Monofer 100mg/ml solution for injection/infusion

One millilitre of solution contains 100 mg iron as iron(III) isomaltoside 1000.

1 ml vial/ampoule contains 100 mg iron as iron(III) isomaltoside 1000

2 ml vial/ampoule contains 200 mg iron as iron(III) isomaltoside 1000

5 ml vial/ampoule contains 500 mg iron as iron(III) isomaltoside 1000

10 ml vial/ampoule contains 1,000 mg iron as iron(III) isomaltoside 1000

For a full list of excipients, see section 6.1.

Solution for injection/infusion.

Dark brown, non transparent solution.

Monofer is indicated for the treatment of iron deficiency anaemia in the following conditions:

• When oral iron preparations are ineffective or cannot be used

• Where there is a clinical need to deliver iron rapidly

The diagnosis of iron deficiency anaemia should be based on appropriate laboratory tests (e.g. serum ferritin, serum iron, transferrin saturation or hypochromic red cells).

Iron replacement in patients with iron deficiency anaemia:

The dose and dosage schedule for Monofer must be individually established for each patient based on a calculation of the total iron deficit. The optimal haemoglobin target level may vary in different patient groups. Please refer to official guidelines. The dose of Monofer is expressed in mg of elemental iron.

The total iron dose is calculated by the following Ganzoni formula, where haemoglobin is abbreviated Hb:

(A) It is recommended to use the patient's ideal body weight or pre-pregnancy weight

(B) To convert Hb [mM] to Hb [g/dl] you should multiply Hb [mM] by factor 1.61145

(C) Factor 2.4 = 0.0034 x 0.07 x 10,000

0.0034: Iron content of haemoglobin is 0.34%

0.07: Blood volume 70 ml/kg of body weight ≈ 7% of body weight

10,000: The conversion factor 1 g/dl = 10,000 mg/l

(D) For a person with a body weight above 35 kg, the iron stores are approximately 500 mg

Iron deficiency anaemia will not appear until essentially all iron stores have been depleted. Iron therapy should therefore replenish both haemoglobin iron and iron stores.

After the total iron deficit has been corrected, patients may require continued therapy with Monofer to maintain target levels of haemoglobin and acceptable limits of other iron parameters.

Iron replacement for blood loss:

Iron therapy in patients with blood loss should supply an amount of iron equivalent to the amount of iron represented in the blood loss.

• If the Hb level is reduced: Use the previous formula considering that the depot iron does not need to be restored:

• If the volume of blood lost is unknown: The administration of 200 mg Monofer results in an increase of haemoglobin which is equivalent to 1 unit blood:

Administration:

Anaphylactoid reactions to parenteral iron are usually evident within a few minutes, and close observation is necessary to ensure recognition. If at any time during the intravenous administration of Monofer, any signs of a hypersensitivity reaction or intolerance are detected, administration must be stopped immediately.

Resuscitative medication and personnel trained to evaluate and handle anaphylactoid reactions should be available whenever a dose of parenteral iron is administered.

Children and adolescents:

Monofer is not recommended for use in children and adolescents < 18 years due to insufficient data on safety and efficacy.

Adults and the elderly:

Monofer can be administered either as an intravenous bolus injection, as a total dose infusion (TDI), as an intravenous drip infusion or as a direct injection into the venous limb of the dialyser.

Monofer should not be administered concomitantly with oral iron preparations, since the absorption of oral iron might be decreased (see section 4.5).

Intravenous bolus injection:

Monofer may be administered as a 100-200 mg intravenous bolus injection up to three times a week at an administration rate of up to 50 mg iron/minute. It may be diluted in 10-20 ml sterile 0.9% sodium chloride.

Total dose infusion (TDI):

Monofer may be administered as a total dose infusion in which the total iron dose is given in a single infusion.

Monofer given as total dose infusion is administered as a single dose of up to 20 mg iron/kg body weight as an intravenous drip infusion.

Doses of 0-10 mg iron/kg body weight must be infused over 30 min.

Doses of 11-20 mg iron/kg body weight must be infused over 60 min.

If the total iron dose exceeds 20 mg iron/kg body weight, the dose must be split in two administrations with an interval of at least one week.

Monofer should be added to 100-500 ml sterile 0.9% sodium chloride. Please refer to section 6.3 and 6.6.

Total dose infusion (TDI) has been associated with an increased incidence of adverse reactions, in particular delayed hypersensitivity-like reactions. The intravenous administration of Monofer by the total dose infusion method should be restricted to hospital use only.

Intravenous drip infusion:

Monofer may be administered in doses of 200-1,000 mg once every week until the total iron dose has been administered.

Doses of 0-5 mg iron/kg body weight must be infused over 15 min.

Doses of 6-10 mg iron/kg body weight must be infused over 30 min.

Doses of 11-20 mg iron/kg body weight must be infused over 60 min.

Monofer should be added to 100-500 ml sterile 0.9% sodium chloride. Please refer to section 6.3 and 6.6.

Injection into dialyser:

Monofer may be administered during a haemodialysis session directly into the venous limb of the dialyser under the same procedures as outlined for intravenous bolus injection.

• Non-iron deficiency anaemia (e.g. haemolytic anaemia)

• Iron overload or disturbances in utilisation of iron (e.g. haemochromatosis, haemosiderosis)

• Hypersensitivity to the active substance or to any of the excipients.

• Patients with a history of asthma, allergic eczema or other atopic allergy

• Decompensated liver cirrhosis and hepatitis

• Rheumatoid arthritis with symptoms or signs of active inflammation

Parenteral administration of all iron complexes may cause immediate severe and potentially lethal hypersensitivity reactions. The risk is enhanced for patients with known (medical) allergies. Resuscitative medication and personnel trained to evaluate and handle anaphylactoid reactions should therefore be available. There is particularly increased risk of allergic reactions to parenteral iron complexes in patients with immune or inflammatory conditions (e.g. systemic lupus erythematosus, rheumathoid arthritis).

Parenteral iron should be used with caution in case of acute or chronic infection.

Monofer should not be used in patients with ongoing bacteraemia.

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

As with all parenteral iron preparations the absorption of oral iron is reduced when administered concomitantly. Oral iron therapy should not be started earlier than 5 days after the last injection of Monofer.

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

Parenteral iron may cause falsely elevated values of serum bilirubin and falsely decreased values of serum calcium.

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

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

There is no information available on the excretion of Monofer in the human breast milk.

No studies on the effects on the ability to drive and use machines have been performed.

Due to limited clinical data on Monofer the mentioned undesirable effects are primarily based on safety data for other parenteral iron solutions.

More than 1% of patients may be expected to experience adverse reactions.

Acute, severe anaphylactoid reactions may occur with parenteral iron preparations, although they are uncommon. They usually occur within the first few minutes of administration and are generally characterised by the sudden onset of respiratory difficulty and / or cardiovascular collapse; fatalities have been reported. Other less severe manifestations of immediate hypersensitivity are also uncommon and include urticaria, rashes, itching, nausea and shivering. Administration must be stopped immediately if signs of an anaphylactoid reaction are observed.

Delayed reactions may also occur with parenteral iron preparations and can be severe. They are characterised by arthralgia, myalgia and sometimes fever. The onset varies from several hours up to four days after administration. Symptoms usually last two to four days and settle spontaneously or following the use of simple analgesics. In addition, exacerbation of joint pain in rheumatoid arthritis can occur and local reactions may cause pain and inflammation at or near injection site and a local phlebitic reaction.

Very common (1/10)

Common (1/100 to <1/10)

Uncommon (1/1,000 to <1/100)

Rare (1/10,000 to <1/1,000)

Very Rare (<1/10,000)

Not known (cannot be estimated with the available data)

Cardiac disorders

Rare: Arrhythmia, tachycardia

Very rare: Foetal bradycardia, palpitations

Blood and lymphatic system disorders

Very rare: Haemolysis

Nervous system disorders

Uncommon: Blurred vision, numbness, dysphonia

Rare: Loss of consciousness, seizure, dizziness, restlessness, tremor, fatigue, altered mental status

Very rare: Headache, paresthesia

Ear and labyrinth disorders

Very rare: Transient deafness

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnoea

Rare: Chest pain

Gastrointestinal disorders

Uncommon: Nausea, emesis, abdominal pain, constipation

Rare: Diarrhoea

Skin and subcutaneous tissue disorders

Uncommon: Flushing, pruritus, rash

Rare: Angioedema, sweating

Musculoskeletal and connective tissue disorders

Uncommon: Cramps

Rare: Myalgias, arthralgia

Vascular disorders

Rare: Hypotension

Very rare: Hypertension

General disorders and administration site conditions

Uncommon: Anaphylactoid reactions, feeling hot, fever, soreness, inflammation near the injection site, local phlebitic reaction

Rare: Fatigue

Very rare: Acute severe anaphylactic reactions

The iron(III) isomaltoside 1000 in Monofer has a low toxicity. The preparation is well tolerated and has a minimal risk of accidental overdosing.

Overdose may lead to accumulation of iron in storage sites eventually leading to haemosiderosis. Monitoring of iron parameters such as serum ferritin may assist in recognising iron accumulation. Supportive measures such as chelating agents can be used.

Pharmacotherapeutic group: Iron trivalent parenteral preparation, ATC code: B03A C06

Monofer solution for injection is a colloid with strongly bound iron in spheroidal iron-carbohydrate particles. Each particle consists of an iron(III) core and a carbohydrate shell of isomaltosides that surrounds and stabilises the core. The chelation of iron(III) with a carbohydrate shell confers to the particles a structure resembling ferritin that is suggested to protect against the toxicity of unbound inorganic iron(III).

The iron is available in a non-ionic water-soluble form in an aqueous solution with pH between 5.0 and 7.0. The toxicity is low and Monofer can therefore be administered in large doses.

Evidence of a therapeutic response can be seen within a few days of administration of Monofer as an increase in the reticulocyte count.

Serum ferritin peaks approximately 7 to 9 days after an intravenous dose of Monofer and slowly returns to baseline after about 3 weeks.

The Monofer formulation contains iron in a strongly bound complex that enables a controlled and slow release of bioavailable iron to iron-binding proteins with little risk of free iron.

Following intravenous administration, iron isomaltoside 1000 is rapidly taken up by the cells in the reticuloendothelial system (RES), particularly in the liver and spleen from where iron is slowly released. The plasma half life is 5 hours for circulating iron and 20 hours for total iron (bound and circulating).

Circulating iron is removed from the plasma by cells of the reticuloendothelial system which split the complex into its components of iron and isomaltoside 1000. The iron is immediately bound to the available protein moieties to form hemosiderin or ferritin, the physiological storage forms of iron, or to a lesser extent, to the transport molecule transferrin. This iron, which is subject to physiological control, replenishes haemoglobin and depleted iron stores.

Iron is not easily eliminated from the body and accumulation can be toxic. Due to the size of the complex, Monofer is not eliminated via the kidneys. Small quantities of iron are eliminated in urine and faeces.

Isomaltoside 1000 is either metabolised or excreted.

Iron complexes have been reported to be teratogenic and embryocidal in non-anaemic pregnant animals at high single doses above 125 mg iron/kg body weight. The highest recommended dose in clinical use is 20 mg iron/kg body weight.

There are no other additional preclinical data of relevance to the prescriber than those already included in other sections of the SPC.

Water for injections

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

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

Shelf life of ampoules as packaged for sale

3 years

Shelf life of vials as packaged for sale

2 years

Shelf life after first opening of the container (undiluted):

From a microbiological point of view, unless the method of opening precludes the risk of microbial contamination, the product should be used immediately.

If not used immediately, in-use storage times and conditions are the responsibility of the user.

Shelf life after dilution with sterile 0.9% sodium chloride:

Chemical and physical in-use stability has been demonstrated for 48 hours at 30°C in dilutions up to 1:250 with sterile 0.9% sodium chloride.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

This medicinal product does not require any special storage conditions.

For storage conditions of the reconstituted and diluted solution see 6.3.

Type 1 glass ampoule.

Pack sizes: 5 x 1 ml, 10 x 1 ml, 5 x 2 ml, 10 x 2 ml, 2 x 5 ml, 5 x 5 ml, 2 x 10 ml, 5 x 10 ml

Type 1 glass vial with chlorobutyle rubber stopper and aluminium cap.

Pack sizes: 5 x 1 ml, 10 x 1 ml, 5 x 2 ml, 10 x 2 ml, 2 x 5 ml, 5 x 5 ml, 2 x 10 ml, 5 x 10 ml

Not all pack sizes may be marketed.

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

Monofer is for single use only and any unused solution should be disposed of in accordance with local requirements.

Monofer must only be mixed with sterile 0.9% sodium chloride. No other intravenous dilution solutions should be used. No other therapeutic agents should be added. For dilution instructions, see section 4.2.

The reconstituted solution for injection should be visually inspected prior to use. Use only clear solutions without sediment.

Pharmacosmos A/S

Roervangsvej 30

DK-4300 Holbaek

Denmark

PL 18380/001

18/01/2010

18/01/2010