Intravenous (IV) Iron Important Information for Patients about the Possible Risk of Serious Allergic Reactions with IV iron treatment (iron given by injection or infusion into a vein)

IV iron. Essential Prescription and Administration Information to Minimise the Risk of Serious Hypersensitivity Reactions

Removal of black triangle and the following associated text: "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." 

And 4.6 Fertility, pregnancy and lactation, "Pregnancy" Section: "There is only limited data from the use of Monover in pregnant women from one study with 100 exposed pregnant women." 

Removal of black triangle and associated text: ""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." Change of text in Pregnancy and breast-feeding "There is limited data from the use of Monover in pregnant women."

Removal of black triangle, Change to section 4.6

Section - 5 How to store Monofer

Section - 6 Content of the pack and other information

Section 2: Qualitative and quantitative composition

Replaced: Iron(III) isomaltoside 1000 to “ferric derisomaltose” in all lines.

Section 4.2 Posology and method of administration

Replaced: Iron(III) isomaltoside 1000 to “ferric derisomaltose” in the paragraph just below the table 4. 

Changed to “Monofer should be infused undiluted or diluted in sterile 0.9% sodium chloride. For stability reasons, Monofer should not be diluted to concentrations less than 1 mg iron/ml (not including the volume of the ferric derisomaltose solution) and never diluted in more than 500 ml. Please refer to section 6.3 and 6.6”

Section 4.9          Overdose

Replaced: Iron(III) isomaltoside 1000 to “ferric derisomaltose”

The ferric derisomaltose in Monofer has a low toxicity. The preparation is well tolerated and has a minimal risk of accidental overdosing.

Section 5.1          Pharmacodynamic properties

Fourth Paragraph changed to

“Each particle consists of a matrix of iron(III) atoms and derisomaltose with an average molecular weight of 1000 Da and a narrow molecular weight distribution that is almost devoid of mono- and disaccharides.

INN name: Ferric derisomaltose (also known as iron(III) isomaltoside 1000).”

Section 5.2          Pharmacokinetic properties

Second Paragraph first line changed to

“Following intravenous administration, ferric derisomaltose is rapidly taken up by the”

Third Paragraph second line

“complex into its components of iron and derisomaltose.”

Fifth paragraph changed to

“Derisomaltose is either metabolised or excreted.”

Section 10. Date of revision of the text changed from 08.05.2020 to 26.05.2020

1.    What Monover is and what it is used for
replaced isomaltoside 1000 to derisomaltose 

6.    Contents of the pack and other information
replaced isomaltoside 1000 to derisomaltose 

    What Monover looks like and contents of the pack
•    1 ml solution corresponding to 100 mg iron as ferric derisomaltose (deleted iron(III) isomaltoside 1000)
•    2 ml solution corresponding to 200 mg iron as ferric derisomaltose (deleted iron(III) isomaltoside 1000)
•    5 ml solution corresponding to 500 mg iron as ferric derisomaltose (deleted iron(III) isomaltoside 1000)
•    10 ml solution corresponding to 1,000 mg iron as ferric derisomaltose (deleted iron(III) isomaltoside 1000)

This leaflet was last revised in 05/2020

Para below table 4 in third line replaced iron isomaltoside 1000 to ferric derisomaltose

PACKAGE LEAFLET

Package leaflet: Information for the user

Monover^® 100 mg/ml solution for injection/infusion

Iron

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or nurse.
• If  you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1.         What Monover is and what it is used for

2.         What you need to know before you receive Monover

3.         How to use Monover is administered

4.         Possible side effects

5. How to store Monover

6.         Contents of the pack and other information

1. What Monover is and what it is used for

Monover contains a combination of iron and isomaltoside 1000  (a chain of sugar molecules). The type of iron in Monover is the same as that found naturally in the body called ‘ferritin’. This means that you can have Monover by injection in high doses.      

Monover is used for low levels of iron (sometimes called ‘iron deficiency’ and ‘iron deficiency anaemia’) if:

            •           Oral iron does not work or you cannot tolerate it

            •           Your doctor decides you need iron very quickly to build up your iron stores

2. What you need to know before you receive Monover

You must not receive Monover:

•        if you are allergic (hypersensitive) to the product or any of the other ingredients of this medicine (listed in section 6).

•        if you have experienced serious allergic (hypersensitive) reactions to other injectable iron preparations.

•        if you have anaemia not caused by iron deficiency

•        if you have too much iron (overload) or a problem in the way your body uses iron

•        if you have liver problems such as ‘cirrhosis’

Warnings and precautions

Talk to your doctor or nurse before receiving Monover:

• if you have a history of medicine allergy
• if you have systemic lupus erythematosus
• if you have rheumatoid arthritis
• if you have severe asthma, eczema or other allergies
• if you have an ongoing bacterial infection in your blood
• if you have reduced liver function

Incorrect administration of Monover may cause leakage of the product at the injection site, which may lead to irritation of the skin and potentially long lasting brown discolouration at the site of injection. The administration must be stopped immediately when this occurs.

You should tell your doctor or nurse immediately so that they can stop the infusion if necessary, if you experience symptoms of angioedema, such as

•        Swollen face, tongue or pharynx

•        Difficulty to swallow

•        Hives and difficulties to breath

Children and adolescents

Monover is for adults only. Children and adolescents should not have this medicine.

Other medicines and Monover

Tell your doctor if you are using, have recently used or might use any other medicines.

Monover given together with oral iron preparations can reduce the absorption of oral iron.

Pregnancy and breast-feeding

Monover has not been tested in pregnant women. It is important to tell your doctor if you are pregnant, think you may be pregnant, or are planning to have a baby. If you become pregnant during treatment, you must ask your doctor for advice. Your doctor will decide whether or not you should be given this medicine.

If you are breast-feeding, ask your doctor for advice before you are given Monover. It is unlikely that Monover represents a risk to the nursing child.

Driving and using machines

Ask your doctor if you can drive or operate machines after having Monover.

3. How to use Monover is administered

Before administration, your doctor will perform a blood test to determine the dose of Monover you require.

Your doctor or nurse will administer Monover by injection or infusion into your vein.

• Monover may be administered as an intravenous injection up to 500 mg up to three times a week.
• Monover may be administered during a dialysis session
• Monover may be administered as an intravenous infusion in a dose up to 20 mg iron/kg body weight or as weekly infusions until the total dose has been administered.

; Monover will be administered in a structure where immunoallergic events can receive appropriate and prompt treatment.

You will be observed for at least 30 minutes by your doctor or nurse after each administration.

If you receive more Monover than you should

A qualified health care professional will give you Monover. It is unlikely that you will have too much. They will monitor your dose and blood to avoid iron building up in your body.

4. Possible side effects

Like all medicines, Monover can cause side effects, although not everybody gets them.

Allergic reactions

Severe allergic reactions may occur, however they are in general rare. Tell your doctor or nurse immediately if you experience any of the following signs and symptoms that may indicate a serious allergic reaction: swollen face, tongue or pharynx, difficulty to swallow, hives and difficulties to breath, and chest pain which can be a sign of a potentially serious allergic reaction called Kounis syndrome.

Common (may affect up to 1 in 10 people):

• Nausea
• Skin reactions at or near injection site including redness of the skin, swelling, burning, pain, bruising, discolouration, leakage to the tissue around the site of infusion, irritation
• Rash

Uncommon (may affect up to 1 in 100 people):

• Hypersensitivity reactions with potential shortness of breath and bronchospasm
• Headache
• Numbness
• Distortion of the sense of taste
• Blurred vision
• Loss of consciousness
• Dizziness
• Fatigue
• Increased heart rate
• Low or high blood pressure
• Chest pain, back pain, pain in your muscles or joints, muscle spasms
• Stomach pain, vomiting, impaired digestion, constipation, diarrhoea
• Itching, hives, rash, skin inflammation
• Flushing, sweating, fever, feeling cold, shivering
• Low level of phosphate in the blood
• Infection
• Liver enzymes increased
• Local inflammation of a vein
• Skin exfoliation

Rare (may affect up to 1 in 1,000 people):

• Irregular heart beat

• Severe allergic reaction
• Arrhythmia
• Angioedema

• Hoarseness
• Seizure
• Tremor
• Altered mental status
• Malaise

Flu-like illness (may affect up to 1 in 1,000 people) may occur a few hours to several days after injection and is typically characterised by symptoms such as high temperature, and aches and pains in the muscles and joints.

Not known

• Skin discoloration at other areas of the body than the injection site

Reporting of side effects

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.hpra.ie, e-mail:medsafety@hpra.ie.
By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Monover

Keep this medicine out of the sight and reach of children.

Do not use Monover after the expiry date which is stated on the ampoule or vial label. EXP is the abbreviation used for expiry date. The expiry date refers to the last day of that month.

This medicinal product does not require any special storage conditions. Hospital staff will make sure that the product is stored and disposed of correctly.

6. Contents of the pack and other information

What Monover contains

•        The active substance in Monover is an Iron(III) isomaltoside 1000. One millilitre of solution contains 100 mg iron (as iron(III) isomaltoside 1000, an .
A 1 ml vial/ampoule contains 100 mg iron carbohydrate compound). The concentration of as iron present in the product is 100 mg per millilitre. (III) isomaltoside 1000, a 2 ml vial/ampoule contains 200 mg iron as iron(III) isomaltoside 1000, a 5 ml vial/ampoule contains 500 mg iron as iron(III) isomaltoside 1000 and a 10 ml vial/ampoule contains 1,000 mg iron as iron(III) isomaltoside 1000.

•        The other ingredients are sodiumWater for injections, Sodium hydroxide (for pH adjustment), hydrochloricadjuster) and Hydrochloric acid (for pH adjustment), and water for injectionadjuster).

What Monover looks like and contents of the pack

Monover is a dark brown, non-transparent solution for injection/infusion.

Monover is suppliedcontained in glass ampoulesampoule or in glass vials containing:vial with chlorobutyle rubber stopper and aluminium cap.

• 1 ml solution corresponding to 100 mg iron as iron(III) isomaltoside 1000
• 2 ml solution corresponding to 200 mg iron as iron(III) isomaltoside 1000
• 5 ml solution corresponding to 500 mg iron as iron(III) isomaltoside 1000
• 10 ml solution corresponding to 1,000 mg iron as iron(III) isomaltoside 1000

The pack sizes are the following:

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

Vial 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.

Marketing Authorisation Holder and Manufacturer

Pharmacosmos A/S

Roervangsvej 30

DK-4300 Holbaek

Denmark

Tel.: +45 59 48 59 59

Fax: +45 59 48 59 60

E-Mail: info@pharmacosmos.com

This medicinal product is authorised in the Member States of the EEA under the following names:

Austria:            Monofer

Bulgaria:                      Monofer

Croatia:            Monofer

Czech Republic:            Monover

Denmark:                     Monofer

Estonia:                        Monofer

Finland:                        Monofer

Germany:                     Monofer

Greece:             Monofer

Iceland:            Monofer

Ireland:             Monover

Italy:                            Monoferric

Latvia:              Monofer

Lithuania:                     Monofer

Luxemburg:                  Monover

Netherlands:                 Monofer

Norway:                       Monofer

Poland:             Monover

Portugal:                       Monofar

Romania:                      Monofer

Slovenia:                      Monofer

Spain:                           Monoferro

Sweden:                       Monofer

United Kingdom:          Monofer

This leaflet was last revised in 02/202022.05.2019

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The following information is intended for medical or healthcare professionals only:

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

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.  

Posology

The posology of Monover follows a stepwise approach: [1] determination of the individual iron need and [2] calculation and administration of the iron dose(s). The steps can be repeated after [3] post-iron repletion assessments.

Step 1: Determination of the iron need:

Calculation of the cumulative iron need:

Iron replacement in patients with iron deficiency:

The dose of Monover is expressed in mg of elemental iron. The iron need and the administration schedule for Monover 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 Monover to maintain target levels of haemoglobin and acceptable limits of other iron parameters.

The cumulative iron need can be determined using either the Simplified Table (iGanzoni formula (1) or the Table below (2). It is recommended to use the Ganzoni formula below (ii). in patients who are likely to require individually adjusted dosing such as patients with anorexia nervosa, cachexia, obesity, pregnancy or anaemia due to bleeding.

The iron need is expressed in mg elemental iron.

i. Haemoglobin is abbreviated Hb.

1.Simplified Table:

Table 1. Simplified Table

ii. Ganzoni formula:

Table 2. 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. For all other patients use actual body weight.

           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(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.

(DE)    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:

iii. Fixed iron need:

A fixed dose of 1000 mg is given and the patient is re-evaluatedIron need

The treatment effect should be monitored by blood tests. To reach the target Hb-level, the cumulative iron dose may need adjustment.

Iron replacement for further blood loss:

Iron therapy in patients with blood loss should supply an amount of iron need accordingequivalent to “Step 3: Post-the amount of iron repletion assessments”. For patients weighing less than 50 kg use the Simplified table or represented in the blood loss.

If the Hb level is reduced: Use the Ganzoni formula forconsidering that the depot iron does not need calculation.to be restored:

Step 2: Calculation andIron 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 the maximum individual iron dose(s):

Based on the iron need determined above the appropriate dose(s) of 200 mg Monover should be administered taking into consideration the followingresults 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 Monover.

Monover 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 Monover injection.

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.  The total dose per week should not exceed 20 mg iron/kg body weight.

A single Monover infusion should not exceed 20 mg iron/kg body weight.

A single Monover bolus injection should not exceed 500 mg iron.

Step 3: Post-iron repletion assessments:

Re-assessment including blood tests should be performed by the clinician based on the individual patient's condition. To evaluate the effect of IV iron treatment the Hb level should be re-assessed no earlier than 4 weeks post final Monover administration to allow adequate time for erythropoiesis and iron utilisation. In the event the patient requires further iron repletion, the iron need should be recalculated.

Children and adolescents:

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

Method of administration:

Adults and the elderly:

Monover mustcan be administered by theeither as an intravenous route either bybolus injection or by, as an intravenous drip infusion or as a direct injection into the venous limb of the dialyser.

Monover should not be administered concomitantly with oral iron preparations, since the absorption of oral iron might be decreased.

Intravenous bolus injection:

Monover 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.

Table 3: Administration rates for intravenous bolus injection

Intravenous drip infusion:

The cumulative iron needdose required may be administered in a single Monover infusion up to 20 mg iron/kg body weight or as weekly infusions until the cumulative iron needdose has been administered.

If the cumulative iron needdose 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.

Table 4: Administration rates for intravenous infusion

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.

Monover should be infused undiluted or diluted inadded to maximum 500 ml sterile 0.9% sodium chloride. For stability reasons, Monover should not be diluted to concentrations less than 1 mg iron/ml (not including the volume of the iron isomaltoside solution) and never diluted in more than 500 ml.

Injection into dialyser:

Monover 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.

Please refer to the SPC for further information on Monover.

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

Monover 100 mg100mg/ml solution for injection/infusion (vials)

2  QUALITATIVE AND QUANTITATIVE COMPOSITION

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

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

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

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

10 ml vial 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

Monover 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

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

Posology

The posology of Monover follows a stepwise approach: [1] determination of the individual iron need and [2] calculation and administration of the iron dose(s). The steps can be repeated after [3] post-iron repletion assessments.

Step 1: Determination of the iron need:

Calculation of the cumulative iron need:

Iron replacement in patients with iron deficiency:

The dose of Monover is expressed in mg of elemental iron. The iron need and the administration schedule for Monover 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 Monover to maintain target levels of haemoglobin and acceptable limits of other iron parameters.

The cumulative iron need can be determined using either the Simplified Table (iGanzoni formula (1) or the Table below (2). It is recommended to use the Ganzoni formula below (ii). in patients who are likely to require individually adjusted dosing such as patients with anorexia nervosa, cachexia, obesity, pregnancy or anaemia due to bleeding.

The iron need is expressed in mg elemental iron.

i. Haemoglobin is abbreviated Hb.

1.Simplified Table:

Table 1. Simplified Table

ii. Ganzoni formula:

Table 2. 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. For all other patients use actual body weight. 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(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.

(DE)    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

The treatment effect should be monitored by blood tests. To reach the target Hb-level, the cumulative iron dose may need adjustment.

iii. Fixed iron need:

A fixed dose of 1000 mg is given and the patient is re-evaluatedIron replacement for further iron need according to “Step 3: Post-iron repletion assessments”. Forblood loss:

Iron therapy in patients weighing less than 50 kg usewith blood loss should supply an amount of iron equivalent to the amount of iron represented in the Simplified table orblood loss.

• If the Hb level is reduced: Use the Ganzoni formula for 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 need calculation.]              [kg]                                    [g/dl]

Step 2: Calculation and  

If the volume of blood lost is known: The administration of the maximum individual iron dose(s):

469252. on the iron need determined above the appropriate dose(s) of 200 mg Monover should be administered taking into consideration the followingresults 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 Monover.

Monover 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 Monover 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.

The total dose per week should not exceed 20 mg iron/kg body weight.

A single Monover infusion should not exceed 20 mg iron/kg body weight.

A single Monover bolus injection should not exceed 500 mg iron.

Step 3: Post-iron repletion assessments:

Re-assessment including blood tests should be performed by the clinician based on the individual patient's condition. To evaluate the effect of IV iron treatment, the Hb level should be re-assessed no earlier than 4 weeks post final Monover administration to allow adequate time for erythropoiesis and iron utilisation. In the event the patient requires further iron repletion, the iron need should be recalculated.

Children and adolescents:

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

Method of administration:

Adults and the elderly:

Monover mustcan be administered by theeither as an intravenous route either bybolus injection or by, as an intravenous drip infusion or as a direct injection into the venous limb of the dialyser.

Monover 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:

Monover 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.

Table 3: Administration rates for intravenous bolus injection

Intravenous drip infusion:

The cumulative iron needdose required may be administered in a single Monover infusion up to 20 mg iron/kg body weight or as weekly infusions until the cumulative iron needdose has been administered.

If the cumulative iron needdose 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.

Table 4: Administration rates for intravenous infusion

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.

Monover should be  infused undiluted or diluted inadded to maximum 500 ml sterile 0.9% sodium chloride. For stability reasons, Monover should not be diluted to concentrations less than 1 mg iron/ml (not including the volume of the iron isomaltoside solution) and never diluted in more than 500 ml. Please refer to section 6.3 and 6.6.

Injection into dialyser:

Monover 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 Monover 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 disease

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. There have been reports of hypersensitivity reactions which progressed to Kounis syndrome (acute allergic coronary arteriospasm that can result in myocardial infarction, see section 4.8).

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).

Monover 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 Monover 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 compensated liver dysfunction, parenteral iron should only be administered after careful benefit/risk assessment. Parenteral iron administration should be avoided in patients with hepatic dysfunction (alanine aminotransferase and/or aspartate aminotransferase > 3 times upper limit of normal) where iron overload is a precipitating factor, in particular Porphyria Cutanea Tarda (PCT). Careful monitoring of iron status is recommended to avoid iron overload.

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

Monover should not be used in patients with ongoing bacteraemia.

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

Caution should be exercised to avoid paravenous leakage when administrating Monover. Paravenous leakage of Monover 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 Monover must be stopped immediately.

4.5  Interaction with other medicinal products and other forms of interactionsinteraction

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 Monover.

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

Pregnancy

There are no adequate and well-controlled trials of Monover in pregnant women. A careful risk/benefit evaluation is therefore required before use during pregnancy and Monover 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. Treatment with Monover 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. In rare cases, foetal bradycardia has been observed in pregnant women with hypersensitivity reactions (see section 4.8).

Foetal bradycardia may occur following administration of parenteral irons. It is usually transient and a consequence of a hypersensitivity reaction in the mother. The unborn baby should be carefully monitored during intravenous administration of parenteral irons to pregnant women.

Breast-feeding

A clinical study showed that transfer of iron from Monover to human milk was very low. At therapeutic doses of Monover no effects on the breastfeed newborns/infants are anticipated.

Fertility

There are no data on the effect of Monover on human fertility. Fertility was unaffected following Monover treatment in animal studies (see section 5.3).

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

The table presents the adverse drug reactions (ADRs) reported during Monover treatment in clinical trials and in-market experience.

Acute severe hypersensitivity reactions may occur with parenteral iron preparations.  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, such as urticaria and itching may also occur. In pregnancy, associated foetal bradycardia may occur with parenteral iron preparations.

Fishbane reaction characterised by flushingFlushing in the face, acute chest and/or back pain and tightness sometimes with dyspnea in association with IV iron treatment may occur (frequency uncommon). This may mimic the early symptoms of an anaphylactoid/anaphylactic reaction. The infusion should be stopped and the patient's vital signs should be assessed. These symptoms disappear shortly after the iron administration is stopped. They typically do not reoccur if the administration is restarted at a lower infusion rate.

Distant skin discolouration has also been reported post marketing following IV iron administration.

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

* Includes the following preferred terms, i.e. injection site erythema, -swelling, -burning, -pain, -bruising,
-discolouration, -extravasation, -irritation, -reaction.

** Influenza like illness whose onset may vary from a few hours to several days.

Description of selected adverse reactions

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.

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:HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; e-mail: medsafety@hpra.ie.

HPRA Pharmacovigilance

Website: www.hpra.ie

4.9  Overdose

The iron(III) isomaltoside 1000 in Monover 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

Monover solution for injection is a colloid with strongly bound iron in spheroidal iron-carbohydrate particles.

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

Each particle consists of a matrix of iron(III) atoms and isomaltoside with an average molecular weight of 1000 Da and a narrow molecular weight distribution that is almost devoid of mono- and disaccharides.

INN name: Ferric derisomaltose

andisomaltoside pentamers. The chelation of iron(III) with carbohydrate 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.

Evidence of a therapeutic response can be seen within a few days of administration of Monover as an increase in the reticulocyte count. Due to the slow release of bioavailable iron serum ferritin peaks within days after an intravenous dose of Monover and slowly returns to baseline after weeks.

Clinical efficacy

The efficacy of Monover has been studied in the different therapeutic areas necessitating IV iron to correct iron deficiency. The main trials are described in more detail below.

Iron deficiency anaemia outside CKD

The P-Monofer-IDA-01 trial was an open-label, comparative, randomised, multi-centre, non-inferiority trial conducted in 511 patients with IDA randomised 2:1 to either Monover or iron sucrose.  90 % of recruited patients were females. The dosing of Monover was performed according to the Simplified Table as described in section 4.2 above and dosing of iron sucrose was calculated according to Ganzoni and administered as 200 mg infusions. The primary endpoint was the proportion of patients with an Hb increase ≥2 g/dldL from baseline at any time between weeks 1 to 5. A higher proportion of patients treated with Monover compared to iron sucrose reached the primary endpoint, 68.5% vs 51.6%, respectively. (FAS, p < 0.0001).

The P-Monofer-IDA-03 trial was an open-label, comparative, randomised, multi-centre trial conducted in 1512 patients with IDA randomised 2:1 to either Monofer 1000 mg infused over 20 min (1009 subjects) or iron sucrose administered as 200 mg IV injections repeated up to a cumulative dose of 1000 mg (503 subjects). For the co-primary efficacy endpoint the change from baseline to week 8 in Hb was 2.49 g/dL in the Monofer group and 2.49 g/dL in the iron sucrose group. The estimated treatment difference [95 % CI] of iron isomaltoside - iron sucrose was 0.00 g/dL [-0.13;0.13]. Since the lower bound of the 95 % CI for the treatment difference was above -0.5 g/dL, non-inferiority was concluded. For the co-primary safety endpoint, a total of 3 treatment emergent serious or severe hypersensitivity reactions in 989 subjects (0.3 %) were adjudicated and confirmed by the adjudication committee in the iron isomaltoside group. The 95 % CI was [0.06 %;0.88 %] and as the upper bound was <3 %, the primary safety objective was considered met. In the iron sucrose group 2 treatment emergent serious or severe hypersensitivity reactions in 494 subjects (0.4 %) were adjudicated and confirmed by the adjudication committee. The risk difference between iron isomaltoside and iron sucrose was estimated to -0.10 % [95% CI: -0.91;0.71].

Nephrology

Non-dialysis-dependent chronic kidney disease

The P-Monofer-CKD-02 trial was an open-label, comparative, randomised, multi-centre, non-inferiority trial conducted in 351 iron deficient non-dialysis dependent (NDD) chronic kidney disease (CKD) patients, randomised 2:1 to either Monover or oral iron sulphate administered as 100 mg elemental oral iron twice daily (200 mg daily) for 8 weeks. The patients in the Monover group were randomisedrandomized to infusion of 1000 mg single dose or bolus injections of 500 mg. Monover was both non-inferior to oral iron at week 4 (p<0.001) and  also sustained a superior increase in Hb compared to oral iron from week 3 until the end of trial at week 8 (p=0.009 at week 3).

The P-Monofer-CKD-04 trial was an open-label, comparative, randomised, multi-centre trial conducted in 1538 NDD-CKD patients with IDA randomised 2:1 to either Monofer 1000 mg infused over 20 min (1027 subjects) or iron sucrose administered as 200 mg IV injections repeated up to a cumulative dose of 1000 mg (511 subjects). For the co-primary efficacy endpoint, the change from baseline to week 8 in Hb was 1.22 g/dL in the Monofer group and 1.14 g/dL in the iron sucrose group. The estimated treatment difference was 0.08 g/dL [95% CI: -0.06;0.23]. Since the lower bound of the 95 % CI was above -0.5 g/dL, non-inferiority was concluded. For the co-primary safety endpoint, a total of 3 treatment emergent serious or severe hypersensitivity reactions in 1019 subjects (0.3 %) were adjudicated and confirmed by the adjudication committee in the iron isomaltoside group. The 95 % CI was [0.06 %;0.86 %] and as the upper bound was <3 %, the primary safety objective was considered met. No treatment emergent serious or severe hypersensitivity reactions were adjudicated and confirmed by the adjudication committee in the iron sucrose group. The risk difference between iron isomaltoside and iron sucrose was estimated to 0.29 % [95% CI: -0.19;0.77].

Haemodialysis-dependent chronic kidney disease

The P-Monofer-CKD-03 trial was an open-label, comparative, randomised, multi-centre, non-inferiority trial conducted in 351 haemodialysis patients randomised 2:1 to either Monover or iron sucrose. Patients were randomised to either a single injection of 500 mg or 500 mg in split doses of Monover or 500 mg iron sucrose in split doses. Both treatments showed similar efficacy with more than 82% of patients with Hb in the target range (non-inferiority, p=0.01).

Oncology

Cancer related anaemia

The P-Monofer-CIA-01 trial was an open-label, comparative, randomised, multi-centre, non-inferiority trial conducted in 350 cancer patients with anaemia randomised 2:1 to either Monover or oral iron sulphate administered as 100 mg elemental oral iron twice daily (200 mg daily) for 12 weeks. The patients in the Monover group were randomised to either an infusion of max 1000 mg single doses over 15 min or bolus injections of 500 mg over 2 min. The primary endpoint was change in Hb concentrations from baseline to week 4. Monover was non-inferior to oral iron at week 4 (p<0.001) and a faster onset of the Hb response was observed with infusion of Monover.

Gastroenterology

Inflammatory bowel disease

The P-Monofer-IBD-01 trial was an open-label, comparative, randomised, multi-centre, non-inferiority trial conducted in 338 inflammatory bowel disease (IBD) patients randomised 2:1 to receive either Monover or oral iron sulphate administered as 100 mg elemental oral iron twice daily for 8 weeks (200 mg daily). The patients in the Monover group were randomised to either an infusion of max 1000 mg single doses over 15 min or bolus injections of 500 mg over 2 min. A modified Ganzoni formula was used to calculate the IV iron need with a target Hb of only 13 g/dldL resulting in an average iron dose of 884 mg elemental iron compared to oral iron administered as 200 mg oral iron sulfate once daily for 8 weeks (11,200 mg elemental

oral iron in total). The primary endpoint was change in Hb concentrations from baseline to week 8. The patients had mild to moderate disease activity. Non-inferiority in change of Hb to week 8 could not be demonstrated. The doseresponse relationship observed with Monover suggests that the true iron demand of IV iron was underestimated by the modified Ganzoni formula. The Hb response(Hb increase ≥2 g/dl) rate was 93% for patients receiving > 1000 mg Monover.

Women's health

Postpartum

The P-Monofer-PP-01 trial was an open-label, comparative, randomised, single-centre, non-inferiority trial conducted in 200 healthy women with  postpartum haemorrhage exceeding 700 mL and ≤1000 ml or PPH >1000 ml and Hb >6.5 g/dl measured >12within 48 hours after delivery. The women were randomised 1:1 to receive either a single dose of 1200 mg Monover or standard medical care. The primary endpoint was the aggregated change in physical fatigue within 12 weeks postpartum. The difference in aggregated change in physical fatigue score within 12 weeks postpartum was
-0.97 (p=0.006), in favour of Monover.

5.2  Pharmacokinetic properties

The Monover 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 toxicity. After administration of a single dose of Monover of 100 to 1000 mg of iron in pharmacokinetic studies, the iron injected or infused was cleared from the plasma with a half-life that ranged from 1 to 4 days. Renal elimination of iron was negligible.

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.

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, Monover 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.

In a fertility study with Monover in rats no effects on female on male reproductive performance and spermatogenic parameters were found at the dose level tested.

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 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.

6.5  Nature and contents of container

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

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

Monover 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

Vials: PA0982/002/002

9  DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 9^th April 2010

Date of lastlatest renewal: 26^th November 2014

10  DATE OF REVISION OF THE TEXT

May 2020

 22.05.2019

In section 2. What you need to know before you receive Monover: Warning and precautions

Following were deleted:

“              You  should tell your doctor or nurse immediately so that they can stop the infusion if necessary, if you experience symptoms of angioedema, such as

•             Swollen face, tongue or pharynx

•             Difficulty to swallow

•             Hives and difficulties to breath”

Section 4: Possible side effects: Following were added

“Allergic reactions

Tell your doctor or nurse immediately if you experience any of the following signs and symptoms that may indicate a serious allergic reaction: swollen face, tongue or pharynx, difficulty to swallow, hives and difficulties to breath, and chest pain which can be a sign of a potentially serious allergic reaction called Kounis syndrome. “

This leaflet was last revised in

Deleted: 22.05.2019

Added: 01/2020

4.4  Special warnings and precautions for use

Following were added in the first paragraph

“There have been reports of hypersensitivity reactions which progressed to Kounis syndrome (acute allergic coronary arteriospasm that can result in myocardial infarction, see section 4.8).”

4.6  Fertility, pregnancy and lactation

In the second paragraph (Pregnancy) following were deleted

“In  rare cases, foetal bradycardia has been observed in pregnant women with hypersensitivity reactions (see section 4.8).”

And following were added

“Foetal bradycardia may occur following administration of parenteral irons. It is usually transient and a consequence of a hypersensitivity reaction in the mother. The unborn baby should be carefully monitored during intravenous administration of parenteral irons to pregnant women.”

4.8 Undesirable effects: in the table- Adverse drug reactions observed during clinical trials and post-marketing experience.

Another column “Not known” were added.

In row three under Cardiac Disorders: Kounis Syndrome was added in the Not known column.

Section 10 Date of revision of the text

Deleted: 18.10.2019

Added: 23.01.2020

Section 4.2:

Change of wording from total iron dose to cumulative iron dose.

Inclusion of a fixed dose table option in addition to the Ganzoni calculation for estimation of the iron need.

Under Iron replacement for blood loss:  Correction of error in previous SPC – unknown blood loss changed to known blood loss.

Under Administration:  Reference to Total Dose Infusion (TDI) has been removed.

Under Intravenous Bolus Injection:  the injectable dose is increased to up to 500 mg at 50 mg/min up to 3 times weekly.

Under Intravenous Drip Infusion:  doses ≤ 1000 mg may be infused over 30 minutes - higher doses still require 60 minutes infusion time.

Section 4.6  Change of title to Fertility, pregnancy and lactation.

Section 10  Date of revision changed to July 1, 2013.