Ferinject 50 mg iron/mL solution for injection/infusion.

One mL 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.

Each 20 ml vial contains 1,000 mg of iron as ferric carboxymaltose.

One mL of solution contains up to 5.5 mg (0.24 mmol) sodium, see section 4.4.

For the full list of excipients, see section 6.1.

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

Ferinject 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.

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

Ferinject 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 Ferinject injection (see section 4.4).

Posology

Determination of the cumulative iron dose

The cumulative dose for repletion of iron using Ferinject is determined based on the patient's body weight and haemoglobin (Hb) level and must not be exceeded. The following table (Table 1) should be used to determine the cumulative iron dose:

Table 1: Determination of the cumulative iron dose

Note: A cumulative iron dose of 500 mg should not be exceeded for patients with a body weight <35 kg.

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

For patients with a 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.

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

Maximum tolerated single dose

A single dose of Ferinject should not exceed 1,000 mg of iron (20 mL) per day. Do not administer 1,000 mg of iron (20 mL) more than once a week.

Intravenous injection

Ferinject may be administered by intravenous injection using undiluted solution up to 1,000 mg iron (up to a maximum of 15 mg/kg body weight). For doses up to 200 mg iron, there is no prescribed administration time. 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 1,000 mg iron, Ferinject should be administered over 15 minutes.

Intravenous infusion

Ferinject may be administered by intravenous infusion up to a maximum single dose of 1,000 mg of iron (up to a maximum of 20 mg/kg body weight).

Method of administration

Ferinject 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 infusion. In case of infusion Ferinject must be diluted only in sterile 0.9% m/V sodium chloride solution as shown in Table 2 below.

Table 2 : Dilution plan of Ferinject for intravenous infusion

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

Ferinject must not 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.

The use of Ferinject is contraindicated in cases of:

• hypersensitivity to the active substance, to Ferinject or any of its excipients listed in section 6.1.

• known serious hypersensitivity to other parenteral iron products.

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

• evidence of iron overload or disturbances in the utilisation of iron

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.

The risk 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).

Ferinject should only be administered when staff trained to evaluate and manage anaphylactic reactions are 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 Ferinject 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 benefit/risk 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 treatment with Ferinject is stopped in patients with ongoing bacteraemia. Therefore, in patients with chronic infection a benefit/risk evaluation has to be performed, taking into account the suppression of erythropoiesis.

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

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

The use of Ferinject has not been studied in children.

Do not administer 20 mL (1,000 mg of iron) as an injection or infusion more than once a week.

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.

Pregnancy

There are no adequate and well-controlled trials of Ferinject in pregnant women. A careful benefit/risk evaluation is required before use during pregnancy and Ferinject should not be used during pregnancy unless clearly necessary.

Iron deficiency occurring in the first trimester of pregnancy can in many cases be treated with oral iron. Treatment with Ferinject should be confined to the second and third trimester if the benefit is judged to outweigh the potential risk for both the mother and the foetus.

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).

Breast-feeding

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).

Ferinject is unlikely to impair the ability to drive and use machines.

Table 3 presents the adverse drug reactions (ADRs) reported during clinical studies in which 6,755 patients received Ferinject, as well as those reported from the post-marketing experience (see table footnotes for details).

The most commonly reported ADR is nausea (occurring in 3.1% of the patients), followed by headache, dizziness, and hypertension. Injection site reactions categorised as common in Table 3 are comprised of several ADRs which individually have been reported with a frequency of either uncommon or rare. Hypophosphataemia (common) may occur. In clinical trials the minimum values were obtained after approximately 2 weeks, and 4 to 12 weeks following Ferinject treatment the values had returned to those within the range of baseline. The most serious ADR is anaphylactoid reactions with a frequency of rare.

Table 3: Adverse drug reactions observed during clinical trials and post-marketing experience

1 Includes the following preferred terms: rash (individual ADR frequency determined as uncommon) and rash erythematous, -generalised, -macular, -maculo-papular, -pruritic (all individual ADRs are frequency determined as rare).

2 Includes the following preferred terms: infusion site burning, -pain, -bruising, -discolouration, -extravasation, -irritation, reaction, (all individual ADRs are frequency determined as uncommon) and -paraesthesia (individual ADR frequency determined as rare).

3 ADRs exclusively reported in the post-marketing setting.

4 ADRs reported in the post-marketing setting which were also observed in the clinical setting.

Note: ADR = Adverse drug reaction.

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:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Malta

ADR Reporting

The Medicines Authority

Post-Licensing Directorate

203 Level 3, Rue D'Argens

GŻR-1368 Gżira

Website: www.medicinesauthority.gov.mt

e-mail: postlicensing.medicinesauthority@gov.mt

Administration of Ferinject 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, treat according to standard medical practice, e.g. consider the use of an iron chelator.

Pharmacotherapeutic group: Iron trivalent, parenteral preparation, ATC code: B03A C01

Ferinject solution for injection/infusion is a colloidal solution of the iron complex ferric carboxymaltose.

The complex is designed to provide, in a controlled way, utilisable iron for the iron transport and storage proteins in the body (transferrin and ferritin, respectively).

Red cell utilisation of ⁵⁹Fe from radio-labelled Ferinject ranged from 91% to 99% in patients with iron deficiency (ID) and 61% to 84% in patients with renal anaemia at 24 days post-dose.

Ferinject treatment of patients with ID anaemia results in an increase in reticulocyte count and serum ferritin levels to within normal ranges.

Clinical efficacy and safety

The efficacy and safety of Ferinject has been studied in different therapeutic areas necessitating intravenous iron to correct iron deficiency. The main studies are described in more detail below.

Nephrology

Haemodialysis-dependent chronic kidney disease

Study VIT-IV-CL-015 was an open-label, randomised parallel group study comparing Ferinject (n=97) to iron sucrose (n=86) in subjects with ID anaemia undergoing haemodialysis. Subjects received Ferinject or iron sucrose 2-3 times per week in single doses of 200 mg iron directly into the dialyser until the individually calculated cumulative iron dose was reached (mean cumulative dose of iron as Ferinject: 1,700 mg). The primary efficacy endpoint was the percentage of patients reaching an increase in Hb of ≥1.0 g/dL at 4 weeks after baseline. At 4 weeks after baseline, 44.1% responded to treatment with Ferinject (i.e. Hb increase of ≥1.0 g/dL) compared to 35.3% for iron sucrose (p=0.2254).

Non-dialysis-dependent chronic kidney disease

Study 1VIT04004 was an open-label, randomised active-control study, evaluating the safety and efficacy of Ferinject (n=147) vs. oral iron (n=103). Subjects in the Ferinject group received 1,000 mg of iron at baseline and 500 mg of iron at days 14 and 28, if TSAT was <30% and serum ferritin was <500 ng/mL at the respective visit. Subjects in the oral iron arm received 65 mg iron TID as ferrous sulphate from baseline to day 56. Subjects were followed-up until day 56. The primary efficacy endpoint was the percentage of subjects achieving an increase in Hb of ≥1.0 g/dL anytime between baseline and end of study or time of intervention. This was achieved by 60.54% of subjects receiving Ferinject vs. 34.7% of subjects in the oral iron group (p<0.001). Mean haemoglobin change to day 56/end of study was 1.0 g/dL in the Ferinject group and 0.7 g/dL in the oral iron group (p=0.034, 95% CI: 0.0, 0.7).

Gastroenterology

Inflammatory bowel disease

Study VIT-CL-IV-008 was a randomised, open-label study which compared the efficacy of Ferinject vs. oral ferrous sulphate in reducing ID anaemia in subjects with inflammatory bowel disease (IBD). Subjects received either Ferinject (n=111) in single doses of up to 1,000 mg iron once per week until the individually calculated iron dose (per Ganzoni formula) was reached (mean cumulative iron dose: 1,490 mg), or 100 mg iron BID as ferrous sulphate (n=49) for 12 weeks. Subjects receiving Ferinject showed a mean increase in Hb from baseline to Week 12 of 3.83 g/dL, which was non-inferior to 12 weeks of twice daily therapy with ferrous sulphate (3.75 g/dL, p=0.8016).

Study FER-IBD-07-COR was a randomised, open-label study comparing the efficacy of Ferinject vs. iron sucrose in subjects with remitting or mild IBD. Subjects receiving Ferinject were dosed according to a simplified dosing grid using baseline Hb and body weight (see Section 4.2) in single doses up to 1,000 mg iron, whereas subjects receiving iron sucrose were dosed according to individually calculated iron doses using the Ganzoni formula in doses of 200 mg iron until the cumulative iron dose was reached. Patients were followed-up for 12 weeks. 65.8% of patients receiving Ferinject (n=240; mean cumulative iron dose: 1,414 mg) vs. 53.6% receiving iron sucrose (n=235; mean cumulative dose 1,207 mg; p=0.004) had responded at Week 12 (defined as Hb increase ≥2 g/dL). 83.8% of Ferinject-treated patients vs. 75.9% of iron sucrose-treated patients achieved a Hb increase ≥2 g/dL or had Hb within normal limits at Week 12 (p=0.019).

Women's health

Post partum

Study VIT-IV-CL-009 was a randomised open-label non-inferiority study comparing the efficacy of Ferinject (n=227) vs. ferrous sulphate (n=117) in women suffering from post-partum anaemia. Subjects received either Ferinject in single doses of up to 1,000 mg iron until their individually calculated cumulative iron dose (per Ganzoni formula) was reached, or 100 mg of iron as oral ferrous sulphate BID for 12 weeks. Patients were followed-up for 12 weeks. The mean change in Hb from baseline to Week 12 was 3.37 g/dL in the Ferinject group (n=179; mean cumulative iron dose: 1,347 mg) vs. 3.29 g/dL in the ferrous sulphate group (n=89), showing non-inferiority between the treatments.

Positron emission tomography demonstrated that ⁵⁹Fe and ⁵²Fe from Ferinject 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 Ferinject of 100 to 1,000 mg of iron in ID patients, maximum total serum iron levels of 37 µg/mL up to 333 µg/mL are obtained after 15 minutes to 1.21 hours respectively. 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 half-life ranged from 7 to 12 hours, the mean residence time (MRT) from 11 to 18 hours. Renal elimination of iron was negligible.

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

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injections

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

The compatibility with containers other than polyethylene and glass 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, 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.

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

Ferinject is supplied in a vial (type I glass) with a stopper (bromobutyl rubber) and an aluminium cap as

- 2 ml solution containing 100 mg iron. Available in pack sizes of 1, 2 and 5 vials

- 10 ml solution containing 500 mg iron. Available in pack sizes of 1, 2 and 5 vials

- 20 ml solution containing 1,000 mg iron. Available in a pack size of 1 vial.

Not all pack sizes may be marketed.

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

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

Ferinject 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.

Vifor France SA

7-13, Boulevard Paul-Emile Victor

92200 Neuilly-sur-Seine

France

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

Fax +33 (0)1 41 06 58 99

United Kingdom: PL 15240/0002

Malta: MA869/00101

Date of latest renewal: 18.06.2012

United Kingdom: October 2013

Malta: October 2013