Iron Therapy. Product Monograph. Version 1.4. low Mw iron dextran

Transcription

1 Iron Therapy low Mw iron dextran Product Monograph Version 1.4

2 Effective and flexible... CosmoFer IV iron therapy significantly increases the response to rhuepo, compared to oral iron supplementation 33,35 CosmoFer is the only globally available parenteral iron formulation that can be administered as a total dose infusion 13,31,33 CosmoFer administered as TDI, improves compliance and reduces the number of injections and hospital visits 61,62 With a well documented safety profile Clinical experience from > 70 million doses 4 CosmoFer is characterized by significantly less adverse events compared to high Mw iron dextran 5-11,45,47,48 CosmoFer is a tightly bound iron complex, more stable than iron-sucrose and irongluconate, and is therefore less likely to lead to toxicity 15-18,53,55

3 Preface Iron is an essential substance in the human body, transporting oxygen to tissues via haemoglobin in red blood cells and functioning as a Co-factor in a number of enzyme systems. Iron deficiency is caused by a deficit in total body iron, resulting from iron requirements that exceed the iron supply. If the iron deficiency is not corrected it will ultimately lead to iron deficiency anaemia with a significant impact on quality of life, morbidity and mortality. 1,2 The World Health Organisation estimates that as many as 2 billion people over 30% of the World s population are anaemic, mainly due to iron deficiency. 3 Therapy for iron deficiency anaemia includes treatment of its underlying cause and restoration of normal haemoglobin concentrations and iron stores. This can be accomplished by the oral or the parenteral route. Although the oral route is preferred, clinical situations exist for which the parenteral route is indicated: Intolerance or non compliance to oral iron preparations Lack of effect of oral iron therapy Malabsorption of oral iron, e.g. due to gastrointestinal disease or surgery Patients in whom the chronic iron loss exceeds the rate of replacement possible with oral iron Patients with a clinical need for rapid delivery of iron to iron stores, e.g. pre- and post operative patients, post partum patients or in cases of autologous blood donation Functional or absolute iron deficiency in connection with erythropoietin therapy (r-huepo) In clinical circumstances, where injectable iron can be used as an alternative to blood transfusion The introduction of r-huepo not only changed the treatment of anaemia - it also highlighted the need for parenteral iron supplementation. From being primarily indicated and used in renal anaemia the use of erythropoietin has now spread to new indications e.g. autologous blood transfusion, gastroenterology and anaemia in cancer. In many of these patients gastrointestinal iron absorption is not sufficient and therefore parenteral iron administration has to be considered. CosmoFer low molecular weight (Mw) iron dextran is a parenteral iron formulation, with a well documented safety profile. Low Mw iron dextran has been used in more than 70 million doses 4 and is characterized by significantly less adverse events compared to high Mw iron dextran. 5-11,45,47,48 The use of cumulative doses of low Mw iron dextran is not, as previously reported for parenteral iron, linked to an increased mortality risk. 12 The formulation is characterized by a strong colloidal complex of a ferric core shielded by dextran chains 13. This gives a strong iron-carbohydrate complex, which is more stable than iron sucrose and iron gluconate, and therefore less likely to lead to toxicity ,53,55 The tightly bound iron and the ph of are the reasons why CosmoFer offers the flexibility of administering the parenteral iron dose, either as an intravenous (IV), intramuscular (IM) injection or as a total dose infusion (TDI). 13 This monograph introduces the scientific rationale and documentation behind low Mw iron dextran developed and produced by Pharmacosmos A/S in Denmark. The CosmoFer brand is promoted by Pharmacosmos A/S, Denmark and distributed outside the US by Pharmacosmos partners. In the US, low Mw iron dextran is sold and distributed under the brand name INFeD, and in France under the brand name of Ferrisat. 1

4 Executive Summary CosmoFer low Mw iron dextran solution for injection contains iron in a stable aqueous iron(iii)-hydroxide dextran complex (50 mg Fe/ml. USP, BP Quality), which is analogous to the physiological form of iron, ferritin. 13 Several publications document that the amount of free ionic iron, which can cause oxidative stress, is lowest in CosmoFer compared to iron sucrose and iron gluconate formulations ,53 Following the IV injection or infusion low Mw iron dextran is rapidly taken up by the cells in the reticuloendothelial system, particularly in the liver and spleen from where iron is slowly released and bound to proteins. 13 The plasma half life is 5 hours for circulating iron and 20 hours for total iron (bound and circulating). 13 Due to the size of the complex (165,000 Daltons) CosmoFer is not eliminated via the kidneys and there is no or minimal removal of iron dextran during haemodialysis which do not warrant a change in the dosage schedule. 13,25-27 CosmoFer is also characterized by a strong toxicological profile compared with iron sucrose and iron gluconate, with less nephrotoxicity, less intracellular iron accumulation and less inhibition of endothelial cell proliferation ,55 Due to the tightly bound iron complex, CosmoFer offers the opportunity of administering the iron dose either as a conventional series of small IV doses or as a total dose infusion (TDI) with up to 20 mg/kg body weight administered over 4-6 hours in one single infusion. 13 The ph of enables CosmoFer to be administered as undiluted intramuscular injections. 13 CosmoFer administered as TDI, improves compliance and reduces the number of injections and hospital visits, resulting in substantial cost savings. 61,62 Administration of CosmoFer as IV injection or infusion improves the erythropoietic response and the patient s quality of life compared to oral iron treatment while decreasing the rhuepo dose at the same time. 30,31,33-35 CosmoFer (low Mw iron dextran) is a well documented parenteral iron formulation with more than 70 mill doses sold 4 and characterized by significantly less adverse events compared with traditional high Mw iron dextran. 5-11,45,47,48 2

5 Table of content: Preface... 1 Executive Summary... 2 Table of content Pharmacological properties Physiochemical properties Iron complex stability Pharmacokinetic and dynamic properties Efficacy profile Erythropoietic response Synergistic effect with rhuepo Effect on quality of life Safety profile CosmoFer - short term safety profile CosmoFer - long term safety profile Liver Renal Endothelial cells Flexible administration; IV, IM or as total dose infusion (TDI) Cost-effectiveness Clinical use of parenteral iron Nephrology Oncology Obstetrics and gynaecology Gastroenterology Surgery and tranfusion medicine Cardiology Geriatrics Pharmaceutical presentation CosmoFer prescribing information References Version 1.4, Pharmacosmos April Print and graphics by Vang Rasmussen A/S (290103) 3

6 1. Pharmacological properties 1.1 Physiochemical properties: CosmoFer solution for injection contains iron in a stable aqueous iron (III)- hydroxide dextran complex, which is analogous to the physiological form of iron, ferritin (ferric hydroxide phosphate protein complex). 13 The formulation is characterized by a strong colloidal complex of a ferric core shielded by tightly bound dextran chains. The sterile solution has a ph of approximately Sodium hydroxide or hydrochloric acid is used to adjust ph. No preservatives are added. 13 There has been some confusion associated with the properties of iron dextran products as the forms which have a high Mw (molecular weight), exhibit different properties compared with the low Mw form. DexFerrum manufactured by Vifor and marketed in the United States by American Regent Laboratories has a high Mw compared with the low Mw of CosmoFer (marketed in the United States as INFeD and in France as Ferrisat ). This confusion is further compounded by the publication of molecular weight masses for the two forms which are inconsistent. The terms high molecular weight and low molecular weight are relative terms and the published molecular masses reflect the chromatographic methodology used, and more importantly the calibration of the system. When using the internationally recognized dextran (sugar polymer) standard the high Mw iron dextran complexes (e.g. DexFerrum ) have an estimated molecular mass in excess of 400,000 daltons 14 relative to low Mw iron dextran (CosmoFer / INFeD ) which has a molecular weight (Mw) of only 165,000 daltons. 13 As will be explained later in this monograph the clinical differences between high and low Mw iron dextran are now recognized. The previously reported high incidence of adverse events, including potentially life-threatening reactions, has been associated with high Mw iron dextran. 5-11,14, Iron complex stability: Lewis et al. (2003) 20 directly measured the amount of bleomycin detectable free iron (BDI) in human serum after the addition of different parenteral iron formulations. The in-vitro analyses were performed on pooled samples of human serum where the IV iron compounds were added to give 42 µg Fe/ml, the theoretical C max of a 125 mg Fe dose in a 70 kg male. Samples were incubated at 37 o C and then analyzed for BDI. Low Mw iron dextran contained significantly less free iron compared to iron sucrose and iron gluconate. Figure A second in-vitro stability work, Iron complex formulations for parenteral administration differ in terms of stability and release rate in serum, was presented by Langguth et al. (2003). 21 Langguth used a colorimetric assay based on complexing with Ferrozine which allows quantification of free, i.e. non-complex bound iron as well as transferrin bound iron in serum. CosmoFer low Mw iron dextran - Strong and robust iron complex 14-17,109 4

7 1 Langguth concluded: Free iron in parenteral iron formulations The release of iron from CosmoFer was below the detection limit of the analytical method, followed by iron gluconate and iron sucrose which released up to 10% of the dose as free iron µm Fe Geisser et al. (1992) 15 categorized the different parenteral iron formulations in three types, according to the robustness and strength of the iron complex, based on the degradation kinetics of the iron complexes. 4 0 Iron gluconate Iron sucrose Low Mw iron dextran Ferumoxytol Type 1: The robust and strong type Type 2: The half robust and medium strong type Type 3: The labile and weak type Figure 1.1.1: Bleomycin detectable free iron in parenteral iron formulations. Adapted from Lewis et al. (2003) 20 According to these criteria Geisser 15 categorized iron dextran as a type 1 iron complex, iron sucrose as a type 2 and iron gluconate as a type 3 iron complex; again highlighting that iron dextran is the iron complex with the most tightly bound iron and the least risk of free iron reactions. 6.0 Labile iron in parenteral iron formulations 8.0 Iron Donation to Tf (%) Van Wyck et al. (2004) 22 analyzed the amount of labile iron in parenteral iron formulations in-vitro by measuring the magnitude of direct donation of iron from iron agents to transferrin (Tf) in-vitro. Dilutions of each IV iron agent were added to fresh serum over a range of concentrations. The resulting samples were passed through an alumina column to remove intact iron agent and the eluate was assayed for Tf-bound iron. Figure Iron gluconate Iron sucrose Low Mw iron dextran High Mw iron dextran Figure 1.1.2: Percentage of direct iron donation to transferrin by iron agent tested. Adapted from Van Wyck et al. (2004) 22 5

8 1. Pharmacological properties Van Wyck concluded: Approximately 2-6% of total iron in commonly used IV iron compounds is available for in-vitro iron donation to transferrin. This fraction may contribute to evidence of bioactive iron in patients after IV iron administration. 22 Henderson et al. (1969) 23 conducted several in-vitro and in-vivo iron dextran exchange studies to assess the effect of total dose infusion with iron dextran on saturation of the unbound iron binding capacity (UIBC). Henderson found that approximately percent of the iron dextran iron was available for direct exchange to transferrin. Although this resulted in saturation of UIBC in the in-vitro study, the in-vivo studies showed no evidence of iron toxicity from the release of sufficient ionic iron to exceed the transferrin UIBC after total dose infusions of 2-3 grams of iron dextran. 23 Henderson explains this by suggesting that the percent iron is in fact not free iron but: These findings are similar to those by Cox et al. (1965). 24 Cox et al. were unable to detect any significant free ionic iron in iron dextran solutions but they did estimate that 1-2 percent of the total iron may be present as a loosely bound iron which is in equilibrium with the ferric iron complex. 24 The labile iron pool that Van Wyck 22 measures in low Mw iron dextran is therefore not the same as free ionic iron. This labile iron pool includes a complex bound iron which can be removed by transferrin but which is otherwise in complex with dextran and which is not likely to dissociate and form free ionic iron. From a toxicological point of view it is the amount of free ionic iron that is interesting. Free unbound ionic iron has a high potential for inducing oxidative stress, which is expected to be a major contributor to the endothelial dysfunction and accelerated atherosclerosis seen in chronic kidney disease. The amount of free ionic iron in the iron formulations is also one of the main explanations behind the huge differences in toxicity of the different formulations, see table on page 25. a loosely bound iron dextran fraction which can be removed by transferrin but is otherwise in a stable complex with dextran and will not dissociate to free ionic iron. 23 CosmoFer low Mw iron dextran - Strong and robust iron complex 14-17,109 6

9 1 1.2 Pharmacokinetic and dynamic properties Following the IV injection or infusion low Mw iron dextran is rapidly taken up by the cells in the reticuloendothelial system (RES), particularly in the liver and spleen from where iron is slowly released and bound to proteins. 13 The plasma half life is 5 hours for circulating iron and 20 hours for total iron (bound and circulating). 13 After intramuscular injection, CosmoFer is absorbed from the injection site into the capillaries and the lymphatic system from where it is cleared by the RES. The major portion of the intramuscularly administered low Mw iron dextran is absorbed within 72 hours; most of the remaining iron is absorbed during the ensuing 3 to 4 weeks. 13 The reticuloendothelial system splits the complex into its components of iron and dextran. The iron is immediately bound to ferritin, the physiological storage forms of iron, or to a lesser extent, to transferrin. This iron which is subject to physiological control replenishes haemoglobin and depleted iron stores. After administration of CosmoFer an increased haematopoiesis can be observed for the following 6-8 weeks Dose 20 remaining in plasma (%) Clearance of iron dextran from plasma Due to the size of the complex (165,000 Daltons) CosmoFer is not eliminated via the kidneys Days post infusion Figure 1.2.1: Percentage of iron dose remaining in plasma. Each coloured line represents a different patient. Adapted from Wood et al. (1968) 28 7

10 1. 2. Pharmacological Efficacy profile properties Hatton et al. (1995) 25, Bailie et al. (1997) 26 and Chen et al. (2008) 27 analyzed the potential removal of CosmoFer during haemodialysis. Hatton used an in-vitro assay with 9 different hemodialyzers using six different membranes. Bailie conducted an in-vivo study in eight patients using Terumo 175 cuprammonium dialyser. Chen conducted an in-vivo study in six patients using F6 (polysulphone membran) and GFSplus12 (hemophane membrane) dialyzers sequentially in each patient. All three investigators concluded that there was no or minimal removal of iron dextran during dialysis which did not warrant a change in the dosage schedule of iron dextran. Wood et al. (1968) 28 investigated the pharmacokinetics and dynamics of iron dextran given as a total dose infusion to six severely iron deficient gynaecological patients (mean Hb = 7.3 g/dl, mean transferrin saturation = 9%). The patients were administered a calculated dose of saline diluted radioactive labelled iron dextran, the dose varied from mg of iron. The radioactivity of the organs (liver, spleen, sacrum, thigh), red blood cells, and urine was measured using a scintillation counter. Figure The results show that iron dextran is cleared from the plasma after 8-10 days, resulting in a biological halflife for the complex in the plasma of approximately days after total dose infusion. 28 There is a marked increase in radioactivity over the liver, spleen and sacrum; the liver shows the greatest increase with a peak at 7-8 days. The steep rise in radioactivity over these organs coincides with the clearance from the plasma, the peaks occurring just prior to the disappearance from the plasma of the last of the complex. 28 Figure The first detectable activity appeared in the red blood cells on day 1-3. After 3-4 weeks the iron stores had been replenished and approximately 50% of the iron had been incorporated into haemoglobin. 28 Figure Roe et al. (1996) 29 conducted a direct comparative prospective study of the iron utilization of low Mw iron dextran compared with high Mw iron dextran given as sequential 100 mg doses to 20 chronic kidney disease patients with evidence of iron deficiency (Hb = 9-12 g/dl, serum ferritin <100 µg/l, transferrin saturation, (TSAT) <20%). Patients were randomized to 500 mg of low Mw iron dextran or 500 mg of high Mw iron dextran in five sequential 100 mg doses during normally scheduled dialysis sessions. Erythropoietin doses were held constant throughout the study and were similar in the two treatment groups. The follow-up time was 30 days. The results showed that there was no statistically significant difference in iron utilization between the two iron dextran formulations. Roe et al. concluded: Degree of iron utilization appears independent of molecular weight within the range we examined. 29 CosmoFer CosmoFer low Mw - Improves iron dextran erythropoiesis - Strong and robust the patient s iron complex quality 14-17,109 of life 8

11 2. Efficacy profile 1 The rate of clearance appeared to be unrelated to the degree of anaemia or the amount of complex given in the study by Wood. 28 Henderson et al. (1969) 23 studied the pharmacokinetics of iron dextran doses of mg in 21 iron deficient patients and found that the initial clearance was exponential for doses less than 500 mg. For doses above 500 mg the clearance rate was relatively constant. For doses above 500 mg the maximum rate of iron dextran uptake into reticuloendothelial cells was mg/hr. 23 The studies by Wood 28, Roe 29 and Henderson 23 clearly illustrate the pharmacokinetics and dynamics of IV iron dextran in doses of 100 to 2,000 3,000 mg. First it is cleared into the reticuloendothelial system, where iron is liberated for later return to circulation and transport to the erythroid marrow as transferrin bound iron Excess organ counts per second Distribution of iron dextran in the body Liver Spleen Sacrum Thigh Days post infusion Figure 1.2.2: Excess organ counts per second. Surface scanning of patient 5. Adapted from Wood et al. (1968) 28 Incorporation of the iron into red blood cells Percentage of dose in red cell mass Days post infusion Figure 1.2.3: Percentage of dose in red cell mass. Each coloured line represents a different patient. Adapted from Wood et al. (1968) 28 CosmoFer - Improves erythropoiesis and the patient s quality of life 9 9

12 2. Efficacy profile 2.1 Erythropoietic response Senger et al. (1996) 30 evaluated the haematologic and economic advantages of using low Mw iron dextran as the sole supplemental agent to safely increase and maintain hematocrit levels and iron availability in patients on chronic haemodialysis. A prospective analysis was performed on 13 clinically stable chronic haemodialysis patients (serum ferritin <100 µg/l, TSAT <20. Low Mw iron dextran 100 mg (2 ml) was administered as slow IV push undiluted three times per week, until the total required dose was attained. The analysis duration was 12 months. The results showed that the use of low Mw iron dextran improved the erythropoietic response while decreasing the rhuepo dose at the same time. Figure Quote from Senger et al.: After 6 months on the protocol, erythropoietin doses decreased an average of 3100 units per patients with an 8% increase in hematocrit and 66% and 78% increase in transferrin saturation and ferritin respectively. 30 Auerbach et al. (1998) 31 investigated the efficacy and safety of intravenous total-dose infusion (TDI) versus divided boluses of low Mw iron dextran in dialysis patients receiving erythropoietin. 47 haemodialysis patients (serum ferritin <100 µg/l or serum ferritin of µg/l, along with a TSAT <19%), were randomized to one of three methods of low Mw iron dextran administration. Total low Mw iron dextran dose did not differ significantly between treatment groups. 5 of the 47 patients received Imferon instead of low Mw iron dextran INFeD at a time of shortage of this product. All patients received approximately 3,000 units rhuepo during dialysis thrice weekly. Group A: Total-dose infusion in 500 ml of 0.9% sodium chloride Dose ranged from 550 to 2,000 mg Group B: 500 mg boluses in 200 ml 0.9% sodium chloride Dose ranged from 400 to 1,500 mg Group C: 100 mg undiluted boluses Dose ranged from 500 to 2,100 mg Patients were observed until the haemoglobin or hematocrit zenith had been reached. The three administration methods did not differ in their efficacy, time to peak hematocrit, and side-effect profile. Figure Auerbach et al. concluded: Total-dose intravenous iron dextran infusion is safe, convenient, less expensive and as efficacious as divided-dose infusions. 31 CosmoFer - Improves erythropoiesis and the patient s quality of life 30,31,35 10

13 Rath et al. (2006) 32 conducted a prospective multicenter study in stable patients on hemodialysis. The objective was to analyse the efficacy and safety of low molecular weight iron dextran (CosmoFer ) compared to the previous treatment with iron gluconate (Ferrlecit ) in a clinical setting. Inclusion criteria were serum ferritin >100 µg/l or cumulative iron gluconate of at least 1000 mg in the past three months before entering the study. 221 patients with a mean age of 63.7 years were included and followed for 12 months. Measures of efficacy were increase of haemoglobin (Hb) or serum ferritin, decrease of EPO dose and the response to iron substitution calculated as ferritin-efficacy and haemoglobinefficacy. All patients completed the twelve months study period. There were no adverse events. Mean Hb and serum ferritin increased significantly (Hb: 11.0 to 11.4 g/dl; ferritin: 476 to 633 µg/l; (p<0,001). Both ferritin-efficacy and haemoglobin-efficacy increased during the treatment with low Mw iron dextran Hematocrit (Hct) values before and 6 months after treatment with low Mw iron dextran Mean Hct (%) - 1 month 6 months Figure 2.1.1: Mean Hematocrit (Hct) values pre low Mw iron dextran and 6 months after initiation of treatment. Adapted from Senger et al. (1996) Hematocrit responses to three different methods of low Mw iron dextran administration Hematocrit 2 Rath et al. concluded: Low-molecular weight iron dextran improves anaemia management even in iron pretreated hemodialysis patients Weeks of therapy Bolus 100 mg 500 mg infusions TDI Figure 2.1.2: Development in mean hematocrit (%) responses to low Mw iron dextran infusion, shown in mean ± standard error. Adapted from Auerbach et al. (1998) 31 11

14 2. Efficacy profile 2.2 Synergistic effect with rhuepo Fishbane (1995) 33 compared intravenous low Mw iron dextran and oral iron in regard to their efficacy and ability to reduce the required dose of rhuepo in 75 haemodialysis patients (serum ferritin >100 µg/l and TSAT >15%). All patients discontinued their current iron therapy and were randomized to either intravenous low Mw iron dextran (100 mg twice weekly) or oral iron therapy (3 x 325 mg ferrous sulfate daily). rhuepo dose was adjusted biweekly to maintain a hematocrit of 30% to 34%. The follow-up time was four months. At 1 month and all subsequent months, mean hemotocrits were significantly higher in the intravenous group than in the oral iron group (34.4% vs. 31.8%). At 2 months and all the subsequent months, mean rhuepo doses were significantly lower in the intravenous iron group. Figure Figure Fishbane concluded: In summary, we have found that the dose of rhuepo can be substantially reduced by using intravenous iron maintenance therapy in the place of oral iron in haemodialysis patients. 33 Besarab et al. (2000) 34 investigated the optimal low Mw iron dextran protocol in ESRD patients on epoetin. 42 patients (TSAT between 19 and 30%, serum ferritin between 150 and 600 µg/l, haemoglobin >9.5 g/dl) were randomized to two different IV low Mw iron dextran protocols, one aiming at a TSAT between 20 to 30% and the other aiming at a TSAT of 30-50%. The low TSAT group received weekly maintenance doses of 25 to 150 mg/ wk of low Mw iron dextran and the high TSAT group received initially four to six doses of 100 mg low Mw iron dextran and thereafter weekly maintenance doses of 25 to 150 mg/ wk to maintain TSAT at 30-50%. The doses of epoetin in the low TSAT group remained essentially constant throughout the 6-months randomized treatment period. Within the high TSAT group, the dose of epoetin progressively decreased over the 6-months randomized treatment period. The reduction in epoetin dose between the study group and the control group reached approximately 40% at each of the months 4, 5 and 6. The study concluded: Maintenance of TSAT between 30-50% reduces rhuepo requirements significantly over a 6-months period. 34 CosmoFer - Improves erythropoiesis and the patient s quality of life 30,31,35 12

15 Development in rhuepo dose after either oral iron or low Mw iron dextran therapy rhuepo dose (Units/Treatment) Oral iron therapy * * * IV low Mw iron dextran Months Figure 2.2.1: Mean rhuepo dose at every month of follow-up in the two study groups. *P < Adapted from Fishbane (1995) 33 Number of patients with a decrease, no change, or an increase in rhuepo dose 20 Change in rhuepo dose Number of patients 10 0 Decrease No change Increase IV low Mw iron dextran Oral iron therapy Figure 2.2.2: The number of patients in each study group who had a decrease, no change, or an increase in rhuepo dose at study completion compared with baseline. Adapted from Fishbane (1995) 33 13

16 2. Efficacy profile 2.3 Effect on quality of life A prospective randomized multi center study by Auerbach et al. (2004) 35 compared the effect of different dosage schedules of intravenous low Mw iron dextran to oral iron in regard to the effect on haemoglobin (Hb) response, EPO dosage requirements and quality of life (QoL) in patients with chemotherapy related anaemia. 157 patients (Hb 10.5 g/dl, serum ferritin 450 pmol/l or 675 pmol/l with a TSAT 9%) with a histological diagnosis of cancer, were randomly assigned into four treatment groups: No iron (N=36) Oral iron (ferrous sulfate) 325 mg twice daily (N=43) Low Mw iron dextran 100 mg IV boluses at each visit to the calculated dose for iron replacement (N=37) Low Mw iron dextran total dose infusion (TDI) (N=41) Mean Hb increases for both IV iron groups were significantly higher than the no-iron and oral-iron groups (P<0.02). The percentage of patients with haematopoietic response was significantly higher in the IV iron groups than in the no-iron and oraliron groups. 68% of patients in the TDI and IV iron bolus groups achieved a haematopoietic response compared with 25% in the no-iron group and 36% in the oral-iron group. One acute hypersensitivity reaction occured during administration of a test-dose. This adverse event occured in one of the two patients that received high Mw iron dextran Dexferrum. Both IV iron groups showed increases in energy, activity and QoL measured by the 100-mm Linear Analog Scale Assessment (LASA score). Figure Auerbach et al. concluded: rhuepo increases Hb levels and improves QoL in patients with chemotherapy-related anaemia. Magnitude of Hb increase and QoL improvements is significantly greater if IV iron is added. 35 Two of the patients received high Mw iron dextran Dexferrum during a brief period when low Mw iron dextran INFeD was not available. All patients received 40,000 Units of rhuepo weekly; rhuepo dose escalation or reduction was not permitted. Patients were followed for 6 weeks, except for those in the bolus arm, who were followed until the end of their treatment course. CosmoFer - Improves erythropoiesis and the patient s quality of life 30,31,35 14

17 Effect of iron therapy on energy, activity and overall Quality of Life (QoL) 25 Change in Energy, Activity and overall Quality of Life (QoL) (LASA Score) (Low Mw iron dextran) CosmoFer /INFeD Energy Activity Overall QoL No iron Oral iron Repeted IV injections TDI Figure 2.3.1: Change in LASA scores from baseline to endpoint. Adapted from Auerbach et al. (2004) 35 15

18 3. Safety profile The safety of parenteral iron can be split into short and long term safety aspects. Historically the literature has been dominated by publications concerning the short term safety aspects - the risk of acute adverse events. This is now slowly changing in the sense that an increasing number of scientific articles are being published dealing with the toxicity of the different parenteral iron formulations 15-18, 36-38,53,55 and therefore the potential long term safety implications related to the effect on residual renal function, endothelial dysfunction, risk of infection and ultimately morbidity and mortality. In the case of for example CKD (Chronic Kidney Disease) patients it is important to evaluate the nephrotoxic potential and thereby the long term safety of the different parenteral iron formulations, considering that the residual renal function is strongly linked to the morbidity and mortality of the individual patient Bargman et al. (2005) 42 published a review concerning residual renal function The importance of residual renal function for patients on dialysis. Bargman concludes: Residual renal function is a valuable asset to those on dialysis, best demonstrated in PD. It is crucial to try to preserve this asset for as long as possible by re-educating ourselves, and our medical colleagues, that we still have to continue to think about protection of renal function, even in the dialysis patient CosmoFer - short term safety profile The nature and frequency of acute adverse reactions after IV iron administration remain the subject to considerable controversy. 43 Clearly some ADEs with dextran based products can be linked to an allergic reaction, but it is only a fraction of the total ADEs that actually requires emergency medication. 44 Walters et al. (2005) 44 published a study on this in 2005: Benchmarking iron dextran sensitivity: reactions requiring resuscitative medication in incident and prevalent patients. In this study the Gambro US health care medical database was searched for evidence of same day administration of IV iron dextran and parenteral epinephrine, corticosteroids or antihistamines. During a 16 month study period from January 1999 through April 2000, 1,066,099 doses of iron dextran were administered to 48,509 patients. In total 337 reports of suspected adverse reactions were reported, without regard to severity of reaction. Only seven patients experienced reactions requiring resuscitative agents, yielding an overall per exposure rate of 7 per 1,066,099 doses. 44 Inappropriate use of supportive care and misinterpretation of moderate adverse events may also result in an over reporting of allergic reactions during the use of iron dextran. In the Lancet 2007 Auerbach et al. 45 describes how the adverse event myalgias sometimes mistakenly is described as anaphylaxis. CosmoFer - Significantly less adverse events compared to high Mw iron dextran 5-11,48 16

19 Quotes from Auerbach et al: Some of the adverse clinical experience with parenteral iron is due to inappropriate supportive care. Myalgias, when they include chest and back discomfort, are mistakenly described as anaphylaxis, prompting unnecessary interventions with antihistamines and pressors and misleading clinicians about the toxicity profile of intravenous iron. The use of antihistamines as premedication can cause vasoactive reactions that are misinterpreted as a reaction to the injected iron......nonetheless, serious adverse events remain a concern. Acute myalgias (chest and back tightness) after a test dose without tachycardia, hypotension, wheezing, stridor, or periorbital oedema occur infrequently. This reaction abates within minutes without treatment and does not recur with rechallenge. This event should not be treated with diphenhydramine or epinephrine. When the total dose administered is less than 200 mg ferric gluconate or 400 mg iron saccharate, acute reactions are very uncommon. Adverse events with iron dextran are not related to the dose or infusion rate. 45 The undesirable effects in connection with the use of CosmoFer is summarized on page in this monograph Total reported serious ADEs per million doses 70 Total reported serious ADEs per million doses of 100 mg High Mw iron dextran 49.6 Iron gluconate 11.6 Low Mw iron dextran (CosmoFer /INFeD ) Figure 3.1.1: Total reported serious ADEs per million doses of 100 mg. Adapted from Chertow et al. (2004) 7 3 Chertow et al. (2004) 7 studied the relative safety of parenteral iron formulations using data from the US 17

20 3. Safety profile Food and Drug Administration on reported adverse drug events relating to the provision of three formulations of intravenous iron during A total of 21,060,000 doses equivalent to 100 mg IV iron were administered in this period. The used parenteral iron formulations were low Mw iron dextran INFeD (used as the reference group), High Mw iron dextran, Dexferrum and Iron gluconate, Ferrlecit. The total number of reported parenteral iron-related ADEs was 1981 among 21,060,000 doses administered, yielding a rate of 9.4 x 10-5, or 94 per million. Relative frequency of total ADEs per formulation = reported total ADEs per mill. administered IV doses of 100 mg iron: 251 for Ferrlecit (n=271/ total number of doses 1,083,000) 220 for Dexferrum (n=1,112/ total number of doses 5,058,000) 40 for INFeD (n=598/ total number of doses 14,919,000) Figure Chertow et al. concluded: Parenteral iron-related ADEs are rare. Using observational data, overall and most specific ADE rates were significantly higher among recipients of higher molecular weight iron dextran and sodium ferric gluconate complex than among recipients of lower molecular weight iron dextran. 7 Chertow et al. (2006) 8 is conducted the same way as the Chertow publication from In this case it is based on adverse events reported to the Food and Drug Administration in the period from attributed to the provision of four different formulations of intravenous iron; - High Mw iron dextran (Dexferrum ) - Low Mw iron dextran (INFeD ) - Iron gluconate (Ferrlecit ) - Iron sucrose (Venofer ) A total of 30,063,000 doses equivalent to 100 mg IV iron were administered in this period. The total number of reported parenteral iron-related ADEs was yielding a rate of 3.8 x 10-5, or roughly 38 per million. Relative frequency of life-threatening and major ADEs per formulation is shown in fig Figure Chertow et al. concluded: The frequency of intravenous iron related ADEs reported to the FDA has decreased, and overall, the rates are extremely low. 8 Fletes et al. (2001) 6 analyzed the frequency of suspected iron dextranrelated adverse drug events in haemodialysis patients, to determine the nature and frequency and associated patient characteristics. The study was based on data from Fresenius Medical Care North America (FMCNA) facilities. Clinical variance reports (CVRs) were analysed and compared with the characteristics of more than 85,000 patients (841,252 administrations) treated at FMCNA facilities as of January The used iron dextran formulations were Dexferrum high Mw iron dextran and INFeD low Mw iron dextran. CosmoFer - Significantly less adverse events compared to high Mw iron dextran 5-11,48 18

21 ADEs were more common among patients administered Dexferrum compared to low Mw Iron dextran INFeD, although the latter agent was more frequently administered. Overall corresponding to an 8,12-fold increased risk with Dexferrum. There were no confounding variables that could explain the increased risk with Dexferrum. Figure Fletes et al. concluded: Total ADEs per mill. administered IV doses of 100 mg iron Serious adverse reactions to IV iron dextran are rare in clinical practice. The risk appears to depend on the specific formulation of IV iron dextran. 6 0 High Mw iron dextran Low Mw iron dextran Iron gluconate (CosmoFer /INFeD ) Major ADEs Life-threatening ADEs Iron sucrose Coyne et al. (2003) 11 analyzed the frequency of adverse reactions to iron dextran. Coyne reported that among 2,338 patients exposed to any form of iron dextran, 1,937 (82.8%) had received low Mw iron dextran (INFeD ) only, 261 (11.2%) had received high Mw iron dextran (Dexferrum ) only, and 140 (6.0%) had received both drugs. Quote from the reference: The incidence of Dexferrum reactions was significantly higher (39/401; 9.7%) than reactions to INFeD (113/2077; 5.4%; P=0.002). 11 McCarthy et al. (2000) 5 also analyzed and compared the frequency of adverse drug events on low Mw iron dextran versus high Mw iron dextran. This study is based on a retrospective analysis of all in-center chronic haemodialysis patients receiving Figure 3.1.2: Total reported and serious ADEs per million doses of 100 mg. Adapted from Chertow et al. (2008) Total reported ADEs per 100,000 doses Total reported ADEs per 100,000 doses 66 High Mw iron dextran (Dexferrum ) 8 Low Mw iron dextran (CosmoFer /INFeD ) Figure 3.1.3: Total reported ADEs per 100,000 doses. Adapted from Fletes et al. (2001) 6 19

22 3. Safety profile intravenous iron dextran at the Mayo Clinic Dialysis Unit from June 1992 through July Six hundred and sixty five courses in 254 patients. McCarthy also found a significant difference between low Mw iron dextran and high Mw iron dextran. McCarthy et al. concluded: In summary, we observed a significant difference in the rate of adverse events during the administration of two different formulations of parenteral iron dextran. This effect remains significant even when adjusting for other factors. 5 Case et al. (1998) 10 reported on the administration of iron dextran as total dose infusion to 156 home dialysis patients. Quote from the reference: Of the 142 INFeD patients, 5 (3.5%) had reactions, which consisted of itching, urticaria, nausea, and vomiting. Of the 14 Dexferrum patients, 4 (28.6%) developed severe back and leg pain, urticaria, and shortness of breath. Two of the patients who had reactions to Dexferrum were subsequently given INFeD and had no reactions. 10 The differential safety profile between low and high Mw iron dextran can also be illustrated by an incidence that happened in the United States in In September 1998, the distribution of low Mw iron dextran was halted by the Food and Drug Administration (FDA) for administrative reasons, leaving high Mw iron dextran as the only product available (iron gluconate and iron sucrose had not yet been introduced in the United States). During that time, there was an 1100% increase in reported adverse events from the use of high Mw iron dextran. Later, low Mw iron dextran was reintroduced into the market. 47,48 Fishbane et al. (1996) 46 conducted a retrospective analysis of 573 patients treated with low Mw iron dextran at four haemodialysis centers between July 1993 to June Quote from the reference: In summary, we found serious adverse reactions to be uncommon in hemodialysis patients treated with intravenous iron dextran. 46 Moniem and Bhandari (2007) 14 reports from two studies with hemodialysis patients that examined the comparative safety and tolerability of low Mw iron dextran CosmoFer versus iron sucrose (Venofer ). One observational study and one prospective crossover study. The observational retrospective single centre study of the use of low Mw iron dextran (CosmoFer ) and iron sucrose (Venofer ) was carried out with analyses of all records for adverse events during administration. A total of 144 patients (85 hemodialysis, 28 peritoneal dialysis, three transplants and 28 predialysis) received CosmoFer - Significantly less adverse events compared to high Mw iron dextran 5-11,48 20

23 CosmoFer (total of 2,294 doses) and 110 patients (88 hemodialysis and 22 peritoneal dialysis) received Venofer (2,111 doses). Fifteen adverse events occurred with no anaphylactic episodes in either group. The prospective crossover study was undertaken in stable hemodialysis patients. Thirty-nine stable patients undergoing hemodialysis were included (28 men and 11 women) with a mean age of 60.5 ± 2.6 years (range years), receiving fortnightly 100 mg of intravenous Venofer were converted to receiving 100 mg of CosmoFer fortnightly for a period of 6 months. Patients were then converted back to the original dose of Venofer and followed up for another 6 months. Side effects were closely monitored and recorded together with haemoglobin concentration, serum ferritin levels and rhuepo dose. 3 No differences in haemoglobin, rhuepo dose or ferritin levels throughout the study were observed. 13 minor adverse events were reported after 546 and 507 doses of CosmoFer and Venofer respectively. Eight were reported in connection with the use of CosmoFer in four patients, five were reported in connection with the use of Venofer in likewise four patients. One patient reacted to both solutions with similar adverse reactions. In those patients with multiple reactions all responded to dose and rate reduction of the infusion to 50 mg of iron over the same period of time. Conversion from Venofer to CosmoFer led to a cost saving of 77 per patient over the 6-month study period

24 3. Safety profile The authors concluded: In this study, the two forms of therapy were equally safe and effective. Examination of a larger cohort of patients is necessary to verify these findings and potentially reassess European Best Practice Guidelines. 14 Sav et al. (2007) 49 also studied the comparative safety and tolerability of low Mw iron dextran CosmoFer versus iron sucrose (Venofer ). A total of 60 end stage renal disease (ESRD) patients were randomized and assigned to one of the two treatment groups (iron dextran, n = 30; iron sucrose, n = 30). The mean age of the patients was 51.5±17.4 years (range, 21 to 80 years). A standard test dose of 25 mg of low Mw iron dextran and iron sucrose was administered over 15 minutes during the initial visit. Patients were monitored closely for adverse reactions. If this dose was well tolerated, 75 mg of iron diluted in 100 ml of normal saline was administered over 30 minutes. All adverse reactions were recorded. Of the 30 patients who received low Mw iron dextran, 11 developed side effects (pruritus, 1 patient; wheezing, 1 patient; chest pain, 1 patient; nausea, 4 patients; hypotension, 1 patient; swelling, 1 patient; headache, 2 patients). Of the 30 patients who received iron sucrose, 13 developed side effects (pruritus, 1 patient; wheezing, 1 patient; diarrhoea, 1 patient; nausea, 4 patients; hypotension, 2 patients; swelling, 1 patient; headache, 3 patients). Adverse events occurred with similar frequency in the two treatment groups in the study (p > 0.05) and they did not observe any serious reactions in the two groups. The authors concluded: The incidence of side effects associated with iron dextran was not different than that of iron sucrose in our study. 49 Critchley and Dundar (2007) 50 carried out a systematic literature review to assess the frequency of adverse drug events (ADEs) associated with low Mw intravenous iron dextran and iron sucrose. Several electronic databases were searched and two reviewers screened all studies identified and extracted data. 60 studies were included in the review, but few directly compared adverse events associated with two or more forms of iron, and most were not specifically designed to evaluate adverse events. In general, with the exception of high Mw iron dextran serious or lifethreatening adverse events appeared rare. Several of the studies showed lower risks of ADEs on low Mw iron dextran compared with high Mw iron dextran, and one large review found a reduced risk on low Mw iron dextran compared with iron gluconate. Two studies showed little difference between iron sucrose and iron gluconate, and two further studies had similar rates of adverse drug events between iron sucrose and low Mw iron dextran. CosmoFer - Comparative short term safety profile as iron sucrose 14,

25 The authors concluded: Serious adverse events appear rare with either low Mw iron dextran or iron sucrose, and intravenous iron preparations may have many benefits in patients with severe iron deficiency. However, as most of the larger studies were not comparative, it is difficult to state conclusively whether any one form is safer than another It has been suggested that high cumulative doses of iron may contribute to increased morbidity and mortality among the end stage renal disease (ESRD) population, perhaps due to elevated risk of infection or increased oxidative stress. 12 In the case of low Mw iron dextran Feldman et al. (2004) 12 have published a comprehensive study, that showed that there is no statistically significant association between cumulative doses and mortality using analytical techniques that account for changing iron dosing and morbidity over time. A retrospective cohort study was conducted among 32,566 patients who received at least 1 year of HD at the Fresenius Medical Corporation dialysis centers during 1996 to In this period, iron dextran was the only available parenteral iron formulation in the US. INFeD low Mw iron dextran had been available since 1992 and Dexferrum high Mw iron dextran was launched in

26 3. Safety profile In summary the short term safety of low Mw iron dextran can be listed as follows. Numerous publications demonstrate a much lower rate of adverse drug events with low Mw iron dextran relative to high Mw iron dextran 5-11,45,47,48 and with no publications showing the contrary Several publications including direct comparative studies indicate that low Mw iron dextran has a comparable short term safety profile to iron sucrose and iron gluconate 7,8,14,49-51 The safety database on low Mw iron dextran is based on clinical experience from the use of more than 70 million doses 4 Despite from this level of documentation low Mw iron dextran still suffers under the stigma created by the historical and continued use of high Mw iron dextran. In 2007 and 2008 several publications 47,48,51 have discussed and challenged the antiquated perception of risk associated with intravenous iron and especially the continued lack of differentiation between low and high Mw iron dextran. Quote from the article: All countries in Western Europe have halted distribution of high Mw iron dextran and removed the black box warning from the package insert or equivalent documents for the low Mw formulation. The clinical community s larger perception of risk associated with the use of intravenous iron is antiquated and probably incorrect. While adverse event rates are driven higher by high Mw iron dextran, both high Mw and low Mw iron dextrans, and to a lesser extent all intravenous iron formulations, suffer this stigma. High Mw iron dextran is unsafe compared with other iron products and is medically unnecessary given the availability of three safer products in the United States*. We urgently recommend avoiding use of high Mw iron dextran in all clinical practice settings. We also recommend that the FDA withdraw this formulation of intravenous iron. 48 *(low Mw iron dextran, Iron sucrose and Iron gluconate) In 2008 an editorial in Journal of the American Society of Nephrology 48 under the title High molecular weight iron dextran: A wolf in Sheep s clothing argued that high Mw iron dextran DexFerrum manufactured by Vifor and marketed in the United States by American Regent Laboratories should be taken of the market: CosmoFer - Comparative short term safety profile as iron sucrose 14,

27 3 Compound LD 50 in white mice in mg Fe/kg (intravenous administration) Salts: FeSO 4 11 Fe(II)-gluconate 13 Mono- and oligonuclear complexes: Fe(III)-ammonium-citrate 16.5 Polynuclear complexes: Ferric hydroxide sucrose > 200 Ferric hydroxide dextran > 2500 Table 3.2.1: The LD 50 toxicity in mice of different iron compounds after intravenous injection. Adapted from Geisser et al. (1992) 15 table 1 page

28 3. Safety profile 3.2 CosmoFer - long term safety profile Ideally the long term safety of parenteral iron formulations should be assessed through large scale clinical trials that run for a sufficient number of years. Unfortunately such trials are currently not available for any parenteral iron formulation. The long term consequences of the toxicological profiles therefore have to be extrapolated from in-vitro and in-vivo animal studies combined with the measurement of surrogate endpoints in humans. The low toxicity of iron dextran was already well documented and described more than 30 years ago. Müller et al. (1974) 52 estimated the LD 50 dose of iron dextran in white mice to be more than 2,500 mg Fe/kg body weight. Table summarizes and compares the LD 50 toxicity in mice for iron compounds. The toxicity of iron dextran is at least 12 times lower compared to other iron complexes that are used for parenteral administration. Table Liver In 1992 Geisser et al. 15 conducted a series of animal studies with the purpose of analyzing and explaining the relationship between the chemical structure of iron complexes and their histo-toxicological properties. As mentioned in section 1.1 Geisser 15 categorized iron dextran as a robust and strong type, iron sucrose as a half robust and medium strong type and iron gluconate as a labile and weak type of iron complex. Figure From the studies Geisser 15 further concluded the following in relation to iron dextran: It became clear in this study that preparations of this type do not, or hardly ever, cause necroses. The main part of iron deposits were found in the RES, and not in the parenchyma, with the advantage that the iron induced radical forming lipid peroxidation, which takes place in the parenchyma only, is not triggered by these preparations. 15 Therefore, practically no liver injuries are to be expected, which is in agreement with our results. Taking into account the complex stability and the above pattern of iron deposit distribution, these iron complexes are clinically safe even in the case of high therapeutical doses. A low rate of iron-induced side effects can therefore be expected. 15 Pai et al. (2007) 53 studied oxidative stress markers after intravenous administration of three different commercially available parenteral iron formulations in patients undergoing hemodialysis. Twelve ambulatory patients undergoing hemodialysis received 100 mg of intravenous low Mw iron dextran, iron gluconate and iron sucrose in random sequence, with a 2-week washout period between treatments. Serum samples for measurements of CosmoFer - Strong toxicological profile compared to iron sucrose and iron gluconate 15-18,53,109 26

29 transferrin saturation, non transferrin-bound iron, and malondialdehyde (MDA; marker of lipid peroxidation) were obtained before (baseline) and 30, 60, 120, and 360 minutes and 2 weeks after each iron infusion. 4 5 Cellular iron deposits in the liver Relative unit Non transferrin-bound iron values were significantly higher 30 minutes after administration of iron gluconate and iron sucrose compared with iron dextran (mean ± SEM 10.1 ± 2.2, 3.8 ± 0.8, and 0.23 ± 0.1 µm, respectively, p<0.001 for sodium ferric gluconate vs iron dextran, p=0.002 for iron sucrose vs iron dextran). Figure Iron dextran: Robust and strong type iron complex Iron sucrose: Half robust and medium strong type iron complex RES (endothelium, Kupffer s cells) Iron gluconate: Labile and weak type iron complex Parenchyma 3 After iron gluconate, significantly more samples showed increases in MDA levels from baseline compared with iron sucrose and iron dextran (p=0.006). The authors concluded: Iron sucrose and iron gluconate were associated with greater non transferrin-bound iron appearance compared with low Mw iron dextran. However, only iron gluconate showed significant increases in lipid peroxidation. The relationship between non transferrin-bound iron from intravenous iron and oxidative stress warrants further exploration. 53 Distribution after 10, 105 min., 4 hrs. and 4 days Figure : Illustrates the relatively elevated risk of liver damage from the use of iron sucrose and iron gluconate. Compared to iron dextran the risk of iron deposits outside the reticuloendothelial system (RES) is 2-3 and 8-10 times higher with iron sucrose and iron gluconate. Adapted from Geisser et al. (1992) Nontransferrinbound iron measured as AUC (µmol min/l) 0 Exposure to non-transferrin-bound iron Iron gluconate Iron sucrose Low Mw iron dextran (CosmoFer /INFeD ) Figure : Exposure to non transferrin-bound iron after intravenous infusion of iron gluconate, iron sucrose and low Mw iron dextran measured as AUC = area under the concentration-time curve. Differences were significant for iron gluconate and iron sucrose versus low Mw iron dextran (p<0.005). Adapted from Pai et al. (2007) 53 27

30 3. Safety profile Renal Zager et al. (2004) 17 conducted a very comprehensive set of in-vitro and invivo studies to investigate the potential mechanisms and consequences of parenteral iron nephrotoxicity. In-vitro studies; Isolated mouse proximal tubular segments (PTS) or cultured human proximal tubular (HK-2) cells were exposed to the following compounds, over a broad dosage range (0, 30 to 1,000 µg Fe/ml); 1: Low Mw iron dextran, INFeD / CosmoFer 2: Iron sucrose, Venofer 3: Iron gluconate, Ferrlecit In-vitro cell injury was assessed by; lactate dehydrogenase (LDH) release adenosine triphosphate (ATP) reductions cell cytochrome c efflux and/or electron microscopy In-vivo studies; Mice were injected via the tail vein with 2 mg of each formulation or with a sham tail vein saline injection. Ninety minutes later they were deeply anesthetized, abdominal cavities opened, and the organs removed for analysis. The in-vivo toxicity was assessed by; plasma/renal/cardiac lipid peroxidation (malondialdehyde (MDA)) renal ferritin (protein)/heme oxygenase-1 (HO-1)(mRNA) expression electron microscopy positron injection PTS susceptibility to attack Quotes from the article: In each test, iron evoked in-vitro toxicity, but up to 30 x differences in severity (e.g. ATP declines) were observed (iron sucrose > iron gluconate > low Mw iron dextran). 17 The in-vitro differences paralleled degrees of cell (HK-2) iron uptake. 17 In-vivo correlates of iron toxicity included variable increases in renal MDA, ferritin and HO-1 mrna levels. Again, these changes appeared to parallel in-vivo (glomerular) iron uptake, (seen with iron sucrose and iron gluconate but not with low Mw iron dextran). 17 The minimum required concentrations for significant ATP depression with iron gluconate and iron sucrose was 60 µg/ml and 30 µg/ml. Low Mw iron dextran caused only a minimal non significant ATP depression at the maximum concentration of 1,000 µg/ml. Figure Table lists the IV dose that in humans would result in a comparable concentration, assuming a plasma volume of 3,500 ml. Table As in the study by Geisser 15, Zager 17 also looked at iron deposits, in this case iron deposits in the renal cortex. Picture CosmoFer - Strong toxicological profile compared to iron sucrose and iron gluconate 15-18,53,109 28

31 Zager concluded that: Iron sucrose and to a lesser extent iron gluconate (but not low Mw iron dextran) did induce histologic damage as assessed by electron microscopy. The most notable change was glomerular iron accumulation, taking the form of electron dense aggregates which were most prominent in the mesangium and in endothelial cells. 17 Zager concluded: Parenteral iron formulations have potent, but highly variable, cytotoxic potentials which appear to parallel degrees of cell iron uptake (iron sucrose > iron gluconate > > low Mw iron dextran). 17 That in-vitro injury can be expressed at clinically relevant iron concentrations, and that in-vivo glomerular iron deposition/injury may result, suggest caution is warranted if these agents are to be administered to patients with active renal disease. 17 The significance of Zager s study was recently documented in a clinical study published by Agarwal et al. (2004). 18 In this study 20 predialysis patients (serum ferritin < 100 ng/ml, TSAT < 20%) had baseline urine and blood draws followed by administration of 100 mg/5 min IV push iron sucrose. Blood and urine specimens were collected at 0.25, 0.5, 1, 2, 3 and 24 hours after administra Analysis of acute mitochondrial damage by measurements of decrease in adenosine triphosphate (ATP) concentrations ATP, nmol/mg FeOS Low Mw iron dextran Iron gluconate Iron sucrose Fe, µg/ml < Figure : Analysis of acute mitochondrial damage by measurements of decrease in proximal tubular segment adenosine triphoshate (ATP) concentrations following 30-minute incubations with different concentrations of the three iron preparations. Adapted from Zager et al. (2004) 17 Iron complex Minimum iron Calculated concentration, human IV dose resulting in resulting in a significant comparable mitochondrial plasma damage concentration Low Mw iron dextran 1000 µg/ml 3300 mg Iron gluconate 60 µg/ml 200 mg Iron sucrose 30 µg/ml 100 mg Table : Minimum required dose leading to significant ATP depression with iron gluconate and iron sucrose. For comparison low Mw iron dextran is included although the ATP depression with 1000 µg/ml of this complex is not significant

32 3. Safety profile tion of the drug. Patients were then randomized to receive 600 mg BID N-acetylcysteine (NAC, an antioxidant) or nothing for 1 week in an open-label fashion. After 1 week, iron sucrose was again administered and tests performed for oxidative stress (plasma MDA), proteinuria and enzymuria. Plasma concentration and urinary excretion rate of MDA increased rapidly within 15 to 30 minutes after iron sucrose administration. This increase in MDA was accompanied by enzymuria and proteinuria. NAC reduced acute generation of systemic oxidative stress but failed to abrogate proteinuria or enzymuria. Quote from the article: The data in humans confirm the suggestion of Zager et al. that there was direct renal injury with injected iron sucrose. Whereas administration of NAC resulted in reduction of oxidative stress there was no protection from injury due to direct drug-induced toxicity. 18 Ishizaka et al. (2004) 54 investigated the renal toxicity of iron dextran in an in-vivo animal model. Rats were administered 240 mg/kg of elemental iron every other day until a total dose of iron dextran of 960 mg/kg body weight. This high dose was selected according to the doses used previously to generate rodent models of iron overload. that iron dextran does not enhance or cause renal dysfunction Endothelial cells Carlini et al. (2006) 55 studied the effect of parenteral iron on endothelial cell proliferation. Bovine aortic endothelial cells (BAEC) were incubated in the presence of increasing concentrations of iron sucrose or low Mw iron dextran CosmoFer. Cell proliferation was measured by 3 H Thymidine incorporation. Iron sucrose significantly decreased endothelial cell proliferation (see figure ) compared to low Mw iron dextran. To test if the reduced endothelial cell proliferation was caused by cytotoxicity, the amount of lactic dehydrogenase (LDH) in the cultured media was measured. There was only a significant increase in LDH at the highest concentration of iron sucrose (1 mg/ml). Apoptosis could also be a reason for reduced cell proliferation in these kinds of experiments, and is characterized by DNA fragmentation. Carlini found that iron sucrose, but not low Mw iron dextran, induced DNA fragmentation. 55 Figure Even with these doses iron dextran did not significantly increase proteinuria or decrease creatinine clearance. The authors therefore concluded CosmoFer - Strong toxicological profile compared to iron sucrose and iron gluconate 15-18,53,109 30

33 Cellular iron deposits in human kidney (HK-2) cells Control Low Mw iron dextran 3 Iron gluconate Iron sucrose Picture : Pelleted human kidney (HK-2) cells after 3 days of control incubations, or exposure to 100 µg/ml of either iron dextran, iron gluconate or iron sucrose treatment. The gross appearances of the iron dextran cells were identical to that of the control cells. However, iron sucrose, and to a lesser extent iron gluconate, caused prominent iron staining. Subsequent electron microscopy analysis confirmed intracellular iron sucrose and iron gluconate iron accumulation. Zager et al. (2004) 17 Effect of iron sucrose and low Mw iron dextran on endothelial cell proliferation *** 3H-T incorporation (cpm) ** ** ** mg/ml Low Mw iron dextran Iron sucrose ** Fe-S vs Control (p < 0.001) *** Fe-S vs Control (p < 0.05) Figure : Cell proliferation measured by 3 H Thymidine incorporation. The lower counts per minute the lower degree of cell proliferation. Adapted from Carlini et al. (2006) 55 31

34 4. Flexible administration: IV, IM or as total dose infusion (TDI) The use of parenteral iron has significantly improved the treatment of iron deficiency anaemia. In patients receiving rhuepo therapy, small doses of frequently administered IV iron have eliminated the side effects of oral iron and have been found to effectively maintain iron stores. 31 However, due to the absence of convenient vascular access and logistical barriers, the above method of IV iron administration is not a feasible option for all patients suffering from iron deficiency anaemia. 56 In the case of ambulatory peritoneal dialysis (PD) patients the need to be present at a dialysis center on a regular, often weekly, basis to receive IV iron can be inconvenient to the PD outpatient as well as labour-intensive for staff members. 56 Due to the tightly bound iron complex and the ph of , CosmoFer offers the opportunity of administering the iron dose either as conventional series of small IV doses or as a total dose infusion with up to 20 mg/ kg body weight administered over 4-6 hours in one single infusion. 13 CosmoFer also offers the opportunity of administering the iron dose as a series of undiluted intramuscular injections. 13 IV injection and total dose infusion: Auerbach et al. (1998) 31 compared the safety and efficacy of three different low Mw iron dextran infusion methods, total dose infusion, 500 mg bolus infusion to total dose, or 100 mg bolus to total dose, in 43 haemodialysis patients (see page 10 for more details). The time to maximum haemoglobin, acute adverse reactions, and delayed adverse reactions were analyzed statistically, and no differences were seen in any of the three groups. Table 4 Auerbach concluded: Total-dose intravenous iron dextran infusion is safe, convenient, less expensive, and as efficacious as divided-dose infusions. 31 In 2004 Auerbach et al. 35 published a new study comparing TDI and 100 mg bolus infusions. 35 This study was conducted in 157 patients with chemotherapy related anaemia (see page 14 for more details). In this study there was no difference in haemoglobin response and safety between the different methods of administration. Reddy et al. (2008) 57 performed a retrospective study on the use of total dose infusion of low Mw iron dextran in patients treated for iron deficiency anaemia at a community hospital and a haematology-oncology clinic in the period January 2000 to October patients were identified. The most frequent side effect of TDI was nausea with a rate of 2.2%. Headache, vomiting, chills and backache were seen in 1.1% of patients and about 0.5% of the patients experienced fever and diarrhoea. No anaphylactic reaction was noted. Observed mean elevation of haematocrit was 5.3% and haemoglobin of 2.0 g/dl (p < ). CosmoFer - The only iron for IV, IM and total dose infusion (TDI) 13 32

35 Total dose 500 mg 100 mg P infusion Bolus Bolus Baseline hematocrit (%) NS Peak hematocrit (%) NS Acute side effects NS Delayed side effects NS Table 4: Baseline, peak hematocrit and safety results from Auerbach et al. (1998)

36 4. Flexible administration: IV, IM or as total dose infusion (TDI) The authors concluded: Total dose infusion of iron dextran is a safe and effective treatment in iron deficiency, in patients unresponsive or intolerant to oral iron. This study suggests that TDI can be adopted in a community setting with a low incidence of side effects and with increased patient convenience. 57 Nasimul Ahsan conducted two studies on the efficacy and safety of total dose infusion in peritoneal dialysis. Ahsan et al. (1996) 58 included 7 PD patients that received intravenous total dose infusions of 1 g iron dextran in an outpatient setting. Mean hematocrit rose from 29.13% to 34.85%, TSAT from 10.15% to 29.33%, ferritin from to ng/ml. No patient developed an adverse or allergic reaction. 58 Ahsan et al. (1998) 59 included 25 PD patients that were randomized to either intravenous total dose infusions of 1 g of low Mw iron dextran or oral iron sulfonate (325 mg) 3 times daily. At the end of the 6 month study, the total dose infusion group had a mean hematocrit of 36.0 ± 1.0% versus 31.4 ± 1.1% in the oral group (p<0.05). In addition the final mean dose of weekly rhuepo was reduced by 52% in the total dose infusion group compared to the oral group. There was no adverse reaction to intravenous iron. 59 Ahsan et al. concluded: In summary, this study found that total dose infusion is a safe, effective and superior method to oral iron in treating iron deficiency anemia in rhue- PO treated patients with PD. 59 The clinical setting in which intravenous iron is used should be considered in the choice of iron preparation. For patients with uncomplicated iron deficiency, a single infusion of the total dose of low Mw iron dextran is the most convenient and cost effective. 31,45 Intramuscular injection (IM): Suh et al. (1992) 60 investigated the efficacy and safety of intramuscular biweekly injections of 100 mg iron dextran in 7 stable PD patients. Hematocrit increased significantly (p<0.01) from 29 to 38% and serum ferritin increased from 267 to 660 ng/ dl after iron dextran. No patient developed an anaphylactic or a delayed reaction. Suh et al. concluded: Weekly/biweekly maintenance intramuscular iron dextran injection was effective and safe iron supplementation therapy in PD patients with poor response or side effects to oral iron. 60 CosmoFer - The only iron for IV, IM and total dose infusion (TDI) 13 34

37 4 35

38 5. Cost-effectiveness Fishbane (1995) 33 and Besarab (2000) 34 (page 12) showed that with the proper IV iron protocol, low Mw iron dextran redu-ces the required doses of rhuepo with up to 46% resulting in significant cost savings on the erythropoietin budget. Besides rhuepo related cost saving, CosmoFer also offers the opportunity of significant additional cost savings by implementing a strategy of total dose infusion. Peebles et al. (2004) 61 conducted an audit to examine the clinical outcomes and financial impact of a change to service provision from intravenous iron sucrose (Venofer ) to intravenous low Mw iron dextran (CosmoFer ) administered as total dose infusion (TDI). The article is based on an interim audit of patients treated for renal anaemia at the Sunderland Royal Hospital, UK in the period August 2002 September The audit included 32 predialysis patients and patients on continuous ambulatory peritoneal dialysis suffering from renal anaemia. The endpoints were the clinical outcomes and the financial impact of a change of the service provision to intravenous total dose infusion with low Mw iron dextran CosmoFer. The mean dose of iron administered was 1,200 mg (range 900-1,500 mg). Clinical outcomes At the end of the audit period patients could be categorized into four groups: those receiving a lower dose of EPO following iron administration (8 patients) those receiving a higher dose of EPO following iron administration (4 patients) those with no change in EPO dose (13 patients) those controlled on intravenous iron supplementation alone (7 patients) The mean post-iron administration heamoglobin level was g/dl. The administration of iron dextran complex infusions by TDI has been uneventful throughout the audit period. Financial impact: The cost drivers in relation to the service configuration were: Travel costs, cost of the parenteral iron, giving sets, canulla, dressings: Table 5 CosmoFer - Reduces hospitals costs and increases convenience 14,33,34,61,62 36

39 Quotes from Peebles et al.: A net saving to local acute and primary care trusts of a minimum of 16,184 and a maximum of 27,976 / year is estimated from the 32 patients embraced within this evaluation. 61 This cost impact study reveals that by adopting a policy of administering low-molecularweight iron dextran complex as a TDI, substantial cost savings can be made while improving clinical outcomes. 61 Cost savings by implementing a strategy of total dose infusion with CosmoFer Iron sucrose Cost driver Cost ( ) Travel costs (to hospital account) (four hospital visits) a Parenteral iron 1,200 mg b c Giving set (four) Cannula (four) 2.96 Dressing (four) 2.16 Total Low Mw iron dextran (CosmoFer ) Moniem and Bhandari (2007) 14 also report on the financial impact from a conversion from iron sucrose (Venofer ) to low Mw iron dextran (CosmoFer ). In this prospective crossover study thirty-nine stable patients undergoing haemodialysis and receiving fortnightly 100 mg of intravenous Venofer were converted to receiving 100 mg of CosmoFer fortnightly for six months. Conversion from Venofer to CosmoFer led to a cost saving of approximately 77 per patient over the study period of 6 months directly related to cost of purchase of the drug from the relevant company according to cost to pharmacy (cost saving of approximately per gram of iron administered). Or equivalent to a potential approximate cost saving of 30,000 in an average sized dialysis unit of 200 dialysis patients per year. 14 Cost driver Cost ( ) Travel costs (to hospital account) (one hospital visit) a Parenteral iron 1,200 mg None c Giving set (one) 7.89 Cannula (one) 0.74 Dressing (one) 0.54 Total Table 5: Costs per patient administered 1200 mg of iron. Peebles et al. (2004)

40 6. Clinical use of parenteral iron 6.1 Nephrology Predialysis and peritoneal dialysis patients: Anaemia begins very early during the course of chronic kidney disease (CKD) and progressively worsens with deteriorating renal function. Even at serum creatinine levels less than 2 mg/dl, 45% of the patients have a Hct less than 36%. 63 By the time these patients were referred to a nephrologist, 59% had a Hct less than 36% and 15% had a Hct less than 30%. 54 The epidemiologic data in the NHANES III study revealed a statistically significant decrease in Hb even with only a modest reduction in creatinine clearance to 70 ml/min or less in men and 50 ml/min or less in women. 64 The PRESAM study 65 was designed to assess the care given to pre-dialysis patients in the 12 months before peritoneal dialysis or haemodialysis, with emphasis on anaemia management. The survey showed that at the first visit to the dialysis center, 68% of the patients have a Hb 11 g/dl and 61% were either absolutely (39%) or functionally (22%) iron deficient. Even when only patients from Western Europe were considered, 78% had a Hb 11 g/dl. Only 26% of the patients received IV iron supplementation. 65 One of the reasons for low degree of IV iron use could be the absence of a convenient vascular access and logistical barriers. For predialysis or PD patients the need to be present on a regular basis to receive IV iron is inconvenient to the outpatient as well as labour-intensive for staff members. The NICE guideline concerning treatment of anaemia in people with chronic kidney disease supports the use of total dose infusion with CosmoFer low Mw iron dextran. This guideline 66 published by the National Institute for Health and Clinical Excellence (NICE) in the UK in 2006 recommends the following administration: Haemodialysis patients: Induction/ loading dose: low molecular weight iron dextran 1 gram 58 Non-haemodialysis patients: low molecular weight iron dextran 1 gram 58 This practice of total dose infusion with low Mw iron dextran has previously been described in this monograph by Auerbach et al. (ref. 31 page 10 and ref. 35 page 14) in haemodialysis patients and cancer patients and by Ahsan et al. (ref. 58 and 59 page 34) in PD patients. Jayne Huff from the West Coast Dialysis Center, Inc. in long Beach, CA, USA, has published the protocol they use for the administration of low Mw iron dextran as total dose infusion in PD patients. 56 The recommended procedure for the total dose administration of CosmoFer is described on page 60 in this monograph. Chronic haemodialysis patients: For chronic haemodialysis patients the current practice is mainly the administration of small doses of frequently administered IV iron injections, conveniently administered at the dialysis sessions. Fishbane et al. (1995) 33 describe this procedure for low Mw iron dextran (see page 12). CosmoFer - low Mw iron dextran - IV, IM and as total dose infusion (TDI) 13 38

41 6 39

42 6. Clinical use of parenteral iron 6.2 Oncology Anaemia is now recognized as a significant consequence of cancer and chemotherapy. 35 Prospective clinical trials have determined that mild to moderate anaemia occurs in up to 75% of cancer patients undergoing treatment with chemotherapy and/or radiation therapy. 35 Data from large, prospective clinical trials have shown that rhuepo increases Hb levels, decreases transfusion requirements, and improves the quality of life (QoL) 35. However, approximately 30% to 50% of cancer patients with chemotherapy related anaemia do not achieve a meaningful response to rhuepo, with iron deficiency implicated as one of the primary reasons for the lack of response. 67 Stacy et al. (2008) 68 published in 2008 in the Journal of the American Pharmacist Association (JAPhA) the results from a retrospective study of patients who had chemotherapy-induced anaemia and who were treated with erythropoiesis-stimulating agents (rhuepo). 50 patients met the study criteria of having been treated with rhuepo and an initial Hb of less than 11g/dL. Of these patients, 20 achieved the target Hb level of 12 grams/dl. Only five patients treated with rhuepo received iron supplementation, one responder and four non-responders. Iron indices were measured in 20 patients (40%); 14 patients were candidates for iron therapy based on transferrin saturation, and 3 of these 14 patients received oral iron supplementation. Six responders and six nonresponders received a transfusion (25%). The Authors concluded: The overall response rate and time to Hb response were consistent with previous reports. Iron indices were not commonly measured before ESA therapy was started, and only a few patients were provided oral iron supplementation at our medical center. 68 In the same issue of JAPhA Auerbach et al 69 wrote: As has been amply demonstrated in the dialysis population, the addition of I.V. iron to the treatment paradigm in oncology is associated with more responses, more rapid achievement of target Hb values, and considerable cost savings. These benefits are driven by decreased ESA exposure for equivalent increments in Hb levels. According to a recent review of the development of ESA use in oncology, oncologists use three times the amount of ESAs to achieve one half the benefit in transfusion reduction achieved by nephrologists treating dialysis-associated anaemia, for which transfusions have been eliminated. Although use of myelo-suppressive chemotherapy in oncology patients may blunt the response to ESA, the most glaring difference between nephrology and oncology anaemia management is the ubiquitous use of IV iron to supplement ESA therapy by nephrologists treating anemic dialysis patients. 69 CosmoFer - low Mw iron dextran - IV, IM and as total dose infusion (TDI) 13 40

43 The relative underuse of both iron tests and iron supplementation in oncology versus the regular use in nephrology is illustrated in figure Figure Oral iron supplementation is often used in patients with iron deficiency, but its effectiveness in patients receiving rhuepo for chemotherapy induced anaemia is limited in that it does not provide iron rapidly enough for EPO-induced erythropiesis. 70 Auerbach et al. (2004) 35 conducted a study with the purpose to evaluate the effect of low Mw iron dextran and its optimal route of administration versus no iron or oral iron in 157 cancer patients with chemotherapyrelated anaemia who were all concomitantly receiving 40,000 IU rhuepo once weekly, (see page 14 for further details). Figure As indicated in figure the percentage of patients with haematopoietic responses was significantly higher in both low Mw iron dextran groups (bolus 100 mg doses and TDI) compared with no iron or oral iron groups. 33 Compared to oral iron, IV iron resulted in a 89% increase in the number of patients with a haematopoietic response. Bastit et al. (2008) 71 studied 396 patients with nonmyeloid malignancies receiving chemotherapy, with Hb less than 11 g/dl but excluding patients with absolute iron deficiency (ferritin <10 ng/ml or transferrin saturation <15%). Patients were treated with 500 µg 90 % of patients with services* Cancer patients receiving iron tests Period Prevalent Cohort Year Cancer patients receiving IV iron Dialysis patients receiving iron tests Dialysis patients receiving IV iron Figure 6.2.1: Trends in iron testing and IV iron dosing in cancer patients receiving Chemotherapy and ESA versus dialysis patients. Adapted from Auerbach et al. (2008) Trends in iron testing and IV iron dosing Percentage of responders and non-responders to rhuepo therapy % of Patients No iron 64 Non-Responders 36 Oral iron 32 Responders 68a,b Bolus 100 mg low Mw iron dextran 32 68a,b TDI low Mw iron dextran Figure 6.2.2: Percentage of responders and non-responders in each treatment group for the intent to treat population. Responders were patients who achieved a maximum Hb level 12 g/dl or an increase in Hb of 2.0 g/dl during the study. a P<0.01 v no-iron group; b P< 0.01 v oral iron group. Adapted from Auerbach et al. (2004)

44 6. Clinical use of parenteral iron every 3 weeks with IV iron versus with local standard practice (oral iron or no iron) for 16 weeks. The haematopoietic response rate (proportion of patients achieving Hb 12 g/dl or Hb increase of 2 g/dl from baseline) was significantly higher in the IV group. This trial also showed a statistically significant reduction in the percentage of patients receiving RBC transfusions (nine vs. 20%) in the IV iron group. Figure The Authors concluded: In conclusion, IV iron supplementation can be used to enhance the efficacy of darbepoetin alfa Q3W in patients with chemotherapyinduced anaemia. Concomitant use of erythropoietin stimulating agents and IV iron is an important advance in anaemia management, allowing more patients to experience the benefit of anaemia treatment, with a shorter lag time to response and fewer transfusions. 71 Pedrazzoli et al. (2008) 72 studied 149 patients with solid tumours receiving chemotherapy who were anaemic but iron replete. Patients were treated with 150 µg of subcutaneous darbepoietin alpha weekly with or without IV iron. Still in this iron replete population, there were statistically significant improvements in Hb and the haematopoietic responses in the IV iron group. Figure The authors concluded: In patients with chemotherapy-related anaemia and no iron deficiency, IV iron supplementation significantly reduces treatment failures to darbepoetin without additional toxicity. 72 Above trials by Auerbach 35, Bastit 71 and Pedrazzoli 72 all demonstrate the benefits of using IV iron in combination with rhuepo in patients with cancer and chemotherapy induced anaemia. Despite these and similar results, IV iron is still not used on a routine basis in this patient population. This inadequate use of IV iron in the oncology setting has recently taken a new urgency with the Medicare & Medicaid Services (CMS), the Oncology Drug Advisory Committee (ODAC) and the FDA s newly imposed restrictions on the use or rhuepo in oncology, as discussed by Auerbach and Ballard in Journal of the American Pharmacist Association The dose of darbepoietin alpha was doubled at four weeks if less than a 1 g/dl Hb increment was observed. The authors pointed out that this trial excluded all patients with absolute or functional iron deficiency. Eligibility for randomization required serum ferritin levels greater than 100 ng/ml and TSATs greater than 20%. CosmoFer - low Mw iron dextran - IV, IM and as total dose infusion (TDI) 13 42

45 Quote from Auerbach and Ballard 2008: Percentage of patients receiving transfusions If total ESA exposure is indeed causing morbidity in oncology patients, is it not reasonable to ask that IV iron, which in all existing studies has improved the magnitude of response, time to maximal response, and cost of therapy by decreasing ESA exposure, becomes routine in the treatment algorithm for anaemic patients with cancer? Percentage of patients receiving transfusions 20 9 In the recent clinical practice guideline of the National Comprehensive Cancer Network (NCCN, V ), IV iron products are recommended for iron repletion in cancer patients with absolute iron deficiency (ferritin <30 ng/ml, transferrin saturation <15%) or in patients receiving erythropoietic drugs IV iron n=200 Standard practice a n=196 Figure 6.2.3: Kaplan-Meyer proportion of patients receiving a RBC transfusion between week 5 and to the end of treatment phase. Adapted from Bastit et al. (2008) 71 a) Standard practice: oral iron or no iron. Time course of mean haemoglobin The guideline recommends the use of iron sucrose, iron gluconate and low Mw iron dextran. Total dose infusion is also recommended but only for low Mw iron dextran. Concerning oral iron versus IV iron the guideline states that substantial evidence suggests that IV iron is superior to oral iron Hb (g/dl) Time (weeks) IV iron No iron Figure 6.2.4: Time course of mean haemoglobin (Hb) level in the two study groups in the per protocol group. Adapted from Pedrazzoli et al. (2008) 72 43

46 6. Clinical use of parenteral iron 6.3 Obstetrics and gynaecology The level of iron stores among fertile women varies around the world according to the median dietary iron intake in each country. Among fertile women in Denmark, 20% have iron reserves of >500 mg, which is the required minimum during pregnancy; 40% have iron stores of mg, and 40% have virtually no iron stores. 74 The American College of Obstetricians and Gynaecologists, and obstetric textbooks recommend routine oral iron supplementation with a daily dose of 30 mg of elemental, ferrous iron during the second and third trimester. The WHO recommends 60 mg of iron per day with 400 µg of folic acid in the areas where prevalence of iron deficiency is <20% in the population and recommends double this amount in areas where the prevalence is higher. 75 Oral iron supplementation is the treatment of choice for the majority of patients, but up to 10-40% may have symptoms attributable to the intake. The principal adverse effects are of gastrointestinal nature. In the case of pregnancy the adverse effect of oral iron is often aggravated by the adverse effect of pregnancy on the gastrointestinal tract, which includes nausea and vomiting and motility disorder with reflux esophagitis. 75 text states that: CosmoFer should not be used during the first trimester of pregnancy. If the benefit of CosmoFer -treatment is judged to outweigh the potential risk to the foetus, it is recommended that treatment, should be confined to the second and third trimester, if treatment is clearly necessary. 13 Mays et al. (1976) 76 reported the efficacy of total dose infusion with iron dextran for the treatment of anaemia in 51 surgical (29), gynaecological-obstetric patients (22). The most frequent indication in the obstetricgynaecologic group for intravenously administered iron was menorrhagia and pre- and post partum anaemias. The patients received between 1,000 and 4,500 mg of elemental iron. The total dose was diluted in 1,000 ml isotonic saline solution and infusion was begun at 10 drops per minute. Vital signs were evaluated every 15 minutes. If there was no adverse reaction, the rate was increased and the entire volume completed within two to four hours, depending upon the cardiac function of the patient. 76 There were no allergic reactions or adverse effects. The average increase in haemoglobin concentration one week after infusion of iron dextran was 1.9 g/dl. 76 Indications for the use of parenteral iron are limited to conditions in which the oral supplementation of iron is not possible or fails, or where there is a clinical need for rapid delivery of iron. For CosmoFer the SPC CosmoFer - low Mw iron dextran - IV, IM and as total dose infusion (TDI) 13 44

47 Quote from the article: Despite tremendous advances in antenatal care, obstetricians, all too often, are called upon to care for patients who first present themselves to their physicians only a few weeks from term, greatly iron deficient and severely anemic. The hazards of such condition are well known. There is not sufficient time to achieve much replenishment of iron stores with oral iron therapy. A pint of transfused blood raises the haemoglobin only about 6 per cent. Intravenous iron dextran therapy is highly effective in these situations. 76 Haemoglobin TDI series Oral iron series level g/dl No. cases % No. cases % Less than 7 nil nil Table 6.3.1: Haemoglobin values in subsequent pregnancy after either total dose infusion with iron dextran or oral iron therapy. Adapted from Bhatt (1996). 77 Bhatt (1996) 77 followed two series of women until their next pregnancy, one with total dose infusion with iron dextran and the other with oral iron therapy. 72% of the women who received a total dose infusion of iron dextran during their previous pregnancy maintained a haemoglobin level of more than 10 g/dl as compared to only 18% in the group of women taking oral iron supplementation see table Table

48 6. Clinical use of parenteral iron Ayub et al. (2008) 78 studied the efficacy and safety of total dose infusion of low Mw iron dextran in the treatment of iron deficiency anaemia during pregnancy in women with gestational age greater than 12 weeks. A group of 100 pregnant women with a confirmed diagnosis of iron deficiency anaemia attending the antenatal clinics were enrolled in the study. Total dose iron infusion of low Mw iron dextran was given to these patients after calculating iron deficit, in a monitored in-patient setting. Control comprised of a second group of 50 pregnant females matched for age, parity and baseline haemoglobin, tolerant to oral iron supplementation (ferrous sulphate 200 mg three times a day) attending the antenatal clinics during the same period. Posttreatment haemoglobin levels of the study group as well as the oral control group were determined between 3 and 4 weeks. In the intervention group, mean preinfusion haemoglobin level was 8.57 ± 0.9 g/dl and mean post-infusion Hb was 11.0 ± 1.1 g/dl. In the control group, mean pre-oral intake Hb level was 9.5 ± 0.9 g/dl and mean post-oral intake Hb was 10.2 ± 1.2 g/dl. Mean increase of Hb in the intervention group was 2.43 g/dl (95% CI ) and for controls it was 0.7 g/dl (95% CI ). The authors concluded: Total parenteral iron replacement with low molecular weight iron dextran is an effective and safe method for the treatment of iron deficiency anaemia in a selected group of pregnant women. 78 Komolafe et al. (2003) 79 conducted a comparative study to evaluate the effectiveness of treatment of iron deficiency anaemia in pregnancy with either intramuscular iron dextran (250 mg thrice weekly until the total dose was given) or oral ferrous sulphate (200 mg 3 times daily). Sixty pregnant women were randomly assigned to either group and treated for 6 weeks. Quote from the article: Thirty-six per cent of patients in the iron dextran group compared to 3.3% in the oral iron group (p=0.004) had their anaemia corrected by the sixth week. No significant side effects accompanied the use of intramuscular iron dextran. 79 Flushing and palpitations were observed in 4% of interventional group patients and none in the control group. No significant adverse reactions were observed in either group. CosmoFer - low Mw iron dextran - IV, IM and as total dose infusion (TDI) 13 46

49 Sharma et al. (2004) 80 reports on a prospective, partially randomized study of pregnancy outcomes and haematologic responses to oral and intramuscular iron treatment in moderate anaemic pregnant women. 148 pregnant women received daily oral doses of 100 mg elemental iron and 500 µg folic acid, and 106 pregnant women received 3 intramuscular doses of 250 mg elemental Fe as iron dextran at 1-monthly intervals and oral doses of 5 mg folic acid twice weekly. Quote from the article: Haemoglobin and iron indicators improved significantly with both treatments. The increase in serum ferritin concentration after parenteral iron treatment was significantly higher than after oral treatment. 80 Systemic side effects were more common in the parenteral iron group, whereas gastrointestinal side effects were more common in the oral group The intramuscular administration of 3 doses of 250 mg Fe at monthly intervals appears to have good compliance and efficacy and may be used in women who cannot tolerate oral administration of iron. 80 For intramuscular use of CosmoFer the maximum recommended dose to be administered at one single injection is 100 mg, please see the administration and dosage recommendations on page

50 6. Clinical use of parenteral iron 6.4 Gastroenterology Anaemia is a common finding in inflam-matory bowel disease (IBD). It affects between 30% and 70% of patients and has a great impact on the quality of their lives. The cause of IDA in IBD is related to blood loss, malabsorption or other medicamental treatment. 81 In the developed world the leading cause of iron deficiency is considered to be blood loss. In the latter case, blood loss in the stomach or intestine cannot be matched by duodenal iron absorption, creating a negative iron balance. This imbalance is often seen in patients with IBD, in fact one third of all IBD patients still have haemoglobin levels below 12 g/dl. 82 The efficacy of oral iron therapy in patients with IBD is often hindered by several factors: Ongoing inflammation processes 82 Side-effects 82 Malabsorption 82 Lack of compliance 82 These limitations of oral iron therapy in inflammatory bowel disease patients mean that alternative routes of iron administration should be considered. 82 Reddy et al. (2008) 57 published results from a retrospective analysis from 194 patients with iron deficiency anaemia (IDA) secondary to gastric surgery recieving low Mw iron dextran as total dose infusion. The average increase of 2.0 g/dl Hb was statistically significant (p<0.0001). See figure Adverse events were noted in less than 5% of the cases. No anaphylactic reactions were noted. Figure Quote from the article: TDI is very convenient because it only requires one visit to a clinic 57 Mamula et al. (2002) 81 analyzed the use of iron dextran administered as total dose infusion (TDI) to children with IBD and iron deficiency anaemia. The analysis covered the use of total dose intravenous iron dextran infusions. Seventy patients received a total of 119 TDI iron dextran infusions. Typical administered iron dose ranged between 500 mg and 2000 mg. 81 The patients experienced an average increase in haemoglobin concentration of 2.9 g/dl (p<0.0001) of the total number of infusions. None of the reactions were considered life threatening, and none of the children required hospitalization. 81 Mamula et al.concluded: This retrospective study suggests that TDI infusion of iron dextran, when appropriately used, is a safe and potentially efficacious treatment for children with IBD and iron deficiency anemia. 81 Peck et al. (1998) 9 also reported on the use of iron dextran as total dose infusion to children with anaemia and inflammatory bowel disease. 51 infusions were given. There were 4 CosmoFer - low Mw iron dextran - IV, IM and as total dose infusion (TDI) 13 48

51 AEs during 44 (9%) INFeD infusions and 5 AEs during 7 (74%) Dexferrum infusions. All AEs responded to IV Benadryl (1mg/kg) and IV fluids. 11 patients received multiple IV iron dextran infusions with INFeD without AEs. 3 patients who had AEs to Dexferrum subsequently received INFeD without sequelae. g/dl Increase in haemoglobin p > ,7 9,65 Peck et al. concluded: Infusion of INFeD is a safe and effective therapy. Clinicians must recognize that the rate of AE may vary widely depending on the iron dextran formulation Pre Total Dose Infusion Post Total Dose Infusion Figure 6.4.1: Low Mw iron dextran given as TDI in patients with IDA secondary to gastric surgery. Adapted from Reddy et al. (2008) 57 n=194 The recent guideline on the diagnosis and management of iron deficiency and anaemia in inflammatory bowel diseases clearly recommends that iron is administered via the intravenous route. 83 Quote from the guideline: The preferred route of iron supplementation in IBD is intravenous, even though many patients will respond to oral iron. Intravenous iron is more effective, better tolerated and improves the quality of life to a greater extent than oral supplements According to the current approved label CosmoFer is not approved in children below the age of 14 years 49

52 6. Clinical use of parenteral iron 6.5 Surgery and transfusion medicine Anaemia may be encountered at any time perioperatively. Patients hospitalized for surgery may have an underlying anaemia from the start or blood loss during and after surgery may produce anaemia. 84 According to Shander et al. (2004) 84 the prevalence of preoperative anaemia varied dramatically, from a low of 5% for geriatric women patients with hip fracture to a high of 75.8% in patients with advanced colon cancer undergoing colectomy. The consequence of anaemia in the surgical setting can be divided in indirect and direct consequences. Direct referring to the risks of a low Hb related increased morbidity and indirect referring to the risks related to the increased use of allogeneic blood transfusions during or after the surgery. See list for the risk of allogeneic transfusions. List Murphy et al. (2007) 86 performed a retrospective cohort study in the UK to quantify associations of transfusion with clinical outcomes and cost in patients having cardiac surgery. The authors concluded: Red blood cell transfusion in patients having cardiac surgery is strongly associated with both infection and ischemic postoperative morbidity, hospital stay, increased early and late mortality, and hospital costs. 86 The management and avoidance of anaemia and the use of allogeneic blood transfusions in the surgical setting can conveniently be split into three parts: Implementation of restrictive transfusion protocols Autologous red blood cell donation Preoperative diagnosis of anaemia and the administration of pharmacological agents to increase erythrocyte production Restrictive transfusion protocols can reduce the relative risk for allogeneic blood transfusions by 25-30%. 87 It is also well known that the preoperative Hb level is one of the strongest predictors for postoperative allogeneic blood transfusions. 87 In the case of iron deficiency anaemia oral iron administration should be the preferred route for iron administration. The challenge is that it often is a time consuming therapy. For example, a person with an Hb of 8.5 g/dl weighing 70 kg would have a body iron deficit of about 1700 mg. 88 Even at the maximum daily iron absorption rate in the presence of iron deficiency (10 mg), it would take several months to replace the iron orally. A timeframe that is unacceptable for most patients who require surgery. 89 If the patient s iron stores were depleted going into the procedure, the blood loss could not be corrected by endogenous red blood cell production. 87 Parenteral iron with or without rhupo is not an alternative to acutely needed red blood cell transfusions, but the timely use of parenteral iron can potentially eliminate a substantial number of allogeneic blood transfusions. CosmoFer - low Mw iron dextran - IV, IM and as total dose infusion (TDI) 13 50

53 Goodnough et al (2005) 89 published an article on detection, evaluation, and management of anaemia in the elective surgical patient and recommends the following practical step: Whenever clinically feasible, elective surgical patients should have a haemoglobin level tested a minimum of 30 days before the scheduled surgical procedure. 89 This provides sufficient time to promote erythropoiesis with iron, vitamin B12, folic acid and erythropoietin stimulating agents to hopefully avoid blood transfusion in the perioperative setting. Statistics on risks of transfusions: Allergic reactions occur in 1%-4% of all blood transfusions 85 Transfusion transmitted virus (TTV) is present in 52% (8-82 percent reported) of all units infused 85 The risk of fatal septic platelet transfusion could be as high as 1 in 25,000 to 50,000 units 85 The risk of transfusion related acute lung injury (TRALI) is 1 in 5,000-10,000 units 85 The risk of tranfusion related deaths is 2-5 per million 85 List Paul Stross published in an article with the title: Anaemia management: intravenous iron can enable a reduction in blood transfusions a benefit for patients and hematology wards. In this article Stross describes how to limit the need for blood transfusion by the timely use of total dose infusion with low Mw iron dextran. Quotes from the article: 6 In contrast to anxieties relating to absorption and compliance with oral iron, intravenous iron therapy is reliable and easy to administer in a hospital practice. Compared with oral iron or blood transfusion, it is a much quicker way of administering iron, particularly when a total-dose infusion program is used. 90 Haemoglobin rises of over 2 g/dl per week have been seen with a latency of approximately 1 week before improvement starts

54 6. 2. Clinical Efficacy use profile parenteral iron 6.6 Cardiology Within cardiology the implications of anaemia for patients with congestive heart failure (CHF) is well known Already in 2000 Silverberg et al. 100 published the first report showing a decrease in haemoglobin content with increasing severity of CHF. In this study the prevalence of anaemia varied between 9.1 and 79.1% of patients depending on the severity of heart disease (NYHA Class). 100 Since then, several studies have documented a greater morbidity and mortality associated with anaemia in patients with CHF Figure Nanas et al. (2006) 101 studied the aetiology of anaemia in patients with advanced heart failure. 37 anaemic patients with a mean age of 57.9 years and a mean left ventricular ejection fraction of 22.5% were evaluated. Of these patients bone marrow aspirations confirmed iron deficiency anaemia in 27 patients equal to 73% of the patients. Figure not receive any treatment for their anaemia. The ACC/AHA 2008 Guidelines for the Management of Adults With Congenital Heart Disease 104 states the following concerning iron deficiency in section Cyanotic Congenital Heart Disease. Quote from the guideline: The treatment for iron deficiency in a patient with destabilized erythropoiesis is challenging. Oral administration of iron frequently results in a rapid and dramatic increase in red cell mass; therefore, caution should be exercised and haemoglobin monitored. Once the serum ferritin and/or transferrin saturation is within the normal range, iron supplementation may be discontinued. Occasionally, patients are intolerant of oral iron and should be placed on pulses of intravenous iron supplementation instead. 104 Studies have shown that the correction of anaemia in patients with advanced CHF significantly improves cardiac function, functional capacity and quality of life. 102,103 Silverberg et al. (2001) 102 used a treatment regimen of subcutaneous erythropoietin (rhuepo) combined with intravenous iron and showed a 42.1% improvement in NYHA class over a mean treatment period of 8.2 months in the group receiving rhuepo and iron relative to the group that did CosmoFer CosmoFer - low Mw - Improves iron dextran erythropoiesis - IV, IM and and as the total patient s dose infusion quality (TDI) of life 13 52

55 2. Efficacy profile Proportion surviving Proportion Surviving Hematocrit >37% Hematocrit >32% to 37% Hematocrit >27% to 32% Hematocrit 27% No. at risk Hematocrit 27% 0.4 Hematocrit >27% to 32% 320 Hematocrit >32% to 37% 641 Hematocrit >37% Days Figure 6.6.1: One year survival in patients with heart failure according to the hematocrit (%) level. Adapted from Kosiborod et al. (2003) Etiologie of anaemia ,0% ,9% ,4% 2,7% Iron deficient anemia Anemia of chronic disease Hemodilution Drug induced Figure 6.6.2: Distribution of various etiologies of anaemia among 37 patients with advanced congestive heartfailure. Adapted from Nanas et al. (2006) 101 CosmoFer - Improves erythropoiesis and the patient s quality of life

56 6. Clinical use of parenteral iron 6.7 Geriatrics Anaemia in the elderly arises from a variety of causes: most are common to all age groups, but some are more characteristic of aging versus younger populations. 105 Anaemia of chronic disease for example is associated with several conditions that are more prevalent in older individuals. 105 Chronic infection Inflammatory disease Malignancies Iron deficiency is also frequently seen as a result of acute or chronic blood loss through the gastrointestinal tract. Other leading causes of anaemia in the elderly include folate and cobalamin deficiencies due to inadequate intake or reduced absorption. 105 Beghé et al. (2004) 105 conducted a systematic review on the prevalence of anaemia in geriatrics. Beghé found reported prevalences from 2.9% to 61% in elderly men and from 3.3% to 41% in elderly women. This variability was related to several factors: The setting of the study Health status of the subject population Criteria used to define anaemia Incidence of anaemia also rises with age; some studies report a particular notable increase in prevalence of anaemia in the oldest subjects 85 years of age. 105 Whereas anaemia is associated with symptoms ranging from weakness and fatigue to increased falls and depression, and in severe cases can lead to congestive heart failure, few studies have systematically examined functional, clinical, and economic outcomes of patient satisfaction in the elderly with anaemia. 105 Beghé et al found three studies that evaluated the complications of anaemia in geriatric patients. Beard et al. (1997) 106 found an almost 2-fold increase in the occurrence of Alzheimer disease among patients with anaemia. Even though there is no known direct causal connection between anaemia and Alzheimers disease, the 2 conditions may have common underlying bases. 106 Salive et al. (1992) 107 examined the association between anaemia in the elderly and morbidity and hospitalization. Men who described themselves as in poor health were 2.7 times more likely to have anaemia than were men in excellent health. Women with self-reported excellent health had significantly higher haemoglobin values than those who described their health as fair. In both sexes, there was an inverse relation between haemoglobin values and hospitalization rates. 107 Kikuchi et al. (2001) 108 studied the relation between anaemia and mortality (5-year survival rates) in the elderly. Anaemic patients had significantly lower survival rates than did control subjects (P<0.001): 48% versus 67% in patients aged 70 to 79 years, 41% versus 62% in patients aged 80 to 89 years, and 13% versus 25% in patients aged 90 to 99 years. 108 CosmoFer - low Mw iron dextran - IV, IM and as total dose infusion (TDI) 13 54

57 6 9 55

58 7. Pharmaceutical presentation CosmoFer solution for injection and infusion contains elemental iron(iii) (50 mg Fe/ml), in a tightly bound iron dextran complex (USP, BP Quality), as the active ingredient. 13 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. 13 The colour of the solution is dark brown and is for single use only. Any unused solution should be discarded. CosmoFer must only be mixed with 0.9% sodium chloride or 5% glucose solution. No other intravenous dilution solutions or therapeutic agents should be used. 13 Before administering the first dose to a new patient, a test dose of CosmoFer corresponding to 25 mg iron or equal to 1/2 ml solution is re-commended. If no adverse reactions are seen after 60 minutes, the remaining dose can be given. 13 CosmoFer is available in single dose glass ampoules containing 2 ml or 10 ml of iron(iii)-hydroxide dextran complex (USP, BP Quality). Not all pack sizes may be marketed in every country. Before administering CosmoFer please consult the full prescribing information. CosmoFer packages: Containing five 2 ml ampoules for injection or infusion, each containing 100 mg of elemental iron in the form of Iron(III)- hydroxide dextran complex. Containing two 10 ml ampoules for injection or infusion, each containing 500 mg of elemental iron in the form of Iron(III)- hydroxide dextran complex. CosmoFer CosmoFer - low Mw - Improves iron dextran erythropoiesis - IV, IM and and as the total patient s dose infusion quality (TDI) of life 13 56

59 The production of dextran by Pharmacosmos A/S in Denmark is certified by the European Directorate for the Quality of Medicines, and the production complies with the highest standards of Good Manufacturing Practice. Pharmacosmos has developed a non organic solvent based technique to fractionate and purify the polymer of dextran molecules according to their size (number of glucose units linked together in the molecules) and is thereby able to very precisely control the molecular weight distribution in each batch. We believe that one of the reasons for the success of Pharmacosmos low Mw iron dextran is the carefully controlled molecular weight distribution of the applied dextran. This implies a reduced risk of anaphylactoid reactions compared to traditional higher Mw iron dextrans, as documented in seven individual publications The iron dextran production process is developed by Pharmacosmos. No other iron dextran formulation is produced the same way as the low Mw iron dextran from Pharmacosmos. Each producer has his own manufacturing process. This is among others reflected in the different molecular weights and molecular weight distribution of the currently available formulations. It is important to have these differences in mind when you compare the safety data of different iron dextran preparations. 7 The new Pharmacosmos factory in Holbaek, Denmark. The production of low Mw iron dextran by Pharmacosmos has been FDA approved since 1992 when INFeD was introduced on the North American market. 57

60 8. CosmoFer prescribing information NAME OF THE MEDICINAL PRODUCT: CosmoFer 50mg/ml solution for infusion and injection. QUALITATIVE AND QUANTITATIVE COMPOSITION: 2 ml ampoule containing 100 mg iron(iii) as Iron(III)-hydroxide dextran complex. 5 ml ampoule containing 250 mg iron(iii) as Iron(III)- hydroxide dextran complex. 10 ml ampoule containing 500 mg iron(iii) as Iron(III)-hydroxide dextran complex. Each ml contains 50 mg Iron (III). For a full list of excipients, see section Pharmaceutical particulars. PHARMACEUTICAL FORM: Solution for infusion and injection. A dark brown solution. CLINICAL PARTICULARS: Therapeutic indications: - For adults only. CosmoFer is indicated for the treatment of iron deficiency in the following indications: When oral iron preparations cannot be used, e.g. due to intolerance, or in case of demonstrated lack of effect of oral iron therapy Where there is a clinical need to deliver iron rapidly to iron stores. The diagnosis of iron deficiency must be based on appropriate laboratory tests (e.g. serum ferritin, serum iron, transferrin saturation and hypochromic red cells). Posology and method of administration: Test dose: (all routes of administration) Before administering the first dose to a new patient, a test dose of CosmoFer corresponding to 25 mg iron or equal to 0.5 ml solution must be administered. If no adverse reactions are seen after 60 minutes, the remaining dose can be given. Anaphylactoid reactions to CosmoFer are usually evident within a few minutes, and close observation is necessary to ensure recognition. If at any time during the intravenous administration of CosmoFer, any signs of a hypersensitivity reaction or intolerance are detected, administration must be stopped immediately. Resuscitative medication and personnel trained to evaluate and rescuscitate anaphylaxis should be available whenever a dose of iron dextran is administered. Administration: CosmoFer solution for injection can be administered by an intravenous drip infusion or by a slow intravenous injection of which the intravenous drip infusion is the preferred route of administration, as this may help to reduce the risk of hypotensive episodes. However, CosmoFer may also be administered as undiluted solution intramuscularly. - Adults and elderly. The total cumulative dose of CosmoFer is determined by haemoglobin level and body weight. The dose and dosage schedule for CosmoFer must be individually estimated for each patient based on a calculation of the total CosmoFer - low Mw iron dextran - IV, IM and as total dose infusion (TDI) 13 58

61 iron deficit. - Children (under 14 years). CosmoFer should not be used for children. There is no documentation for efficacy and safety. Dosage: (The normal recommended dosage schedule is mg iron corresponding to 2-4 ml, two or three times a week depending on the haemoglobin level. However, 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 20 mg iron/kg body weight. The CosmoFer injection should not be administered concomitantly with oral iron preparations as the absorption of oral iron will be reduced (please refer to section Interaction with other medicinal products and other forms of interaction ). Subsequent doses Intravenous drip infusion: CosmoFer must be diluted only in 0.9% sodium chloride solution (normal saline) or in 5% glucose solution. CosmoFer in a dose of mg iron (2-4ml) may be diluted in 100 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 of not more than 100 ml in 30 minutes. Intravenous injection: CosmoFer may be administered in a dose of mg iron (2-4 ml) Calculation of dose: a) Iron replacement in patients with iron deficiency anaemia: Factors contributing to the formula are shown below. The required dose has to be individually adapted according to the total iron deficit calculated by the following formula haemoglobin in g/l or mmol/l. Total dose (mg Fe) Hb in g/l: Body weight (kg) x (target Hb - actual Hb) (g/l) x mg iron for iron stores. The factor 0.24 is derived from the following assumptions: a) Blood volume 70 ml/kg of body weight 7% of body weight. b) Iron content of haemoglobin 0.34% Factor 0.24 = x 0.07 x 1000 (conversion from g to mg). Total dose (mg Fe) Hb in mmol/l: Body weight in kg x (target Hb in mmol/l actual Hb in mmol/l) x mg iron for iron stores. The factor 3.84 is derived from the following assumptions: a) Blood volume 70 ml/kg of body weight 7% body weight. b) Iron content of haemoglobin 0.34%. c) Factor for conversion from haemoglobin g/l to mmol/l is Factor 3.84 = x 0.07 x 1000 / Table 8.1 shows the number of millilitres of CosmoFer injection solution to be used at various degrees of iron deficiency anaemia. The figures in the table below are based on a target haemoglobin of 150 g/l or 9.3 mmol/l and iron stores of 500 mg which apply to a body weight exceeding 35 kg. 8 59

62 8. CosmoFer prescribing information by slow intravenous injection (0.2 ml/ min) preferably diluted in ml 0.9% 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. Total dose infusion: Immediately before administration the total amount of CosmoFer required, determined from the dosage table or by calculation, is added aseptically to the required volume, usually 500 ml of sterile normal sodium chloride or 5% glucose solutions. The total amount of CosmoFer, up to 20 mg/kg bodyweight, is infused intravenously over 4 6 hours. The first 25 mg of iron should be infused over a period of 15 minutes. The patient must be kept under close medical observation during this period. 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 drops per minute. Patients should be observed carefully during the infusion and for at least 1 hour after completion. Total Dose Infusion (TDI) has been associated with an increased incidence of adverse reactions, in particular delayed hypersensitivity like reactions. The intravenous administration of CosmoFer by the total dose infusion method should be restricted to hospital use only. 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: Following a test dose prior to the first injection the entire dose is administered at once for subsequent intramuscular injections. The total 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 100 mg iron (2.0 ml) each determined by the patient s body weight. If the patient is moderately active, injections may be given daily into alternate buttocks. In inactive or bedridden patients, the frequency of injections should be reduced to once or twice weekly. CosmoFer must be given by deep intramuscular injection to minimise the risk of subcutaneous staining. It should be injected only into the muscle mass of the upper outer quadrant of the buttock - never into the arm or other exposed areas. A gauge needle at least 50 mm long should be used for normal adults. For obese patients the length should be mm whereas for small adults a shorter and smaller needle (23 gauge x 32 mm) is used. The patient should be lying in the lateral position with the injection site uppermost, or standing bearing their weight on the leg opposite the injection site. To avoid injection or leakage into the subcutaneous tissue, a Z-track technique (displacement of the skin laterally prior to injection) is recommended. CosmoFer is injected slowly and smoothly. It is important to wait for a CosmoFer - low Mw iron dextran - IV, IM and as total dose infusion (TDI) 13 60

63 Total dose of CosmoFer in millilitres to be administered in iron deficiency anaemia Haemoglobin 60 g/l 75 g/l 90 g/l 105 g/l 120 g/l 135 g/l content Body weight (kg) mmol/l mmol/l mmol/l mmol/l mmol/l mmol/l Table 8.1 Note: The table and accompanying formula are applicable for dose determination only in patients with iron deficiency anaemia. They are not to be used for dose determination in patients requiring iron replacement for blood loss. b) Iron replacement for blood loss: Iron therapy in patients with blood loss should be directed toward replacement of an amount of iron equivalent to the amount of iron represented in the blood loss. The table and formula described are not applicable for simple iron replacement values. Quantitative estimates of the individual s periodic blood loss and hematocrit during the bleeding episode provide a convenient method of calculation of the required iron dose. The required CosmoFer dose to compensate the iron deficit is calculated according to the following formulas: If the volume of blood lost is unknown: The administration of 200 mg i.v. iron (4 ml CosmoFer ) results in an increase of haemoglobin which is equivalent to 1 unit blood (= 400 ml with 150 g/l Hb content or 9.3 mmol Hb/l equivalent to 0.34% of 0.4 x 150 or 204 mg iron). Iron to be replaced [mg] = number of blood units lost x 200. Millilitres of CosmoFer needed = number of blood units lost x 4. If the Hb level is reduced: Use the previous formula considering that the depot iron does not need to be restored. Mg iron to be replaced = body weight (kg) x 0.24 x (target Hb in g/l - actual Hb in g/l). Or Mg iron to be replaced = body weight (kg) x 3.84 x (target Hb in mmol/l actual Hb in mmol/l). E.g.: body weight 60 kg, Hb deficit = 10 g/l or 0.62 mmol/l: Iron to be replaced = 60 x 0.24 x 10 = 60 x 3.84 x 0.62 = 143 mg ( 3 millilitres CosmoFer ) 8 61

64 8. CosmoFer prescribing information few seconds before withdrawing the needle to allow the muscle mass to accommodate the injection volume. To minimise leakage up the injection track, the patient should be encouraged not to rub the injection site. Although there are significant variations in body build and weight distribution among males and females, the accompanying table and formula represent a convenient means for estimating the total iron required. This total iron requirement reflects the amount of iron needed to restore haemoglobin concentration to normal or near normal levels plus an additional allowance to provide adequate replenishment of iron stores in most individuals with moderately or severely reduced levels of haemoglobin. It should be remembered that iron deficiency anaemia will not appear until essentially all iron stores have been depleted. Therapy, thus, should aim at not only replenishment of haemoglobin iron but of iron stores as well. If the total necessary dose exceeds the maximum allowed daily dose, the administration has to be split. Evidence of a therapeutic response can be seen within a few days of administration of CosmoFer as an increase in the reticulocyte count. Serum ferritin levels usually provide a good guide to the replenishment of iron stores. In renal dialysis patients receiving CosmoFer, this correlation may not be valid. Contraindications: Non-iron deficiency anaemia (e.g. haemolytic anaemia). Iron overload or disturbances in utilisation of iron (e.g. haemochromatosis, haemosiderosis). Patients with a history of asthma, eczema or other atopic allergic should not be treated by intravenous injection. Drug hypersensitivity including iron mono- or disaccharide complexes and dextran. Decompensated liver cirrhosis and hepatitis. Acute or chronic infection, because parenteral iron administration may exacerbate bacterial or viral infections. Rheumatoid arthritis with symptoms or signs of active inflammation. Acute renal failure. Special warning and precautions for use: 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 1:1000 adrenaline solution. Additional treatment with antihistamines and/or corticosteroids should be given as appropriate. For administration of test dose, please refer CosmoFer - low Mw iron dextran - IV, IM and as total dose infusion (TDI) 13 62

65 to section Posology and method of administration. There is particularly increased risk of allergic reactions in patients with immune or inflammatory conditions (e.g. systemic lupus erythematosus, rheumathoid arthritis). When parenteral iron therapy is considered essential in patients with asthma, allergic disorders and inflammatory disorders, the intramuscular route is to be preferred. The intramuscular and subcutaneous injection of iron-carbohydrate complexes in very large doses under experimental conditions in animals produced sarcoma in rats, mice, rabbits, possibly hamsters but not in guinea pigs. Cumulative information and independent assessment indicate that the risk of sarcoma formation in man is minimal. Hypotensive episodes may occur if intravenous injection is administered too rapidly. Interaction with other medicinal products and other forms of interaction: The CosmoFer injection 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. Pregnancy and lactation: There are no adequate data from the use of CosmoFer in pregnant women. Studies in animals have shown reproductive toxicity (see section Preclinical safety data ). CosmoFer should not be used during the first trimester of pregnancy. If the benefit of CosmoFer -treatment is judged to outweigh the potential risk to the foetus, it is recommended that treatment, should be confined to the 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 breastfeeding. Effects on ability to drive and use machines: No studies on the effect on the ability to drive and use machines have been performed. Large doses of iron dextran (5 ml or more) have been reported to give a brown colour to serum from a blood sample drawn four hours after administration. 8 63

66 8. CosmoFer prescribing information Undesirable effects: Approximately 5% of patients can be expected to experience adverse reactions. These are mainly dose dependent. 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; fatalities have been reported. Overdose: Iron(III)-hydroxide dextran complex in CosmoFer injection has a very low toxicity. The preparation is well tolerated and has a minimal risk of accidental overdosing. Overdose can cause acute iron overloading which may manifest itself as haemosiderosis. Supportive measures such as iron chelating agent can be used. With chronic repeated administration of iron at high dose, the excess iron will accumulate in the liver and induce an inflammatory process, which may lead to fibrosis. Delayed reactions are well described and may be severe. They are characterised by arthralgia, myalgia and sometimes fever. The onset varies from several hours up to four days after administration. Symptoms usually last two to four days and settle spontaneously or following the use of simple analgesics. 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. Local complications at the injection site after intramuscular injection such as staining of the skin, bleeding, formation of sterile abscesses, tissue necrosis or atrophy and pain are observed. CosmoFer - low Mw iron dextran - IV, IM and as total dose infusion (TDI) 13 64

67 Organ System Uncommon Rare Very rare (>1/1,000, <1/100) (>1/10,000, <1/1,000) (<1/10,000) Blood and lymphatic system disorders Haemolysis Cardiac disorders Arrythmia, tachycardia Foetal bradycardia, palpitations Ear and labyrinth disorders Transient deafness Gastrointestinal Nausea, emesis, Diarrhoea disorders abdominal pain General disorders and Feeling hot Fatigue, pain and brown administration site pigmentation at conditions at injection site Immune system and Anaphylactoid reactions Acute, severe disorders including dyspnoea, anaphylactoid reactions urticaria, rashes, itching, (sudden onset of nausea and shivering respiratory difficulty and /or cardiovascular collapse) Musculoskeletal Cramps Myalgias connective tissue disorders Nervous system disorders Blurred vision, numbness Loss of consciousness, seizure, dizziness, restlessness, tremor Headache, paresthesia Respiratory, thoracic and Dyspnea Chest pain mediastinal disorders Psychiatric disorders Mental status changes Skin and subcutaneous Flushing, pruritus, rash Angioedema, sweating tissue disorders Vascular disorders Hypotension Hypertension 8 65

68 8. CosmoFer prescribing information PHARMACOLOGICAL PROPERTIES: Pharmacodynamic properties: Pharmacotherapeutic group: Iron trivalent parenteral preparation ATC code: B03A C06 CosmoFer solution for infusion and injection contains iron as a stable iron(iii)-hydroxide dextran complex, which is analogous to the physiological form of iron, ferritin (ferric hydroxide phosphate protein complex). The iron is available in a non-ionic watersoluble form. It has a very low toxicity and can be given in large doses. Serum ferritin peaks approximately 7 to 9 days after an intravenous dose of CosmoFer and slowly returns to baseline after about 3 weeks. Examination of the bone marrow for iron stores may not be meaningful for prolonged periods following iron dextran therapy because residual iron dextran may remain in the reticuloendothelia cells. Pharmacokinetic properties: Following the i.v. infusion the iron dextran is rapidly taken up by the cells in the reticuloendothelial system (RES), particularly in the liver and spleen from where iron is slowly released and bound to proteins. After administration an increased hematopoiesis can be observed for the next 6-8 weeks. The plasma half life is 5 hours for circulating iron and 20 hours for total iron (bound and circulating). Circulating iron is removed from the plasma by cells of the reticuloendothelial system which split the complex into its components of iron and dextran. The iron is immediately bound to the available protein moieties to form hemosiderin or ferritin, the physiological forms of iron, or to a lesser extent, to transferrin. This iron which is subject to physiological control replenishes haemoglobin and depleted iron stores. Iron is not easily eliminated from the body and accumulation can be toxic. Due to the size of the complex (165,000 Daltons) it is not eliminated via the kidneys. Small quantities of iron are eliminated in urine and faeces. After intramuscular injection, iron dextran is absorbed from the injection site into the capillaries and the lymphatic system. The major portion of the intramuscularly administered iron dextran is absorbed within 72 hours; most of the remaining iron is absorbed during the ensuing 3 to 4 weeks. Dextran is either metabolised or excreted. Preclinical safety data: CosmoFer has been reported to be teratogenic and embryocidal in nonanaemic pregnant animals at high single doses above 125 mg/kg. The highest recommended dose in clinical use is 20 mg/kg. However, no detailed information is available from these studies. In vitro and in vivo genotoxicity studies have showed mutagenic activity after the administration of high doses of iron-dextran complexes. However the significance of these results is not clear. Iron dextran was not mutagenic at sub-toxic dose levels. CosmoFer - low Mw iron dextran - IV, IM and as total dose infusion (TDI) 13 66

69 There are no other additional preclinical data of relevance to the prescriber than those already included in other sections of the prescribing information. please refer to section Shelf life. Nature and contents of container: Colourless, Type 1 glass ampoules. Single dose container. PHARMACEUTICAL PARTICULARS: List of excipients: Water for injections Sodium hydroxide (ph adjuster) Hydrochloric acid (ph adjuster) Incompatibilities: This medicinal product must not be mixed with other medicinal products except those mentioned in section Special precaution for disposal. Shelf life: 3 years From a microbiological point of view, the product should be used immediately after opening of the container. After dilution: Chemical and physical in-use stability has been demonstrated for 24 hours at 25 C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 C, unless dilution has taken place in controlled and validated aseptic conditions. Special precautions for storage: This medicinal product does not require any special storage conditions. For storage of the diluted product, Pack sizes: 5 x 2 ml, 10 x 2 ml, 10 x 5 ml, 2 x 10 ml and 5 x 10 ml. Not all pack sizes may be marketed. Special precaution for disposal: CosmoFer is for single use only. Any unused product or waste material should be disposed of in accordance with local requirements. CosmoFer must only be mixed with 0.9% sodium chloride or 5% glucose solution. No other intravenous dilution solutions or therapeutic agents should be used. The reconstituted solution for infusion and injection is to be visually inspected prior to use. Only clear solutions without particles should be used. MARKETING AUTHORISATION HOLDER: Pharmacosmos A/S Roervangsvej 30 DK-4300 Holbaek Denmark DATE OF FIRST AUTHORISATION: September 23, 1999 (Denmark). DATE OF REVISION OF THE TEXT: August 28, 2007 (Denmark). 8 67

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