Venofer 20 mg iron / ml, solution for injection or concentrate for solution for infusion.

One millilitre of solution contains 20 mg of iron as iron sucrose (iron(III)-hydroxide sucrose complex).

Each 5 ml ampoule of Venofer contains 100 mg iron as iron sucrose (iron(III)-hydroxide sucrose complex).

Each 2.5 ml vial of Venofer contains 50 mg iron as iron sucrose (iron(III)-hydroxide sucrose complex).

Each 5 ml vial of Venofer contains 100 mg iron as iron sucrose (iron(III)-hydroxide sucrose complex).

For a full list of excipients, see section 6.1.

Solution for injection or concentrate for solution for infusion.

Venofer is a dark brown, non transparent, aqueous solution.

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

• where there is a clinical need to deliver iron rapidly to iron stores,

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

• in active inflammatory bowel disease where oral iron preparations are ineffective.

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

Administration: Venofer must only be administered by the intravenous route. This may be by a slow intravenous injection or by an intravenous drip infusion. Before administering the first dose to a new patient, a test dose of Venofer should be given.

Venofer must not be used for intramuscular injection.

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

Total iron deficit [mg] = body weight [kg] x (target Hb - actual Hb) [g/l] x 0.24* + depot iron [mg]

• Below 35 kg body weight: target Hb = 130 g/l and depot iron = 15 mg/kg body weight

• 35 kg body weight and above: target Hb = 150 g/l and depot iron = 500 mg

*Factor 0.24 = 0.0034 x 0.07 x 1000 (Iron content of haemoglobin 0.34%; Blood volume 7% of body weight; Factor 1000 = conversion from g to mg)

The total amount of Venofer required in mg is determined from above calculation.

Alternatively, the total amount of Venofer required in ml is determined from the following formula or dosage table.

Total amount of Venofer required [ml] =

To convert Hb (mM) to Hb (g/l), multiply the former by 16.1145.

Example: For a patient of 60 kg body weight with an actual Hb of 60 g/l 90 ml should be administered. (Alternatively 18 ampoules/vials of 5 ml or 36 vials of 2.5 ml should be administered.)

Dosage: The total single dose must not exceed 200 mg of iron given not more than three times per week. If the total necessary dose exceeds the maximum allowed single dose, then the administration has to be split.

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

Intravenous drip infusion: Venofer must be diluted only in sterile 0.9% m/V sodium chloride solution:

• 2.5 ml Venofer (50 mg iron)

in max. 50 ml sterile 0.9% m/V sodium chloride solution

• 5 ml Venofer (100 mg iron)

in max. 100 ml sterile 0.9% m/V sodium chloride solution

• 10 ml Venofer (200 mg iron)

in max. 200 ml sterile 0.9% m/V sodium chloride solution

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

Dilution must take place immediately prior to infusion and the solution should be administered as follows:

• 100 mg iron (5 ml Venofer) in at least 15 minutes

• 200 mg iron (10 ml Venofer) in at least 30 minutes

The first 25 mg of iron (i.e. 25 ml of solution) should be infused as a test dose over a period of 15 minutes. If no adverse reactions occur during this time then the remaining portion of the infusion should be given at an infusion rate of not more than 50 ml in 15 minutes.

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.

Before administering a slow intravenous injection, a test dose of 1 ml (20 mg of iron) should be injected slowly over a period of 1 to 2 minutes. If no adverse events occur within 15 minutes of completing the test dose, then the remaining portion of the injection may be given.

Injection into dialyser: Venofer may be administered during a haemodialysis session directly into the venous limb of the dialyser under the same procedures as those outlined for intravenous injection.

The use of Venofer is contraindicated in cases of:

• known hypersensitivity to Venofer or any of its excipients

• anaemias not attributable to iron deficiency

• iron overload or disturbances in utilisation of iron

• patients with a history of asthma, eczema or other atopic allergy, because they are more susceptible to experience allergic reactions

• pregnancy first trimester.

Parenterally administered iron preparations can cause allergic or anaphylactoid reactions, which may be potentially fatal. Therefore, treatment for serious allergic reactions and facilities with the established cardio-pulmonary resuscitation procedures should be available.

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 must be used with caution in case of acute or chronic infection. It is recommended that the administration of iron sucrose is stopped in patients with ongoing bacteraemia. In patients with chronic infection a risk/benefit evaluation has to be performed, taking into account the suppression of erythropoiesis.

Hypotensive episodes may occur if the injection is administered too rapidly. Allergic reactions, sometimes involving arthralgia, have been more commonly observed when the recommended dose is exceeded.

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

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.

Data on a limited number of exposed pregnancies indicated no adverse effects of Venofer on pregnancy or on the health of the foetus/newborn child. No well-controlled studies in pregnant women are available to date. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

Nevertheless, risk/benefit evaluation is required.

Venofer should only be used in pregnant women in whom oral iron is ineffective or cannot be tolerated and the level of anaemia is judged sufficient to put the mother or foetus at risk.

Pregnancy first trimester: see contraindications.

Non metabolised Venofer is unlikely to pass into the mother's milk. No well-controlled clinical studies are available to date. Animal studies do not indicate direct or indirect harmful effects to the nursing child.

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.

The most frequently reported adverse drug reactions (ADRs) of Venofer in clinical trials were transient taste perversion, hypotension, fever and shivering, injection site reactions and nausea, occurring in 0.5 to 1.5% of the patients. Non-serious anaphylactoid reactions occurred rarely.

In general anaphylactoid reactions are potentially the most serious adverse reactions (see “Special warnings and Precautions for Use” section 4.4).

In clinical trials, the following adverse drug reactions have been reported in temporal relationship with the administration of Venofer, with at least a possible causal relationship:

Nervous system disorders

Common ( 1/100, < 1/10): transient taste perversions (in particular metallic taste).

Uncommon ( 1/1000, < 1/100): headache, dizziness.

Rare ( 1/10000, < 1/1000): paraesthesia, syncope, loss of consciousness, burning sensation.

Cardio-vascular disorders

Uncommon ( 1/1000, < 1/100): hypotension and collapse, tachycardia and palpitations.

Rare ( 1/10000, < 1/1000): hypertension.

Respiratory, thoracic and mediastinal disorders

Uncommon ( 1/1000, < 1/100): bronchospasm, dyspnoea.

Gastrointestinal disorders

Uncommon ( 1/1000, < 1/100): nausea; vomiting, abdominal pain, diarrhoea.

Skin and subcutaneous tissue disorders

Uncommon ( 1/1000, < 1/100): pruritus, urticaria, rash, exanthema, erythema.

Musculoskeletal, connective tissue and bone disorders

Uncommon ( 1/1000, < 1/100): muscle cramps, myalgia.

General disorders and administration site disorders

Uncommon ( 1/1000, < 1/100): fever, shivering, flushing, chest pain and tightness. Injection site disorders such as superficial phlebitis, burning, swelling.

Rare ( 1/10000, < 1/1000): arthralgia, peripheral oedema, fatigue, asthenia, malaise, feeling hot, oedema.

Immune system disorders

Rare ( 1/10000, < 1/1000): anaphylactoid reactions.

Moreover, in spontaneous reports the following adverse reactions have been reported:

Isolated cases: reduced level of consciousness, light-headed feeling, confusion, angio-oedema, swelling of joints, hyperhidrosis, back pain, bradycardia, chromaturia.

Overdosage can cause acute iron overloading which may manifest itself as haemosiderosis. Overdosage should be treated, if required, with an iron chelating agent.

The ferrokinetics of Venofer labelled with ⁵⁹Fe and ⁵²Fe were assessed in 5 patients with anaemia and chronic renal failure. Plasma clearance of ⁵²Fe was in the range of 60 to 100 minutes. ⁵²Fe was distributed to the liver, spleen and bone marrow. At two weeks after administration, the maximum red blood cell utilisation of ⁵⁹Fe ranged from 62% to 97%.

Following intravenous injection of a single dose of Venofer containing 100 mg iron in healthy volunteers, maximum iron levels, averaging 538 μmol/l, were obtained 10 minutes after injection. The volume of distribution of the central compartment corresponded well to the volume of plasma (approximately 3 litres).

The iron injected was rapidly cleared from the plasma, the terminal half-life being approx. 6 h. The volume of distribution at steady state was about 8 litres, indicating a low iron distribution in the body fluid. Due to the lower stability of iron sucrose in comparison to transferrin, a competitive exchange of iron to transferrin was observed. This resulted in iron transport of approx. 31 mg iron/24 h.

Renal elimination of iron, occurring in the first 4 h after injection, corresponds to less than 5% of the total body clearance. After 24 h the plasma levels of iron were reduced to the pre-dose iron level and about 75% of the dosage of sucrose was excreted.

There are no preclinical data of relevance to the prescriber that are additional to information already in other sections of the SPC.

Water for injections

Sodium hydroxide

Venofer must only be mixed with sterile 0.9% m/V sodium chloride solution. No other solutions and therapeutic agents should be used as there is the potential for precipitation and/or interaction. The compatibility with containers other than glass, polyethylene and PVC is not known.

Shelf life of the product as packaged for sale:

3 years.

Shelf life after first opening of the container:

From a microbiological point of view, the product should be used immediately.

Shelf life after dilution with sterile 0.9% m/V sodium chloride solution:

From a microbiological point of view, the product should be used immediately after dilution with sterile 0.9% m/V sodium chloride solution.

Store in original carton. Do not store above 25°C. Do not freeze.

5 ml solution in one ampoule (type I glass) in pack sizes of 5.

2.5 ml solution in one vial (type I glass) in pack sizes of 5.

5 ml solution in one vial (type I glass) in pack sizes of 5.

Not all pack-sizes may be marketed.

Ampoules or vials should be visually inspected for sediment and damage before use. Only those with sediment free and homogenous solution must be used.

The diluted solution must appear as brown and clear.

See also 6.3 shelf-life.

Each ampoule or vial of Venofer is intended for single use only. Discard any remaining contents after first use.

Vifor France SA

7-13, Bd Paul Emile Victor

92200 Neuilly-sur-Seine

France

Tel. +33 (0)1 41 06 58 90

Fax +33 (0)1 41 06 58 99

UK: PL 15240/0001

UK: 08.06.1998 / 20.05.2008

02/2011