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Venofer^® (iron sucrose injection, USP) can be given as a bolus injection into the venous limb of the patient's vascular access. This mode of administration avoids the need for filter needles, infusion pumps, bags of normal saline, and IV sets. No test dose is required. (In US clinical trials, some physicians administered a test dose at their discretion).  Venofer^® is packaged in vials rather than ampules to decrease the risk for injury from broken glass to the healthcare professional administering the dose. This simple, user-friendly method of administration helps reduce the physician and nursing time required for intravenous iron therapy.

Optimization of Anemia Management in NDD-CKD Without Erythropoietin Therapy
Iron deficiency commonly complicates anemia in patients with non-dialysis dependent - chronic kidney disease (NDD-CKD).  As many as 25 to 40% of males and 35 to 85% of females with anemia and NDD-CKD show evidence of iron deficiency.¹  IV iron therapy can provide effective anemia management, even in the absence of an erythropoietin, in a substantial fraction of these patients.  A randomized, controlled, multicenter trial examined response to iron therapy in patients with NDD-CKD Stage 3-5, anemia and moderately low iron indices (TSAT <25%, ferritin <300 ng/ml).  Among 47 patients who did not receive erythropoietin therapy, 18 (38%) achieved a Hgb increase of ≥ 1.0 g/dl and 28 (60%) achieved a K/DOQI-recommended Hgb level of ≥ 11 g/dl after administration of 1,000 mg of IV iron sucrose in divided doses.¹  Thus, IV iron sucrose alone can be effective in the management of CKD-associated anemia in non-dialysis patients, even in the absence of erythropoietin therapy.

Optimization of Erythropoietin Therapy
Aggressive intravenous iron therapy with products such as Venofer^® is increasingly recognized as a means of optimizing the response to erythropoietin. Evidence from 10 studies^2-11 conducted since 1992, including a total of more than 450 patients, shows that intensive intravenous iron supplementation (iron dextran, iron sucrose, or sodium ferric gluconate in sucrose complex) allows a reduction in erythropoietin dose of 19% to 70%. ¹²

Nyvad O et al. ⁴ Data were collected from 34 end-stage renal failure patients (26 on hemodialysis, 8 on other types of dialysis) to measure the effect of iron sucrose on erythropoietin usage in a dialysis center in Denmark.  All patients were receiving erythropoietin (median weekly dose 5,300 IU) for anemia. Oral iron had not resulted in a significant rise in ferritin (ferritin ranges from 10 to 120 µg/L).  All patients received an initial cumulative dose of 1,150 mg iron sucrose (1,000 mg iron sucrose is the FDA-approved cumulative dose). Adjustment of erythropoietin dose was based on assessment of clinical and lab data. Data were collected from 3 months before to 3 months after the first dose of iron sucrose. None of the patients had very low ferritin or TSAT values, yet IV iron sucrose therapy permitted a 27% reduction in the dose of erythropoietin with unchanged hematocrit and hemoglobin after 3 months.

Macdougall et al. ¹³ Macdougall et al examined the effects of adopting an aggressive IV iron policy in the United Kingdom. Data were collected from 116 patients attending a single hemodialysis center.  All patients with a serum ferritin level between 150 and 1,000 ng/mL received regular weekly IV iron supplementation (100 mg of iron sucrose as a bolus injection).  Intravenous iron was withheld only if the serum ferritin level exceeded 1,000 ng/mL at any stage.  Patients whose serum ferritin levels were less than 150 ng/mL were given a more aggressive regimen of IV iron until the levels reached above this threshold. Among 116 patients included in the study, ferritin and hemoglobin levels increased, while there was a dramatic reduction in mean erythropoietin dose from 13,227 IU/wk to 8976 IU/wk.

Free Iron and Labile Iron
All IV iron preparations are colloids.  IV iron agents are distinguished by colloid particle size, core size, and the nature of the carbohydrate shell. ¹⁴  Particles consist of a core of ferric oxide/oxyhydroxide surrounded by a shell of carbohydrate.  The generic name of each agent derives from the carbohydrate, for example, sucrose, dextran, or gluconate for iron sucrose, iron dextran, and iron gluconate, respectively.  There is no unbound iron in the agents themselves: neither free iron nor intact iron compounds are found in dialysate.^14-17  However, all iron agents show evidence of iron bioactivity after exposure to blood, cells or other tissues.  Evidence of the bioactivity of IV iron agents takes several forms, including oxidative stress,^14,18,19 direct donation of iron to transferrin, ^20-22 and alteration of neutrophil function. ^23-25  Manifestations of the bioactivity of IV iron agents are taken to be evidence that all agents contain a bioactive or labile iron fraction.

Oxidative stress is manifested by indirect measures of the oxidation of lipid membranes and plasma protein.  Not all reports show oxidative stress related to IV iron agents.  How much, if any, oxidative stress occurs after exposure to IV iron agents depends on the specific test used, the type of IV iron agent, and the concentration of the IV iron agent itself.  Many causes of oxidative stress in chronic kidney disease patients receiving IV iron are unrelated to iron administration.^26,27 Oxidative stress may contribute to the pathogenesis of atherosclerosis and, in particular, coronary artery disease (CAD).  CAD is a leading cause of death in patients with chronic kidney disease. Although iron is a known and potent cause of oxidative stress, experimental ²⁸ and clinical evidence that IV iron causes CAD or contributes to atherogenesis or heart disease in renal failure is lacking. More generally, most experts agree that naturally occurring causes of iron excess do not lead to higher rates of CAD. ²⁹

Infection is the other leading cause of death in patients with chronic kidney disease. Since iron is an essential nutrient for bacterial growth and IV iron agents provide iron in abundance, the potential role of IV iron administration in the pathogenesis of infection in patients has been explored. Despite evidence that IV iron agents may enhance bacterial growth in vitro, prospective multicenter clinical trials²⁹ and large scale retrospective studies in chronic kidney disease patients have found no discernable relationship between the incidence of infection and either IV iron dosing or levels of iron status tests.  A retrospective analysis by Aronoff et al found that the mortality rate from infection or sepsis among patients receiving iron sucrose in this trial compared favorably with that of the overall United States hemodialysis population.  They also found that the hospitalization rate from infection among patients receiving iron sucrose injection in the trial was significantly lower than that of the general US hemodialysis population.³⁰

Labile or bioactive iron in IV iron agents also plays a role in immune defense. Evidence on the effect of IV iron on neutrophil function is mixed. Since part of the neutrophil’s killing potential stems from oxidative destruction of bacteria, some iron is needed for optimum neutrophil function. Too much iron, however, impairs phagocytosis of bacteria by neutrophils. Carefully designed, prospective studies have shown no relationship between IV iron treatment and risk of infection.³¹

Finally, labile iron in IV iron agents may be manifested by a rise in the transferrin saturation. ³² Transferrin is the sole extracellular iron-binding protein. Since the entire iron-binding capacity of transferrin in the bloodstream of an adult is <17 mg, rapid administration of large doses of IV iron may lead to sudden oversaturation or supersaturation of transferrin. Non–transferrin-bound iron (NTBI) is a theoretical mechanism to explain increased oxidative stress or bacterial growth.¹⁹ NTBI may contribute to hypotension and cramping, symptoms which limit the dose and rate of IV iron administration. Difficulty in detecting supersaturation and the observation that NTBI is found in renal failure patients without IV iron therapy^19,33 render the clinical relevance of this phenomenon uncertain, however.

Markers of oxidative stress include levels of lipid peroxidation (often measured indirectly by determining levels of malonyldialdehyde (MDA)) ^18,34 or protein oxidation, including advanced oxidation protein products (AOPP),³⁵ and carbonylated fibrinogen.³⁶ Markers of neutrophil function include in vitro neutrophil killing capacity, ²⁴ neutrophil oxidative burst,²⁴ and neutrophil phagocytosis. Markers of iron donation to transferrin, of course, include the transferrin saturation (TSAT), ³¹ bleomycin-detectable iron (BDI),³⁵ and NTBI.^18,19,37

In short, while no IV iron agent contains free iron, all IV iron agents (including iron gluconate, iron dextran and iron sucrose) have biologically active or labile iron. Labile iron is manifested by several worrisome test results related to CAD and infection; CAD and infection are common causes of death and hospitalization in dialysis patients, but there is no evidence linking IV iron agents or IV iron administration to an increased risk of CAD or infection in patients with chronic kidney disease.


IMPORTANT SAFETY INFORMATION
Venofer^® (iron sucrose injection, USP) is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer^® or any of its inactive components, and in patients with anemia not caused by iron deficiency.  Hypersensitivity reactions have been reported with IV iron products.  Hypotension has been reported frequently in hemodialysis dependent-CKD patients receiving IV iron, and has also been reported in non-dialysis dependent and peritoneal dialysis dependent-CKD patients receiving IV iron.  Hypotension following administration of Venofer^® may be related to rate of administration and total dose delivered.

In multi-dose efficacy studies in hemodialysis dependent-CKD patients (N=231), the most frequent adverse events (>5%), whether or not related to Venofer^® administration, were hypotension, cramps/leg cramps, nausea, headache, graft complications, vomiting, dizziness, hypertension, chest pain and diarrhea.  In post-marketing safety studies in hemodialysis dependent-CKD patients (N=1051), the most frequent adverse events reported (>1%) were congestive heart failure, sepsis and taste perversion.  In multi-dose efficacy studies in non-dialysis dependent-CKD patients (N=91), the most frequent adverse events (≥5%) whether or not related to Venofer® administration, were taste disturbance, peripheral edema, diarrhea, constipation, nausea, dizziness, and hypertension.  In the study of peritoneal dialysis dependent-CKD patients (N=75), the most frequent adverse events, whether or not related to Venofer ^®, reported by ≥5% of these patients were diarrhea, peritoneal infection, vomiting, hypertension, pharyngitis, peripheral edema and nausea.

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^References

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15. Venofer^® (iron sucrose injection, USP) [package insert]. Shirley, NY: American Regent, Inc.; 2007.
16. INFeD^® [package insert]. Florham Park, NJ: Schein Pharmaceutical, Inc; 1998.
17. Ferrlecit^® [package insert]. Florham Park, NJ: Schein Pharmaceutical, Inc; 2001.
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22. Macdougall IC, Tucker B, Thompson J, et al. A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int. 1996;50:1694-1699.
23. Patruta SI, Edlinger R, Sunder-Plassmann G, et al. Neutrophil impairment associated with iron therapy in hemodialysis patients with functional iron deficiency. J Am Soc Nephrol. 1998;9:655-663.
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37. Kooistra MP, Kersting S, Gosriwatana I, et al. Nontransferrin-bound iron in the plasma of haemodialysis patients after intravenous iron saccharate infusion. Eur J Clin Invest. 2002;32(suppl 1):36-41.