.
The blood tests that are taken each month will give your doctor a picture of how
healthy your red blood cells are. It will show if they are receiving enough iron. (These
tests may be taken less often if your red blood count remains good.)
There are blood tests that show how
your red blood cells are doing and there
are blood tests that show where the iron
is in your body and how it is being used.
What happens when the kidneys don’t work properly?
4
1. Hemoglobin: This is the part of the red blood cell which contains iron and
carries oxygen.
2. Hematocrit: a percentage of red blood cells (RBCs) within a sample of blood.
1. Ferritin: This is a protein that reflects stored
iron. Think of ferritin as gas in the tank. You need
to have enough gas to keep a car running. This
is why it is important to measure and track these
values regularly. Remember, when you lose blood
you lose iron and RBCs. Losing iron is like losing
gas from your car.
When you have a serious infection, it is possible that your body will hold onto the iron
in storage. In this case, your ferritin levels will be high but you don’t have enough iron
in your red blood cells. The infection should be treated before continuing your iron
therapy.
2. Transferrin Saturation (TSAT): Transferrin is a protein that takes the iron from
the storage protein (ferritin), or the iron that you’re being treated with, and
brings it to the bone marrow where it may be used to build healthy red blood
cells. This lab value is a percentage. Think of it as the tube that brings the
gas to the engine. It’s the transportation vehicle for iron. A TSAT of <20%
means that you do not have enough iron for your RBCs.
Reticulocyte Hemoglobin Content (CHr): This test measures the amount of
iron in the youngest red blood cells, known as reticulocytes. This lets you see
iron status earlier in the newest RBCs and is a more sensitive test when you
have an infection or inflammation. During infection or inflammation,
your ferritin levels can be higher even if you do not have enough iron. The
CHr level is not affected in this way, and can help show if you need iron
therapy. This new test has been added to the NKF-KDOQI guidelines for 2006.
Your most important red blood cell tests are:
The two iron blood tests you should know about are:
Other:
5
Lab Values Hemodialysis
Dependent CKD
Non-Dependent Dialysis
CKD & Peritoneal Dialysis
Hemoglobin
Ferritin
Transferrin Saturation
CHr
>11 g/dL
200 - 500 ng/mL
>20%
>29 pg/cell
>11 g/dL
100 - 500 ng/mL
>20%
None Recommended
Reading this booklet is one of the first
steps to preventing and controlling
anemia. It’s very important to find the
reason for a low iron level. Talk to your
doctor or nurse if you think you might
have anemia. A blood test will probably
be done to diagnose anemia. GI
bleeding many times is undetected. If you develop dark tarry stools, report it
immediately to your doctor or nurse. Other tests may be needed to find out what’s
causing the anemia. Early and controlled treatment can reduce some of the symptoms
of anemia.
Taking an erythropoietin stimulating agent (ESA). Since as a patient with chronic
kidney disease you may not be making enough erythropoietin, you will receive a manmade
form of erythropoietin. An ESA may be given during your hemodialysis treatment
through the blood lines or by an intravenous (IV) injection. It may also be given by a
very small injection under your skin. This is a subcutaneous or S.C. injection.
Taking Iron. Taking iron by mouth (oral iron) may be enough if you are not receiving
an ESA. However, some patients with chronic kidney disease and almost all patients
on hemodialysis who are taking an ESA will need to receive injectable iron. Oral iron is
not fast enough to replace the iron that’s needed once the ESA begins to make new
red blood cells.
What can be
done to prevent or
control anemia?
National Kidney Foundation (NKF) KDOQI Guidelines
Based on recent recommendations the target range is between 11.0 g/dL to 12.0 g/dL. Each patient should discuss how
best to treat their anemia with their doctor and such treatment should be based on their individual healthcare needs.
*
6
*
Stored iron will be used when needed but eventually will need to be replaced for future
use. Without enough iron, an ESA cannot completely correct anemia.
If you are on an ESA and you are not getting enough iron, your doctor may
treat you with intravenous (IV) iron. You will receive intravenous iron during your
hemodialysis treatment or when you come to your doctor’s office or clinic visit.
There are two ways of receiving iron if diet alone is not enough. Your doctor may
prescribe oral iron (pills that you may buy without a prescription). Oral iron is usually
given three times a day between meals. How and when you take oral iron is very
important:
• Take iron one hour before or two hours after a meal
• Do not take with antacids
• Do not take phosphate binders at the same time
• Avoid alcohol
If you begin to get constipated, have nausea, or a feeling of fullness, consult your
doctor. You may take stool softeners to help avoid constipation, and let your doctor
know if you begin to have this problem. If you are not able to obtain a good blood
count with oral iron, your doctor may prescribe intravenous iron. This is the iron
injected into your bloodstream.
An ESA and iron work together to help your body make healthy new red blood cells.
Your doctor will decide how to give you these drugs based on the procedures in your
dialysis unit and the suggestions from the NKF-KDOQI™ guidelines.
The Food and Drug Administration (FDA) has approved four types of intravenous
iron injectable products for use in the United States. These are iron sucrose, iron
dextran, iron gluconate* and ferumoxytol. All of these will help to increase the amount
of iron you have in your body. There are some differences among them, however.
*Iron gluconate: also known as sodium ferric gluconate in sucrose injection.
What type of iron may my doctor prescribe?
7
These differences have to do with the approved uses, how quickly they work, whether
or not a test dose is required, the types of side effects you may see, and the size of
your dose. Your doctor will decide which is best for you. Like many other treatments,
IV iron may be partially covered through your medical insurance.
A person can experience an allergic reaction to intravenous iron just as they do to
other medications. It is important for you to notify your doctor or a member of the
dialysis staff immediately if you experience:
• Flushing
• Difficulty breathing
• Itching
• Rash
• Any unusual symptoms during or just after the drug was given
If you have had an allergic reaction to intravenous iron in the past, you need to
discuss with your doctor whether a different type of intravenous iron may be better
for you.
Conclusion
We hope this booklet has helped you understand the importance of iron in your
body to help correct the problem of anemia. If you still have questions about iron or
anemia, talk to your doctor. We salute you for taking the time to learn about your
health, and hope you will continue to take steps to be an active participant in your
care.
8
Anemia: A decrease in the amount of red blood cells that are needed
to carry enough oxygen to meet the body’s needs.
CHr: Reticulocyte Hemoglobin Content. This lab value measures
the iron status of a young red blood cell usually 24
hours before it becomes a mature red blood cell.
CKD: Chronic Kidney Disease (reduced kidney function).
EPO: (Erythropoietin). A hormone produced by the kidney. It
stimulates the bone marrow to produce red blood cells.
ESA: Erythropoietin stimulating agent. Drugs that replace the hormone
erythropoietin when the kidneys fail to produce it.
Ferritin: A form of storage iron.
Hematocrit: Measures the amount of red blood cells within a specific
amount of blood.
Hemoglobin: The part of the red blood cells that carries oxygen from
the lungs to the tissues.
RBC: Red blood cell.
Transferrin: A protein in the blood that carries iron.
Transferrin Saturation:
(TSAT) measures the amount of iron that is immediately
available to produce RBCs.
Glossary
9
10
Aronoff G, Van Wyck D. Iron sucrose in hemodialysis patients: Safety of replacement and maintenance regimens.
Kidney International 2004;66:1-6.
Bailie GR, Clark JA, Lane CE, Lane PL. Hypersensitivity reactions and deaths associated with intravenous iron
preparations. Nephrology Dialysis Transplantation (2005); Advance Access Publication.
Bailie G, Johnson C, Mason N. Parenteral Iron Use in the Management of Anemia in End-Stage Renal Disease
Patients. Am J Kidney Dis 35:1, pp. 1-12, January 2000.
Bailie G, Johnson C, Mason N. Parenteral iron products for anemia in end-stage renal disease: Comparative
considerations. Formulary 35:6, June 2000.
Blaustein D, Schwenk M, Chattopadhyay J, Singh H, Daoui R, Gadh R, Avram M. The safety and efficacy of an
accelerated iron sucrose dosing regimen in patients with chronic kidney disease. Kidney International 2003;64(S
87);S72-S77.
Charytan C. Comparison of intravenous iron sucrose to oral iron in the treatment of anemic patients with chronic
kidney disease not on dialysis. Nephron Clinical Practice 2005;100:c55-c62.
Charytan C, Levin N, Al-Saloum M, Hafeez T, Gagnon S, Van Wyck D. Efficacy and safety of iron sucrose for
iron deficiency in patients with dialysis-associated anemia: North American clinical trial. Am J Kidney Dis
2001;37:300-307.
Charytan C, Schwenk M, Al-Saloum M, Spinowitz B. Safety of iron sucrose in hemodialysis patients intolerant to
other parenteral iron products. Nephron Clinical Practice 2004;96:c63-c66.
Macdougall IC, Roche A. Administration of intravenous iron sucrose as a 2-minute push to CKD patients: A
prospective evaluation of 2,297 injections. Am J Kidney Dis 2005;46(2):283-289
NKF - K/DOQI: Clinical practice guidelines for Anemia of Chronic Kidney Disease: Update 2006. American Journal
of Kidney Diseases, Vol 47, No 5, Suppl 3(May), 2006: pp S58-S70.
Schiesser D, Binet I, Tsinalis D, Dickenmann M, Keusch G, Schmidli M, Ambuhl PM, Luthi L, Wuthrich RP.
Weekly low-dose treatment with intravenous iron sucrose maintains iron status and decreases epoetin requirement
in iron-replete haemodialysis patients. Nephrology Dialysis Transplantation 2006.
Singh H, Reed J, Noble S, Cangiano JL, Van Wyck D. Effect of intravenous iron sucrose in peritoneal dialysis
patients who receive erythropoiesis-stimulating agents for anemia: A randomized, controlled trial. Clin J Am Soc
Nephrol 2006.
Van Wyck D, Cavallo G, Spinowitz B, Adhikaria R, Gagnon S, Charytan C, Levin N. Safety and Efficacy of Iron
Sucrose in Patients Sensitive to Iron Dextran: North American Clinical Trial. Am J Kidney Dis 36:1, pp. 88-97, July
2000.
Van Wyck D, Roppolo M, Martinez CO, Mazey RM, McMurray S. A randomized, controlled trial comparing IV iron
sucrose to oral iron in anemic patients with nondialysisdependent CKD. Kidney International 2005;68:2846-2856.
Yee J, Besarab A. Iron sucrose: the oldest iron therapy becomes new. Am J Kidney Dis, 2002;40(6):1111-21.
Bibliography For Further Reading
11
Resources
American Association of Kidney Patients (AAKP): www.aakp.org
Dialysis Patient Citizens: www.dialysispatients.org
National Anemia Action Council: www.anemia.org
Renal Support Network: www.rsnhope.org
Society for the Advancement of Blood Management: www.sabm.org
TISEV2
Rev. 1/2010
One Luitpold Drive, PO Box 9001
Shirley, NY 11967
1-800-645-1706
www.americanregent.com
www.venofer.com
Copyright © 2010 American Regent, Inc.
Leading anemia management.™
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
Venofer<> (ironsucrose injeclion, USP)is a brown, sterile, aqueous, complex of polynuclear iron(1I1)-hydroxide in sucrose for
inlravenous use. Ironsucrose injection hasa molecular weight of approximately 34,000 - 60,000 daltons enda proposed
structural formula:
[Na2FesOa(OH) • 3(H~)ln • m(C12H22011)
where: n is the degree of iron polymerization and m is the number of sucrose molecules associated ~th the iron (111)hydroxide.
EachmLcontains 20mgelemental ironas ironsucrose in waterfor injeclion. Venofer<> is available in5 mLsingle dosevials
(100mgeiemental ironper5 mL)and10mLsingle dosevials(200mgelemental ironper10mL), Thedrugproducl contains
apprOXimately 30% sucrose w/v (300mg/mL) and has a pH of 10.5-11.1. The product contains no preservatives. The
osmolarity of the injection is 1,250mOsmoVL.
Therapeutic class: Hematinic
CLINICAL PHARMACOLOGY
Phannacodynamics: FolI~ng intravenous administration ofVenafer<>, ironsucrose is dissociated bythereticuloendothelial
system into iron and sucrose. In 22 hemodialysis patients on erythropoietin (recombinant human erythropoietin) therapy
treated ~th ironsucrose containing 100mgof 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
sucrose treatment.
Phannacokinetics: In healthy adults treated ~th intravenous dosesof Venofer<>, its ironcomponent exhibits first order
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
for ironin the ironstores andironutilizing tissues of the body, serum clearance of ironis expected to bemore rapid in iron
deficient patients treated ~th Venofer<> as compared to healthy individuals, The effects of age and gender on the
phannacokinetics of Venofer<> havenotbeen studied.
Venofer<> is notdialyzable through CA210 (Baxter) HighEfficiency or Fresenius F80AHighFluxdialysis membranes. Inin
vitrostudies, theamount of ironsucrose in thedialysate fluidwasbelowthelevels of detection oftheassay (iessthan2 parts
permillion),
Distribution: In heallhy adullsreceiving intravenous doses of Venofer<>, its ironcomponent appears to distribute mainly in
bloodandtosomeexlentin extravascular fluid, Astudyevaluating Venofer<> containing 100mgof ironlabeled with52FelS9Fe
in patients with iron deficiency shows thata significant amount of the administered iron distributes in the liver, spleen and
bonemanrow andthatthebonemarrow isan irontrapping compartment andnota reversible volume of distribution,
Metabolismand Elimination: FolI~ng intravenous administration of Venofer<>, ironsucrose is dissociated into ironand
sucrose by the reticuloendothelial system. The sucrose component is eliminated mainly by urinary excretion, In a study
evaiuating a singleintravenous doseof Venofer<> containing 1,510mgof sucrose and 100mgof ironin 12healthy adults
(9female, 3 male: agerange 32-52), 68.3% ofthesucrose waseliminated in urine in 4 hand 75.4% in24h, Some ironalso
is eliminated intheurine, Neither transferrin nortransferrin receptor levelschanged immediately afterthedoseadministration
[1].In thisstudyandanother studyevaluating a single intravenous doseof ironsucrose containing 500-700 mgof ironin 26
anemic patients onerythropoietin therapy (23female, 3 male; agerange 16-60), approximately 5%oftheironwaseliminated
in urinein 24 h at eachdoselevel[2].
Drug-drugInteraelions: Drug-drug interactions involving Venofer<> havenot been studied. However, like otherparenteral
ironpreparations, Venofer<> maybe expected to reduce theabsorption of concomitantly administered oralironpreparations.
CLINICAL TRIALS
Venofer<> is used to replenish body iron stores in non-dialysis dependent-chronic kidney disease (NDD-CKD) patients
receiving erythropoietin and in NDD-CKD patients not receiving erythropoietin, and in hemodialysis dependent-chronic
kidney disease (HDD-CKD) and peritoneal dialysis dependent-chronic kidney disease (PDD-CKD) patients receiving
erythropoietin. Iron deficiency may be caused by blood loss during dialysis, increased erythropoiesis secondary to
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 andnonheme
compounds. Mostdialysis patients require intravenous ironto maintain sufficient ironstores,
Sixclinical trialswereconducted to assess the safety andefficacy of Venofer<>. Fivestudies wereconducted in the United
States (516patients) andonewasconducled in South Africa (131 patients).
StudyA: Hemodialysis Dopendent-Chronic KidneyDisease (HDD-CKD)
StUdyAwasa mullicenter, open-label, historically-controlled stUdy in 101 hemodialysis patients \T7 patients ~th Venofer<>
treatment and24 in the historical control group) ~th iron deficiency anemia. Eligibility for Venofer<> treatment included
patients undergoing chronichemodialysis threelimesweekly, receiving erythropoietin, hemoglobin concentration greater
than8.0andlessthan11.0g/dLfor at leasttwoconsecutive weeks, transferrin saturation < 20%,andserum ferritin <300
ng/mL. Themean ageof the patients in thetreatment groupwas65 years~th theagerange being31 to 85yearsof age.
The erythropoietin dosewasto be held constant throughoul the study, The protocol did not require administration of a
testdose;however, some patients received a testdoseat the physician'S discretion. Exclusion criteria included significant
underlying disease, asthma, activeinflammatory disease, or serious bacterial or viralinfection. Venofer<> 5 mLcontaining
100mg of elemental ironwas administered through the dialysisline at eachdialysis session eitheras slowinjection or a
saline diluted slowinfusion foratotalof10dialysis sessions ~th acumulative doseof 1,000 mgelemental iron, A maximum
of 15mLs(300mgof elemental iron)of Venofer<> wasadministered perweek,
Noadditional ironpreparations wereallowed untilaftertheDay57evaluation. Themean change inhemoglobin frombaseline
to Day24 (endof treatment), Day36, andDay57 wasassessed, Thehistorical control population consisted of 24 patients
~th similarferritin levels as patients treated ~th Venofer<>, whowereoff intravenous ironfor at leasl2weeks andwhohad
received erythropoietin therapy ~Ih hematocrit averaging 31-36for at leasttwo rnomhs priorto stUdy entry. Themean age
of patients in the historical control groupwas56years, ~th anagerange of 29to 80years. Patient ageandserum ferritin
levelweresimilar between treatment andhistorical control patients. Ofthe77patients in thetreatment group, 44(57%) were
maleand33 (43%) werefemale. Themean baseline hemoglobin andhematocrit, werehigheranderythropoietin dosewas
lowerin the historical control population thantheVenofer<> treated population.
Patients in theVenofer<> treated population showed a statistically significantly greater increase in hemoglobin andhematocrit
thandidpatients in the historical control population. SeeTable 1.
Table1. Changesfrom Baselinein Hemoglobin and Hematocrit
Efficacy
parameters
End of Treatment 2 Week follow-up 5 week follow-up
Venofer0
(n=69)
Historical
Control
(n=18)
Venofer'>
(n=73)
Historical
Control
(n=18)
Venofer0
(n=71)
Historical
Control
(n=15)
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
Hematocrit (%) 3,1±O.37~ -{).3±O.65 3.6±O,44~ -1.2±O.76 3,3±O.54 0.2±O,86
~p<0.01 and·p<0,05compared to historical control fromANCOVA analysis ~th baseline hemoglobin, serum ferritin and
erythropoietin doseascovariates.
Serum ferritin increased significantly (p=0.0001) at endpoint of studyfrom 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
significantly (p=0,0016) at endpoint of stUdy frombaseline in theVenofer<>-treated population (8.8±1.6%) compared to this
historical control population (-5.1±4.3%) [3J.
StudyB: HemodialysisDopendent-Chronic KidneyDisease (HDD-CKD)
StUdy B was a multicenter, openlabelstudyof Venofer<> (iron sucrose injection, USP)in 23 iron deficient hemodialysis
patients whohadbeendiscontinued fromirondexlran dueto intolerance, Eligibility criteria andVenofer<> administration were
otherwise idenlical to Study A.Themean ageof thepatients in thisstUdy was53years, withagesranging from21-79years,
Ofthe23patients enrolled in thestudy, 10(44%) weremaleand13(56%) werefemale. Theethnicity breakdown of patients
enrolled in thisstudywasas follows: Caucasian (35%); Black (35%); Hispanic (26%); Asian (4%), Themean change from
baseline to theendof treatment (Day24)in hemoglobin, hematocrit, andserum ironparameters wasassessed.
All 23 enrolled patients wereevaluated for efficacy. Statistically significant increases in mean hemoglobin (1.1±O.2 g/dL),
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.
Study C: HemodialysisDopendent-Chronic KidneyDisease (HDD-CKD)
Study C was a multicenter, open-label, two period (treatment foilowed by observation period) study in iron deficient
hemodialysis patients. Eligibility for this studyincluded chronic hemodialysis patients ~th a hemoglobin lessthanor equai
to 10g/dL, a serum transferrin saturation lessthanor equal to 20%,anda serum ferritin lessthanor equal to 200ng/mL,
whowereundergoing maintenance hemodialysis 2 to 3 timesweekly. Themean age of the patients enrolled in this study
was41years, ~th agesranging from16-70 years. Of 130patients evaluated for efficacy in thisstudy, 68 (52%) weremale
and62 (48%) werefemale. Theethnicity 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
oraliron.Exclusion criteria weresimilar to those in Studies A andB. Venofer<> wasadministered in doses of 100mgduring
sequential dialysis sessions untila pre-detennined (celcelateo) totaldoseof ironwasadministered,
Patients received Venofer<> at eachdialysis session, twoto threetimesweekly. Onehourafterthestartof eachsession,S
mLironsucrose (100mgiron)in 100mL0.9%NaCI wasadministered intothe hemodialysis line. A 50mgdose(2.5mL)
wasgivento patients ~thin two weeksof studyentry. Patients weretreated untiltheyreached anindividually calculated totai
irondosebased on baseline hemoglobin levelandbodyweight. Twenty-seven patients (20%) werereceiving erythropoietin
treatment at studyentryandtheycontinued to receive thesame erythropoietin doseforthe duration of thestUdy.
Changes frombaseline to observation week2 andobservation week4 (endof study) wereanalyzed,
Themodified intention-to-treat populaton consisted of 131 patients. Significant (p<0.0001) increases frombaseline in mean
hemoglobin (1.7g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), andserum transferrin saturation (14%) wereobserved
at week 2 of the observalion period and these values remained significantly increased (p<0,0001) at week 4 of the
observalion period.
Study 0: Non-DialysisDopendent-Chronic KidneyDisease (NDD-CKD)
StUdy D wasa randomized, open-label, multicenter, active-controlled studyof the safety andefficacy of oral iron versus
intravenous ironsucrose (Venofer<» in NDD-CKD patients ~th or ~thout erythropoietin therapy. Erythropoietin therapy was
stabiefor 8 weeks priorto randomization. In the study188patients ~th NDD-CKD, transferrin saturation s 25%,ferritin
s 300ng/mLandanaverage baseline hemoglobin ofs 11.0g/dLwererandomized to receive oraliron(325mgferrous sulfate
threetimes dailyfor 56 days); or Venofer<> (either200mgover2-5minutes 5 times ~thin 14daysor two 500mginfusions
on Day1 andDay14,administered over3,5-4hours). Ofthe 188randomized patients, 182weretreated andfollowed for
upto 56 days. Efficacy assessments weremeasured ondays14,28,42 and56. Themean ageof the91treated patients
in theVenofer<> groupwas61.6years(range 25to 86years) and64 years(range 21to 86years) forthe91 patients in the
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
(4.4%), Other(1,1%), Patient demographic characteristics werenotsignificantly different between thegroups. Astatistically
significantly greater proportion of Venofer<> subjects (35179; 44.3%) compared to oral iron SUbjects (23/82; 28%)had an
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
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%) hadanincrease in hemoglobin 21g/dLandferritin 2160 ng/mL at anytime during thestudy(p<0.OOO1).
Study E: Peritoneal DialysisDopendent-Chronic KidneyDisease (PDD-CKD)
StUdy Ewasa randomized [2:1 treatment: contrail, open-label, multicenter studycomparing PDD-CKD patients receiving an
erythropoietin and IV iron to PDD-CKD patients receiving an erythropoietin alone ~thout iron supplementation. 126
patients~th PDD-CKD, stableerythropoietin for 8 weeks,TSATs 25%,Ferritins 500ng/mL andanaverage baseline
hemoglobin of s 11.5g/dLwererandomized to receive eithernoiron or Venofer<> (ironsucrose injection, USP)(300mgin
250mL0.9%NaCI over1.5hours on Day1 and15and400mgin 250mL0.9%NaCI over2.5 hours on Day29). 121 of
the126randomized patients weretreated andfollowed forupto71days~th a totalof 88patients whocompleted thestudy.
Efficacy assessments were measured on days 15, 29, 43, 57 and 71. Patient demographic characteristics were not
significantly different between thegroups. Themean ageof the75 treated patients in theVenofer<> I erythropoietin group was
51,9years(range 21 to 81 years) vs. 52.8years(range 23 to 77 years) for 46 patients in the erythropoietin alonegroup,
Ethnicity breakdown ofthepetients in theVenofer<>1 erythropoietin Group wasasfollows: Caucasian (36%); Hispanic (32%);
Black(21.3%); Other(10.7%). Ethnicity breakdown for the erythropoietin alonegroup was: Hispanic (43,5%); Caucasian
(30.4%); Biack (15.2%); Ofher(10,9%). Patients in theVenofer<> 1erythropoietin group hadstatistically significantly greater
mean change frombaseline to the highest hemoglobin value (1.3g/dL), compared to subjects whoreceived erythropoietin
alone (0.6g/dL)(p < 0.01). A statistically significantly greater proportion of subjects treated ~th Venofer<> 1erythropoietin
(59.1 %) hadan inaeasein hemoglobin of 2 1 g/dLat anytimeduring the stUdy compared to the subjecls who received
erythropoietin only(33,3%) (p < 0,05),
CUNICALINDICATIONS ANDUSAGE
Venofer<> is indicated in thetreatment of irondeficiency anemia in thefollowing patients:
• non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving an erythropoietin
• non-dialysis dependent-chronic kidney disease (NDD-CKD) patients notreceiving anerythropoietin
• hemodialysis dependent-chronic kidney disease (HDD-CKD) patients receiving anerythropoielin
• peritoneal dialysis dependent-chronic kidney disease (PDD-CKD) patients receiving anerythropoietin.
CONTRAINDICATIONS
Theuseof Venofer<> is contraindicated in patients withevidence of ironoverload, in patients ~lh known hypersensitivity to
Venofer<> or anyof its inactive components, andin patients ~th anemia notcaused by irondeficiency.
WARNINGS
Hypersensitivity reactions have been reported ~th injectable iron products, See PRECAUTIONS and ADVERSE
REACTIONS,
PRECAUTIONS
General:
Because bodyironexcretion is limited andexcess tissueironcanbehazardous, caution should beexercised to ~thhold iron
administration in the presence of evidence of tissue ironoverload. Palients receiVing Venofer<> require periodic monitoring of
hematologic and hematinic parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Iron therapy
should be ~thheld in patienls ~th evidence of iron overload. Transferrin saturation values increase rapidly after IV
administration of ironsucrose; thus,serum iron values maybe reliably obtained 48 hours afterIV dosing, (SeeDOSAGE
ANDADMINISTRATION andOVERDOSAGE),
HypersensitivityReaelions:
Serious hypersensitivity reactions havebeenreported in patients receiving Venofer<>. No life-threatening hypersensitivity
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
receiving Venofer<>. SeeADVERSE REACTIONS.
Hypotension:
Hypotension hasbeen reported frequently in hemodialysis dependent-chronic kidney disease patients receiving intravenous
iron. Hypotension also has been reporled in non-dialysis dependent and peritoneal dialysis dependent-chronic kidney
disease patients receiving intravenous iron. Hypotension foll~ng administration of Venofer<> maybe related to rate of
administration andtotaidoseadministered, Caution should be taken to administer Venofer<> according to recommended
guidelines. SeeDOSAGE ANDADMINISTRATION.
Carcinogenesis, Mutagenesis, and Impairmentof Fertility:
Nolong-tenn studies in animals havebeenperfonned to evaiuate thecarcinogenic potential of Venofer<>.
Venofer<> wasnotgenotoxic in theAmestest,themouse lymphoma cell(L5178YfTK+I-) forward mutation test, thehuman
lymphocyte chromosome aberration test, orthemouse micronucleus test.
Venofer<> atIVdoses upto 15mgiron/kg/day (about 1.2timestherecommended maximum human doseona bodysurface
areabasis) wasfound to havenoeffectonfertility andreproduclive perfonnance of maleandfemale rats.
Pregnancy CategoryB:
Teratology studies havebeen perfonned in ratsat IV dosesup to 13 mg iron/kg/day (about 0.5 times the recommended
maximum human doseon a bodysurface areabasis) andrabbits at IV doses up to 13 mg iron/kg/day (about 1 timesthe
recommended maximum human doseona bodysurface areabasis) andhevereveaied noevidence of impaired fertility or
harmto the fetusdue to Venofer<>, There are, however, no adequate and well controlled studies in pregnant women.
Because animal reproduclion studies are not always predictive of human response, this drug should be usedduring
pregnancy onlyif ciearly needed.
NursingMothers:
Venofer<> is excreted in milkof rats, It is not known whether thisdrugis excreted in human milk.Because manydrugs are
exaeted inhuman milk, caution should beexercised lNhen venofer«> isadministered toa nursing woman.
PediatricUse:
Safety andeffectiveness ofVenofer<> in pediatric patients havenotbeen established. In acountry where Venafer<> is available
for usein children, at a single site,fivepremature infants (weight lessthan1,250g) developed necrotizing enterocolitis and
two of the five expired during or follo~ng a period when they received Venofer<>, several other medications and
erythropoietin. Necrotizing enterocolitis may be a complication of prematurity In verylowbirth weight infants, Nocausal
relationship toVenofer<> oranyother drugs could be established,
GeriatricUse:
Studies A through E did not include sufficient numbers of subjects aged65 yearsandolderto detennine whether they
respond differently fromyounger subjects. Ofthe1,051 patients in two post-marl<eting safetystudies of Venafer<>, 40%were
65years andolder, Nooverall differences in safety wereobserved between these SUbjects andyounger SUbjects, andother
reported clinical experience hasnotidentified differences in responses between theelderly andyounger patients, butgreater
sensitivity of some olderindividuals cannot beruledout.
ADVERSE REACTIONS
AdverseEventsobservedin atl treated populations
Thefrequency ofadverse events associated ~th theuseofVenofer<> hasbeen documented in sixrandomized clinical trials
involving 231hemodialysis dependent, 139non-dialysis dependent and75peritoneal dialysis dependent-CKD patients; and
in twopost-marketing sefetystudies involving 1,051 hemodialysis dependent-CKD patients for a totalof 1,496patients. In
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
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
(MultidoseSafetyPopulation)
"NOS= Nototherwise specified
Adverse Events
(Preferred Tenm)
HDD-CKD NDD-CKD PDD-CKD
Venofer0
(N=231)
%
Venofer'>
(N=139)
%
Oral Iron
(N=139)
%
Venofer0
(N=75)
%
EPOOnly
(N=46)
%
Subjects with any adverse event 78.8 76.3 73.4 72.0 65.2
Ear and Labyrinth Disorders
Ear Pain 0 2.2 0.7 0 0
Eye Disorders
Conjunctivitis 0.4 0 0 2,7 0
Gastrointestinal Disorders
Abdominal pain NOS" 3.5 1.4 2.9 4.0 6.5
Constipation 1.3 4.3 12.9 4.0 6.5
Diarrhea NOS 5,2 7,2 10.1 8.0 4.3
Dysgeusia 0.9 7.9 0 0 0
Nausea 14.7 8,6 12,2 5.3 4.3
Vomiting NOS 9.1 5.0 8,6 8.0 2.2
General Disorders and
Administration Site Conditions
Asthenia 2.2 0.7 2.2 2.7 0
Chest pain 6.1 1.4 0 2.7 0
Edema NOS 0.4 6,5 6.5 0 2.2
Fatigue 1.7 3,6 5.8 0 4.3
Feeling abnormal 3.0 0 0 0 0
Infusion site buming 0 3.6 0 0 0
Injection site extravasation 0 2.2 0 0 0
Injection site pain 0 2,2 0 0 0
Peripheral edema 2.6 7.2 5,0 5.3 10,9
Pyrexia 3.0 0.7 0.7 1.3 0
Infections and Infestations
Catheter site infection 0 0 0 4.0 8.7
Nasopharyngitis 0.9 0.7 2.2 2.7 2.2
Peritoneal infection 0 0 0 8.0 10.9
Sinusitis NOS 0 0.7 0.7 4.0 0
Upper respiratory tract infection NOS 1.3 0.7 1.4 2.7 2.2
Urinary tract infection NOS 0.4 0.7 5,0 1.3 2,2
Injury, Poisoning and
Procedural Complications
Graft complication 9.5 1.4 0 0 0
Investigations
Cardiac murmur NOS
Fecal occult blood positive
0.4
0
2.2
1.4
2,2
3,6
0
2.7
0
4,3
Table 2 continued on reverse side.
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 CommonAdverse Events Related to Study Drug Reported in ;, 2% of Patients by Dose Group
(MultidoseSafetyPopulation)- CONTINUED (MultidoseSafetyPopulation) - CONTINUED
Adverse Events
(Preferred Term)
HDD-CKD NDD-CKD PDD-CKD
Venofer®
(N=231)
Venofer®
(N=139)
Oral Iron
(N=139)
Venofer®
(N=75)
EPOOnly
(N=46)
% % % % %
Metabolism and Nutrition Disorders
Fluid overload 3.0 1.4 0.7 1.3 a
Gout a 2.9 1.4 a a
HyperglycemiaNOS a 2.9 a a 2.2
HypoglycemiaNOS 0.4 0.7 0.7 4.0 a
Musculoskeletal and Connec1ive
Tissue Disorders
Arthralgia 3.5 1.4 2.2 4.0 4.3
Arthritis NOS a a a a 4.3
Sack pain 2.2 2.2 3.6 1.3 4.3
Muscle cramp 29.4 0.7 0.7 2.7 a
Myalgia a 3.6 a 1.3 a
Pain in extremity 5.6 4.3 a 2.7 6.5
Nervous System Disorders
Dizziness 6.5 6.5 1.4 1.3 4.3
Headache 12.6 2.9 0.7 4.0 a
Hypoesthesia a 0.7 0.7 a 4.3
Respiratory,Thoracic and
Mediastinal Disorders
Cough 3.0 2.2 0.7 1.3 a
Dyspnea 3.5 3.6 0.7 1.3 2.2
Dyspnea exacerbated a 2.2 0.7 a a
Nasal congestion a 1.4 2.2 1.3 a
Pharyngitis 0.4 a a 6.7 a
Rhinitis allergic NOS a 0.7 2.2 a a
Skin and Subcutaneous lissue
Disorders
Pruritus 3.9 2.2 4.3 2.7 a
Rash NOS 0.4 1.4 2.2 a 2.2
Vascular Disorders
HypertensionNOS 6.5 6.5 4.3 8.0 6.5
HypotensionNOS 39.4 2.2 0.7 2.7 2.2
Adverse Events
(Preferred Term)
HDD-CKD NDD-CKD PDD-CKD
100mg
(N=231)
%
200mg
(N=109)
%
SOOmg
(N=30)
%
300 mg for 2 doses
followed by
400 mg for 1 dose
(N=75)
%
General Disorders and
Administration Site
Conditions
Infusion site burning a 3.7 a a
Injeelion site pain a 2.8 a a
Peripheraledema a 1.8 6.7 a
Nervous System Disorders
Dizziness a 2.8 6.7 a
Headache a 2.8 a a
Vascular Disorders
HypotensionNOS 5.2 a 6.7 a
NOS= Nototherwise specified
Treatment-emergent adverse events reported in ;,2%of patients bydosegroupareshown in Table 3.
Table3.MostCommonTreatment-Emergent AdverseEventsReported in ;,2% of Patientsby DoseGroup(Multidose
SafetyPopulation)
Adverse Events
(Preferred Term)
HDD-CKD NDD-CKD PDD-CKD
100mg
(N=231)
%
200mg
(N=109)
%
500mg
(N=30)
%
300 mg for 2 doses
followed by
400 mg for 1 dose
(N=75)
%
Subjects with any adverse event 78.8 75.2 80.0 72.0
Ear and Labyrinth Disorders
Ear Pain a 0.9 6.7 a
Eye Disorders
Conjunctivitis 0.4 a a 2.7
Gastrointestinal Disorders
Abdominal pain NOS· 3.5 1.8 a 4.0
Constipation 1.3 3.7 6.7 4.0
DiamheaNOS 5.2 6.4 10.0 8.0
Dysgeusia 0.9 9.2 3.3 a
Nausea 14.7 9.2 6.7 5.3
Vomiting NOS 9.1 5.5 3.3 8.0
General Disorders and
Administration Site Conditions
Asthenia 2.2 0.9 a 2.7
Chest pain 6.1 0.9 3.3 2.7
Edema NOS 0.4 7.3 3.3 a
Fatigue 1.7 4.6 a a
Feeling abnormal 3.0 a a a
Infusion site burning a 3.7 3.3 a
Injection site pain a 2.8 a a
Peripheraledema 2.6 5.5 13.3 5.3
Pyrexia 3.0 0.9 a 1.3
Infections and Infestations
Catheter site infection a a a 4.0
Nasopharyngitis 0.9 0.9 a 2.7
Perrtoneal infection a a a 8.0
Sinusitis NOS a a 3.3 4
Upper respiratory trael infeelion 1.3 0.9 a 2.7
Injury, Poisoning and
Procedural Complications
Graft complication 9.5 1.8 a a
Investigations
Cardiac mumnur NOS
Fecal occult blood positive
0.4
a
2.8
1.8
a
a
a
2.7
Metabolism and Nutrition Disorders
Fluid overload 3.0 1.8 a 1.3
Gout a 1.8 6.7 a
HyperglycemiaNOS a 3.7 a a
HypoglycemiaNOS 0.4 0.9 a 4.0
Musculoskeletal and Connective
lissue Disorders
Arthralgia 3.5 0.9 3.3 4.0
Sack pain 2.2 1.8 3.3 1.3
Muscle cramp 29.4 a 3.3 2.7
Myalgia a 2.8 6.7 1.3
Pain in extremity 5.6 4.6 3.3 2.7
Nervous System Disorders
Dizziness 6.5 5.5 10.0 1.3
Headacihe 12.6 3.7 a 4.0
Respiratory, Thoracic and
Mediastinal Disorders
Cough 3.0 0.9 6.7 1.3
Dyspnea 3.5 1.8 10.0 1.3
Pharyngitis 0.4 a a 6.7
Skin and Subcutaneous lissue Disorders
Pruritus 3.9 0.9 6.7 2.7
Vascular Disorders
HypertensionNOS 6.5 6.4 6.7 8.0
HypotensionNOS 39.4 0.9 6.7 2.7
'NOS= Nototherwise specified
Drug related adverse events reported by;, 2%ofVenofe'"treated patients areshown bydose group in Table 4.
Table 4. Most Common Adverse Events Related to Study Drug Reported in ;, 2% of Patients by Dose Group
(MultidoseSafetyPopulation)
Adverse Events
(Preferred Term)
HDD-CKD NDD-CKD PDD-CKD
100 mg
(N=231)
%
200 mg
(N=109)
%
500 mg
(N=30)
%
300 mg for 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
DiamheaNOS'
Dysgeusia
Nausea
0.9
0.9
1.7
a
7.3
2.8
a
3.3
a
2.7
a
1.3
'NOS = Notofherwise specified
AdverseEventsObserved in Hemodialysis Dependent-Chronic KidneyDisease (HDD-CKD) Patients
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,andCwereasfollows: 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%), anddiarrhea (5.2%).
In the firstpost-marKeting safety study, 665chronic hemodialysis patients weretreated withVenofe'"doses of 100mgat
eachdialysis session forupto 10consecutive dialysis sessions for theiriron deficiency or on a weekly basis for 10weeks
for maintenance of iron stores. In this study, 72%of the patients received up to 10 doses, 27%received between 11-30
doses, and1% received 40to SO doses ofVenofe"'. Serious adverse events anddrug-related non-serious adverse events
werecolleeled. In the seoond post-marKeting safety study, 386hemodiaiysis patients wereexposed to a single dose of
Venofe'"(100mgIV by slowinjeelion over2 minutes or 200mgIV by slowinjeelion over5 minutes). Themean ageof
patients enrolled intothetwopost-marKeting safetystudies was59 years, witha range of 2()'93years. Malesmade up60%
of the population. The ethnicity of the patients enrolled in the two studies included Blacks (44%), Caucasians (41 %),
Hispanics (11%), Asians (3%), andothers (1%). Adverse events reported by> 1%of 1,051 treated patients were: cardiac
failure congestive, sepsis NOSanddysgeusia.
AdverseEventsObserved in Non-Dialysis Dependent-Chronic KidneyDisease (NDD-CKD) Patients
In Study D of 162treated NDD-CKD patients, 91 were exposed to Venofe"'. Adverse events, whether or not related to
Venofe"', reported by;,5%oftheVenofe'" exposed patients wereasfollows: dysgeusia (7.7%), peripheral edema (7.7%),
diarrhea (5.5%), oonstipation (5.5%), nausea (5.5%), dizziness (5.5%), and hypertension (5.5%). One serious related
adverse reaelion wasreported (hypotension andshortness of breath notrequiring hospitalization in aVenofe'"patient). Two
patients experienced possibie hypersensitivity/allergic reaelions (local edema/hypotension) during the study. Of the 5
patients whoprematurely discontinued the treatment phase of the studydueto adverse events (2 oral irongroupand3
Venofe'"group), threeVenofe'"patients hadevents thatwereconsidered drug-reiated (hypotension, dyspnea andnausea).
In an additional study of Venofe.., with varying erythropoietin doses in 96 treated NDD-CKD patients, adverse events,
whether or notrelated toVenofe'"reported by25%of Venofe'"exposed patients areasfollows: diarrhea (16.5%), edema
(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
hypersensitivity/allergic reaction during the stUdy. Of thepatients whoprematurely discontinued thetreatment phase of the
studydueto adverse events (2.1% oralirongroupand12.5% Venofe'"group), onlyonepatient (Venofe'"group) hadevents
thatwereconsidered drug-related (anxiety, headache, andnausea). Ninety-one (91)patients in thisstudywereexposed to
Venofe'"eitherduring thetreatment or extended follow-up phase.
AdverseEventsObserved in Peritoneal DialysisDependent-Chronic KidneyDisease (PDD-CKD) Patients
in StUdy Eof 121 treated PDD-CKD patients, 75patients wereexposed to Venofe"'. Adverse events, whether ornotrelated
to Venofe'" reported by z 5% of these patients are as follows: diarrhea, peritoneal infection, vomiting, hypertension,
pharyngitis, peripheral edema andnausea.
In these 75patients exposed to Venofe"', 9 patients experienced serious adverse events asfollows: peritoneal infeelion (2
patients) and 1 patient eachwith cardiopulmonary arrest, myocardiai infarelion, upperrespiratory infeelion NOS, anemia,
gangrene, hypovolemia andtuberculosis. None of these events were considered drug-related. TwoVenofe'" patients
experienced a moderate hypersensitivity/allergic reaction (rashor sweliinglitching) during thestudy.
Theonlydrugrelated adverse reaction to Venofe'"administration reported by22%of patients wasdiarrhea.
Three patients in the Venofe,., studygroupdiscontinued study treatment due to adverse events (cardiopuimonary arrest,
peritonitis andmyocardial infarelion, hypertension) which wereconsidered to benotdrug-reiated.
HypersensitivityReactions: SeeWARNINGS andPRECAUTIONS.
In clinical studies, several patients experienced hypersensitivity reactions presenting withwheezing, dyspnea, hypotension,
rashes, or pruritus. Serious episodes of hypotension occurred in 2 patients treated withVenofe'"at a dose of500mg.
Thepost-marKeting spontaneous reporting system inciudes reports of patients whoexperienced serious or life-threatening
reaelions (anaphylaelic shock, lossof consciousness or collapse, bronchospasm withdyspnea, or convulsion) associated
withVenofe'"administration.
Onehundred thirty(11%) of the 1,151 patients evaluated in the 4 U.S. trialsin HDD-CKD patients (studies A, B andthetwo
postmarketing studies) hadpriorotherintravenous irontherapy andwerereported to beintolerant (defined as precluding
further useof that iron produel). When these patients weretreated withVenofe'"therewereno occurrences of adverse
events thatprecluded further useof Venofe"'.
OVERDOSAGE
Dosages ofVenofe'"(ironsucrose injeelion, USP) in excess of ironneeds mayleadto accumulation of ironin storage sites
leading tohemosiderosis. Periodic monitoring ofiron parameters such asserum fanilin and transferrin saturation may assist
in recognizing iron accumulation. Venofe'" should not be administered to patients with iron overload and should be
discontinued whenserum ferritin levelsequal orexceed established guidelines [5). Particular caution should beexercised to
avoid iron overload where anemia unresponsive totreatment has been incorrectly diagnosed asiron deficiency anemia.
Symptoms associated withoverdosage orinfusing Venofe'"toorapidly included hypotension, dyspnea, headache, vomiting,
nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. Most
symptoms havebeen successfully treated with IV fluids, hydrocortisone, and/orantihistamines. Infusing the solution as
recommended or at a slower ratemayalsoalleviate symptoms.
PreclinicalData:
Single IV doses of Venofe'"at lSOmgiron/kg in mice (about 3 timesthe recommended maximum human doseon a body
surface areabasis) and100mgiron/kg in rats(about 6 timestherecommended maximum human dose on a body surface
areabasis) werelethal.
Thesymptoms of acute toxicjty weresedation, hypoaelivity, paleeyes, andbleeding in thegastrointestinal tractandiungs.
DOSAGE ANDADMINISTRATION
Thedosage ofVenofe'"is expressed in terms ofmgof elemental iron. Each mLcontains 20mgof elemental iron.
MostCKDpatients will require a minimum cumulative repletion dose of 1,000 mg of elemental iron, administered over
sequential sessions, to achieve a favorable hemoglobin response andto replenish ironstores (ferritin, TSAl). Hemodialysis
patients maycontinue to require therapy withVenofe'"or otherintravenous ironpreparations at thelowest dosenecessary
to maintain target ievelsof hemoglobin, andlaboratory parameters of ironstorage within acceptable limits.
Administration:Venofe'"mustonlybeadministered intravenously eltharbyslowinjection or by infusion.
Recommended Adult Dosage:
Hemodialysis Dependent-Chronic Kidney Disease Patients (HDD-CKD): Venofe'"maybeadministered undiluted as a
100mgslowintravenous injection over2 to 5 minutes orasaninfusion of 100mg,diluted in a maximum of 100mLof 0.9%
NaCi overa period of at least15minutes per oonsecutive hemodialysis session fora totalcumulative doseof 1,000 mg.
Non-Dialysis Dependent-Chronic Kidney Disease Patients(NDD-CKD): Venofe'"is administered as a totalcumulative
doseof 1,000mgovera 14dayperiod asa 200mgslowIV injeelion undiluted over2 to 5 minutes on5 different occasions
within the 14dayperiod. There is limited experience withadministration of aninfusion of SOO mgof Venofe"', diluted in a
maximum of250mLofO.9% NaCI, overa period of3.5-4hours onday1andday14;hypotension occurred in2 of30patients
treated. (SeeCLINICAL TRIALS, Study0: Non-Dialysis Dependenl-Chronic KidneyDisease (NDD-CKD) Patientsand
ADVERSE REACTIONS, AdverseEventsObserved in Non-Dialysis Dependent Chronic Kidney Disease (NDD-CKD)
Patientssections.)
Peritoneal Dialysis Dependenl-Chronic Kidney Disease Patients (PDD-CKD): Venofe'" is administered as a total
cumulative dose of 1,000 mg in 3 divided doses, givenby slowintravenous infusion, wrthin a 28 dayperiod: 2 infusions of
300mgover1.5hours 14daysapart followed byone400mgInfusion over2.5hours 14dayslater. TheVenofe'"doseshould
bediluted in a maximum of250mLof 0.9%NaCI.
HOWSUPPLIED
Venofe'"is supplied in 5 mLand10mLsingle dosevials. Each 5 mLvialcontains 100mgelemental iron(20mg/mL) and
each 10 mLvial contains 200mg elemental iron(20 mg/mL). Contains no preservatives. Store in original carton at 25'C
(77'F). Excursions permitted to 15'-30'C (59'-86'F).[SeetheUSPoontrolled room temperature]. Donotfreeze.
Sterile
100mg/5mLSingle Dose Vial
100mg/5mLSingle Dose Vial
100mg/5mLSingle Dose Vial
NDC-0517-234()'01
NDC-0517-234()'10
NDC0517-234()'25
Individually Boxed
Packages of 10
Packages of 25
200mg/l0 mLSingle Dose Vial
200mg/10 mLSingle Dose Vial
200mg/l0 mLSingle Dose Vial
NDC-0517-231()'01
NDC-0517-231()'05
NDC-0517-231()'10
Individually Boxed
Packages of 5
Packages of 10
RxOnly
