Regulatory Decision Summary for Monoferric

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.

Product type:


Medicinal ingredient(s):

iron isomaltoside 1000

Therapeutic area:

Antianemic Preparations

Type of submission:

New Drug Submission

Control number:

What was the purpose of this submission?


This New Drug Submission was filed to obtain approval for the new active substance, Monoferric (iron isomaltoside 1000), an intravenous iron product indicated for the treatment of iron deficiency when oral iron preparations are ineffective or cannot be used and where there is a clinical need for the rapid delivery of iron. Upon review, the proposed indication was revised and the following indication was recommended:

Monoferric (Iron Isomaltoside 1000 for Injection) is indicated for the treatment of iron deficiency anemia (IDA) in adult patients who have intolerance or unresponsiveness to oral iron therapy.


Why was the decision issued?


Data to support the efficacy and safety of Monoferric for the treatment of IDA in adult patients who have intolerance or unresponsiveness to oral iron therapy were provided in three studies: IDA-01, CKD-02 and CKD-03.

IDA-01 was a Phase III, 2:1 randomised, open-label study comparing Monoferric to intravenous iron sucrose in patients with IDA of different etiologies, including gastroenterology, gynecology, oncology and unknown or unspecified IDA. Patients enrolled in the study were intolerant or unresponsive to oral iron therapy or had a clinical need for iron to be delivered rapidly. Although iron sucrose is not approved in Canada for all-cause IDA indication, it was considered to be an appropriate comparator for this study given that it is the standard of care in this patient population. Monoferric was administered to 333 patients by intravenous (IV) infusions of 1000 mg or as IV injections of 500 mg, for up to a maximum cumulative dose of 2000 mg. IV iron sucrose was administered as recommended under its approved conditions of use by 200 mg infusion twice weekly up to a cumulative dose of 2000 mg. Monoferric increased haemoglobin (Hb) by ≥ 2 g/dL from baseline up to week 5 in more patients (68.5%) compared with the iron sucrose group (51.6%). The secondary endpoints were supportive of the superiority claim for Monoferric compared to iron sucrose (where the secondary endpoints included: median time to Hb increase ≥ 2 g/dL, change in Hb concentration from baseline, and change from baseline in the iron indices [s-ferritin and transferrin saturation (TSAT)]).

CKD-02 was a Phase III, 2:1 randomised, open-label study comparing Monoferric to oral iron sulfate 200 mg daily in non-dialysis-dependant chronic kidney disease (CKD) patients with IDA. Monoferric significantly increased Hb concentration from baseline to week 4 compared to iron sulfate (0.57 g/dL vs. 0.35 g/dL). The secondary endpoints were supportive of the results for the primary endpoint (where the secondary endpoints included: change from baseline in s-ferritin and TSAT).

The use of Monoferric in hemodialysis-dependent CKD patients was supported by the results from Study CKD-03. This was a phase III, 2:1 randomised, open-label study comparing Monoferric to intravenous iron sucrose. Treatment with Monoferric maintained Hb between 9.5 and 12.5 g/dL at week 6 in the majority (> 82 %) of patients and was determined to be non-inferior to intravenous iron sucrose. The secondary endpoints were supportive of the results for the primary endpoint (where the secondary endpoints included: s-ferritin concentration, s-iron concentration, TSAT and reticulocyte count from baseline to week 1, 2, and 4).

The efficacy of Monoferric in IDA patients with various etiologies was reinforced by 9 supporting studies that showed treatment with Monoferric to consistently improve iron stores and Hb status.

Out of 1640 patients treated with Monoferric in all of the phase II and III clinical trials, 869 (53%) patients reported a total of 2048 treatment-emergent adverse events (TEAEs). The most common TEAEs (reported in more than 3 % of patients) were headache (52 [3%]), nasopharyngitis and nausea (45 [3%] each), vomiting (43 [3%]), and constipation (41 [3%]). Of the 2048 TEAEs, 193 (9.4%) were serious adverse events (SAEs). No treatment-emergent SAEs were reported in >1% of patients treated with Monoferric. The most common SAE was pneumonia (10 patients) followed by malignant neoplasm progression (8 patients). A total of 10 SAEs reported in 9 patients (<1%) were considered as probably or possibly related to Monoferric. These SAEs included: anaphylactic reaction, staphylococcal sepsis, angina unstable, grand mal convulsion, dyspnea, rash pruritic, syncope and three cases of hypersensitivity. Of the 1640 patients treated with Monoferric in clinical trials, 43 (3%) patients experienced TEAEs leading to withdrawal from the study.

A total of 21 (1%) patients given Monoferric experienced 24 fatal adverse events (AEs) during the clinical studies; none of them were considered to be related to the study drug treatment. From the pooled safety data analysis of all the studies which had iron sucrose as the comparator, the reporting rates for AEs, SAEs, and adverse drug reactions (ADRs) were comparable between the Monoferric group and the iron sucrose group.

Hypersensitivity reaction is a known risk with all IV iron products. Overall, in the pooled clinical trial safety analysis, 15 (0.87%) patients in the Monoferric group, 3 (1.06%) patients in the IV iron sucrose group, 1 (0.30%) patient in the oral iron sulphate group, and 1 (3.33%) patient receiving placebo experienced serious or severe hypersensitivity according to the standardised MedDRA queries definition. A total of 6 (0.35%) patients in the Monoferric group and 2 (0.71%) patients in the iron sucrose group reported a serious or severe hypersensitivity reaction within one day of dosing. Based on post-market information from other jurisdictions, the number of hypersensitivity cases associated with Monoferric each year remained stable and fatal cases were very rare despite the increasing post-market patient exposure. Overall, the risk of hypersensitivity was found to be sufficiently well characterised by the current clinical trials and post-market data, and it was of comparable frequency and severity with other IV iron products authorised in Canada. The risk of hypersensitivity was also found to be adequately addressed by the following sections in the product monograph (PM): Contraindications, Serious Warnings and Precautions box and Warnings and Precautions.

Other identified risks, such as hypophosphatemia, hypotension, infection and higher frequency of serious AEs in elderly patients were adequately mitigated through sufficient labelling under the Warnings and Precautions section of the Monoferric PM. Non-clinical reports of developmental delays and malformations in rats and rabbits were also adequately addressed by the warning that Monoferric should not be used during pregnancy and that if pregnancy occurs while on treatment, the patients should be informed of the potential risk.

In conclusion, several clinical trials have shown Monoferric to have consistent efficacy and adverse events were considered to be tolerable and manageable. The overall benefit-harm-uncertainty assessment was determined to be positive, where Monoferrics benefits were found to outweigh the harms associated with the treatment of IDA in adult patients who have intolerance or unresponsiveness to oral iron therapy.

For more information on Health Canadas decision, please view the Summary Basis of Decision.


Decision issued

Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.