High Molecular Weight Iron Dextran Research Articles

Reducing unnecessary premedication prior to parenteral iron therapy: A quality improvement project.

Intravenous (IV) iron carries risks of mild, self-limiting, tryptase-negative Fishbane and complement activation-related pseudo-allergy reactions, with rare reports of anaphylaxis. Historically, high-molecular-weight iron dextran (HMWID) was associated with a higher incidence of anaphylaxis and empiric premedication with antihistamines/corticosteroids have been used to mitigate this risk. HMWID is no longer available and the risk of hypersensitivity reactions with newer IV iron formulations is low. Therefore, the use of routine prophylactic premedication in all patients is not justified but should be considered in high-risk patients. Our primary aim was to reduce inappropriate premedication before IV iron administration by 50% so that our institution's hematology providers only prescribe premedications to patients at high risk of having a severe reaction. Interventions included a multidisciplinary education initiative to highlight current evidence against universal administration of premedications and revision of the IV iron informed consent form and electronic order set. We measured the success of our intervention by comparing data collected during a 6-month pre-intervention period (837 infusions) to a 6-month post-intervention period (947 infusions). Inappropriate administration of premedications decreased from 79% in the pre-intervention period compared to 65% in the post-intervention period. We found no significant difference in the number of Fishbane reactions, severe reactions, and emergency room admissions, despite this reduction in premedication use. Although we did not reach our goal of a 50% reduction in inappropriate premedication use, opportunities for process improvements were uncovered and are being explored in the next cycle of this quality improvement project.

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Iron deficiency: a new alternative when oral iron fails

Iron deficiency is the most common nutritional deficiency worldwide. The estimated prevalence in the US is about 7% among preschool-aged children and 10%-20% among adolescent females. Although most patients will not develop overt anemia, even mild deficiency may cause acute symptoms and result in long-term cognitive defects, underscoring the importance of effective treatment. In theory, correction of iron deficiency is simple: deliver sufficient amounts of bio-available iron to the duodenum and upper jejunum and let nature takes its course. In practice, therapeutic doses of oral iron often are accompanied by unpleasant gastrointestinal symptoms, and the formulations suitable for young children are all unpalatable to some degree. Thus, compliance with oral iron is often poor, and even excellent compliance may be inadequate for individuals with malabsorption or ongoing blood loss. The original parenteral iron formulation, high molecular weight iron dextran, is no longer available in the US due to its relatively high incidence of hypersensitivity reactions. Although low-molecular weight iron dextran is less likely to cause such reactions, test doses and careful monitoring for anaphylaxis are still recommended. Two newer parenteral formulations, iron sucrose and sodium ferric gluconate, are considered relatively safe and are approved for both adults and children, but typically require multiple doses to achieve adequate iron replacement. A newer iron formulation, ferric carboxymaltose, requires no test dose and the recommended infusion time is only 15 minutes. Although not yet approved for pediatric use, it is approved in both Europe and the US for adults “who have intolerance to oral iron or have had unsatisfactory response to oral iron.” In this volume of The Journal, Powers et al report their experience using ferric carboxymaltose in 72 children and adolescents with iron deficiency anemia. Mild, transient side effects were experienced by only 16% of patients, and almost one-half of the subjects required only a single infusion; all but one patient demonstrated improved hematologic values, with two-thirds showing a complete hematologic response. Although expensive compared with other parenteral formulations—all of which, in turn, are much more expensive than oral iron—its convenience and safety profile may make it an attractive option for many patients in whom oral iron therapy is not feasible. Article page 212 ▶ Intravenous Ferric Carboxymaltose in Children with Iron Deficiency Anemia Who Respond Poorly to Oral IronThe Journal of PediatricsVol. 180PreviewTo assess the benefits and risks of intravenous (IV) ferric carboxymaltose (FCM) in children with iron deficiency anemia (IDA). Full-Text PDF

Safety of intravenous iron use in chronic kidney disease.

Purpose of reviewIron deficiency anaemia (IDA) is common and associated with fatigue, reduced quality of life and poorer clinical outcomes. Treatment with oral iron is often inadequate and international guidelines recommend intravenous (i.v.) iron as the preferred option for the treatment of IDA in certain clinical situations. In this review, we assess the safety of using i.v. iron with a particular focus on patients with chronic kidney disease.Recent findingsRecent publications have raised safety concerns regarding the incidence of serious reactions accompanying i.v. infusion, as well as the subsequent risk of infections and cardiovascular events. Methodological flaws influence the interpretation of these data that lack evidence from the use of modern irons. The latter have been investigated in several randomized control trials.SummaryThere is a need for better understanding and definition of the nature of i.v. iron reactions, as many are nonserious infusion reactions rather than true anaphylaxis. Retrospective identification of anaphylaxis is difficult and we suggest the importance of reanalysing data using fatalities or standardized terms as outcome measures. With the exception of high molecular weight iron dextran, serious or life-threatening reactions are rare with the use of i.v. irons, and they can be used safely for the treatment of IDA.

Is low-molecular weight iron dextran really the most risky iron?--Unconvincing data from an unconvincing study.

Is low-molecular weight iron dextran really the most risky iron?--Unconvincing data from an unconvincing study.

Intravenous ferric carboxymaltose for the treatment of iron deficiency anemia.

Nutritional iron deficiency anemia is the most common deficiency disorder, affecting more than two billion people worldwide. Oral iron supplementation is usually the first choice for the treatment of iron deficiency anemia, but in many conditions, oral iron is less than ideal mainly because of gastrointestinal adverse events and the long course needed to treat the disease and replenish body iron stores. Intravenous iron compounds consist of an iron oxyhydroxide core, which is surrounded by a carbohydrate shell made of polymers such as dextran, sucrose or gluconate. The first iron product for intravenous use was the high molecular weight iron dextran. However, dextran-containing intravenous iron preparations are associated with an elevated risk of anaphylactic reactions, which made physicians reluctant to use intravenous iron for the treatment of iron deficiency anemia over many years. Intravenous ferric carboxymaltose is a stable complex with the advantage of being non-dextran-containing and a very low immunogenic potential and therefore not predisposed to anaphylactic reactions. Its properties permit the administration of large doses (15 mg/kg; maximum of 1000 mg/infusion) in a single and rapid session (15-minute infusion) without the requirement of a test dose. The purpose of this review is to discuss some pertinent issues in relation to the history, pharmacology, administration, efficacy, and safety profile of ferric carboxymaltose in the treatment of patients with iron deficiency anemia.

Evaluation of Serum Oxidative Stress Indices Following Intravenous Iron Delivery in Women with Iron Deficiency Anemia

Introduction: Intravenous (IV) iron is an important treatment for clinicians to properly treat iron deficiency anemia (IDA). In this context, there is a concern that giving a bolus of IV iron can induce oxidative stress. Oxidative stress depends on the stability of the IV iron complex administered. As transferrin saturation (TSAT) is low in anemic patients, transferrin has the ability to trap labile iron present in the preparations and would minimize oxidative stress. In this study, we evaluated a panel of oxidative stress markers for changes to serum components (lipids and proteins) in three IV iron products, ferric carboxymaltose (FCM), iron sucrose (IS), and high molecular weight iron dextran (HMWID).Methods: This was an open-label, multicenter, randomized study that compared the oxidative stress induced by three IV iron preparations. Female subjects with IDA as defined as hemoglobin ≤ 10 g/dL or ≤ 12 g/dL with symptoms and ferritin ≤ 100 ng/mL or ≤ 300 ng/mL with a TSAT of ≤ 30% were included. Subjects were randomized to either Group A (FCM) or Group B (IS or HMWID). The study was performed with two cohorts within each group. Cohort 1 was administered a dose of 500 mg of undiluted FCM solution at a rate of 100 mg/minute and a dose of 500 mg as IS diluted in 250 ml of 0.9% NaCl infused over 4 hours. Cohort 2 was administered a dose of 750 mg as undiluted FCM at a rate of 100 mg/minute and a dose 725 mg as HMWID diluted in 250 ml of 0.9% NaCl infused over 3 hours, with a 25 mg test dose having been administered over 5 minutes prior to the infusion. If no reactions to the 25 mg test dose were observed during a 60 minute observational period subjects went on to receive the remaining 725 mg dose of HMWID. Blood was collected at 6 different time points; screening, baseline (prior to injection), and at 2 hours, 1 day, 7 days, and 30 days post administration. Degree of oxidative stress on proteins was measured by the presence of carbonyl group and the presence of 8-isoprostane for evidence of lipid peroxidation.Results: The safety population (all patients receiving a dose of study drug) was composed of 49 females with a mean age of 32 years, around half of them being African Americans. In the evaluable population (those in the safety group that did not have an intervention and had completed their 24 hour and Day 30 visit, did not have an infection that require IV antibiotics or antivirals after Day 0 ), a total of 22 patients were evaluated in Group A and 21 in Group B. None of the three formulations were associated with significant increases in oxidative modification to proteins or increases in lipid peroxidation. There were more variations apparent in the IS group at 30 days than in the FCM or HMWID groups for oxidative stress in proteins. In regards to lipid peroxidation, the IS group had a large range above the median compared to the other groups at 1 day post-injection, but did not differ significantly from baseline. At all time periods, the range of FCM did not vary as much as the other two formulations.Conclusion: These data indicate no considerable increase in the proteins modified by oxidation (carbonyl group) nor do they indicate evidence of lipid peroxidation (presence of 8-isoprostane). Post-administration oxidative stress was found not to be a significant clinical concern for the IV iron formulations in this study. DisclosuresConnor:Luitpold Pharmaceuticals: Consultancy, Honoraria, Research Funding. Butcher:Luitpold Pharmaceuticals: Employment. Off Label Use: The dose of the study drugs are different from the package insert that is approved by the FDA.

Safety of total dose iron dextran infusion in geriatric patients with chronic kidney disease and iron deficiency anemia

There are limited data on total dose infusion (TDI) using iron dextran in geriatric chronic kidney disease (CKD) patients with iron-deficiency anemia (IDA). Our goal was to evaluate the safety of TDI in this setting. We conducted a retrospective chart review spanning a 5 year period (2002–2007), including all patients with CKD and IDA who were treated with iron dextran TDI. Patient demographics were noted, and laboratory values for creatinine, hemoglobin and iron stores were recorded pre- and post-dose. TDI diluted in normal saline was administered intravenously over 4-6 hours after an initial test dose. One hundred fifty-three patients received a total of 250 doses of TDI (mean ± SD = 971 ± 175 mg); age was 69 ± 12 years and creatinine 3.3 ± 1.9 mg/dL. All stages of CKD were represented (stage 4 commonest). Hemoglobin and iron stores improved post-TDI (P < 0.001). None of the patients experienced an anaphylactic reaction or death. Adverse events (AEs) were noted in 8 out of 250 administered doses (3.2%). The most common AEs were itching, chills and back pain. One hundred and ten doses of high molecular weight (HMW) iron dextran produced 6 AEs (5.45%), whereas 140 doses of low molecular weight (LMW) iron dextran produced 2 AEs (1.43%), a non-significant trend (P = 0.1433 by Fishers Exact Test). Iron dextran TDI is relatively safe and effective in correcting IDA in geriatric CKD patients. Fewer AEs were noted with the LMW compared to the HMW product. LMW iron dextran given as TDI can save both cost and time, helping to alleviate issues of non-compliance and patient scheduling.

Iron in hematology: Danger with IV iron: Real or perceived?

To the editor: This is the first of a series or monthly updates on the treatment of iron deficient states. This regular column will address in real time relevant issues concerning indications and therapeutic modalities for the use of iron supplements. Questions and comments from the AJH readership are welcome. Iron deficiency is associated with fatigue, dietary abnormalities including pagophagia, decreased work performance, restless legs syndrome, and sleep disturbance and most strikingly in neonates, delayed growth and development and an increment in cognitive and behavioral abnormalities up to 10 years after iron repletion 1. In the past decade, the medical community has witnessed incremental increases in the use of intravenous (IV) iron for conditions where oral iron is not tolerated, ineffective or contraindicated. This paradigm shift in the treatment of one of the most common maladies on earth was at least in part, motivated by the development and availability of four new formulations in which the carbohydrate core binds iron more tightly, allowing slower release for erythropoiesis, minimizing infusion related hypersensitivity reactions, and allowing complete replacement dosing in 15–60 min 2, not possible with the more widely used salts, iron sucrose, and ferric gluconate which release higher amounts of free iron after administration. These include low molecular weight (LMW) iron dextran, ferumoxytol, ferric carboxymaltose, and iron isomaltoside. Millions of doses in patients on dialysis, those with inflammatory bowel disease, previous bariatric surgery, heavy uterine bleeding, gravidas, and other well individuals intolerant of oral iron, have been given seamlessly with marginal toxicity. Nonetheless, safety concerns abound, many of which are fueled by publications reporting differences in the safety profile of available formulations based on methodologies, such as spontaneous adverse event reporting, that have been specifically proscribed by regulatory agencies 3. Further confounding safety concerns, was the use of high molecular weight (HMW) iron dextran, which was associated with a significant increase in serious adverse events 4. Minor infusion reactions consisting of mild arthralgias of the chest and flank or flushing occur infrequently with all of the formulations. These reactions routinely abate without therapy and serum tryptase levels are always normal. Without any evidence to support its use, diphenhydramine is used as premedication. This antihistamine can cause somnolence, hypotension, diaphoresis, and tachycardia often ostensibly attributed to the iron. It is, therefore, not surprising that practitioners with pre-existing notions of danger with IV iron, frequently intervene with pressors, and more antihistamines, converting minor infusion reactions into hemodynamically significant serious adverse events (SAEs). In all prospective comparisons between LMW ID, ferric carboxymaltose, and ferumoxtol to iron sucrose, no negative safety signal was identified with the new formulations. The same conclusion can be drawn with large intrainstitutional retrospective analyses 5. Recently, ferric carboxymaltose was compared to the no longer available and more dangerous HMW ID, which erroneously concluded that ferric carboxymaltose was safer than iron dextran 6. Until such a comparison is made to LMW iron dextran, no conclusion can or should be inferred. In conclusion, the new formulations of IV iron are extremely safe, and probably much safer than most physicians realize. When proper interpretation and management of minor infusion reactions is understood and undertaken, serious adverse events are vanishingly rare with an estimated incidence of <1:200,000 doses 4. Hematologists should be more familiar with the available formulations, their profiles, and administration. Michael Auerbach Auerbach Hematology and Oncology, 9110 Philadelphia Rd Suite 314, Baltimore, Maryland 21237

Lower molecular weight intravenous iron dextran for restless legs syndrome

Various techniques used to assess brain iron concentrations have demonstrated the presence of low iron stores in patients with restless legs syndrome (RLS). Previous open-label and randomized studies generally support the value of iron treatment for RLS symptoms. Only one of these studies assessed iron therapy response to changes in brain iron status. The current study was designed to assess the effect of iron therapy on RLS symptoms and on CSF measures of brain iron status. Idiopathic RLS patients drawn from the Korean population received four weekly intravenous (IV) doses of 250 mg low-molecular weight iron dextran for a total dose of 1g. One week after the last dose, any subject on RLS medication tapered off the RLS medications. Blood and CSF samples were taken to measure iron parameters at baseline and again, three weeks after the last dose. We have been following their response to the drug for two years after treatment. Twenty-five patients (age 55.2 ± 9.3, 18 female) enrolled in this study without serious adverse reactions. Seventeen of the 25 patients (68%) showed moderate or complete improvement of all RLS symptoms after treatment based on the Korean-translated versions of the International RLS Severity scale (K-IRLS). Changes in the K-IRLS did not correlate significantly with changes in CSF ferritin. The response to IV iron could not be predicted by patients' demographics, or by blood or CSF iron baseline characteristics. RLS symptom improvement started between one and six weeks after treatment and the treatment benefits lasted from one month to 22 months. Fourteen patients, (56%) completely stopped all medications, for a mean duration of 31.3 ± 33.1 weeks. These results are comparable to those from a prior study with high molecular weight dextran. Intravenous low-molecular weight iron dextran produced significant improvement of RLS symptoms in a majority of patients without any significant adverse effects. Serious anaphylaxis occurs with high molecular weight, but rarely, if ever, with this low molecular weight dextran. Given apparent comparable efficacy the low molecular weight and not the high molecular weight iron dextran, should be considered for RLS treatment. Although changes in CSF ferritin were seen following therapy, these changes were not related to clinical improvements.

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.

Intravenous Low Molecular Weight Iron Dextran (LMWID) in the Treatment of Children with Iron Deficiency Anemia,

Abstract 3184 Background: While iron deficiency anemia (IDA) is among the most common hematologic disorders during childhood, management strategies for patients poorly responsive to oral iron therapy have not been well studied. Children treated for IDA often have a poor response to oral iron due to noncompliance, intolerance of side effects, malabsorption, ongoing blood loss, or a combination of these factors. Alternative treatment approaches are therefore needed. Intravenous (IV) iron, including low molecular weight iron dextran (LMWID), offers the possibility of correcting the anemia and repleting iron stores using a single dose, potentially decreasing the overall burden of treatment. Use of LMWID in children has been limited due to concerns about anaphylaxis associated with high molecular weight iron dextran preparations, even though in adults the risk of anaphylaxis is decreased when alternative IV iron preparations, including LMWID, are employed. In this study we report our initial experience with LMWID in children with IDA. Methods: We performed a retrospective record review of patients receiving IV LMWID for IDA in the Center for Cancer and Blood Disorders at Children's Medical Center Dallas between December 1, 2010 and July 31, 2011. Records were reviewed for age, indication for LMWID, concurrent medical problems, use of premedication, initial and follow-up hemoglobin values, adverse events (AEs), and prior or subsequent receipt of other IV iron preparations. The primary study aim was to characterize the clinical course of patients receiving LMWID to inform a planned prospective cohort study of IV iron in children with IDA poorly responsive to oral iron therapy. Results: A total of 18 patients, age 11 months (mos) to 18 years (yrs), received IV LMWID during the study period. 11 of them (median age 13 yrs) received LMWID for IDA secondary to external blood loss due to menorrhagia (n=3), gastrointestinal disease (n=3), hemophilia (n=2), Von Willebrand disease (n=2), and immune thrombocytopenia (n=1). Five (median age 2 yrs) had IDA due to nutritional deficiency, and two patients had multiple causes for their IDA. 14 patients (77.8%) received their initial LMWID infusion without AEs, and all demonstrated an increase in hemoglobin (mean 3 g/dL) 4 to 7 weeks following infusion. Premedication with diphenhydramine, acetaminophen, hydrocortisone, or a combination of these was given to 6 of the 14 patients (42.8%) at the discretion of the treating physician based on history of atopy. The average dose of LMWID was 600 mg (20.2mg/kg) with a range of 150 mg to 1 gram (6.9 mg/kg to 30.9 mg/kg). 3 of these 14 patients (21.4%) required a subsequent infusion to achieve and maintain a normal hemoglobin due to ongoing blood loss. 6 patients (33.3%) had transient AEs during LMWID infusion including hives (n=3), tachycardia (n=2), chest tightness (n=1), fever (n=2), nausea (n=1), vomiting (n=1), sweating (n=2), and cough (n=1). 2 of them were able to complete the infusion without further sequelae after receiving diphenhydramine or hydrocortisone. Only one of the patients with AEs had received premedication, although on review 3 of the 6 patients with AEs had a concurrent medical problem affecting immune function including asthma and orthotopic liver transplant. No patient required hospital admission or treatment of the AE beyond the day of their clinic visit. 4 of the 6 patients with AEs related to LMWID subsequently received IV iron sucrose infusions without any complications. Conclusions: Among 18 children with IDA receiving LMWID planned as a single dose infusion, treatment was well tolerated and effective in 14 of them and associated with only transient AEs in 6. The latter patients were able to either receive the remainder of the LMWID infusion or an alternative iron preparation without complication. Some patients with ongoing blood loss needed additional infusions, although the majority of children were treated effectively with a single dose. These encouraging results support the need for further study of LMWID in children with IDA unresponsive to oral iron therapy or even as an initial treatment alternative to the oral route. Disclosures: No relevant conflicts of interest to declare.

Intravenous iron sucrose for children with iron deficiency failing to respond to oral iron therapy

For decades, parenteral iron has been used in patients with iron deficiency unresponsive to oral iron therapy and in hemodialysis-dependent patients receiving erythropoietin. Newer intravenous (IV) iron formulations such as iron sucrose have replaced high-molecular weight iron (HMW) dextran in dialysis patients; however, the use of parenteral iron in children without renal disease has not been well defined. Pharmacy records were reviewed on children (≤ 18 years of age) who received IV iron sucrose at Children's Medical Center Dallas between January 1, 2004 and June 30, 2009. Patients who received iron sucrose for chronic renal disease were excluded from analysis. Thirty-eight children received iron sucrose for non-renal indications, 13 with iron deficiency refractory to oral iron therapy, 13 with iron malabsorption or dependence on parenteral nutrition, 7 for chronic gastrointestinal blood loss, and 5 for miscellaneous indications. Among these 38 children, who received a total of 510 doses of IV iron sucrose, there were only six adverse reactions. Patients in all categories had a good response to the iron sucrose, with a median hemoglobin rise of 1.9-3.1 g/dl depending on the indication. Parenteral iron is a safe and effective means to treat iron deficiency in children who cannot receive or do not respond to oral iron due to intolerance, poor adherence, or iron malabsorption.

Comparison of the renal, cardiovascular and hepatic toxicity data of original intravenous iron compounds

Intravenous (i.v.) iron is essential for managing haemoglobin levels in haemodialysis patients. However, i.v. iron may cause variable degrees of toxicity. This is mainly related to the pharmacological characteristics of any given i.v. iron compound. This blinded study examines the effects of five i.v. iron preparations on haemodynamic and functional parameters. Sixty Sprague-Dawley rats (n = 10/group) received high or low molecular weight (HMW/LMW) iron dextran, ferric gluconate (FG), ferric carboxymaltose (FCM), iron sucrose (ISC) or isotonic saline solution (control). Five i.v. doses of iron (40 mg iron/kg) or saline were administered over 4 weeks. Systolic blood pressure was significantly reduced in the LMW dextran group, whereas serum iron and percentage transferrin saturation were significantly elevated in all treatment groups. Creatinine clearance was reduced and urinary protein excretion increased in the FG group only (P < 0.01). Liver enzyme levels in the blood were increased (P < 0.01) in the FG and two dextran groups compared with the FCM and ISC groups. Analysis of liver, heart and kidney homogenates showed a significant increase in catalase and malondialdehyde levels in the FG group, and an increase in CuZn-superoxide dismutase and glutathione (GSH) peroxidase activity accompanied with a decrease in the reduced-to-oxidized GSH ratio in the FG and two dextran groups (P < 0.01). Tumour necrosis factor alpha and interleukin-6 levels were significantly elevated in liver, heart and kidney samples from the FG and two dextran groups but not the FCM, ISC or control groups. These findings indicate that FG and HMW/LMW iron dextran have less favourable safety profiles than FCM and ISC in normal rats.

Intravenous iron dextran for severe refractory restless legs syndrome

Reduced brain iron is strongly associated with restless legs syndrome (RLS). Oral iron supplements are commonly recommended for RLS but are largely ineffective due to poor absorption and poor tolerability at required doses. Intravenous iron dextran has been shown to increase brain iron content. Surprisingly only a few reports have ever presented data on the clinical effect of high dose intravenous iron for RLS. We retrospectively identified 25 subjects (age 53.2 ± 11.9, 7 male) that received intravenous iron for RLS refractory to conventional treatments. We infused 1 g of high molecular weight iron dextran over five hours. The age of RLS onset was 32.6 ± 13.0 years and 15 subjects had a positive family history of RLS. Patients attempted 7.5 ± 2.7 medications for RLS prior to iron therapy. Baseline ferritins ranged from 5 to 248 ng/ml (mean 43.5 ± 58.0) and 20/25 had ferritins of less than 50. Two subjects did not complete their entire infusion due to anaphylactic type symptoms but are included. Overall, 2 subjects reported complete amelioration of all RLS symptoms, 11 reported marked improvement, 2 moderate improvement, 3 mild improvement, and 6 reported no improvement. For those with improvement, the duration of effect was highly variable (mean 15.8 ± 17.7 weeks, range 1–60 weeks). Twelve subjects had multiple infusions. Iron dextran can dramatically improve refractory RLS but results are inconsistent and not predicted by patient demographics. Although burdened by a higher rate of anaphylactic reactions, iron dextran may be superior to other IV iron preparations.

Is There a Difference in the Preclinical Safety Parameters of Different Intravenous Iron Compounds?.

Abstract 5097 BackgroundIntravenous (i.v.) iron has been effectively used to manage anemia in hemodialysis, chemotherapy-induced anemia and cardiac failure patients. However, i.v. iron preparations may cause different degree of oxidative stress and tissue inflammation. In the current study the effects of five i.v. iron preparations on haemodynamic, oxidative stress and inflammatory response were examined. MethodsSixty rats (n=10/group) received high molecular weight (HMW) iron dextran (Dexferrum®, American Regent, Inc., USA), low molecular weight (LMW) iron dextran (INFeD®, Watson Pharmaceuticals, USA/CosmoFer®, Vitaline Pharma, UK), ferric gluconate (Ferrlecit®, Watson Pharmaceuticals, USA), ferric carboxymaltose (Ferinject®, Vifor Pharma, Switzerland), iron sucrose (Venofer®, Vifor Pharma, Switzerland) or isotonic saline solution (control) in a blinded controlled study. Five i.v. doses of iron (40 mg iron/kg) or saline were administered over 4 weeks. ResultsSystolic blood pressure was significantly reduced in the LMW dextran group, whereas serum iron and percentage transferrin saturation were significantly elevated in all treatment groups. Creatinine clearance was reduced and proteinuria increased in the ferric gluconate group only (p<0.01) (day 1 to 29). Liver enzyme levels in the blood were significantly increased in the ferric gluconate and two dextran groups on days 1, 8 and 29 compared with the ferric carboxymaltose and iron sucrose groups. Analysis of liver, heart and kidney homogenates on day 29 showed a significant increase in catalase and malondialdehyde levels in the ferric gluconate group, and an increase in CuZn-superoxide dismutase and glutathione peroxidase activity accompanied with a decrease in the reduced-to-oxidized glutathione ratio in the ferric gluconate and two dextran groups (p<0.01). TNF-α and IL6 levels were significantly elevated in liver, heart and kidney samples from the ferric gluconate and two dextran groups but not the ferric carboxymaltose, iron sucrose or control groups on day 29. DiscussionIn this study, there was a difference in the hemodynamic and functional response to the different i.v. iron preparations. These findings indicate that HMW/LMW iron dextran and ferric gluconate have less favourable safety profiles in rats than ferric carboxymaltose and iron sucrose. DisclosuresToblli:Vifor Pharma: Research Funding.

Safety Issues With Intravenous Iron Products in the Management of Anemia in Chronic Kidney Disease

Anemia is a very common clinical problem in patients with chronic kidney disease (CKD) and is associated with increased morbidity and mortality in these patients. Erythropoietin is a hormone synthesized that is deficient in the majority of patients with advanced kidney disease, thereby predisposing these patients to anemia. The other cause of anemia is deficiency of iron. Iron deficiency anemia is common in people with CKD and its importance in supporting erythropoiesis is unquestioned, especially in those patients treated with erythropoietin. Intravenous iron is frequently used to treat anemia in CKD patients and is very efficacious in increasing hemoglobin but at the same time there are some safety issues associated with it. The objective of this review is to assess the frequency of adverse drug events associated with four different iron formulations: two iron dextran products known as high and low molecular weight iron dextran, iron sucrose, and sodium ferric gluconate complex. Several electronic databases were searched. In general, with the exception of high molecular weight iron dextran, serious or life-threatening adverse events appeared rare. Iron sucrose has the least reported adverse events and high molecular weight iron dextran has the highest number of reported adverse events. Low molecular weight iron dextran and ferric gluconate fall in between these two for number of adverse drug events.

Iron Deficiency Anemia: Safety and Cost-Effectiveness of Treatment with Various Intravenous Iron Preparations

Introduction: Iron deficiency anemia is one of the most commonly encountered hematologic medical conditions in general practice. Oral replacement of iron can be a slow and suboptimal process, limited by low absorption rates and disease-enhanced malabsorption. When clinicians are faced with patients with large iron deficits, intravenous (IV) iron is the best option. Currently there are four IV preparations available; iron sucrose, iron gluconate, low-molecular weight iron dextran and high-molecular weight iron dextran. Upon informal questioning, we found reluctancy by many physicians to use iron dextran due to fear of allergic reactions. We examine these four preparations for clinical utility, adverse drug events (ADEs), and cost-effectiveness.Methods: We performed a systematic review and retrospective meta-analysis of studies investigating various forms of intravenous iron preparations for toxicity, ADEs, and costs. Also, we obtained actual costs of infusing intravenous iron at four hospitals in metro Louisville, KY.Results: Fourteen studies met the criteria and were reviewed. One study compared all four iron preparations, two compared three preparations and the rest compared two. Eight had a small sample size. The number of ADEs were quite small. Data from FDAderived ADE reporting of the four IV iron preparations from 2001–2003 showed a total of 1141 per 30,063,800 doses administered, yielding an ADE rate of approximately 38 per million. Absolute rate of all ADEs for iron sucrose, iron gluconate, low molecular weight iron dextran and high molecular weight iron dextran were 19.2, 18.5, 36.9, and 117.8 per million, respectively. Absolute rates of life-threatening ADEs were significantly lower at 0.6, 0.9, 3.3, and 11.3 per million respectively for iron sucrose, iron gluconate, low molecular weight iron dextran, and high molecular weight iron dextran. Based on cost differences between iron sucrose and dextran preparations, the cost to prevent one lifethreatening ADE related to the use of lower molecular weigh iron dextran was estimated to be $5.0–7.8 million. Also the cost to prevent one low-molecular weight iron dextran related death was estimated to be $33 million. These calculations are based on cost of preparations only. Estimates based on hospital-related costs incurred due to multiple infusions vs total dose infusion (TDI) puts the estimate of cost to prevent one lower molecular weight related death over $150 million.Conclusions: The perceived rate of ADEs related to infusion of IV iron preparations in medical practice has been overstated. Smaller studies with lower patient and total infusion numbers, and anecdotal evidence, tended to overestimate the frequency of life-threatening reactions. The incidence of ADEs and serious life-threatening ADEs, is exceedingly low for all IV iron preparations. In light of costs associated with the use of iron sucrose and iron gluconate vs iron dextran, we recommend that all clinicians re-assess the clinical utility of low molecular weight iron dextran for iron deficiency anemia necessitating parenteral iron replacement. Moreover, large doses of iron dextran can be safely given, thereby reducing costs associated with multiple small infusions of iron sucrose.

Retrospective Review of Total-Dose Iron Dextran in Iron-Deficiency Anemia of Chronic Disease and Relevance to Blood Transfusion Requirements: An Individual Institution Experience

Background: Erythrocyte stimulating agents, iron replacement, and blood transfusions are options in the treatment of chronic anemia. Patients with iron deficiency anemia who cannot tolerate or unable to absorb oral iron may receive intravenous iron. Recent studies have been conducted proving the effectiveness of total-dose low molecular weight iron dextran for the treatment of chronic anemia. Low molecular weight iron dextran (Infed) is FDA approved for to treat iron-deficient anemia and is generally safe and effective. Low molecular weight iron dextran was chosen for this review due to decrease in reported adverse reactions in the literature as compared to high molecular weight iron dextran. Iron dextran may be administered as total dose infusion in one dose, whereas other forms of IV iron require multiple doses for iron replacement. Blood conservancy programs are evaluating ways to reduce blood transfusion requirements due to limitations of available blood supply, transfusion reactions, fluid restrictions and iron overload. We report a retrospective review of the St Joseph/Candler Health System (SJCHS) experience with total dose iron dextran (Infed).Methods: September 2006 to September 2007, 181 adult patients with anemia of chronic disease that were treated with iron dextran (Infed) were identified. Inclusion criteria were patients with anemia of chronic disease, to include hematological and non-hematological malignancies, iron dextran infusion greater than 200mg and anemia defined as hemoglobin level ≤10.5g/dl. A total of 54 patients met the inclusion criteria. There were 27 patients in the study group, which was identified as patients who received total-dose iron dextran (Infed), 27 patients in the control group, which was identified as patients who received a transfusion and no IV iron. Patients that received epoetin were excluded from the review. Age, gender, height, weight, diagnosis, tests of iron status (serum ferritin concentration, transferrin concentration/TIBC, serum iron, and transferrin saturation), CBC, vitamin B12 level, temperature, blood pressure, dose of iron dextran, number of transfusions, and signs or reports of adverse reactions was recorded. All uses of premedication and medications to treat adverse reactions were recorded.Results: In the iron group 85.2%(23/27) did not require blood transfusion. In the transfusion group 70.4%(19/27) required only one transfusion and reached an adequate hemoglobin response. The p-value was 0.19. The average dose of iron dextran(Infed) was 1000mg. The average number of transfusion at treatment failure was 2.25 in the Infed group and 2 in the transfusion alone group. Average hemoglobin prior to iron infusion was 8.8 and prior to initial transfusion was 7.54. Infed patients that were transfused has an average hemoglobin of 8.1 prior to transfusion and 2nd transfusion patients (transfusion alone arm) had a hemoglobin of 8.29 when transfused a second time. No patients in either group had reports of adverse reactions. However, in the screening phase of the study 9 out of 181 patients (4.9%) had a documented adverse reaction to the iron test dose. All of these patients may have received Dexferrum, not Infed, and were excluded from the review. In the iron group 44.4% of patients had a hemoglobin(HgB) response greater than or equal to 10gm/dL. In the transfusion group 48.1% of patients had a hemoglobin response of greater than or equal to 10gm/dL. The p-value was 0.78.Conclusion: Total-dose iron dextran was equally effective at reducing the incidence of transfusion compared to the transfusion control group. Both groups were equally effective at achieving a hemoglobin of greater that or equal to 10 gm/dL. This review should result in increased use of total-dose iron dextran in patients with chronic anemia without iron overload, decreased the number of transfusions by using total-dose iron dextran when appropriate, and increased awareness of intravenous iron replacement therapy.

Intravenous Iron in Oncology

Intravenous iron (IV Fe) as an adjunct to therapy with erythropoiesis- stimulatory agents (ESAs) is standard care in dialysis-associated anemia, adding huge increments in hemoglobin and hematopoietic responses and decreased transfusions without significant toxicity. Cost savings, decreased exposure to ESAs, and decreased times to reach target hemoglobins are realized. Although similar benefits have been seen in all studies performed in patients with chemotherapy-induced anemia (CIA), experts are reluctant to incorporate routine use of IV Fe into treatment, largely because of misinterpretation and misunderstanding of the clinical nature of adverse events reportedly associated with its administration. IV Fe is therefore underused in oncology patients with anemia. Published experience with more than 1000 patients in clinical trials involving the use of IV Fe suggests minimal toxicity and substantial benefit are experienced when high molecular weight iron dextran is avoided. This article presents evidence recommending routine incorporation of IV Fe into treatment for CIA.