Summary Basis of Decision for Feraheme
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:
Feraheme
Ferumoxytol, 30 mg/mL, Solution, Intravenous
Takeda Canada Inc.
Submission control no: 133250
Date issued: 2012-06-26
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02377217
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On December 8, 2011, Health Canada issued a Notice of Compliance to Takeda Canada Inc. for the drug product Feraheme.
Feraheme contains the medicinal ingredient ferumoxytol which is a haematinic agent.
Feraheme is indicated for the treatment of iron deficiency anaemia in adult patients with chronic kidney disease (CKD).
Feraheme helps to facilitate replenishment of the body's iron storage. Iron is a key component required by red blood cells to carry oxygen throughout the body.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy and safety was established in three multicentre, randomized, open-label, 5-week controlled studies in a total of 923 patients with CKD stages 1-5 and 5D on haemodialysis (including 31 kidney transplant recipients). Two of these trials enrolled patients with non-dialysis dependent CKD and one enrolled patients who were undergoing haemodialysis. In all three studies, patients were randomized to receive either two 510 mg intravenous (IV) single doses of Feraheme or one single oral dose of 200 mg iron (ferrous fumerate) for 21 days. The primary efficacy endpoint in all three studies was the mean change in haemoglobin (Hgb) from baseline to Day 35 (Week 5) post-initial dose of study medication. Results from all three studies showed that the difference in mean change in Hgb from baseline between the Feraheme and the oral iron treatment groups was statistically significant. The mean increase in Hgb on Day 35 ranged from 0.82 g/dL to 1.21 g/dL in patients treated with Feraheme as compared to 0.15 g/dL to 0.51 g/dL in the oral iron treatment group. This result was consistent across subgroups, including those defined by use of erythropoiesis stimulating agents. In addition, results from the secondary efficacy endpoints (the difference in mean change from baseline in ferritin at three weeks post-initial dose of study medication and the proportion of patients with an increase of at least 1.0 g/dL in Hgb at five weeks post-initial dose of study medication) were consistent with the primary efficacy analysis results.
Feraheme (30 mg/mL, ferumoxytol) is presented as a solution for IV injection. Each millilitre (mL) of Feraheme contains the equivalent of 30 mg of elemental iron as superparamagnetic iron oxide particles with polyglucose sorbitol carboxymethylether (PSC) coating in water for injection. The initial recommended dose is 510 mg IV injection followed by a second 510 mg IV injection 2 to 8 days later. Feraheme is to be administered as an undiluted intravenous injection delivered at a rate of up to 1 mL/sec (30 mg/sec). Patients should be assessed for any signs and symptoms of hypersensitivity for at least 30 minutes following each Feraheme injection. The monitoring for any signs and symptoms of hypotension should also be conducted following each Feraheme injection. Feraheme should only be administered when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions. For patients receiving haemodialysis, Feraheme should be administered once the blood pressure is stable and the patient has completed at least one hour of haemodialysis. Evaluation of the haematologic response [for example (e.g.) haemoglobin, serum ferritin, iron and transferrin saturation] should be conducted at least one month following the second Feraheme injection. Additional dosing guidelines are available in the Product Monograph.
Feraheme is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Feraheme is also contraindicated in patients with evidence of iron overload or anaemia not caused by iron deficiency. Feraheme should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Feraheme are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Feraheme is favourable for the treatment of iron deficiency anaemia in adult patients with CKD.
3 Scientific and Regulatory Basis for Decision
A New Drug Submission for Feraheme was first filed at Health Canada on December 18, 2009. During the review, there were major issues pertaining to the presence of free polyglucose sorbitol carboxymethylether (PSC) in the drug product. The free PSC was considered a new excipient and a non-clinical safety evaluation was required to establish permissible and safe limits for this substance. In addition, Feraheme was shown to be teratogenic in some rabbits treated at a minimally maternally toxic dose equivalent to approximately 14 times (x) the cumulative therapeutic dose in a 70 kg human. A complete benefit/risk assessment of Feraheme could not be completed at that time and therefore the submission received a Notice of Non-Compliance (NON) on January 26, 2011. The Sponsor then submitted a response to the NON on May 26, 2011. Health Canada assessed the additional data and revisions were made to the Feraheme Product Monograph. It was concluded that the overall benefits of Feraheme outweighed the risks for the proposed indication, and there were adequate studies to characterize the safety profile of PSC and the ferumoxytol drug product. A Notice of Compliance (NOC) was subsequently issued for Feraheme on December 8, 2011.
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Ferumoxytol, the medicinal ingredient of Feraheme, is a haematinic agent. Ferumoxytol consists of a superparamagnetic iron oxide core that is coated with PSC. This carbohydrate shell helps to isolate the bioactive iron from plasma components until the iron-carbohydrate complex is taken up by the reticuloendothelial system macrophages of the liver, spleen, and bone marrow. The iron is then released from the complex within vesicles in the macrophages. Iron then either enters the intracellular storage iron pool or is transferred to plasma transferrin for transport to erythroid precursor cells for incorporation into haemoglobin.
Manufacturing Process and Process Controls
Ferumoxytol is manufactured via a multi-step synthesis. In-process controls performed during manufacture were reviewed and are considered acceptable. The drug substance specifications were found to be satisfactory.
Characterization
The structure of ferumoxytol has been adequately elucidated. Physical and chemical properties have been described and were found to be satisfactory.
Impurities arising from manufacturing were reported and characterized. These products were found to be within International Conference on Harmonisation (ICH) limits and therefore are considered acceptable.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of ferumoxytol.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term, real-time, and accelerated stability data submitted, the proposed retest period for the drug substance were supported and are considered satisfactory.
3.1.2 Drug Product
Description and Composition
Feraheme is a black to reddish brown sterile aqueous colloidal solution containing the drug substance, ferumoxytol. Each millilitre of Feraheme contains the equivalent of 30 mg of elemental iron as superparamagnetic iron oxide particles with PSC coating in Water for Injection. Additional PSC and mannitol are added to adjust tonicity, and sodium hydroxide may be added to adjust the pH. The product has a pH of 6.0 to 8.0. The formulation is isotonic and contains no preservatives. The product has low bleomycin-detectable iron.
Feraheme is available in single-use vials in cartons of 10 vials.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of ferumoxytol with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Feraheme is tested to verify that its identity, appearance, assay, pH, magnetic susceptibility, particle size, volume per vial, osmolality, particulates, uniform of dosage units, sterility, levels of bacterial endotoxins and impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable.
Validation reports submitted for all analytical procedures used for in-process and release testing of the drug product are considered satisfactory. Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Stability
Based on the real-time, long-term, and accelerated stability data submitted, the proposed 48-month shelf-life for Feraheme is considered acceptable when the product is packaged in glass type I vials with gray chlorobutyl rubber stoppers, sealed with aluminum crimp-on seals, and stored at 15-30°C, protected from light and freezing.
The compatibility of the drug product with the container closure system was demonstrated through stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production of Feraheme are considered suitable for the activities and products manufactured.
All sites are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. The excipients used in the drug product formulation are not of animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Feraheme 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.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Ferumoxytol is a nanoparticle with a core of iron oxide with a carbohydrate coating. The carbohydrate layer is formed from PSC. The molecular construct is a variation of a marketed parenteral iron replacement product.
The primary pharmacodynamics, reflecting effects consistent with the incorporation of iron from ferumoxytol into the red blood cells, was evaluated in a rat model of diet-induced iron deficiency. Anaemia was induced and established prior to injection of a single intravenous (IV) injection of 30 mg Fe/kg of Feraheme. The effect was evaluated approximately 3 weeks later and showed a partial or complete reversal of the decreases in red bloodcell parameters consistent with bioavailability of the iron in the iron oxide colloid. There were no other dedicated non-clinical studies evaluating the primary pharmacodynamics but the results provided were clearly indicative of the iron from ferumoxytol entering and being utilized in erythron iron metabolism. Also, scientific publications have reported that intramuscular/subcutaneous/intraperitoneal administration of iron dextran formulations resulted in effects consistent with iron incorporation in the endogenous iron pool in normal and anaemic animals as well as in animal models for shock and inflammation.
In safety pharmacology studies, there were no effects on the central nervous system after IV administration of a single dose of 1,000 mg Fe/kg in male mice. The effects on respiratory, renal and cardiovascular systems were evaluated in anesthetized male and female dogs at single doses up to 200 mg Fe/kg. There were no effects on arterial blood pressure (systolic, diastolic and mean), heart rate, femoral artery blood flow and respiratory (respiratory rate, pulmonary volume and pulmonary flow) parameters in anesthetized beagle dogs. The minor increases in urinary flow rate and the excretion of sodium and potassium, and a decrease in urinary chloride excretion were consistent with, and attributed to, the mannitol content of the ferumoxytol formulation.
3.2.2 Pharmacokinetics
Ferumoxytol is not a single entity; it is composed of a magnetic iron oxide colloid which serves as a reservoir for iron to be incorporated in the endogenous pool. The colloid is surrounded by a PSC coat. To characterize the kinetics, multiple bioanalytical assays have been employed. Depending on the bioanalytical method used and study design (mainly duration of sampling), the kinetics of the three components [that is (i.e.) the magnetic colloid, the carbon coat and the iron] have been characterized.
Early studies were conducted on male animals; a single IV dose of ferumoxytol was administered and blood was sampled up to 6 hours post-dose. These were small studies (3 males/study) and characterization was limited to determination of terminal half-life (t½). Across species and doses (2.2 and 6 mg/kg, IV) the t½ of ferumoxytol was 1-2 hours. This half-life represents the elimination of the ferumoxytol (i.e. the core with the carbon coating).
Distribution studies in rats after a single IV dose of 2.2 mg Fe/kg and 6 mg Fe/kg indicated that levels in tissues peaked 1 to 7 days post-dose and returned to baseline by 56 or 84 days. Tissue uptake was indicated in the spleen, liver, central lymph gland pool, bone marrow, and peripheral lymph gland system. All other tissues had no or minimal uptake. In rats, after a single IV radiolabelled dose of 2.2 mg Fe/kg, peak tissue levels were detected 1 day after administration with tissue uptake being greatest in the central lymph gland pool, followed by the spleen, and then the liver. Levels in tissues declined and by 84 days post-dose <0.5% of the dose remained in the carcass. The urine and the faeces accounted for the bulk of the recovered dose, 72% in the urine and 19% in the faeces. Distribution and excretion were determined after a radiolabelled single IV dose of 19 mg Fe/kg in rabbits 48 hours post-dose. Similar to the rat, tissue uptake was detected in the bone marrow, spleen, liver, central and peripheral lymph gland pools. There were minimal levels in the urine and faeces.
Studies designed to detect catalytic free iron (bleomycin-detectable iron) indicated that the free iron was low in rat serum both in vitro and after IV injection of ferumoxytol at 1.4 mg Fe/kg.
3.2.3 Toxicology
The non-clinical safety of Feraheme has been evaluated in a toxicology program consisting of acute and repeat-dose intravenous studies in rats and dogs, genotoxicity and immunotoxicity evaluations, and reproductive toxicity studies in rats and rabbits. Iron homeostasis is highly conserved in mammals and the use of rats, dogs and rabbits are appropriate models for the safety evaluation. The clinical formulation manufactured under GMP conditions has been utilized in all studies and administered IV (the clinical route of administration). The use of the clinical formulation is of particular importance for nanomaterials since it has been shown that for nanomaterials, chemical composition alone does not determine the toxicity profile but that particle size, surface, shape, coating, charge and stability may influence the results.
Single-Dose Toxicity
Single IV doses of 450 mg/kg (the maximal dose that can be administered based on solubility and volume limitations) were tolerated in rats and dogs. Results showed low acute toxicity with no mortality or severe clinical signs.
Repeat-Dose Toxicity
Repeat daily dosing was clinically well-tolerated at maximal doses administered (37 mg/kg for 4 weeks in rats and dogs; 12 mg/kg for 13 weeks in rats and dogs; and 360 mg/kg for 2 weeks in rats). Dose-dependent decreases in body weight and food consumption did occur, and as expected, the administration of ferumoxytol resulted in dose-related increases in serum iron and increases in total iron-binding capacity (TIBC) and decreased unbound-iron binding capacity (UIBC). There was an absence of overt haematotoxicity.
Mild increases in activated partial thromboplastin time (APTT) and/or prothrombin time (PT) were reported after daily dosing of 37 mg/kg for 4 weeks in rats and dogs. However, there was no effect on APTT or PT at lower dose levels of ferumoxytol in animals.
Dose-related deposition/accumulation of a yellow or brown pigment that stained positive for iron was reported in organs/tissues. There were no no-effect dose levels in the repeat-dose studies and the organs with the greatest pigment load were generally the liver, spleen, and lymph nodes, consistent with the results of the distribution studies. The pigment accumulation and accompanying phagocytic cell response were moderately severe or severe for these organs/tissues. At the end of the dosing period (4 weeks at 37 mg/kg or 13 weeks at 12 mg/kg), there was generally no histopathologic indication of parenchymal cell damage despite the pigment deposition. However, the pigment deposition was present for up to 26 weeks in the treatment-free recovery periods and haemorrhage, necrosis, and bile duct hyperplasia were present in the livers of female rats from the 18 and 37 mg/kg groups (4-week treatment) followed by the 26-week recovery period.
Increases in aspartate transaminase (AST), alanine transaminase (ALT) and/or alkaline phosphatase were observed in high dose male rats after 13 weeks of dosing at 12 mg/kg, and in some rats at 6 mg/kg, without correlative parenchymal cell damage based on histopathology.
The dosing regimens used in the repeat-dose toxicity studies in rats and dogs greatly exceed the proposed dosing regimen in human patients; thus the relevance and significance of calculated projected margins of safety based on results of these studies should not be over-interpreted. Of importance, the evaluation of toxicity of ferumoxytol in the general toxicity studies did not identify potential toxicities other than those related to high dose iron administration and prominent iron storage in organs/tissues.
Genotoxicity
Ferumoxytol showed no evidence of mutagenic activity in an in vitro Ames test or clastogenic activity in either an in vitro chromosomal aberration assay or an in vivo micronucleus assay.
Carcinogenicity
No carcinogenicity studies were performed with ferumoxytol.
Reproductive and Developmental Toxicity
There were no treatment-related effects of ferumoxytol on male or female fertility in mature rats at the highest dose administered (18 mg/kg/day), although the maximum tolerated dose was not attained in this study.
There were treatment-related effects of ferumoxytol in reproductive toxicity studies. Daily administration of ferumoxytol during organogenesis in rats at a dose of 10 mg/kg and rabbits at a dose of 16.5 mg/kg resulted in no embryo/foetal effects. In rabbits, ferumoxytol was foetotoxic and teratogenic at a dose associated with minimal maternal toxicity (45.3 mg/kg). It caused external and/or soft tissue foetal malformations, and decreased foetal weights. These foetal malformations included dome-shaped head; incomplete ossification of the skull; malrotated limbs; flexed front paws; microglossia and cleft palate; hydrocephaly; and anencephaly. In rats, ferumoxytol was not teratogenic but there were dose-related maternal reductions in body weight, weight gain, and food consumption at 31.6 and 100 mg/kg/day accompanied by an increased incidence in the occurrence of wavy/bent ribs and/or decreases in foetal body weight.
In the pre- and post-natal development study in rats, the mid and high doses administered to pregnant dams and throughout lactation were higher than the highest dose administered in the fertility study. There were no effects on maternal delivery and neonatal survival data at the high dose (60 mg/kg/day). However, there were significantly decreased first filial generation (F1) neonatal body weights during weaning at both 30 and 60 mg/kg but no effect on F1 behavior, learning, and memory at any dose. There were effects on maturation and/or reproductive competency in the F1 generation from treated dams treated at 30 and 60 mg/kg/day. Treatment of dams at 60 mg/kg/day was associated with delayed sexual maturation in the F1 males (preputial separation) and decreased reproductive competence in the initial and subsequent breedings. The F1 females from dams treated at 30 and 60 mg/kg/day had disruption of the estrous cycle and decreased reproductive competence in the initial and subsequent breeding. In addition, delayed sexual maturation (vaginal opening) was also observed in the 60 mg/kg/day F1 females. Therefore, the no-adverse-effect-levels (NOAELs) for reproductive competence were 30 and 10 mg/kg/day for the F1 males and females, respectively.
A lactation study showed that there was minimal transfer of ferumoxytol into the milk in rats after a single IV dose of 100 mg/kg to lactating dams.
Given that Feraheme was teratogenic in rabbits at a minimally maternal toxic dose equivalent to approximately 14 times the human cumulative therapeutic dose (2 x 510 mg iron based on an estimated exposure to iron for a 70 kg human), justification of the acceptability of the risk of significant teratogenicity in the context of the proposed indication and marketed alternative treatments was required.
It was found that the teratogenic and foetotoxic effects with Feraheme in rabbits were observed only at high doses much above the therapeutic range (approximately 14 times the estimated cumulative therapeutic dose). Given the available data for the other marketed IV iron products, namely Venofer, Ferrlecit, Infufer, and Dexiron, it is not known whether teratogenic and foetotoxic effects similar to those observed with high doses of Feraheme would also occur with these products, if given at the high dose of 45.3 mg Fe/kg/day for 14 days in rabbits. However, the IV dextran-based products, specifically Infufur and Dexiron, have been shown to be teratogenic and embryocidal in nonanaemic mice, rats, rabbits, dogs and monkeys when given in doses of about 3 times the maximum human dose (although the published information available for iron dextran does not provide definite information whether the safety multiples are based on single or cumulative doses). Proper labelling to provide information about the teratogenic findings was incorporated in the Product Monograph.
Local Tolerance
Ferumoxytol was not irritating at the site of injection.
Immunotoxicity
Ferumoxytol was not antigenic and did not induce hypersensitive or anaphylactic responses in the dedicated immunotoxicity studies. The paw swelling in rats (in dedicated immunotoxicity, single-dose and repeat-dose toxicity studies) was consistent with a high-dose effect. When compared with other dextran and/or unmodified dextran based iron preparations, ferumoxytol demonstrated only a weak anaphylactoid response potential in the rat paw model.
Assessment of PSC
Following Health Canada's review of the quality of Feraheme, PSC was considered to be a new excipient. As such, Health Canada had concern with the non-clinical safety evaluation of PSC alone, as it may not be possible to determine whether PSC was contributing to the risk of serious adverse events (hypersensitivity and hypotension reactions) associated with Feraheme. However, the sponsor had conducted a comprehensive ferumoxytol non-clinical toxicology and safety studies program. These studies were conducted with either PSC alone or the ferumoxytol drug product. In the assessment for immunologic potential, PSC alone induced no rat paw oedema. Immunogenic testing of PSC to react with rat anti-dextran antibodies found that it had low binding ability to rat anti-dextran antibodies. In the haemodynamic response assessment, PSC demonstrated minimal change in mean arterial pressure; therefore, the hypotensive potential of PSC appeared to be low. Therefore, Health Canada concluded that there were no additionaltoxicity concerns for free PSC when compared with PSC-iron complexes based on the totality of the non-clinical toxicology and safety studies data.
3.2.4 Summary and Conclusion
Overall, the results of the non-clinical pharmacology, safety pharmacology, pharmacokinetic, and toxicology studies support the intended clinical usage of Feraheme. The findings in the general toxicology studies are consistent with expected effects related to high dose iron administration and prominent iron storage in organs/tissues. There was no indication of mutagenicity or immunotoxicity at clinically relevant doses, or local irritation of the formulation. The effects in reproductive toxicity, as well as the effects on embryo-foetal effects in the teratology studies are reflected in the Feraheme Product Monograph.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
The pharmacodynamics of ferumoxytol in terms of its effect on cardiac electrophysiology was evaluated in a randomized, positive- and placebo-controlled, parallel-group study, in which healthy volunteers were given a supratherapeutic regimen of Feraheme (1.02 g given as two 510 mg doses within 24 hours), placebo, or a single dose of 400 mg moxifloxacin (positive control). Results showed that ferumoxytol did not have any noteworthy effects on electrocardiogram (ECG) intervals. Also, no clinically meaningful effect on heart rate was observed. Except for more frequent tachycardic outlier events (7% of subjects for ferumoxytol as compared to 2% and 4% for moxifloxacin and placebo, respectively), there were no outliers in ECG measures noted in the ferumoxytol group. T-wave changes in ECG waveform morphology were identified in 5% of the ferumoxytol volunteers and were deemed to be of no clinical importance. There was no effect of gender on QTc.
3.3.2 Pharmacokinetics
The pharmacokinetics (PK) of ferumoxytol were determined following intravenous administration to healthy volunteers in two Phase I studies and in a single study involving patients with chronic kidney disorder (CKD).
Overall, ferumoxytol showed dose-dependent, capacity-limited elimination from plasma with a half-life of approximately 15 hours in humans. The clearance (CL) was decreased as the dose was increased. The volume of distribution (Vd) was consistent with the plasma volume, and the mean maximum plasma concentration (Cmax) and t½ values increased with the dose. The estimated values of CL and Vd following two 510 mg doses of ferumoxytol administered intravenously within 24 hours were 69.1 mL/hour and 3.16 L, respectively. The Cmax and time of maximum concentration were 206 mcg/mL and 0.32 hours, respectively. The rate of infusion had no influence on its PK parameters. No gender differences in the PK parameters.
3.3.3 Clinical Efficacy
The efficacy and safety of Feraheme for the treatment of iron deficiency anaemia in CKD (Stages 1-5 and 5D) was investigated in three pivotal Phase III randomized, open-label, controlled, multicentre clinical studies (Studies A, B, and C). A total of 923 patients with CKD (Stages 1-5 and 5D on haemodialysis), including 31 kidney transplant recipients, were included. In all three studies, patients with CKD and iron deficiency anaemia were randomized to treatment with Feraheme or oral iron. Feraheme was administered as two 510 mg IV single doses and oral iron (ferrous fumarate) was administered as a daily dose of 200 mg elemental iron for 21 days. These studies also included an uncontrolled, follow-up phase in which patients with persistent iron deficiency anaemia could receive two additional 510 mg IV injections of Feraheme.
The primary efficacy endpoint in all three studies was the mean change in Hgb from baseline to Day 35 (five weeks after the initial dose of study medication). Secondary efficacy endpoints included the mean change from baseline in ferritin at three weeks post-initial dose of study medication and the proportion of patients with an increase of at least 1.0 g/dL in Hgb at five weeks post-initial dose of study medication (i.e., Hgb responders).
All three pivotal studies showed that the differences in mean change in Hgb from baseline between the Feraheme groups and the oral iron groups were statistically significant based on the intent-to-treat (ITT) and evaluable populations. The mean increase in Hgb on Day 35 (Week 5) ranged from 0.82 g/dL to 1.21 g/dL in the Feraheme groups as compared to a range of 0.15 g/dL to 0.51 g/dL in the oral iron groups. The results from the secondary efficacy endpoints analyses were consistent with the primary efficacy analysis results. However, it should be noted that the clinical benefit of Feraheme on clinical endpoints such as survival or quality of life was not studied in the clinical program of this submission.
At the end of the randomized phase in all three studies, patients from both the Feraheme and oral iron groups could enter an optional retreatment phase and receive an open-label course of Feraheme as two doses of 510 mg, provided they continued to meet the original study entry criteria. Overall, 69 patients received two additional 510 mg IV injections of Feraheme.
Treatment of patients from the ferumoxytol group of the randomized stage with a second course of ferumoxytol resulted in increases in haemoglobin at Day 35 after retreatment compared to retreatment baseline. In Study B, a statistically significant change in Hgb from the retreatment baseline [0.55 g/dL; probability (p) = 0.0083] was observed at 5 weeks (35 days) after retreatment was started, and significant changes from the retreatment baseline in most of the other efficacy variables were observed at the Day 21R and Day 35R visits. However, in Study A and Study C, the mean change in Hgb from the retreatment baseline observed at 5 weeks was only an increase of 0.31 g/dL and 0.56 g/dL, respectively, which did not reach statistical significance. It was noted that the magnitude of increases in Hgb from baseline was not nearly as high as those observed in the randomized phase for both studies. Treatment of patients for the first time with ferumoxytol in the retreatment phase resulted in significant increases of Hgb from the retreatment baseline in all three studies: Study B, Study A, Study C with 0.69 g/dL, 1.08 g/dL, and 0.80 g/dL; p<0.0001 respectively. A significant change from the retreatment baseline in most of the other efficacy variables analyzed was observed at the Day 21R and Day 35R visits.
It should be noted that there were only minimal data with retreatment of Feraheme in CKD patients. Although retreatment was assessed in a non-randomized phase of the three pivotal studies, only 69 patients received a second course of Feraheme treatment. Furthermore, the primary endpoint of Hgb increase from baseline at 35 days was found to be statistically significant in only one of these studies. Finally, the magnitude of increase was not as high as the results obtained in the randomized phase, and the retreatment phase lacked a control group.
3.3.4 Clinical Safety
In the clinical studies, 1,726 patients were exposed to Feraheme; 1,562 of the patients had CKD and 164 did not have CKD. These studies included the three Studies A,B and C noted above (see section 3.3.3 Clinical Efficacy), as well as, a placebo-controlled, double-blinded cross-over study of a single 510 mg dose of Feraheme vs. saline placebo.
There were 31 deaths in the clinical program, none of which were considered by the investigator to be related to study treatment.
The overall incidence of treatment-emergent adverse events (TEAEs), irrespective of relationship to study medication, was lower in patients following treatment with Feraheme 2 x 510 mg (44.0%) than in those following treatment with oral iron (53.9%). Nausea, dizziness, hypotension, constipation, and peripheral oedema occurred with a frequency of >2% in the patients that received 2 times (x) the 510 mg Feraheme dose, and except for dizziness and hypotension, all of these TEAEs occurred with a higher frequency in the patients treated with oral iron. The incidence of TEAEs was higher after the first injection of Feraheme compared to after the second, third, and fourth. Adverse events (AEs) leading to treatment discontinuation and occurring in ≥2 Feraheme-treated patients included hypotension, infusion site swelling, chest pain, diarrhoea, dizziness, ecchymosis, pruritus, chronic renal failure, and urticaria.
Feraheme may cause serious hypersensitivity reactions, including anaphylaxis/anaphylactoid reactions. An anaphylactoid reaction was reported in 1 out of 1,726 patients during the clinical studies. Serious hypersensitivity reactions were reported in 0.2% (3/1,726) of patients treated with Feraheme. Other adverse reactions potentially associated with hypersensitivity, including pruritus, rash, urticaria, or wheezing, were reported at 3.7% (63/1,726). In the clinical studies of Feraheme in patients with CKD, the rates of pruritus and rash were each 0.8% and the rate of urticaria was 0.1%; the rate of related skin reactions was 0.4%, 0.5% and 0.1% for pruritus, rash and urticaria, respectively. The rate of dyspnoea or wheezing was 1.3%, with only 0.1% considered treatment related. One patient had an anaphylactoid event characterized by hypotension (0.1%), and another (0.1%) had a non-serious AE of flushing characterized as hypersensitivity (0.1%). By comparison, the rates of pruritus, rash and urticaria were 0.7%, 0.3%, and 0%, respectively, with oral iron, and 0.8%, 0% and 0.1% with placebo. Dyspnoea was reported in 1.7% and 1.0% of oral iron and placebo groups, respectively.
Overall, 1.9% (33/1,726) of patients in the Feraheme treatment groups had hypotension AEs, compared with 0.3% in the oral iron group, and 0.8% in the placebo group. Of the 1.9% of patients who reported hypotension with Feraheme, the majority of the events were mild [number (n) = 19; 58%], 12 were moderate, and 3 severe in intensity; of the 0.3% (n = 5) of patients in the Feraheme treatment group who reported serious adverse events of hypotension, two of these patients were also included in the reported cases of serious hypersensitivity reaction. Nearly all of the patients who reported hypotension following Feraheme experienced hypotension alone with no other associated AEs potentially associated with a hypersensitivity reaction. Most hypotensive episodes were transient, managed by observation or volume expansion, and patients recovered without sequelae. Only 4 patients reported hypotension in conjunction with one or more symptoms potentially associated with hypersensitivity reactions. Of the 4 patients, two had preexisting dyspnoea and pruritus, and both cases were judged by clinical investigators as unrelated events. Among the remaining 2 patients, one had non-serious adverse events of hypotension, pruritus, and urticaria within minutes after the first dose of Feraheme (510 mg); subsequently, the patient experienced accelerated hypertension, dizziness, and dyspnoea. The other patient had severe hypotension that was considered an anaphylactoid reaction within minutes after the first dose of Feraheme (510 mg) and was discussed in the corresponding section above. Twenty one (1.2%) of the patients with hypotension events occurred within 24 hours after Feraheme administration.
There were also some observational data from two haemodialysis treatment clinics in the United States with patients receiving more than one course of treatment. These data included over 5,260 CKD patients treated with a total of over 19,500 doses of Feraheme with more than half of the patients having received multiple courses of Feraheme. These observational data suggested that the safety of Feraheme on a retreatment basis is not a concern. However, Health Canada does not recommend the inclusion of retreatment in the Indication section of the Product Monograph.
Post-marketing Data
Review of the post-marketing data revealed 43 cases of serious immune system disorders of which 20 were coded as anaphylactic or anaphylactoid reactions, and 23 were hypersensitivity or drug hypersensitivity reactions. All occurred within 30 minutes post-dosing and were resolved or recovered with treatment except in eight cases where the outcome was unknown. Based on an estimated 186,686 vials, this represents a reporting rate of 23 per 100,000 exposures (0.023%). In addition, there were 8 further serious cases with events suggestive of hypersensitivity, including 1 case with urticaria, 3 cases with pruritus/pruritus generalized and hypotension, dyspnoea, swollen tongue and lip swelling, and 3 cases with angioedema. Of these 8 cases, 4 resolved or recovered with treatment and 4 have an unknown outcome. Including these cases, the reporting rate for serious reactions is 0.027% (28 per 100,000 exposures).
In terms of cardiac disorders reported in the post-market setting, 8 fatal cases and 36 serious events were identified. Based on the review of the 8 fatal cases, no definitive pattern emerged to suggest that the events were associated with systemic hypersensitivity reactions or hypotension, although in three cases treatment-related hypotension may have contributed to death, and in a fourth case systemic hypersensitivity reaction cannot be ruled out.
Review of the post-market data also showed 53 serious adverse events coded as hypotension representing a reporting rate of 0.028%. These were either isolated cases of hypotension or occurring in conjunction with other adverse events, including hypersensitivity reactions. Thus, some of these events overlap with the above cases.
The number of spontaneous fatal cases received for Feraheme was 9 cases from the post-marketing reporting period of June 30, 2009 to September 30, 2010, representing a reporting rate of 0.004% which is lower than the rate observed in the clinical studies (1.2%). While some of the fatal cases reported have a temporal relationship to Feraheme administration, all of these events occurred in patients with multiple, significant confounding factors. No clear mortality signal was identified from the review of the cumulative safety data collected to date since the approval of the drug in the United States. There were also no definitive patterns to suggest that these fatal events were associated with systemic hypersensitivity reactions or hypotension.
This drug submission lacked clinical data for the long term efficacy and safety of the product. It is conceivable that repeated cycles of Feraheme may be needed in clinical practice. There were only 69 patients who received a second course of Feraheme treatment in the non-randomized phase in the whole database. The efficacy and safety of Feraheme on a retreatment basis should be further studied in clinical studies.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
In all three pivotal studies, a positive treatment effect of Feraheme on the mean change from baseline in Hgb was demonstrated, and this effect was similar and consistently greater than oral iron across all patient subgroups regardless of age, gender, race, geographic region, CKD stage, kidney transplant status, erythropoietin-stimulating agent (ESA) therapy, baseline Hgb, baseline ferritin, and use of selected concomitant medications. These results demonstrated that the positive treatment effect of Feraheme is likely to be effective in CKD patients with or without ESA therapy. However, the benefit of Feraheme on clinical endpoints, such as survival or quality of life, was not assessed. In addition, the duration of oral iron therapy is not considered sufficient to allow a proper assessment of its effectiveness.
Only minimal data are currently available for retreatment with Feraheme. Although in the retreatment stage of the pivotal studies a second course of iron therapy with Feraheme resulted in increases in Hgb in patients following a previous course of Feraheme, the primary endpoint of Hgb increase from retreatment baseline at 35 days was found to be statistically significant in only one of the studies. Furthermore, there was no control group and, in general, the extent of the magnitude in the mean increase in Hgb at Week 5 was not nearly as high as that observed in the first course of treatment. There were also some observational data from two haemodialysis treatment clinics in the United States with patients receiving more than one course of treatment. These observational data suggested that the safety of Feraheme on a retreatment basis is not a concern. However, there were no sufficiently robust data to demonstrate efficacy of Feraheme on retreatment. Therefore, Health Canada does not recommend the inclusion of retreatment in the Indication section of the Product Monograph.
The sponsor indicated that the rates of adverse events in the Feraheme clinical development program are consistent with or lower than the rates of adverse events reported in the published literature with other IV iron agents. Feraheme is a colloidal iron oxide, coated with a semi-synthetic carbohydrate specifically designed to minimize immunological reactivity. The ability to administer Feraheme at relatively high doses without dilution or as an infusion has a number of potential benefits, including reducing the number of visits required for providing the full therapeutic course of 1 gram from as many as five or ten down to two visits. It can limit the need for repeated venipuncture and IV catheter placement.
The risks identified with Feraheme included hypersensitivity reactions, hypotension, iron overload and safety in pregnant women.
Feraheme may cause serious and life-threatening hypersensitivity reactions, including anaphylaxis and/or anaphylactoid reactions. In the clinical studies, serious hypersensitivity reactions were reported in 0.2% (3/1726) of the patients receiving Feraheme. Other adverse reactions potentially associated with hypersensitivity (e.g. pruritus, rash, urticaria or wheezing) were reported in 3.7% (63/1726) of these patients. To mitigate the risks, Feraheme is contraindicated in patients with hypersensitivity to this drug or to any ingredient in the formulation. The Product Monograph also includes warnings to observe patients for signs and symptoms of hypersensitivity for at least 30 minutes following each Feraheme injection. Administration of the drug should only take place when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.
Hypotension may also occur and was reported in the clinical studies at 1.9% (33/1,726), including three patients with serious hypotension reactions; two of these serious hypotension reactions were also included in the 0.2% of patients with a serious hypersensitivity reaction. Acute hypotension is defined as a decrease in systolic blood pressure from baseline of >30% or a decrease of >20 mm Hg with symptoms. Among CKD subjects treated with Feraheme, the incidence of hypotension was 3% and 1.3% in subjects treated with Feraheme 2 x 510 mg and 1 x 510 mg, respectively, with 1.6% and 0.3%, respectively, considered related to treatment. The incidence of hypotension was 0.3% in the oral iron group, and 0.8% following placebo. Monitoring of patients for signs and symptoms of hypotension following each Feraheme administration is recommended.
Excessive therapy with parenteral iron including Feraheme can lead to excess storage of iron with the possibility of iatrogenic haemosiderosis. There should be regular monitoring of the haematologic response and iron parameters, such as serum ferritin and transferrin saturation, during parenteral iron therapy (the use of Feraheme). Patients with a serum ferritin of >600 ng/mL were not studied in the Feraheme clinical studies. Feraheme is contraindicated in patients with iron overload.
In regards to teratogenicity, some animal studies showed that ferumoxytol caused foetal malformations and decreased foetal weights. In rabbits, administration of ferumoxytol during organogenesis at a dose of 45 mg Fe/kg/day, which lead to minimal maternal toxicity and is approximately 14 times the estimated human cumulative therapeutic dose (2 x 510 mg iron, based on an estimated exposure to iron for a 70 kg human), resulted in foetotoxicity and external and/or soft tissue fetal malformations in some of the animals. In rats, administration of ferumoxytol during organogenesis at a maternally toxic dose of 100 mg Fe/kg/day, approximately 13.3 times the cumulative human therapeutic ferumoxytol dose, caused a decrease in foetal weights. There are no studies of Feraheme in pregnant women. Feraheme should not be used during pregnancy, and if pregnancy occurs, the patient should be informed of the risks.
The concern regarding free polyglucose sorbitol carboxymethylether (PSC) as a new excipient did not affect the risk/benefit assessment of Feraheme because Health Canada considered there were no additional toxicity concerns for free PSC when compared with PSC-iron complexes based on the totality of the non-clinical toxicology and safety studies data. Health Canada considered the studies submitted in the new drug submission to be adequate to characterize the safety profile of PSC (free and bound) and the ferumoxytol drug product.
Overall, the benefits of Feraheme outweigh the risks for the approved indication. Restrictions to manage the risks associated with the identified safety concerns have been incorporated into the Feraheme Product Monograph.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Feraheme is favourable in the treatment of iron deficiency anaemia in adult patients with chronic kidney disease (CKD). The New Drug Submission (NDS) complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the NOC pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Feraheme
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2009-01-14 |
| Submission filed: | 2009-12-18 |
| Screening 1 | |
| Screening Deficiency Notice issued: | 2010-02-04 |
| Response filed: | 2010-02-18 |
| Screening Acceptance Letter issued: | 2010-04-01 |
| Review 1 | |
| Quality Evaluation complete: | 2011-01-26 |
| Clinical Evaluation complete: | 2011-01-26 |
| Labelling Review complete: | 2011-01-26 |
| Notice of Non-Compliance issued by Director General (safety issues): | 2011-01-26 |
| Response filed: | 2011-01-26 |
| Screening 2 | |
| Screening Acceptance Letter issued: | 2011-07-11 |
| Review 2 | |
| Quality Evaluation complete: | 2011-12-06 |
| Clinical Evaluation complete: | 2011-12-07 |
| Labelling Review complete: | 2011-12-07 |
| Notice of Compliance issued by Director General: | 2011-12-08 |