Section 4.2 (Posology and method of administration) has been amended to reflect an increase in the maximal single dose of Ferinject from 15 to 20mg/kg bodyweight for IV infusion (For IV injection we have the same limitation of 15mg/kg bodyweight)

In section 4.3 (Contraindications), the contraindication for pregnancy in the first trimester has been removed and a more stringent wording included in section 4.6 (Fertility, pregnancy and lactation)

Section 4.6 (Pregnancy and lactation) now reads as follows

Pregnancy

There are no data from the use of Ferinject in pregnant women. A careful risk/benefit evaluation is required before use during pregnancy and Ferinject should not be used during pregnancy unless clearly necessary. Animal data suggest that iron released from Ferinject can cross the placental barrier and that its use during pregnancy may influence skeletal development in the fetus (see section 5.3).

Iron deficiency occurring in the first trimester of pregnancy can in many cases be treated with oral iron. If the benefit of Ferinject treatment is judged to outweigh the potential risk to the fetus, it is recommended that treatment should be confined to the second and third trimester.

Lactation

Clinical studies showed that transfer of iron from Ferinject to human milk was negligible (≤1%). Based on limited data on nursing women it is unlikely that Ferinject represents a risk to the nursing child.

Fertility

There are no data on the effect of Ferinject on human fertility. Fertility was unaffected following Ferinject treatment in animal studies (see section 5.3).

1.         Name of the Medicinal Product

FERINJECTFerinject 50 mg iron/ml solution for injection/infusion.

2.         Qualitative and Quantitative Composition

One milliliterml of solution contains 50 mg of iron as ferric carboxymaltose.

Each 2 ml vial contains 100 mg of iron as ferric carboxymaltose.

Each 10 ml vial contains 500 mg of iron as ferric carboxymaltose.

Ferinject contains sodium hydroxide. One milliliterml of solution contains up to 5.5 mg (0.24 mmol (5.5 mg) sodium, see section 4.2.4. For a full list of excipients, see section 6.1.

3.         Pharmaceutical Form

Solution for injection/infusion. Dark brown, non-transparent, aqueous solution.

4.         Clinical Particulars

4.1       Therapeutic indications

FERINJECTFerinject is indicated for treatment of iron deficiency when oral iron preparations are ineffective or cannot be used.

The diagnosis must be based on laboratory tests.

4.2       Posology and method of administration

CalculationDetermination of the cumulative iron dose

The adequate cumulative dose of FERINJECT must be calculated for each patient individually and must not be exceeded. For overweight patients, a normal body weight/blood volume relation should be assumed when determining the iron requirement. The dose of FERINJECT is expressed in mg of elemental iron.

The cumulative dose required for Hb restoration and repletion of iron stores is calculated by the following Ganzoni formula:

Cumulative iron deficit [mg] =

body weight [kg] x (target Hb* - actual Hb) [g/dl]** x 2.4*** +

iron storage depot [mg]****

The cumulative dose for repletion of iron using Ferinject is determined based on the patient’s body weight and haemoglobin level and must not be exceeded. The following table should be used to determine the cumulative iron dose:

Note: A cumulative iron dose of 500 mg should not be exceeded for patients with body weight

< 35 kg.

For overweight patients, a normal body weight/blood volume relationship should be assumed when determining the iron requirement.

For patients £ 66 kg: the calculated cumulative dose is to be rounded down to the nearest 100 mg.

For patients > 66 kg: the calculated cumulative dose is to be rounded up to the nearest 100 mg.

For patients with an Hb value ≥ 14 g/dL, an initial dose of 500 mg iron should be given and iron parameters should be checked prior to repeat dosing.

Patients may continue to require therapy with FERINJECT at the lowest dose necessary to maintain target levels of haemoglobin, and other laboratory values of iron storage parameters within acceptable limits.

Post repletion, regular assessments should be completed to ensure that iron levels are corrected and maintained.

Maximum tolerated single dose

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

A single dose of Ferinject should not exceed 1000 mg of iron (20 ml) per day or 15 mg of iron (0.3 ml) per kg body weight. Do not administer 1000 mg of iron (20 ml) more than once a week.

Intravenous bolus injection:

FERINJECTFerinject may be administered by intravenous injection up to a maximum single dose of 4 ml (200 mg of iron) per day but not more than three times a weekusing undiluted solution up to 1000 mg iron. For doses greater than 200 and up to 500 mg iron, Ferinject should be administered at a rate of 100 mg/min. For doses greater than 500 and up to 1000 mg iron, Ferinject should be administered over 15 minutes.

Intravenous drip infusion:

FERINJECTFerinject may be administered by intravenous infusion up to a maximum single dose of 20 ml of FERINJECT (1000 mg of iron) but not exceeding 0.3 ml of FERINJECT (15 mg of iron) per kg body weight or the calculated cumulative dose. Do not administer 20 ml (1000 mg of iron) as an infusion more than once a week. (20 ml).

The use of Ferinject has not been studied in children, and therefore is not recommended in children under 14 years.

Method of administration

FERINJECTFerinject must be administered only by the intravenous route: by bolus injection, or during a haemodialysis session undiluted directly into the venous limb of the dialyser, or by drip infusion. In case of drip infusion FERINJECTFerinject must be diluted only in sterile 0.9% m/V sodium chloride solution as follows:

Dilution plan of FERINJECTFerinject for intravenous drip infusion

Note: For stability reasons, dilutions to concentrations less than 2 mg iron/ml are not permissible.

FERINJECTFerinject must not to be administered by the subcutaneous or intramuscular route.

Haemodialysis-dependent chronic kidney disease

A single maximum daily injection dose of 200 mg iron should not be exceeded in haemodialysis-dependent chronic kidney disease patients (see also section 4.4).

Paediatric population

The use of Ferinject has not been studied in children, and therefore is not recommended in children under 14 years.

4.3       Contraindications

The use of FERINJECTFerinject is contraindicated in cases of:

·         known hypersensitivity to Ferinject or to any of its excipients

·         anaemia not attributed to iron deficiency, e.g. other microcytic anaemia

·         evidence of iron overload or disturbances in utilisation of iron

·         pregnancy in the first trimester

4.4       Special warnings and precautions for use

Parenterally administered iron preparations can cause hypersensitivity reactions including anaphylactoid reactions, which may be potentially fatal (see section 5.34.8). Therefore, facilities for cardio-pulmonary resuscitation must be available. If allergic reactions or signs of intolerance occur during administration, the treatment must be stopped immediately.

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.

No safety data on haemodialysis-dependent chronic kidney disease patients receiving single doses of more than 200 mg iron are available.

Parenteral iron must be used with caution in case of acute or chronic infection, asthma, eczema or atopic allergies. It is recommended that the administration of FERINJECTFerinject 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.

Caution should be exercised to avoid paravenous leakage when administering FERINJECTFerinject. Paravenous leakage of FERINJECTFerinject at the injection site may lead to brown discolouration and irritation of the skin. In case of paravenous leakage, the administration of FERINJECTFerinject must be stopped immediately.

One millilitreml of undiluted FERINJECTFerinject contains up to 5.5 mg (0.24 mmol (5.5 mg) of sodium. This has to be taken into account in patients on a sodium-controlled diet.

One ml of undiluted Ferinject contains maximally 75 µg aluminium. This should be considered in the treatment of patients undergoing dialysis.

The use of FERINJECTFerinject has not been studied in children.

Do not administer 20 ml (1000 mg of iron) as an injection or infusion more than once a week.

4.5       Interaction with other medicinal products and other forms of interaction

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

4.6       Pregnancy and lactation

Clinical data on pregnant women are not available. A careful risk/benefit evaluation is required before use during pregnancy.

Animal data suggest that iron released from FERINJECTFerinject can cross the placental barrier and that its use during pregnancy may influence skeletal development in the fetus

Clinical studies showed that transfer of iron from FERINJECTFerinject to human milk was negligible (£ 1%). Based on limited data on nursing women it is unlikely that FERINJECTFerinject represents a risk to the nursing child.

4.7       Effects on ability to drive and use machines

FERINJECTFerinject is unlikely to impair the ability to drive or operate machines.

4.8       Undesirable effects

The most commonly reported ADR is headache, occurring in 3.3% of the patients.

There are no undesirable effects with unknown frequency.

Immune System Disorders

Uncommon (>1/1,000, <1/100): Hypersensitivity including anaphylactoid reactions

Nervous system disorders

Common (>1/100, <1/10): Headache, dizziness

Uncommon (>1/1,000, <1/100): Paraesthesia

Vascular disorders

Uncommon (>1/1,000, <1/100): Hypotension, flushing

Respiratory, thoracic and mediastinal disorders 

Rare (>1/10,000, <1/1,000): Dyspnoea

Gastrointestinal disorders

Common (>1/100, <1/10): Nausea, abdominal pain, constipation, diarrhoea

Uncommon (>1/1,000, <1/100): Dysgeusia, vomiting, dyspepsia, flatulence

Skin and subcutaneous tissue disorders

Common (>1/100, <1/10): Rash

Uncommon (>1/1,000, <1/100): Pruritus, urticaria

Musculoskeletal and connective tissue disorders

Uncommon (>1/1,000, <1/100): Myalgia, back pain, arthralgia

General disorders and administration site conditions

Common (>1/100, <1/10): Injection Site Reactions

Uncommon (>1/1,000, <1/100): Pyrexia, fatigue, chest pain, rigors, malaise, oedema peripheral

Investigations

Common (>1/100, <1/10): Transient blood phosphorus decreased, alanine aminotransferase increased

Uncommon (>1/1,000, <1/100): Aspartate aminostransferase increased,  gamma-glutamyltransferase increased, blood lactate dehydrogenase increased

4.9       Overdose

Administration of FERINJECTFerinject in quantities exceeding the amount needed to correct iron deficit at the time of administration may lead to accumulation of iron in storage sites eventually leading to haemosiderosis. Monitoring of iron parameters such as serum ferritin and transferrin saturation may assist in recognising iron accumulation. If iron accumulation has occurred, the use of an iron chelator may be considered.

5.         Pharmacological Properties

5.1       Pharmacodynamic properties

Pharmacotherapeutic group: Iron trivalent, parenteral preparation

ATC Code: B03A C01

Ferinject solution for injection/infusion contains iron in a stable ferric state as a complex of a polynuclear iron-hydroxide core with a carbohydrate polymerligand. The complex is designed to releaseprovide, in a controlled way, utilisable iron tofor the iron transport and storage proteins in the body (ferritin and transferrin and ferritin, respectively). Clinical studies showed that the haematological response and the filling of the iron stores was faster after intravenous administration of Ferinject than with orally administered comparators.

Using positron emission tomography (PET) it was demonstrated that red cell utilisation of ⁵⁹Fe and ⁵²Fe from FERINJECTradio-labelled Ferinject ranged from 61% to 99%. PatientsAfter 24 days, patients with iron deficiency showed utilisation of radio-labelled iron of 91% to 99% after 24 days, and patients with renal anaemia showed utilisation of radio-labelled iron of  61% to 84% after 24 days.%.

One millilitre of undiluted Ferinject contains less than 75 mg aluminium. This should be considered in the treatment of patients undergoing dialysis.

5.2       Pharmacokinetic properties

Using positron emission tomography (PET) it was demonstrated that ⁵⁹Fe and ⁵²Fe  from FERINJECTFerinject was rapidly eliminated from the blood, transferred to the bone marrow, and deposited in the liver and spleen.

After administration of a single dose of FERINJECTFerinject of 100 to 1000 mg of iron in iron deficient patients, maximum total serum iron levels of 37 µg/ml up to 333 µg/ml after 15 minutes to 1.21 hours respectively are obtained. The volume of the central compartment corresponds well to the volume of the plasma (approximately 3 litres).

The iron injected or infused was rapidly cleared from the plasma, the terminal halflifehalf-life ranged from 7 to 12 hours, the mean residence time (MRT) from 11 to 18 hours. Renal elimination of iron was negligible.

5.3              Pre-clinical safety data

Pre-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeat dose toxicity and genotoxicity. Animal studies indicate that iron released from FERINJECTFerinject does cross the placental barrier and is excreted in milk. In reproductive toxicology studies using iron replete animals FERINJECTFerinject was associated with minor skeletal abnormalities in the fetus. No long-term studies in animals have been performed to evaluate the carcinogenic potential of FERINJECTFerinject. No evidence of allergic or immunotoxic potential has been observed. A controlled in-vivo test demonstrated no cross-reactivity of FERINJECTFerinject with anti-dextran antibodies. No local irritation or intolerance was observed after intravenous administration.

6.         Pharmaceutical Particulars

6.1       List of excipients

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injections

6.2       Incompatibilities

This medicinal product must not be mixed with other medicinal products thanexcept those mentioned in section 6.6.

The compatibility with containers other than polyethylene and glass is not known.

6.3       Shelf-life

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, preparations for parenteral administration should be used immediately.

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

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

6.4.      Special precautions for storage

Store in the original package. Do not store above 30 °C. Do not refrigerate or freeze.

6.5.      Nature and contents of container

2 ml of solution in a vial (type I glass) with bromobutyl rubber stopper and aluminium cap in pack sizes of 1 and 5 vials.

10 ml of solution in a vial (type I glass) with bromobutyl rubber stopper and aluminium cap in pack sizes of 1 and 5 vials.

Not all pack sizes may be marketed.

6.6       Special precautions for disposal and other handling

Inspect vials visually for sediment and damage before use. Use only those containing sediment-free, homogeneous solution.

Each vial of FERINJECTFerinject is intended for single use only. Any unused product or waste material should be disposed of in accordance with local requirements.

FERINJECTFerinject must only be mixed with sterile 0.9% m/V sodium chloride solution. No other intravenous dilution solutions and therapeutic agents should be used, as there is the potential for precipitation and/or interaction. For dilution instructions, see section 4.2.

7.         Marketing Authorisation Holder

Vifor France SA

7-13, BdBoulevard Paul- Emile Victor

92200 Neuilly-sur-Seine

France

Tel.  +33 (0)1 41 06 58 90

Fax  +33 (0)1 41 06 58 99

e-mail: contact@vifor-france.fr

8.         Marketing Authorisation Number

PL 15240/0002

9.         Date of First Authorisation/Renewal of THE Authorisation

19.07.2007

10.       Date of Revision of the Text

July 201109.07.2009

• Minor formatting changes have been made to sections 4.2 (Posology and method of administration) and 4.6 (Pregnancy and Lactation)
• The company contact details have been changed from:
Syner-Med (Pharmaceuticals Products) Ltd
Beech House,
840 Brighton road,
Purley,
Surrey,
CR8 2BH
Telephone: +44 (0)845 634 2100
Fax: +44 (0)845 634 2101

to

Vifor Pharma UK Limited
The Old Stables
Bagshot Park
Bagshot
Surrey
GU19 5PJ
Telephone: +44 (0)1276 853600
Fax: +44 (0)1276 452341