Version 3.0, 04/2013 SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET

Transcription

1 Version 3.0, 04/2013 SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET 1

2 SUMMARY OF PRODUCT CHARACTERISTICS 2

3 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT CosmoFer 50mg/ml solution for infusion and injection 2. 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 the full list of excipients, see section PHARMACEUTICAL FORM Solution for infusion and injection A dark brown solution. 4. CLINICAL PARTICULARS 4.1 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). 4.2 Posology and method of administration Monitor carefully patients for signs and symptoms of hypersensitivity reactions during and following each administration of CosmoFer. CosmoFer should only be administered when staff trained to evaluate and manage anaphylactic reactions is immediately available, in an environment where full resuscitation facilities can be assured. The patient should be observed for adverse effects for at least 30 minutes following each CosmoFer injection (see section 4.4). 3

4 Administration: CosmoFer solution for infusion and 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 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 4.5). 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) 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 30 minutes after completion. 4

5 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: 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 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. 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 0.24) + 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 / The table below shows the number of millilitres of CosmoFer injection solution to be used at various degrees of iron deficiency anaemia. 5

6 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. 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. Haemoglobin content Body weight (kg) Total dose of CosmoFer in Millilitres to be administered in iron deficiency anaemia 60 g/l 3.7 mmol/l 75 g/l 4.7 mmol/l 90 g/l 5.6 mmol/l 105 g/l 6.5 mmol/l 120 g/l 7.4 mmol/l 135 g/l 8.4 mmol/l 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: 6

7 If the volume of blood lost is known: 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 ) 4.3 Contraindications Hypersensitivity to the active substance, to CosmoFer or any of its excipients listed in section 6.1. Known serious hypersensitivity to other parenteral iron products. Non-iron deficiency anaemia (e.g. haemolytic anaemia). Iron overload or disturbances in utilisation of iron (e.g. haemochromatosis, haemosiderosis). Decompensated liver cirrhosis and hepatitis. Acute or chronic infection, because parenteral iron administration may exacerbate bacterial or viral infections. Acute renal failure. 4.4 Special warnings and precautions for use Parenterally administered iron preparations can cause hypersensitivity reactions including serious and potentially fatal anaphylactic/anaphylactoid reactions. Hypersensitivity reactions have also been reported after previously uneventful doses of parenteral iron complexes. The risk is enhanced for patients with known allergies including drug allergies, including patients with a history of severe asthma, eczema or other atopic allergy. There is also an increased risk of hypersensitivity reactions to parenteral iron complexes in patients with immune or inflammatory conditions (e.g. systemic lupus erythematosus, rheumatoid arthritis). CosmoFer should only be administered when staff trained to evaluate and manage anaphylactic reactions is immediately available, in an environment where full resuscitation facilities can be assured. Each patient should be observed for adverse effects for at least 30 minutes following each CosmoFer injection. If hypersensitivity reactions or signs of intolerance occur during administration, the treatment must be stopped immediately. Facilities for cardio respiratory resuscitation and equipment for handling acute anaphylactic/anaphylactoid reactions should be available, including an injectable 1:1000 adrenaline solution. Additional treatment with antihistamines and/or corticosteroids should be given as appropriate. 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 7

8 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. 4.5 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. 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. The drug may cause falsely elevated values of serum bilirubin and falsely decreased values of serum calcium. 4.6 Fertility, pregnancy and lactation There are no adequate and well-controlled trials of CosmoFer in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). A careful risk/benefit evaluation is therefore required before use during pregnancy and CosmoFer should not be used during pregnancy unless clearly necessary (see section 4.4). Iron deficiency anaemia occurring in the first trimester of pregnancy can in many cases be treated with oral iron. Treatment with CosmoFer should be confined to second and third trimester if the benefit is judged to outweigh the potential risk for both the mother and the foetus. It is unknown whether the complex iron-dextran is excreted in human or animal breast milk. It is preferable to not use CosmoFer during breast-feeding. 4.7 Effects on ability to drive and use machines No studies on the effect on the ability to drive and use machines have been performed. 4.8 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. 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. Organ System Blood and lymphatic Uncommon (>1/1,000, <1/100) Rare (>1/10,000, <1/1,000) Very rare <1/10,000 Haemolysis 8

9 system disorders Cardiac disorders Arrythmia, tachycardia Foetal bradycardia, palpitations Ear and labyrinth disorders Transient deafness Gastrointestinal disorders Nausea, emesis, abdominal pain Diarrhoea General disorders and administration site conditions Feeling hot Immune system disorders Anaphylactoid reactions including dyspnoea, urticaria, rashes, itching, nausea and shivering Musculoskeletal and connective tissue disorders Nervous system disorders Cramps Blurred vision, numbness Fatigue Pain and brown pigmentation at injection site Myalgias Loss of consciousness, seizure, dizziness, restlessness, tremor Chest pain Acute, severe anaphylactoid reactions (sudden onset of respiratory difficulty and / or cardiovascular collapse) Headache, paresthesia Respiratory, thoracic and Dyspnea mediastinal disorders Psychiatric disorders Mental status changes Skin and subcutaneous Flushing, pruritus, rash Angioedema, Sweating tissue disorders Vascular disorders Hypotension Hypertension Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions {via the national reporting system listed in Appendix V*}. 4.9 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. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties 9

10 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 water-soluble 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 reticuloendothelial cells. 5.2 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. 5.3 Preclinical safety data CosmoFer has been reported to be teratogenic and embryocidal in non-anaemic 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. There are no other additional preclinical data of relevance to the prescriber than those already included in other sections of the SPC. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Water for injections Sodium hydroxide (ph adjuster) Hydrochloric acid (ph adjuster) 10

11 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products except those mentioned in section Shelf life 30 months for 2 ml ampoules 24 months for 5 ml and 10 ml ampoules 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 25ºC 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. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. Do not freeze. For storage of the diluted product, please refer to section Nature and contents of container Colourless, Type 1 glass ampoules. Single dose container. 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. 6.6 Special precautions for disposal and other handling Inspect ampoules visually for sediment and damage before use. Use only those containing sediment-free, homogeneous solution. 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. 7. MARKETING AUTHORISATION HOLDER Pharmacosmos A/S Roervangsvej 30 DK-4300 Holbaek Denmark 11

12 8. MARKETING AUTHORISATION NUMBER(S) <[To be completed nationally]> 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first approval: 23 September DATE OF REVISION OF THE TEXT January

13 LABELLING 13

14 Only labelling for the pack sixe 5 x 2 ml and 2 x 10 ml are enclosed since these are the only pack sizes currently to be marketed. PARTICULARS TO APPEAR ON <THE OUTER PACKAGING> <AND> <THE IMMEDIATE PACKAGING> Carton 1. NAME OF THE MEDICINAL PRODUCT CosmoFer 50 mg/ml Solution for for infusion and injection Iron(III) 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each ml contains 50 mg iron(iii) as iron(iii) dextran complex. Each 2 ml ampoule contains 100 mg of iron(iii) as iron(iii) dextran complex 3. LIST OF EXCIPIENTS Water for injections, sodium hydroxide (ph adjuster), hydrochloric acid (ph adjuster) 4. PHARMACEUTICAL FORM AND CONTENTS 5 x 2 ml ampoules 5. METHOD AND ROUTE(S) OF ADMINISTRATION Intramuscular use and intravenous use Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY CosmoFer is for single use only and any unused solution should be discarded. For use under medical direction. 8. EXPIRY DATE Expiry: 9. SPECIAL STORAGE CONDITIONS No special precautions for storage 14

15 Do not freeze 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Pharmacosmos A/S Rørvangsvej 30 DK-4300 Holbaek Denmark Distributor: 12. MARKETING AUTHORISATION NUMBER(S) <[To be completed nationally]> 13. BATCH NUMBER Batch No.: 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 15

16 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Ampoule 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION CosmoFer 50 mg/ml Solution for infusion and injection Iron(III) 2 ml=100 mg iron (III) 2. METHOD OF ADMINISTRATION Intramuscular use and intravenous use 3. EXPIRY DATE Exp.: 4. BATCH NUMBER Batch No.: 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 2 ml 6. OTHER 16

17 PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton 1. NAME OF THE MEDICINAL PRODUCT CosmoFer 50 mg/ml Solution for infusion and injection Iron(III) 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each ml contains 50 mg iron(iii) as iron(iii) dextran complex. Each 10 ml ampoule contains 500 mg of iron(iii) as iron(iii) dextran complex 3. LIST OF EXCIPIENTS Water for injections, sodium hydroxide (ph adjuster), hydrochloric acid (ph adjuster) 4. PHARMACEUTICAL FORM AND CONTENTS 2 x 10 ml ampoules 5. METHOD AND ROUTE(S) OF ADMINISTRATION Intramuscular use and intravenous use Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children 7. OTHER SPECIAL WARNING(S), IF NECESSARY CosmoFer is for single use only and any unused solution should be discarded. For use under medical direction. 8. EXPIRY DATE Expiry: 9. SPECIAL STORAGE CONDITIONS No special precautions for storage Do not freeze 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 17

18 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Pharmacosmos A/S Rørvangsvej 30 DK-4300 Holbaek Denmark Distributor: 12. MARKETING AUTHORISATION NUMBER(S) <[To be completed nationally]> 13. BATCH NUMBER Batch No.: 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 18

19 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Ampoule 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION CosmoFer 50 mg/ml Solution for infusion and injection Iron(III) 10 ml=500 mg iron (III) 2. METHOD OF ADMINISTRATION Intramuscular use and intravenous use 3. EXPIRY DATE Exp.: 4. BATCH NUMBER Batch No.: 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 10 ml 6. OTHER 19

20 PACKAGE LEAFLET 20

21 Package leaflet: Information for the user CosmoFer, 50 mg/ml solution for injection and for infusion Iron(III) This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you start using this medicine because it contains important information for you Keep this leaflet. You may need to read it again. If you have any further questions, ask your doctor or nurse. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or nurse. What is in this leaflet 1. What CosmoFer is and what it is used for 2. What you need to know before you receive CosmoFer 3. How CosmoFer is given 4. Possible side effects 5. How to store CosmoFer 6. Content of the pack and other information 1. What CosmoFer is and what it is used for CosmoFer contains a combination of iron and dextran (a long chain of sugar molecules). The type of iron in CosmoFer is the same as that found naturally in the body called ferritin. This means that you can have CosmoFer by injection in high doses. CosmoFer is used for low levels of iron (sometimes called iron deficiency ) if: you cannot take iron by mouth, for example you cannot tolerate it you have taken iron by mouth and it has not worked your doctor decides you need iron very quickly to build up your iron stores. 2. What you need to know before you receive CosmoFer You must not receive CosmoFer: if you are allergic (hypersensitive) to the product or any of the other ingredients of this medicine (listed in section 6) if you have experienced serious allergic (hypersensitive) reactions to other injectable iron preparations if you have anaemia that is not caused by low levels of iron (deficiency), such as haemolytic anaemia if you have too much iron (overload) or a problem in the way your body uses iron if you have liver problems such as cirrhosis or hepatitis if you have a bacterial or viral infection if you have kidney problems, such as acute kidney failure. Warnings and precautions Talk to your doctor or nurse before receiving CosmoFer: if you have a history of medicine allergy if you have systemic lupus arthritis if you have rheumatoid arthritis 21

22 if you have severe asthma, eczema or allergies Children CosmoFer is for adults only. Children under 14 should not have this medicine. Other medicines and CosmoFer Please tell your doctor or nurse if you are taking or have recently taken any other medicines. This includes medicines obtained without a prescription and herbal medicines. This is because CosmoFer can affect the way some medicines work. Also some other medicines can affect the way CosmoFer works. In particular tell your doctor or nurse if you are taking any of the following medicines: vitamins and minerals iron containing medicines you take by mouth. You should not take iron by mouth until at least 5 days after finishing CosmoFer. Pregnancy and breast-feeding CosmoFer has not been tested in pregnant women. It is important to tell your doctor if you are pregnant, think you may be pregnant, or are planning to have a baby. If you become pregnant during treatment, you must ask your doctor for advice. Your doctor will decide whether or not you should be given this medicine. If you are breast-feeding, ask your doctor for advice before you are given CosmoFer. Driving and using machines Ask your doctor if you can drive or operate machines after having CosmoFer. Having blood tests while you are having CosmoFer CosmoFer may affect the results of some blood tests to measure bilirubin and calcium. Tell your doctor if you have any blood test while you are having CosmoFer. 3. How CosmoFer is given Your doctor or nurse will administer CosmoFer by injection or infusion into your vein or you may have it injected into your muscle; the CosmoFer will be administered in a structure where immunoallergic events can receive appropriate and prompt treatment. You will be observed for at least 30 minutes by your doctor or nurse after each administration. The dose depends on your blood iron (haemoglobin) level and your weight. Your doctor will calculate the dose for you. It is usually given to you two or three times each week. If you get more CosmoFer than you should A trained and qualified person will give you CosmoFer. It is unlikely that you will have too much. They will monitor your dose so that an iron build up does not happen in your body. If you think you have been given too much, tell your doctor or nurse straight away. 4. Possible side effects Like all medicines CosmoFer can cause side effects, although not everybody gets them. The following side effects may happen with this medicine: Allergic reactions (affecting less than 1 in 100 people) 22

23 If you have an allergic reaction to CosmoFer tell your doctor or nurse straight away so that they can stop it if necessary. The signs of this may include: shortness of breath nettle rash or hives, flushing, rashes, itching nausea and shivering. More serious allergic reactions, may happen in the first few minutes of having CosmoFer (affecting less than 1 in 10,000 people). The signs may include: sudden onset of difficulty breathing (respiratory difficulty) serious problems with your heart and circulation (cardiovascular collapse) fatalities have been reported. Also, there have been reports of delayed allergic reactions, that may happen a few hours or up to four days after being given CosmoFer. The signs may include: pain in your joints or muscles sometimes a high temperature (fever). Please contact your doctor if you have any of these signs. Other side effects include Uncommon (affecting less than 1 in 100 people): pain in and around the stomach (abdominal pain), being sick (vomiting) blurred vision feeling hot cramps numbness. Rare (affecting less than 1 in 1,000 people): loss of consciousness altered mental status seizure (fits) dizziness, restlessness, fatigue low blood pressure angioedema, a type of severe allergic reaction, signs may include swelling uneven (irregular) heart beat, high pulse rate, chest pain diarrhoea, sweating and tremor. Very rare (affecting less than 1 in 10,000 people): lower red blood cells than usual (this would show up in some blood tests) headache unusual feeling on the surface of your body raised blood pressure temporary deafness palpitations in pregnancy, the baby s heart rate may slow. Some other side effects have been reported. People with rheumatoid arthritis may have worsening of joint pain. Possible side effects after an injection into your vein If you have CosmoFer into a vein, there may be reactions, such as soreness and swelling (inflammation) around the vein. There have also been reports of inflammation of the vein. Possible side effects after an injection into your muscle If you have CosmoFer into a muscle, there may be reactions, such as staining of the skin, bleeding, formation of boils, tissue damage (necrosis or atrophy) and pain. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or nurse. Reporting of side effects 23

24 If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via {the national reporting system listed in Appendix V}*. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store CosmoFer This medicinal product does not require any special storage conditions. Do not freeze. Inspect ampoules visually for sediment and damage before use. Use only those containing sediment-free, homogeneous solution. Hospital staff will make sure that the product is stored and disposed of correctly. CosmoFer should not be used after the expiry date which is stated on the ampoule. Exp. is the abbreviation used for expiry date. The expiry date refers to the last day of that month. Keep out of the reach and sight of children. 6. Contents of the pack and other information What CosmoFer contains The active substance in CosmoFer is an Iron(III)-hydroxide dextran complex. A 2 ml ampoule contains 100 mg iron(iii), a 5 ml ampoule contains 250 mg iron(iii) and a 10 ml ampoule contains 500 mg iron(iii) The other ingredients are Water for injections, Sodium hydroxide (ph adjuster) and Hydrochloric acid (ph adjuster). What CosmoFer looks like and contents of the pack CosmoFer is contained in clear glass ampoules. The pack sizes are the following: Packing containing 5 x 2 ml, packing containing 10 x 2 ml, packing containing 10 x 5 ml, packing containing 2 x 10 ml and packing containing 5 x 10 ml. Marketing Authorisation Holder and Manufacturer Pharmacosmos A/S Roervangsvej 30 DK-4300 Holbaek Denmark This leaflet was last revised in 01/ The following information is intended for healthcare professionals only: Monitor carefully patients for signs and symptoms of hypersensitivity reactions during and following each administration of CosmoFer. CosmoFer should only be administered when staff trained to evaluate and manage anaphylactic reactions is immediately available, in an environment where full resuscitation facilities can be assured. The patient should be observed for adverse effects for at least 30 minutes following each CosmoFer injection. Administration: 24

25 CosmoFer solution for infusion and 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 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. 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) 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 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 30 minutes 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: 25

26 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: The total amount of CosmoFer required 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 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. 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 0.24) + 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 / 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. 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: 26

27 If the volume of blood lost is known: The administration of 200 mg i.v. iron results in an increase of haemoglobin which is equivalent to 1 unit blood. Iron to be replaced [mg] = number of blood units lost x 200. If the Hb level is reduced: Use the previous formula considering that the depot iron does not need to be restored. 27