Summary Basis of Decision for Triferic AVNU
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 Triferic AVNU is located below.
Recent Activity for Triferic AVNU
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.
Summary Basis of Decision (SBD) for Triferic AVNU
Date SBD issued: 2021-07-29
The following information relates to the new drug submission for Triferic AVNU.
Iron (supplied as ferric pyrophosphate citrate)
Drug Identification Number (DIN):
- DIN 02515334 - 1.5 mg/mL iron (supplied as ferric pyrophosphate citrate), solution, intravenous administration
Rockwell Medical Inc.
New Drug Submission Control Number: 239850
On April 22, 2021, Health Canada issued a Notice of Compliance to Rockwell Medical Inc. for the drug product Triferic AVNU.
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 Triferic AVNU is favourable for the replacement of iron to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease (CKD-HD). Triferic AVNU is not intended for use in patients receiving peritoneal dialysis and has not been studied in patients receiving home hemodialysis.
1 What was approved?
Triferic AVNU, an iron preparation, was authorized for the replacement of iron to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease (CKD-HD). Triferic AVNU is not intended for use in patients receiving peritoneal dialysis and has not been studied in patients receiving home hemodialysis.
Triferic AVNU is not authorized for use in pediatric patients (<18 years of age), as its safety and effectiveness have not been established in this population. No overall differences in efficacy or safety were observed in geriatric patients (≥65 years of age) compared to younger patients in clinical trials.
Triferic AVNU is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation, or component of the container.
Triferic AVNU 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.
Triferic AVNU (1.5 mg/mL iron [supplied as ferric pyrophosphate citrate]) is presented as a solution. In addition to the medicinal ingredient, the solution contains 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 Triferic AVNU Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Triferic AVNU approved?
Health Canada considers that the benefit-harm-uncertainty profile of Triferic AVNU is favourable for the replacement of iron to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease (CKD-HD). Triferic AVNU is not intended for use in patients receiving peritoneal dialysis and has not been studied in patients receiving home hemodialysis.
Chronic kidney disease (CKD) is a worldwide public health concern. One of the most common comorbidities of CKD-HD patients is anemia, which may be due to low body iron stores (as a result of blood loss during dialysis) and impaired utilization of iron. Consequently, there is an ongoing need to replenish body iron in CKD-HD patients.
Iron deficiency anemia in CKD-HD patients is generally treated using parenteral (intravenous) iron administration used in conjunction with erythropoiesis stimulating agents (ESAs). Intravenous administration is preferred, as oral iron is not well absorbed and gastrointestinal intolerance is common. At the time of authorization of Triferic AVNU, there were four other intravenous iron products marketed in Canada: Dexiron, an iron dextran (≥1,000 mg/dose); Ferrlecit (sodium ferric gluconate; 125 mg/dose); Venofer (iron sucrose; 200 mg/dose); and the more recently approved Monoferric (Iron Isomaltoside 1,000; up to 500 mg/bolus injection and up to 1,500 mg/infusion). Each of these intravenous iron products are indicated for the treatment of iron deficiency anemia and are associated with safety concerns for hypersensitivity reactions. Serious hypersensitivity reactions have been reported, including life threatening and fatal anaphylactic/anaphylactoid reactions.
Triferic AVNU is an iron replacement product delivered via intravenous infusion into the blood lines pre- and post-dialyzer in CKD-HD patients at each hemodialysis treatment. It is a preservative-free sterile solution containing 1.5 mg elemental iron/mL in water for injection.
Triferic AVNU has been shown to be efficacious in maintaining hemoglobin (Hb) during the treatment period in CKD-HD patients. The market authorization was primarily based on the results of two pivotal, randomized, placebo-controlled, single blind, Phase III clinical studies (Studies SFP-4 and SFP-5). Both studies were identical in design and enrolled a combined total of 599 adult patients with CKD-HD who were iron-replete. Patients were randomized to receive either Triferic AVNU added to bicarbonate concentrate with a final concentration of 110 μg of iron/L in dialysate or placebo (standard dialysate) administered 3 to 4 times per week during hemodialysis. All patients were to remain randomized in their treatment group until pre-specified Hb or ferritin criteria were met, indicating the need for a change in anemia management, or until they had completed 48 weeks of treatment. After randomization, patients’ ESA product, doses, or route of administration were not to be changed and oral or intravenous iron administration were not allowed.
The primary efficacy endpoint (mean change in Hb level from baseline to the end-of-treatment period) was met in both pivotal studies. In Study SFP-4, the mean Hb decreased 0.04 g/dL in the Triferic AVNU group compared to 0.39 g/dL in the placebo group. In Study SFP-5, the mean Hb decreased 0.09 g/dL in the Triferic AVNU group compared to 0.45 g/dL in the placebo group. In both studies, the treatment difference in mean hemoglobin change was 0.36 g/dL (p = 0.011) between the Triferic AVNU and the placebo groups. This value was statistically significant for both studies. The treatment difference of 0.35 g/dL was also statistically significant (p = 0.010) for both studies in the analysis using the intent-to-treat population. A high proportion of patients did not complete the planned 48 weeks of study treatment mainly due to protocol-mandated changes in anemia management (ESA dose changes). However, the proportion was similar for both arms and the analysis of Hb change in this subgroup was consistent with that of the primary efficacy analysis. Secondary endpoints which included changes in reticulocyte Hb content, serum ferritin, and pre-dialysis serum iron panel to the end of treatment, were consistent with the primary efficacy results.
The safety of Triferic AVNU was evaluated in seven controlled and uncontrolled Phase II/III studies, which included the two pivotal studies. In total, 1,411 CKD-HD patients were exposed to Triferic AVNU in the clinical program. In the pivotal studies, 78% of patients in the Triferic AVNU group and 75% of patients in the placebo group had at least one treatment-emergent adverse event (TEAE). The most common TEAEs in the Triferic AVNU group (which were higher than the placebo group) were procedural hypotension (21.6%), muscle spasms (9.6%), headache (9.2%), pain in extremity (6.8%), edema peripheral (6.8%) and dyspnoea (5.8%). Serious TEAEs were reported at similar rates for the two groups at 27.7% for the Triferic AVNU group and 27.4% for the placebo group. The most common serious TEAEs occurring in the Triferic AVNU group (which were higher than the placebo group) were cardiac arrest (1.7%), arteriovenous fistula thrombosis (1.7%), and pulmonary edema (1.4%). Few patients discontinued study treatment due to TEAEs (4.5% in the Triferic AVNU group and 2.4% in the placebo group).
In the overall clinical program, there were two cases (0.1%) of hypersensitivity reactions related to treatment out of the 1,411 patients treated with Triferic AVNU. There were no cases of serious hypersensitivity reaction and no cases of anaphylaxis related to Triferic AVNU treatment. A Serious Warnings and Precautions box describing a warning for hypersensitivity reaction has been included in the Product Monograph for Triferic AVNU.
A Risk Management Plan (RMP) for Triferic AVNU was submitted by Rockwell Medical Inc. to Health Canada. 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. In the RMP, the sponsor included ‘hypersensitivity reactions’ as an important identified risk; ‘systemic/serious infections’ as an important potential risk; and ‘use in pregnant and breastfeeding women’, ‘use in children’ and ‘concomitant use with other intravenous iron product’ as missing information. Labelling for these safety concerns has been included in the Product Monograph and the sponsor has committed to systemically review clinical and post-marketing safety data as part of routine pharmacovigilance activities. Upon review, the RMP was considered to be acceptable.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Triferic AVNU Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Triferic AVNU was accepted.
Overall, the therapeutic benefits of Triferic AVNU therapy seen in the pivotal studies are positive and are considered to outweigh the potential risks. Triferic AVNU has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Triferic AVNU Product Monograph to address the identified safety concerns.
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 Triferic AVNU?
Submission Milestones: Triferic AVNU
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2016-06-28 |
| Submission filed | 2020-05-25 |
| Screening | |
Screening Acceptance Letter issued | 2020-06-05 |
| Review | |
Review of Risk Management Plan complete | 2021-01-28 |
Request granted to pause review clock for 7 days (extension to clarifax response) | 2021-02-02 |
Labelling Review complete | 2021-02-15 |
Biopharmaceutics Evaluation complete | 2021-03-18 |
Quality Evaluation complete | 2021-04-12 |
Non-Clinical Evaluation complete | 2021-04-13 |
Biostatistics Evaluation complete | 2021-04-14 |
Clinical/Medical Evaluation complete | 2021-04-20 |
Notice of Compliance issued by Director General, Therapeutic Products Directorate | 2021-04-22 |
The Canadian regulatory decision on the review of Triferic AVNU was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration (FDA) was used as an added reference.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications 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
Triferic AVNU contains iron in the form of ferric pyrophosphate citrate. Once delivered into the circulation, the iron from ferric pyrophosphate citrate binds to transferrin for transport to erythroid precursor cells to be incorporated into hemoglobin.
The clinical pharmacology of Triferic AVNU was characterized in seven clinical pharmacology studies. The key findings from these studies are discussed below.
A dose-escalation study was conducted in healthy volunteers who were administered intravenous (IV) Triferic AVNU over a dose range of 2.5 mg to 10 mg via 4 hours continuous infusion, or a dose range of 15 mg to 20 mg via 12 hours continuous infusion. The results of the study showed a dose-proportional increase in the baseline corrected exposure levels for serum iron and transferrin-bound iron as measured by the maximum concentration (Cmax) and the area under the plasma concentration-time curve (AUC). At the doses studied, transferrin saturation (TSAT) did not exceed 100% and the amount of non-transferrin-bound iron was not greater than normally expected. The elimination of serum total iron and transferrin bound iron following Triferic AVNU infusion was relatively rapid with an apparent terminal elimination half-life of approximately 2 hours or less across treatments. The pharmacokinetic profile of transferrin-bound iron was comparable to that observed for total serum iron, indicating that all the iron was bound to transferrin.
Iron exposure from Triferic AVNU was comparable between adult healthy volunteers and adult CKD-HD patients.
Previous IV iron products have demonstrated increases in the level of hepcidin-25 consequently limiting iron bioavailability and treatment efficacy. The results from the submitted clinical pharmacology studies demonstrated that Triferic AVNU had no induction effect on hepcidin-25 concentrations.
An in vitro drug-drug interaction study showed that Triferic AVNU did not significantly impact the anticoagulation properties of three tested types of heparin when used in clinically relevant concentrations.
A dedicated QT/QTc study was not conducted with Triferic AVNU in humans.
Comparative Bioavailability
The efficacy and safety of Triferic AVNU have been established based on studies of ferric pyrophosphate citrate solution for hemodialysis.
Study RMFPC-20 was a pivotal, open-label, four-period, randomized, crossover comparative bioavailability study conducted in adult CKD-HD patients to establish the equivalence of Triferic AVNU administered via hemodialysis compared to intravenous administration. The results of the study demonstrated that Triferic AVNU (6.5 mg ferric pyrophosphate citrate) administered intravenously via the pre-dialyzer (arterial) or post-dialyzer (venous drip chamber) was bioequivalent to Triferic AVNU administered via the hemodialysate.
These findings support the methods of administration for Triferic AVNU: slow continuous infusion over 3 to 4 hours via the pre-dialyzer infusion line, post-dialyzer infusion line, or a separate connection to the venous blood line during hemodialysis.
The clinical pharmacology data support the use of Triferic AVNU for the recommended indication. For further details, please refer to the Triferic AVNU Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Triferic AVNU was evaluated in two pivotal, randomized, placebo-controlled, single blind, Phase III studies (Studies SFP-4 and SFP-5). Both studies were identical in design and enrolled a total of 599 adult patients with CKD-HD who were iron-replete. Study SFP-4 included 305 CKD-HD patients with a mean age of 59 years (range: 23-89 years). Of these patients, 68% were male, 32% were female, 55.2% were White, 32.1% were Black, and 12.7% were of other races. Study SFP-5 included 294 CKD-HD patients with a mean age of 60 years (range: 20-89 years). Of these patients, 59% were male, 41% were female, 53.5% were White, 39.9% were Black, and 6.6% were of other races. The patients enrolled in both studies had hemoglobin (Hb) concentrations of 9 g/dL to 12 g/dL with TSAT >20% and serum ferritin concentrations >200 µg/L were enrolled.
Randomization was stratified by the pre-randomized Hb value and by the erythropoiesis stimulating agent (ESA) dose at the time of randomization. Patients were randomized in a 1:1 ratio to receive either Triferic AVNU added to bicarbonate concentrate with a final concentration of 110 μg of iron/L in dialysate or placebo (standard dialysate) administered 3 to 4 times per week during hemodialysis. Study drug administration was withheld for a minimum of 4 weeks if any one of the following criteria was met: pre-dialysis TSAT >50%; or serum ferritin >1,200 μg/L. Patients were to remain randomized in their treatment group until pre-specified Hb or ferritin criteria were met, indicating the need for a change in anemia management, or until they had completed 48 weeks of treatment. After randomization, patients’ ESA product, doses, or route of administration were not to be changed and oral or intravenous iron administration were not allowed.
In Study SFP-4, the mean treatment duration in the randomized phase was 157.7 days for the Triferic AVNU group and 164.6 days for the placebo group. In Study SFP-5, the values were 161.2 days for the Triferic AVNU group and 157.9 days for the placebo group.
The primary efficacy endpoint for both studies was the mean change in hemoglobin (Hb) level from baseline to the end-of-treatment period. This endpoint was met in both pivotal studies. In Study SFP-4, the mean Hb decreased 0.04 g/dL in the Triferic AVNU group compared to 0.39 g/dL in the placebo group. In Study SFP-5, the mean Hb decreased 0.09 g/dL in the Triferic AVNU group compared to 0.45 g/dL in the placebo group. In both studies, the treatment difference in Hb calculated as the least square mean difference was 0.36 g/dL between the Triferic AVNU groups (0.06 g/dL in SFP-4 and -0.05 g/dL in SFP-5) and the placebo groups (-0.30 g/dL in SFP-4 and -0.40 g/dL in SFP-5). These values were statistically significant (p = 0.011) in both studies after adjusting for baseline Hb and ESA stratum. The treatment difference of 0.35 g/dL was also statistically significant (p = 0.010) for both studies in the analysis using the intent-to-treat population.
A high proportion of patients (82%) did not complete the planned 48 weeks of study treatment mainly due to protocol-mandated changes in anemia management (ESA dose changes); however, the proportion was similar for both arms. Prior to their removal from study, final Hb and serum ferritin levels were measured in patients who had to discontinue due to a protocol-mandated change in anemia management. Analysis of these values showed that more patients in the placebo group had Hb <9 g/dL or serum ferritin <100 ug/L than patients in the Triferic AVNU group. In addition, more patients in the Triferic AVNU group had Hb >12.0 g/dL than those in the placebo group. The results of this subgroup analysis were consistent with those of the primary efficacy analysis.
Secondary endpoints which included changes in reticulocyte Hb content, serum ferritin, and pre-dialysis serum iron panel to the end of treatment, were consistent with the primary efficacy results.
Indication
| Sponsor's proposed indication | Health Canada-approved indication |
|
Triferic AVNU (ferric pyrophosphate citrate injection) is an iron replacement product indicated for:
Triferic AVNU is not intended for use in patients receiving peritoneal dialysis. Triferic AVNU has not been studied in patients receiving home hemodialysis. |
Triferic AVNU (ferric pyrophosphate citrate injection) is an iron replacement product indicated for:
Triferic AVNU is not intended for use in patients receiving peritoneal dialysis. Triferic AVNU has not been studied in patients receiving home hemodialysis. |
The proposed indication used the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines classification term CKD-5HD. Health Canada revised the indication to remove reference to this guideline to only include patients classified as having hemodialysis-dependent chronic kidney disease (CKD-HD) to reflect the population enrolled in the clinical studies.
For more information, refer to the Triferic AVNU Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The safety of Triferic AVNU was primarily evaluated in seven controlled and uncontrolled Phase II/III studies, and focused mainly on the results of the two pivotal studies (Studies SFP-4 and SFP-5) described in the Clinical Efficacy section. In total, 1,411 CKD-HD patients were exposed to Triferic AVNU in the clinical program. In the pivotal studies, 78% of patients in the Triferic AVNU group and 75% of patients in the placebo group had at least one treatment-emergent adverse event (TEAE). The most common TEAEs in the Triferic AVNU group (which were higher than the placebo group) were procedural hypotension (21.6%), muscle spasms (9.6%), headache (9.2%), pain in extremity (6.8%), peripheral edema (6.8%) and dyspnoea (5.8%). Serious TEAEs were reported at similar rates for the two groups at 27.7% for the Triferic AVNU group and 27.4% for the placebo group. The most common serious TEAEs occurring in the Triferic AVNU group (which were higher than the placebo group) were cardiac arrest (1.7%), arteriovenous fistula thrombosis (1.7%), and pulmonary edema (1.4%). Few patients discontinued study treatment due to TEAEs (4.5% in the Triferic AVNU group and 2.4% in the placebo group). Overall, the safety profile of Triferic AVNU was similar for female and male patients, between patients <65 years of age and patients ≥65 years of age, and between white and non-white patients, with similar incidences of TEAEs between groups.
The most common TEAEs (occurring in at least two patients) leading to study discontinuation in the Triferic AVNU group were asthenia, dizziness and headache. In the pivotal studies, twelve patients in the Triferic AVNU group and five patients in the placebo group died during the study, corresponding to a crude mortality rate of 4% and 2%, respectively. These values were within the range observed in this patient population. Most deaths were due to cardiac arrest (6 cases in the Triferic AVNU group vs. 2 cases in the placebo group), sudden death/unknown (4 cases in the Triferic AVNU group vs. 1 case in the placebo group), myocardial infarction (1 case in the Triferic AVNU group vs. 2 cases in the placebo group), and bronchopneumonia (1 case in the Triferic AVNU group vs. none in the placebo group). These patients all had important underlying comorbidities such as diabetes, cardiac disorders, and/or chronic kidney disease (end-stage). No deaths occurred during the dialysis session and all deaths were considered as “unlikely related” or “not related” to the study drug by the investigator and “not related” by the Sponsor medical monitor.
In the pivotal studies, there was one case (0.3%) of hypersensitivity reaction (procedural hypotension) related to Triferic AVNU treatment. In the overall clinical program (which included the pivotal studies), there were two cases (0.1%) of hypersensitivity reaction (one case of procedural hypotension and one case of drug hypersensitivity) related to Triferic AVNU treatment in the 1,411 patients treated with Triferic AVNU. There were no cases of serious hypersensitivity reaction and no cases of anaphylaxis related to Triferic AVNU treatment. A Serious Warnings and Precautions box has been included in the Product Monograph for Triferic AVNU indicating that serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving parenteral iron products. This warning indicates that patients are to be monitored for signs and symptoms of hypersensitivity during and after hemodialysis until clinically stable. Triferic AVNU should only be administered when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.
The number of patients with confirmed iron parameters (TSAT ≥50%; ferritin level ≥1200 µg/L) indicative of possible iron toxicity (overload) was low. Patients with these iron parameters were withheld from Triferic AVNU treatment. Overall, it did not appear that patients treated with Triferic AVNU developed iron overload or related liver abnormalities.
The occurrence of other adverse events of special interest, including intradialytic (procedural) hypotension, composite cardiovascular events, hemodialysis vascular access thrombotic events, and systemic or serious infections, was similar for the Triferic AVNU group and the placebo group. The TEAEs observed in the open label phase of the clinical studies were similar to those observed in the randomized treatment period.
For more information, refer to the Triferic AVNU Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Results from submitted non-clinical pharmacology studies provided evidence demonstrating that in a biochemical assay conducted in vitro, ferric pyrophosphate citrate (FPC) can rapidly and efficiently donate iron to both iron-binding sites on human apo-transferrin and can obtain the crystal structure of FPC bound to transferrin.
Safety pharmacology studies demonstrated that single intravenous FPC administration in rats did not produce adverse effects on central nervous system (CNS) function at doses of up to 500 mg/kg or significant adverse effects on the respiratory system at doses of up to 250 mg/kg.
Ferric pyrophosphate citrate did not affect blood pressure, heart rate or electrocardiogram parameters in dogs given single intravenous doses of up to 250 mg/kg (26,700 µg iron/dL), which was the no-observed-effect level (NOEL) for cardiovascular effects determined in dogs. The NOEL for effects on the human Ether-à-go-go-Related Gene (hERG)-mediated current in vitro was determined to be 11,500 µg iron/dL. The NOEL for effects on action potential duration was determined to be 1,150 µg iron/dL. Effects observed in dogs are at concentrations 2-3 or more orders of magnitude greater than the maximum concentration of FPC-related iron that can theoretically be delivered following intravenous infusion of FPC (6.75 mg iron per 4.5 mL) or during hemodialysis (11 µg iron/dL).
In repeat-dose toxicity studies, FPC was administered to rats for 26 weeks by 1-hour intravenous infusion three times a week. This caused local irritation at the infusion site and iron accumulation in numerous tissues. The no-observed-adverse-effect level (NOAEL) was determined to be ≤20/10/2 mg FPC/kg. At this dose level, the average values for maximum concentration (Cmax) and area under the concentration-time curve from time 0 to 25 hours AUC(0-25hrs) for iron were approximately 840 µg iron/dL and 8,300 h*µg iron/dL, respectively, after the first dose at 20 mg FPC/kg. After repeated doses at 10 mg and then at 2 mg FPC/kg, these values were approximately 290 to 610 µg iron/dL and 4,800 to 6,700 h*µg iron/dL, respectively.
Similar tissue iron accumulation and local irritation at the infusion site was observed following repeat FPC administration in dogs. While dogs tolerated intravenous infusion of FPC at doses up to 30 mg/kg given three times a week via intravenous infusion for up to 39 weeks, a NOAEL was not determined. Effects related to FPC included iron accumulation in tissues and a heightened incidence of hepatic microgranulomas at all dose levels, minimal gallbladder mucosal lymphoid hyperplasia in a few dogs at ≥20 mg FPC/kg, and minimal renal tubular basophilia in two females at 30 mg FPC/kg.
In both rats and dogs, there was no evidence of increased serum transaminase activities or altered bilirubin levels or any other signs of hepatocellular injury following chronic dosing with FPC. Tissue iron accumulation following chronic dosing with FPC was not unexpected.
Ferric pyrophosphate citrate was negative for genotoxicity in the Ames Assay and negative for clastogenic activity in vivo. In the presence of metabolic activation, FPC induced structural chromosomal aberrations in Chinese Hamster Ovary (CHO) cells.
Carcinogenicity studies were not provided, however, reference to carcinogenicity studies conducted for other iron-containing products demonstrated no evidence that these products pose a carcinogenic risk.
The potential effects of FPC on reproduction and development were evaluated in rats and rabbits. In rats, the NOAEL for male reproductive performance and fertility was 10 mg/kg/day. In female rats, an NOAEL of 30 mg/kg/day (3.5 mg Fe/kg/day) for both maternal and developmental toxicity was established. Additionally, at 30 mg/kg/day, FPC had no effects on the F1 generation in terms of sexual maturation, learning and memory or fertility and reproductive capacity, and did not result in any FPC-related abnormalities in the F2 generation. In rabbits, an NOAEL for maternal toxicity of 20 mg/kg/day (2.3 mg Fe/kg/day) was established with higher doses (40 mg/kg/day) resulting in maternal toxicity. At doses up to 40 mg/kg/day, FPC did not cause developmental toxicity. The NOAEL for fetal toxicity can therefore be considered 40 mg/kg/day. Together these data indicate that it is unlikely that FPC will have effects on male and female reproduction or cause embryo-fetal toxicity at clinical plasma levels in humans.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Triferic AVNU Product Monograph. In view of the intended use of Triferic AVNU, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Triferic AVNU 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 Triferic AVNU 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 protected from light in the aluminum pouch at room temperature (15 ºC to 30 ºC).
Proposed limits of drug-related impurities are considered adequately qualified (i.e. within International Council for Harmonisation [ICH] limits and/or qualified from toxicological studies).
All sites involved in production are compliant with Good Manufacturing Practices.
None of the excipients used in the formulation of Triferic AVNU are of human or animal origin. All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.