IV Iron in haematology An alternative to blood transfusions?

Transcription

1 11TH CONGRESS OF THE EUROPEAN HAEMATOLOGY ASSOCIATION AMSTERDAM 15TH JUNE 2006 Nebo Satellite Symposium IV Iron in haematology An alternative to blood transfusions? Chairman: Dr. Michael Auerbach, USA The administration of parenteral iron as a total dose infusion offers an alternative to frequent blood transfusions for many chronically iron deficient patients. Reduction in blood transfusions, a benefit for patients and haematology wards Patient management can be improved through pro-active management and using the logical physiological pathway for treatment. Report of a presentation by Dr Paul Stross Consultant Haematologist, St Richard s Hospital, Chichester, UK Key assumptions for reducing the need for blood transfusions To implement a policy whereby the need for blood transfusions can be reduced there needs to be first an acceptance that IV iron can be used instead of blood for many patients that would normally receive blood. Secondly, that substituting blood with IV iron provides benefits to both patients and the healthcare system. It is recognised that the administration of iron cannot replace the role of blood transfusion in the acute treatment of hypo-volaemic shock in patients who are haemorrhaging. How can the use of IV iron reduce blood transfusions and improve patient outcomes? In clinical practice the use of blood is often a reflex response to patients that are referred with anaemia. However, many patients who currently receive blood can be managed more effectively. CONTINUED ON PAGE 2

2 CONTINUED FROM PAGE 1 An accurate diagnosis is required to establish iron deficiency. Establishing the cause will enable the clinician to anticipate any future anticipated iron deficiency. For example, patients with a persistent loss of blood can be predicted to require further treatment at a later date. Whilst the use of a blood transfusion can provide an acute improvement in anaemic status it does not impact the longer-term management of the patient. By administering IV iron, instead of a transfusion, the acute symptoms may take longer to resolve (time for natural erythropoeisis) but the administration of IV iron will build iron stores which will provide the substrate to enable the patient to undertake a prolonged erythropoeisis to replace chronic blood loss. By monitoring such patients, they can be given more iron before their iron stores fall, thereby sustaining their quality of life and avoiding acute crisis and hospitalisation. Dr Stross emphasised the need to train blood bank personnel to question why blood was being requested and to trigger the process of medical staff considering iron deficiency by examining MCV, trends in haemoglobin levels, faecal occult blood and the diagnosis history. There is a need to educate clinicians to recognise the importance and benefits of IV iron. He indicated that he has treated patients with haemoglobin levels as low as 4g/dl with IV iron. What are the benefits of using IV iron instead of a blood transfusion? The risks associated with a blood transfusion are avoided. These include risks associated with cross matching, the risk of alloimmunisation (making matching more difficult) and the risk of transferring human prions and bacterial disease. The shelf-life of blood is short. In contrast IV iron does not have to be cross matched. The risks associated with administration are much lower than with blood. It is much cheaper than blood (one eigth the price of blood in the UK). Administration is easier with fewer infusion episodes, given over a shorter infusion time with no cross match delays. It is more readily available. The shelf life of IV iron is years not weeks. Storage is at room temperature with stocks constantly available. From a clinical perspective IV iron offers several benefits. Dr Stross emphasised that in his department IV iron is given as a total dose infusion. This method of administration allows the clinician to give much more iron by IV infusion than by blood transfusion and can therefore be used to replenish and build iron stores. He illustrated this by indicating that 3 units of blood will be infused over 6 hours, equivalent to 600mg iron whereas in the same period 1400mg of iron can be infused into a person weighing 70kg by total dose infusion. It allows the clinician to anticipate blood loss and build iron stores to sustain erythropoeisis in chronic blood loss or poor iron absorption conditions. Thus a pro-active approach to the management of these patients can avoid emergency hospitalisation caused by intolerable symptoms and a continuous repeat of blood transfusions. By avoiding the extreme symptoms and hospitalisation positively impacts a patient s quality of life. Replenishment of iron stores is a key benefit that IV iron offers compared with a blood transfusion There is a temptation to transfuse the minimum amount of blood to restore haemoglobin levels to a target e.g. 10g/dl, however this leaves patients iron deficient. There is seldom a consistent approach to the replenishment of iron stores post discharge but frequently the haemoglobin level falls subsequent to transfusion and the patient again becomes symptomatic. The use of IV iron to replete stores results in the patient s own natural haemoglobin levels being restored (not an artificial target) in addition to optimising the haemoglobin level for longer. The use of IV iron also removes anxieties about oral iron compliance and absorption. Dr Stross indicated that 50% of patients administered IV iron had repeated episodes of iron therapy. By monitoring the symptoms, haemoglobin and especially the ferritin levels, (falling ferritin), pro-active management allows booked clinic visits for administering iron infusions. In patients receiving erythropoietin IV iron predictably replaces stores despite malabsorption or compliance issues associated with oral iron. Iron replete status increases sensitivity to both endogenous or administered erythropoietin. Additionally, Jehovah s witnesses, who decline red cell transfusions, will accept IV iron. Take home messages The use of IV iron, especially administered as a total dose infusion, improves clinical management of many chronically anaemic patients. Haemoglobin levels rise and ferritin levels rise. The more subtle indicators also improve (MCV and reticulocyte count). Transfusion requirements can be substantially reduced which, in addition to avoiding transfusion risk, improves the management of patients impacting their quality of life (reduced symptoms; predictable visits to hospital). In implementing a policy no blood transfusions should be allowed for sub-acute or recurrent iron deficient anaemia. This can be achieved whilst saving money for the local healthcare system.

3 Parenteral iron is the preferred form of iron supplementation The evidence is building to suggest that different parenteral iron formulations cause different levels of oxidative stress and tissue injury. These events appear to be caused by separate distinctive pathways. Intravenous irons: Not all iron formulations are alike The early expectations that oxidative stress is the cause of tissue injury in haemodialysis patients is now challenged by evidence that tissue injury is the result of another, perhaps more direct mechanism The absorption of oral iron from the gastro-intestinal tract is minimal (0-5%) in patients with a serum ferritin above 50ng/ml. Patients with iron deficiency anaemia, including those on dialysis receiving erythropoietin, need a continuous supply of iron administered by the intravenous route. Free iron radicals can contribute to the disease process The administration of parenteral iron is associated with lipid peroxidation, cell injury and enhanced bacterial growth. Potent hydroxyradicals cause oxidative stress but are usually neutralized by enzymes in the kidney. In patients with chronic kidney disease this neutralizing capacity is reduced and therefore the impact that differing parenteral iron formulations may have on oxidative stress and cell injury is important. Do all IV iron preparations donate iron to transferrin in a similar manner? Studies by Dr Agarwal (2004) conclude that non-dextran IV iron formulations directly transfer iron to transferrin in a dose and time dependant manner resulting in saturation of transferrin. This ability to saturate transferrin was not seen with iron dextran formulations indicating that there is not the Report of a presentation by Dr Rajiv Agarwal Associate Professor of Medicine Indiana University School of Medicine and VA Medical Center, Indianapolis, Indiana same direct transfer of iron to transferrin with these products. Iron gluconate rapidly forms monoferric and diferric transferrin (the form that is absorbed into cells). Whilst this may contribute to a quicker erythropoietic response it may also contribute to greater exposure to oxidative stress. In these studies IV iron sucrose behaves similar to iron gluconate forming the monoferric and diferric forms but marginally less rapidly. What is the impact on injury at the cellular level? Zager (2002) has investigated lipid peroxidation and cellular injury assessed by LDH (lactate dehydrogenase) formation and MTT (tetrazolium dye) uptake (marker of cell injury and cell viability) in cultures of HK-2 (human kidney) cells. Differences in the preparations were observed with iron dextran causing the least levels of cellular toxicity. Roob (2000) studied lipid peroxidation caused by IV iron sucrose in patients receiving haemodialysis and found that MDA (malondialdehyde) levels rise post IV iron administration, these levels are reduced but not nullified by co-administering vitamin E. This suggests severe oxidative stress. Free iron was also demonstrated to correlate to levels of MDA indicating the potential for cell injury. Additional studies undertaken by Rooyakkers (2002) in healthy volunteers found that FMD (flow mediated dilation), a marker of endothelial injury, decreased rapidly (10 minutes), but was less marked at 4 hours. This did not parallel free iron levels which peak at about 4 hours suggesting therefore that more than one causative mechanism may be responsible for oxidative stress and cell injury. Is there more than one potential causative mechanism or pathway? Additional evidence for more than one pathway causing oxidative stress and injury came from a study Dr Agarwal had undertaken examining oxidative stress and cell injury caused by iron sucrose in patients with advanced chronic kidney disease. Parenteral iron administration caused plasma and urinary MDA to peak rapidly (15-30minutes) before returning to baseline, as did NAG (N-acetyl galactosamine) and proteinuria levels, indicators of oxidative stress and injury. However, in contrast, TSAT peaks at about 3 hours after the infusion. The administration of N-acetylcysteine reduced the level of oxidative stress but transient proteinuria and tubular damage (cellular injury) were still observed. The rapid production of oxidative stress, even when transferrin is not completely saturated, suggests that a free iron independent mechanism is causing oxidative stress and transient renal injury. Dr Agarwal completed this review by referring to results of collaborative work with Dr Leehey (2005) in which sodium ferric gluconate was administered to patients with chronic kidney disease. This was a placebo controlled four-way cross over study. Iron gluconate was found to cause oxidative stress but not proteinuria or enzymuria which are markers of tissue injury. Different toxicological profiles of IV iron formulations Current evidence indicates that iron gluconate and iron sucrose are implicated with oxidative stress and that iron sucrose (but not iron gluconate) can cause cellular injury. Whilst suggestive of two separate pathways these have yet to be identified. The impact of such pathways is currently open to speculation and will be clarified with further studies.

4 Total dose infusion can positively impact the efficiency of administering IV iron and the economics of administering IV iron without jeopardising the clinical efficacy of administering IV iron. Clinical experience with total dose IV iron infusion (TDI) Total dose infusion of intravenous iron is convenient for patients, improves compliance and is cost effective. Whilst much of the early uptake of this administration regimen was in nephrology patients the accruing benefits can be enjoyed by a much broader population of iron deficient patients. Advantages of total dose infusion Irrespective of the need for IV iron supplementation (CAPD, pre-dialysis, pre-operatively [especially orthopaedic surgery], oncology, haematology, chronic iron deficiency, pregnancy) the administration of the iron as a total dose infusion avoids constant visits to the hospital. Furthermore, the established safety of administering high doses of iron is beneficial in a number of situations, for example patients with functional iron deficiency. In such circumstances a large amount of IV iron may be required to provoke adequate erythropoiesis in conjunction with erythropoietin. This can often be achieved with a single total dose infusion of iron. The introduction of erythropoietin in the 1980s provoked a plethora of studies in nephrology patients which outlined the importance of adequate iron stores to optimise the erythropoietic response. Is there similar evidence in non-renal patients? Does TDI administration impact outcome? Report of a presentation by Dr Michael Auerbach, Private Practice, Baltimore, Maryland, Clinical Professor of Medicine, Georgetown University School of Medicine, Washington, DC Dr Auerbach referred to a study he published in 1988 in which the benefits of pre-medication with aspirin, diphenhydramine and steroids were assessed when administering iron dextran at different rates of infusion including total dose infusion. Methylprednisolone was the only agent found to be significantly beneficial. It reduced the incidence of mild arthralgia and myalgia associated with administering the iron dextrans available at that time (low molecular weight iron dextran was not available at that time). However, sub-group analysis of patients receiving a total dose infusion of iron dextran demonstrated a remarkable improvement in haemoglobin levels in patients suffering a variety of non-renal conditions. Further studies published by Dr Auerbach (1998) confirmed that the impact on haemoglobin levels was irrespective of whether the desired amount of IV iron supplement was administered as a frequent bolus, 500mg infusion or total dose infusion in haemodialysis patients, or in oncology patients. A prospective, randomised multicentre study published in 2004 on patients with anaemia associated with cancer or chemotherapy induced anaemia examined the impact of either no iron supplementation, oral iron, or low molecular weight iron dextran, as 100mg boluses, or total dose infusion in patients receiving erythropoietin. Parenteral iron was found to optimise the erythropoiesis and resulted in improvements in haemoglobin levels, energy levels, activity and quality of life (all statistically significant). Oral iron was found to be only marginally effective. The results were similar for both bolus and total dose iron infusion delivery. Adverse events associated with parenteral iron ADRs should be rationalised firstly in the historical context. High molecular weight iron dextran formulations were initially introduced and established a context for reporting ADRs associated with parenteral iron dextran. This legacy remains in the literature and is referred to without discriminating between the molecular weights of the various IV iron dextrans. Imferon was withdrawn from the market in 1990 yet still reference to side effects caused by this formulation are made and extrapolated to low molecular weight iron dextran. High molecular

5 Chertow s study (2004) of ADRs reported to the FDA, in which low molecular weight iron dextran (INFed ) ADRs are segregated from high molecular weight iron dextran, show a much lower incidence/million doses of 100mg than either Dexferrum or Ferrlecit. This reflects the findings by both McCarthy (2000) and Fletes (2001) that low molecular weight iron dextran is associated with less ADRs than high molecular weight iron dextran. weight iron dextran, Dexferrum remains on the market. Reported side effects to it are attributed to low molecular weight iron dextran, without justification. Severe side effects associated with low molecular weight iron dextran are very rare. In practice, patients do occasionally complain of arthralgia and myalgia and infrequently with mild chest and back pain but this is without the tachycardia, hypotension, stridor or periorbital oedema that would qualify as a severe reaction. Such events are invariably mild and transient with no continuing symptoms after five minutes when re-challenged. This can result in misreporting, which can impact published incidences of ADRs. Reference was made to a study published by Michael et al (2002) which reported higher levels of life threatening events and drug intolerance to iron dextran than ferric gluconate. There was no stratification or discrimination for the molecular weight of iron dextran (comparator arm). Size matters. The frequency of adverse events is significantly lower with low molecular weight compared to high molecular weight iron dextran. Low molecular weight iron dextran has a low incidence of adverse events, and because of its pharmacodynamic profile is suited for administration as a total dose infusion. Total dose infusion dosage regimen for the future The talk by Dr Auerbach indicated how adequate iron supplementation can stimulate erythropoiesis in the absence of erythropoietin or improve the effectiveness of erythropoietin therapy. This is demonstrated across a variety of conditions previously treated with blood transfusions, where iron deficiency is a feature of the condition. Oral iron is often only marginally effective (as demonstrated in oncology and haemodialysis patients). Whilst debate continues on the safest and most effective IV iron formulation, the comparative safety of low molecular weight iron dextran, compared to the higher molecular weight forms and other IV iron formulations, plus the pharmacodynamic profile that allows it to be administered as a total dose infusion, provides the clinician and patient with an effective, efficient and economical method for IV iron supplementation.

6 Health care policy in the UK has highlighted the need to address the conservation and appropriate use of blood. The role of iron supplementation in this context has contributed to significant reductions in blood use in many hospitals. Inappropriate use of blood Patients are referred to hospital, frequently to haematologists, who are chronically anaemic and who routinely receive one or two units of blood. As individuals that can donate blood in the UK is restricted and in decline, blood is an increasingly scarce and expensive resource. Supplies need to be conserved and used appropriately. For many patients, where acute blood loss has not occurred but who are referred because of their anaemic status, investigation will often result in a diagnosis of chronic iron deficiency anaemia. Iron deficiency is common in these referrals. It is essential to establish the underlying cause of the anaemia and to rule out malignancies. Oral or IV iron? Blood transfusions are not without risk. There are significant numbers of patients receiving blood transfusions inappropriately. These patients may be identified and receive a cost effective, less risky alternative. Total dose infusion Iron supplementation (IV iron instead of a blood transfusion) Oral iron should be the first consideration but some patients are intolerant, poor compliers or poor absorbers of iron. There are therefore patients who would benefit from Report of a presentation by Dr Anil Lakhani Consultant Haematologist, Princess Royal University Hospital, Bromley Hospitals NHS Trust, Kent, UK IV iron as the oral forms will not meet their demands. The newer forms of IV iron have less side effects than those initially available, and are safer. These preparations can be used to treat iron deficiency anaemia, instead of blood, in many patients. Case histories of patients where IV iron has been used successfully The first example is a female aged 59 years with a diagnosis of hereditary haemorrhagic telangectasia presenting with recurrent severe epistaxis. Treatment included regular cautery and laser treatment and she had received tranexamic acid and oestrogens. Oral iron supplementation as oral ferrous sulphate (tds) had been prescribed but although compliance was good, the response was poor with haemoglobin levels frequently falling to 7g/dl. These levels of haemoglobin triggered blood transfusions (50 units of blood were administered in at an estimated cost to the NHS of 11,000 Euros during the two year period). Oral iron was then replaced with weekly infusions of iron sucrose which sustained the haemoglobin above 11g/dl. In 2003 the inconvenient weekly infusions of iron sucrose were replaced with the administration of low molecular weight iron dextran (CosmoFer ) as a total dose infusion. The patient now receives just 3 or 4 infusions each year. At her last hospital visit her haemoglobin level was 13.5g/dl and ferritin level 33ng/ml. She has not required a blood transfusion since The second case history was a young man (24 years) with chronic iron deficiency referred by the gastroenterologist to the haematology department in May He was investigated thoroughly and no cause found. Oral iron was unsatisfactory in restoring haemoglobin and ferritin levels. In January of 2002 his haemoglobin level fell to 4.6g/dl and he received 4 units of blood. Four units of blood were again given in July 2002 when his haemoglobin level fell to 4.5g/dl. He was reinvestigated. No cause could be determined albeit FOBs were positive. Intravenous iron was administered weekly (200mg) until his haemoglobin and ferritin levels were restored to acceptable levels. He then received a monthly maintenance regimen. Following capsule endoscopy Chrohn s disease has been subsequently diagnosed. To improve his quality of life (reducing visits to the hospital) he is now receiving low molecular weight iron dextran as a total dose infusion (1200mg) every six months (twice a year) to manage his anaemia. Selection of patients for IV iron supplementation A specific clinic has been established within the haematology clinic schedule to receive and assess anaemic patients. Referrals are made by surgeons, physicians and GPs. All patients are investigated to establish true iron deficiency and the cause, so that it may be treated.

7 Patient management Those patients identified for iron supplementation are prescribed oral iron but if they are intolerant (to several formulations), are poor compliers, do not respond or are malabsorbers then they are designated for IV iron administered as low molecular weight iron dextran. The target haemoglobin is 13g/dl and the dose calculated from the CosmoFer dose table. It is administered in the day unit. The aim is to keep the haemoglobin and ferritin levels in the normal range. Results of the infusion are assessed after four weeks and then regular checks are made depending on these results and the patient s condition. Monitoring is undertaken by a day treatment nurse or transfusion nurse. Ferritin levels, symptoms and FBC results are reviewed, discussed with the consultant and repeat infusions organised when required. Choice of IV iron Since 2003 low molecular weight iron dextran is used for all regular patients as this can be administered at 20mg/kg body weight (ie 1400mg for a 70kg person). Administration using TDI requires fewer hospital visits and fewer infusions. Often, patients only require one TDI administration if the cause of the iron deficiency can be diagnosed and corrected. Iron deficiency associated with pregnancy is an example where most patients require only a single infusion. Experience in the department indicates that side effects are few (minor allergic; slight fever) which respond to hydrocortisone or chlorphenamine. for patients where there is no acute large blood loss and that the physiological response to iron is cheaper, less risky and often results in a long-term better outcome for patients. Patients are happy with the outcome. It would appear that iron has a major role to play in a conservation and appropriate use of blood strategy Selected patients with iron deficiency anaemia, however they are referred benefit from receiving IV iron. The newer preparations are safe with very few side effects seen in clinical practice. Administration of low molecular weight iron dextran, as a total dose infusion, reduces the number of clinic visits and infusions and improves the quality of life for patients. By adopting this care pathway for iron deficiency anaemia patients blood is being conserved and patients avoid the risks associated with a transfusion. The use of iron is very cost effective producing very significant savings. To pursue this care pathway there is a need to have a system to identify patients, to establish awareness with referring clinicians (including an educational programme) and to encourage proactivity within the haematology team and laboratory staff to question and challenge blood use in iron deficient patients. Day treatment facilities are needed with consultant and nursing resources to diagnose, follow-up and monitor patients. Currently in the department, 40 patients have chronic conditions requiring regular IV iron. These include patients with conditions such as hereditary haemorrhagic telangectasia where there is continued excessive blood loss. Can IV iron be used in the acute setting? These patients need to be identified with intervention through the auspices of a pro-active laboratory team, transfusion nurse and haematologist. Transfusions can be avoided for many patients but clinicians need to be educated and convinced that iron supplementation can be appropriate

8 COSMOFER ABBREVIATED PRESCRIBING INFORMATION: Before prescribing CosmoFer (low Mw iron dextran) please refer to full local approved data sheet. Presentation: Solution for infusion and injection in the form of 2ml ampoules containing a solution of Iron (III) -hydroxide dextran complex 312.5mg equivalent to 50mg elemental iron (III) per ml. Indications: Iron deficiency anaemia when oral iron therapy is impossible or inadequate in patients above 14 years of age. Dosage: The normal recommended dosage schedule is mg corresponding to 2-4ml, two or three times a week depending on the haemoglobin level. If clinical circumstances require rapid delivery of iron to the body iron stores, CosmoFer may be administered as a total dose infusion up to a total replacement dose corresponding to 20mg iron/kg body weight. Administration: CosmoFer solution for injection can be administered by an intravenous drip infusion or by a slow intravenous injection. Intravenous drip infusion is the preferred route of administration, as this may help to reduce the risk of hypotensive episodes. CosmoFer may also be administered as undiluted solution intramuscularly. Intravenous drip infusion: CosmoFer must be diluted only in 0.9% sodium chloride 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 not more then 100 ml in 30 minutes. Slow intravenous injection: CosmoFer may be administered in a dose of mg iron 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. Intramuscularly injection: For intramuscular injection, the amount of CosmoFer required is determined either from the dosage table or by calculation; it is administered as a series of undiluted injections of up to 100mg iron (2.0ml) each, determined by the patient s body weight. CosmoFer must be given by deep intramuscular injection to minimise the risk of subcutaneous staining, it is recommended to use the Z-track technique. Total dose infusion: For total dose infusion the amount of CosmoFer required is determined either from the dosage table or by calculation, it is added to the required volume of 0.9% sodium chloride or 5% glucose solution and infused intravenously over 4-6 hours. On each occasion the first 25 mg of iron should be infused over a period of 15 minutes. If no adverse reactions occur during this time, then the remaining portion of the infusion should be given. The rate of infusion may be increased progressively to drops per minute. 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 recommended. If no adverse reactions are seen after 60 minutes, the remaining dose can be given. Contraindications: Non-iron deficiency anaemia, iron overload or disturbances in utilisation of iron, patients with a history of asthma, eczema or other atopic allergy, drug hypersensitivity, decompensated liver cirrhosis and hepatitis, acute or chronic infection, rheumatoid arthritis with symptoms or signs of active inflammation, acute renal failure. Pregnancy and lactation: CosmoFer should not be used during the first trimester but can be used during second and third trimester and during lactation if oral iron therapy is ineffective or impracticable. Warnings/Precautions: The use of CosmoFer as with the parenteral use of other iron-carbohydrate complexes carries a risk of immediate severe and potentially lethal anaphylactoid reactions. Patients should be closely observed during and for 1 hour after administration. The risk is enhanced for patients with known (medical) allergy. CosmoFer may only be administered when anaphylactic emergency measures, including an injectable 1:1000 adrenaline solution are available. Additional treatment with antihistamine and/or corticosteroids should be given as appropriate. Administration to patients with (auto) immune disorder or inflammatory conditions may cause a type III allergic reaction. Hypotensive episodes may occur if intravenous injection is administered too rapidly. Drug interactions: CosmoFer should not be administered concomitantly with oral iron preparations, as the absorption of oral iron will be reduced. Oral iron therapy should not be started earlier than 5 days after the last injection of CosmoFer. The drug may cause falsely elevated values of serum bilirubin and falsely decreased values of serum calcium. Incompatibilities: CosmoFer must only be mixed with 0.9% sodium chloride or 5% glucose solution. No other intravenous dilution solutions or therapeutic agents should be used. Side effects: Acute, severe anaphylactoid reactions which are uncommon occur usually within the first few minutes of administration and are generally characterised by the sudden onset of respiratory difficulty and/or cardiovascular collapse. Other less severe manifestations include urticaria, rashes, itching, nausea and shivering. Delayed reactions are well described and may be severe and are characterised by arthralgia, myalgia and sometimes fever. Symptoms usually last two to four days and settle spontaneously or following the use of simple analgesics. Other uncommon to rare adverse reactions are loss of consciousness, altered mental status, seizure, dizziness, restlessness, fatigue, hypotension, angiedoema, arrythmia, chest pain, diarrhoea, diaphoresis, myalagias, tremors, dyspnoea, nausea, emesis, abdominal pain, flushing, puritus, rash, blurred vision, feeling hot, cramps and numbness. Exacerbation of joint pain in rheumatoid arthritis can occur. Local reactions reported are soreness and inflammation at or near injection site and local phlebitic reaction. After intramuscular injection local complications such as staining of the skin, bleeding, formation of sterile abscesses, tissue necrosis or atrophy and pain are observed. Legal Category: POM. Pharmaceutical Precautions: CosmoFer is for single use only and any unused solution should be discarded. The reconstituted solution for injection is to be visually inspected prior to use. Only clear solutions without particles should be used. Package Quantities: 5 ampoules per pack. Date of preparation: January Pharmacosmos A/S Roervangsvej 30 DK-4300 Holbaek Denmark Vang Rasmussen A/S Jan. 2007