ferric-carboxymaltose and Kidney-Failure--Chronic

A number of intravenous iron formulations have been developed over the past 65 years which rely on dextran or other compounds to prevent uncontrolled release of free iron to the circulation. High molecular weight dextran was associated with a number of serious adverse reactions and was removed from markets worldwide in 2009. The preponderance of published evidence suggests that the formulations of parenteral iron currently available in the United States, including low molecular weight iron dextran, are all safe and effective and there are no major, clinically important differences among them in terms of either efficacy or safety. For patients with chemotherapy induced anemia or with anemia of end stage renal disease who are being treated with hemodialysis, it is reasonable to use any of the iron formulations, including iron sucrose and ferric gluconate, as frequent patient encounters with health caregivers are a routine part of care and the need to administer multiple low doses of IV iron is not a major disadvantage. However, a single infusion of a total iron dose is as effective and safe when giving iron preparations containing low molecular weight iron dextran, ferumoxytol, iron isomaltoside, or ferric carboxymaltose. Use of a single total dose infusion results in a decreased number of intravenous infusions with a lower cumulative risk for infusion reactions or extravasations, a reduced need for multiple office visits and repeated utilization of medical staff, and increased convenience for physicians and patients.

Topics: Anemia; Drug Compounding; Ferric Compounds; Ferrosoferric Oxide; Humans; Infusions, Intravenous; Iron; Kidney Failure, Chronic; Maltose; Renal Dialysis

Iron deficiency is common in patients on chronic dialysis, and most require iron-replacement therapy. In addition to absolute iron deficiency, many patients have functional iron deficiency as shown by a suboptimal response to the use of erythropoietin-stimulating agents. Both absolute and functional iron-deficiency anemia have been shown to respond to intravenous (IV) iron replacement. Although parenteral iron is an efficacious method and superior to standard doses of oral iron in patients on hemodialysis, there are ongoing safety concerns about repeated exposure potentially enhancing infection risk and cardiovascular disease. Each IV iron product is composed of an iron core with a carbohydrate shell. The avidity of iron binding and the type of carbohydrate shell play roles in the safe maximal dose and the frequency and severity of acute infusion reactions. All IV iron products are taken up into the reticuloendothelial system where the shell is metabolized and the iron is stored within tissue ferritin or exported to circulating transferrin. IV iron can be given as large intermittent doses (loading therapy) or in smaller doses at frequent intervals (maintenance dosing regimen). Limited trial data and observational data suggest that a maintenance dosing regimen is more efficacious and possibly safer than loading therapy. There is no consensus regarding the preferred method of iron repletion in patients on peritoneal dialysis, although small studies comparing oral and parenteral iron regimens in these patients have shown the latter to be more efficacious. Use of IV iron in virtually all hemodialysis and many peritoneal dialysis patients remains the standard of care.

Topics: Administration, Intravenous; Anemia, Iron-Deficiency; Disaccharides; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Ferrosoferric Oxide; Glucaric Acid; Hematinics; Hemoglobins; Humans; Iron Compounds; Iron-Dextran Complex; Kidney Failure, Chronic; Maltose; Renal Dialysis; Transferrin

Iron deficiency often occurs in patients with chronic kidney disease and can be effectively treated with parenteral supplementation of iron. In these patients, prompt application of iron therapy can help to reduce the dependence of erythropoietin-stimulating agents and effectively treat anemia. Correct evaluation of iron metabolism in CKD patients can be difficult. Duration of and response to therapy should always be considered while planning parenteral supplementation of iron. The main safety aspects of parenteral iron preparations relate to their possible anaphylactic potential and the potential induction of oxidative stress due to the release of free iron. However, parenteral iron supplementation is usually safe and without major side effects. Regarding current data, none of the iron preparations is showing definitive superiority. Although uncommon, iron preparations containing dextran can lead to severe side effects, therefore these preparations appear to have an inferior safety profile. Due to limited data, a comparison of third-generation iron preparations with previous preparations is not possible. Recently, for the first time, the third generation iron preparation ferumoxytol has been directly compared to iron sucrose. From this data and others, it remains unclear whether third generation iron preparations show safety-relevant superiority.

Topics: Administration, Oral; Anaphylaxis; Anemia, Iron-Deficiency; Disaccharides; Ferric Compounds; Ferric Oxide, Saccharated; Ferrosoferric Oxide; Glucaric Acid; Humans; Infusions, Intravenous; Iron Compounds; Iron-Dextran Complex; Kidney Failure, Chronic; Maltose; Oxidative Stress; Renal Dialysis

Iron deficiency is a common cause of anaemia and hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) in non-dialysis-dependent chronic kidney disease (ND-CKD) patients. Current intravenous iron agents cannot be administered in a single high dose because of adverse effects. Ferric carboxymaltose, a non-dextran parenteral iron preparation, can be rapidly administered in high doses.. This open-label trial randomized 255 subjects with glomerular filtration rates ≤ 45 mL/min/1.73 m(2), haemoglobin ≤ 11 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL, and stable ESA dose to either intravenous ferric carboxymaltose 1000 mg over 15 min (with up to two additional doses of 500 mg at 2-week intervals) or oral ferrous sulphate 325 mg thrice daily for a total of 195 mg elemental iron daily for 56 days.. In the modified intent-to-treat population, the proportion of subjects achieving a haemoglobin increase ≥ 1 g/dL at any time was 60.4% with ferric carboxymaltose and 34.7% with oral iron (P < 0.001). At Day 42, mean increase in haemoglobin was 0.95 ± 1.12 vs 0.50 ± 1.23 g/dL (P = 0.005), mean increase in ferritin was 432 ± 189 ng/mL vs 18 ± 45 ng/mL (P < 0.001) and mean increase in transferrin saturation was 13.6 ± 11.9% vs 6.1 ± 8.1% (P < 0.001). Treatment-related adverse events were significantly fewer with ferric carboxymaltose than with oral iron (2.7% and 26.2%, respectively; P < 0.0001).. We conclude that 1000 mg ferric carboxymaltose can be rapidly administered, is more effective and is better tolerated than oral iron for treatment of iron deficiency in ND-CKD patients.

Topics: Administration, Oral; Aged; Anemia, Iron-Deficiency; Female; Ferric Compounds; Glomerular Filtration Rate; Humans; Injections, Intravenous; Iron; Kidney Failure, Chronic; Male; Maltose; Prognosis

There is limited safety information about ferric carboxymaltose (FCM), a new intravenous iron preparation. This randomized, crossover study compared the safety and tolerability of double-blinded intravenous doses of FCM or placebo in patients with iron deficiency anemia. Subjects (559) with iron deficiency anemia received a dose of either FCM (15 mg/kg, maximum 1000 mg) over 15 minutes or placebo on day 0. On day 7, subjects received the other agent. Safety evaluations were performed on days 7 and 14. The primary endpoint was the incidence of treatment-emergent adverse events during each 7-day study period. During the first 24 hours and during the 7-day treatment period, at least one treatment-emergent adverse event was experienced by 15.0% and 29.3% of subjects after FCM and 11.4% and 19.7% after placebo, respectively. Most were classified as Grade 1 or 2. Six subjects had Grade 3 treatment-emergent adverse events after FCM and 9 subjects after placebo. One subject had a Grade 4, and 1 subject had a Grade 5 treatment-emergent adverse event, but neither was considered study drug-related. During the first 24 hours of the treatment period, drug-related adverse events were reported in 9.3% of subjects receiving FCM and 4.8% receiving placebo. Of drug-related Grade 3 events, 4 subjects received FCM and 5 subjects received placebo. Administration of FCM (15 mg/kg, maximum of 1000 mg) over 15 minutes was well tolerated and associated with minimal risk of adverse reactions in patients with iron deficiency anemia.

Topics: Adult; Anemia, Iron-Deficiency; Cross-Over Studies; Double-Blind Method; Female; Ferric Compounds; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Male; Maltose; Middle Aged; Treatment Outcome

Intravenous (IV) iron preparations are widely used in the treatment of anemia in patients undergoing hemodialysis (HD). All IV iron preparations carry a risk of causing hypersensitivity reactions. However, the pathophysiological mechanism is poorly understood. We hypothesize that a relevant number of these reactions are mediated by complement activation, resulting in a pseudo-anaphylactic clinical picture known as complement activation-related pseudo allergy (CARPA).. First, the in-vitro complement-activating capacity was determined for 5 commonly used IV iron preparations using functional complement assays for the 3 pathways. Additionally, the preparations were tested in an ex-vivo model using the whole blood of healthy volunteers and HD patients. Lastly, in-vivo complement activation was tested for one preparation in HD patients.. In the in-vitro assays, iron dextran, and ferric carboxymaltose caused complement activation, which was only possible under alternative pathway conditions. Iron sucrose may interact with complement proteins, but did not activate complement in-vitro. In the ex-vivo assay, iron dextran significantly induced complement activation in the blood of healthy volunteers and HD patients. Furthermore, in the ex-vivo assay, ferric carboxymaltose and iron sucrose only caused significant complement activation in the blood of HD patients. No in-vitro or ex-vivo complement activation was found for ferumoxytol and iron isomaltoside. IV iron therapy with ferric carboxymaltose in HD patients did not lead to significant in-vivo complement activation.. This study provides evidence that iron dextran and ferric carboxymaltose have complement-activating capacities in-vitro, and hypersensitivity reactions to these drugs could be CARPA-mediated.

Topics: Administration, Intravenous; Anemia, Iron-Deficiency; Complement Activation; Complement C1q; Complement C3d; Complement Membrane Attack Complex; Disaccharides; Ferric Compounds; Ferric Oxide, Saccharated; Ferrosoferric Oxide; Glucaric Acid; Hematinics; Humans; In Vitro Techniques; Iron Compounds; Iron-Dextran Complex; Kidney Failure, Chronic; Maltose; Mannose-Binding Lectin; Properdin; Renal Dialysis

Treatment with parenteral iron causes oxidative stress, inflammation and endothelial dysfunction. Ferric carboxymaltose (FCM) is a new preparation of non-dextran iron which, due to its pharmacokinetics and stability, may induce less toxicity than other iron molecules. The aim of this study was to analyse the effect of FCM on inflammation and adhesion molecules in chronic kidney disease (CKD).. Forty-seven patients with predialysis CKD and iron-deficiency anaemia received a single dose of FCM (15 mg/kg, maximum dose 1 gram). At baseline and after 60 minutes (acute effect) and after 3 weeks and 3 months (sub-acute effect), we determined inflammatory markers: C-reactive protein (CRP), interleukin-6 (IL-6) and endothelial dysfunction: intercellular adhesion molecule (ICAM) and vascular adhesion molecule (VCAM).. Treatment with FCM was associated with a significant increase in haemoglobin levels: 10 (0.7) vs. 11.4 (1.3)g/dl, p<.0001. CRP, IL-6, ICAM and VCAM levels did not correlate with baseline haemoglobin or ferritin levels and there was no relationship between changes in these markers and those of haemoglobin after administration of FCM. No significant, acute or sub-acute changes occurred in any of the inflammatory or endothelial markers studied. Statin therapy was associated with lower VCAM concentrations.. Treatment with high doses of FCM in patients with predialysis CKD has no proinflammatory effect and does not alter levels of adhesion molecules ICAM and VCAM in this population.

Topics: Aged; Anemia, Iron-Deficiency; Cell Adhesion Molecules; Female; Ferric Compounds; Humans; Inflammation; Kidney Failure, Chronic; Male; Maltose; Prospective Studies

Topics: Adult; Female; Ferric Compounds; Glomerular Filtration Rate; Humans; Hypophosphatemia; Injections, Intravenous; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Maltose; Phosphates; Polycystic Kidney Diseases; Reference Values; Transplantation, Homologous

Iron deficiency is common in patients with chronic kidney disease and in kidney transplant recipients.. We analyzed the safety and tolerability of the new intravenous iron preparation ferric carboxymaltose (FCM) in these two patient groups. Adverse events after administration of the drug were assessed by using a questionnaire. Vital signs and laboratory data were collected before and after the application of FCM. A total of 46 FCM doses were applied to 44 patients (17 with chronic kidney disease and 27 kidney transplant recipients) either as single injection of 100 or 200 mg (n = 42) or as short infusion with up to 500 mg (n = 4).. Mild and transient adverse events (metallic taste, headache, dizziness) occurred in six patients. The estimated glomerular filtration rate remained unchanged by the FCM administration.. We conclude that safety and tolerability of FCM were excellent. Compared with other intravenous iron preparations the considerably shorter administration time of FCM allows to save time and to reduce costs.

Topics: Anemia, Iron-Deficiency; Female; Ferric Compounds; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Kidney Transplantation; Male; Maltose; Prospective Studies; Statistics, Nonparametric; Surveys and Questionnaires; Treatment Outcome