Intravenous Iron Management for Pharmacists:
Safety, Efficacy, Dosing and Pharmacoeconomic Considerations
Medical Education Resources - Pharmacist CE Symposium, December, 2003

Thomas Comstock , PharmD

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HDCN is pleased to make available this web program devoted to the continuing education of pharmacists.
Pharmacy accreditation:
Medical Education Resources (MER) is approved by the American Council of Pharmaceutical Education as a provider of continuing pharmaceutical education. MER designates this continuing education activity for 1.0 contact hours (0.10 CEUs) of the American Council on Pharmaceutical Education. Expires December 30, 2005. Universal Program Number: # 816-000-03-020-H04

Intended Audience: Pharmacists. This program is NOT intended for physicians or nurses; no CME physician credit or CE nursing credit is available.

Needs Statement: Studies and clinical experience have demonstrated the important role for pharmacists in helping care for patients with anemia. Staying abreast of developments in anemia therapy is vital for the pharmacist to be able to optimize such care.

IV Iron Management: Safety, Efficacy, Dosing, and Pharmacoeconomic Considerations
December 2003 2.0 hours (2.0 CEU)
This lesson is no longer valid for CE credit after December 31, 2005

CE credit for this program has expired.
After participating in this activity, participants should be able to:
Assess the need for intravenous iron therapy to support erythropoiesis in selected patient populations
Identify and differentiate the IV iron products available in the US market today
Evaluate the published clinical data regarding the safety of IV iron infusion regimens
Identify the factors necessary to consider when establishing cost-effective guidelines for the use of IV iron therapy
Thomas Comstock, PharmD., is a Consultant and member of the Speaker Bureau for Watson Pharma, Inc.

The CE policy statements of Medical Education Resources, Inc which is the accrediting organization for this talk, are given in detail on the Symposium Home Page. CE policy and disclosure statements of HDCN are listed on this page.


Dr. Thomas Comstock: It's a pleasure to be with you this afternoon to talk with you about IV Iron Management. For the next 50 minutes or so, we will be talking about safety, efficacy, dosing and some pharmacoeconomic considerations with regards to intravenous iron therapy.


Learning Objectives
The objectives for today's presentation include the assessment of the need for intravenous iron therapy to support erythropoiesis in selected patient populations, and specifically we'll be talking mostly about patients with kidney disease, but also other populations; oncology patients; patients in the critical care units; and also patients who may qualify for autologous transfusions in terms of surgical populations.

Second, we will talk about identifying and differentiating the IV iron products that are on the US market today.

Thirdly, we will evaluate some of the clinical data with regards to the safety of IV iron infusions. You may be familiar with some of the different regimens that may be used, some of them are product-specific, and so it's important to be able to differentiate among these products with regards to infusions.

Then lastly, we'll talk about identifying the factors that are necessary to consider when establishing cost effective guidelines for the use of IV iron therapy.


Anemia overview
Let's begin with an overview of anemia. Anemia, very simply, can be stated as too few red blood cells in the circulation. Normal values for healthy adult men and non-menstruating women would be 15.5, plus or minus 2 grams per deciliter; for menstruating women, approximately 14 plus-or-minus 2 grams per deciliter. Values less than that would qualify as anemia. Patients with compromised kidney function, and the terminology that is more commonly used today is CKD, or chronic kidney disease, these patients are diagnosed with anemia when their hemoglobin values are less than 11 grams per deciliter, and the same for the oncology population. There seems to be a consensus that those patients also would fall into the anemia category with hemoglobin values of less than 11 grams per deciliter.

Iron deficiency anemia, specifically, then is a result of inadequate iron stores or iron availability in order to support the necessary erythropoiesis to produce the adequate levels of red cells in the circulation.


Source: Fellner SK et al. Kidney Int. 1993 Dec;44(6):1309-15.
Source: Cannella G et al. Nephrol Dial Transplant. 1991;6(1):31-7.
Source: Sikole A et al. Artif Organs. 1993 Dec;17(12):977-84.
Source: Lim VS. Am J Kidney Dis. 1991 Oct;18(4 Suppl 1):34-7.
Source: Evans RW et al. JAMA. 1990 Feb 9;263(6):825-30.
Source: Pickett JL et al. Am J Kidney Dis. 1999 Jun;33(6):1122-30.
Source: Harnett JD et al. Am J Kidney Dis. 1995 Apr;25(4 Suppl 1):S3-7.
Source: Churchill DN et al. Clin Nephrol. 1995 Mar;43(3):184-8.
Source: Powe NR et al. J Am Soc Nephrol. 1994 Jan;4(7):1455-65.

Adverse consequences of anemia
There are a number of adverse consequences of anemia that you are probably quite familiar with. Left ventricular hypertrophy is a very significant adverse event from anemia development; fatigue; dizziness; shortness of breath; poor quality of life have been very well documented in both the oncology population, as well as the hemodialysis population; an increase in mortality risk and also an increase in the number of hospitalizations per patient.


Source: Foley RN et al. Kidney Int. 1995 Jan;47(1):186-92.
Source: Harnett JD et al. Am J Kidney Dis. 1995 Apr;25(4 Suppl 1):S3-7.

Source: Ludwig H et al. Semin Oncol. 2001 Apr;28(2 Suppl 8):7-14.
Source: Cella D. Oncology (Huntingt). 2002 Sep;16(9 Suppl 10):125-32.

CV risk factors of anemia
Now, as I mentioned earlier, the cardiovascular risk is something that is very important and has been largely studied in the CKD, or the kidney disease population, mostly in the hemodialysis patients. A number of cardiovascular complications, for example, include a recent observation that about a third of the patients with end-stage renal disease develop or have existing cardiac failure. Seventy-four percent of the patients in this observation set had LVH, left ventricular hypertrophy. Cardiovascular consequences are the leading cause of death in patients with end-stage renal disease undergoing therapies to treat their ESRD. Anemia also has been demonstrated to be an independent predictor of heart failure and mortality, and impairs cognitive function and, as we'll see later, quality of life. Moreover, it increases the risk of angina, and myocardial infarction, as well as transient ischemic events.

Thinking of these adverse consequences of anemia, one can then imagine the therapeutic interventions and pharmacotherapy. When we talk about pharmacotherapy for anemia, we're really focusing on two primary areas: one is erythropoietic therapy, and the second is iron therapy as adjunctive therapy for erythropoietic therapy in these patients.


Source: Churchill DN et al. Clin Nephrol. 1995 Mar;43(3):184-8.
Source: Carletti P et al. Kidney Int Suppl. 1993 Jun;41:S70-1.
Source: Sikole A et al. Artif Organs. 1993 Dec;17(12):977-84.
Source: Pickett JL et al. Am J Kidney Dis. 1999 Jun;33(6):1122-30.
Source: Powe NR et al. J Am Soc Nephrol. 1994 Jan;4(7):1455-65.
Source: Cannella G et al. Nephrol Dial Transplant. 1991;6(1):31-7.
Source: Evans RW et al. JAMA. 1990 Feb 9;263(6):825-30.
Source: Henry DH. Oncologist. 1998;3(4):275-278.

Benefits of correcting anemia
The benefits of correcting anemia are very similar to what you would find in terms of the adverse consequences. There's a reduction in hospitalization days and mortality. There's reduced cost of dialysis in patients undergoing dialysis. There's an improvement in cardiac parameters, such as LVH and cardiac output in patients. Certainly improvements in overall quality of life in patients, including functional abilities and energy levels, satisfaction, eating, sleeping behaviors are improved in patients who have anemia, improvements in brain functioning have been demonstrated in patients. It's important to recognize that functional iron deficiency, when it occurs, is going to be very rate limiting for erythropoietic therapy. As I mentioned, these two therapies often times are hand in hand. Erythropoietic therapy and iron therapy are important to consider, so evaluating one or the other, automatically one should think of the alternative therapy, as well.


Patient populations at risk for iron deficiency anemia
The populations at risk that I mentioned earlier include kidney disease. In the kidney disease population, the dialysis patients would be hemodialysis patients, the majority of patients that fall into the ESRD category, as well as peritoneal dialysis patients, and also the third group, which would be chronic kidney disease patients, or also referred to as those that will be non-ESRD or patients that would be categorized as predialysis patients, patients with reduced kidney function but not requiring transplantation at this time or not requiring therapy to maintain normal homeostasis. Oncology patients, whom I referred to earlier, are also patients at risk for iron deficiency anemia; surgical patients, again, with autologous blood transfusions, and the development of the evolving area of bloodless medicine; and lastly, critical care patients.


Source: No authors listed. Am J Kidney Dis. 2001 Jan;37(1 Suppl 1):S182-238.
Source: Eschbach JW et al. Ann Intern Med. 1977 Dec;87(6):710-3.
Source: Eschbach JW. Semin Nephrol. 2000 Jul;20(4):320-9.
Source: Sakiewicz P. J Nephrol. 1998 Jan-Feb;11(1):5-15.

Reasons for iron deficiency in hemodialysis patients
Looking more specifically at hemodialysis patients, erythropoietic therapy is the mainstay of treatment. Probably about 95 percent or more of patients who are undergoing hemodialysis will be receiving erythropoietic therapy. Erythropoietic therapy creates a tremendous demand for iron, and so iron is an important adjunctive therapy in these patients.

Blood loss also occurs in these patients, specifically in hemodialysis because each dialysis treatment leads to a small degree of blood loss in the dialyzer that cannot be returned to the patient. So there is an obligatory red cell loss, and with red cell loss there is iron loss. These patients have an ongoing iron loss that occurs. Blood sampling, phlebotomy for a multitude of laboratory tests that are performed, surgical losses, access interventions, revision of vascular access that occurs, also add to probable blood loss, as well as potential GI losses that may occur in terms of increasing their rate of elimination of red cells and hence of iron from the patient.

Total losses per year in patients that are undergoing hemodialysis are usually in the range of 1,000 to 3,000 mg. That's an important number to keep in mind. These patients undergoing hemodialysis usually will require 1 to 3 grams of iron administration per year in order to balance the amount that is lost because of the reasons mentioned earlier.

There is reduced iron availability in the diet in these patients, often times because of challenges of nutrition in these patients, as well as decreased absorption that we'll see shortly.


Source: Henry DH. Oncologist. 1998;3(4):275-278.
Source: Ludwig H et al. Ann Oncol. 1993 Feb;4(2):161-7.
Source: Henry DH et al. Semin Oncol. 1994 Apr;21(2 Suppl 3):21-8.

Causes of cancer-related anemia
Now, the oncology patient population is not as well-studied with regards to iron needs versus the hemodialysis patient population, but these patients also certainly will have a significant degree of anemia that is present, primarily for a couple of reasons. The first is that there may be chronic disease factors, such as an inhibitory effect of cytokines on erythropoietic response, as well as a reduced erythropoietin production because of the disease state. And then secondly, because the chemotherapy or radiation that the patient is being treated with may result in bone marrow suppression, and there may be toxic effects on erythropoietin production from the kidneys; for example, with therapy with cisplatinum, which may lead to nephrotoxicity and decreased production of erythropoietin. These patients also have nutritional deficiencies in terms of poor appetite, and so an inability to absorb the normal amounts of factors that are necessary to support erythropoiesis in their diet. And lastly, certainly, as with the hemodialysis patient population, these patients may also have additional blood loss, as well, and in particular in those patients with GI and GU malignancies.


Source: Chin-Yee I et al. Transfus Sci. 1997 Sep;18(3):447-58.
Source: Purdy FR et al. Can J Anaesth. 1997 Dec;44(12):1256-61.
Source: Vincent JL et al. JAMA. 2002 Sep 25;288(12):1499-507.
Source: Corwin HL et al. Crit Care Med. 2000 Aug;28(8):3098-9.
Source: Rodriguez RM et al. J Crit Care. 2001 Mar;16(1):36-41.

Emerging trends in EPO utilization
Some of the other areas, and these are labeled as what we could say are emerging trends in terms of erythropoietic utilization, include autologous blood donation or, as I referred to earlier, this category of bloodless medicine. Stored red blood cells are not as effective as endogenously produced red blood cells in terms of their oxygen-carrying capacity, nor in terms of their life span. Studies have demonstrated that there is an increased mortality when patients are transfused with older blood, and so the life span of those cells decreases the longer that blood is stored.

In critical care, intensive care patients tend to be anemic. Hemoglobin values will fall during the length of stay. A recent observation is that about one third to perhaps up to one half of the patients who have stays in the ICU will receive on average about five red cell transfusions per stay: so very significant degree of levels of transfusion occurring in the ICU patients. Anemia of this critical illness is not as well studied, again, as it has been with hemodialysis patients, but it's thought to be an under-production anemia that is driven by a relative erythropoietin deficiency in this population.


Source: Goodnough LT et al. J Lab Clin Med. 1991 Sep;118(3):289-96.
Source: Corwin HL et al. JAMA. 2002 Dec 11;288(22):2827-35.

EPO utilization increases iron utilization in non-HD patients


RCB development
A simple schematic to look at the process of development of red cells over this three-week period when reticulocytes are released in the bone marrow. The important factor is that there are two primary products from a pharmacotherapy perspective to keep in mind: one is erythropoietin, which will facilitate differentiation and proliferation of cells within the marrow; and secondly, iron therapy, which will facilitate the ability of the hemoglobin molecule to carry oxygen. So both of these therapies (both erythropoietin and iron) are absolutely essential for the production of red cells moving into the circulation.

So we're going to be focusing primarily on the iron production, but remember, the purpose of iron therapy is not to treat iron deficiency. The purpose of iron therapy is to facilitate correction of an anemia that may be present because the anemia is associated with significant adverse effects in all of these populations.


Body iron distribution and pathways: Average adult
This schematic shows a configuration that points to several things with regards to iron balance in the body. It's a schematic representing the normal physiologic processes in terms of iron handling, and several points should be made. Number one is that iron is a very highly conserved element in the body. There are about 3 to 4 grams of iron that are present in the body. This steady-state value of 3 to 4 grams is sustained by the absorption of only 1 mg/day of iron from the diet. The balance occurs because of the sloughing of GI cells from the gastrointestinal tract and a loss of about 1 mg/day. So at steady-state, a very small amount of iron is absorbed, and a very small amount of iron is lost. The majority of iron is present in the circulating red blood cells. About 2 1/2 grams depicted on this slide is present in the red cells. The other large storage area for iron in the body is in the reticuloendothelial stores, depicted here by approximately 800 mg. That accounts for the majority of iron present in the body. There is a very small amount that is present in the circulating plasma. And this iron is present in a bound state to transferrin.
So we'll talk about some of the laboratory values a bit later, but the transferrin molecule will bind iron and serves as a shuttle, if you will, between the storage iron in the reticuloendothelial system and into the bone marrow, where it is incorporated into new blood cells. And so the amount of iron in total is very small in the circulation, and the transferrin serves as a shuttle, if you will, to move it from the storage locations into the red blood cells eventually as a result of production in the marrow. There are other locations certainly of iron in the body. Iron is incorporated in myoglobin. So it's a very highly conserved system, very small amount in, and very small amount out, per day.



Body iron distribution and pathways: Hemodialysis patient
Now, in contrast let's take a look at the appearance of this altered physiology that occurs in the hemodialysis patient. In this case, again, the similar schematic is shown, but several observations can be made. Number one is that there is reduced absorption ... about 50 percent of normal: 1/2 milligram on average per day, which--as we'll see--is not sufficient to sustain normal erythropoiesis or maintain normal iron stores. Secondly, there is an increased loss of iron per day. Beyond the 1-mg loss that normally occurs, there is the additional loss because of dialysis in the hemodialysis population, as well as perhaps other losses from GI blood loss. There is an increased loss, and so this tells us immediately that we're not at steady state conditions and that the iron values over time, unless it's replaced, will decrease to values that will not support normal erythropoiesis.

The second point is that the body load of iron is going to be reduced overall in patients, and that's a result of number one, a decrease in the red blood cell volume that is present, and so hence a decrease in the amount of iron that is present in the circulation that is part of hemoglobin. Secondly, there may be reduced amounts of iron in the reticuloendothelial system. This is very difficult to assess because under conditions of patients who may have been administered large numbers of transfusions, for example, in the pre-erythropoietin era, these patients may have large amounts of iron present in the reticuloendothelial system but they were unable to use it because of inadequate amounts of erythropoietin to produce those new cells. And so it may be quite variable, but in general, this amount is going to be reduced in the patient who is actively producing red blood cells. Transferrin is still present in the plasma. Small amounts of iron will be available to transferrin that will be shuttled from the reticuloendothelial system to the red cells, and iron certainly is still present in tissue stores. There is a reduced amount of iron in the body that may be inadequate to support erythropoiesis, and there is an increased loss per day primarily because of the additional losses due to hemodialysis.


Distribution of body iron before and after EPO treatment
This simple schematic illustrates the differences in the distribution of iron in the body that occurs in the otherwise healthy individual, labeled as normal, and you can see that about 75% of the iron in the body is present in the red cells, as depicted in the first of the two slides looking at distribution of iron. Secondly, if we look at the distribution of iron in patients with chronic kidney disease before the advent of erythropoietin, what you notice are two things. One is there is a reduction in the total amount of iron in the body, and secondly, there is an increased proportion of iron in the stores because again iron cannot be utilized because erythropoietin is not present to stimulate new red cell production. In order for iron to be utilized, there needs to be production of new red cells, which again goes back to the point being made that when we talk about erythropoietin, hand in hand one needs to be thinking about iron in these patients.

So we begin erythropoietin therapy in these patients, and lo and behold, in the CKD population after erythropoietin what we still see is an overall similar level of iron that is reduced compared to normal, but the shift is that iron has now moved from the storage site into the red cells because now we're actively creating these new red cells and, as a result, it leads to a condition of iron deficiency. These patients now will have a blunted response to erythropoietin because the storage iron is now insufficient to support normal erythropoiesis.



Measurieng iron definciency
What are the measures? How do we assess iron deficiency in patients?


Assesment of iron stores
There are a number of laboratory parameters that have been suggested. Some of them are listed here on this slide. For example, the serum ferritin is a value that really is an indirect measure of the iron stores. The circulating ferritin that is in the plasma is a very, very small value. Ferritin is a form of storage iron present in the tissue. The difficulty with the assessment of the ferritin value is that the ferritin value itself is an acute phase reactant molecule. And so, under conditions of stress, inflammation, and infection, these patients will have elevations in the serum ferritin value, which may be a false indicator of adequate amounts of iron present in the body. So ferritin has somewhat of a limited value to really reflect what the body storage amount of iron is.

What's important in the ferritin in monitoring is to look sequentially over time and look for trends in patients as to whether or not those values are increasing, whether they're decreasing relative to erythropoietic therapy and iron therapy. And often times, it may be a sign that the patient has an underlying infection--when the value--is elevated that perhaps has not been detected, leading to resistance to erythropoietin therapy. So ferritin has some value, but it's important to recognize that limitation.

The TSAT, or the transferrin saturation, is a value that is derived by calculating the serum iron concentration divided by the total iron binding capacity present in the plasma, and so it will be a fraction. The normal value that one would like to see in patients is beyond 20% in the range of about 20% to 50% for an adequate transferrin saturation to support erythropoiesis. This value is a marker that gives one a better sense of the immediate availability of iron to support erythropoiesis. Again, though, under conditions of inflammation, there may be an increase in the iron binding capacity, which may lead to a decrease in the transferrin saturation, and as a result, it may be difficult to interpret, as well. But the TSAT seems to be perhaps the better marker of these two relative to evaluating the immediate availability of iron to support erythropoiesis.

The last value listed on this slide is the reticulocyte hemoglobin content (CHr). And reticulocytes, as you recall, are the immediate cells that are released from the marrow, and so they reflect perhaps the status of iron that is present in the marrow at a very near point in time to evaluating the iron status in the patient. So, for example, if the reticulocyte hemoglobin value is low, it may reflect the patient not having adequate amounts of iron in the marrow. As opposed to looking at the TSAT or the ferritin, the argument is that the CHr is a more sensitive indicator of the current status of iron stores. It's a value that is now becoming available in some centers. It's not widely available at all hospitals, and the dilemma currently with CHr is that there does not seem to be a consensus with regards to what a normal value is for this term to predict iron deficiency and then evaluate the response to iron therapy in patients. And so it's a test that is in further development, and it may prove to be very useful as an additional diagnostic tool in patients with iron deficiency.


Source: No authors listed. Am J Kidney Dis. 2001 Jan;37(1 Suppl 1):S182-238.
Source: Fishbane S et al. Am J Kidney Dis. 1997 Mar;29(3):319-33.

Types of iron deficiency in the HD patient
There are several types of iron deficiency that one can categorize for patients. The first of these would be considered an absolute iron deficiency. Again, as I mentioned earlier, the transferrin saturation value should be greater than 20%. When that value is less than 20% and the serum ferritin value is less than 100 ng/mL, which is again the lower limit of where we would like to see the serum ferritin value in patients, the combination of those is an absolute iron deficiency that may be because of increased blood losses, it may be because of decreased absorption. These patients will generally require, especially in the hemodialysis patients, IV therapy with iron. The reason for that is because oral administration of iron simply cannot be absorbed to the extent to overcome an absolute deficiency. These patients will require IV iron therapy in order to support erythropoiesis.

The next category is a functional iron deficiency. And in this case, the TSAT value may be below 20% or it may be in the low normal range, but the corresponding ferritin value is within the normal range. These patients have an intense stimulation of red cells, but there may not be enough iron immediately available to support the erythropoiesis. This is referred to as a functional iron deficiency. These patients often times also will respond to intravenous iron therapy.

The third category is perhaps the most problematic of these. This is a condition referred to as reticuloendothelial blockade, where there is an abrupt increase in the serum ferritin, again reflecting this as a marker of an acute phase reactant protein, along with an abrupt drop in the TSAT, again because of the increase in the TIBC. So in this condition, these patients will tend not to respond to erythropoietin therapy, and will also not respond to additional iron therapy, as well. It's important to try and differentiate these conditions diagnostically in terms of guiding what your pharmacotherapy options will be in patients.


Source: Henry DH. Oncologist. 1998;3(4):275-278.

Measuring iron stores in oncology and non-dialysis patients
The guidelines now for other populations outside of hemodialysis are not as well-established as they are with hemodialysis. This population has been very extensively studied, as well as the chronic kidney disease population. But in the oncology population, in the other areas in terms of critical care, we don't have as much information. Nonetheless, the NCCN, or the National Comprehensive Cancer Network's Anemia Practice Guidelines, have suggested very similar values for targeting the TSAT again of 20%, and the ferritin value of 100 ng/mL.
There actually needs to be further study to really define what appropriate levels of iron or the TSAT or the ferritins should be in these other populations. Oncology practices may vary. Some clinicians will use the K/DOQI guidelines, which are the hemodialysis guidelines and kidney disease guidelines that I've mentioned of 20% for the TSAT and 100 ng/mL for the ferritin. These will be used as guidelines for supplementation. Others may be looking for further evidence-based guidelines to guide therapy in that population. In the autologous transfusions and critical care arena, again, iron dosing is somewhat subjective. There's just not been enough study to really identify precisely what the appropriate values are as to when to replace therapy in patients.


Treatment options for iron deficiency anemia
Let's turn our attention now to look at some of the treatment options for iron deficiency anemia in these different populations.


Iron preparations
I'll divide this into two areas, one being oral iron therapy, and the second being IV iron therapy, with our focus primarily on IV products and depending on how you count, there are three types of products available for IV iron. There are actually two iron dextran products that are different molecules: and also, sodium ferric gluconate and iron sucrose are all available in the US market for IV administration.


Source: Wingard RL et al. Am J Kidney Dis. 1995 Mar;25(3):433-9.

Efficacy of oral iron in EPO-treated hemodialysis patients
Let me begin, though, with a quick picture, if I can, with the response in hemodialysis patients to oral iron therapy. This is a paper published by Wingard and colleagues looking at intensive oral iron therapy administered at doses of 200 mg of elemental iron per day with a variety of different iron products, some of these with vitamin C. Vitamin C was provided as supplemental therapy in those whose regimens did not contain vitamin C. And what one looks at in terms of the percent on the Y-axis as a function of the different products, the percentage of patients achieving adequate values defined as 20% for the TSAT and 100 ng/mL for the ferritin are all very low, ranging from 3% for one to 16% for another. Not adequate in terms of achieving what the target values are for iron supplementation.

Secondly, if one looks now at response, which is ultimately what we're more interested in, in this case the hematocrit as a function of the different products, all of these products achieve values either near 30% or below 30%. Inadequate in terms of what our target values are. We're trying to achieve hematocrit values in patients of 33% to 36% and corresponding hemoglobin values of 11 to 12 g/dL.


Source: Fudin R et al. Nephron. 1998;79(3):299-305.

IV iron: Superior improvement in iron parameters
Moreover, if one looks specifically now at comparing oral therapy with IV therapy, in this small sample size of patients that were naive to erythropoietin therapy, patients administered IV iron in the left-hand side, at baseline you can see the baseline values with IV iron and oral iron were very similar. IV iron shows at 12 months a very dramatic increase in hemoglobin to nearly 10 g/dL; and at 26 months, to 11 g/dL, versus oral iron therapy or no iron therapy: Both of these populations over time showing continued declines in hemoglobin. Oral iron therapy is simply not adequate to sustain iron stores necessary to support erythropoiesis in patients.


Efficacy in IV iron therapy in patients receiving EPO therapy
IV iron therapy is essential for effective erythropoiesis in patients, specifically in the hemodialysis population, where we have most of the evidence.


Source: No authors listed. Am J Kidney Dis. 2001 Jan;37(1 Suppl 1):S182-238.
Source: Eschbach JW. Semin Nephrol. 2000 Jul;20(4):320-9.
Source: Panesar A et al. Am J Kidney Dis. 2002 Nov;40(5):924-31.
Source: Henry DH et al. Semin Oncol. 1994 Apr;21(2 Suppl 3):21-8.

Source: Brugnara C et al. Blood. 1993 Feb 15;81(4):956-64.

IV iron is essential for effective erythropoiesis
Patients will require IV iron in order to achieve target hemoglobin or hematocrit values and to compensate for this annual loss. Recall the annual losses being in the range of 1 to 3 g/yr, which cannot be supplemented with oral therapy, so IV therapy is a requirement in these patients. In chronic kidney disease patients, these would be patients that are predialysis that are not undergoing these weekly losses of iron, IV iron therapy compared has been more effective in terms of achieving the target values of 12.5 in this case grams per deciliter versus 11.5 g/dL with iron alone, again indicating that erythropoietin therapy plus iron therapy combined, increases overall response with regards to hemoglobin.

Now, in oncology and surgical patients, there has been evidence of functional iron deficiency and this may lead to inadequate iron supply, inadequate iron storage necessary to produce new red cells. Patients do respond, but the data are not as clear cut. There are ongoing trials evaluating the response of iron in these populations. Finally, the enhanced plasma iron and TSAT may provide for a greater marrow response in patients that are in the category of bloodless medicine where erythropoietin is being used for autologous transfusions.


Source: Fishbane S et al. Am J Kidney Dis. 1995 Jul;26(1):41-6.

Maintenance IV vs oral iron therapy in hemodialaysis patients
Another interesting observation in comparing intravenous therapy with oral therapy was provided by Fishbane and colleagues a number of years ago now looking at maintenance therapy of IV iron in hemodialysis patients. Prior to this study, it was very common that once patients became iron deficient, a large dose of iron was administered to boost the stores of iron, and then after another period of time, perhaps four to six months, patients would become iron deficient again and be given another large dose. In this trial, the investigators looked at weekly administration of IV iron to sustain erythropoietic response and achieve higher hematocrit values. And so what we're looking at on the left-hand panel, the hematocrit expressed as percentage in the IV iron population versus oral iron population baseline values represented by the green bar are similar. At two months, a significant increase in hematocrit percent that was sustained at four months with IV iron. Oral iron shows not much of a change, no significant difference, but not an increase in hematocrit percent over time.

What is perhaps more interesting, rather than simply looking at the outcome variable of hematocrit, is an evaluation of the utilization of erythropoietin in both of these groups. For example, on the right-hand panel, if we're looking at the erythropoietin prescription in units per prescription as a function of IV iron versus oral iron, you can see the very dramatic reduction at two months, again sustained at four months, in need for erythropoietin to support this value that was achieved with IV iron. On the other hand, what you see is a very slight increase actually in the erythropoietin dose in the oral iron, so it is important to consider the erythropoietin dose as well as the outcome, whether it's hemoglobin or hematocrit when really evaluating the efficacy of iron products. In this case, not only did IV iron increase the hematocrit, but it also significantly reduced the erythropoietin requirement to achieve that value. It's important from an economic perspective to keep that in the larger picture.


Evidence of enhanced erythropoiesis with IV iron
These data had used a fairly large dose of weekly IV iron. It was iron dextran. It was administered at 200 mg/wk, much larger than what is presently used in contemporary practice today, and a number of other investigators have demonstrated that weekly maintenance iron in the hemodialysis patient population is very effective. It's been demonstrated for iron dextran, iron saccharate, which is the European equivalent of the US product iron sucrose, as well as ferric gluconate. All of these, you can see, have resulted in very significant reductions in the erythropoietin dose necessary to achieve adequate hemoglobin values.


IV iron compounds
Let's focus on the products, again, on the US market, and depending on how one counts, there are three or four products. There are two iron dextran products. These are different molecules. They're not simply different tradenames of these products, but actually different molecules. Iron dextran is available as INFeD and Dexferrum. Iron sucrose is available as Venofer, and ferric gluconate is available as Ferrlecit.

There are some very clear distinctions that can be made between, or among, these products. The first that I would point out is that between the dextran products and let's say the non-dextran products, the dextran products have a black-box warning, whereas a general warning in the product labeling exists for ferric gluconate and iron sucrose. A need for a test dose, again related to this black box warning. There is no need for a test dose with either of the non-dextran products. Both of the dextran molecules do require administration of a test dose prior to administration of the full dose. All of the products can be given by IV push administration. And another differentiating factor that may be advantageous in some cases is that iron dextran has been used as a total dose infusion: in other words, a large dose, perhaps 1 g, administered over a longer period of time as a single administration, versus larger doses of ferric gluconate and iron sucrose at that same level is not recommended. We'll talk about some of the larger doses for these products later in the presentation.


Pharmacokinetic properties of IV iron compounds
Some of the pharmacokinetic differences among these molecules. Basically, you can see that these are all large molecules, in the range of several hundred thousand daltons, for example, for sodium ferric gluconate. Iron sucrose is smaller. One of the questions that certainly may be raised when one looks at these molecules and the large amount of use in the hemodialysis patient is if these iron products are administered during dialysis, are they removed by the dialyzer? Well, these molecules are too large. They will not cross the membranes, and so all of these products are not removed. And this is an important PK consideration.

The half-life you can see is very long for the iron dextrans, in the range of 40 to 60 hours; much shorter for the sucrose and gluconate molecules; shortest for the sodium ferric gluconate. All of these molecules will directly transfer iron into the reticuloendothelial system, which is the storage iron in the body. Direct transfer of transferrin is another issue. Transferrin, remember, is the circulating protein in the plasma that is responsible for carrying the iron between the reticuloendothelial stores and the marrow. Iron dextrans and sodium ferric gluconate do not directly release iron in the plasma to the transferrin molecule. Iron sucrose has been reported to show direct transfer to transferrin, and we'll talk briefly about that again later.


Iron dextrans: risk vs benefits
Iron dextrans, risks versus benefits. I want to focus now on some of the iron dextran data. The products seem to have similar efficacy, whether we're looking at either of the two molecules. The primary benefit, again, as I mentioned, may be the ability to use total dose infusion: again, perhaps 1 gram, in some cases, publications may support larger amounts. Again, this is a potential benefit, but certainly may be offset by the very serious adverse effects: Anaphylactoid reaction and possible death that can occur as a result of dextran administration. A number of deaths, 31, have been reported following iron dextran administration in patients.


Source: Fletes R et al. Am J Kidney Dis. 2001 Apr;37(4):743-9.
Source: McCarthy JT et al. Am J Nephrol. 2000 Nov-Dec;20(6):455-62.
Source: Coyne DW et al. Kidney Int. 2003 Jan;63(1):217-24.

Safety profiles of IV iron dextran therapies
The safety profile of the iron dextrans. If one compared the two molecules between the Dexferrum and the INFeD product, a number of different reports have supported the idea that there is a much greater incidence of reactions--8.1-fold in this particular case --in Dexferrum compared with INFeD. These are both dextran products. A 2.8-fold increase with the Dexferrum molecule versus the INFeD; 7.9-fold increase in children with inflammatory bowel disease; a 1.8-fold increase of intolerance reactions with Dexferrum. There does appear to be a differentiation. So one of the considerations when looking at dextran molecule is that a dextran is not a dextran and that there may be advantages of one product over the other. The incidence, or the increased incidence of adverse reactions with Dexferrum, is certainly of note and been supported in many observations.


Source: Coyne DW et al. Am J Kidney Dis. 2002 Jul;40(1):219-20. No Abstract Available.
Source: Faich G et al. Am J Kidney Dis. 1999 Mar;33(3):464-70.

Spontaneous reports of anaphylactoid reactions to IV iron products
If one looks at these anaphylactoid reactions now among the products, and if we were to focus on the larger data sets that we have, primarily on the sodium ferric gluconate, again observations over a 20-year period, sodium ferric gluconate being used extensively in Europe, Germany, and Italy. These data are derived from those experiences: 74 anaphylactoid reactions occurring over that 20-year period. The iron dextrans over the same period of time, 20 years, primarily US data, 196 adverse reactions. You can see the relative rates of reactions for--or if one were to discount manufacturing issues in one year--in the 1995 data with the sodium ferric gluconate, reaction rates of about 1/2 per 100,000 patients exposed. We don't have the same extent of data availability in terms of safety. With regards to sucrose in an abstract at the American Society of Nephrology two years ago, a reaction rate of about five per 100,000 patients, and in the iron sucrose labeling about four. You can see these products seem to be lower than what the dextran molecules support.


Source: Michael B et al. Kidney Int. 2002 May;61(5):1830-9.

US safety study of SFGC
As a result of sodium ferric gluconate being brought to the US market, the FDA was very interested in identifying a safer IV iron product. So as a result of approval of this product, one of the requirements was the performance of a prospective trial evaluating the safety of sodium ferric gluconate.

The next couple of slides will summarize the results of this trial. This was a very large prospective randomized trial evaluating the safety of sodium ferric gluconate in approximately 2,500 patients, the largest prospective hemodialysis trial to evaluate drug response.

In this case, this schematic illustrates the very simple design of the study. Hemodialysis number one patients were screened for eligibility for participation. Hemodialysis treatment two patients were administered either 125 mg IV over 10 minutes of sodium ferric gluconate without a test dose, or placebo. The third treatment, patients were crossed over to receive the other treatment. So initially if the patient received the iron product, they received placebo in the third treatment. And then the fourth hemodialysis treatment was followed, making it a very well-designed and thought-out clinical trial evaluating in a prospective fashion the safety of sodium ferric gluconate.


Source: Michael B et al. Kidney Int. 2002 May;61(5):1830-9.

US safety study of SFGC
The results in terms of life-threatening reactions between the sodium ferric glucose and placebo are as follows. One reaction that was considered life-threatening, this was a patient who developed shortness of breath, back pain. It resolved. Dialysis treatment was continued, the patient was not admitted to the hospital, so while it was labeled by the investigator as a life-threatening reaction, there were no serious consequences, and the patient was discharged home following the dialysis therapy. In the placebo group, there were no life-threatening reactions. Based upon sample size, not a significant difference between these two groups in terms of this rate of reaction.

Secondly, for drug intolerance, defined as a patient who exhibited an adverse event that would preclude the clinician from giving another dose of the drug; so the patient was labeled as being drug intolerant, there were 11 of those events in the sodium ferric gluconate group. There were two in the placebo group. And the differences were significant at the level of 0.02. If one were to compare these now with the adverse reaction rates using a historical control for dextran: Dextran was not part of this trial. But if one compares it with dextran, the life-threatening adverse reaction rate with iron dextran is approximately .61 percent, highly significantly lowered incidence with sodium ferric gluconate compared to the historical control of iron dextran. And secondly, if one looks at drug intolerance, that drug intolerance rate was about 3.4 percent in patients, a very, very high rate relative to the .4 percent that was exhibited in sodium ferric gluconate. Compared with iron dextran, sodium ferric gluconate is a very safe product.


Iron sucrose interim safety data
We also have data on [iron sucrose] in terms of its overall safety, not to the same extent with regards to a prospective trial. But interim safety analysis of 344 patients with more than 4,000 doses in 61 centers showed that 100-mg doses administered at each treatment over 10 cycles for up to one year showed results ... an adverse reaction rate of about four percent, and again there were no life-threatening reactions or discontinuations.


Source: Kosch M et al. Nephrol Dial Transplant. 2001 Jun;16(6):1239-44.

Safety of SFGC and iron sucrose
The safety of these two non-dextran products, now, one can conclude that in a small prospective trial ... the only head-to-head comparison between these two products that used actually different dosage regimens ... one can see that with iron sucrose given at 250 mg over 2 hours, a different rate of administration than the administration of sodium ferric gluconate, which was administered at 62.5 mg IV push over 5 minutes ... in this comparison of patients there was no drug intolerance in either group, equivalent changes in iron parameters and in hemoglobin response ... were the same. The serum ferritin values rose over six months, and again, was not different between the two groups. Small, head-to-head comparison. That's the only comparison that we have directly between these two products.


Importance of pharmacokinetic differences
One of the other considerations is why might some of these pharmacokinetic differences perhaps be important when trying to differentiate these products? One question might be relative to the dose. Is the size of the dose important in patients? Secondly, what is the maximum dose that can be administered? We know that for iron dextran there are reports of up to perhaps 1 gram, not to the same extent for the sodium ferric gluconate or the iron sucrose.

What is the role of iron in infection? Certainly an important consideration that one needs to keep in mind is a reference to a non-transferrin-bound iron (designated as NTBI) that this unbound iron in the circulation may be important in terms of the development of infections in patients, small reports looking at in vitro Staph epidermidis growth.

There may be a role of iron in development of atherogenesis, the non-transferrin-bound iron can catalyze lipid peroxidation.

What is the role of iron in oxidative stress in patients?

What are the transferrin levels in these patients? Is that an important consideration in terms of the amount of binding sites available when IV iron is given? So how iron is handled when it's administered from these various products is very important as to whether or not there maybe bound iron, perhaps unbound, or the non-transferrin-bound iron, and potentially the consequences of these. There are ongoing trials continuing to evaluate whether or not there are significant differences among these products, and finally, whether or not there are differences in what we're concerned about, which are the outcomes in these patients.


Non-dextran higher dose studies
There are some indications of using--and I don't mean indications in the sense of FDA-approved indications--but there are some publications that support with some evidence that larger doses perhaps can be used, rather than the labeled doses for both sodium ferric gluconate and iron sucrose. The next couple of slides will summarize these results


Source: Folkert VW et al. Am J Kidney Dis. 2003 Mar;41(3):651-7.

Safety of SFGC
The first of these trials was published in American Journal of Kidney Disease by Folkert and colleagues, where larger doses, 250 mg, of IV iron, sodium ferric gluconate, was administered intravenously over one hour, a total dose was given of 1250 mg. Seven of the patients receiving these larger doses had prior iron dextran allergies, six of them had multiple drug allergies. Almost all of the patients (143 of the 144 patients) were tolerant of the administration, including 20 who received large doses, but again, these numbers are too small certainly to reach any conclusions of any safety issues with doses greater than 250 mg. One patient was intolerant due to itching, and there were no hospitalizations or adverse effects.

Many centers are involved in a non-labeled use of sodium ferric gluconate, using doses as large as 250 mg as an infusion over a 60-minute period.


Source: Chandler G et al. Am J Kidney Dis. 2001 Nov;38(5):988-91.

Safety of iron sucrose
Likewise with iron sucrose, there is some evidence by Chandler and others that suggests that larger doses of iron sucrose beyond 100 mg may be safely administered to patients, and these investigators initially looked at larger doses of 200 mg in 89 patients and found no adverse effects, and so the dose was increased to 500 mg. There were eight adverse events in 22 patients receiving the 500-mg dose. The dose was reduced to 400 mg and there were two adverse reactions, and at 300 mg there were no adverse reactions. The data seem to suggest that doses perhaps up to 200 to 300 mg IV again infused in this case over an hour may be safe for iron sucrose. All of the adverse events included hypotension, and so it appeared to be a dose-related or rate of infusion-related reaction with iron sucrose. None of the adverse events required hospitalization.


Source: Senger JM et al. ANNA J. 1996 Jun;23(3):319-23; discussion 324-5.
Source: Sunder-Plassmann G et al. Nephrol Dial Transplant. 1995 Nov;10(11):2070-6.
Source: Taylor JE et al. Nephrol Dial Transplant. 1996 Jun;11(6):1079-83.
Source: Michael B et al. Kidney Int. 2002 May;61(5):1830-9.
Source: Panesar A et al. Am J Kidney Dis. 2002 Nov;40(5):924-31.

Benefits of increased iron utilization
Lastly, let me put on the table some issues related to bringing together some of the clinical considerations with IV iron products and some of the economic considerations that I think in your current position certainly are very important issues to keep in mind. These are fairly general, but it's important to think about in your institutions, which IV iron product is most appropriate. What is the patient mix in your particular institution? Is it a population where there is a lot of CKD or a lot of hemodialysis? Is it a population where there is a lot of oncology patients? What is the pattern of erythropoietin use? Again, as I mentioned at the outset, when one sees erythropoietin use and knows there is active production of red cells, in the back of your mind you need to be thinking about iron therapy and whether or not that iron therapy is going to be present to support erythropoiesis. All of these factors come into play when we look at the pharmacoeconomic considerations.


Pharmacoeconomic considerations
The first certainly is on the economic side, looking at the current IV iron cost.


Assess current IV iron cost
There's certainly very clearly a drug cost associated with any of the products, whether it's sodium ferric gluconate or iron sucrose or the dextran molecules. How is it to be administered? What are the IV solution and supply costs? If it's going to be administered as a solution, that increases the overall cost.

What are the labor costs in terms of ordering, of receiving and storage? Are there compounding issues? If we're IV admixing these products and infusing them over long periods of time, how does one factor that into the overall equation for cost and overall administration costs from the economic perspective? Inventory holding costs also need to be considered for the various products and what is going to be driven by the utilization by the individual institution.

Patient transportation costs may not seem to be a direct cost involved, but nonetheless, in an outpatient environment, for example, where patients receive their iron and travel back and forth, administration perhaps of larger doses may be beneficial. While that may not have a direct impact on the overall cost of the product in your institution, those costs are important relative to how the patient is going to be managed with regards to multiple visits to the clinic or to the hospital for therapy, or whether larger doses may be safely administered to the patient. Overall costs are going to be important factors.


Variables to consider in analysis
When one analyzes and brings these ideas together thinking about the economics, certainly in a larger perspective, one needs to look at individual contracts, purchasing incentives, the cost is not the cost is not the cost. One can look at average wholesale prices, but those really are not real costs. One needs to look at individual and incentives that often times drive purchasing by various institutions, by looking at current product purchasing structure within the institution, and how those individual decisions are made, then the reliability among the products, individual facility specialties that I mentioned earlier: oncology, hemodialysis, surgery, what is going to be the use of IV iron in the individual institution. That may be a driving factor for which IV iron product is going to be most important.
What is the current product utilization versus the potential utilization? This is an important point to keep in mind. It's one issue to say, "In our institution we're using IV iron at this rate." You can look back six months, you can look forward six months, and maybe that rate is okay. But when one looks at the appropriate utilization of iron relative to these conditions--oncology, hemodialysis--is it being used enough? Is there a need for additional iron? It's not simply a matter of how much is being used, but what is the potential market for using iron, and it's not from a profit and loss perspective, but it's from the perspective of achieving the outcomes that we're looking for. And it's not achieving just adequate iron studies or a certain hemoglobin or hematocrit, but it's really the outcome in terms of decreasing mortality, decreasing hospitalizations, cardiovascular disease, and improving quality of life. Those are really the outcomes that we're most concerned about.

Lastly, in the individual institution, depending on the practice setting, there certainly the pharmacy department can have a very important impact on prescribing practice; and monitoring and evaluating, again, targeted erythropoietic use and evaluation of iron along with that is probably a very easy and early steppingstone to move forward in improving utilization of iron.

One can look at the cost side of the equation, but to balance that, one also has to look at the benefit side of the equation and this refers back to the number of issues that were mentioned at the outset, and that is there is decrease in erythropoietic requirements ... whether that product epoietin alfa or the newer product, darbepoietin alfa. Both of these products, in terms of their overall utilization, will decrease with appropriate iron utilization, decreased potential for anaphylactoid reaction to adverse events with the non-dextran products, and decreased need for transfusions, perhaps, in patients in the critical care unit with appropriate amounts of iron and erythropoietic therapy to stimulate red cell production. Lastly, and certainly this is an oversimplification of what we're really interested in, is improved outcomes. There are a variety of outcomes that one can look at with regard to iron therapy and erythropoietic therapy.


In conclusion, we can summarize by saying that the correction of anemia will lead to reversal of the cardiovascular damage and improvement to the quality of life in patients and quality of life parameters. Iron and erythropoietin are essential for effective erythropoiesis. Again, thinking of these two hand in hand, they are separate products, but they work together in terms of increasing red cell production.

All IV iron forms are equally effective at achieving iron store to support erythropoiesis--iron dextran, iron sucrose, sodium ferric gluconate. They will all achieve that outcome. The issue, though, is how do you differentiate? Adverse events are important, and again, perhaps the issue related to total dose infusion, depending upon your individual population.

Safety differences, though, are probably the highlight of what really is important when thinking of these products. Fewer adverse events with INFeD versus Dexferrum, if you're looking at just iron dextran products. Secondly, if one looks at anaphylactoid reactions with these products, sodium ferric gluconate and iron sucrose are very clearly much safer alternatives to the dextrans.

Finally, to capture the point of the pharmacoeconomic evaluation, it really needs to be institution-specific. What is your utilization? What is your patient mix? How is erythropoietin being used? How can you most appropriately use iron therapy to achieve the overall outcomes that you're trying to see in your patients? With that, I will stop and thank you for your attention.


Questions and discussion


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This educational activity is supported by an educational grant from Watson Pharmaceuticals Inc.