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Objectives: Intravenous iron is the recommended treatment for patients with iron deficiency anemia (IDA) where oral iron is ineffective or rapid iron replenishment is required. Two high-dose, rapid-administration intravenous iron formulations are currently available in the UK: iron isomaltoside 1000/ferric derisomaltose (IIM) and ferric carboxymaltose (FCM). An indirect treatment comparison (ITC) recently showed that improvement from baseline hemoglobin was significantly larger with IIM than FCM. The objective was to use the ITC findings to evaluate the cost-effectiveness of IIM versus FCM from the UK healthcare payer perspective.Methods: A patient-level simulation model was developed in R to evaluate the cost per patient experiencing hematological response with IIM versus FCM. The model generated a simulated cohort from parametric distributions of baseline hemoglobin and bodyweight. Changes in hemoglobin were modeled based on data from the ITC, covaried with baseline hemoglobin based on patient-level data from a randomized controlled trial. Posological models of the iron formulations were developed based on the summaries of product characteristics. UK-specific costs were based on healthcare resource groups.Results: The proportion of patients experiencing hematological response was 9.0% higher with IIM relative to FCM (79.0% versus 70.0%), based on modeling of clinically realistic, correlated distributions of baseline hemoglobin and change from baseline hemoglobin. The mean number of infusions needed to administer the required dose was 1.92 with FCM, versus 1.38 with IIM, resulting in costs of £637 and £457 per treated patient with FCM and IIM respectively, corresponding to respective costs of £910 and £579 per responder.Conclusions: The analysis showed that using IIM rather than FCM in patients with IDA was dominant and would reduce the number of iron infusions required to correct iron deficiency, thereby reducing the costs associated with IDA treatment and simultaneously increasing the proportion of patients with IDA experiencing a clinically meaningful hematological response.

Background The optimal intravenous (IV) iron would allow safe correction of iron deficiency at a single infusion over a short time. The FERWON-NEPHRO trial evaluated the safety and efficacy of iron isomaltoside 1000/ferric derisomaltose (IIM) in patients with non-dialysis-dependent chronic kidney disease and iron deficiency anaemia. Methods In this randomized, open-label and multi-centre trial conducted in the USA, patients were randomized 2:1 to a single dose of 1000 mg IIM or iron sucrose (IS) administered as 200 mg IV injections up to five times within a 2-week period. The co-primary endpoints were serious or severe hypersensitivity reactions and change in haemoglobin (Hb) from baseline to Week 8. Secondary endpoints included incidence of composite cardiovascular adverse events (AEs). Results A total of 1538 patients were enrolled (mean estimated glomerular filtration rate 35.5 mL/min/1.73 m2). The co-primary safety objective was met based on no significant difference in the incidence of serious or severe hypersensitivity reactions in the IIM and IS groups [0.3% versus 0%; risk difference: 0.29% (95% confidence interval: –0.19; 0.77; P > 0.05)]. Incidence of composite cardiovascular AEs was significantly lower in the IIM versus IS group (4.1% versus 6.9%; P = 0.025). Compared with IS, IIM led to a more pronounced increase in Hb during the first 4 weeks (P ≤ 0.021), and change in Hb to Week 8 showed non-inferiority, confirming that the co-primary efficacy objective was met. Conclusions Compared with multiple doses of IS, a single dose of IIM induced a non-inferior 8-week haematological response, comparably low rates of hypersensitivity reactions, and a significantly lower incidence of composite cardiovascular AEs., Graphical Abstract

Introduction Intravenous (IV) iron is typically the preferred treatment for patients with iron deficiency anemia (IDA) who cannot tolerate or absorb oral iron, or who require fast replenishment of iron stores pre-operatively. Several IV iron formulations are available with different dosing characteristics affecting infusion speed and maximum dose. The aim was to develop a resource impact model to calculate the cost of establishing an IV iron clinic and model resource impact of different IV irons to inform clinicians and service providers implementing innovative pre-operative IV iron services in Ireland. Methods A resource impact tool was developed to model resource utilization and IDA treatment costs. Two fast-administration, high-dose formulations of IV iron are available in Ireland: iron isomaltoside 1000/ferric derisomaltose (IIM) and ferric carboxymaltose (FCM). The tool modeled clinic throughput based on their different dosing characteristics in a specific IDA population, capturing fixed overheads, variable costs, clinic income from private and publicly-funded patients, and savings associated with IV iron. Results Based on a 70:30 split between public and private patients in a new pre-operative service with capacity for 12 infusion slots weekly, IIM would facilitate correction of iron deficits in 474 patients annually, resulting in a net annual clinic balance of €42,736 on income of €159,887 and net costs of €117,151. FCM would facilitate treatment of 353 patients, resulting in a net annual clinic balance of €36,327 on income of €116,050 and costs of €79,722, a difference of €6408 and 121 patients treated in favor of using IIM over FCM. Conclusion Based on this provider-perspective analysis, IIM would maximize clinic throughput relative to other IV iron formulations, allowing clinicians in Ireland to optimize their current service provision and expenditure, and model the impact of introducing IV iron clinics for pre-operative patients with IDA.

Aysegül Aksan,1,2 Ian LP Beales,3 Garth Baxter,4 Antonio Ramirez de Arellano,5 Simona Gavata,6 William J Valentine,7 Barnaby Hunt7 1Interdisciplinary Crohn Colitis Centre, Rhein-main, Frankfurt/Main, Germany; 2Institute of Nutritional Science, Justus-Liebig University, Giessen, Germany; 3Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich, UK; 4Vifor Pharma Group, HEOR, London, UK; 5Vifor Pharma Group, HEOR, Glattbrugg, Switzerland; 6Vifor Pharma Group, Market Access, Glattbrugg, Switzerland; 7Ossian Health Economics and Communications, Basel, SwitzerlandCorrespondence: Antonio Ramirez de ArellanoVifor Pharma Group, HEOR, Flughofstrasse 61, Glattbrugg, 8152, SwitzerlandTel +41 58 851 82 43Email antonio.ramirez@viforpharma.comIntroduction: In patients with inflammatory bowel disease (IBD), iron deficiency anaemia (IDA) can impair quality of life and increase healthcare costs. Treatment options for IDA-associated IBD include oral iron and intravenous iron formulations (such as ferric carboxymaltose [FCM], ferric derisomaltose [FD, previously known as iron isomaltoside 1000], and iron sucrose [IS]). The present analysis compared the cost-effectiveness of FCM versus FD, IS, and oral iron sulfate in terms of additional cost per additional responder in the UK setting.Methods: Cost-effectiveness was calculated for FCM versus FD, IS, and oral iron individually in terms of the additional cost per additional responder, defined as haemoglobin normalisation or an increase of ≥ 2 g/dL in haemoglobin levels, in a model developed in Microsoft Excel. Relative efficacy inputs were taken from a previously published network meta-analysis, since there is currently no single head-to-head trial evidence comparing all therapy options. Costs were calculated in 2020 pounds sterling (GBP) capturing the costs of iron preparations, healthcare professional time, and consumables.Results: The analysis suggested that FCM may be the most effective intervention, with 81% of patients achieving a response. Response rates with FD, IS, and oral iron were 74%, 75%, and 69%, respectively. Total costs with FCM, FD, IS, and oral iron were GBP 296, GBP 312, GBP 503, and GBP 56, respectively. FCM was found to be more effective and less costly than both FD and IS, and therefore was considered dominant. Compared with oral iron, FCM was associated with an incremental cost-effectiveness ratio of GBP 2045 per additional responder.Conclusions: FCM is likely to be the least costly and most effective IV iron therapy in the UK setting. Compared with oral iron, healthcare payers must decide whether the superior treatment efficacy of FCM is worth the additional cost.Keywords: cost, cost-effectiveness, inflammatory bowel disease, iron deficiency anaemia, United Kingdom

Intravenous iron-carbohydrate complex preparations (IVIP) are noninterchangeable pro-drugs: their pharmacokinetics (PK) varies determined by semi-crystalline iron core and carbohydrate shell structures, influences pharmacodynamics (PD) and thus efficacy and safety. Examining PK/PD relationships of three IVIP we identify a two-pathway model of transient non-transferrin-bound iron (NTBI) generation following single dose administration. Twenty-eight hypoferremic non-anemic patients randomized to 200 mg iron as ferric carboxymaltose (Fe-carboxymaltose), iron sucrose (Fe-sucrose), iron isomaltoside 1000 (Fe-isomaltoside- 1000), n=8/arm, or placebo, n=4, on a 2-week PK/PD study, had samples analysed for total serum iron, IVIP-iron, transferrin-bound iron (TBI) by high-performance liquid chromatography in combination with inductively coupled plasma mass spectrometry (HPLC-ICP-MS), transferrin saturation (TSAT), serum ferritin (s-Ferritin) by standard methods, NTBI and hepcidin as published before. IVIP-dependent increases in these parameters returned to baseline in 48-150 hours (h), except for s-Ferritin and TSAT. NTBI was low with Fe-isomaltoside-1000 (0.13 μM at 8 h), rapidly increased with Fe-sucrose (0.8 μM at 2 h, 1.25 μM at 4 h), and delayed for Fe-carboxymaltose (0.57 μM at 24 h). NTBI area-under-curve (AUC) were 7-fold greater for Fe-carboxymaltose and Fe-sucrose than for Fe-isomaltoside-1000. Hepcidin peak time varied, but not AUC or mean levels. s-Ferritin levels and AUC were highest for Fe-carboxymaltose and greater than placebo for all IVIP. We propose two mechanisms for the observed NTBI kinetics: rapid and delayed NTBI appearance consistent with direct (circulating IVIP-to-plasma) and indirect (IVIP-to-macrophage-to-plasma) iron release based on IVIP plasma half-life and s-Ferritin dynamics. IVIP generate different, broadly stability- and PK-dependent, NTBI and s-Ferritin signatures, which may influence iron bioavailability, efficacy and safety. Longer-term studies should link NTBI exposure to subsequent safety and efficacy parameters and potential clinical consequences.

The incidence of inflammatory bowel disease (IBD) in Denmark is among the highest in the world, with Crohn’s disease and ulcerative colitis occurring at rates of 9.1 and 18.6 per 100,000 person-years respectively in 2010–2013. Anemia is the most prevalent extraintestinal complication of IBD, most commonly caused by iron deficiency. In treating IBD-associated iron deficiency anemia (IDA), intravenous iron is more effective and better tolerated and shows a faster response than oral iron. The present study evaluated resource use and costs associated with using iron isomaltoside (Monofer; IIM) versus ferric carboxymaltose (Ferinject; FCM) in patients with IDA and IBD in Denmark. A budget impact model was developed to evaluate the cost of IIM compared with FCM from a Danish healthcare payer perspective. Iron deficits were modeled using dosing tables and a joint distribution of bodyweight [mean 75.4 kg, standard deviation (SD) 17.4 kg] and hemoglobin (mean 10.8 g/dL, SD 1.4 g/dl) based on observational data from patients with IBD. Retreatment frequency was modeled using a pooled retrospective analysis of randomized trial data, and costs were modeled using diagnosis-related groups with an outpatient infusion cost of DKK 2855. Using IIM required 1.2 infusions (per treatment) to correct the mean iron deficit compared with 1.6 with FCM. Treating 2.54 patients with IIM would therefore avoid one infusion compared with FCM. Patients using IIM required multiple infusions in 25.0% of cases compared with 64.3% with FCM. Over 5 years, total estimated costs were DKK 21,406 per patient with IIM compared with DKK 28,137 with FCM, corresponding to savings of DKK 6731 with IIM. Using IIM in place of FCM markedly reduced the number of iron infusions required in patients with IBD and IDA in Denmark. The reduction in infusions was accompanied by reductions in cost compared with FCM. Pharmacosmos A/S.

Dear Editor,We read with interest the analysis of Pollock and Biggar [1] concerning the comparative safety of ferric derisomaltose/iron isomaltoside 1000 (FDI), ferric carboxymaltose (FCM), and iro...

Approximately a dozen of intravenous iron nanomedicines gained marketing authorization in the last two decades. These products are generally considered as safe, but have been associated with an increased risk for hypersensitivity-like reactions of which the underlying mechanisms are unknown. We hypothesized that iron nanomedicines can trigger the innate immune system. We hereto investigated the physico-chemical properties of ferric gluconate, iron sucrose, ferric carboxymaltose and iron isomaltoside 1000 and comparatively studied their interaction with Toll-like receptors, the complement system and peripheral blood mononuclear cells. Two out of four formulations appeared as aggregates by Scanning Transmission Electron Microscopy analysis and were actively taken up by HEK293T- and peripheral blood mononuclear cells in a cholesterol-dependent manner. These formulations triggered in vitro activation of intracellular Toll-like receptors 3, -7 and -9 in a dose- and serum-dependent manner. In parallel experiments, we determined that these compounds activated the complement system. Finally, we found that uptake of aggregation-prone iron nanomedicines by peripheral blood mononuclear cells in whole blood induced production of the proinflammatory cytokine IL-1β, but not IL-6.

Objectives: The benefits of intravenous (IV) iron greatly outweigh the risks, but IV iron formulations carry a small risk of hypersensitivity reactions (HSRs). The objective was to use standardized Medical Dictionary for Regulatory Activities queries (SMQs) to compare the safety of ferric derisomaltose/iron isomaltoside 1000 (FDI), iron sucrose (IS), and ferric carboxymaltose (FCM) using prospective trial data.Methods: Prospective trials reporting the incidence of SMQ-coded serious or severe HSRs were identified in the literature. Four SMQs were used: narrow hypersensitivity terms (A), and broad terms pertaining to potential respiratory HSRs (B), skin HSRs (C), and cardiovascular HSRs (D). Bayesian inference, naive pooling, and adjusted indirect approaches were employed to compare HSR incidence.Results: Twenty one prospective trials including over 8,000 patients receiving FDI, FCM or IS were retrieved. Odds ratios of any serious or severe HSR (all groups) with FDI relative to FCM were 0.41, 0.39, and 0.45 according to the Bayesian, naive and adjusted approaches, respectively.Conclusions: The risk of serious or severe HSRs was lower with FDI relative to FCM and IS. Using data from prospective trials including over 8,000 patients coded using a well-defined standard (SMQs) enabled a robust comparison of HSR incidence between the iron formulations.

Iron deficiency anemia (IDA) is prevalent, and intravenous iron, especially if given in a single dose, may result in better adherence compared with oral iron. The present trial (FERWON‐IDA) is part of the FERWON program with iron isomaltoside 1000/ferric derisomaltose (IIM), evaluating safety and efficacy of high dose IIM in IDA patients of mixed etiologies. This was a randomized, open‐label, comparative, multi‐center trial conducted in the USA. The IDA patients were randomized 2:1 to a single dose of 1000 mg IIM, or iron sucrose (IS) administered as 200 mg intravenous injections, up to five times. The co‐primary endpoints were adjudicated serious or severe hypersensitivity reactions, and change in hemoglobin from baseline to week eight. A total of 1512 patients were enrolled. The frequency of patients with serious or severe hypersensitivity reactions was 0.3% (95% confidence interval: 0.06;0.88) vs 0.4% (0.05;1.45) in the IIM and IS group, respectively. The co‐primary safety objective was met, and no risk difference was observed between groups. The co‐primary efficacy endpoint of non‐inferiority in hemoglobin change was met, and IIM led to a significantly more rapid hematological response in the first two weeks. The frequency of cardiovascular events was 0.8% and 1.2% in the IIM and IS group, respectively (P = .570). The frequency of hypophosphatemia was low in both groups. Iron isomaltoside administered as 1000 mg resulted in a more rapid and more pronounced hematological response, compared with IS, which required multiple visits. The safety profile was similar with a low frequency of hypersensitivity reactions and cardiovascular events.

Background Treatment of iron deficiency with intravenous (i.v.) iron is a first-line strategy to improve anaemia of chronic kidney disease. Previous in vitro experiments demonstrated that different i.v. iron preparations inhibit differentiation of haematopoietic stem cells to monocytes, but their effect on monocyte differentiation to macrophages and mature dendritic cells (mDCs) has not been assessed. We investigated substance-specific effects of iron sucrose (IS), sodium ferric gluconate (SFG), ferric carboxymaltose (FCM) and iron isomaltoside 1000 (IIM) on monocytic differentiation to M1/M2 macrophages and mDCs. Methods Via flow cytometry and microRNA (miRNA) expression analysis, we morphologically and functionally characterized monocyte differentiation to M1/M2 macrophages and mDCs after monocyte stimulation with IS, SFG, FCM and IIM (0.133, 0.266 and 0.533 mg/mL, respectively). To assess potential clinical implications, we compared monocytic phagocytosis capacity in dialysis patients who received either 500 mg IS or IIM. Results Phenotypically, IS and SFG dysregulated the expression of macrophage (e.g. CD40, CD163) and mDC (e.g. CD1c, CD141) surface markers. Functionally, IS and SFG impaired macrophage phagocytosis capacity. Phenotypic and functional alterations were less pronounced with FCM, and virtually absent with IIM. In miRNA expression analysis of mDCs, IS dysregulated miRNAs such as miR-146b-5p and miR-155-5p, which are linked to Toll-like receptor and mitogen-activated protein kinase signalling pathways. In vivo, IS reduced monocytic phagocytosis capacity within 1 h after infusion, while IIM did not. Conclusions This study demonstrates that less stable i.v. iron preparations specifically affect monocyte differentiation towards macrophages and mDCs.

Intravenous infusions of iron have evolved from a poorly effective and dangerous intervention to a safe cornerstone in the treatment of iron deficiency. Modern iron formulations are composite nanoparticles composed of carbohydrate ferric oxy-hydroxides. Iron dextran, iron derisomaltose (formely known as iron isomaltoside 1000), ferric carboxymaltose, ferrumoxytol, iron sucrose and sodium ferric gluconate can be infused at different doses and allow correction of total iron deficit with single or repeated doses in 1-2 weeks depending on the specific formulation. All iron preparations are associated with a risk of severe infusion reactions. In recent prospective clinical trials, the risk of moderate to severe infusion reactions was comparable among all modern preparations affecting

Background Anemia is a frequent complication after cardiac surgery especially following reoperation due to previous prosthetic valve failure or multiple valve surgery (including combined coronary artery bypass grafting). This trial explores whether intravenously administered iron isomaltoside 1000 (Monofer®) results in better clinical outcomes in patients undergoing complex heart valve surgery who are expected to receive transfusion. Methods/design In this prospective, single-center, double-blinded, randomized controlled trial, 214 patients undergoing reoperation or multiple valve surgery are randomly allocated to either the iron isomaltoside 1000 (IVFe) or the control group from August 2016 to August 2018. The IVFe group receives iron isomaltoside 1000 mg (maximum dose 20 mg/kg) intravenously 3 days before and after the surgery. The control group receives an equivalent volume of normal saline. The primary endpoint is transfusion requirement (more than 1 unit of packed erythrocytes) for postoperative care until discharge and secondary endpoint are major complications, such as delayed ventilator therapy, acute kidney injury, and mortality. Reticulocyte count, plasma hepcidin, iron profiles (serum iron, serum ferritin, total iron-binding capacity, transferrin, transferrin saturation), coagulation profiles, urinary analysis, and chemical profiles are measured for three preoperative baseline-data days and just before surgery, except for hepcidin. After surgery, daily routine basic laboratory tests are measured just before discharge and reticulocyte count, iron profiles, and hepcidin are repeatedly checked for three postoperative days. Discussions From our study, we can clarify the following points: the first is the perioperative IVFe effect on the demand for transfusion, and clinical outcomes in reoperation or complex valve surgery and the second is the role of hepcidin in the effect of IVFe on the hemoglobin level increase. Trial registration ClinicalTrials.gov, Identifier: NCT02862665. Registered on August 2016. Electronic supplementary material The online version of this article (10.1186/s13063-018-2545-3) contains supplementary material, which is available to authorized users.

The advantage of the new generation IV iron preparations ferric carboxymaltose (FCM), ferumoxytol (FMX), and iron isomaltoside 1000 (IIM) is that they can be administered in relatively high doses in a short period of time. We investigated the physico-chemical properties of these preparations and compared them with those of the older preparations iron sucrose (IS), sodium ferric gluconate (SFG), and low molecular weight iron dextran (LMWID). Mossbauer spectroscopy, X-ray diffraction, and Fe K-edge X-ray absorption near edge structure spectroscopy indicated akaganeite structures (β-FeOOH) for the cores of FCM, IIM and IS, and a maghemite (γ-Fe2O3) structure for that of FMX. Nuclear magnetic resonance studies confirmed the structure of the carbohydrate of FMX as a reduced, carboxymethylated, low molecular weight dextran, and that of IIM as a reduced Dextran 1000. Polarography yielded significantly different fingerprints of the investigated compounds. Reductive degradation kinetics of FMX was faster than that of FCM and IIM, which is in contrast to the high stability of FMX towards acid degradation. The labile iron content, i.e. the amount of iron that is only weakly bound in the polynuclear iron core, was assessed by a qualitative test that confirmed decreasing labile iron contents in the order SFG ≈ IS > LMWID ≥ FMX ≈ IIM ≈ FCM. The presented data are a step forward in the characterization of these non-biological complex drugs, which is a prerequisite to understand their cellular uptake mechanisms and the relationship between the structure and physiological safety as well as efficacy of these complexes.

Iron deficiency is the leading cause of anemia in patients with inflammatory bowel disease (IBD). Intravenous iron is the first-line treatment for clinically active IBD or previous oral iron intolerance. The aim of the present study was to develop a comparative model of iron deficiency and delivery for iron isomaltoside (IIM), ferric carboxymaltose (FCM), low molecular weight iron dextran (LMWID), and iron sucrose (IS) in the treatment of iron deficiency anemia associated with IBD. Areas covered: A model was developed to evaluate iron delivery characteristics, resource use and costs associated with IIM, FCM, LMWID and IS. Iron deficiency was modeled using dosing tables and retreatments were modeled based on a pooled retrospective analysis. The analyses were conducted over 5 years in patients with IBD with mean bodyweight of 75.4 kg and hemoglobin levels of 10.77 g/dL based on observational data. Expert opinion: The modeling analysis showed that using IIM required 1.2 infusions (per treatment) to correct the mean iron deficit, compared with 1.6, 1.2, and 7.1 with FCM, LMWID and IS, respectively. Costs were estimated to be 2,518 pounds sterling (GBP) per patient with IIM or LMWID, relative to GBP 3,309 with FCM or GBP 14,382 with IS.

Background The prodrug-like intravenous iron-carbohydrate complex preparations (IVIPs) should not be considered interchangeable but with due regard to their different pharmacodynamics (PD) which is determined by the semi-crystalline iron core and carbohydrate shell structures (Bhandari et al, 2018). The pharmacokinetics (PK) of IVIPs influences PD profiles and thus efficacy and safety. Here we examine the complex PK/PD relationships with 3 IVIPs, for the first time identifying a 2-compartment model of transient NTBI generation following a single dose administration. Patients and Methods 28 hypoferremic patients randomized (n=8/arm) to 200mg (iron) of ferric carboxymaltose (FCM), iron sucrose (IS) and iron isomaltoside 1000 (IIM) or placebo (n=4), were followed up for 2 wks on an exploratory PK/PD study. Serum samples (0-312h) were analyzed for total serum iron (Fe), plasma IVIP-iron (IVIP-Fe), transferrin (Tf)-bound iron (TBI) by inductively coupled plasma mass spectrometry, Tf saturation (TSAT) by Tf ELISA and a tripyridyl triazine assay, serum ferritin (SF) by turbidimetry, and non-TBI (NTBI) and hepcidin (hepc) as published (Garbowski et al, Transl Med 2016), (Bansal et al, Rapid Commun Mass Spectrom 2010). A p value Results Pts were hypoferremic but non-anemic at baseline: SF 12.4±7.4µg/L, TSAT 18.6±8.5%, hemoglobin 128±8g/L. IVIP-dependent rises in Fe, IVIP-Fe, TSAT, SF, hepc, and NTBI returned to baseline in 2 wks or sooner, except for SF and TSAT. Large differences in the Fe AUCs on study, explainable by large differences in the IVIP-Fe AUCs, were consistent with the known relative differences of plasma half-lives (t1/2) of the IVIPs compared. IVIP-Fe at 4h was highest for IIM and smallest for IS, as was their AUC. With IIM, TSAT reached 80% at 16h, with IS 100% by 4h, and with FCM 98% at 24h; but AUC differences were small. NTBI was low with IIM (0.13µM at 8h), rapidly increased and high with IS (0.8µM at 2h, 1.25µM at 4h), and delayed for FCM (0.58µM at 24h). NTBI appeared after near- (for IIM) or full saturation of Tf but disappeared when TSAT fell Discussion We propose 2 mechanisms for the observed kinetic NTBI profiles. For IS these have 2 distinct components: a rapid onset and an early peak (2-4h), then decay and a secondary peak/shoulder (16h), disappearing at 36h (Fig). The 1st peak reflects the rapid release of labile iron in plasma directly from circulating IVIPs, occurring 4 t1/2, when >90% of IS entered macrophages (SF half-maximal), the 16h peak likely represents iron re-released from macrophages (indirect NTBI). For IIM with long t1/2, the small NTBI peak at 8h thus represents direct NTBI, while the indirect release at 24h occurs at a rate where Tf does not fully saturate, with NTBI being consequently virtually absent (Fig). FCM first follows the IIM profile with minimal generation of direct NTBI, but displays a starkly different behavior reflecting indirect iron release shown as a strong NTBI peak at 24h, when ~4 plasma t1/2 have passed (Fig). This difference between IIM and FCM is accounted for by the difference in t1/2 of FCM and IIM i.e. by the amount of polymer having been taken up by macrophages (so only 6% of FCM and 30% of IIM still circulates). We conclude that, following IVIP administration, NTBI can arise by 2 mechanisms (direct early release and indirect later release). Different IVIPs generate different NTBI and serum ferritin signatures that are broadly PK-dependent, and may have a bearing both on the iron bio-availability and safety. Longer-term studies with common doses (1g for FCM and IIM) are warranted to link the initial NTBI exposure to subsequent safety and response parameters. Disclosures Garbowski: Vifor Pharma: Consultancy; Imara: Consultancy. Porter:Celgene: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Protagonism: Honoraria; La Jolla: Honoraria; Vifor: Honoraria; Silence therapeutics: Honoraria; Bluebird bio: Consultancy, Honoraria. Burckhardt:Vifor Pharma (previously): Employment. Hider:Vifor Pharma: Research Funding; Renapharma AB: Research Funding.

The National Service Framework advocates correction of anaemia in patients with chronic kidney disease (CKD). Oral iron is insufficient, while intravenous (IV) supplementation replenishes and maintains iron stores. Previously, effective delivery of iron therapy using available parenteral preparations has been hampered by dosing schedules and the need in some cases of a test dose. The introduction in Europe of newer iron preparations, including iron isomaltoside 1000 (Monofer) and iron carboxymaltose (Ferinject), now offers a potentially safe, effective and time-efficient method of outpatient iron repletion. This may potentially lead to better cost-effectiveness in a resource-limited service.

SUMMARY Lack of iron is one of the main causes of anemia in the general population and iron deficiency anemia (IDA) is associated with increased morbidity and mortality. Treatment of iron deficiency with oral iron supplements is a simple and inexpensive, but oral iron is a less-than-ideal treatment because of gastrointestinal side-effects and long treatment times needed to resolve anemia and replenish body iron stores. Nonadherence is common, and even in compliant patients poor intestinal absorption fails to compensate for the iron need in the presence of ongoing blood losses or inflammatory conditions. Modern intravenous (IV) iron formulations have emerged as safe and effective alternatives to oral iron for the treatment of IDA. Given their demonstrated effectiveness and favorable safety profile in a broad spectrum of diseases associated with IDA, the current paradigm that oral iron is first-line therapy should be reconsidered. In the past few years, three new IV iron compounds (ferric carboxymaltose, ferumoxytol and iron isomaltoside 1000) have been released for clinical use in patients with IDA. These new preparations with more favorable administration regimens have the potential to improve the convenience and cost-effectiveness of IV iron therapy.

The physicochemical characteristics of intravenous iron complexes affect the extent of weakly-bound iron and thus the degree of oxidative stress. The new preparation iron isomaltoside 1000 (IIM) was compared to iron sucrose (IS) and a control group in terms of biochemistry, oxidative stress, inflammatory markers and iron deposition in the liver, heart and kidneys of healthy rats. Renal function was significantly impaired in the IIM group versus both IS and controls. Liver enzymes were also significantly higher in IIM-treated animals versus the other groups, indicative of hepatic injury. Systolic blood pressure was significantly lower following IIM administration compared to IS or control animals. Oxidative stress in the liver, heart and kidneys was greater in the IIM group, as indicated by significantly increased levels of malondialdehyde and antioxidant enzyme activity, accompaniedby a significantly lower ratio of reduced to oxidized glutathione. Microscopy demonstrated more extensive positive staining for iron, and a smaller area of ferritin staining, in the liver, heart and kidneys of rats treated with IIM versus IS.Levels of the inflammatory markers TNF-alpha and IL6 were both significantly higher in the IIM group versus IS in all assessed tissues. These findings indicate that IIM has a less favorable safety profile than IS in healthy rats, adversely affecting iron deposition, oxidative stress and inflammatory responses, with impaired liver and renal function.

Background: Patients with chronic kidney disease (CKD) often suffer from iron deficiency anemia necessitating treatment with intravenous iron. This study was designed to assess the safety of iron isomaltoside 1000 (Monofer) in CKD patients. The secondary objective was to assess its effect on iron deficiency anemia. Methods: This open-label, noncomparative, multi-center trial assigned 182 patients with CKD (n=161 in dialysis and n=21 in predialysis) to iron isomaltoside 1000 either as 4 intravenous bolus injections of 100-200 mg iron per dose or as a fast high-dose infusion at baseline. Patients were generally undergoing erythropoiesis-stimulating agent (ESA) treatment (82%), and the dosage was to be kept constant during the trial. They were either switched from an existing parenteral maintenance therapy (n=144) or were not currently being treated with parenteral iron (n=38). Frequency of adverse events (AEs) and changes in markers of iron deficiency anemia were measured during 8 weeks from baseline. Results: Nineteen treatment-related AEs occurred in 13 patients (7.1%) and after 584 treatments (3.3%). No anaphylactic or delayed allergic reactions were observed. There were no clinically significant changes in routine clinical laboratory tests or vital signs. Hemoglobin increased from 99.2 g/L (SD=9.0) at baseline to 111.2 g/L (SD=14.7) at week 8 in patients not currently treated with parenteral iron (p

Introduction: Iron deficiency anemia (IDA) is prevalent and associated with reduced quality of life (QoL) and worsened disease outcomes. Oral iron administration remains the front line standard but its use is associated with an unacceptably high incidence of gastrointestinal side effects and low adherence. Further, in many conditions associated with blood loss, iron losses may exceed the capacity for oral iron absorption. Use of intravenous (IV) iron, especially if given in a single dose, may result in better compliance, fewer visits to the medical practitioner, and overall improvement in QoL. To date, no product has been licensed in the USA for single visit complete replacement dosing. To address this issue, this trial compared the safety and efficacy of iron isomaltoside 1000 with the most commonly prescribed IV formulation, iron sucrose, in patients intolerant of, or unresponsive to oral iron or likely to receive a blood transfusion. Methods: This was a randomized, open-label, comparative, multi-center trial conducted in the USA. Patients with IDA were randomized 2:1 to either iron isomaltoside administered as a single dose of 1000 mg infused over 20 min at baseline or iron sucrose administered as 200 mg IV injections according to label and repeated up to 5 times. The primary endpoints were adjudicated serious or severe hypersensitivity events starting on or after the first dose of treatment (if the upper bound of the 95 % CI was Results: A total of 1512 patients were enrolled of whom 26 % had gastrointestinal and 50 % gynecologic blood loss. The mean (standard deviation [SD]) age was 44 (15) years. The mean (SD) cumulative dose of iron was 975 (145) mg and 905 (217) mg in the iron isomaltoside and iron sucrose group, respectively. All required 1 visit for iron correction with iron isomaltoside and 4 to 5 visits for iron sucrose. The frequency of subjects with serious or severe hypersensitivity reactions was 0.3% in the iron isomaltoside group versus 0.4 % in the iron sucrose group (95% CI: 0.88 for iron isomaltoside and 1.45 for iron sucrose), meeting the primary safety endpoint. The treatment groups had statistically similar adverse drug reactions (ADRs), 12.5 % in the iron isomaltoside group and 12.8 % in the iron sucrose group. Only 0.2 % of patients in iron isomaltoside group and 0.4 % in iron sucrose group experienced serious ADRs. There were no related fatalities. The frequency of composite cardiovascular safety endpoint was 0.8 % in the iron isomaltoside group and 1.2 % in the iron sucrose group (p = 0.57). The frequency of hypophosphatemia (s-phosphate The primary efficacy endpoint of non-inferiority in Hb change from baseline to week 8 was met. Iron isomaltoside lead to a significantly more rapid and increased Hb response in the first 2 weeks. This was reflected in both Hb change from baseline and proportion of responders with Hb increases ≥2 g/dL. Hb increased with least square means of 0.70 and 0.44 g/dL at week 1 (p Conclusion: Iron isomaltoside 1000 administered as 1000 mg in a single visit resulted in a faster and more pronounced hematological response and improvement in fatigue compared to iron sucrose which requires multiple visits. The safety profile was similar with a low frequency of hypersensitivity reactions, cardiovascular events, and serious ADRs. The frequency of hypophosphatemia was low in both treatment groups and no patients had s-phosphate Disclosures Auerbach: AMAG Pharmaceuticals: Research Funding; Pharmacosmos A/S: Research Funding. Lykke:Pharmacosmos A/S: Employment.

SUMMARY Intravenous iron preparations have shown benefit in patients with chronic heart failure (CHF) and iron deficiency. Iron isomaltoside 1000 (Monofer) is a novel intravenous iron compound with low immunological activity of the isomaltoside and low free-iron-related toxicity. The primary objective of this open-label, non-comparative, multicenter pilot study was to test the safety of iron isomaltoside 1000 in patients with CHF and anemia. In addition, its effect on markers of iron deficiency, anemia and on quality of life was assessed. Twenty patients with CHF and iron deficiency anemia attended six visits during the 8-week study period. Iron isomaltoside 1000 was infused at baseline (mean dose 868 mg, range 650–1000 mg). No treatment-related adverse reactions, no acute anaphylactic or delayed allergic reactions and no clinically significant changes in routine clinical laboratory safety tests or vital signs were observed. Markers of iron deficiency, anemia and quality of life improved from baseline with increase in mean value of 49% at 4 weeks in overall quality of life. Iron isomaltoside 1000 administered as a fast single infusion without a test dose to patients with CHF improved quality-of-life assessments and was well tolerated in this pilot safety study.

Anemia is a common complication of inflammatory bowel diseases (IBD) This multicenter study tested the noninferiority and safety of a new intravenous iron preparation, ferric carboxymaltose (FeCarb), in comparison with oral ferrous sulfate (FeSulf) in reducing iron deficiency anemia (IDA) in IBD. Two hundred patients were randomized in a 2:1 ratio (137 FeCarb:63 FeSulf) to receive FeCarb (maximum 1,000 mg iron per infusion) at 1-wk intervals until the patients' calculated total iron deficit was reached or FeSulf (100 mg b.i.d.) for 12 wk. The primary end point was change in hemoglobin (Hb) from baseline to week 12. The median Hb improved from 8.7 to 12.3 g/dL in the FeCarb group and from 9.1 to 12.1 g/dL in the FeSulf group, demonstrating noninferiority (P= 0.6967). Response (defined as Hb increase of >2.0 g/dL) was higher for FeCarb at week 2 (P= 0.0051) and week 4 (P= 0.0346). Median ferritin increased from 5.0 to 323.5 mug/L at week 2, followed by a continuous decrease in the FeCarb group (43.5 mug/L at week 12). In the FeSulf group, a moderate increase from 6.5 to 28.5 mug/L at week 12 was observed. Treatment-related adverse events (AEs) occurred in 28.5% of the FeCarb and 22.2% of the FeSulf groups, with discontinuation of study medication due to AEs in 1.5% and 7.9%, respectively. FeCarb is effective and safe in IBD-associated anemia. It is noninferior to FeSulf in terms of Hb change over 12 wk, and provides a fast Hb increase and a sufficient refill of iron stores

Objective. Iron isomaltoside 1000 (Monofer®) is a high-dose intravenous (IV) iron, which in a recent 8 weeks trial in inflammatory bowel disease (IBD) subjects with iron deficiency anemia (IDA) demonstrated good tolerability and efficacy. The present trial is an extension to this trial, which evaluates the need for additional high IV iron doses to maintain a stable hemoglobin (Hb) ≥12.0 g/dl. Material and methods. This was a prospective, open-label, 12 months trial of European IBD subjects willing to participate after completing the lead-in trial. Subjects were allowed re-dosing with 500–2000 mg single doses of iron isomaltoside 1000 infused over ∼15 min at 3 months intervals depending on a predefined algorithm. Outcome measures included Hb, safety parameters and need for additional iron dosing. Results. A total of 39 subjects were enrolled of which 34 subjects required re-dosing with a median cumulative 1-year dose of 1.8 g (mean cumulative dose 2.2 g). The mean (SD) Hb was 12.3 (1.5) g/dl at baseline, 12.8 (1.6) g/dl at 3 months, 12.8 (1.6) g/dl at 6 months, 12.9 (1.4) g/dl at 9 months and 12.9 (1.6) g/dl at 12 months. Seventy-four percent of subjects who had an Hb ≥12.0 g/dl at baseline were able to maintain Hb ≥12.0 g/dl till the end of the trial at 12 months. Nonserious probably related hypersensitivity reactions without significant hypotension were reported at the beginning of the infusion in two subjects, who recovered without sequelae. Conclusion. Repeated treatment of iron deficiency with iron isomaltoside 1000 could avoid episodes of IDA without major safety issues.

Supplemental orally-administered iron has been available for centuries, but parenteral administration of iron as a therapeutic agent dates from the 1930s. The original agents were iron salts, and their administration to man was associated with severe and unacceptable side-effects even with doses of 4-8 mg. The modern-day practice of IV iron supplementation was transformed in the 1940s with the introduction of iron incorporated into a carbohydrate shell, to allow slow release in the circulation and rapid binding to plasma transferrin. The older iron-carbohydrate complexes included iron dextran, iron sucrose, and iron gluconate, with different iron release kinetics. Iron dextran had significant toxicity with possible anaphylactic reactions. Other iron preparations can also induce hypersensitivity reactions, although recent evidence suggests that these are not immunoglobulin-mediated, but may be due to free iron in circulation or mediated via complement, the so-called CARPA reactions (complement activation-related pseudo-allergy). Newer oral iron preparations include ferric citrate which is much more tolerable than ferrous sulphate, while newer IV iron compounds include ferric carboxymaltose, iron isomaltoside 1000 , and ferumoxytol. Iron supplementation has traditionally been used to ameliorate iron deficiency anaemia, and in the early 1990s, IV iron was found to be mandatory in dialysis patients to support erythropoiesis under stimulation with recombinant human erythropoietin. Recent data also suggest that IV iron may have benefits in chronic heart failure, independent of any effect on haemoglobin or red cell production, possibly by enhancing cardiac myocyte mitochondrial function. Although most RCTs suggest better efficacy with IV iron versus oral iron, there are some concerns regarding the safety of parenteral iron, not only in relation to hypersensitivity reactions, but also exacerbation of oxidative stress or infections. Several ongoing RCTs are seeking to provide further evidence in this regard, e.g. the PIVOTAL trial. Newer strategies for replenishing iron stores include HIF prolyl hydroxylase inhibitors (HIF PHIs), antagonists of the hepcidin pathway, or dialysate iron administration as ferric pyrophosphate citrate. HIF PHIs (such as roxadustat and vadaddustat) have been shown to reduce hepcidin, probably indirectly via stimulation of erythropoiesis, as well as by stimulating a number of iron-regulatory genes, and allowing greater amounts of iron to be absorbed orally. Many molecules designed to interfere with hepcidin activity are in varying stages of clinical development, including monoclonal antibodies against hepcidin or its signalling pathway, spiegelmers, anticalins, and antisense oligonucleotides. Administering ferric pyrophosphate citrate (Triferric™) across dialysis has recently become clinical reality in the US, although this is not available in Europe. Thus, strategies to supplement iron have developed considerably over the last two decades, with several novel approaches transitioning from bench to bedside. Disclosures Macdougall: Astellas: Honoraria, Research Funding; GlaxoSmithKline: Consultancy; Akebia: Consultancy; Vifor Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacosmos: Honoraria; AMAG: Consultancy, Honoraria, Research Funding; FibroGen: Consultancy, Speakers Bureau.

Iron deficiency (ID) and anemia of chronic diseases (ACD) are the most common causes of anemia in inflammatory bowel disease (IBD), and frequently coexist. In these circumstances, detection of ID may be difficult as inflammation influences the parameters of iron metabolism. The prevalence of iron deficiency anemia (IDA) ranges between 36% and 76% in this population of patients. Anemia may impair physical condition, quality of life (QOL), and cognitive function, negatively affecting almost every aspect of daily life. Furthermore, it may be one of the causes of death in IBD. Consequently, iron replacement therapy should be initiated as soon as ID or IDA is detected, together with the treatment of underlying inflammation. Oral iron therapy is a simple and cheap treatment, but often is poorly tolerated and may worsen the intestinal damage. Moreover, in inflammatory states, duodenal iron absorption is blocked by a cytokine-mediated mechanism. Consequently, intravenous iron therapy is preferred in the presence of severe anemia, intolerance or lack of response to oral iron, and moderately to severely active disease. Recently, new intravenous iron compounds (iron carboxymaltose, iron isomaltoside 1000, ferumoxytol) have become available. Iron carboxymaltose has been shown to be safe and effective in IBD patients with IDA. Furthermore, it allows for rapid administration of high single doses, saving time and costs. If proven to be efficacious and well tolerated, it may become the standard therapy in the near future.

Production of minute concentrations of superoxide (O2(*-)) and nitrogen monoxide (nitric oxide, NO*) plays important roles in several aspects of cellular signaling and metabolic regulation. However, in an inflammatory environment, the concentrations of these radicals can drastically increase and the antioxidant defenses may become overwhelmed. Thus, biological damage may occur owing to redox imbalance-a condition called oxidative and/or nitrosative stress. A complex interplay exists between iron metabolism, O2(*-), hydrogen peroxide (H2O2), and NO*. Iron is involved in both the formation and the scavenging of these species. Iron deficiency (anemia) (ID(A)) is associated with oxidative stress, but its role in the induction of nitrosative stress is largely unclear. Moreover, oral as well as intravenous (iv) iron preparations used for the treatment of ID(A) may also induce oxidative and/or nitrosative stress. Oral administration of ferrous salts may lead to high transferrin saturation levels and, thus, formation of non-transferrin-bound iron, a potentially toxic form of iron with a propensity to induce oxidative stress. One of the factors that determine the likelihood of oxidative and nitrosative stress induced upon administration of an iv iron complex is the amount of labile (or weakly-bound) iron present in the complex. Stable dextran-based iron complexes used for iv therapy, although they contain only negligible amounts of labile iron, can induce oxidative and/or nitrosative stress through so far unknown mechanisms. In this review, after summarizing the main features of iron metabolism and its complex interplay with O2(*-), H2O2, NO*, and other more reactive compounds derived from these species, the potential of various iron therapies to induce oxidative and nitrosative stress is discussed and possible underlying mechanisms are proposed. Understanding the mechanisms, by which various iron formulations may induce oxidative and nitrosative stress, will help us develop better tolerated and more efficient therapies for various dysfunctions of iron metabolism.

Background: Iron deficiency anemia is common in patients with chronic kidney disease, and intravenous iron is the preferred treatment for those on dialysis. We investigated the pharmacokinetics, pharmacodynamics, and safety of three doses (100 mg, 200 mg, and 500 mg) of iron isomaltoside 1000administered as bolus injections in patients with stage 5 chronic kidney disease on dialysis therapy. Methods: This prospective, randomized, open-label pharmacokinetic study was conducted in 18 patients at one center. Patients were randomly assigned in a 1:1:1 ratio to receive a single dose of 100 mg, 200 mg, or 500 mg intravenous bolus injection (6 patients each) of iron isomaltoside 1000 at baseline visit. The pharmacokinetic, pharmacodynamics, and safety parameters were assessed over seven days and increases in serum-iron was used as a surrogate for iron isomaltoside 1000. Results: There was a dose-dependent increase in the geometric mean values of area under serum concentration-time curve (AUC) from injection to last measurable data point, area under serum concentration-time curve from injection to infinity (AUC0-t), and maximum serum concentration (Cmax), whereas time to reach maximum concentration (Tmax) decreased with increasing doses of iron isomaltoside 1000. Thegeometric mean of half-life (T½) was approximately 30 h and the elimination rate constant (Ke) remained similar across the three doses. Serum-iron, transferrin saturation, and serum-ferritin increased significantly, and the increases were related to iron dose. No major change was observed in the mean hemoglobin, reticulocyte count, reticulocyte hemoglobin content, ortotal iron binding capacity across the three doses. Three adverse events occurred of which one, asthma exacerbation, was considered probably related to the treatment. Conclusions: The pharmacokinetic characteristics and simplicity of administration of iron isomaltoside 1000 suggest it to be a convenient iron replacement therapy over this dosage range.

Today, erythropoiesis-stimulating agents (ESAs), together with iron supplementation, are the main tool for anemia correction in chronic kidney disease patients. Over the past decades, a number of attempts have been made to modify the erythropoietin molecule in order to improve its pharmacokinetic and pharmacodynamic properties. More recently, small peptides, which are unrelated to erythropoietin but bind to the same receptor, have been developed. In addition to this, other strategies to stimulate erythropoiesis have been followed, such as activin inhibition or stabilization of hypoxia-inducible transcription factors. Interestingly, the latter have the advantage of being administered orally. New iron molecules, such as ferumoxytol, ferric carboxymaltose and iron isomaltoside 1000, have recently been marketed. These new agents can administered at high doses while releasing minimal free iron. Their safety profile is good, but long- term post- marketing data are still needed to evaluate the occurrence of rare adverse events.

Background. We previously compared the safety profile of three formulations of intravenous iron used during 1998–2000 and found higher rates of adverse drug events (ADEs) associated with the use of higher molecular weight iron dextran and sodium ferric gluconate complex compared with lower molecular weight iron dextran. Since that time, iron sucrose has become widely available and clinicians have gained additional experience with sodium ferric gluconate complex. Methods. We obtained data from the United States Food and Drug Administration (FDA) on ADEs attributed to the provision of four formulations of intravenous iron during 2001–2003, including higher and lower molecular weight iron dextran, sodium ferric gluconate complex and iron sucrose. We estimated the odds of intravenous iron-related ADEs using 2 � 2 tables and the 2 test. Results. The total number of reported parenteral ironrelated ADEs was 1141 among approximately 30 063 800 doses administered, yielding a rate of 3.8 � 10 � 5 , or roughly 38 per million. Eleven individuals died in association with the ADE. Relative to lower molecular weight iron dextran, total and lifethreatening ADEs were significantly more frequent among recipients of higher molecular weight iron dextran and significantly less frequent among recipients of sodium ferric gluconate complex and iron sucrose. The absolute rates of life-threatening ADEs were 0.6, 0.9, 3.3 and 11.3 per million for iron sucrose, sodium ferric gluconate complex, lower molecular weight iron dextran and higher molecular weight iron dextran, respectively. Based on differences in the average wholesale price of iron sucrose and lower molecular weight iron dextran in the US, the cost to prevent one life-threatening ADE related to the use of lower molecular weight iron dextran was estimated to be $5.0–7.8 million. The cost to prevent one lower molecular weight iron dextran-related death was estimated to be $33 million. Conclusions. The frequency of intravenous ironrelated ADEs reported to the FDA has decreased, and overall, the rates are extremely low. This is the fourth report suggesting increased risks associated with the provision of higher molecular weight iron dextran. Life-threatening and other ADEs appear to be lower with the use of non-dextran iron formulations, although the cost per ADE prevented is extremely high.

During an industry-sponsored symposium at the ERA–EDTA meeting in Munich 2010, four experts gathered to debate and provide an update on the treatment of anaemia in chronic kidney disease (CKD) patients, especially the relative contributions of erythropoiesis-stimulating agents (ESAs) and iron in its management. I chaired this symposium and invited these experts in collaboration with the sponsor to summarize their opinions. As the results of the largest of the ESA trial, TREAT, were available, many presenters focused on those results. The expert opinions were partly supported by available data, and there were, on occasions, differences in opinion between the experts on the interpretation of the data. For example, Dr Coyne’s statement that stroke risk is independent of ESA hyporesponsiveness is not a view that I share. I believe that the analysis of Solomon et al. in which Dr Coyne’s statement was based was simply not sufficiently powered to detect this relationship. Dr Locatelli states that the TREAT study was not a ‘placebo’ randomized controlled trial because the placebo group experienced an increase in haemoglobin (Hgb) over time. I disagree. The Hgb levels increased over time because the placebo group had a rescue feature which allowed administration of darbepoietin should Hgb fall below 9 g/dL. Dr Bhandari states that the profile of the ideal iron preparation should be capable of delivering sufficient quantities of intravenous iron to correct iron deficiency rapidly, with minimal potential side effects including low catalytic/labile iron release and negligible immunogenicity (risk of anaphylaxis). Yes, but I believe that the long-term safety of intravenous iron is the most important attribute which needs to be evaluated; long-term toxicity would trump any convenience afforded by the drug. Dr Kalra states that the drug should have reduced immunogenic potential and reduced risk for free iron toxicity. Although these claims may be true, they remain to be validated in larger safety studies especially among patients with multiple drug allergies. Below are opinions provided by the experts. There are several statements where consensus was not achieved. However, the experts do have a right to their opinions, and I present them below as they were presented to me, even when I am in disagreement. The highlights of this symposium, as I see it, are as follows: Normalizing Hbg among people with CKD is associated with cardiovascular and thrombotic risk. These risks can only be partially managed by correcting anaemia. Hyporesponsiveness to ESAs is associated with increased cardiovascular risk. Whether it is the dose of ESAs, poor response to ESA dose, a combination of the two or some other traits that confer this increased risk is unknown. Therefore, it should not be taken as a foregone conclusion that the dose of ESA is toxic. However, it is prudent to limit the dose of ESA to the minimum required to achieve a satisfactory Hbg response. The upper limit of ESA dose is unknown. Iron deficiency remains an important cause of ESA hyporesponsiveness. The diagnosis of iron deficiency among patients with CKD remains difficult. The pitfalls in making a diagnosis of iron deficiency anaemia are discussed. No gold standard is established. Therefore, when in doubt, a therapeutic trial of intravenous iron may be useful to establish a firm diagnosis. Among haemodialysis patients, the preferred route of iron administration is intravenous. However, it must be noted that patients with CKD who are not on haemodialysis can receive iron either orally or intravenously; there is no preference. The various parenteral irons, which are currently marketed, and their risks and benefits are discussed. Normalizing Hbg with ESAs in patients with CKD increases cardiovascular risk, whereas hyporesponsiveness to ESAs is associated with increased risk. Thus, it is logical to hypothesize that the cardiovascular risk of ESA use in patients with CKD may be mitigated with iron administration. Whether iron administration reduces ESA hyporesponsiveness or decreases or increases cardiovascular risk is currently unknown. The risk–benefit ratio of iron administration in CKD patients needs to be evaluated in well-designed prospective randomized controlled trials with cardiovascular and renal outcomes. Iron isomaltoside 1000 may be an attractive intravenous iron that may allow rapid repletion and theoretically a better safety profile.

Introduction Parenteral iron has been used increasingly over the last decade to treat specific patient groups with iron deficiency (ID) anaemia. There is, however, limited evidence of safety and efficacy in all patients with ID, particularly those with underlying malignancy or inflammation. Methods Data from all outpatients receiving iv iron isomaltoside (Monofer) for confirmed ID between 1st April and 31st December 2012 at our UK District General Hospital was analysed, regardless of underlying diagnosis or comorbidity. Patients received their infusions under the care of Gastroenterology on our Medical Investigations Unit, a 7-day nurse led unit that works extended hours and is located within the main hospital. ID was defined by ferritin Results 85 patients received monofer infusions for confirmed ID over the study period, with 80 of these having ID anaemia. Referrals were from a range of medical, surgical and oncological specialities. 55 patients (65%) were female and the age range was 18–92 years (median 73 years). Baseline bloods (median and interquartile range (IQR)) were Hb 90 g/l (80–99), Mean Cell Volume 81 fl (72–88), Mean Cell Haemoglobin 24.8 pg (22.2–28.0), ferritin 15mcg (9–24) and TSAT 9% (5–15). Most patients had extensive comorbidity; 29(34%) had active malignancy and 44(77%) of those without malignancy had active inflammation. The median iron dose was 14.6 mg/kg (IQR 11.2–17.5). No significant adverse reactions occurred and all patients received the full infusion. Post infusion bloods demonstrated a median increase in Hb of 23 g/l (Figure 1) with 52% having a Hb increase of >20 g/l. The Hb rise was significantly higher in individuals with a lower baseline Hb; regression slope of baseline against change in Hb = -5.9 Hb, p Conclusion Treatment of ID anaemia with parenteral iron is safe and effective in all patients including those with cancer or active inflammation. A rapid rise in Hb within 4 weeks is seen in many patients particularly where the baseline Hb is low. Disclosure of Interest None Declared.

Kim Nordfjeld, Hans Andreasen, Lars L ThomsenPharmacosmos A/S, Holbaek, DenmarkBackground: Iron isomaltoside 1000 is a novel injectable iron compound which offers potential advantages in the treatment of subjects with iron-deficiency anemia. We studied the pharmacokinetics (PK) of this novel compound in subjects with mild-to-moderate inflammatory bowel disease (IBD).Methods: This open-label, crossover, single-center trial was conducted in 12 subjects with IBD who were allocated to one of the two single intravenous (IV) bolus sequences of iron isomaltoside 1000: 100 mg followed by 200 mg, or vice-versa. PK variables were analyzed according to a single-compartment model.Results: The concentration-versus-time relationship for isomaltoside-bound iron (IBI) and total iron (TI) showed first-order kinetics with small deviations from dose-linearity. The area under the concentration-time curve (AUC) values in h * µg/mL for IBI following 100 mg and 200 mg doses were 888 and 2141 respectively, and for TI following 100 mg and 200 mg doses, the AUC values were 1010 and 2319 respectively. The corresponding maximum serum concentration (Cmax) values in µg/mL were 35.6 and 68.6 for IBI, and 37.3 and 71.1 for TI. The half-life (T½) values for IBI and TI were between 20.8–23.5 hours. The apparent volume of distribution (VD) ranged from 3.0–3.5 L. Only approximately 1% of the doses administered were excreted in the urine. No serious adverse event (SAE) was reported. One subject was withdrawn after the 100 mg dose due to abdominal pain and flushing.Conclusion: At the administered doses, iron isomaltoside 1000 showed first-order PK, and did not raise safety concerns in patients with IBD. The PK parameters for IBI were close to those of TI.Keywords: inflammatory bowel disease, iron deficiency anemia, iron treatment, iron isomaltoside, pharmacokinetics

The treatment of iron deficiency anemia with polynuclear iron formulations is an established therapy in patients with chronic kidney disease but also in other disease areas like gastroenterology, cardiology, oncology, pre/post operatively and obstetrics’ and gynecology. Parenteral iron formulations represent colloidal systems in the lower nanometer size range which have traditionally been shown to consist of an iron core surrounded by a carbohydrate shell. In this publication, we for the first time describe the novel matrix structure of iron isomaltoside 1000 which differs from the traditional picture of an iron core surrounded by a carbohydrate. Despite some structural similarities between the different iron formulations, the products differ significantly in their physicochemical properties such as particle size, zeta potential, free and labile iron content, and release of iron in serum. This study compares the physiochemical properties of iron isomaltoside 1000 (Monofer®) with the currently available intravenous iron preparations and relates them to their biopharmaceutical properties and their approved clinical applications. The investigated products encompass low molecular weight iron dextran (CosmoFer®), sodium ferric gluconate (Ferrlecit®), iron sucrose (Venofer®), iron carboxymaltose (Ferinject®/Injectafer®), and ferumoxytol (Feraheme®) which are compared to iron isomaltoside 1000 (Monofer®). It is shown that significant and clinically relevant differences exist between sodium ferric gluconate and iron sucrose as labile iron formulations and iron dextran, iron carboxymaltose, ferumoxytol, and iron isomaltoside 1000 as stable polynuclear formulations. The differences exist in terms of their immunogenic potential, safety, and convenience of use, the latter being expressed by the opportunity for high single-dose administration and short infusion times. Monofer is a new parenteral iron product with a very low immunogenic potential and a very low content of labile and free iron. This enables Monofer, as the only IV iron formulation, to be administered as a rapid high dose infusion in doses exceeding 1000 mg without the application of a test dose. This offers considerable dose flexibility, including the possibility of providing full iron repletion in a single infusion (one-dose iron repletion).