Iron (III)-Hydroxide Dextran Complex

Registered South African indications:

• Severe iron deficiency
  - In adult patients, intolerant to or not responding to oral iron when confirmed by appropriate investigations

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Known hypersensitivity to other parenteral iron products
• 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 allergies such as of asthma, eczema, or other atopic allergy
• 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

South African recommendations

Caution in the following patient groups

• Pregnancy
• Breastfeeding

Hypersensitivity reactions

• Parenteral iron preparations, like iron (III)-hydroxide dextran complex, can cause hypersensitivity reactions, which can be serious and potentially fatal anaphylactic/anaphylactoid reactions
• These reactions have also occurred after doses that were previously uneventful
• The risk of these reactions is higher in patients with known allergies, including medicine allergies, a history of severe asthma, eczema, or other atopic allergies
• There's also an increased risk in patients with immune or inflammatory conditions, such as systemic lupus erythematosus or rheumatoid arthritis
• Iron (III)-hydroxide dextran complex should only be given when staff trained to manage anaphylactic reactions are immediately available in an environment with full resuscitation facilities. Patients must be observed for adverse effects for at least 60 minutes after each injection

Rapid administration

• Hypotensive episodes may occur if intravenous injection is administered too rapidly

Large doses

• Large doses (5ml or more) have been reported to give a brown colour to serum from a blood sample drawn four hours after administration

Effect on serum levels

• Iron (III)-hydroxide dextran complex may cause falsely elevated values of serum bilirubin and falsely decreased values of serum calcium

Effects on ability to drive and use machines

• No studies on the effect on the ability to drive and use machines have been performed. Adverse reactions such as blurred vision, dizziness, tremor may influence ability to drive and use machines

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Severe iron deficiency
- In adult patients, intolerant to or not responding to oral iron when confirmed by appropriate investigations

• IV/IM: Normal recommended dosage schedule: 100-200mg (2-4ml), 2-3 times a week depending on the haemoglobin level
• IM: Up to 100mg iron (2ml) 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 1-2 times a week

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Intramuscular Injection

Administer as a series of undiluted injections 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 lie in the lateral position with the injection site uppermost, or stand 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

Deep intramuscular administration should be injected slowly

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• IV drip infusion: Initial (and on each occasion): Infuse 25mg over 15 min; If no adverse reactions, remaining portion of infusion should be given: 100-200mg (2-4ml) at a rate of not more than 100ml in 30 min

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Diluted only in 0.9% sodium chloride solution (normal saline) or in 5% glucose solution. Iron (III)-hydroxide dextran complex in a dose of 100 to 200 mg elemental iron (2 to 4 ml) may be diluted in 100ml

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• IV injection: Initial (and on each occasion): Inject 25mg slowly over 1-2 min; If no adverse reactions occur within 15 min, remaining portion of injection may be given: 100-200mg iron (2-4ml) by slow intravenous injection (0.2ml/min)

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Dilute in 10 to 20ml of 0.9% sodium chloride or 5% glucose solution

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• Total dose infusion (TDI): Initial: Infuse 25mg over 15 min; Total required is determined from the dosage table or by calculation, up to 20mg/kg body weight, infused over 4-6hrs

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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 iron (III)-hydroxide dextran complex by the Total Dose Infusion method should be restricted to hospital use only

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• Injection into dialyser: May be administered during a haemodialysis session directly into the venous limb of the dialyser under the same procedures as outlined for intravenous administration

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Anaphylactoid reactions are usually evident within a few minutes, and close observation is necessary to ensure recognition. Monitor for signs and symptoms of hypersensitivity reactions during and following each administration
Iron (III)-hydroxide dextran complex should only be administered when staff trained to evaluate and manage anaphylactic reactions is immediately available, in an environment where full resuscitation facilities is assured
Observe for adverse effects for at least 60 minutes following each injection. If at any time during the intravenous administration, any signs of a hypersensitivity reaction or intolerance are detected, administration must be stopped immediately

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Method of administration

May 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. May also be administered as undiluted solution intramuscularly

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Iron (III)-hydroxide dextran complex should not be administered concomitantly with oral iron preparations as the absorption of oral iron will be reduced

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See additional prescribing points for calculation of dose

Not established for use in children under 14 years

Pregnancy

South African recommendations

• First trimester: Caution; not recommended
• Second and third trimester: Caution
• There are no adequate and well controlled trials on safety from the use of iron (III)-hydroxide dextran complex in pregnant women. Studies in animals have shown reproductive toxicity
• A careful risk/benefit evaluation is therefore required before use during pregnancy
• Iron deficiency anaemia occurring in the first trimester of pregnancy can in most cases be treated with oral iron
• Treatment with iron (III)-hydroxide dextran complex should be confined to second and third trimester
• Foetal bradycardia may occur following administration of parenteral irons. It is usually transient and a consequence of a hypersensitivity reaction in the mother

Breastfeeding

South African recommendations

• Caution; not recommended
• It is unknown whether the complex iron-dextran is excreted in human or animal breast milk. It is preferable to not use iron (III)-hydroxide dextran complex during breastfeeding

Fertility

South African recommendations

• No information available

South African recommendations

• No dose adjustment recommended
• Acute renal failure: Contraindicated

South African recommendations

• No dose adjustment recommended
• Decompensated liver cirrhosis and hepatitis: Contraindicated

South African recommendations

• ≥ 65 years: No dose adjustment recommended

Blood and Lymphatic System disorders

Very rare

• Haemolysis

Cardiac Disorders

Rare

• Dysrhythmia
• Tachycardia

Very rare

• Foetal bradycardia
• Palpitations

Ear and Labyrinth Disorders

Very rare

• Transient deafness

Gastrointestinal Disorders

Uncommon

• Nausea and vomiting
• Abdominal pain

Rare

• Diarrhoea

General Disorders and Administration Site Conditions

Uncommon

• Feeling hot

Rare

• Fatigue
• Pain
• Brown pigmentation at injection site

Not known

• Influenza like illness whose onset may vary from a few hours to several days

Immune system disorders

Uncommon

• Anaphylactoid/ anaphylactic reactions
  • Dyspnoea
  • Urticaria
  • Rashes
  • Itching
  • Nausea
  • Shivering
  • Cardiovascular collapse

Musculoskeletal and Connective Tissue Disorders

Uncommon

• Cramps

Rare

• Myalgias

Nervous System Disorders

Uncommon

• Blurred vision
• Numbness

Rare

• Loss of consciousness
• Seizures
• Dizziness
• Restlessness
• Tremor

Very rare

• Headache
• Paraesthesia

Respiratory Disorders

Uncommon

• Dyspnoea

Rare

• Chest pain

Psychiatric Disorders

Rare

• Mental status changes

Skin and Subcutaneous Tissue Disorders

Uncommon

• Flushing
• Pruritus
• Rash

Rare

• Sweating

Vascular Disorders

Rare

• Hypotension

Very rare

• Hypertension

• Oral iron therapy
  (See additional prescribing points)

• Haemoglobin level
• Body weight
• Haematocrit
• Reticulocyte count
• Serum ferritin
• Serum iron

Additional observations

• Signs and symptoms of hypersensitivity reactions

Coadministration with oral iron

• 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 iron (III)-hydroxide dextran complex

Dose calculation

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 (haemoglobin) 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 1 000 / 0.06205

• The table below shows the number of millilitres of iron (III)-hydroxide dextran complex solution for injection/infusion 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 500mg which apply to a body weight exceeding 35kg
• 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 iron (III)-hydroxide dextran complex 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

Table 1: Total dose of iron (III)-hydroxide dextran complex in millilitres (ml) to be administered in iron deficiency anaemia

Body weight (kg)		Hb content
		60g/l ≈ 3,7  mmo/l	75g/l ≈ 4,7  mmol/l	90g/l ≈ 5,6 mmol/l	105g/l ≈ 6,5 mmol/l	120g/l ≈ 7,4 mmol/l	135g/l ≈ 8 mmol/l
	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

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 iron (III)-hydroxide dextran complex dose to compensate the iron deficit is calculated according to the following formulas:
  • If the volume of blood lost is unknown: The administration of 200mg I.V. iron (4ml) results in an increase of haemoglobin which is equivalent to 1 unit blood (= 400ml with 150g/l Hb content or 9.3 mmol Hb/l – equivalent to 0.34% of 0.4 x 150 or 204mg iron)
    - Iron to be replaced mg = number of blood units lost x 200
    - Millilitres of iron (III)-hydroxide dextran complex 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 60kg, Hb deficit = 10g/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 iron (III)-hydroxide dextran complex)

Iron(III)-hydroxide dextran complex, 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 iron(III) hydroxide dextran complex and slowly returns baseline after about 3 weeks.

Injection (per ml) 50mg

• Cosmofer (Iron Dextran) originator