Monofer
SUMMARY OF PRODUCT CHARACTERISTICS
This medicinal product is subject to additional
monitoring. This will allow quick identification of new safety
information. Healthcare professionals are asked to report any
suspected adverse reactions. See section 4.8 for how to report
adverse reactions.
1. NAME OF THE MEDICINAL PRODUCT
Monofer 100 mg/ml solution for injection/infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
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 the full list of excipients, see section 6.1.
3. PHARMACEUTICAL form
Solution for injection/infusion.
Dark brown, non-transparent solution.
4. Clinical particulars
4.1 Therapeutic indications
Monofer is indicated for the treatment of iron deficiency 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 must be based on laboratory tests.
4.2 Posology and method of administration
Calculation of the cumulative iron need:
Iron replacement in patients with iron deficiency:
The dose of Monofer is expressed in mg of elemental iron. The iron need and the administration 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.
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 need can be determined using either the Ganzoni formula (1) or the 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 need = Body weight(A) x (Target Hb(E) – 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 for obese patients or pre-pregnancy weight for pregnant women. Ideal body weight may be calculated in a number of ways e.g. by calculating weight at BMI 25 i.e. ideal body weight = 25 * (height in m)2
(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. Iron stores of 500 mg are at the lower limit normal for small women. Some guidelines suggest using 10-15 mg iron /kg body weight.
(E) Default Hb target is 15 g/dl in the Ganzoni formula. In special cases such as pregnancy consider using a lower haemoglobin target.
2. Simplified Table:
Iron need
|
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:
Iron need = 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:
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 patient should be observed for adverse effects for at least 30 minutes following each Monofer injection (see section 4.4).
Each IV iron administration is associated with a risk of a hypersensitivity reaction. Thus, to minimise risk the number of single IV iron administrations should be kept to a minimum.
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 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 250 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. It is recommended whenever possible to give 20 mg iron/kg body weight in the first administration. Dependent on clinical judgement the second administration could await follow-up laboratory tests.
Doses up to 1000 mg must be administered over more than 15 minutes.
Doses exceeding 1000 mg must be administered over 30 minutes or more.
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.
4.3 Contraindications
-
Hypersensitivity to the active substance, to Monofer or any of its excipients listed in section 6.1
-
Known serious hypersensitivity to other parenteral iron products
-
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
4.4 Special warnings and precautions for use
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).
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.
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. 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.
4.6 Fertility, pregnancy and lactation
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.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
Undesirable effects
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
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 the national reporting system listed in Appendix V.
4.9 Overdose
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
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Iron parenteral preparation, ATC code: B03AC
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.
5.2 Pharmacokinetic properties
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.
5.3 Preclinical safety data
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.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Water for injections
Sodium hydroxide (for pH adjustment)
Hydrochloric acid (for pH adjustment)
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6
6.3 Shelf life
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.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
For storage conditions of the reconstituted and diluted solution, see section 6.3.
Nature and contents of container
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.
6.6 Special precautions for disposal and other handling
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.
7. MARKETING AUTHORISATION HOLDER
Pharmacosmos A/S
Roervangsvej 30
DK-4300 Holbaek
Denmark
8. MARKETING AUTHORISATION NUMBER(S)
<[To be completed nationally]>
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 2009-11-26
Date of latest renewal: 2014 -11-26
10. DATE OF REVISION OF THE TEXT
2015-10-15
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