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. In relation to acute blood loss, haemoglobin is sufficient as a diagnostic laboratory test.

4.2. Posology and method of 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.

Posology

The posology of Monofer 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:

The iron need can be determined using either the Simplified Table (i) or the Ganzoni formula below (ii).

The iron need is expressed in mg elemental iron.

i. Simplified Table:

Table 1. Simplified Table

Hb (g/dl)

Hb (mmol/l)

Patients with bodyweight <50 kg

Patients with bodyweight 50 kg to <70 kg

Patients with body weight ≥70 kg

≥10

≥6.2

500 mg

1000 mg

1500 mg

<10

<6.2

500 mg

1500 mg

2000 mg

ii. Ganzoni formula:

Table 2. Ganzoni formula

(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) 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.

(D) Default Hb target is 15 g/dl in the Ganzoni formula. In special cases such as pregnancy consider using a lower haemoglobin target.

iii. Fixed iron need:

A fixed dose of 1000 mg is given and the patient is re-evaluated for further iron need according to “Step 3: Post-iron repletion assessments”. For patients weighing less than 50 kg use the Simplified table or Ganzoni formula for iron need calculation.

Step 2: Calculation and administration of the maximum individual iron dose(s):

Based on the iron need determined above the appropriate dose(s) of Monofer should be administered taking into consideration the following:

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

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

A single Monofer 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 Monofer 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:

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

Method of administration:

Monofer must be administered by the intravenous route either by injection or by infusion.

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.

Table 3: Administration rates for intravenous bolus injection

Volume of Monofer

Equivalent iron dose

Administration rate/ Minimum administration time

Frequency

≤5 ml

≤500 mg

250 mg iron/minute

1-3 times a week

Intravenous infusion:

The iron need 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 need has been administered.

If the iron need 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

Iron dose

Minimum administration time

≤1000 mg

>1000 mg

More than 15 minutes

30 minutes or more

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.

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 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).

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.

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.

Monofer 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 Monofer. Paravenous leakage of Monofer 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 Monofer must be stopped immediately.

Monofer contains up to 9.4 mg (0.41 mmol) sodium per iron dose of 100 mg, equivalent to 0.47% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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.

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 is only limited data from the use of Monofer in pregnant women from one study with 100 exposed pregnant women. A careful risk/benefit evaluation is therefore required before use during pregnancy.

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.

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 Monofer to human milk was very low. At therapeutic doses of Monofer no effects on the breastfeed newborns/infants are anticipated.

Fertility

There are no data on the effect of Monofer on human fertility. Fertility was unaffected following Monofer 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 Monofer 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 flushing 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

System Organ Class

Common (≥1/100 to <1/10)

Uncommon (≥1/1000 to <1/100)

Rare (≥1/10000 to <1/1000)

Not known

Immune system disorders

Hypersensitivity, including severe reactions

Anaphylactoid/ anaphylactic reactions

Nervous system disorders

Headache, paraesthesia, dysgeusia, blurred vision, loss of consciousness, dizziness, fatigue

Dysphonia, seizure, tremor, altered mental status

Cardiac disorders

Tachycardia

Arrhythmia

Kounis syndrome

Vascular disorders

Hypotension, hypertension

Respiratory, thoracic and mediastinal disorders

Chest pain, dyspnoea, bronchospasm

Gastrointestinal disorders

Nausea

Abdominal pain, vomiting, dyspepsia, constipation, diarrhoea

Skin and subcutaneous tissue disorders

Rash

Pruritus, urticaria, flushing, sweating, dermatitis

Angioedema

Distant skin discolouration

Metabolism and nutritional disorders

Hypophosphataemia

Musculoskeletal and connective tissue disorders

Back pain, myalgia, arthralgia, muscle spasms

General disorders and administration site conditions

Injection site reactions*

Pyrexia, chills/shivering, infection, local phlebitic reaction, skin exfoliation

Malaise, influenza like illness**

Investigations

Hepatic enzyme increased

* 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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.

4.9. Overdose

The active substance 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.