Intravenous Iron Preparations Research Articles

Distinct immunologic effects of different intravenous iron preparations on monocytes

BackgroundIron deficiency contributes to anaemia in patients with chronic kidney disease. I.v. iron is therefore widely used for anaemia treatment, although it may induce oxidative stress and activate monocytes. Different i.v. iron preparations are available, but interestingly their substance-specific immunologic effects are poorly studied.MethodsWe analysed the effect of iron sucrose, ferric carboxymaltose, iron isomaltoside 1000, low-molecular-weight iron dextran and ferumoxytol on classical, intermediate and nonclassical monocyte biology. We therefore stimulated in vitro mature monocytes and haematopoietic CD34+ stem cells during their differentiation into monocytes with different concentrations (0.133, 0.266, 0.533 mg/mL) of i.v. iron preparations. Alterations of monocyte subset distribution, expression of surface markers (CD86, CCR5, CX3CR1), as well as production of pro-inflammatory cytokines (TNF-α, IL-1β) and reactive oxygen species were measured using flow cytometry. Additionally, we analysed phagocytosis and antigen presentation capacity.ResultsWe found specific immunologic effects after stimulation with iron sucrose which were not induced by the other iron preparations. Iron sucrose activated monocyte subsets leading to significantly increased CD86 expression. Simultaneously CD16 and CX3CR1 expression and monocytic phagocytosis capacity were decreased. Additionally, differentiation of monocytes from haematopoietic CD34+ stem cells was almost completely abolished after stimulation with iron sucrose.ConclusionsOur findings demonstrate that specific immunologic effects of distinct i.v. iron preparations exist. The clinical relevance of these findings requires further investigation.

Intravenous iron therapy in non-dialysis CKD patients

Iron deficiency anaemia in non-dialysis-dependent chronic kidney disease patients is common, with a study (admittedly from more than 10 years ago) suggesting that >800 000 such patients in the USA are affected [1]. This may significantly impact on quality of life and exercise capacity, and it is also associated with significant morbidity and mortality. Correction of the anaemia will require iron replacement therapy, with or without erythropoiesis-stimulating agents (ESAs). The optimum route of administration of iron is controversial, with a wide variability in clinical practice among different countries, different renal units and indeed among different nephrologists within the same unit. The use of oral versus intravenous iron as the first-line management of this condition varies, partly because of the individual nephrologist’s beliefs and also partly due to a paucity of scientific evidence in this clinical setting, but is also influenced by the accessibility to a service that is readily able to provide intravenous iron supplementation. Thus, in primary care, general practitioners are likely to start with oral iron, whereas renal units that support an intravenous iron clinic (usually nurse-led) are more likely to start with intravenous iron. Reimbursement policies for intravenous iron in the non-dialysis CKD setting are also variable throughout the world, and this too may impact on the relative use of IV versus oral iron. Until recently, with the exception of iron dextran-containing preparations (which themselves have generated concerns about anaphylactic or hypersensitivity reactions), the available intravenous iron compounds were unable to provide high doses of iron as a single administration. Thus, for iron gluconate (used in the USA, Italy and Germany), doses of 62.5–125 mg of iron were the maximum recommended at a single sitting [2], whereas for iron sucrose (IS) - used widely in the USA, Europe, and Australia, bolus doses of up to only 200 mg were recommended [3]. Thus, many patients were required to attend for repeated boluses of IV iron, e.g. three or more injections of IS, 200 mg at a time, to replenish their iron deficits. Within the last few years, three new intravenous iron preparations have been licensed [4]. These include ferumoxytol (Feraheme® in the USA; Rienso® in Europe), ferric carboxymaltose (FCM, Ferinject® in Europe; Injectafer® in the USA) and iron isomaltoside-1000 (Monofer® in Europe). Data comparing these new preparations to the more traditional IV iron compounds are sparse, with small numbers of patients included in the clinical trials, most of which were not randomized, and with short follow-up. Qunibi et al .[ 5] performed a randomized controlled trial comparing intravenous FCM with oral iron for the treatment of iron deficiency anaemia in nondialysis-dependent chronic kidney disease patients, and showed that the response to intravenous iron was slightly greater with intravenous iron compared with oral iron, with an acceptable safety profile. However, the total number of patients exposed to intravenous FCM was 152 and the period of follow-up was only 8 weeks. In another recent randomized controlled trial, Charytan et al .[ 6] administered 15 mg/kg of FCM intravenously up to a maximum of 1000 mg in 204 nondialysis CKD patients and compared the haemoglobin responses with a group of patients treated with standard medical care (IV, oral or no iron, as determined by the investigator). Otherwise, head-to-head comparisons of IV iron preparations in the non-dialysis CKD population have been lacking. Onken et al. [7], in this issue of Nephrology Dialysis Transplantation, however, have gone some way to correcting this deficit in the evidence base, by reporting the results of the REPAIR-IDA trial. This was a large randomized controlled

Double bull's eye for post-operative intravenous iron in patient blood management: better outcome and cost-effective.

Double bull's eye for post-operative intravenous iron in patient blood management: better outcome and cost-effective.

High dose intravenous iron, mineral homeostasis and intact FGF23 in normal and uremic rats.

BackgroundHigh iron load might have a number of toxic effects in the organism. Recently intravenous (iv) iron has been proposed to induce elevation of fibroblast growth factor 23 (FGF23), hypophosphatemia and osteomalacia in iron deficient subjects. High levels of FGF23 are associated with increased mortality in the chronic kidney disease (CKD) population. CKD patients are often treated with iv iron therapy in order to maintain iron stores and erythropoietin responsiveness, also in the case of not being iron depleted. Therefore, the effect of a single high iv dose of two different iron preparations, iron isomaltoside 1000 (IIM) and ferric carboxymaltose (FCM), on plasma levels of FGF23 and phosphate was examined in normal and uremic iron repleted rats.MethodsIron was administered iv as a single high dose of 80 mg/kg bodyweight and the effects on plasma levels of iFGF23, phosphate, Ca2+, PTH, transferrin, ferritin and iron were examined in short and long term experiments (n = 99). Blood samples were obtained at time 0, 30, 60, 180 minutes, 24 and 48 hours and in a separate study after 1 week. Uremia was induced by 5/6-nephrectomy.ResultsNephrectomized rats had significant uremia, hyperparathyroidism and elevated FGF23. Iron administration resulted in significant increases in plasma ferritin levels. No significant differences were seen in plasma levels of iFGF23, phosphate and PTH between the experimental groups at any time point within 48 hours or at 1 week after infusion of the iron compounds compared to vehicle.ConclusionsIn non-iron depleted normal and uremic rats a single high dose of either of two intravenous iron preparations, iron isomaltoside 1000, and ferric carboxymaltose, had no effect on plasma levels of iFGF23 and phosphate for up to seven days.

Physicochemical and structural characterization of iron–sucrose formulations: a comparative study

Intravenous polynuclear iron formulations are vital components in the treatment of iron deficiency anemia associated with chronic kidney disease as well as other diseases associated with gastro-intestinal and cardio-vascular system. Intravenous iron preparations consist of iron–carbohydrate nanoparticles with iron–oxyhydroxide as a core covered by carbohydrate shell. These preparations should be very well characterized in terms of their physicochemical properties and pharmacological profile in order to establish safety and efficacy. The present research work was aimed to physicochemically characterize a new generic iron–sucrose preparation (IS-Claris) and establish its equivalency with the reference product (Venofer®). Various analytical techniques including gel permeation chromatography (GPC), mass spectroscopy (MALDI-TOF), absorption spectroscopy, X-ray diffraction analysis (XRD), nuclear magnetic resonance spectroscopy (proton and 13C NMR), Fourier transform infrared spectroscopy (FTIR) and thermal gravimetric analysis (TGA) were employed. It was observed that the specifications of IS-Claris obtained through these analyses reflect those of Venofer® and hence the two formulations were considered comparable.

Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women

Fibroblast growth factor 23 (FGF23) is an osteocyte-derived hormone that regulates phosphate and vitamin D homeostasis. Through unknown mechanisms, certain intravenous iron preparations induce acute, reversible increases in circulating FGF23 levels that lower serum phosphate in association with inappropriately low levels of calcitriol, similar to genetic diseases of primary FGF23 excess. In contrast, studies in wild-type mice suggest that iron deficiency stimulates fgf23 transcription but does not result in hypophosphatemia because FGF23 is cleaved within osteocytes by an unknown catabolic system. We tested the association of iron deficiency anemia with C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) levels in 55 women with a history of heavy uterine bleeding, and assessed the longitudinal biochemical response over 35 days to equivalent doses of randomly-assigned, intravenous elemental iron in the form of ferric carboxymaltose (FCM) or iron dextran. Iron deficiency was associated with markedly elevated cFGF23 (807.8 ± 123.9 relative units [RU]/mL) but normal iFGF23 (28.5 ± 1.1 pg/mL) levels at baseline. Within 24 hours of iron administration, cFGF23 levels fell by approximately 80% in both groups. In contrast, iFGF23 transiently increased in the FCM group alone, and was followed by a transient, asymptomatic reduction in serum phosphate <2.0 mg/dL in 10 women in the FCM group compared to none in the iron dextran group. Reduced serum phosphate was accompanied by increased urinary fractional excretion of phosphate, decreased calcitriol levels, and increased parathyroid hormone levels. These findings suggest that iron deficiency increases cFGF23 levels, and that certain iron preparations temporarily increase iFGF23 levels. We propose that intravenous iron lowers cFGF23 in humans by reducing fgf23 transcription as it does in mice, whereas carbohydrate moieties in certain iron preparations may simultaneously inhibit FGF23 degradation in osteocytes leading to transient increases in iFGF23 and reduced serum phosphate.

An analysis of the health service efficiency and patient experience with two different intravenous iron preparations in a UK anaemia clinic

Background:Historically, the Renal Unit at King’s College Hospital used intravenous (IV) iron sucrose (IS) to treat iron deficiency anaemia in patients with chronic kidney disease who were not on dialysis (CKD-ND). As part of a service initiative to improve patient experience, new products were considered as alternatives. This study investigated the potential impact on patient experience and service costs by switching from IS to ferric carboxymaltose (FCM).Methods:A decision analytical model was used to calculate the impact of switching from IS to FCM for a cohort of CKD-ND patients. Service provision data were collected for 365 patients who received 600 mg IS within a 12 month period, creating the IS data set. The service provision data, along with a clinically relevant FCM administration protocol (stipulating total doses of 500 mg FCM), were used to calculate a corresponding theoretical data set for FCM for the same cohort of patients.Results:The FCM protocol saved each patient two hospital visits and 2.66 hours of time (equating to approximately a saving of £36.21 in loss of earnings) and £19 in travel costs. Direct attributable costs for iron administration (which included drug, disposables, nursing staff, and hospital-provided patient transport costs) were £58,646 for IS vs £46,473 for FCM. Direct overhead costs (which included nursing preparation time, administration staff, clinic space, and consultant time costs) were £40,172 for the IS service vs £15,174 for the FCM service.Limitations:Based on clinical experience with the products, this analysis assumes that 500 mg FCM is therapeutically equivalent to 600 mg IS. Consultant time costs are assumed to be the same between the two treatment groups. IV iron administration protocols and data are specific to King’s College Hospital. The design is retrospective and changes to the management of the clinic, including service delivery optimization, may also affect real costs.Conclusion:FCM was associated with fewer hospital visits and reduced transport costs for CKD-ND patients receiving IV iron and has the potential to save 19–37% in service costs. Owing to increased administration efficiency, FCM can improve the overall patient experience while reducing the total cost of the King’s College Hospital IV iron service for CKD-ND patients, compared with treatment with IS.

Iron Sucrose Impairs Phagocytic Function and Promotes Apoptosis in Polymorphonuclear Leukocytes

Background: With the recent implementation of bundling reimbursement policy, the use of intravenous (IV) iron preparations for the management of anemia in the end-stage renal disease (ESRD) population has dramatically increased. Iron overload increases the risk of infections in individuals with or without kidney disease. IV iron administration in ESRD patients impairs bacteriocidal capacity of polymorphonuclear leukocytes (PMNs) against Escherichia coli. These preparations consist of an elemental iron core and a carbohydrate shell. In addition to the iron core, the carbohydrate shell may affect PMNs. We therefore examined the effect of iron sucrose, a commonly used preparation, on phagocytic capacity of PMNs from a group of normal individuals against Gram-positive (Staphylococcus aureus) and Gram-negative (E. coli) bacteria. Methods: Iron sucrose was added to heparinized blood samples at pharmacologically-relevant concentrations and incubated for 4 and 24 h at 37°C to simulate in vivo condition. Blood samples mixed with equal volume of saline solution served as controls. To isolate the effects of the carbohydrate shell, blood samples were co-treated with the iron chelator, desferrioxamine. Results: Iron sucrose caused significant PMN apoptosis and dose-dependent suppression of phagocytic function against both Gram-positive and Gram-negative bacteria. These abnormalities were prevented by desferrioxamine which precluded contribution of the carbohydrate shell to the PMN dysfunction. Conclusions: At pharmacologically-relevant concentrations, iron sucrose promotes apoptosis and inhibits phagocytic activities of PMNs. The deleterious effect of iron sucrose is mediated by its elemental iron core, not its carbohydrate shell, and as such may be shared by other IV iron preparations.

PMO-257 Cost-effectiveness and cost comparison of intravenous iron preparations in patients with IBD-associated iron deficiency anaemia based on the FERGImain trial

IntroductionAnaemia is a costly complication of IBD and a common trigger of hospitalisation. The FERGImain trial, a multi-centre, randomised, placebo-controlled study, demonstrated that on-demand ferric carboxymaltose (FCM) reduced recurrence of...

Safety and Efficacy of Intravenous Ferric Carboxymaltose (750 mg) in the Treatment of Iron Deficiency Anemia: Two Randomized, Controlled Trials

Background. Iron deficiency anemia (IDA) is a common hematological complication with potentially serious clinical consequences that may require intravenous iron therapy. Ferric carboxymaltose (FCM) is a stable, nondextran iron formulation administered intravenously in large single doses to treat IDA. Objective. Two open-label, randomized, placebo-controlled trials evaluated safety of multiple or single 750 mg FCM doses compared to standard medical care (SMC) in IDA patients. Secondary endpoints were improvements in hemoglobin and iron indices. Design and Patients. Adults with hemoglobin ≤12 g/dL, ferritin ≤100 or ≤300 ng/mL with transferrin saturation ≤30% were randomized to receive single (n = 366) or weekly (n = 343) FCM or SMC (n = 360 and n = 366). Results. Significantly greater (P ≤ 0.001) increases in hemoglobin and iron indices occurred in FCM groups versus SMC. In the multidose study, up to two infusions of FCM were needed to reach target iron levels versus 3–5 of intravenous iron comparators. FCM and SMC groups had similar incidences and types of adverse events and serious adverse events. Transient hypophosphatemia not associated with adverse events or clinical sequelae occurred in the FCM groups. Conclusion. Intravenous FCM is safe, well tolerated, and associated with improvements in hemoglobin and iron indices comparable to SMC when administered in single doses of up to 750 mg at a rate of 100 mg/min. Fewer FCM infusions were required to reach target iron levels compared to other intravenous iron preparations.

Role of Iron Deficiency and Anemia in Cardio-Renal Syndromes

Chronic heart failure is a common disorder associated with unacceptably high mortality rates. Chronic renal disease and anemia are two important comorbidities that significantly influence morbidity and mortality in patients with chronic heart failure (CHF). Progress in CHF again may cause worsening of kidney function and anemia. To describe this vicious cycle, the term cardio-renal anemia syndrome has been suggested. Iron deficiency is part of the pathophysiology of anemia in both CHF and chronic kidney disease, which makes it an interesting target for treatment of anemia in cardio-renal anemia syndrome. Recently, studies have highlighted the potential clinical benefits of treating iron deficiency in patients with CHF, even if these patients are nonanemic. This article summarizes studies investigating the influence of iron deficiency with or without anemia in chronic kidney disease and CHF and gives an overview of preparations of intravenous iron currently available.

Iron Sucrose Promotes Endothelial Injury and Dysfunction and Monocyte Adhesion/Infiltration

Background/Aims: Intravenous (IV) iron preparations are widely used in the management of anemia in ESRD populations. Recent changes in reimbursement policy have dramatically increased the use of IV iron to lower the use of costly erythropoiesis-stimulating agents. These preparations are frequently administered with insufficient attention to the total body iron stores or presence of inflammation which is aggravated by excess iron. Endothelial injury and dysfunction are critical steps in atherosclerosis, thrombosis and cardiovascular disease. IV iron preparations raise plasma non-transferrin-bound iron which can promote oxidative stress, endothelial damage and dysfunction. We explored the effect of an IV iron preparation on endothelial cells, monocytes and isolated arteries. Methods: Primary cultures of human aortic endothelial cells (HAEC) were treated with pharmacologically relevant concentrations of iron sucrose (10–100 µg/ml) for 4–24 h. Endothelial cell morphology, viability, and monocyte adhesion were tested. Endothelial function was assessed by measuring the vasorelaxation response to acetylcholine in normal rat thoracic aorta rings preincubated with iron sucrose (200 µg/ml). Results: In contrast to the control HAEC which showed normal cobblestone appearance, cells treated with iron sucrose (50–100 µg/ml) for 4 h showed loss of normal morphological characteristics, cellular fragmentation, shrinkage, detachment, monolayer disruption and nuclear condensation/fragmentation features signifying apoptosis. HAEC exposure to iron sucrose (10–100 µg/ml) increased monocyte adhesion 5- to 25-fold. Incubation in media containing 200 µg/ml iron sucrose for 3 h caused marked reduction in the acetylcholine-mediated relaxation in phenylephrine-precontracted rat aorta. Conclusion: Pharmacologically relevant concentration of iron sucrose results in endothelial injury and dysfunction and marked increase in monocyte adhesion.

Effects of intravenous iron on mononuclear cells during the haemodialysis session

This study analysed, in vivo and in vitro, the effects of four different intravenous iron preparations (iron gluconate, iron sucrose, iron dextran and ferric carboxymaltose) on activation and damage of mononuclear cells. A randomized prospective study was conducted in 10 haemodialysis (HD) patients. Blood samples were collected at baseline (T0); 1 h after starting HD, just before the iron or saline administration (T1); 30 min after the iron or saline infusion (T2) and at the end of HD (T3). In addition, peripheral blood mononuclear cells from 10 healthy individuals and 9 chronic kidney disease Stage-5 (CKD-5) without HD treatment were cultured with the 4 iron preparations. Iron infusion during the HD session increased the percentage of mononuclear cells with reactive oxygen species (ROS) production, Inter-Cellular Adhesion Molecule-1 (ICAM-1) and apoptosis. There were no significant differences between the four iron preparations. Culture of mononuclear cells from healthy individuals and CKD-5 patients with the different iron preparations resulted in a significant increase in ROS, ICAM-1 and apoptosis as compared with control. In an additional study, the effect of original iron sucrose formulation on mononuclear cells was compared with that of one generic formulation. The generic formulation produced a greater increase in ROS, ICAM-1 and apoptosis than the original iron sucrose. Our results suggest that intravenous iron has deleterious effects on mononuclear cells. The four iron compounds evaluated produced similar effects on oxidative stress, cell activation and apoptosis. However, the effects of iron compounds with the same formulation were different, thus further investigation may be required to establish the safety of iron preparations that theoretically have the same composition.

The new generation of intravenous iron: chemistry, pharmacology, and toxicology of ferric carboxymaltose

An ideal preparation for intravenous iron replacement therapy should balance effectiveness and safety. Compounds that release iron rapidly tend to cause toxicity, while large molecules can induce antibody formation and cause anaphylactic reactions. There is therefore a need for an intravenous iron preparation that delivers appropriate amounts of iron in a readily available form but with minimal side effects and thus with an excellent safety profile. In this paper, a review is given on the chemistry, pharmacology, and toxicology of ferric carboxymaltose (FCM, Ferinject), a stable and robust complex formulated as a colloidal solution with a physiological pH. The complex is gradually taken up mainly from the hepatic reticulo-endothelial system (RES), followed by effective delivery of iron to the endogeneous transport system for the haem synthesis in new erythrocytes, as shown in studies on the pharmacodynamics and pharmacokinetics with radio-labelled FCM. Studies with radio-labelled FCM also demonstrated a barrier function of the placenta and a low transfer of iron into the milk of lactating rats. Safety pharmacology studies indicated a favourable profile with regard to cardiovascular, central nervous, respiratory, and renal toxicity. A high maximum non-lethal dose was demonstrated in the single-dose toxicity studies. Furthermore, based on the No-Observed-Adverse-Effect-Levels (NOAELs) found in repeated-dose toxicity studies and on the cumulative doses administered, FCM has good safety margins. Reproductive and developmental toxicity studies did not reveal any direct or indirect harmful effects. No genotoxic potential was found in in vitro or in vivo studies. Moreover, antigenicity studies showed no cross-reactivity of FMC with anti-dextran antibodies and also suggested that FCM does not possess sensitizing potential. Lastly, no evidence of irritation was found in local tolerance studies with FCM. This excellent toxicity profile and the high effectiveness of FCM allow the administration of high doses as a single infusion or bolus injection, which will enhance the cost-effectiveness and convenience of iron replacement therapy. In conclusion, FCM has many of the characteristics of an ideal intravenous iron preparation.

Pharmacodynamics and safety of ferric carboxymaltose: a multiple-dose study in patients with iron-deficiency anaemia secondary to a gastrointestinal disorder

This multiple-dose Phase I/II study provided pharmacodynamics and pharmacokinetics data on the therapeutic benefit of ferric carboxymaltose (FCM, Ferinject) and evaluated the safety and tolerability of this intravenous (i.v.) iron preparation. Two doses of iron as FCM were given as i.v. infusion over 15 min, 500 mg iron given once weekly for up to 4 weeks (Cohort 1) or 1000 mg iron weekly for 2 weeks (Cohort 2), in patients with a total requirement > or = 1000 mg iron (total cumulative maximum dose < or = 2000 mg iron). Adults with moderate to severe, stable iron-deficiency anaemia (IDA) (haemoglobin [Hb] < or = 11.0 g/dl, serum ferritin < 100 microg/l, transferrin saturation [TSAT] < 16%) due to a gastrointestinal (GI) disorder were included. Pharmacodynamics variables: proportion of patients achieving values within the reference range for Hb (men: 14.0-18.0 g/dl, women: 12.0-16.0 g/dl), serum ferritin (20-500 microg/l), TSAT (16-45%) and proportion of patients with an increase in Hb of at least 2.0 g/dl. Pharmacokinetics variables: total serum iron levels at time of maximum serum iron concentration during the fast elimination phase and at trough time-points. Safety assessments: the incidence of adverse events (AEs) and changes in vital signs, physical examinations, and clinical laboratory parameters. In Cohorts 1 and 2, 14/20 (70%) versus 19/26 (73%) of patients completed the study. Individual calculated iron deficits were 1000-2100 mg. The mean cumulative dose of FCM in Cohorts 1 and 2 was 1800 mg and 1563 mg iron, respectively. At baseline, patients in both cohorts had similar Hb levels (mean 8.7 g/dl in both cohorts). More than 97% of patients demonstrated a clinically meaningful increase in Hb levels (> or = 1.0 g/dl) during the study. By the week 4 follow-up visit, an increase of at least 2.0 g/dl was achieved by 15/20 (75%) and by 19/26 (73.1%) patients in Cohorts 1 and 2, respectively, and the mean increase in Hb was 3.2 g/dl in Cohort 1 and 3.3 g/dl in Cohort 2. By day 28, 3/6 (50%) patients in Cohort 1 had achieved normal Hb levels, and by the 4-week post-treatment followup visit 7/19 patients (37%) in Cohort 1 and 12/25 (48%) in Cohort 2 had reached Hb levels within the reference range. Serum ferritin levels increased rapidly at the start of treatment and remained in the reference range throughout the study; increases were greater in Cohort 2. Mean baseline TSAT values were similar in both cohorts (24.2% in Cohort 1, 20.7% in Cohort 2), and were within the reference range at the week 4 follow-up visit for 41.0 and 39.1% of the patients in Cohorts 1 and 2, respectively. The incidence of AEs occurring after the first administration of FCM (treatment-emergent AEs, TEAE) was generally low and similar in Cohorts 1 (11/20 [55.0%]) and 2 (13/26 [50.0%]). Most TEAEs were mild; only 2/ 20 patients (10.0%) in Cohort 1 and 3/26 (11.5%) in Cohort 2 had TEAEs of moderate intensity. There were no AEs of severe intensity, serious AEs, or deaths. Most AEs were considered by the investigator to be unrelated or unlikely to be related to the study medication. Since accumulation of serum iron was not observed, a dosing interval of 3-4 days (500 mg iron) or 1 week (1000 mg iron) was demonstrated to be adequate. The increase in serum ferritin and TSAT at the 4-week follow-up visit is indicative of a repletion of the iron stores. The results suggest that doses up to 1000 mg i.v. iron administered as FCM over 15 min arewell tolerated and effective in the treatment of patients with IDA due to a GI disorder.

The efficacy and safety of current intravenous iron preparations for the management of iron-deficiency anaemia: a review

Iron-deficiency anaemia (IDA) is a major health problem worldwide, but responds well to iron supplementation. New approaches are leading to more effective management of this condition. Iron deficiency (ID) is usually suspected in at-risk patients with declining haemoglobin (Hb) levels and then confirmed by measuring serum ferritin levels and transferrin saturation. However, regular monitoring of these iron indicators and other laboratory parameters in susceptible individuals may lead to early recognition of falling iron stores and facilitate pre-emptive therapeutic intervention before anaemia develops. Patients with ID are commonly prescribed oral iron preparations because of convenience and low cost. However, the efficacy of these agents is limited by their reduced absorption rate and gastrointestinal side-effects. Alternatively, treatment of IDA in patients requiring erythropoiesis-stimulating agents (ESAs) is more predictably achieved by use of intravenous (i.v.) iron. Unfortunately, the development of serious adverse events (SAEs) from high molecular-weight iron dextran has led to reluctance to use i.v. iron in the treatment of IDA. Similarly, but to a much lesser extent, low molecular-weight iron dextran is associated with a number of SAEs, including allergic or anaphylactic reactions. The introduction of second-generation i.v. iron formulations, including iron sucrose and ferric gluconate, was clearly an improvement over i.v. iron dextran. These formulations proved to be effective in the management of IDA and are not associated with the serious allergic reactions encountered with i.v. iron dextran. For these reasons, use of these preparations became more widespread in the treatment of IDA across a wide range of clinical conditions. An important advantage of i.v. iron over oral iron is that it may bypass hepcidin actions by directly loading transferrin and making iron available to macrophages. Despite a reduction in the short-term risks, there is still concern about the potential for long-term toxicity of i.v. iron use (e. g. atherosclerosis development, infection and increased mortality). The association of atherosclerosis with iron overload remains unclear. Alternatively, the relative risk for mortality or hospitalization from infection in patients undergoing haemodialysis (HD) who received i.v. iron was shown not to be higher than that observed in the overall HD population. Indeed, doses of i.v. iron up to 400 mg/month were associated with improved patient survival. Second-generation i.v. iron formulations are more frequently used for treating IDA than i.v. iron-dextran in patients with various chronic conditions including those with chronic kidney disease. In the latter, IDA should be corrected before initiation of ESA therapy, as iron deficiency can lead to hyporesponsiveness to ESA. However, a major limitation of the second-generation i.v. iron agents is that they cannot be administered in large doses and the typical 1000 mg therapy requires several clinic visits. Thus, there is a need for an i.v. iron agent that can be safely administered in a single dose of 1000 mg of iron and therefore requires less frequent clinic visits. This limitation has now been overcome with the introduction of newer i.v. iron preparations. Ferric carboxymaltose offers effective and rapid correction of IDA by overcoming the limitations observed with previous i.v. iron preparations. This agent has been shown to be effective and well tolerated in a number of randomized controlled trials in a variety of chronic conditions.

Evaluation of cost savings with ferric carboxymaltose in anemia treatment through its impact on erythropoiesis-stimulating agents and blood transfusion: French healthcare payer perspective

Objective:To evaluate the economic impact of intravenous iron (in the form of intravenous iron preparation of ferric carboxymaltose) in three different clinical settings of iron deficiency anemia: chemotherapy-induced anemia in breast cancer, chemotherapy-induced anemia in digestive cancer, and perioperative anemia in knee and hip surgery.Methods:The economic model compared the usual therapeutic strategies of anemia without intravenous iron and strategies including intravenous iron, in each of the three clinical settings selected. Costs related to anemia treatment by erythropoiesis-stimulating agents (ESA), blood transfusion, and intravenous iron were estimated and compared inside each setting. Cost savings were calculated from the French healthcare payer perspective. Data included in the economic model were obtained from scientific literature, public health agencies, and medical experts.Results:The most prominent annual cost savings were observed in chemotherapy-induced anemia in breast cancer (€997 and €360 per patient for metastatic and non-metastatic breast cancers, respectively; global cost saving, €33.6 million). This large impact of intravenous iron on costs was mainly explained by both a lower number of women treated and lower ESA dosing. Mean annual cost saving in digestive cancers and knee and hip surgery were estimated to €168 and €216 per patient and global cost savings of €7.5 and €12.1 million, respectively. Overall, annual cost savings in these three settings were estimated to €53 million including €39 million for ESA cost savings. Sensitivity analysis showed that strategies including intravenous iron remained cost-effective even with wide variations in the assumptions, particularly for cost savings on ESA.Limitations:Economic model based on literature data and expert opinions.Conclusions:The present economic model suggests that use of intravenous iron, according to recommendations of international guidelines, is cost saving, particularly in chemotherapy-induced anemia in breast cancers.

In vitro study on the effects of iron sucrose, ferric gluconate and iron dextran on redox-active iron and oxidative stress

Concerns exist that administration of intravenous (i.v.) iron preparations is associated with oxidative stress. Therefore iron sucrose (CAS 8047-67-4), ferric gluconate (CAS 34098-81-1) and iron dextran (CAS 9004-66-4) were assessed for redox-active iron by a dichlorofluorescein assay and for intracellular reactive oxygen species (ROS) generation and cytotoxicity in HepG2 cells. Examining each i.v. iron preparation at its maximum concentration achieved following clinically frequently used doses in a 70 kg individual in in vitro experiments, redox-active iron was highest with ferric gluconate, followed by iron dextran and iron sucrose. Interestingly, when the i.v. iron preparations were diluted in human serum instead of buffer, redox-active iron was highest with iron dextran, followed by iron sucrose, and practically disappeared with ferric gluconate. ROS production in HepG2 cells was increased by all i.v. iron preparations. However, in the neutral red cytotoxicity assay all i.v. iron preparations were non-toxic. In conclusion, ferric gluconate showed the highest increase in intracellular ROS-production in HepG2 cells and the highest amount of redox-active iron in buffer in the in vitro assays. In contrast to the other i.v. iron preparations, redox-active iron from ferric gluconate was rendered completely redox-inactive by serum, indicating that redox-active iron in the various preparations has different chemical properties.

Physicochemical and toxicological characterization of a new generic iron sucrose preparation

Intravenous iron preparations are key components in the management of anaemia of various etiologies. These iron-carbohydrate complexes permit safe systemic delivery of iron, whilst protecting from the potential toxic effects of over-saturation. This in turn permits efficient haematopoiesis following erythropoietin administration. Since the rate of release of iron is dependent upon the structure of this iron-carbohydrate complex, it is essential to ensure that an intravenous iron preparation is well characterized and its properties documented. This report describes physicochemical and toxicological studies into a new iron sucrose generic preparation, "Iron Sucrose Azad (ISA)", using the original iron sucrose product as reference. It could be demonstrated that the specifications and physicochemical characteristics of ISA reflect those of the reference product. Furthermore, in a rat model previously shown to identify possible toxicological effects of "unsimilar" iron sucrose preparations, ISA was found to have the same properties as the reference product, with both being well tolerated.

Differences in spontaneously reported hypersensitivity and serious adverse events for intravenous iron preparations: comparison of Europe and North America

Spontaneously-reported rates of adverse events (AEs) of intravenous (i.v.) iron products have not been compared since 2007. AEs in Europe (Eur) and North America (NA) have never been compared. New products have been marketed and many changes in prescribing habits have occurred since then, and the effect on AEs reporting is unclear. It was hypothesized that changing practices for i.v. iron products has caused changes in the rates of serious AEs and large differences exist between Eur and NA. Rates of AEs for three i.v. iron preparations (iron sucrose [IS], ferric gluconate [FG] and high and low MW iron dextran [HMWID, LMWID]) were compared by product and continent from January 1, 2003 to June 30, 2009 for selected countries in Eur and NA, using the Uppsala Monitoring Center's database. Rates of total, anaphylaxis and other serious allergic AEs were calculated as number of AEs divided by i.v. iron sales standardized to 100 mg dose equivalents (DEq) of iron. Quarterly sales (millions of 100 mg DEq of iron) increased from the first quarter 2003 to the end of the second quarter of 2009 by 1% for FG, 16% for IS and 2% for ID. Total AEs for NA plus Eur were similar for FG and IS, but total AEs were 6- to 7-fold higher for ID. Rates of anaphylaxis were 6- to 11-fold higher in Eur plus NA combined for ID than for IS or FG. In NA, there were substantially higher reports for total, anaphylaxis and other serious allergic AEs with FG compared to IS, whereas the reverse was the case in Eur. Odds ratios (OR) showed higher risks of anaphylaxis with FG in NA vs. Eur (OR = 4.40, P < 0.0001) and lower risks with IS (OR = 0.24, P < 0.0001). Odds of anaphylaxis with LMWID in Eur vs. FG and IS were 42.08 and 16.92 (both P < 0.0001), respectively. In NA, odds of anaphylaxis with ID vs. FG and IS were 2.36 and 17.73 (both P < 0.0001), respectively. Differences between NA and Eur may be related to varied treatment practices. ID had the highest rates of all types of AEs, and IS and FG had a continued trend for lowest rates of AEs.