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MONOFERRIC (ferric derisomaltose [also known as iron isomaltoside 1000])
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MONOFERRIC® (ferric derisomaltose for injection) is indicated for:
- the treatment of iron deficiency anemia in adult patients who have intolerance or unresponsiveness to oral iron therapy.
The diagnosis must be based on laboratory tests.
Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
A careful risk benefit assessment is required before MONOFERRIC is used in patients aged > 65 years and close monitoring for adverse events is required (see 7 WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics).
MONOFERRIC is contraindicated in the following situations:
- Patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
- Patients who are hypersensitive to this drug or any of the excipients. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING
- Known serious hypersensitivity to other parenteral iron products
- Non-iron deficiency anaemia (e.g. hemolytic anaemia)
- Iron overload or disturbances in utilization of iron (e.g. hemochromatosis, hemosiderosis)
- Decompensated liver cirrhosis or active hepatitis
3 Serious Warnings and Precautions Box
Serious Warnings and Precautions
MONOFERRIC is contraindicated in patients with any allergy to this drug or known serious hypersensitivity to other parenteral iron products.
The following are clinically significant adverse events:
- Serious hypersensitivity reactions including life threatening and fatal anaphylaxis/anaphylactoid reactions have been reported in patients receiving intravenous iron products including MONOFERRIC (see Immune, Hypersensitivity below).
- Serious cases of hypotension (see Cardiovascular below).
MONOFERRRIC should only be administered when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions (see Immune, Hypersensitivity below).
Patients should be carefully monitored for signs and symptoms of hypersensitivity reactions including monitoring of blood pressure and pulse during and for at least 30 minutes following each administration of MONOFERRIC.
4 Dosage and Administration
4.1 Dosing Considerations
- The dose of MONOFERRIC (ferric derisomaltose for injection) is expressed in terms of mg of elemental iron, with each mL of undiluted MONOFERRIC containing 100 mg of elemental iron.
- The patient’s total body iron deficit (cumulative amount of iron needed to replete body iron stores and correct IDA) is not the same as the allowable iron dose per infusion which is limited to 20 mg iron/kg body weight with MONOFERRIC. The optimal hemoglobin (Hb) target level and iron stores may vary in different patient groups and between patients. Iron deficiency anemia will not appear until essentially all iron stores have been depleted. Iron therapy should therefore replenish both hemoglobin iron and iron stores.
4.2 Recommended Dose and Dosage Adjustment
- The iron dose and administration schedule for MONOFERRIC must be individually established for each patient, with allowance for clinical judgement. Clinicians may choose between calculating the cumulative dose for iron repletion based on patient’s Hb and body weight based on the Simplified Table or Ganzoni formula, or treating with a fixed dose (repeated dose might be needed if the patient requires further iron repletion).
1. Treatment approach based on calculating total body iron deficit
The posology of MONOFERRIC can follow a stepwise approach:  determination of the individual iron need  calculation and administration of the iron dose(s),  post-iron repletion assessments.
Step 1: Determination of the iron need:
The cumulative iron need can be determined using either the Simplified Table (i) or the Ganzoni formula below (ii). In the clinical studies with CKD patients, the Ganzoni formula was used and in the clinical study with IDA patients of various causes other than CKD, the Simplified table was used.
The iron need is expressed in mg elemental iron.
i. Simplified Table:
|Hb (g/dL)||Patients with|
bodyweight <50 kg
|Patients with bodyweight|
50 kg to <70 kg
|Patients with bodyweight|
|≥10||500 mg||1000 mg||1500 mg|
|<10||500 mg||1500 mg||2000 mg|
ii. Ganzoni formula:
|=||Body weight(A)||x||(Target Hb(D) – Actual Hb)(B)||x||2.4||+||Iron for iron stores(C)|
|[mg iron]||[kg]||[g/dl]||[mg iron]|
Step 2: Calculation and administration of the maximum individual iron dose(s):
Based on the iron need determined above the appropriate dose(s) of MONOFERRIC should be administered taking into consideration the following:
A single MONOFERRIC infusion should not exceed 20 mg iron/kg body weight. Single doses above 1500 mg are not recommended.
Step 3: Post-iron repletion assessments:
Re-assessment should be performed by the clinician based on the individual patient's condition. The Hb level should be re-assessed no earlier than 4 weeks post final MONOFERRIC 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.
2. Fixed dose approach
For both NDD-CKD patients and patients of various causes other than CKD with IDA receiving an IV infusion weighing more than 50 kg, a fixed dose of 1000 mg can be given, and the patient is re-evaluated for further iron need. Re-assessment should be performed by the clinician based on the individual patient's condition. The Hb level should be re-assessed no earlier than 4 weeks post MONOFERRIC administration to allow adequate time for erythropoiesis and iron utilisation. For patients weighing less than 50 kg, MONOFERRIC should be administered as 20 mg/kg actual body weight.
MONOFERRIC can be administered either as an intravenous drip infusion, as an intravenous bolus injection, or as a direct injection into the venous limb of the dialyzer.
Inspect vials visually for sediment and damage before use. Use only those containing sediment-free, homogeneous solution. The reconstituted solution for injection should be visually inspected prior to use. Use only clear solutions without sediment.
MONOFERRIC should only be administered when personnel trained to evaluate and manage anaphylactic reactions are immediately available, in an environment where full resuscitation facilities can be assured. Monitor patients carefully for signs and symptoms of hypersensitivity reactions during and following each administration of MONOFERRIC. The patient should be observed for adverse effects for at least 30 minutes following each MONOFERRIC administration (see 7 WARNINGS AND PRECAUTIONS, Immune, Hypersensitivity and Monitoring and Laboratory Tests).
Each IV iron administration is associated with a risk of a hypersensitivity reaction. Thus, to minimize risk the number of single IV iron administrations should be kept to a minimum.
Intravenous drip infusion:
The MONOFERRIC dose required may be administered in a single infusion up to 20 mg iron/kg body weight or as weekly infusions until the cumulative iron need has been addressed. Single doses above 1500 mg are not recommended.
If the cumulative iron need exceeds 20 mg iron/kg body weight, the dose must be split into 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.
|MONOFERRIC dose||Minimum administration time|
MONOFERRIC must only be diluted in sterile 0.9 % sodium chloride solution. For stability reasons, MONOFERRIC 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 sterile 0.9 % sodium chloride. When diluting, there is no lower volume limit of 0.9 % sodium chloride solution.
Intravenous bolus injection:
MONOFERRIC may be administered as an intravenous bolus injection up to 500 mg up to once 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.
|Equivalent iron dose||Administration rate /|
|≤5 mL||≤500 mg||250 mg iron/minute||1 time a week|
Injection into dialyzer:
MONOFERRIC may be administered during a hemodialysis session directly into the venous limb of the dialyzer under the same procedures as outlined for intravenous bolus injection.
Overdose may lead to accumulation of iron in storage sites eventually leading to hemosiderosis. Monitoring of iron parameters such as serum ferritin may assist in recognizing iron accumulation. Supportive measures such as chelating agents can be used.
Do not administer MONOFERRIC to patients with iron overload. See 2 CONTRAINDICATIONS.
6 Dosage Forms, Strengths, Composition and Packaging
Table 1: Dosage Forms, Strengths, Composition and Packaging
Route of Administration
Dosage Form / Strength / Composition
100 mg/mL elemental iron (as ferric derisomaltose)
hydrochloric acid, sodium hydroxide, water for injection
MONOFERRIC (ferric derisomaltose [also known as iron isomaltoside 1000] for injection) is a dark brown, non-transparent, sterile aqueous colloidal preservative-free solution. Each mL of MONOFERRIC contains the equivalent of 100 mg of elemental iron in Water for Injection (WFI). Hydrochloric acid and sodium hydroxide may be added to adjust the pH.
MONOFERRIC is available in glass single use vials.
MONOFERRIC is available in the following formats:
Single dose vial size
Number of vials per box
7 Warnings and Precautions
Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX
Excessive therapy with parenteral iron can lead to excess storage of iron and possible iatrogenic hemosiderosis. Do not administer MONOFERRIC to patients with iron overload (see 2 CONTRAINDICATIONS).
Carcinogenesis and Mutagenesis
Carcinogenicity studies have not been conducted. MONOFERRIC showed no evidence of genotoxicity or mutagenicity in a standard battery of tests. These included an in vitro Ames test with and without metabolic activation, an in vitro human lymphocyte chromosome aberration test with and without metabolic activation and an in vivo mouse micronucleus test.
In clinical studies hypotension was reported in 0.7 % (29/3922) of patients, including serious events in 0.03 % (1/3922) of patients who received MONOFERRIC. Hypotension has also been reported in the post-marketing experience. Hypotensive episodes may occur if intravenous injection is administered too rapidly. Observe patients for signs and symptoms of hypersensitivity including hypotension during and for at least 30 minutes following each administration.
MONOFERRIC is contraindicated in patients with decompensated liver cirrhosis or active hepatitis (see 2 CONTRAINDICATIONS). 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.
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. MONOFERRIC is contraindicated in patients with known serious hypersensitivity to other parenteral iron products (see 2 CONTRAINDICATIONS).
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).
MONOFERRIC may cause life-threatening and fatal hypersensitivity reactions, including anaphylaxis and/or anaphylactoid reactions. In clinical trials, severe or serious hypersensitivity reactions were reported in 0.7% (28/3922) of patients who received MONOFERRIC and 0.2 % (8/3922) of these patients reported a severe or serious hypersensitivity reaction within 1 day of dosing. Hypersensitivity reactions have been seen in spontaneously reported adverse events from post-marketing experience (see 8 ADVERSE REACTIONS, Post-market Adverse Reactions).
Fishbane reaction is an infusion reaction characterised by flushing in the face, acute chest and/or back pain and tightness sometimes with dyspnoea that may occur with IV iron treatment (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.
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.
MONOFERRIC should only be administered when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitive reactions. Observe patients for signs and symptoms of hypersensitivity during and for at least 30 minutes following each administration of MONOFERRIC. If hypersensitivity reactions or signs of intolerance occur during administration, the treatment must be stopped immediately.
There is a risk that iron preparations enhance bacterial growth and inhibit leucocyte function and phagocytosis. Parenteral iron should be used with caution in case of severe acute or chronic infection. In patients with chronic infection a risk/benefit evaluation has to be performed, taking into account the suppression of erythropoiesis. MONOFERRIC should not be used in patients with ongoing bacteraemia.
Monitoring and Laboratory Tests
Patients must have confirmed iron deficiency anemia (IDA) based on appropriate laboratory tests before treatment (see 7 WARNINGS AND PRECAUTIONS, General).
Regularly monitor the haematologic response and iron parameters, such as serum ferritin and transferrin saturation, during parenteral iron therapy. Monitoring of iron parameters such as serum ferritin may assist in recognizing iron accumulation.
Monitor patient’s blood pressure and heart rate for signs and symptoms of hypotension before, during and for 30 minutes after each MONOFERRIC administration. Each patient should be observed for adverse effects, including signs and symptoms of hypersensitivity reactions (e.g., urticaria, oedema, bronchospasm, hypotension, cardiorespiratory arrest, syncope, unresponsiveness, or loss of consciousness) during administration and for at least 30 minutes following each MONOFERRIC administration. If hypersensitivity reactions or signs of intolerance occur during administration, the treatment must be stopped immediately.
In clinical trials the frequencies of a transient drop in phosphate below 2 mg/dL have been 5 20 % in patients treated with MONOFERRIC from the studies in patients with iron deficiency anemia (IDA) of various aetiologies and 1-2 % in studies with chronic kidney disease (CKD) patients. Nadir was in the first weeks. No clinical symptoms were reported. One of the risks with profound hypophosphataemia is osteomalacia which has been reported after repeated use of IV iron. No cases of osteomalacia after MONOFERRIC use have been received.
Reproductive Health: Female and Male Potential
MONOFERRIC did not affect fertility in male or female rats when administered intravenous (IV) at up to 19 mg/kg/day in males and 32 mg/kg/day in females (3 and 2.5 times the maximum recommended human (2000 mg in a 70 kg human) exposure from a single course of MONOFERRIC). Degenerative changes of the male reproductive system of unknown reversibility were observed in male rats at 80 mg/kg/day thrice weekly (5 times the maximum recommended human exposure from a single course of MONOFERRIC) (see 16 NON-CLINICAL TOXICOLOGY).
MONOFERRIC should be administered with caution to avoid paravenous leakage during administration. Paravenous leakage may lead to irritation of the skin and long-lasting brown discoloration at the injection site. In case of paravenous leakage, the administration of MONOFERRIC must be stopped immediately. Distant skin discolouration has also been reported.
7.1 Special Populations
7.1.1 Pregnant Women
There are no studies of MONOFERRIC in pregnant women.
Based on findings in nonclinical studies, MONOFERRIC should not be used during pregnancy; if pregnancy occurs, the patients should be informed of the potential risk. MONOFERRIC should not be used in women of childbearing potential not using adequate contraception.
Administration of ferric derisomaltose in pregnant rats at IV doses of 11 and 32 mg Fe/kg/day for 14 days prior to cohabitation and 17 days during gestation (2 and 6 times the maximum recommended human (2000 mg in a 70 kg human) exposure from a single course of MONOFERRIC) resulted in an increase in the incidence of skeletal developmental delays (see 16 NON-CLINICAL TOXICOLOGY).
In pregnant rabbits, administration of 43 mg Fe/kg/day ferric derisomaltose for 14 days (7 times the maximum recommended human exposure from a single course of MONOFERRIC) resulted in an increased mortality, abortion, and/or premature delivery, a higher mean litter proportion of postimplantation loss, a corresponding lower mean number and litter proportion of viable fetuses, and lower mean fetal weights. Fetal malformations indicating teratogenicity were noted in the 25 and 43 mg Fe/kg/day groups (4 and 7 times the maximum recommended human exposure from a single course of MONOFERRIC, respectively), and fetal developmental variations were noted in the 43 mg Fe/kg/day (see 16 NON-CLINICAL TOXICOLOGY).
Fetal bradycardia may occur following administration of parenteral irons. It is usually transient and a consequence of a hypersensitivity reaction in the mother. Patients should be advised of the potential risk to the fetus. If intravenous administration of MONOFERRIC to a pregnant woman occurs, the unborn baby should be carefully monitored.
The available data on the use of MONOFERRIC in lactating women demonstrate that iron is present in breast milk. However, the data do not inform the potential exposure of iron for the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for MONOFERRIC in addition to any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition (see 10 CLINICAL PHARMACOLOGY). Monitor breastfed children for gastrointestinal toxicity (constipation, diarrhea).
Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
Clinical studies with MONOFERRIC have not identified differences in adverse reactions between elderly and younger adult patients, but there was a higher percentage of patients experiencing serious adverse events (SAEs) and adverse events (AEs) leading to fatal outcome in patients ≥ 65 years (SAEs: < 65 years at 5 %, ≥ 65 years at 11 %; AEs leading to fatal outcome: < 65 years at < 1 %, ≥ 65 years at 1 %). A careful risk benefit assessment is required before MONOFERRIC is used in patients aged > 65 years and close monitoring for adverse events is required.
8 Adverse Reactions
8.1 Adverse Reaction Overview
In phase II and III clinical trials, 3922 patients were treated with MONOFERRIC. 1638 (42 %) patients reported a total of 3622 adverse events (AEs). The most common treatment-emergent adverse events (TEAEs) (all causality) reported in more than 5 % of patients by preferred term were constipation (63 (2 %)), diarrhoea (71 (2 %)), dizziness (59 (2 %)) headache (92 (2 %)), nasopharyngitis (80 (2 %)) and nausea (97 (2%)).
Of the 3622 AEs, 346 serious adverse events (SAEs) were reported in 273 patients (7 %). No treatment-emergent SAEs were reported in > 1 % in patients treated with MONOFERRIC. The most common SAE was pneumonia (11 patients) and congestive heart failure (10 patients).
In the 3922 patients treated with MONOFERRIC, a total of 17 SARs reported in 16 patients (< 1 %) were considered as probably or possibly related to MONOFERRIC (all whom recovered). These were anaphylactic reaction, staphylococcal sepsis, angina unstable, generalized tonic-clonic seizure, dyspnea, rash pruritic, syncope, and eight cases of hypersensitivity, acute myocardial infarction, and infusion related reaction.
Of the 3922 patients treated with MONOFERRIC in clinical trials, 65 (2 %) patients experienced TEAEs leading to withdrawal from study.
Overall in clinical trials, a total of 28/3922 (0.7 %) patients reported a serious or severe hypersensitivity reaction, in which 8 of these cases occurred within one day of dosing with MONOFERRIC.
8.2 Clinical Trial Adverse Reactions
Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials, therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.
Across five randomized clinical trials a total of 2799 patients received MONOFERRIC.
Iron Deficiency Anemia (IDA) Studies:
In Study IDA-01, a total of 333 patients with IDA of various causes other than CKD were exposed to MONOFERRIC, of which, 32 (9.6 %) received a cumulative dose of 1000 mg, 164 (49.2 %) received a cumulative dose of 1500 mg, and 130 (39.0 %) received a cumulative dose of 2000 mg. Seven (2.1 %) patients were listed as receiving ‘other’ cumulative dose. MONOFERRIC was administered either as an IV infusion of 1000 mg over approximately 15 minutes or as an IV injection of 500 mg over 2 minutes per week, for an individual dose up to a maximum cumulative dose of 2000 mg. A total of 168 patients received 200 mg of IV iron sucrose by infusion up to twice weekly up to a cumulative dose of 2000 mg.
In Study IDA-03, a total of 989 patients with IDA of various causes were exposed to MONOFERRIC, which was administered as an IV infusion of a single fixed 1000 mg dose over 20 minutes. A total of 494 patients received iron sucrose administered as 200 mg IV injections repeated up to five times for a cumulative dose of 1000 mg. A total of three serious or severe hypersensitivity reactions occurred in 3/989 (0.3%; 95% CI 0.06; 0.88) patients in the MONOFERRIC group. The number of patients with adjudicated cardiovascular adverse events was 0.8% in the MONOFERRIC group.
Non-Dialysis-Dependent Chronic Kidney (NDD-CKD) Disease
A total of 228 non dialysis dependent patients with CKD (NDD-CKD) were exposed to MONOFERRIC in Study CKD-02. MONOFERRIC was administered either as IV infusions or IV bolus injections. The infusion was given in weekly doses for up to 2 weeks, to a maximum of 1000 mg iron each week until full replacement dose was achieved. The dose was diluted in 100 mL 0.9 % sodium chloride and given over approximately 15-20 minutes. Bolus injections of 500 mg were administered undiluted over approximately 2 minutes, once per week until full replacement dose was achieved. Oral iron was administered as 200 mg iron sulphate daily for 8 weeks. The mean cumulative dose of MONOFERRIC administered to the patients in the infusion and bolus subgroups were 907 ± 170 mg (range: 750:1500 mg) and 926 ± 241 mg (range: 500:2000 mg), respectively. The mean cumulative dose of MONOFERRIC was 916 ± 208 mg (range: 500:2000 mg).
In Study CKD-04, a total of 1019 non-dialysis dependent CKD (NDD-CKD) patients were exposed to MONOFERRIC, which was administered as an IV infusion of a single fixed 1000 mg dose over 20 minutes. A total of 506 patients received iron sucrose administered as 200 mg IV injections repeated up to five times for a cumulative dose of 1000 mg. A total of three serious or severe hypersensitivity reactions occurred in 3/1019 (0.3%; 95% CI 0.06; 0.86) patients in the MONOFERRIC group. The incidence of adjudicated and confirmed composite cardiovascular AEs in the MONOFERRIC group was 4.1%.
Dialysis-Dependent Chronic Kidney Disease (DD-CKD) Studies
In Study CKD-03, a total of 230 hemodialysis-dependent CKD (DD-CKD) patients were exposed to MONOFERRIC, of which, 114 (50 %) received a dose of 500 mg by IV single bolus injection and 116 (50 %) received a total dose of 500 mg as fractionated (100 mg + 200 mg + 200 mg) IV bolus injections. A total of 117 patients received 500 mg of IV iron sucrose administered as 500 mg fractionated (100 mg + 200 mg + 200 mg) IV bolus injections.
|Iron Deficiency Anemia|
|Chronic Kidney Disease|
|Chronic Kidney Disease|
|Chronic Kidney Disease|
|iron sucrose||ferric derisomaltose||iron sucrose|
|N [%]||N [%]||N [%]||N [%]||N [%]||N [%]||N [%]||N [%]|
|Safety Analysis Set||1322||662||228||117||230||114||1019||506|
|Any AE(s)||460 (35%)||208 (31%)||95 (42%)||53 (45%)||110 (48%)||47 (41%)||335 (33%)||168 (33%)|
|Infections and infestations||97 (7%)||41 (6%)||25 (11%)||12 (10%)||22 (10%)||15 (13%)||81 (8%)||40 (8%)|
|- Nasopharyngitis||19 (1%)||5 (<1%)||7 (3%)||4 (3%)||6 (3%)||1 (<1%)||10 (<1%)||2 (<1%)|
|- Urinary tract infection||19 (1%)||8 (1%)||4 (2%)||1 (<1%)||25 (2%)||16 (3%)|
|- Lower respiratory tract infection||1 (<1%)||1 (<1%)||4 (2%)||3 (3%)||2 (<1%)|
|Gastrointestinal disorders||128 (10%)||59 (9%)||22 (10%)||15 (13%)||19 (8%)||6 (5%)||58 (6%)||24 (5%)|
|- Faeces discoloured||4 (<1%)||5 (4%)||1 (<1%)|
|- Nausea||48 (4%)||23 (3%)||2 (<1%)||2 (2%)||1 (<1%)||16 (2%)||7 (1%)|
|- Diarrhoea||17 (1%)||9 (1%)||7 (3%)||4 (3%)||5 (2%)||2 (2%)||15 (1%)||7 (1%)|
|- Vomiting||15 (1%)||11 (2%)||6 (3%)||1 (<1%)||3 (1%)||2 (2%)||10 (<1%)||5 (<1%)|
|Injury, poisoning and procedural complications||21 (2%)||19 (3%)||2 (<1%)||25 (11%)||9 (8%)||16 (2%)||19 (4%)|
|- Fall||2 (<1%)||1 (<1%)||1 (<1%)||7 (3%)||3 (<1%)||9 (2%)|
|- Procedural hypotension||5 (2%)||1 (<1%)|
|General disorders and administration site|
|87 (7%)||48 (7%)||23 (10%)||9 (8%)||10 (4%)||5 (4%)||40 (4%)||26 (5%)|
|- Pyrexia||15 (1%)||4 (<1%)||7 (3%)||4 (3%)||1 (<1%)||3 (<1%)||2 (<1%)|
|- Oedema peripheral||8 (<1%)||1 (<1%)||5 (2%)||2 (2%)||13 (1%)||5 (<1%)|
|Nervous system disorders||83 (6%)||62 (9%)||14 (6%)||6 (5%)||13 (6%)||6 (5%)||35 (3%)||22 (4%)|
|- Headache||40 (3%)||25 (4%)||2 (<1%)||2 (2%)||7 (3%)||4 (4%)||9 (<1%)||10 (2%)|
|- Dizziness||32 (2%)||18 (3%)||5 (2%)||1 (<1%)||5 (<1%)||8 (2%)|
|- Dysgeusia||3 (<1%)||15 (2%)||1 (<1%)||3 (<1%)||1 (<1%)|
|Metabolism and nutrition disorders||24 (2%)||8 (1%)||12 (5%)||2 (2%)||8 (3%)||8 (7%)||62 (6%)||30 (6%)|
|- Hyperphosphataemia||1 (<1%)||1 (<1%)||5 (2%)||4 (4%)||5 (<1%)||1 (<1%)|
|- Hyperkalaemia||4 (<1%)||1 (<1%)||6 (3%)||1 (<1%)||1 (<1%)||25 (2%)||9 (2%)|
|Musculoskeletal and connective tissue disorders||66 (5%)||27 (4%)||10 (4%)||3 (3%)||16 (7%)||1 (<1%)||32 (3%)||15 (3%)|
|- Back pain||17 (1%)||4 (<1%)||5 (2%)||7 (<1%)||3 (<1%)|
|- Pain in extremity||7 (<1%)||7 (1%)||1 (<1%)||1 (<1%)||5 (2%)||3 (<1%)||4 (<1%)|
|Skin and subcutaneous tissue disorders||89 (7%)||14 (2%)||10 (4%)||1 (<1%)||26 (3%)||11 (2%)|
|- Rash||35 (3%)||4 (<1%)||2 (<1%)||11 (1%)||2 (<1%)|
|Cardiac disorders||12 (<1%)||9 (1%)||6 (3%)||3 (3%)||31 (3%)||29 (6%)|
|- Cardiac failure congestive||1 (<1%)||1 (<1%)||1 (<1%)||8 (<1%)||11 (2%)|
|Investigations||48 (4%)||25 (4%)||11 (5%)||5 (4%)||46 (5%)||28 (6%)|
|- C-reactive protein increased||5 (<1%)||3 (<1%)||6 (3%)||1 (<1%)||1 (<1%)|
|Vascular disorders||34 (3%)||19 (3%)||8 (4%)||4 (3%)||8 (3%)||1 (<1%)||29 (3%)||19 (4%)|
|- Hypertension||13 (<1%)||6 (<1%)||7 (3%)||2 (2%)||3 (1%)||1 (<1%)||14 (1%)||13 (3%)|
8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data
Clinical trial findings
In Study IDA-01, 65 (19.5 %) patients in the MONOFERRIC group and 7 (4.2 %) patients in the iron sucrose group had serum phosphate (s-phosphate) level < 2 mg/dL. Hypophosphataemia defined as s-phosphate < 2 mg/dL was reported in 3 patients in CKD-02 and 4 patients in CKD‑03 (1.3 % and 1.7 %, respectively) in the MONOFERRIC group compared to 1 patient (< 1 %) in the oral iron sulfate group in Study CKD-02 and 2 patients (1.8 %) in the iron sucrose group in Study CKD-03.
One (1) patient treated with MONOFERRIC had s-phosphate level < 1 mg/dL (0.8 mg/dL) at week 4 which was normalised (2.6 mg/dL) at the following visit in Study IDA-01. Two patients in the MONOFERRIC group had s-phosphate level < 1 mg/dL in Study CKD-03 and none in Study CKD-02.
Most patients exposed to MONOFERRIC had low s-phosphate values for 1-4 weeks and 7 (2.2 %) patients had s-phosphate < 2 mg/dL at week 5 in Study IDA-01. In the iron sucrose group, most patients had low s-phosphate values for 1-2 weeks and 1 patient had s-phosphate < 2 mg/dL at week 5. Thus, the hypophosphataemia events were transient and, in most cases, normalised at the end of the trial.
No event of hypophosphataemia was considered as an AE in both Study CKD-02 and CKD-03 but was reported as an AE in Study IDA-01 in 6 (2 %) patients.
8.5 Post-Market Adverse Reactions
Because these adverse events are spontaneously reported in a voluntary manner from a population of uncertain size, it is not possible to reliably estimate their frequency. The following adverse reactions have been reported from the post-marketing spontaneous reports with MONOFERRIC:
Fetal bradycardia due to maternal hypersensitivity reactions, cardiac arrest, tachycardia
General disorders and administration site conditions:
Asthenia, chest discomfort, chest pain, chills, feeling abnormal, feeling hot, Fishbane reaction, influenza like illness, infusion site erythema, injection site discolouration, injection site extravasation, pain, pyrexia
Immune system disorders:
Hypersensitivity, anaphylactic and anaphylactoid reactions, including very rare cases of anaphylactic shock with a fatal outcome, have been reported
Blood pressure decreased, blood pressure increased, body temperature increased
Musculoskeletal and connective tissue disorders:
Joint swelling, pain in extremity
Nervous system disorders:
Burning sensation, cerebrovascular accident, generalized tonic-clonic seizure, head discomfort, loss of consciousness, paraesthesia, seizure, syncope, tremor
Respiratory, thoracic and mediastinal disorders:
Asphyxia, bronchospasm, pharyngeal edema, respiratory arrest, respiratory distress, wheezing
Skin and subcutaneous tissue disorders:
Angioedema, dermatitis allergic, erythema, generalized erythema, purpura, rash generalized, skin discolouration, swelling face, urticaria
Circulatory collapse, flushing, hypotension, shock
9 Drug Interactions
9.2 Drug Interactions Overview
As with all parenteral iron preparations the absorption of oral iron is reduced when administered concomitantly. Therefore, clinical judgment is required to consider when oral iron should be restarted.
9.3 Drug-Behavioural Interactions
No studies on the effects on the ability to drive and use machines have been performed.
9.4 Drug-Drug Interactions
Interactions with other drugs have not been established.
9.5 Drug-Food Interactions
Interactions with food have not been established.
9.6 Drug-Herb Interactions
Interactions with herbal products have not been established.
9.7 Drug-Laboratory Test Interactions
Parenteral iron may cause falsely elevated values of serum bilirubin and falsely decreased values of serum calcium.
Large doses of parenteral iron have been reported to give a brown colour to serum from a blood sample drawn four hours after administration.
10 Clinical Pharmacology
10.1 Mechanism of Action
Iron is essential to the synthesis of haemoglobin to maintain oxygen transport and to the function and formation of the physiologically important heme and non-heme compounds.
MONOFERRIC (ferric derisomaltose for injection) is a colloid with strongly bound iron in spheroidal iron-carbohydrate particles. The MONOFERRIC 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. MONOFERRIC is an iron carbohydrate complex with a matrix structure composed of alternating layers of ferric hydroxide and the carbohydrate derisomaltose. Derisomaltose consists of linear, hydrogenated isomaltooligosaccharides with an average molecular weight of 1000 Da and a narrow molecular weight distribution that is almost devoid of mono- and disaccharides.
The derisomaltose component of MONOFERRIC consists of 3-5 glucose units with an average molecular weight of approximately 1000 Da. It has no detectable branching structures as evidenced by careful 13C and 1H NMR spectroscopic analysis. Furthermore derisomaltose does not contain any reducing sugar residues, which can be involved in complex redox reactions.
The MONOFERRIC formulation contains iron in a complex with derisomaltose that releases bioavailable iron to iron-binding proteins.
Evidence of a therapeutic response can be seen within a few days of administration of MONOFERRIC as an increase in the reticulocyte count.
Serum ferritin peaks approximately 7 days after an intravenous dose of MONOFERRIC and slowly returns to stable levels after about 4 weeks.
In a subgroup of 32 patients randomised to MONOFERRIC a thorough QT monitoring of ECG was performed. Results demonstrated no effect of MONOFERRIC on QT interval durations. No clinically meaningful effect of MONOFERRIC on heart rate was observed.
MONOFERRIC pharmacokinetics was examined across four patient populations. In patients with inflammatory bowel disease (IBD), non-haematological malignancies associated with chemotherapy induced anaemia (CIA), in stage 5 chronic kidney disease on dialysis therapy and non-dialysis dependent chronic kidney disease (CKD). MONOFERRIC pharmacokinetics was examined across a dose range of 100 to 1000 mg. There is no data investigating the pharmacokinetics of single or multiple doses of MONOFERRIC above 1000 mg. There seems to be a dose-dependent increase in AUC and Cmax which is observed within all 3 patient populations; IBD, CKD, and CIA. T1/2 varies between 23.2 to 87.9 h with the highest value observed for patients dosed with 1000 mg of MONOFERRIC.
MONOFERRIC demonstrates dose proportional increases up to 500 mg. MONOFERRIC demonstrated linear pharmacokinetics up to 500 mg, with higher doses demonstrating dose dependent pharmacokinetics.
Following intravenous administration of iron complex, it is 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 RES. 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.
After administration of a single dose of MONOFERRIC of 100 to 1000 mg of iron in the 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.
Iron is not easily eliminated from the body and accumulation can be toxic. Due to the size of the complex, MONOFERRIC is not eliminated via the kidneys. Small quantities of iron are eliminated in urine and faeces.
IV iron complexes are not clinically interchangeable, as they differ in their structures, which impact their comparative pharmacokinetic profiles.
Special Populations and Conditions
- Pregnancy and Breast-feeding
In a subset of patients (n=65) in a post-partum hemorrhage study, the mean maternal milk iron level was higher in the MONOFERRIC group (72.1 μg/dL) than in the standard medical care (oral iron treatment) group (40.0 μg/dL) at day 3. However, at week 1 the mean maternal milk iron level in the MONOFERRIC group had decreased to the same level as in the standard medical care group (46.8 μg/dL and 44.2 μg/dL, respectively).
A total of 8 patients in the MONOFERRIC group had an abnormally high maternal milk iron level (i.e. > 80 μg/dL) at day 3 (81-164.4 μg/dL) compared to 1 patient in the standard medical care group (99.4 μg/dL). At week 1, the corresponding numbers were 1 patient in the MONOFERRIC group (99.8 μg/dL) and 2 patients in the standard medical care group (115.4 μg/dL).
11 Storage, Stability and Disposal
Store between 15-30 ºC. Do Not Freeze.
For storage conditions of the diluted solution, see below.
MONOFERRIC (ferric derisomaltose for injection) must be only 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 4 DOSAGE AND ADMINISTRATION.
MONOFERRIC is for single use only and any unused solution should be disposed of in accordance with local requirements.
Shelf life after first opening (undiluted):
From a microbiological point of view, the product should be used immediately.
Shelf life after dilution with sterile 0.9 % sodium chloride:
From a microbiological point of view, preparations for parenteral administration should be used immediately after dilution with sterile 0.9 % sodium chloride solution.
12 Special Handling Instructions
No special handling instructions are required for this product.
Control #: 263715
November 03, 2022
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