CosmoFer

CosmoFer^® 50mg/ml solution for infusion and injection

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).

Solution for infusion and injection

A dark brown solution.

- 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).

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:

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 100-200 mg iron corresponding to 2-4 ml, two or three times a week depending on the haemoglobin level.).

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 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.

Intravenous injection:

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 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 45 - 60 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:

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 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 deficiency anaemia.

The figures in the table below are based on a target haemoglobin of 150 g/l or 9.3 mmol/l and iron stores of 500 mg which apply to a body weight exceeding 35 kg.

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.

Total dose of CosmoFer^® in Millilitres to be administered in iron deficiency anaemia

Note: The table and accompanying formula are applicable for dose determination only in patients with iron deficiency anaemia. They are not to be used for dose determination in patients requiring iron replacement for blood loss.

b) Iron replacement for blood loss:

Iron therapy in patients with blood loss should be directed toward replacement of an amount of iron equivalent to the amount of iron represented in the blood loss. The table and formula described are not applicable for simple iron replacement values. Quantitative estimates of the individual's periodic blood loss and hematocrit during the bleeding episode provide a convenient method of calculation of the required iron dose.

The required CosmoFer^® dose to compensate the iron deficit is calculated according to the following formulas:

- If the volume of blood lost is 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^®)

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.

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 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.

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.

There are no adequate and well-controlled trials of CosmoFer^® in pregnant women. Studies in animals have shown reproductive toxicity. A careful risk/benefit evaluation is therefore required before use during pregnancy and CosmoFer^® should not be used during pregnancy unless clearly necessary.

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.

No studies on the effect on the ability to drive and use machines have been performed.

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.

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 Yellow Card Scheme,

Website: www.mhra.gov.uk/yellowcard

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.

Pharmacotherapeutic group: Iron parenteral preparation, ATC code: B03AC

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.

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.

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.

Water for injections

Sodium hydroxide (pH adjuster)

Hydrochloric acid (pH adjuster)

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 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.

This medicinal product does not require any special storage conditions.

Do not freeze.

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.

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.

Pharmacosmos A/S

Roervangsvej 30

DK-4300 Holbaek

Denmark

PL 18380/0002

Date of first authorisation: 04/2001

Date of first renewal: 09/2009

February 2014