4.1. Therapeutic indications

Diafer is indicated in adults for the treatment of iron deficiency in patients with chronic kidney disease on dialysis, when oral iron preparations are ineffective or cannot be used.

The diagnosis of iron deficiency 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

Posology

Diafer may be administered as an up to 200 mg dosage with a maximum weekly administration of 1000 mg. If higher doses than 200 mg of iron are needed, other iron medicinal products intended for intravenous use should be used.

The iron dose must be individualised based on the clinical response to treatment including evaluation of haemoglobin, ferritin and transferrin saturation, concomitant treatment with an erythropoiesis stimulating agent (ESA) and the dose of ESA treatment. Targets may vary from patient to patient and depending on local guidelines.

Maintenance therapy with iv iron treatment may be given as small doses administered at regular intervals to maintain iron status tests stable within specific limits with the intent of avoiding development of iron deficiency or decline of iron test parameters below specific levels.

Paediatric population:

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

Method of administration:

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

Diafer 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 Diafer injection (see section 4.4).

Diafer can be administered either as an intravenous bolus injection or during a haemodialysis session directly into the venous limb of the dialyser. It may be administered undiluted or diluted in up to 20 ml sterile 0.9% sodium chloride.

Diafer should not be administered concomitantly with oral iron preparations, since the absorption of oral iron might be decreased (see section 4.5).

4.3. Contraindications

• Non-iron deficiency anaemia (e.g. haemolytic anaemia)

• Iron overload or disturbances in utilisation of iron (e.g. haemochromatosis, haemosiderosis)

• Hypersensitivity to the active substance, to Diafer or any of its excipients listed in section 6.1

• Known serious hypersensitivity to other parenteral iron products

• 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).

Diafer 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 Diafer 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 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.

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

This medicinal product contains up to 5.4 mg sodium per ml, equivalent to 0.27 % 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.

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 ferric derisomaltose 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 Diafer 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. The unborn baby should be carefully monitored during intravenous administration of parenteral irons to pregnant women.

Breastfeeding

A clinical study with ferric derisomaltose administered to lactating women showed transfer of iron to the breast milk with mean iron concentrations within normal range at all samples times. At therapeutic doses of ferric derisomaltose no negative effects on the breastfed newborns/infants are anticipated.

Fertility

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

4.7. Effects on ability to drive and use machines

Diafer has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

The table presents the adverse drug reactions (ADRs) reported during Diafer 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, rashes, itching and nausea 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)

Very rare

(<1/10000)

Not known

Blood and lymphatic system disorders

Haemolysis

Immune system disorders

Hypersensitivity, including severe reactions

Anaphylactoid/ anaphylactic reactions

Nervous system disorders

Blurred vision, hypoesthesia, dysphonia dysgeusia

Loss of consciousness, seizure, dizziness, restlessness, tremor, fatigue, altered mental status

Headache, paresthesia

Ear and labyrinth disorders

Transient deafness

Cardiac disorders

Arrhythmia, tachycardia

Foetal bradycardia, palpitations

Kounis syndrome

Vascular disorders

Hypotension

Hypertension

Respiratory, thoracic and mediastinal disorders

Dyspnoea, bronchospasm

Chest pain

Gastrointestinal disorders

Nausea, emesis, abdominal pain, constipation, dyspepsia

Diarrhoea

Skin and subcutaneous tissue disorders

Flushing, pruritus, rash, urticaria

Angioedema, sweating

Skin discolouration

Musculoskeletal and connective tissue disorders

Muscle spasm, back pain

Myalgia, arthralgia

General disorders and administration site conditions

Injection site reactions**

Feeling hot, pyrexia, soreness, inflammation near the injection site, local phlebitic reaction

Malaise

Influenza like illness*

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

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

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

Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard, or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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

Large doses of parenteral iron (500 mg or more) have been reported to give a brown colour to serum from a blood sample drawn four hours after administration.

Excessive therapy with parenteral iron can lead to excess iron storage and possibly iatrogenic hemosiderosis or hemochromatosis.

Monitoring of iron parameters such as serum ferritin may assist in recognising iron accumulation. Supportive measures such as chelating agents can be used.