For the use of Registered Medical Practitioner of Hospital or a Laboratory only
Iron (III) Isomaltoside 1000 Solution for Injection/Infusion 100mg per ml
COMPOSITION
Each ml contains:
Iron (III) Isomaltoside 1000 100mg
Water for Injection USP q.s.
CLINICAL PHARMACOLOGY
Pharmacodynamic properties
Pharmacotherapeutic group: Anti-anaemic preparation, iron, parenteral preparation
ATC code: B03AC
Mechanism of action
The Iron (III) Isomaltoside 1000 Solution for Injection 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 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 Iron (III) Isomaltoside 1000 Solution for Injection 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 Iron (III) Isomaltoside 1000 Solution for Injection and slowly returns to baseline after weeks.
Clinical efficacy
The efficacy of Iron (III) Isomaltoside 1000 Solution for Injection 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 Iron (III) Isomaltoside 1000 Solution for Injection -01 trial was an open-label, comparative, randomised, multi- centre, non-inferiority trial conducted in 511 patients with IDA randomised 2:1 to either Iron (III) Isomaltoside 1000 Solution for Injection or iron sucrose. 90 % of recruited patients were females. The dosing of Iron (III) Isomaltoside 1000 Solution for Injection was performed according to the Simplified Table as described in 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/dL from baseline at any time between weeks 1 to 5. A higher proportion of patients treated with Iron (III) Isomaltoside 1000 Solution for Injection compared to iron sucrose reached the primary endpoint, 68.5% vs 51.6%, respectively.(FAS, p < 0.0001).
Nephrology
Non-dialysis-dependent chronic kidney disease
The Iron (III) Isomaltoside 1000 Solution for Injection-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 Iron (III) Isomaltoside 1000 Solution for Injection or oral iron sulphate administered as 100 mg elemental oral iron twice daily (200 mg daily) for 8 weeks. The patients in the Iron (III) Isomaltoside 1000 Solution for Injection group were randomized to infusion of 1000 mg single dose or bolus injections of 500 mg.Iron (III) Isomaltoside 1000 Solution for Injection 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).
Haemodialysis-dependent chronic kidney disease
The Iron (III) Isomaltoside 1000 Solution for Injection-CKD-03 trial was an open-label, comparative, randomised, multi- centre, non-inferiority trial conducted in 351 haemodialysis patients randomised 2:1 to either Iron (III) Isomaltoside 1000 Solution for Injection or iron sucrose. Patients were randomised to either a single injection of 500 mg or 500 mg in split doses of Iron (III) Isomaltoside 1000 Solution for Injection 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 Iron (III) Isomaltoside 1000 Solution for Injection-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 Iron (III) Isomaltoside 1000 Solution for Injection or oral iron sulphate administered as 100 mg elemental oral iron twice daily (200 mg daily) for 12 weeks. The patients in the Iron (III) Isomaltoside 1000 Solution for Injection 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. Iron (III) Isomaltoside 1000 Solution for Injection 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 Iron (III) Isomaltoside 1000 Solution for Injection.
Gastroenterology
Inflammatory bowel disease
The P-Iron (III) Isomaltoside 1000 Solution for Injection-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 Iron (III) Isomaltoside 1000 Solution for Injection or oral iron sulphate administered as 100 mg elemental oral iron twice daily for 8 weeks (200 mg daily). The patients in the Iron (III) Isomaltoside 1000 Solution for Injection 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/dL 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 dose-response relationship observed with Iron (III) Isomaltoside 1000 Solution for Injection suggests that the true iron demand of IV iron was underestimated by the modified Ganzoni formula. The Hb response rate was 93% for patients receiving > 1000 mg Iron (III) Isomaltoside 1000 Solution for Injection.
Women’s health
Postpartum
The Iron (III) Isomaltoside 1000 Solution for Injection-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 within 48 hours after delivery. The women were randomised 1:1 to receive either a single dose of 1200 mg Iron (III) Isomaltoside 1000 Solution for Injection 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 Iron (III) Isomaltoside 1000 Solution for Injection.
Pharmacokinetic properties
The Iron (III) Isomaltoside 1000 Solution for Injection 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 Iron (III) Isomaltoside 1000 Solution for Injection 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, Iron (III) Isomaltoside 1000 Solution for Injection is not eliminated via the kidneys. Small quantities of iron are eliminated in urine and faeces.
Isomaltoside 1000 is either metabolised or excreted.
INDICATION AND USAGE
Treatment of iron deficiency anaemia in the following conditions:
• When oral iron preparations are ineffective or cannot be used;
• Where there is a clinical need to deliver iron rapidly.
The diagnosis of iron deficiency anaemia should be based on appropriate laboratory tests
(e.g. serum ferritin, serum iron, transferrin saturation or hypochromic red cells).
CONTRA-INDICATION
-
Hypersensitivity to the active substance, to Iron (III) Isomaltoside 1000 Solution for Injection or any of its excipients listed.
-
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
DRUG INTERACTIONS
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 Iron (III) Isomaltoside 1000 Solution for Injection.
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.
WARNINGS AND PRECAUTIONS
Parenterally administered iron preparations can cause hypersensitivity reactions including serious and potentially fatal anaphylactic/anaphylactoid reactions.
Hypersensitivity reactions have also been reported after previously uneventful doses of parenteral iron complexes.
The risk is enhanced for patients with known allergies including drug allergies, including patients with a history of severe asthma, eczema or other atopic allergy.
There is also an increased risk of hypersensitivity reactions to parenteral iron complexes in patients with immune or inflammatory conditions (e.g. systemic lupus erythematosus, rheumatoid arthritis).
Iron (III) Isomaltoside 1000 Solution for Injection 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 Iron (III) Isomaltoside 1000 Solution for Injection 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.
Iron (III) Isomaltoside 1000 Solution for Injection 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 Iron (III) Isomaltoside 1000 Solution for Injection. Paravenous leakage of Iron (III) Isomaltoside 1000 Solution for Injection 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 Iron (III) Isomaltoside 1000 Solution for Injection must be stopped immediately.
SIDE EFFECTS
The table presents the adverse drug reactions (ADRs) reported during Iron (III) Isomaltoside 1000 Solution for Injection 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.
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.
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) |
|
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 |
|
|
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 |
Pruritus, urticaria, rash, flushing, sweating, dermatitis |
Angioedema |
|
|
Metabolismand nutritional disorders |
Hypophosphataemia |
||
|
Musculoskeletal and connective tissue disorders |
Back pain, myalgia, arthralgia, muscle spasms |
||
|
General disorders and administration site conditions Investigations |
Injection site reactions* |
Pyrexia, chills/shivering, infection, local phlebitic reaction Hepatic enzyme increased |
Malaise, influenza like symptoms |
* 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.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
No studies on the effects on the ability to drive and use machines have been performed.
OVERDOSE
The Iron (III) Isomaltoside 1000 Solution for Injection 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.
DOSAGE & MODE OF ADMINISTRATION
The dose and dosage schedule for iron isomaltoside 1000 must be individually established for each patient based on a calculation of the total iron deficit. The optimal haemoglobin target level may vary in different patient groups.
Intravenous bolus injection: Iron isomaltoside 1000 may be administered as a 100 to 200mg intravenous bolus injection up to three times a week at an administration rate of up to 50mg iron/minute. It may be diluted in 10 to 20mL sterile 0.9% sodium chloride.
Total dose infusion (TDI): Iron isomaltoside 1000 may be administered as a total dose infusion in which the total iron dose is given in a single infusion. Iron isomaltoside 1000 given as total dose infusion is administered as a single dose of up to 20mg iron/kg body weight as an intravenous drip infusion. The intravenous administration of iron isomaltoside 1000 by the total dose infusion method should be restricted to hospital use only. Intravenous drip infusion: Iron isomaltoside 1000 may be administered in doses of 200 to 1,000mg once every week until the total iron dose has been administered.
PREGNANCY AND LACTATION
Pregnancy
There are no adequate and well-controlled trials of Iron (III) Isomaltoside 1000 Solution for Injection in pregnant women. A careful risk/benefit evaluation is therefore required before use during pregnancy and Iron (III) Isomaltoside 1000 Solution for Injection 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 Iron (III) Isomaltoside 1000 Solution for Injection 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.
Breast-feeding
A clinical study showed that transfer of iron from Iron (III) Isomaltoside 1000 Solution for Injection to human milk was very low. At therapeutic doses of Iron (III) Isomaltoside 1000 Solution for Injection no effects on the breastfeed newborns/infants are anticipated.
Fertility
There are no data on the effect of Iron (III) Isomaltoside 1000 Solution for Injection on human fertility. Fertility was unaffected following Iron (III) Isomaltoside 1000 Solution for Injection treatment in animal studies.
STORAGE CONDITION
Protect from light. Do not store above 30 °C.
Do not freeze.
KEEP OUT OF REACH OF CHILDREN
PRESENTATION
5ml Vial packed in cardboard carton along with pack insert.
MANUFACTURED IN INDIA
INDUS PHARMA PRIVATE LIMITED
A 181, RIICO Ghiloth, Alwar, Rajasthan 301705
A WHO GMP Certified Company