SUMMARY OF
`
`PRODUCT CHARACTERISTICS
`
`Pharmacosmos, Exh. 1024, p. 1
`
`

`

`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.
`
`2. Dosing Table:
`
`Cumulative iron dose
`Hb (g/dL)
`Hb (mmol/l)
`
`Patients with bodyweight 50 kg to <70 kg
`
`Patients with body weight ≥70 kg
`
`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 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).
`
`4.2 Posology and method of administration
`
`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
` [mg iron]
`[kg]
`
`(Target Hb – Actual Hb)(B) x 2,4(C) + Iron for iron stores(D)
`[g/dl]
`[mg iron]
`
`It is recommended to use the patient’s ideal body weight or pre-pregnancy weight
`(A)
`(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
`
`≥10
`
`<10
`
`≥6,2
`
`<6,2
`
`1000 mg
`
`1500 mg
`
`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
`
`[mg iron]
`[kg]
`
`(Target Hb – Actual Hb) x 2,4
`[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 im-
`mediately 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).
`
`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 ad-
`ministration 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.
`
`Pharmacosmos, Exh. 1024, p. 2
`
`

`

`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 im-
`mediately 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..
`
`4.8 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 uncom-
`mon. 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 administra-
`tion. 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.
`
`Pharmacosmos, Exh. 1024, p. 3
`
`

`

`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 base-
`line 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 reticuloendo-
`thelial 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 mole-
`cule 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, Mono-
`fer 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. 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.
`
`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.
`
`6.5 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
`
`10. DATE OF REVISION OF THE TEXT
`
`2014-03-10
`
`Pharmacosmos, Exh. 1024, p. 4
`
`

`

`Pharmacosmos A/S
`Rørvangsvej 30
`4300 Holbæk
`www.pharmacosmos.com
`www.monofer.com
`
`Pharmacosmos, Exh. 1024, p. 5
`
`