4.1. Therapeutic indications

Venofer is indicated for the treatment of iron deficiency in the following indications:

• Where there is a clinical need for a rapid iron supply,

• In patients who cannot tolerate oral iron therapy or who are non-compliant,

• In active inflammatory bowel disease where oral iron preparations are ineffective,

• In chronic kidney disease when oral iron preparations are less effective.

The diagnosis of iron deficiency must be based on appropriate laboratory tests (e.g. Hb, serum ferritin, TSAT, serum iron, etc.).

(Hb haemoglobin, TSAT transferrin saturation)

4.2. Posology and method of administration

Monitor carefully patients for signs and symptoms of hypersensitivity reactions during and following each administration of Venofer.

Venofer 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 Venofer administration (see section 4.4).

Posology

The cumulative dose of Venofer must be calculated for each patient individually and must not be exceeded.

Calculation of dosage

The total cumulative dose of Venofer, equivalent to the total iron deficit (mg), is determined by the haemoglobin level (Hb) and body weight (BW). The dose of Venofer must be individually calculated for each patient according to the total iron deficit calculated with the following Ganzoni formula, for example:

Total iron deficit [mg] = BW [kg] x (target Hb - actual Hb) [g/dL] x 2.4* + storage iron [mg]

• Below 35 kg BW: Target Hb = 13 g/dL and storage iron = 15 mg/kg BW

• 35 kg BW and above: Target Hb = 15 g/dL and storage iron = 500 mg

* Factor 2.4 = 0.0034 (iron content of Hb = 0.34%) x 0.07 (blood volume = 7% of BW) x 1000 (conversion of [g] to [mg]) x 10

Total amount of Venofer (mL) to be administered according to body weight, actual Hb level and target Hb level*:

BW

Total amount of Venofer (20 mg iron per mL) to be administered

Hb 6.0 g/dL

Hb 7.5 g/dL

Hb 9.0 g/dL

Hb 10.5 g/dL

30 kg

47.5 mL

42.5 mL

37.5 mL

32.5 mL

35 kg

62.5 mL

57.5 mL

50 mL

45 mL

40 kg

67.5 mL

60 mL

55 mL

47.5 mL

45 kg

75 mL

65 mL

57.5 mL

50 mL

50 kg

80 mL

70 mL

60 mL

52.5 mL

55 kg

85 mL

75 mL

65 mL

55 mL

60 kg

90 mL

80 mL

67.5 mL

57.5 mL

65 kg

95 mL

82.5 mL

72.5 mL

60 mL

70 kg

100 mLl

87.5 mL

75 mL

62.5 mL

75 kg

105 mL

92.5 mL

80 mL

65 mL

80 kg

112.5 mL

97.5 mL

82.5 mL

67.5 mL

85 kg

117.5 mL

102.5 mL

85 mL

70 mL

90 kg

122.5 mL

107.5 mL

90 mL

72.5 mL

* Below 35 kg BW:

Target Hb = 13 g/dL

35 kg BW and above:

Target Hb = 15 g/dL

To convert Hb (mM) to Hb (g/dL), multiply the former by 1.6.

If the total necessary dose exceeds the maximum allowed single dose, then the administration must be divided.

Posology

Adults

5 - 10 mL of Venofer (100 - 200 mg iron) 1 to 3 times a week. For administration time and dilution ratio see “Method of administration”.

Paediatric population

The use of Venofer has not been adequately studied in children and, therefore, Venofer is not recommended for use in children.

Method of administration

Venofer must only be administered by the intravenous route. This may be by a slow intravenous injection, by an intravenous drip infusion or directly into the venous line of the dialysis machine.

Intravenous drip infusion

Venofer must only be diluted in sterile 0.9% m/V sodium chloride (NaCl) solution. Dilution must take place immediately prior to infusion and the solution should be administered as follows:

Venofer dose

(mg of iron)

Venofer dose

(mL of Venofer)

Maximum dilution volume of sterile 0.9% m/V NaCl solution

Minimum Infusion Time

50 mg

2.5 mL

50 mL

8 minutes

100 mg

5 mL

100 mL

15 minutes

200 mg

10 mL

200 mL

30 minutes

For stability reasons, dilutions to lower Venofer concentrations are not permissible.

Intravenous injection

Venofer may be administered by slow intravenous injection at a rate of 1 mL undiluted solution per minute and not exceeding 10 mL Venofer (200 mg iron) per injection.

Injection into venous line of dialysis machine

Venofer may be administered during a haemodialysis session directly into the venous line of the dialysis machine under the same conditions as for intravenous injection.

4.3. Contraindications

The use of Venofer is contraindicated in the following conditions:

• Hypersensitivity to the active substance, to Venofer or any of its excipients listed in section 6.1

• Known serious hypersensitivity to other parenteral iron products

• Anaemia not caused by iron deficiency

• Evidence of iron overload or hereditary disturbances in utilisation of iron.

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 including iron sucrose. There have been reports of hypersensitivity reactions which progressed to Kounis syndrome (acute allergic coronary arteriospasm that can result in myocardial infarction, see section 4.8). In several studies performed in patients who had a history of a hypersensitivity reaction to iron dextran or ferric gluconate, Venofer was shown to be well tolerated. For known serious hypersensitivity to other parenteral iron product see section 4.3.

The risk of hypersensitivity reactions 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).

Venofer 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 Venofer 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.

In patients with liver dysfunction, parenteral iron should only be administered after careful risk/benefit assessment. Parenteral iron administration should be avoided in patients with hepatic dysfunction where iron overload is a precipitating factor, in particular Porphyria Cutanea Tarda (PCT). Careful monitoring of iron status is recommended to avoid iron overload.

Parenteral iron should be used with caution in the case of acute or chronic infection. It is recommended that the administration of Venofer is stopped in patients with bacteraemia. In patients with chronic infection, a risk/benefit evaluation should be performed.

Paravenous leakage must be avoided because leakage of Venofer at the injection site can lead to pain, inflammation and brown discoloration of the skin.

Venofer contains up to 7 mg sodium per mL, equivalent to 0.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5. Interaction with other medicinal products and other forms of interaction

As with all parenteral iron preparations, Venofer should not be administered concomitantly with oral iron preparations since the absorption of oral iron is reduced. Therefore, oral iron therapy should be started at least 5 days after the last injection of Venofer.

4.6. Fertility, pregnancy and lactation

Pregnancy

There is no data from the use of iron sucrose in pregnant women in the first trimester. Data (303 pregnancy outcomes) from the use of Venofer in pregnant women in the second and third trimester showed no safety concerns for the mother or newborn.

A careful risk/benefit evaluation is required before use during pregnancy and Venofer 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 Venofer 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.

Foetal bradycardia may occur following administration of parenteral irons. It is usually transient and a consequence of a hypersensitivity reaction in the mother. The unborn baby should be carefully monitored during intravenous administration of parenteral irons to pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Breast-feeding

There is limited information on the excretion of iron in human milk following administration of intravenous iron sucrose. In one clinical study, 10 healthy breast-feeding mothers with iron deficiency received 100 mg iron in the form of iron sucrose. Four days after treatment, the iron content of the breast milk had not increased and there was no difference from the control group (n=5). It cannot be excluded that newborns/infants may be exposed to iron derived from Venofer via the mother's milk, therefore the risk/benefit should be assessed.

Preclinical data do not indicate direct or indirect harmful effects to the nursing child. In lactating rats treated with 59Fe-labelled iron sucrose, low secretion of iron into the milk and transfer of iron into the offspring was observed. Non metabolised iron sucrose is unlikely to pass into the mother's milk.

Fertility

No effects of iron sucrose treatment were observed on fertility and mating performance in rats.

4.7. Effects on ability to drive and use machines

In the case of symptoms of dizziness, confusion or light headedness following the administration of Venofer, patients should not drive or use machinery until the symptoms have ceased.

4.8. Undesirable effects

The most commonly reported adverse drug reaction in clinical trials with Venofer was dysgeusia, which occurred with a rate of 4.5 events per 100 subjects. The most important serious adverse drug reactions associated with Venofer are hypersensitivity reactions, which occurred with a rate of 0.25 events per 100 subjects in clinical trials. Anaphylactoid/anaphylactic reactions were reported only in the post-marketing setting (estimated as rare); fatalities have been reported. See section 4.4.

The adverse drug reactions reported after the administration of Venofer in 4,064 subjects in clinical trials as well as those reported from the post-marketing setting are presented in the table below.

System Organ Class

Common (≥1/100, <1/10)

Uncommon (≥1/1,000, <1/100)

Rare (≥1/10,000, <1/1,000)

Frequency not known1)

Immune system disorders

Hypersensitivity

Anaphylactoid/anaphylactic reactions, angioedema

Nervous system disorders

Dysgeusia

Headache, dizziness, paraesthesia, hypoaesthesia

Syncope, somnolence

Depressed level of consciousness, confusional state, loss of consciousness, anxiety, tremor

Cardiac disorders

Palpitations

Bradycardia, tachycardia, Kounis syndrome

Vascular disorders

Hypotension, hypertension

Flushing, phlebitis

Circulatory collapse, thrombophlebitis

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Bronchospasm

Renal and urinary disorders

Chromaturia

Gastrointestinal disorders

Nausea

Vomiting, abdominal pain, diarrhoea, constipation

Skin and subcutaneous tissue disorders

Pruritus, rash

Urticaria, erythema

Musculoskeletal and connective tissue disorders

Muscle spasm, myalgia, arthralgia, pain in extremity, back pain

General disorders and administration site conditions

Injection/infusion site reaction2)

Chills, asthenia, fatigue, oedema peripheral, pain

Chest pain, hyperdrosis, pyrexia

Cold sweat, malaise, pallor, influenza like illness3)

Investigations

Alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased, serum ferritin increased

Blood lactate dehydrogenase increased

1) Spontaneous reports from the post- marketing setting; estimated as rare

2) The most frequently reported are: injection/infusion site pain, -extravasation, -irritation, -reaction, -discolouration, -haematoma, -pruritus.

3) Onset may vary from a few hours to several days.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Overdose can cause iron overload which may manifest itself as haemosiderosis. Overdose should be treated, as deemed necessary by the treating physician, with an iron chelating agent or according to standard medical practice.