INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo COSMOFER (Parenteral Solution)

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form)

COSMOFER (Parenteral Solution)

COMPOSITION
Each mL contains
iron(III)–hydroxide dextran complex equivalent to 50 mg iron(III).
Contains no preservatives.

PHARMACOLOGICAL CLASSIFICATION
A.8.3 Erythropoietics (Haematinics)

PHARMACOLOGICAL ACTION
Pharmacodynamics
CosmoFer Parenteral Solution contains iron as a stable iron(III)-hydroxide dextran complex, which is analogous to the physiological form of iron, ferritin. The iron is available in a non-ionic water-soluble form.
Serum ferritin peaks approximately 7 to 9 days after an intravenous dose of iron(III)–hydroxide dextran complex 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.
Pharmacokinetics
Following the IV 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 haematopoiesis can be observed for the next 6 to 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 haemosiderin 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.

INDICATIONS
Severe iron deficiency in adult patients intolerant to or not responding to oral iron when confirmed by appropriate investigations.

CONTRA-INDICATIONS
Non-iron deficiency anaemia e.g. haemolytic anaemia and anaemia of chronic disease.
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.

WARNINGS
CosmoFer should only be used for the approved indications.
The use of CosmoFer carries a risk of immediate severe and potentially lethal anaphylactoid reactions. The risk is enhanced for patients with known (medical) allergy. CosmoFer may only be administered when facilities and equipment for handling anaphylactic reactions are available, including an injectable 1:1000 epinephrine solution. Additional treatment with antihistamines and/or corticosteroids should be given as appropriate. For administration of test dose, please refer to Dosage and Directions for Use.
There is particularly increased risk of allergic reactions in patients with immune or inflammatory conditions (e.g. systemic lupus erythematosus, rheumathoid arthritis).
When CosmoFer is considered essential in patients with asthma, allergic disorders and inflammatory disorders; the intramuscular route is to be preferred.
Hypotensive episodes may occur if intravenous injection is administered too rapidly.
CosmoFer must not be mixed with other medicines for simultaneous administration. A 0,9% sodium chloride solution or 5% glucose solution are the only recommended diluents for an infusion.

INTERACTIONS
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 CosmoFer (5 mL or more) have been reported to give a brown colour to serum from a blood sample drawn four hours after administration.
CosmoFer may cause falsely elevated values of serum bilirubin and falsely decreased values of serum calcium.

PREGNANCY AND LACTATION
There are no adequate data on safety from the use of CosmoFer in pregnant women. CosmoFer should not be used during the first trimester of pregnancy. If the benefit of CosmoFer treatment is judged to outweigh the potential risk to the foetus, it is recommended that treatment should be confined to the second and third trimester, if treatment is clearly necessary.
It is unknown whether the complex iron-dextran is excreted in human or animal breast milk CosmoFer should not be used during breast-feeding.

DOSAGE AND DIRECTIONS FOR USE
Test dose: (All routes of administration)
Before administering the first dose to a new patient, a test dose of CosmoFer corresponding to 25 mg iron or equal to 0,5 mL solution must be administered. If no adverse reactions are seen after 60 minutes, the remaining dose can be given.
Anaphylactoid reactions to CosmoFer are usually evident within a few minutes, and close observation is necessary to ensure recognition. If at any time during the intravenous administration of CosmoFer, any signs of a hypersensitivity reaction or intolerance are detected, administration must be stopped immediately.
Resuscitative medication and personnel trained to evaluate and resuscitate anaphylaxis should be available whenever a dose of CosmoFer is administered.
Administration:
CosmoFer Parenteral Solution 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 to 200 mg of iron corresponding to 2 to 4 mL, two or three times a week depending on the haemoglobin level.
The CosmoFer injection should not be administered concomitantly with oral iron preparations as the absorption of oral iron will be reduced (see Interactions).
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 to 200 mg iron (2 to 4 mL) 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 to 200 mg iron (2 to 4 mL) by slow intravenous injection (0,2 mL/min) preferably diluted in 10 to 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 0,9% sodium chloride or 5% glucose solutions. The total amount of CosmoFer, up to 20 mg/kg body weight, is infused intravenously over 4 to 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 to 60 drops per minute (based on a standard infusion set delivering 20 drops/mL of 0,9% sodium chloride or 5% glucose). Patients should be observed carefully during the infusion and for at least 1 hour after completion.
Total Dose Infusion (TDI) has been associated with an increased incidence of adverse reactions, in particular delayed hypersensitivity-like reactions. The intravenous administration of CosmoFer by the Total Dose Infusion method should be restricted to hospital use only.
Injection into Dialyser: CosmoFer may be administered during a haemodialysis session directly into the venous limb of the dialyser under the same procedures as outlined for intravenous administration.
Intramuscular Injection: Following a test dose prior to the first injection the entire dose is administered at once for subsequent intramuscular injections. The total amount of CosmoFer required is determined either from the dosage table or by calculation. It is administered as a series of undiluted injections of up to 100 mg iron (2,0 mL) each determined by the patient’s body weight. If the patient is moderately active, injections may be given daily into alternate buttocks. In inactive or bedridden patients, the frequency of injections should be reduced to once or twice a week.
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 buttocks; never into the arm or other exposed areas. 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 is recommended.
CosmoFer is injected slowly. 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 encourage 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 (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% of 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 Parenteral 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
Haemoglobin content 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
Body weight (kg)
35 25 23 20 18 15 12,5
40 27 24 22 19 16 13
45 29 26 23 20 16,5 13
50 32 28 24 21 17 13,5
55 34 30 26 22 18 14
60 36 32 27 23 18,5 14,5
65 38 33 29 24 19,5 14,5
70 40 35 30 25 20 15
75 42 37 32 26 21 15,5
80 45 39 33 27 21,5 16
85 47 41 34 28 22 16
90 49 42 36 29 23 16,5
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 towards 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 haematocrit during the bleeding episode provide a convenient method of calculation of the required iron dose.
The required CosmoFer dose to compensate the iron deficit is calculated according to the following formulas:
If the volume of blood lost is unknown: The administration of 200 mg I.V. iron (4 mL CosmoFer) results in an increase of haemoglobin which is equivalent to 1 unit blood (= 400 mL with 150 g/L Hb content or 9,3 mmol Hb/L – equivalent to 0,34% of 0,4 x 150 or 204 mg iron). Iron to be replaced [mg] = number of blood units lost x 200. Millilitres of CosmoFer needed = number of blood units lost x 4.
If the Hb level is reduced: Use the previous formula considering that the depot iron does not need to be restored.
Mg iron to be replaced = body weight (kg) x 0,24 x (target Hb in g/L –actual Hb in g/L).
or
Mg iron to be replaced = body weight (kg) x 3,84 x (target Hb in mmol/L –actual Hb in mmol/L).
e.g.: body weight 60 kg, Hb deficit = 10 g/L or 0,62 mmol/L:
Iron to be replaced = 60 x 0,24 x 10 = 60 x 3,84 x 0,62 = 143 mg (˜ 3 millilitres CosmoFer)

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-Effects
Approximately 5% of patients can be expected to experience adverse reactions. These are mainly dose dependent.
Anaphylactoid reactions 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 Uncommon
(>1/1000, <1/100)
Rare
(>1/10000, <1/1000)
Very rare
(<1/10000)
Blood and lymphatic system disorders     Haemolysis
Cardiac disorders   Dysrythmia, 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 Fatigue, pain and brown pigmentation at injection site  
Immune system disorders Anaphylactoid reactions including dyspnoea, urticaria, rashes, itching, nausea and shivering   Acute, severe anaphylactoid reactions (sudden onset of respiratory difficulty and/or cardiovascular collapse)
Musculoskeletal and connective tissue disorders Cramps Myalgias  
Nervous system disorders Blurred vision, numbness Loss of consciousness, seizures, dizziness, restlessness, tremor  
Respiratory, thoracic and mediastinal disorders Dyspnoea Chest pain  
Psychiatric disorders   Mental status changes  
Skin and subcutaneous tissue disorders Flushing, pruritus, rash Angioedema, sweating  
Vascular disorders   Hypotension Hypertension

Special Precautions
Exacerbation of joint pain in rheumatoid arthritis can occur. Patients with other inflammatory disorders such as lupus erythematosus may be at increased risk of delayed reactions.
Effects on ability to drive and use machines
No studies on the effect on the ability to drive and use machines have been performed.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
See “SIDE-EFFECTS AND SPECIAL PRECAUTIONS”. Treatment is symptomatic and supportive.
Overdose can cause acute iron overloading which may manifest as haemosiderosis. Particular caution should be exercised to avoid iron overload where anaemia, unresponsive to treatment, has been incorrectly diagnosed as iron deficiency anaemia.
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.

IDENTIFICATION
CosmoFer is a dark brown solution filled into a 2 mL or 10 mL clear glass ampoule.

PRESENTATION
CosmoFer is packed into Type I clear 2 mL or 10 mL glass ampoules with break point. An outer carton box contains 5 or 10 ampoules.

STORAGE INSTRUCTIONS
Store in a cool dark place below 25 ºC. Store in the carton until required for use.
Inspect ampoules visually for sediment and damage before use. Use only those containing sediment-free homogeneous solution. Do not freeze.
KEEP OUT OF REACH OF CHILDREN.
CosmoFer is for single use only and any unused solution should be discarded. The product should be used immediately after opening of the container.
In-use stability has been demonstrated for 24 hours at 25°C after dilution with 0,9% sodium chloride or 5% glucose solution.

REGISTRATION NUMBER
37/8.3/0434

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
Pharmaplan (Pty) Ltd
106 16th Road
Midrand

DATE OF PUBLICATION OF THE PACKAGE INSERT
15 April 2011

New addition to this site: May 2014
Source: Pharmaceutical Industry

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