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).

Calculation of the cumulative iron dose:
Iron replacement in patients with iron deficiency anaemia:
The dose and dosage schedule for Monofer must be individually established for each patient. The optimal haemoglobin target level and iron stores may vary in different patient groups and between patients. Please refer to official guidelines. The dose of Monofer is expressed in mg of elemental iron.
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 current 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.
The cumulative iron dose can be determined using either the Ganzoni formula (1) or the dosing table below (2). It is recommended to use the Ganzoni formula in patients who are likely to require individually adjusted dosing such as patients with anorexia nervosa, cachexia, obesity, pregnancy or anaemia due to bleeding.
Haemoglobin is abbreviated Hb.
1. Ganzoni formula:
Iron dose = Body weight(A) x (Target Hb – Actual Hb)(B) x 2.4(C) + Iron for iron stores(D)
[mg iron] [kg] [g/dl] [mg iron]
(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 500 mg or above

2. Dosing Table:
Cumulative iron dose

Hb (g/dL)	Patients with bodyweight 50 kg to <70 kg	Patients with body weight ≥70 kg
≥10	1000 mg	1500 mg
<10	1500 mg	2000 mg

 

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 Ganzoni formula considering that the depot iron does not need to be restored:
Cumulative iron dose = Body weight x (Target Hb – Actual Hb) x 2.4
[mg iron] [kg] [g/dl]
• If the volume of blood lost is known: The administration of 200 mg Monofer results in an increase of haemoglobin which is equivalent to 1 unit blood:
Iron to be replaced = Number of units blood lost x 200.
[mg iron]
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.
Monitor carefully patients for signs and symptoms of hypersensitivity reactions during and following each administration of Monofer.
Monofer 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 patient3
should be observed for adverse effects for at least 30 minutes following each Monofer injection (see section 4.4).
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 offers the flexibility of administration either as an intravenous bolus injection, 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 an intravenous bolus injection up to 500 mg up to three times a week at an administration rate of up to 50 mg iron/minute. It may be administered undiluted or diluted in maximum 20 ml sterile 0.9% sodium chloride.
Intravenous drip infusion:
The cumulative iron dose required may be administered in a single Monofer infusion up to 20 mg iron/kg body weight or as weekly infusions until the cumulative iron dose has been administered.
If the cumulative 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.
Doses up to 1000 mg must be infused over 30 min.
Doses exceeding 1000 mg must be infused over 60 min.
Monofer should be added to maximum 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.

• Hypersensitivity to the active substance, to Monofer or any of its excipients listed in section 6.1 • Non-iron deficiency anaemia (e.g. haemolytic anaemia) • Iron overload or disturbances in utilisation of iron (e.g. haemochromatosis, haemosiderosis) • Decompensated liver cirrhosis and hepatitis

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, previous severe hypersensitivity to other parenteral iron products, and 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).
Monofer 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 Monofer 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.
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 (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 Monofer 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.
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 parenteral preparation, ATC code: B03AC
Monofer solution for injection is a colloid with strongly bound iron in spheroidal iron-carbohydrate particles. The structure of the Monofer particle has been carefully characterised by carbon 13 NMR spectroscopic analysis which reveals that the complex forms a stable matrix type structure with about 10 iron(III) atoms to one molecule of isomaltoside pentamer with the iron(III) bound in cavities of the 3-D structure of isomaltoside pentamers. As a consequence of the strong binding of iron in the matrix the free iron content in Monofer solution is very low.
The isomaltoside 1000 component of Monofer consists of 3-5 glucose units with an average molecular weight of approximately 1000 kDa. It is completely devoid of branching structures as evidenced by careful 13C and 1H NMR spectroscopic analysis. Furthermore isomaltoside 1000 does not contain any reducing sugar residues, which can be involved in complex redox reactions. These characteristics of the complexing carbohydrate isomaltoside 1000 make it highly unlikely that isomaltoside 1000 will induce immune reactions in vivo.
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 3 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.

Store below 30°C. Do not freeze.
For storage conditions of the reconstituted and diluted solution, see section 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: 1 x 1 ml, 5 x 1 ml, 10 x 1 ml, 5 x 2 ml, 10 x 2 ml, 1 x 5 ml, 2 x 5 ml, 5 x 5 ml, 1 x 10 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.