Challenges in Parenteral Iron Supplementation

Transcription

1 57883-FE:195 FE Report 12/6/7 15:33 Side 1 CosmoFer abbreviated prescribing information When comparing and contrasting the profiles of parenteral iron formulations they are frequently categorised as iron sucrose, sodium ferric gluconate and iron dextran. This is confusing and misleading. Iron dextran is available as high molecular weight and low molecular weight formulations. Low molecular weight iron dextran is associated with fewer, and less severe adverse events and should be categorised separately in evidence based comparisons with iron sucrose and sodium ferric gluconate. period. The higher molecular weight iron dextran was significantly higher ADE rate than the lower molecular weight formulation (INFeD/CosmoFer). Patients in this study were closely monitored at the bedside (i.e. not relying on voluntary submissions to the FDA). There was a threefold greater incidence of ADEs in the high, compared to the low, molecular weight iron dextran group. McCarthy et al (AM J Nephrol 2;2: ) Short-term safety and the adverse events associated with parenteral iron 5.% 4.% 3.% Why administer parenteral iron in iron deficiency anaemia associated Renal physicians administer parenteral iron as an integral component of managing iron deficiency anaemia associated with chronic kidney disease. The role of parenteral iron is to augment erythropoiesis and to correct erythropoietic hyporesponsiveness. These roles, and the impact that parenteral iron may have in increasing the efficiency of administering erythropoietin, which may result in dose reductions and cost savings, are evidence based. Patient benefits, of parenteral iron administration, are gained indirectly through the impact on erythropoiesis resulting in improved haemoglobin levels and improved haematocrit which affect well-being and quality of life. 1.% Prof Glenn M. Chertow, MD, MPH University of California San Francisco Division of Nephrology, San Francisco, California carry a risk of adverse events. There are risks associated with the administration of parenteral iron and it is the natural tendency for clinicians to seek to reduce these risks for their patients. The comparative adverse event profile of available formulations may be the deciding factor. In this regard, decisions should be based on current evidence, not folklore. This is particularly relevant when evaluating iron dextran. SIZE MATTERS! Iron dextran is available as high molecular weight and low molecular weight formulations. Iron dextran formulations should not be considered as a single class with a single profile. Examination of the evidence base reveals that the low molecular weight form produces substantially less adverse events (ADEs), and less severe ADEs than the high molecular weight forms..% A choice is made regarding the selection of the type of iron to be administered, as all medications Where is the evidence? McCarthy et al. described iron dextran-related ADEs during 665 courses of parenteral iron dextran given to 254 patients over a 5-year McCarthy et al. described iron dextran-related ADEs during 665 courses of parenteral FE dextran given to 254 patients over a 5-year period. The higher molecular weight iron dextran was significantly higher ADE rate than with the low molecular weight formulation. Courses with an ADE In a study conducted over a six month period, patients being treated at FMCNA (Fresenius Medical Care North America) affiliated dialysis units were closely monitored. Healthcare professionals were vigilant at the bedside to record ADEs when administering parenteral iron to dialysis patients. Fletes et al. (AJKD 21) evaluated 165 cases of iron dextran-related ADEs from the administration of 841,252 doses of intravenous iron dextran. The higher molecular weight iron dextran was significantly higher ADE rate than the lower molecular weight formulation. Two thirds of the events occurred in patients receiving Dexferrum, albeit it was used in a smaller number of patients. The incidence of observed ADEs was a multiple of eight times higher than in those patients who received INFeD/CosmoFer. Fletes et al AJKD 21;37(4): The choice of parenteral iron formulation includes risk analysis. Nephrology Dialysis Transportation 24;19(6): % 2.% The evidence that molecular size plays a major role in determining the clinical properties of iron dextran formulations is overwhelming and consistent. reports from ,. reported weight iron dextran was 5.5-fold increase in odds of ADEs and a 3.6-fold increase in odds of death (NDT, 24). Whilst the data is voluntarily supplied to the FDA, the scale of the number of patients receiving the various types of iron dextran and the volume of administrations (estimated at 21 million during the observation period), provides further formidable evidence in support of the strong safety profile of low molecular weight iron dextran Rate per 1million administrations Fletes et al. evaluated 165 cases of Fe dextranrelated ADEs (from 841,252 intravenous iron dextran doses) at FMCNA-affiliated dialysis units during a six month study period (case cohort design). The higher molecular weight Fe dextran was associated with a significantly higher ADE rate than with the low molecular weight formulation reports from ,. reported 5.5-fold increase in odds of ADE and a 3.6-fold increase in odds of death. A similar review of the FDA Medwatch data over the sequential period (.) found weight iron dextran was 3.2-fold increase in odds of ADEs and a 3.4-fold increase in odds of life-threatening ADEs. Submitted for publication reports from 21-23,. reported 3.2-fold increase in odds of ADE and a 3.4-fold increase in odds of life threatening ADEs. So has the historical problem of comparing oranges with apples been resolved? Evidently not! Whilst the evidence clearly indicates that low molecular weight iron dextran has a better ADE profile than the high molecular weight iron dextran there is an on-going dilemma wherein misleading studies are published and continue to compare iron dextran to other parenteral iron supplements, without discriminating between the forms of iron dextran. This can be illustrated by reference to a study recently published by Bailie et al. Using the Freedom of Information Act FDA data from , ADEs following IV iron administration are analysed. They report a higher rate of hypersensitivity ADEs with iron dextran, compared with iron gluconate and iron sucrose. No distinction is made between high molecular weight and low molecular weight iron dextran (NDT, 25). When considering the clinical merits of available iron formulations there is a need to distinguish between the molecular weights of the various dextran formulations, ensuring that the low molecular weight iron dextran product profile is not attributed the properties of high molecular weight products. SIZE MATTERS. Before prescribing CosmoFer (low Mw iron dextran) please refer to full local approved data sheet. Presentation: Solution for infusion and injection in the form of 2 ml ampoules containing mg iron(iii) as Iron(III)-hydroxide dextran complex. Each ml contains 5 mg Iron(III). Indications: CosmoFer is indicated for parenteral treatment of iron deficiency in cases where oral iron preparations cannot be used, e.g. due to intolerance, or in case of demonstrated lack of effect of oral iron therapy or where there is a clinical need to deliver iron rapidly to iron stores. CosmoFer is indicated for patients above 14 years of age. Dosage: The normal recommended dosage schedule is -2 mg iron corresponding to 2-4 ml, two or three times a week depending on the haemoglobin level. If clinical circumstances require rapid delivery of iron to the body iron stores, CosmoFer may be administered as a total dose infusion up to a total replacement dose corresponding to 2mg iron/kg body weight. Administration: CosmoFer solution for injection can be administered by an intravenous drip infusion or by a slow intravenous injection. Intravenous drip infusion is the preferred route of administration, as this may help to reduce the risk of hypotensive episodes. CosmoFer may also be administered as undiluted solution intramuscularly. Test dose: Before administering the first dose to a new patient, a test dose of CosmoFer corresponding to 25 mg iron or equal to.5 ml solution must be administered for all routes of administration. If no adverse reactions are seen after minutes, the remaining dose can be given. Intravenous drip infusion: CosmoFer must be diluted only in.9% sodium chloride or in 5% glucose solution. CosmoFer in a dose of -2 mg iron (2-4ml) may be diluted in ml. On each occasion the first 25 mg of iron should be infused over a period of 15 minutes. If no adverse reactions occur during this time the remaining portion of the infusion should be given at an infusion rate not more than ml in 3 minutes. Intravenous injection: CosmoFer may be administered in a dose of 2 mg iron by slow intravenous injection (.2 ml/min) preferably diluted in 1 2 ml.9% sodium chloride or 5% glucose solution. On each occasion before administering a slow intravenous injection, 25 mg of iron should be injected slowly over a period of 1 to 2 minutes. If no adverse reactions occur within 15 minutes, the remaining portion of the injection may be given. Injection into dialyser: CosmoFer may be administered during a haemodialysis session directly into the venous limb of the dialyser under the same procedures as outlined for intravenous administration. Intramuscular injection: For intramuscular injection, the amount of CosmoFer required is determined either from the dosage table or by calculation; it is administered as a series of undiluted injections of up to mg iron (2. ml) each, determined by the patient s body weight. CosmoFer must be given by deep intramuscular injection to minimise the risk of subcutaneous staining, it is recommended to use the Z-track technique. Total dose infusion: For total dose infusion the amount of CosmoFer required is determined either from the dosage table or by calculation, it is added to the required volume (usually 5 ml) of.9% sodium chloride or 5% glucose solution and infused intravenously over 4-6 hours. On each occasion the first 25 mg of iron should be infused over a period of 15 minutes. If no adverse reactions occur during this time, then the remaining portion of the infusion should be given. The rate of infusion may be increased progressively to 45 drops per minute. Contraindications: Non-iron deficiency anaemia, iron overload or disturbances in utilisation of iron, patients with a history of asthma, allergic eczema or other atopic allergy, drug hypersensitivity, decompensated liver cirrhosis and hepatitis, acute or chronic infection, rheumatoid arthritis with symptoms or signs of active inflammation, acute renal failure. Pregnancy and lactation: CosmoFer should not be used during the first trimester, but can be used during second and third trimester if treatment is clearly necessary. It is unknown whether the complex iron-dextran is excreted in human or animal breast milk. It is preferable to not use CosmoFer during breast feeding. Warnings/Precautions: The use of CosmoFer as with the parenteral use of other iron-carbohydrate complexes carries a risk of immediate severe and potentially lethal anaphylactoid reactions. Patients should be closely observed during and immediately after administration. The risk is enhanced for patients with known (medical) allergy. CosmoFer may only be administered when facilities and equipment for handling acute anaphylactic reactions are available, including an injectable 1: adrenaline solution. Additional treatment with antihistamine and/or corticosteroids should be given as appropriate. There is particularly increased risk of allergic reactions in patients with immune or inflammatory conditions. Hypotensive episodes may occur if intravenous injection is administered too rapidly. Drug interactions: CosmoFer should not be administered concomitantly with oral iron preparations, as the absorption of oral iron will be reduced. Oral iron therapy should not be started earlier than 5 days after the last injection of CosmoFer. The drug may cause falsely elevated values of serum bilirubin and falsely decreased values of serum calcium. Incompatibilities: CosmoFer must only be mixed with.9% sodium chloride or 5% glucose solution. No other intravenous dilution solutions or therapeutic agents should be used. Side effects: Anaphylactoid reactions are uncommon and include urticaria, rashes, itching, nausea and shivering. Administration must be stopped immediately when signs of an anaphylactoid reaction are observed. Acute, severe anaphylactoid reactions are very rare. They usually occur within the first few minutes of administration and are generally characterised by the sudden onset of respiratory difficulty and / or cardiovascular collapse. Delayed reactions are well described and may be severe and are characterised by arthralgia, myalgia and sometimes fever. Symptoms usually last two to four days and settle spontaneously or following the use of simple analgesics. Other adverse reactions are: Uncommon (>1/1,, <1/): nausea, emesis, abdominal pain, feeling hot, cramps, blurred vision, numbness, dyspnea, flushing, pruritus and rash. Rare (>1/1,, <1/1,): arrhythmia, tachychardia, diarrhoea, fatigue, myalgia, loss of consciousness, seizure, dizziness, restlessness, tremor, chest pain, mental status changes, angioedema, sweating, hypotension. Very rare (<1/1,): haemolysis, foetal bradycardia, palpitations, transient deafness, headache, paresthesia, hypertension. Exacerbation of joint pain in rheumatoid arthritis can occur. Local reactions reported are soreness and inflammation at or near injection site and local phlebitic reaction. After intramuscular injection local complications such as staining of the skin, bleeding, formation of sterile abscesses, tissue necrosis or atrophy and pain are observed. Legal Category: POM. Pharmaceutical Precautions: CosmoFer is for single use only and any unused solution should be discarded. The reconstituted solution for injection is to be visually inspected prior to use. Only clear solutions without particles should be used. Package Quantities 5 ampoules per pack. Date of preparation: June 27. Pharmacosmos A/S, Roervangsvej 3, DK-43 Holbaek, Denmark. THE WORLD CONGRESS OF NEPHROLOGY SINGAPORE 26TH 3TH JUNE 25 Official Lunch-time Symposium Held on 28th June Sponsored by Nebo a/s Challenges in Parenteral Iron Supplementation Iron store repletion may be achieved effectively with a single infusion of low molecular weight iron dextran. Do administration benefits compromise clinical outcomes? Low molecular weight iron dextran well tolerated and safe for administration as a total dose infusion Parenteral iron is increasingly administered to patients with iron deficiency anaemia variety of conditions, either alone, to replete iron stores, or to compliment the administration of erythropoiesis stimulating agents. To achieve target iron levels, it may be necessary to administer large doses of parenteral iron. There are constraints that restrict the amount of elemental iron that can be delivered in the form of iron gluconate or iron sucrose at a single administration. The dosage ceiling for administering low molecular weight iron dextran is considerably higher, providing the clinician with the opportunity to administer a total dose infusion, thereby being able to administer the total supplementation requirement for the majority of patients with a single infusion. Michael Auerbach, MD, FACP Private Practice, Baltimore, Maryland Clinical Professor of Medicine Georgetown University School of Medicine Washington, DC CONTINUED ON PAGE 2 Competitive Partnerships, UK

2 CONTINUED FROM PAGE 1 Frequently, blood is used to correct iron deficiency anaemia in patients presenting with chronic anaemia. What are the downsides of this practice? Is there a role for IV iron? The use of IV iron has to be considered in the context of the problems associated with blood transfusions. Whilst alloimmunisation and organism transmission are well acknowledged as risks associated with blood transfusion, the situation has been compounded with the occurrence of transfusion induced acute lung injury (TRALI) which, whilst rare, is severe and can potentially cause a fatal injury. Furthermore, there is a lack of recognition that iron in transfused blood is unavailable for chronically ill patients (the iron cannot be accessed), that iron overload is frequently observed and that the more frequently that blood is transfused the shorter the benefit lasts. A study by Hamstra, and published in JAMA (198), demonstrated the efficacy of IV iron dextran in alleviating anaemia, but reported short-term side effects, including arthralgia/myalgia. Whilst the incidence of ADRs associated with iron dextran administration were small in 1988 Dr Auerbach undertook a prospective study seeking to establish if pre-medication with aspirin, diphenhydramine or steroids could reduce side-effects. He also examined the effect of different rates of infusion. Like the Hamstra study, the administration of IV iron was concluded as being effective and safe. Only the administration of steroids (methylprednisolone) showed any difference in reducing the incidence of ADRs. It was also found that the rate of infusion made no difference. This paved the way for administering IV iron dextran at a faster rate and thereby administering high doses of IV iron as a total dose infusion. The use of methylprednisolone was subsequently examined in more detail in a further study. Methylprednisolone was given both before, and after iron administered as a total dose infusion, to examine if the incidence of arthralgia/myalgia could be reduced. The results confirmed that this ADR could be significantly reduced with the use of such a regimen. The availability of erythropoietin has had a dramatic impact on the treatment of iron deficiency anaemia in renal disease. Is administration of iron supplementation as TDI, in conjunction with erythropoietin in patients with chronic kidney disease, as effective as a bolus or frequent infusion regimen? To address this question a study was undertaken in patients receiving erythropoietin and who were undergoing dialysis. Iron administration was administered as three different regimens: Bolus of mg at each dialysis session 5mg infusion until required amount of iron was administered Total dose infusion The clinical outcomes, measured by peak haematocrit and time to peak haematocrit, were similar in the three cohorts of patients (no significant difference). This study demonstrated that low molecular weight iron dextran administered as a TDI achieves similar outcomes to administering the iron as a bolus or multiple infusion in anaemic patients with chronic kidney disease, when receiving erythropietic stimulating agents and dialysis treatment (Auerbach et al, American J Kidney Disease 1998). Erythropoietin is now used to treat anaemia associated with cancer and cancer treatments. Can concomitant IV iron also be delivered as a total dose infusion? The results of a prospective, randomised multicentre study, in which patients with chemotherapy induced anaemia were being treated with sub-cutaneous erythropoietin were published in 24 (J Clin Oncol). Patients received either: no iron supplement, oral iron, or low molecular weight iron dextran as mg boluses or as a total dose infusion. The study end-point was to establish if intravenous iron acts in a similar way as when administered in renal patients. The conclusions from this study were that IV iron optimizes the response to EPO, in patients with anaemia related to cancer, and demonstrated significant improvements in hemoglobin levels, energy, activity and quality of life. Oral iron was only marginally effective, and mirrors experience in dialysis patients. Response was independent of baseline iron parameters. The results indicated that outcomes were similar for the bolus and total dose infusion delivery of IV iron. IV iron supplementation, administered by total dose infusion, is only possible using iron dextran formulations. Will this influence IV iron supplementation administration procedures? There is much debate associated with the use of iron dextran. The historical folklore is very much linked with high molecular weight iron dextran and the side effects associated with its administration. Having administered iron dextran on an estimated 1, occasions (many as TDI) Dr Auerbach has not experienced a single anaphylactic shock. CosmoFer/INFeD (low molecular weight iron dextran) has much fewer side effects. From clinical experience, and studies in which he has been involved, the administration of IV iron, by total dose infusion, results in a similar clinical outcome to when administered by IV infusion/bolus however there are substantial non-clinical benefits that can be realised. For patients there is a need for fewer clinic visits, which improves compliance, reduces travel costs, is time saving and less disruptive to a patient s normal lifestyle. This is of particular importance for patients who are on CAPD or in the low-clearance stage of renal disease or who are pregnant. For the clinician and health care providers, in addition to being time saving, there are also cost savings dministration eg giving sets, pharmacy costs and from the more efficient use of EPO.

3 ADRs associated with IV iron administration traditionally have focused on acute reactions. There is growing interest in the longer-term implications of IV iron. Long-term safety aspect: Parenteral iron-induced tissue injury not all formulations are alike Nothing comes for free all have (IV iron formulations) a side effect. Historically the debate regarding the safety of IV iron has been around the incidence and severity of acute reactions. In the context of administration of iron dextran, the major concern surrounds anaphylaxis. In contrast, oxidative stress and tissue injury may occur with non-dextran iron formulations. Clinical differentiation that influences the balance between risk and benefit will require long-term studies. Dr Rajiv Agarwal, Associate Professor of Medicine, Indiana University School of Medicine and VA Medical Center, Indianapolis, Indiana Free iron can upset the equilibrium of the oxidative stress process. In the oxidative stress process, oxygen derived free radicals, influence endothelial function and fight infection. A neutralising action is undertaken by catalase, glutathione peroxidase and superoxide dismutase. The introduction of iron can change this balance by provoking the formation of the most toxic radical hydroxyl radical. Free iron is known to provoke lipid peroxidation, cellular injury and enhanced bacterial growth. It is therefore important to consider the capacity for commercially available parenteral iron formulations to contribute to creating a pool of free iron. The pharmokinetic profiles of the different parenteral irons affect dosage posology. How might this impact oxidative stress levels? Apotransferrin, can exist in three states, reflecting the binding of iron either zero, one or two molecules (unsaturated, monoferric or diferric). By measuring the degree of saturation the binding properties of the various iron formulations can be determined. It was established (Agarwal 24) that when iron sucrose and iron gluconate are administered, iron gluconate is quickly bound to form mono or diferric transferrin, the speed of uptake from iron sucrose is slower. However, the uptake of iron from iron dextran is much slower than from iron sucrose. After 24 hours, the apotransferrin remains substantially unsaturated when exposed to iron dextran. These properties are reflected in the administration directions for the various forms of parenteral iron. This relative speed of uptake can also be demonstrated using different (higher) concentrations of the three IV iron formulations and by titration. In summary, non-dextran IV iron is directly transferred to transferrin in a dose dependent and time dependent

4 manner whilst iron dextrans differ significantly in their ability to donate free iron. Are there clinical or pathological implications of oxidative stress? In-vitro investigation by Zager to determine the impact of iron formulations on cytotoxicity, established that iron sucrose, iron gluconate and iron dextran all cause similar degrees of lipid peroxidation but result in marked differences in cell death. Proximal tubule cells and cultured aortic endothelial cells die more rapidly when exposed to iron sucrose, and less rapidly when exposed to iron gluconate. Iron dextran appears to exhibit little cytotoxicity. In humans receiving iron sucrose and undergoing dialysis, lipid peroxidation, measured by malondialdehyde (MDA), was found to rise rapidly and then to return to baseline by the end of dialysis. When administered in conjunction with vitamin E there is a reduction in the peak and the area under the curve is reduced. A weak, but significant, relationship between bleomycin detectable (free) iron and lipid peroxidation exists (Roob 2). In healthy males (Rooyakkers 22) it was found that iron sucrose increased the non-transferrin bound free iron over twofold at 1 minutes, and greater than four-fold at 4 hours, post injection. At 1 minutes and 4 hours post injection, levels of superoxide were significantly increased. It was found that ferrous sucrose significantly reduced FMD (flow mediated dilation), an endothelium (nitric oxide) dependent process at 1 minutes, but not NTG (response to sublingual nitroglycerine) induced dilation (endothelium independent). If free iron was causing the endothelial dysfunction it may be expected to be observed at 4 hours and not 1 minutes but the reverse was found. Free radical activity tracked the levels of non-transferrin bound iron but it appears that the functional consequence was not caused by free iron but some other factor. Are there implications for patients Agarwal et al (24) administered mg of iron sucrose to humans who were undergoing haemodialysis in a study designed to investigate whether iron sucrose increases oxidative stress in patients with chronic kidney disease and to determine if oxidative stress is associated with renal injury. The results showed that peak transferrin saturation occurred at 18 minutes post iron sucrose injection. The concomitant administration of N-acetylcysteine delayed the time to achieve peak saturation. It was therefore reasonable to expect that if free iron was the factor that caused tubular injury that this would be on a similar time scale of 18 minutes. However, the results demonstrated high MDA (malondialdehyde) levels at 15-3 minutes with parallel elevations of urinary MDA, urinary enzymes and proteinuria. Oxidative stress was reduced by N-acetylcysteine but did not prevent cell injury. Thus whilst the TSAT peaked at the three hour interval all other markers peaked between 15 and 3 minutes, again suggesting that a factor, other than free iron, is responsible for the injury perhaps a result of direct action. Evidence from Leehey, wherein 8 patients were administered sodium ferric gluconate in a four way cross over study, showed that whilst more transferrin was saturated using a double dose of ferrous gluconate, the plasma MDA was elevated irrespective of the dose of ferrous gluconate. Urinary MDA had a similar elevation. However, in the presence of an increase in transferrin saturation and oxidative stress no proteinuria was detected. Albuminuria was not increased and there was no change in the albumin/creatinine ratio. It was concluded that iron gluconate generates oxidative stress but not proteinuria or enzymuria which are markers of tissue injury. This study, when considered in the context of Agarwal 24, suggests that both iron sucrose and iron gluconate administration result in oxidative stress but that tissue injury is caused only by iron sucrose, indicating that there may be two independent pathways. These pathways have not yet been defined. A comparative study is needed to examine the long term implications and to clarify the situation.

5 57883-FE:195 FE Report 12/6/7 15:33 Side 1 CosmoFer abbreviated prescribing information When comparing and contrasting the profiles of parenteral iron formulations they are frequently categorised as iron sucrose, sodium ferric gluconate and iron dextran. This is confusing and misleading. Iron dextran is available as high molecular weight and low molecular weight formulations. Low molecular weight iron dextran is associated with fewer, and less severe adverse events and should be categorised separately in evidence based comparisons with iron sucrose and sodium ferric gluconate. period. The higher molecular weight iron dextran was significantly higher ADE rate than the lower molecular weight formulation (INFeD/CosmoFer). Patients in this study were closely monitored at the bedside (i.e. not relying on voluntary submissions to the FDA). There was a threefold greater incidence of ADEs in the high, compared to the low, molecular weight iron dextran group. McCarthy et al (AM J Nephrol 2;2: ) Short-term safety and the adverse events associated with parenteral iron 5.% 4.% 3.% Why administer parenteral iron in iron deficiency anaemia associated Renal physicians administer parenteral iron as an integral component of managing iron deficiency anaemia associated with chronic kidney disease. The role of parenteral iron is to augment erythropoiesis and to correct erythropoietic hyporesponsiveness. These roles, and the impact that parenteral iron may have in increasing the efficiency of administering erythropoietin, which may result in dose reductions and cost savings, are evidence based. Patient benefits, of parenteral iron administration, are gained indirectly through the impact on erythropoiesis resulting in improved haemoglobin levels and improved haematocrit which affect well-being and quality of life. 1.% Prof Glenn M. Chertow, MD, MPH University of California San Francisco Division of Nephrology, San Francisco, California carry a risk of adverse events. There are risks associated with the administration of parenteral iron and it is the natural tendency for clinicians to seek to reduce these risks for their patients. The comparative adverse event profile of available formulations may be the deciding factor. In this regard, decisions should be based on current evidence, not folklore. This is particularly relevant when evaluating iron dextran. SIZE MATTERS! Iron dextran is available as high molecular weight and low molecular weight formulations. Iron dextran formulations should not be considered as a single class with a single profile. Examination of the evidence base reveals that the low molecular weight form produces substantially less adverse events (ADEs), and less severe ADEs than the high molecular weight forms..% A choice is made regarding the selection of the type of iron to be administered, as all medications Where is the evidence? McCarthy et al. described iron dextran-related ADEs during 665 courses of parenteral iron dextran given to 254 patients over a 5-year McCarthy et al. described iron dextran-related ADEs during 665 courses of parenteral FE dextran given to 254 patients over a 5-year period. The higher molecular weight iron dextran was significantly higher ADE rate than with the low molecular weight formulation. Courses with an ADE In a study conducted over a six month period, patients being treated at FMCNA (Fresenius Medical Care North America) affiliated dialysis units were closely monitored. Healthcare professionals were vigilant at the bedside to record ADEs when administering parenteral iron to dialysis patients. Fletes et al. (AJKD 21) evaluated 165 cases of iron dextran-related ADEs from the administration of 841,252 doses of intravenous iron dextran. The higher molecular weight iron dextran was significantly higher ADE rate than the lower molecular weight formulation. Two thirds of the events occurred in patients receiving Dexferrum, albeit it was used in a smaller number of patients. The incidence of observed ADEs was a multiple of eight times higher than in those patients who received INFeD/CosmoFer. Fletes et al AJKD 21;37(4): The choice of parenteral iron formulation includes risk analysis. Nephrology Dialysis Transportation 24;19(6): % 2.% The evidence that molecular size plays a major role in determining the clinical properties of iron dextran formulations is overwhelming and consistent. reports from ,. reported weight iron dextran was 5.5-fold increase in odds of ADEs and a 3.6-fold increase in odds of death (NDT, 24). Whilst the data is voluntarily supplied to the FDA, the scale of the number of patients receiving the various types of iron dextran and the volume of administrations (estimated at 21 million during the observation period), provides further formidable evidence in support of the strong safety profile of low molecular weight iron dextran Rate per 1million administrations Fletes et al. evaluated 165 cases of Fe dextranrelated ADEs (from 841,252 intravenous iron dextran doses) at FMCNA-affiliated dialysis units during a six month study period (case cohort design). The higher molecular weight Fe dextran was associated with a significantly higher ADE rate than with the low molecular weight formulation reports from ,. reported 5.5-fold increase in odds of ADE and a 3.6-fold increase in odds of death. A similar review of the FDA Medwatch data over the sequential period (.) found weight iron dextran was 3.2-fold increase in odds of ADEs and a 3.4-fold increase in odds of life-threatening ADEs. Submitted for publication reports from 21-23,. reported 3.2-fold increase in odds of ADE and a 3.4-fold increase in odds of life threatening ADEs. So has the historical problem of comparing oranges with apples been resolved? Evidently not! Whilst the evidence clearly indicates that low molecular weight iron dextran has a better ADE profile than the high molecular weight iron dextran there is an on-going dilemma wherein misleading studies are published and continue to compare iron dextran to other parenteral iron supplements, without discriminating between the forms of iron dextran. This can be illustrated by reference to a study recently published by Bailie et al. Using the Freedom of Information Act FDA data from , ADEs following IV iron administration are analysed. They report a higher rate of hypersensitivity ADEs with iron dextran, compared with iron gluconate and iron sucrose. No distinction is made between high molecular weight and low molecular weight iron dextran (NDT, 25). When considering the clinical merits of available iron formulations there is a need to distinguish between the molecular weights of the various dextran formulations, ensuring that the low molecular weight iron dextran product profile is not attributed the properties of high molecular weight products. SIZE MATTERS. Before prescribing CosmoFer (low Mw iron dextran) please refer to full local approved data sheet. Presentation: Solution for infusion and injection in the form of 2 ml ampoules containing mg iron(iii) as Iron(III)-hydroxide dextran complex. Each ml contains 5 mg Iron(III). Indications: CosmoFer is indicated for parenteral treatment of iron deficiency in cases where oral iron preparations cannot be used, e.g. due to intolerance, or in case of demonstrated lack of effect of oral iron therapy or where there is a clinical need to deliver iron rapidly to iron stores. CosmoFer is indicated for patients above 14 years of age. Dosage: The normal recommended dosage schedule is -2 mg iron corresponding to 2-4 ml, two or three times a week depending on the haemoglobin level. If clinical circumstances require rapid delivery of iron to the body iron stores, CosmoFer may be administered as a total dose infusion up to a total replacement dose corresponding to 2mg iron/kg body weight. Administration: CosmoFer solution for injection can be administered by an intravenous drip infusion or by a slow intravenous injection. Intravenous drip infusion is the preferred route of administration, as this may help to reduce the risk of hypotensive episodes. CosmoFer may also be administered as undiluted solution intramuscularly. Test dose: Before administering the first dose to a new patient, a test dose of CosmoFer corresponding to 25 mg iron or equal to.5 ml solution must be administered for all routes of administration. If no adverse reactions are seen after minutes, the remaining dose can be given. Intravenous drip infusion: CosmoFer must be diluted only in.9% sodium chloride or in 5% glucose solution. CosmoFer in a dose of -2 mg iron (2-4ml) may be diluted in ml. On each occasion the first 25 mg of iron should be infused over a period of 15 minutes. If no adverse reactions occur during this time the remaining portion of the infusion should be given at an infusion rate not more than ml in 3 minutes. Intravenous injection: CosmoFer may be administered in a dose of 2 mg iron by slow intravenous injection (.2 ml/min) preferably diluted in 1 2 ml.9% sodium chloride or 5% glucose solution. On each occasion before administering a slow intravenous injection, 25 mg of iron should be injected slowly over a period of 1 to 2 minutes. If no adverse reactions occur within 15 minutes, the remaining portion of the injection may be given. Injection into dialyser: CosmoFer may be administered during a haemodialysis session directly into the venous limb of the dialyser under the same procedures as outlined for intravenous administration. Intramuscular injection: For intramuscular injection, the amount of CosmoFer required is determined either from the dosage table or by calculation; it is administered as a series of undiluted injections of up to mg iron (2. ml) each, determined by the patient s body weight. CosmoFer must be given by deep intramuscular injection to minimise the risk of subcutaneous staining, it is recommended to use the Z-track technique. Total dose infusion: For total dose infusion the amount of CosmoFer required is determined either from the dosage table or by calculation, it is added to the required volume (usually 5 ml) of.9% sodium chloride or 5% glucose solution and infused intravenously over 4-6 hours. On each occasion the first 25 mg of iron should be infused over a period of 15 minutes. If no adverse reactions occur during this time, then the remaining portion of the infusion should be given. The rate of infusion may be increased progressively to 45 drops per minute. Contraindications: Non-iron deficiency anaemia, iron overload or disturbances in utilisation of iron, patients with a history of asthma, allergic eczema or other atopic allergy, drug hypersensitivity, decompensated liver cirrhosis and hepatitis, acute or chronic infection, rheumatoid arthritis with symptoms or signs of active inflammation, acute renal failure. Pregnancy and lactation: CosmoFer should not be used during the first trimester, but can be used during second and third trimester if treatment is clearly necessary. It is unknown whether the complex iron-dextran is excreted in human or animal breast milk. It is preferable to not use CosmoFer during breast feeding. Warnings/Precautions: The use of CosmoFer as with the parenteral use of other iron-carbohydrate complexes carries a risk of immediate severe and potentially lethal anaphylactoid reactions. Patients should be closely observed during and immediately after administration. The risk is enhanced for patients with known (medical) allergy. CosmoFer may only be administered when facilities and equipment for handling acute anaphylactic reactions are available, including an injectable 1: adrenaline solution. Additional treatment with antihistamine and/or corticosteroids should be given as appropriate. There is particularly increased risk of allergic reactions in patients with immune or inflammatory conditions. Hypotensive episodes may occur if intravenous injection is administered too rapidly. Drug interactions: CosmoFer should not be administered concomitantly with oral iron preparations, as the absorption of oral iron will be reduced. Oral iron therapy should not be started earlier than 5 days after the last injection of CosmoFer. The drug may cause falsely elevated values of serum bilirubin and falsely decreased values of serum calcium. Incompatibilities: CosmoFer must only be mixed with.9% sodium chloride or 5% glucose solution. No other intravenous dilution solutions or therapeutic agents should be used. Side effects: Anaphylactoid reactions are uncommon and include urticaria, rashes, itching, nausea and shivering. Administration must be stopped immediately when signs of an anaphylactoid reaction are observed. Acute, severe anaphylactoid reactions are very rare. They usually occur within the first few minutes of administration and are generally characterised by the sudden onset of respiratory difficulty and / or cardiovascular collapse. Delayed reactions are well described and may be severe and are characterised by arthralgia, myalgia and sometimes fever. Symptoms usually last two to four days and settle spontaneously or following the use of simple analgesics. Other adverse reactions are: Uncommon (>1/1,, <1/): nausea, emesis, abdominal pain, feeling hot, cramps, blurred vision, numbness, dyspnea, flushing, pruritus and rash. Rare (>1/1,, <1/1,): arrhythmia, tachychardia, diarrhoea, fatigue, myalgia, loss of consciousness, seizure, dizziness, restlessness, tremor, chest pain, mental status changes, angioedema, sweating, hypotension. Very rare (<1/1,): haemolysis, foetal bradycardia, palpitations, transient deafness, headache, paresthesia, hypertension. Exacerbation of joint pain in rheumatoid arthritis can occur. Local reactions reported are soreness and inflammation at or near injection site and local phlebitic reaction. After intramuscular injection local complications such as staining of the skin, bleeding, formation of sterile abscesses, tissue necrosis or atrophy and pain are observed. Legal Category: POM. Pharmaceutical Precautions: CosmoFer is for single use only and any unused solution should be discarded. The reconstituted solution for injection is to be visually inspected prior to use. Only clear solutions without particles should be used. Package Quantities 5 ampoules per pack. Date of preparation: June 27. Pharmacosmos A/S, Roervangsvej 3, DK-43 Holbaek, Denmark. THE WORLD CONGRESS OF NEPHROLOGY SINGAPORE 26TH 3TH JUNE 25 Official Lunch-time Symposium Held on 28th June Sponsored by Nebo a/s Challenges in Parenteral Iron Supplementation Iron store repletion may be achieved effectively with a single infusion of low molecular weight iron dextran. Do administration benefits compromise clinical outcomes? Low molecular weight iron dextran well tolerated and safe for administration as a total dose infusion Parenteral iron is increasingly administered to patients with iron deficiency anaemia variety of conditions, either alone, to replete iron stores, or to compliment the administration of erythropoiesis stimulating agents. To achieve target iron levels, it may be necessary to administer large doses of parenteral iron. There are constraints that restrict the amount of elemental iron that can be delivered in the form of iron gluconate or iron sucrose at a single administration. The dosage ceiling for administering low molecular weight iron dextran is considerably higher, providing the clinician with the opportunity to administer a total dose infusion, thereby being able to administer the total supplementation requirement for the majority of patients with a single infusion. Michael Auerbach, MD, FACP Private Practice, Baltimore, Maryland Clinical Professor of Medicine Georgetown University School of Medicine Washington, DC CONTINUED ON PAGE 2 Competitive Partnerships, UK

6 57883-FE:195 FE Report 12/6/7 15:33 Side 1 CosmoFer abbreviated prescribing information When comparing and contrasting the profiles of parenteral iron formulations they are frequently categorised as iron sucrose, sodium ferric gluconate and iron dextran. This is confusing and misleading. Iron dextran is available as high molecular weight and low molecular weight formulations. Low molecular weight iron dextran is associated with fewer, and less severe adverse events and should be categorised separately in evidence based comparisons with iron sucrose and sodium ferric gluconate. period. The higher molecular weight iron dextran was significantly higher ADE rate than the lower molecular weight formulation (INFeD/CosmoFer). Patients in this study were closely monitored at the bedside (i.e. not relying on voluntary submissions to the FDA). There was a threefold greater incidence of ADEs in the high, compared to the low, molecular weight iron dextran group. McCarthy et al (AM J Nephrol 2;2: ) Short-term safety and the adverse events associated with parenteral iron 5.% 4.% 3.% Why administer parenteral iron in iron deficiency anaemia associated Renal physicians administer parenteral iron as an integral component of managing iron deficiency anaemia associated with chronic kidney disease. The role of parenteral iron is to augment erythropoiesis and to correct erythropoietic hyporesponsiveness. These roles, and the impact that parenteral iron may have in increasing the efficiency of administering erythropoietin, which may result in dose reductions and cost savings, are evidence based. Patient benefits, of parenteral iron administration, are gained indirectly through the impact on erythropoiesis resulting in improved haemoglobin levels and improved haematocrit which affect well-being and quality of life. 1.% Prof Glenn M. Chertow, MD, MPH University of California San Francisco Division of Nephrology, San Francisco, California carry a risk of adverse events. There are risks associated with the administration of parenteral iron and it is the natural tendency for clinicians to seek to reduce these risks for their patients. The comparative adverse event profile of available formulations may be the deciding factor. In this regard, decisions should be based on current evidence, not folklore. This is particularly relevant when evaluating iron dextran. SIZE MATTERS! Iron dextran is available as high molecular weight and low molecular weight formulations. Iron dextran formulations should not be considered as a single class with a single profile. Examination of the evidence base reveals that the low molecular weight form produces substantially less adverse events (ADEs), and less severe ADEs than the high molecular weight forms..% A choice is made regarding the selection of the type of iron to be administered, as all medications Where is the evidence? McCarthy et al. described iron dextran-related ADEs during 665 courses of parenteral iron dextran given to 254 patients over a 5-year McCarthy et al. described iron dextran-related ADEs during 665 courses of parenteral FE dextran given to 254 patients over a 5-year period. The higher molecular weight iron dextran was significantly higher ADE rate than with the low molecular weight formulation. Courses with an ADE In a study conducted over a six month period, patients being treated at FMCNA (Fresenius Medical Care North America) affiliated dialysis units were closely monitored. Healthcare professionals were vigilant at the bedside to record ADEs when administering parenteral iron to dialysis patients. Fletes et al. (AJKD 21) evaluated 165 cases of iron dextran-related ADEs from the administration of 841,252 doses of intravenous iron dextran. The higher molecular weight iron dextran was significantly higher ADE rate than the lower molecular weight formulation. Two thirds of the events occurred in patients receiving Dexferrum, albeit it was used in a smaller number of patients. The incidence of observed ADEs was a multiple of eight times higher than in those patients who received INFeD/CosmoFer. Fletes et al AJKD 21;37(4): The choice of parenteral iron formulation includes risk analysis. Nephrology Dialysis Transportation 24;19(6): % 2.% The evidence that molecular size plays a major role in determining the clinical properties of iron dextran formulations is overwhelming and consistent. reports from ,. reported weight iron dextran was 5.5-fold increase in odds of ADEs and a 3.6-fold increase in odds of death (NDT, 24). Whilst the data is voluntarily supplied to the FDA, the scale of the number of patients receiving the various types of iron dextran and the volume of administrations (estimated at 21 million during the observation period), provides further formidable evidence in support of the strong safety profile of low molecular weight iron dextran Rate per 1million administrations Fletes et al. evaluated 165 cases of Fe dextranrelated ADEs (from 841,252 intravenous iron dextran doses) at FMCNA-affiliated dialysis units during a six month study period (case cohort design). The higher molecular weight Fe dextran was associated with a significantly higher ADE rate than with the low molecular weight formulation reports from ,. reported 5.5-fold increase in odds of ADE and a 3.6-fold increase in odds of death. A similar review of the FDA Medwatch data over the sequential period (.) found weight iron dextran was 3.2-fold increase in odds of ADEs and a 3.4-fold increase in odds of life-threatening ADEs. Submitted for publication reports from 21-23,. reported 3.2-fold increase in odds of ADE and a 3.4-fold increase in odds of life threatening ADEs. So has the historical problem of comparing oranges with apples been resolved? Evidently not! Whilst the evidence clearly indicates that low molecular weight iron dextran has a better ADE profile than the high molecular weight iron dextran there is an on-going dilemma wherein misleading studies are published and continue to compare iron dextran to other parenteral iron supplements, without discriminating between the forms of iron dextran. This can be illustrated by reference to a study recently published by Bailie et al. Using the Freedom of Information Act FDA data from , ADEs following IV iron administration are analysed. They report a higher rate of hypersensitivity ADEs with iron dextran, compared with iron gluconate and iron sucrose. No distinction is made between high molecular weight and low molecular weight iron dextran (NDT, 25). When considering the clinical merits of available iron formulations there is a need to distinguish between the molecular weights of the various dextran formulations, ensuring that the low molecular weight iron dextran product profile is not attributed the properties of high molecular weight products. SIZE MATTERS. Before prescribing CosmoFer (low Mw iron dextran) please refer to full local approved data sheet. Presentation: Solution for infusion and injection in the form of 2 ml ampoules containing mg iron(iii) as Iron(III)-hydroxide dextran complex. Each ml contains 5 mg Iron(III). Indications: CosmoFer is indicated for parenteral treatment of iron deficiency in cases where oral iron preparations cannot be used, e.g. due to intolerance, or in case of demonstrated lack of effect of oral iron therapy or where there is a clinical need to deliver iron rapidly to iron stores. CosmoFer is indicated for patients above 14 years of age. Dosage: The normal recommended dosage schedule is -2 mg iron corresponding to 2-4 ml, two or three times a week depending on the haemoglobin level. If clinical circumstances require rapid delivery of iron to the body iron stores, CosmoFer may be administered as a total dose infusion up to a total replacement dose corresponding to 2mg iron/kg body weight. Administration: CosmoFer solution for injection can be administered by an intravenous drip infusion or by a slow intravenous injection. Intravenous drip infusion is the preferred route of administration, as this may help to reduce the risk of hypotensive episodes. CosmoFer may also be administered as undiluted solution intramuscularly. Test dose: Before administering the first dose to a new patient, a test dose of CosmoFer corresponding to 25 mg iron or equal to.5 ml solution must be administered for all routes of administration. If no adverse reactions are seen after minutes, the remaining dose can be given. Intravenous drip infusion: CosmoFer must be diluted only in.9% sodium chloride or in 5% glucose solution. CosmoFer in a dose of -2 mg iron (2-4ml) may be diluted in ml. On each occasion the first 25 mg of iron should be infused over a period of 15 minutes. If no adverse reactions occur during this time the remaining portion of the infusion should be given at an infusion rate not more than ml in 3 minutes. Intravenous injection: CosmoFer may be administered in a dose of 2 mg iron by slow intravenous injection (.2 ml/min) preferably diluted in 1 2 ml.9% sodium chloride or 5% glucose solution. On each occasion before administering a slow intravenous injection, 25 mg of iron should be injected slowly over a period of 1 to 2 minutes. If no adverse reactions occur within 15 minutes, the remaining portion of the injection may be given. Injection into dialyser: CosmoFer may be administered during a haemodialysis session directly into the venous limb of the dialyser under the same procedures as outlined for intravenous administration. Intramuscular injection: For intramuscular injection, the amount of CosmoFer required is determined either from the dosage table or by calculation; it is administered as a series of undiluted injections of up to mg iron (2. ml) each, determined by the patient s body weight. CosmoFer must be given by deep intramuscular injection to minimise the risk of subcutaneous staining, it is recommended to use the Z-track technique. Total dose infusion: For total dose infusion the amount of CosmoFer required is determined either from the dosage table or by calculation, it is added to the required volume (usually 5 ml) of.9% sodium chloride or 5% glucose solution and infused intravenously over 4-6 hours. On each occasion the first 25 mg of iron should be infused over a period of 15 minutes. If no adverse reactions occur during this time, then the remaining portion of the infusion should be given. The rate of infusion may be increased progressively to 45 drops per minute. Contraindications: Non-iron deficiency anaemia, iron overload or disturbances in utilisation of iron, patients with a history of asthma, allergic eczema or other atopic allergy, drug hypersensitivity, decompensated liver cirrhosis and hepatitis, acute or chronic infection, rheumatoid arthritis with symptoms or signs of active inflammation, acute renal failure. Pregnancy and lactation: CosmoFer should not be used during the first trimester, but can be used during second and third trimester if treatment is clearly necessary. It is unknown whether the complex iron-dextran is excreted in human or animal breast milk. It is preferable to not use CosmoFer during breast feeding. Warnings/Precautions: The use of CosmoFer as with the parenteral use of other iron-carbohydrate complexes carries a risk of immediate severe and potentially lethal anaphylactoid reactions. Patients should be closely observed during and immediately after administration. The risk is enhanced for patients with known (medical) allergy. CosmoFer may only be administered when facilities and equipment for handling acute anaphylactic reactions are available, including an injectable 1: adrenaline solution. Additional treatment with antihistamine and/or corticosteroids should be given as appropriate. There is particularly increased risk of allergic reactions in patients with immune or inflammatory conditions. Hypotensive episodes may occur if intravenous injection is administered too rapidly. Drug interactions: CosmoFer should not be administered concomitantly with oral iron preparations, as the absorption of oral iron will be reduced. Oral iron therapy should not be started earlier than 5 days after the last injection of CosmoFer. The drug may cause falsely elevated values of serum bilirubin and falsely decreased values of serum calcium. Incompatibilities: CosmoFer must only be mixed with.9% sodium chloride or 5% glucose solution. No other intravenous dilution solutions or therapeutic agents should be used. Side effects: Anaphylactoid reactions are uncommon and include urticaria, rashes, itching, nausea and shivering. Administration must be stopped immediately when signs of an anaphylactoid reaction are observed. Acute, severe anaphylactoid reactions are very rare. They usually occur within the first few minutes of administration and are generally characterised by the sudden onset of respiratory difficulty and / or cardiovascular collapse. Delayed reactions are well described and may be severe and are characterised by arthralgia, myalgia and sometimes fever. Symptoms usually last two to four days and settle spontaneously or following the use of simple analgesics. Other adverse reactions are: Uncommon (>1/1,, <1/): nausea, emesis, abdominal pain, feeling hot, cramps, blurred vision, numbness, dyspnea, flushing, pruritus and rash. Rare (>1/1,, <1/1,): arrhythmia, tachychardia, diarrhoea, fatigue, myalgia, loss of consciousness, seizure, dizziness, restlessness, tremor, chest pain, mental status changes, angioedema, sweating, hypotension. Very rare (<1/1,): haemolysis, foetal bradycardia, palpitations, transient deafness, headache, paresthesia, hypertension. Exacerbation of joint pain in rheumatoid arthritis can occur. Local reactions reported are soreness and inflammation at or near injection site and local phlebitic reaction. After intramuscular injection local complications such as staining of the skin, bleeding, formation of sterile abscesses, tissue necrosis or atrophy and pain are observed. Legal Category: POM. Pharmaceutical Precautions: CosmoFer is for single use only and any unused solution should be discarded. The reconstituted solution for injection is to be visually inspected prior to use. Only clear solutions without particles should be used. Package Quantities 5 ampoules per pack. Date of preparation: June 27. Pharmacosmos A/S, Roervangsvej 3, DK-43 Holbaek, Denmark. THE WORLD CONGRESS OF NEPHROLOGY SINGAPORE 26TH 3TH JUNE 25 Official Lunch-time Symposium Held on 28th June Sponsored by Nebo a/s Challenges in Parenteral Iron Supplementation Iron store repletion may be achieved effectively with a single infusion of low molecular weight iron dextran. Do administration benefits compromise clinical outcomes? Low molecular weight iron dextran well tolerated and safe for administration as a total dose infusion Parenteral iron is increasingly administered to patients with iron deficiency anaemia variety of conditions, either alone, to replete iron stores, or to compliment the administration of erythropoiesis stimulating agents. To achieve target iron levels, it may be necessary to administer large doses of parenteral iron. There are constraints that restrict the amount of elemental iron that can be delivered in the form of iron gluconate or iron sucrose at a single administration. The dosage ceiling for administering low molecular weight iron dextran is considerably higher, providing the clinician with the opportunity to administer a total dose infusion, thereby being able to administer the total supplementation requirement for the majority of patients with a single infusion. Michael Auerbach, MD, FACP Private Practice, Baltimore, Maryland Clinical Professor of Medicine Georgetown University School of Medicine Washington, DC CONTINUED ON PAGE 2 Competitive Partnerships, UK