Summary Basis of Decision for Monoferric
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Monoferric is located below.
Recent Activity for Monoferric
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Monoferric
Updated:
The following table describes post-authorization activity for Monoferric, a product which contains the medicinal ingredient iron (supplied as iron isomaltoside 1000). For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Drug Identification Number (DIN):
- DIN 2477777 - 100 mg/mL, iron (supplied as iron isomaltoside 1000), solution, intravenous
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Drug product (DIN 02477777) market notification | Not applicable | Date of first sale:2018-10-17 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 193890 | 2016-04-28 | Issued NOC2018-06-22 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Monoferric
Date SBD issued: 2018-11-20
The following information relates to the new drug submission for Monoferric.
Iron (iron isomaltoside 1000)
100 mg/mL, solution, intravenous
Drug Identification Number (DIN):
- 02477777
Pharmacosmos A/S
New Drug Submission Control Number: 193890
On June 22, 2018, Health Canada issued a Notice of Compliance to Pharmacosmos A/S for the drug product Monoferric.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-harm-uncertainty profile of Monoferric is favourable for the treatment of iron deficiency anemia in adult patients who have intolerance or unresponsiveness to oral iron therapy.
1 What was approved?
Monoferric, a parenteral preparation of iron, was authorized for the treatment of iron deficiency anemia in adult patients who have intolerance or unresponsiveness to oral iron therapy. The diagnosis of iron deficiency anemia must be based on laboratory tests.
Clinical studies with Monoferric did not identify differences in adverse reactions between elderly and younger adult patients, but there was a higher percentage reported of patients who experienced serious adverse events and adverse events leading to fatal outcome in patients aged 65 years and over. Therefore, in patients over 65 years of age, a careful risk-benefit assessment should be conducted prior to the administration of Monoferric. In addition, close monitoring for adverse events is required.
Monoferric has not been evaluated in patients younger than 18 years of age.
Monoferric is contraindicated in:
- patients who are hypersensitive to this drug or any of the excipients
- patients with known serious hypersensitivity to other parenteral iron products
- patients with history of multiple allergies
- patients with non-iron deficiency anemia (e.g., hemolytic anemia)
- patients with iron overload or disturbances in utilization of iron (e.g., hemochromatosis, hemosiderosis)
- patients with decompensated liver cirrhosis or active hepatitis
Monoferric was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Monoferric (100 mg/mL iron, as iron isomaltoside 1000) is presented as a solution. In addition to the medicinal ingredient, the solution contains hydrochloric acid, sodium hydroxide, and water for injection.
For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Monoferric Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Monoferric approved?
Health Canada considers that the benefit-harm-uncertainty profile of Monoferric is favourable for the treatment of iron deficiency anemia in adult patients who have intolerance or unresponsiveness to oral iron therapy. The diagnosis of iron deficiency anemia must be based on laboratory tests.
Iron deficiency anemia is a condition that occurs when there is insufficient iron in the body to produce adequate amounts of hemoglobin. Hemoglobin is a protein found in red blood cells that is responsible for carrying oxygen throughout the body. When there is an iron deficiency, the body produces fewer and smaller red blood cells. This results in a reduction in the oxygen carrying capacity of the blood.
Low iron in the body can result from inadequate dietary intake, blood loss (e.g. heavy menstrual bleeding, gastrointestinal bleeding), or gastrointestinal absorption problems (e.g. celiac disease). The increased demand for iron associated with pregnancy or during growth spurts in children can also be risk factors for iron deficiency.
Symptoms of iron deficiency anemia can include fatigue, weakness, shortness of breath, headaches, and pallor. Anemia in children may result in growth and developmental delays. Severe iron deficiency anemia in pregnancy has been linked to premature births and low birth weight babies.
Iron deficiency anemia is characterized by a reduction in the blood concentration of hemoglobin. The current standard of iron deficiency anemia treatment consists of replenishing iron through oral supplements or intravenous therapy, with the treatment aim to return iron stores and hemoglobin back to normal levels (135-180 g/L for males and 120-160 g/L for females).
Oral iron therapy is the treatment of choice for the majority of iron deficiency anemia subjects because of its effectiveness, safety, and economy. However, there are patients for whom oral iron is not appropriate due to abnormal absorption, poor tolerability, or an inadequate response to therapy.
Parenteral administration of iron is preferred in patients who are unable to absorb sufficient iron in the gastrointestinal tract or those who do not tolerate sufficient amounts of oral iron; in patients in whom blood transfusions should be avoided; and in patients with chronic loss exceeding the rate of replacement possible with oral treatment.
There are currently three parenteral iron replacement products approved for use in Canada. Dexiron (iron dextran) is the only parenteral iron treatment currently available in Canada that is indicated for patients with documented iron deficiency in whom oral administration is unsatisfactory or impossible. The other two parenteral iron replacement products are Ferrlecit (sodium ferric gluconate complex in sucrose) and Venofer (iron sucrose) and are both indicated for the treatment of iron deficiency anemia in patients with chronic kidney disease. Ferrlecit is indicated in patients undergoing chronic hemodialysis who are receiving supplemental erythropoietin therapy. Venofer is indicated in the following patients: non-dialysis-dependent chronic kidney disease (NDD-CKD) patients receiving an erythropoietin, non-dialysis-dependent chronic kidney disease (NDD-CKD) patients not receiving an erythropoietin, hemodialysis dependent chronic kidney disease (HDD-CKD) patients receiving an erythropoietin, peritoneal dialysis dependent chronic kidney disease (PDD-CKD) patients receiving an erythropoietin.
Monoferric (iron isomaltoside 1000) is another parenteral iron product. It is a colloid with strongly bound iron in spheroidal iron-carbohydrate particles. It contains iron in a complex with isomaltoside 1000 that releases bioavailable iron to iron-binding proteins to form hemosiderin or ferritin. This iron replenishes hemoglobin and depleted iron stores.
Monoferric has been shown to be efficacious for the treatment of iron deficiency anemia in adult patients who have an intolerance or unresponsiveness to oral therapy. The market authorization was based on three clinical trials IDA-01, CKD-02, and CKD-03.
As for safety, Monoferric was generally well-tolerated. The most common treatment-emergent adverse events (TEAEs) reported >3% by patients were headache, nasopharyngitis, nausea, vomiting, and constipation.
Of the 2,048 adverse events reported, 193 TEAEs were serious adverse events (SAEs). Treatment-emergent SAEs were reported in 153 patients. The most common SAE was pneumonia (10 patients) followed by malignant neoplasm progression (8 patients). A total of 10 SAEs reported in 9 patients were considered as probably or possibly related to Monoferric.
Clinically significant adverse events observed with use of Monoferric included serious hypersensitivity reactions including life-threatening and fatal anaphylaxis/anaphylactoid reactions. Serious cases of hypotension have also been noted. A Serious Warnings and Precautions box describing these serious warnings has been included in the Monoferric Product Monograph.
A Risk Management Plan (RMP) for Monoferric was submitted by Pharmacosmos A/S to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Monoferric Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A Look-alike Sound-alike brand name assessment was performed and the proposed name Monoferric was accepted.
Overall, the therapeutic benefits of Monoferric therapy seen in the pivotal trials (IDA-01, CKD-02, and CKD-03) are positive and Monoferric has been shown to have a favourable benefit-harm-uncertainty profile based on non-clinical and clinical studies. The identified safety concerns can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Monoferric Product Monograph to address the identified safety concerns. Non-clinical reports of developmental delays and malformations seen in rats and rabbits were also adequately addressed by indicating 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.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Monoferric?
Monoferric (iron isomaltoside 1000 for injection) New Drug Submission was initially filed on April 28, 2016. During the review cycle, a Notice of Deficiency was issued on April 27, 2017 due to insufficient characterization of the risk of hypersensitivity in patients taking Monoferric. Other deficiencies identified included uncertainties regarding the efficacy of Monoferric due to the pivotal trials' designs, inaccurate comparative estimate of the risks compared to other IV iron products and the lack of consideration for hypophosphatemia associated with Monoferric administration. Therefore, it was determined there was insufficient efficacy and safety data to conduct an appropriate benefit-harm-uncertainty assessment. The sponsor submitted a response to the Notice of Deficiency to Health Canada on July 18, 2017. The response contained additional post-market safety information and addressed the clinical trials' shortcomings which permitted the conduct of an appropriate benefit-harm-uncertainty assessment. Following completion of the review, a Notice of Compliance was issued to the sponsor on June 22, 2018.
Submission Milestones: Monoferric
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2015-09-09 |
| Submission filed: | 2016-04-28 |
| Screening 1 | |
| Screening Deficiency Notice issued: | 2016-06-10 |
| Response filed: | 2016-07-05 |
| Screening Acceptance Letter issued: | 2016-07-13 |
| Review 1 | |
| Biostatistics Evaluation complete: | 2017-03-09 |
| Notice of Deficiency (NOD) issued by Director General, Therapeutic Products Directorate (safety issues): | 2017-04-27 |
| Response filed: | 2017-07-18 |
| Screening 2 | |
| Screening Acceptance Letter issued: | 2017-08-28 |
| Review 2 | |
| Medical Evaluation complete: | 2018-04-06 |
| Review of Risk Management Plan complete: | 2018-05-18 |
| Quality Evaluation complete: | 2018-06-21 |
| Clinical Evaluation complete: | 2018-06-21 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2018-06-21 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2018-06-22 |
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Iron is essential to the synthesis of hemoglobin to maintain oxygen transport and to the function and formation of the physiologically important heme and non-heme compounds. Use of parenteral iron is an integral component in managing iron deficiency anemia.
Monoferric is an intravenous (IV) iron product. Monoferric is a colloid with strongly bound iron in spheroidal iron-carbohydrate particles. It contains iron in a complex with isomaltoside 1000 that releases bioavailable iron to iron-binding proteins to form hemosiderin or ferritin. This iron replenishes hemoglobin and depleted iron stores.
The clinical pharmacology data included reports on the human pharmacodynamic and pharmacokinetic studies.
In a subset of patients (number 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).
Six clinical pharmacokinetic trials have been carried out with different dosages (100, 200, 250, 500, and 1,000 mg) of Monoferric in patients with inflammatory bowel disease, non-hematological malignancies associated with chemotherapy-induced anemia, in stage 5 chronic kidney disease on dialysis therapy and non-dialysis dependent chronic kidney disease. There seems to be a dose-dependent increase in the drug plasma exposure and maximum plasma concentration (Cmax) which is observed within all three patient populations: inflammatory bowel disease, non-dialysis dependent chronic kidney disease, and chemotherapy-induced anemia. The half-life of Monoferric varies between 23.2 to 87.9 hours with the highest value observed for patients dosed with 1,000 mg of Monoferric.
The clinical pharmacological data support the use of Monoferric for the recommended indication.
For further details, please refer to the Monoferric Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
Monoferric has been shown to be efficacious for the treatment of iron deficiency anemia in adult patients who have an intolerance or unresponsiveness to oral therapy. The market authorization was based on three clinical studies IDA-01, CKD-02, and CKD-03. These three Phase III studies evaluated the use of Monoferric for the treatment of iron deficiency arising from different etiologies.
Study IDA-01: Iron Deficiency Anemia
Clinical study IDA-01was a Phase III, 2:1 randomized, open-label, comparative, non-inferiority study which compared Monoferric to IV iron sucrose in patients with iron deficiency anemia and who were intolerant or unresponsive to oral iron therapy or who needed iron rapidly. Iron sucrose, although not approved in Canada for all-cause iron deficiency anemia indication, was chosen as the comparator for this study given that it is a widely used parental iron product. Iron sucrose is approved in Europe for the treatment of iron deficiency in both chronic kidney disease (CKD) and non-CKD patients.
Based on the full analysis set of 491 patients, a total of 330 patients received Monoferric and 161 patients received iron sucrose. Monoferric was administered to patients by IV infusions of 1,000 mg over approximately 15 minutes or as an IV bolus injection of maximum 500 mg over 2 minutes, for up to a maximum cumulative dose of 2,000 mg. Intravenous iron sucrose was administered as recommended under its approved conditions of use by administering a 200 mg infusion over approximately 30 minutes twice weekly, for up to a maximum cumulative dose of 2,000 mg.
The primary outcome measure of this study was to assess the proportion of patients with an Hb increase of ≥2 g/dL from baseline at any time from week 1 to week 5. 'Any time' implied that if the endpoint was met at a time-point to or at week 5, the effect (increase of ≥2 g/dL) did not have to be maintained throughout the trial in order for a patient to be a responder.
The secondary outcome measures were to assess the effect on Hb and other relevant iron related biochemical parameters, fatigue symptoms measured by the Functional Assessment of Chronic Illness Therapy scale, quality of life (measured by the short form-36 questionnaire), and safety.
Monoferric increased hemoglobin (Hb) by ≥2 g/dL from baseline up to week 5 in more patients (68.5%) compared with the iron sucrose group (51.6%). Based on this primary outcome measure, the study results showed that there were more responders in the Monoferric group compared with the iron sucrose group, with a risk difference of 16.7 % points in the full analysis set (FAS) and 15.9% points in the per protocol (PP) analysis set. Since the lower end of the 95 % confidence interval (CI) for the risk difference was above 12.5% points in both the FAS and PP analysis set, non-inferiority of Monoferric to iron sucrose could be claimed. As non-inferiority was proven, the predetermined test for superiority was performed, which also confirmed superiority of Monoferric compared with iron sucrose (p<0.0001).
The secondary endpoints were supportive of the superiority claim of Monoferric compared to iron sucrose (median time to Hb increase of ≥2 g/dL, change in Hb concentration from baseline, change from baseline in the iron indices serum ferritin and transferrin saturation [TSAT]).
Study CKD-02: Iron Deficiency Anemia in Non-dialysis-dependent Chronic Kidney Disease
Clinical study CKD-02 was a Phase III, 2:1 randomized, comparative, open-label, non-inferiority study which compared Monoferric to oral iron sulfate 200 mg daily in non-dialysis-dependant CKD patients with iron deficiency anemia.
A total of 351 patients were included in the study. Patients treated with Monoferric either received IV infusion (group A1) of maximum 1,000 mg Monoferric as single doses over 15 minutes; full iron replacement achieved by 1 or up to 2 doses at a weekly interval or IV bolus injections (group A2) of 500 mg Monoferric administered over 2 minutes once weekly until full replacement dose was achieved. The maximum dosage per infusion was 1,000 mg for patients with a weight >45 kg, 750 mg for patients with a weight between 35.1 and 45 kg, and 500 mg for patients with a weight of 30-35 kg. The maximum dose per bolus injection was 500 mg. Patients who received iron sulphate (group B) were treated daily for 8 weeks with 200 mg.
The primary outcome measure of this study was to assess the change in Hb concentration from baseline to week 4.
The secondary outcome measures included:
- Number of patients who had a change in Hb concentration ≥ 1.0 g/dL from baseline to week 4;
- Change in Hb (g/dL) from baseline to week 8;
- Change in concentrations of s-ferritin (µmol/L) from baseline to week 4;
- Change in TSAT (%) from baseline to week 4.
Based on the primary outcome measure, the study results showed that Monoferric was non-inferior to iron sulphate in its ability to increase Hb from baseline to week 4 in both the FAS and PP data sets (FAS: p = 0.039; PP: p = 0.047). In addition, the secondary endpoints were supportive of the results for the primary outcome measure.
Study CKD-03: Iron Deficiency Anemia in Hemodialysis-dependent Chronic Kidney Disease Patients
Clinical study CKD-03 was a Phase III, 2:1 randomized, open-label, non-inferiority study which compared Monoferric to IV iron sucrose. A total of 351 patients with chronic kidney disease were included in the study, 234 of whom received Monoferric administered as a single IV bolus injection of 500 mg over 2 minutes at baseline or administered in 500 mg fractionated doses of 100 mg at baseline and 200 mg each at weeks 2 and 4 as IV bolus injections over 2 minutes. A total of 117 patients received iron sucrose administered as 500 mg fractionated doses of 100 mg at baseline and 200 mg each at weeks 2 and 4 as IV bolus injections.
The primary outcome measure of this study was to assess the proportion of patients who were able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at Week 6. Hemoglobin was measured by a blood sample at the different visits. All blood samples were taken before the dialysis from the dialysis catheter. Intravenous iron was administered during dialysis, at least 30 minutes after the start and at least one hour before the end of dialysis.
The secondary outcome measures include assessment of the change in Hb concentration from baseline to week 2, 4, and 6, and change in concentration of s-iron, TSAT, s-ferritin and reticulocyte count during this time period.
Based on the primary outcome measure, the study results showed that the majority (>82%) of patients treated with either Monoferric or iron sucrose were able to maintain Hb between 9.5 and 12.5 g/dL at week 6. The test for non-inferiority showed that Monoferric was non-inferior to iron sucrose. The secondary endpoints were supportive of the results for the primary endpoint (serum ferritin concentration, serum iron and TSAT concentration, reticulocyte count from baseline to week 1, 2, and 4). The efficacy of Monoferric in the above patient populations was supported by 9 supportive clinical studies which showed consistent ability of Monoferric to improve iron stores and Hb status.
Indication
The New Drug Submission for Monoferric was filed by the sponsor with the following indication:
- Monoferric (iron isomaltoside 1000) 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
To ensure safe and effective use of the product, Health Canada approved the following indication:
- Monoferric (Iron Isomaltoside 1000 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.
The removal of the second bulleted condition from the indication was due to the unclear clinical significance of needing rapid iron delivery for a product meant to replenish iron stores, which leads to an increased hemoglobin concentration detectable two weeks after administration. It was also considered that the inclusion criterion for patients with a clinical need of rapid iron delivery was too subjective and that the number of patients included in the trials who met this inclusion criterion was very small.
For more information, refer to the Monoferric Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The evaluation of the clinical safety of Monoferric was based on pooled safety data from three Phase III clinical studies (described in the Clinical Efficacy section) in addition to several supportive Phase II studies. The pooled safety data consisted of 1,640 patients who had been exposed to Monoferric.
Out of 1,640 patients treated with Monoferric, 869 (53%) patients reported a total of 2,048 treatment-emergent adverse events (TEAEs). The most common TEAEs (reported in more than 3% of patients) were: headache, in 52 (3%) patients; nasopharyngitis and nausea, in 45 (3%) patients; vomiting, in 43 (3%) patients; and constipation, in 41 (3%) patients.
Of the 2,048 adverse events (AEs), 193 (9.4%) TEAEs were serious adverse events (SAEs). No treatment-emergent SAEs were reported in >1% in 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 were anaphylactic reaction, staphylococcal sepsis, unstable angina, grand mal convulsion, dyspnea, pruritic rash, syncope and three cases of hypersensitivity.
Of the 1,640 patients treated with Monoferric in clinical studies, 43 (3%) patients experienced TEAEs leading to withdrawal from study.
A total of 21 (1%) patients given Monoferric experienced 24 fatal AEs during participation in 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 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 pooled clinical trial safety, 17 (1.04%) patients in the Monoferric group, 3 (1.06%) patients in the IV iron sucrose group, 2 (0.59%) patient in the oral iron sulphate group, and 1 (3.3%) patient receiving placebo experienced serious or severe hypersensitivity. A total of 7 (0.43%) 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 the submitted post-market information provided in response to the Notice of Deficiency, the number of overall hypersensitivity cases each year remained stable and fatal cases were very rare despite the increasing post-marketing patient exposure. Overall, the risk of hypersensitivity was found to be sufficiently well characterized by the current clinical studies and additional post-market data and of comparable frequency and severity with other IV iron products authorized in Canada. The risk of hypersensitivity was also found to be adequately addressed in the Monoferric Product Monograph in the Contraindications, Serious Warnings box and Warnings and Precautions section.
Other identified risks, such as hypophosphatemia, hypotension, infection and higher serious AEs in elderly patients were adequately mitigated through sufficient labelling under Warnings and Precautions section of the Monoferric Product Monograph. Non-clinical reports of developmental delays and malformations in rats and rabbits were also adequately addressed by indicating 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.
The efficacy of Monoferric has been consistently demonstrated in different clinical trials and the reported AEs are considered tolerable and manageable. Therefore, the benefit-harm-uncertainty profile of Monoferric is considered to be positive for the treatment of iron deficiency anemia in adult patients who have intolerance or unresponsiveness to oral iron therapy.
For more information, refer to the Monoferric Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
In dogs, no overt adverse effects on cardiorespiratory parameters were noted. At a human equivalent dose that exceeds the maximal proposed human dose, Monoferric treatment transiently increased heart rate. No hypotensive effects were observed. In mice, no adverse effects were noted on central nervous system functional endpoints. In the 4-week rat study, degenerative changes of unknown reversibility were noted in the male reproductive system. These changes were observed at an intravenous dose of 80 mg Fe/kg, 3 times per week for 4 weeks (human equivalent dose (HED) 14 mg/kg corresponding to HED 40 mg/kg/week) which is more than the proposed maximal dose of Monoferric in humans (20 mg/kg/week). It is not known whether these degenerative changes may impact male fertility. These changes were observed at an intravenous dose of 80 mg Fe/kg, 3 times per week for 4 weeks (5 times the maximum recommended human exposure from a single course of Monoferric). In a dedicated fertility study in rats, Monoferric treatment up to a human equivalent dose of 3.1 mg/kg/day had no impact on male reproductive performance. In vitro, Monoferric was non-mutagenic and did not induce numerical or structural chromosomal aberrations. Monoferric was also non-clastogenic in an in vivo mouse bone marrow micronucleus assay.
Long term carcinogenicity studies have not been conducted. Monoferric treatment of rats had no impact on female reproductive performance. Based on embryo-fetal development studies in rats and rabbits, Monoferric is teratogenic. Monoferric may cause fetal harm if administered to pregnant women. In non-clinical models of systemic and passive cutaneous anaphylaxis, Monoferric generally demonstrated a decreased incidence and severity of anaphylactic reactions compared to iron dextran preparations and dextran.
One limitation of the non-clinical package is that most studies were conducted with an earlier development formulation of Monoferric, which differs from the commercial formulation only in the iron/oligosaccharide ratio. The lack of bio-distribution studies was also considered to be a deficiency of the non-clinical package. The degenerative changes observed in the male reproductive system are of concern given that the male reproductive system is not an established target organ of toxicity for iron, despite the wealth of literature on iron-mediated toxicity. The risks to male patients are highlighted in the Monoferric Product Monograph.
In summary, the non-clinical toxicology profile of Monoferric has been adequately characterized in support of the proposed indication. No additional non-clinical studies are deemed necessary to support authorization of the product.
For more information, refer to the Monoferric Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The Chemistry and Manufacturing information submitted for Monoferric has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored between 15ºC to 30ºC.
Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation limits and/or qualified from toxicological studies).
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
None of the excipients used in the formulation of Monoferric is of human or animal origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| MONOFERRIC | 02477777 | PHARMACOSMOS A/S | IRON (FERRIC DERISOMALTOSE) 100 MG / ML |