Monofer 100; 500 and 1 000 mg Solution for injection/infusion.

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.

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.

Calculation of the cumulative iron dose needed:

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] (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 u2248 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 and others 1000 mg iron as stores. (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 a bodyweight 50 kg to < 70 kg Patients with a bodyweight u2265 70 kg

u2265 10 1 000 mg 1 500 mg

< 10 1 500 mg 2 000 mg

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

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

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 1 000 mg must be administered over 15 minutes or more. Doses exceeding 1 000 mg must be administered over 30 minutes or more. Monofer should be added to maximum 500 ml sterile 0,9 % sodium chloride (see section 6.4).

Injection into dialyser

Monofer may be administered during a haemodialysis session directly into the venous limb of the dialyser under the same procedures as outlined for intravenous bolus injection.

• Hypersensitivity to ferric derisomaltose or to any of the excipients of Monofer (see 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).
• Monofer should not be used in patients with ongoing bacteraemia.

Parenterally administered iron preparations such as Monofer, can cause hypersensitivity reactions, including serious and potentially fatal anaphylactic/anaphylactoid reactions. Hypersensitivity reactions have also been reported after previously uneventful doses of other parenteral iron complexes.

The risk is enhanced for patients with known allergies including medicine allergies, including patients with a history of severe asthma, eczema or other atopic allergy. There is also an increased risk of hypersensitivity reactions to Monofer in patients with immune or inflammatory conditions (e.g., systemic lupus erythematosus, rheumathoid 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 epinephrine (adrenaline) solution. Additional treatment with antihistamines and/or corticosteroids should be given as appropriate.

In patients with liver impairment, Monofer should only be administered after careful benefit/risk assessment. Monofer administration should be avoided in patients with hepatic impairment (alanine aminotransferase (ALAT) and/or aspartate aminotransferase (ASAT) > 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.

Monofer should be used with caution in cases of acute or chronic infection. Hypotensive episodes may occur especially if the intravenous injection of Monofer 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 long lasting brown discolouration at the site of injection. In case of paravenous leakage, the administration of Monofer must be stopped immediately.

The absorption of oral iron is reduced when administered concomitantly with Monofer. Oral iron therapy should not be started earlier than 5 days after the last injection of Monofer.

Large doses of Monofer (5 ml or more) have been reported to give a brown colour to serum from a blood sample drawn four hours after administration. Monofer may cause falsely elevated values of serum bilirubin and falsely decreased values of serum calcium.

Pregnancy

There is only limited data from the use of Monofer in pregnant women from one study with 100 exposed women. A careful risk/benefit evaluation is required before use during pregnancy and Monofer should not be used during pregnancy unless clearly necessary. Iron deficiency anaemia occurring in the first trimester of pregnancy can in most cases be treated with oral iron. Treatment with Monofer should be confined to the 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.

Breastfeeding

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. Women using Monofer should not breastfeed their infants.

Fertility

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

No studies on the effects on the ability to drive and use machines have been performed.

a. Summary of the safety profile

The table presents Tthe adverse drug reactions (ADRs) reported during Monofer treatment in clinical trials and during post-marketing experience. Acute, severe hypersensitivity reactions may occur with Monofer. They usually occur within the first few minutes of administration and are 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, including Monofer. Fishbane reaction characterised by flushing in the face, acute chest and/or back pain and tightness sometimes with dyspnoea in association with IV iron treatment may occur. 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 may 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.

b. Tabulated summary of adverse reaction

System organ class Common (u2265 1/100 to < 1/10) Uncommon (u22651/1 000 to <1/100) Rare (u2265 1/10 000 to < 1/1 000) Not Known

Immune system disorders Hypersensitivity, including severe reactions Anaphylactoid reactions, 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

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 nutrition 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, discomfort- burning, -pain, -bruising, - discolouration,-pigmentation -extravasation, -irritation, -reaction.

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

c. Description of selected adverse reactions

Delayed reactions may also occur with Monofer 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 may last two to four days.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: SAHPRA : https://www.sahpra.org.za/Publications/Index/8 Acino Pharma (Pty) Ltd: E-mail: [email protected] Tel: 060 998 7896

Overdose may lead to accumulation of iron in storage sites 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.

Treatment of overdose

Treatment is symptomatic and supportive.