40474814 12.04.2005 11:38 Uhr Seite 1
`
`CosmoFer® 50mg/ml
`
`Iron(III)-hydroxide dextran complex
`solution for injection and infusion,
`single dose container
`Please read all of this leaflet carfully before you are given CosmoFer®
`- Keep this leaflet. You may need to read it again.
`- If you have further questions, please ask your doctor or your pharmacist.
`In this leaflet:
`1. What CosmoFer® is and what it is used for
`2. Before you are given CosmoFer®
`3. How CosmoFer® will be given to you
`4. Possible side effects
`5. Storing CosmoFer®
`CosmoFer®, Iron (III)-hydroxide dextran complex
`1 ampoule of 2ml contains:
`625mg Iron (III)-hydroxide dextran complex equivalent to 100mg iron(III)
`1 ampoule of 5ml contains:
`1562.5mg Iron (III)-hydroxide dextran complex equivalent to 250mg iron(III)
`The other ingredients are water for injections, sodium hydroxide (pH adjuster),
`hydrochloric acid (pH adjuster)
`The Marketing Authorisation holder and Manufacturer of CosmoFer® is:
`Nebo a/s
`Roervangsvej 30, 4300 Holbaek
`Denmark
`1. WHAT CosmoFer® IS AND WHAT IT IS USED FOR
`CosmoFer® is a solution of iron (III)-hydroxide dextran complex for injection and infusion. It will be given to you when you
`are suffering from iron deficiency and it is not possible to give iron orally.
`Pharmaceutical form:
`Packing containing 5 x 2ml
`Packing containing 10 x 2ml
`Packing containing 10 x 5ml
`Not all pack sizes may be marketed
`2. BEFORE YOU ARE GIVEN CosmoFer®
`You should not be given CosmoFer® :
`-
`If you are a child under the age of 14 years
`-
`If you are pregnant and in the first 3 months of pregnancy
`-
`If you are allergic (hypersensitive) to iron (III)-hydroxide dextran complex or other iron mono- or disaccharide complexes
`-
`If you have anaemia that is not caused by a lack of iron (haemolytic anaemia).
`-
`If you have iron overload or disturbances in utilisation of iron (e.g. haemochromatosis, haemosiderosis).
`-
`If you have decompensated liver cirrhosis.
`-
`If you have infectious hepatitis
`-
`If you have a cold or any other infection.
`-
`If you are suffering from inflammation due to rheumatoid arthritis
`-
`If you have acute kidney failure
`Please note that if you have a history of asthma, eczema or other allergies, you should not be given CosmoFer® by injection
`or infusion into a vein.
`Take special care with CosmoFer®:
`Large doses of iron dextran (5 ml or more) have been reported to give a brown colour to serum from a blood sample that
`has been drawn four hours after administration.
`Having a course of CosmoFer® can interfere with some tests to determine your iron or calcium levels.
`If you have a history of asthma, eczema or other allergies you should only receive CosmoFer® by injection into a muscle.
`Some animal experiments have shown that large doses of an iron containing medicine, such as CosmoFer®, injected into mus-
`cle or the skin can cause a form of soft tissue cancer. From an independent assessment of information gathered it has been
`shown that the risk of this occurring in humans is low.
`
`CosmoFer® 50mg/ml
`
`Iron(III)-hydroxide dextran complex
`solution for injection and infusion,
`single dose container
`The following information is intended for medical or healthcare professionals only
`4.2 Posology and method of administration
`AAdduullttss aanndd eellddeerrllyy:: 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.
`CChhiillddrreenn ((uunnddeerr 1144 yyeeaarrss))::CosmoFer® should not be used for children. There is no documentation for efficacy and safety.
`DDoossaaggee::The normal recommended dosage schedule is 100-200 mg iron corresponding to 2-4 ml, two or three times a week depen-
`ding 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.
`AAddmmiinniissttrraattiioonn::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.
`TTeesstt ddoossee::(all routes of administration) Before administering the first dose to a new patient, a test dose of CosmoFer® cor-
`responding 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. 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. Facilities for cardio-
`pulmonary resuscitation including adrenaline (1:1000) must be available when administering CosmoFer®.
`Subsequent doses
`IInnttrraavveennoouuss ddrriipp iinnffuussiioonn::CosmoFer® must be diluted only in 0.9% sodium chloride solution (normal saline) or in 5% glucose
`solution. CosmoFer® in a dose of 100-200 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.
`IInnttrraavveennoouuss iinnjjeeccttiioonn::CosmoFer® may be administered in a dose of 100 – 200 mg iron (2-4 ml) by slow intravenous injection
`(0.2 ml/min) preferably diluted in 10 – 20 ml 0.9% sodium chloride or 5% glucose solution. On each occasion before admini-
`stering 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.
`TToottaall ddoossee iinnffuussiioonn::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 reac-
`tions occur during this time, then the remaining portion of the infusion should be given. The rate of infusion may be increased progres-
`sively to 45 – 60 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 hyper-
`sensitivity–like reactions. The intravenous administration of CosmoFer® by the total dose infusion method should be restric-
`ted to hospital use only.
`IInnjjeeccttiioonn iinnttoo ddiiaallyysseerr::CosmoFer® may be administered during a haemodialysis session directly into the venous limb of the dia-
`lyser under the same procedures as outlined for intravenous administration.
`IInnttrraammuussccuullaarr iinnjjeeccttiioonn::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 calcula-
`tion. 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 20 –
`21 gauge needle at least 50 mm long should be used for normal adults. For obese patients the length should be 80 – 100 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 = 0.0034 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 3.84 + 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 0.06205
`Factor 3.84 = 0.0034 x 0.07 x 1000 / 0.06205
`The table below shows the number of millilitres of CosmoFer® injection solution to be used at various degrees of iron defi-
`ciency 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.
`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 thera-
`peutic 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.
`Total dose of CosmoFer® in Millilitres to be administered in iron deficiency anaemia
`113355 gg//ll ≈≈
`HHaaeemmoogglloobbiinn ccoonntteenntt
`6600 gg//ll ≈≈
`7755 gg//ll ≈≈
`9900 gg//ll ≈≈
`110055 gg//ll ≈≈
`112200 gg//ll ≈≈
`33..77 mmmmooll//ll
`88..44 mmmmooll//ll
`BBooddyy wweeiigghhtt (kg)
`44..77 mmmmooll//ll
`55..66 mmmmooll//ll
`66..55 mmmmooll//ll
`77..44 mmmmooll//ll
`12.5
`35
`25
`23
`20
`18
`15
`13
`40
`27
`24
`22
`19
`16
`13
`45
`29
`26
`23
`20
`16.5
`13.5
`50
`32
`28
`24
`21
`17
`14
`55
`34
`30
`26
`22
`18
`14.5
`60
`36
`32
`27
`23
`18.5
`14.5
`65
`38
`33
`29
`24
`19.5
`15
`70
`40
`35
`30
`25
`20
`15.5
`75
`42
`37
`32
`26
`21
`16
`80
`45
`39
`33
`27
`21.5
`16
`85
`47
`41
`34
`28
`22
`16.5
`90
`49
`42
`36
`29
`23
`NNoottee:: The table and accompanying formula are applicable for dose determination only in patients with iron deficiency anae-
`mia. 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 hae-
`moglobin 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 x150 or 204 mg iron).
`
`Pharmacosmos, Exh. 1057, p. 1
`
`

`
`40474814 12.04.2005 11:38 Uhr Seite 2
`
`Pregnancy
`CosmoFer® should not be used during the first 3 months of pregnancy but can be used during the last months.
`Breast-feeding
`CosmoFer® can be used when you are breast feeding.
`Taking other medicines:
`You should not be given an injection of CosmoFer® if you are also taking other iron supplements.
`Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines, even those you have
`bought yourself.
`3. HOW YOU WILL BE GIVEN CosmoFer®
`CosmoFer® can be given to you by an injection into a vein (intravenously), by infusion into a vein (intravenous infusion) or by
`injection into a muscle (intramuscularly). To avoid adverse reactions the injection will be given to you slowly and may be dilu-
`ted in sodium chloride or glucose solution.
`CosmoFer® may be given two or three times a week depending on your haemoglobin level. As a precaution a small test dose
`will be given to you the first time CosmoFer® is administered to make sure that you have no reactions to it. Provided you show
`no reactions to this, the remaining dose can be given to you. On the second day of treatment, the dose of CosmoFer® given
`to you will be increased to the equivalent of 100 mg iron. Following this, you may be given a CosmoFer® dose equivalent to
`100 to 200 mg iron daily or every other day.
`You may also be given the complete dose in a single infusion, diluted in sodium chloride or glucose. This will be given to you
`over a period of 4 to 6 hours.
`If you are given more CosmoFer® than you should:
`Since a trained person will give you CosmoFer®, it is highly unlikely that you will be given too much. If you think a child or anyo-
`ne else has accidentally taken any of this treatment, let a hospital casualty department or hospital staff know immediately.
`4. POSSIBLE SIDE EFFECTS
`Like all medicines, CosmoFer® can have side effects. There is an uncommon risk of severe allergic reactions (anaphylactoid
`reactions). The necessary emergency equipment will be immediately available before you are given CosmoFer® to counter
`the effects of this. Other allergic reactions such as difficulty breathing (dyspnoea), flushing, stomach pain, nausea, vomiting,
`blurred vision, itchy rash, numbness, feeling hot and cramps and are also uncommon.
`On rare occasions you may experience chest pains, heart troubles, low blood pressure, loss of consciousness, seizure, confu-
`sion or feeling different to normal, dizziness, tiredness or restlessness, sweating, diarrhoea or muscle pain or tremors. You
`may have increased joint pain if you have rheumatoid arthritis
`You may feel some pain and also some inflammation at the site of injection in addition to some discolouration of the skin.
`You may also experience localised swelling, local tissue damage and bleeding at the site of injection.
`If you notice any side effects not mentioned in this leaflet, please inform the person giving you CosmoFer® or your doctor.
`5. STORING CosmoFer®
`It is unlikely that you will be asked to store CosmoFer® yourself, however if you have to please:
`Keep out of the reach and sight of children
`No special precaution for storage
`Do not use after the expiry date stated on the ampoule or carton
`This leaflet was last approved on
`Further information
`For any information about this medicinal product, please contact the local representative of Nebo A/S as given below.
`United Kingdom and Ireland
`Vitaline Pharmaceuticals UK Ltd
`8 Ridge Way, Drakes Drive
`Crendon Business Park
`Long Crendon
`Buckinghamshire
`HP18 9BF
`Tel: 01844 202044
`
`404748-14 12/04
`
`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
`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 allergy 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.
`4.4 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 administra-
`tion. The risk is enhanced for patients with known (medical) allergy. CosmoFer® may only be administered when anaphylac-
`tic emergency measures, including an injectable 1:1000 adrenaline solution are available. Additional treatment with antihi-
`stamines and/or corticosteroids should be given as appropriate. Administration to patients with (auto) immune disorder or
`inflammatory conditions (e.g. systemic lupus erythematosus, rheumathoid arthritis) may cause a type III allergic reaction.
`Where 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 condi-
`tions 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.
`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 Pregnancy and lactation
`CosmoFer® should not be used during the first trimester but can be used during second and third trimester and during lacta-
`tion if oral iron therapy is ineffective or impracticable. Iron deficiency anaemia occurring in the first trimester of pregnancy
`can normally be adequately treated with oral iron. If the benefit of CosmoFer® treatment is judged to outweigh the potenti-
`al risk to the foetus, it is recommended that treatment should be confined to the second and third trimester if oral iron the-
`rapy is ineffective or impracticable. There is no information available on the excretion of CosmoFer® in the human breast milk.
`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. Acute,
`severe anaphylactoid reactions are uncommon. They usually occur within the first few minutes of administration and are gene-
`rally characterised by the sudden onset of respiratory difficulty and / or cardiovascular collapse; fatalities have been reported.
`Other less severe manifestations of immediate hypersensitivity are also uncommon and include urticaria, rashes, itching, nau-
`sea and shivering. Administration must be stopped immediately when signs of an anaphylactoid reaction are observed.
`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 ste-
`rile abscesses, tissue necrosis or atrophy and pain are observed.
`OOrrggaann ssyysstteemm
`CCoommmmoonn
`UUnnccoommmmoonn
`((>>11//110000,, <<11//1100))
`((>>11//11,,000000,,<<11//110000))
`
`Nervous system
`
`Cardiovascular
`
`Respiratory, thoracic
`and mediastinal
`Gastrointestinal
`
`Skin and subcutaneous
`Musculoskeletal,
`connective tissue
`and bone
`General
`
`Dyspnoea
`
`Nausea, emesis, abdominal
`pain
`Flushing, pruritus, rash
`
`Blurred vision, feeling hot,
`cramps, numbness
`
`RRaarree
`((>>11//1100,,000000,, <<11//11,,000000))
`Loss of consciousness, altered
`mental status, seizure, dizziness,
`restlessness, fatigue
`Hypotension, angiedoema,
`arrhythmia, tachycardia
`Chest pain
`
`Diarrhoea
`
`Diaphoresis
`Myalgias, tremor
`
`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 inflam-
`matory process, which may lead to fibrosis.
`6. Pharmaceutical Particulars
`6.1 List of excipients
`Water for injections
`Sodium hydroxide (pH adjuster)
`Hydrochloric acid (pH adjuster)
`6.2 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.
`6.3 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.
`6.4 Special precautions for storage
`No special precautions for storage..
`6.5 Nature and contents of container
`Type 1 glass ampoules.
`Packing containing 5 x 2 ml.
`Packing containing 10 x 2 ml.
`Packing containing 10 x 5 ml.
`Not all pack sizes may be marketed.
`6.6 Instructions for use and handling
`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.
`10. Date of revision of the text
`March 10, 2005
`
`404748-14 12/04
`
`Pharmacosmos, Exh. 1057, p. 2