Summary Basis of Decision for Accrufer

Clinical Pharmacology

Accrufer (ferric maltol) contains iron in a stable ferric state as a complex with a trimaltol ligand. The complex is designed to provide utilizable iron for uptake across the intestinal wall and transfer to the iron transport and storage proteins in the body (transferrin and ferritin, respectively). The complex dissociates on uptake from the gastrointestinal tract allowing iron and maltol to be absorbed separately. The complex itself does not enter the systemic circulation.

Overall, the clinical pharmacology data package contained 24 studies, including 4 prospective pharmacokinetic studies to support the proposed indication.

In a drug-drug interaction study (CYP0747 R3), no significant effect on the permeability of fluoroquinolone antibiotics, ciprofloxacin, or ofloxacin, in the presence of either ferrous sulphate or ferric maltol, were observed. However, this study failed to identify the known in vivo interaction between ferrous sulfate and the fluoroquinolones. Therefore, the lack of observed interaction for ferric maltol was not considered informative. In uridine 5'-diphospho-glucuronosyltransferase (UGT) phenotyping studies, maltol was found glucuronidated exclusively by UGT1A6. No other interaction studies were performed with ferric maltol.

Published study reports demonstrated that iron is absorbed in a rapid and sustained manner from ferric trimaltol. Ferric maltol was not absorbed as a single entity and most of the ingested ferric maltol was found excreted as the glucuronide conjugate. No ferric maltol, maltol, or iron was found in the urine.

In a pharmacokinetic and initial tolerability study (ST10-01-101), after single and repeated twice-daily oral doses of 30 mg, 60 mg, and 90 mg ferric maltol for 8 days in iron-deficient subjects, maltol was found rapidly glucuronidated and renally excreted while iron was independently absorbed. Across the three dosing regimens investigated, exposure to maltol glucuronide was found to increase proportionally to dose. In study ST10-01-102, the pharmacokinetics and iron uptake of 30 mg twice daily ferric maltol was investigated in 15 patients with inflammatory bowel disease from the open-label phase of the pivotal Phase III studies (ST10-01-301 [AEGIS 1] and ST10-01-302 [AEGIS 2]) (see Clinical Efficacy section). Consistent with the findings of study ST10-01-101, study ST10-01-102 also demonstrated that maltol undergoes rapid glucuronidation and is renally excreted. Study ST10-01-103 demonstrated an increased iron uptake in pediatric subjects administered 7.8 mg, 16.6 mg, or 30 mg of ferric maltol twice daily.

Published studies were also submitted to demonstrate that the absorption of iron from ferric maltol was comparable to equivalent doses of ferrous sulfate regardless of strength, formulation type, and vehicle. However, it is important to note that these studies were too limited in their sample sizes to be able to draw definitive conclusions. The effect of food on iron absorption and the tolerability of ferric maltol was investigated in a published randomized, cross-over study. This study showed that iron absorption was greater following the administration of ferric maltol on an empty stomach compared with ferrous sulphate administered after food. In a published single-dose study, iron absorption following administration of ferric maltol (10 mg in aqueous solution) was greater in patients with iron deficiency anemia compared to healthy subjects.

A pharmacokinetic study was conducted to assess the intrinsic factors that may predict the response to oral iron supplementation in patients with inflammatory bowel disease. The study showed that neither C-reactive protein (an indicator of chronic inflammation) nor hepcidin (a master iron regulator) were associated with hemoglobin response.

Two population pharmacokinetic models were used to describe the serum iron concentrations in the targeted population and to determine the significance of possible covariates which may contribute to the differences in iron pharmacokinetic estimates among individuals. The first population pharmacokinetic analysis included data from 243 subjects who had participated in the pharmacokinetic ST10-01-01 and ST10-01-102 studies and the pivotal Phase III ST10-01-301, ST10-01- 302, and ST10-01-303 studies. No covariates tested in this analysis had an effect on the clearance and the absorption constant rate of serum iron from ferric maltol. The second population pharmacokinetic analysis utilized the previously built population pharmacokinetic model. For this analysis, 1,000 patients were simulated using bootstrapped covariates for 30 mg twice-daily and 60 mg once-daily dosing on Day 1 and Day 8 of ferric maltol administration. Based on the population pharmacokinetic analysis, the exposure of ferric maltol was found to be similar between both dosing regimens.

Overall, the clinical pharmacology data are considered appropriate to the use of Accrufer for the specified indication.

For further details, please refer to the Accrufer Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The safety and efficacy of Accrufer for the treatment of iron deficiency anemia was studied in three pivotal Phase III randomized, double-blind, placebo-controlled, multicentre studies: ST10-01-301 (AEGIS 1) in patients with ulcerative colitis and concomitant iron deficiency anemia where oral ferrous preparations have failed or could not be used, ST10-01-302 (AEGIS 2) in patients with Crohn’s disease and concomitant iron deficiency anemia where oral ferrous preparations have failed or could not be used, and ST10-01-303 (AEGIS 3) in patients with non-dialysis dependent chronic kidney disease and concomitant iron deficiency anemia.

Study AEGIS 1/2

Studies AEGIS 1 and AEGIS 2 were identical in protocol and study design. Thus, the two studies were reviewed as one (AEGIS 1/2). The primary objective of AEGIS 1/2 was to demonstrate the efficacy of Accrufer over placebo in the treatment of iron deficiency anemia. These studies enrolled 128 patients (aged 18 to 76 years; 45 males, 83 females) with quiescent inflammatory bowel disease (58 patients with ulcerative colitis, 70 patients with Crohn’s disease), baseline hemoglobin concentrations between 9.5 g/dL and 12 or 13 g/dL (for females or males, respectively) and ferritin concentrations <30 mcg/L. All patients had discontinued prior treatment with oral ferrous preparations due to lack of efficacy or inability to tolerate oral iron replacement products. Patients were randomized 1:1 to receive either 30 mg of Accrufer twice daily or a matched placebo control for 12 weeks. Following completion of the 12-week placebo-controlled phase of the study, eligible patients transitioned to an open-label treatment with Accrufer 30 mg twice daily for an additional 52 weeks.

The primary efficacy endpoint in AEGIS 1/2 was the mean change in hemoglobin concentration from baseline to Week 12. At Week 12, the least squares (LS) mean change in hemoglobin concentration from baseline was 2.25 g/dL in the Accrufer group and 0.06 g/dL in the placebo group. A statistically and clinically significant increase in hemoglobin concentration from baseline to Week 12 was observed with Accrufer compared to placebo (the difference between LS mean change for Accrufer compared to placebo was 2.18 g/dL [p<0.0001]). The secondary efficacy endpoints included the proportion of patients that, at Week 12, were within a normal range or achieved an increase from baseline in hemoglobin concentration of ≥1 g/dL or ≥2 g/dL. The secondary efficacy endpoints (not multiplicity controlled) were supportive of the primary efficacy outcomes. Notably, more patients administered Accrufer achieved a clinically relevant increase of 1 g/dL from baseline at Week 12 compared to those who received placebo (78.1% of Accrufer -treated patients and 10.9% of placebo-treated patients). Fewer (36 [56.3%]) Accrufer-treated patients and no placebo-treated patients achieved an increase of at least 2 g/dL from baseline hemoglobin concentration at Week 12. A total of 42 (65.6%) patients in the Accrufer group and 8 (12.5%) patients in the placebo group achieved normalized hemoglobin concentrations at Week 12.

The results demonstrated that in the Accrufer group, hemoglobin concentrations started increasing from baseline, reaching 13.20 g/dL by Week 12, and stabilizing around 13.0 g/dL between Week 12 and Week 16. The clinically significant difference in hemoglobin concentration from baseline of 1 g/L was observed in the Accrufer group as early as Week 4 of treatment. Similarly, a 1 g/L change in hemoglobin concentration from baseline was observed in the placebo group after the switch to Accrufer in the open-label extension (from Week 12 to Week 16). The small increase in hemoglobin concentration was apparent at Week 24, with only small increases observed thereafter (hemoglobin levels between 13.57 g/dL and 13.95 g/dL). A similar trend was observed in the placebo group after the switch to Accrufer (reaching a maximum hemoglobin concentration after 3 months of administration, with small variations thereafter); however, while still within normal range, the hemoglobin concentrations were lower in this group throughout the study. The data appear to support the recommended duration of treatment of 12 weeks, or longer if required. The subgroup analysis results demonstrated that the treatment effect was independent of gender, age, inflammatory bowel disease activity (based on the Crohn's Disease Activity Index, CDAI), proton-pump inhibitor use, anti-tumor necrosis factor agent use, and acetylsalicylic acid use. The treatment effect was demonstrated in both Crohn’s disease and ulcerative colitis subpopulations. The objective of the study was met; the efficacy of oral Accrufer over the placebo was demonstrated in the treatment of iron deficiency anemia in patients with quiescent inflammatory bowel disease where oral ferrous preparations have failed or cannot be used. Overall, the evidence from the clinical studies support the efficacy of Accrufer in patients with inflammatory bowel disease with a history of prior failure to treatment with oral ferrous preparations.

Mean ferritin levels in the Accrufer group improved steadily from 8.6 mcg/L (standard deviation[SD] of 6.77) at baseline to 26.0 mcg/L (SD of 30.57) at Week 12, demonstrating a mean overall improvement of 17.3 mcg/L. The ferritin value in the Accrufer group continued to steadily increase over the course of the study, whereas the mean ferritin levels in the placebo group showed a mean overall change of 1.2 mcg/L at Week 12 compared to baseline. Overall, mean iron indices (ferritin, iron, transferrin, transferrin receptor, total iron binding capacity, and transferrin saturation) in the Accrufer group improved from baseline over the 12-week course of the double-blind phase of AEGIS 1/2. Conversely, overall, mean iron indices in the placebo group remained largely unchanged over the same period.

Study AEGIS 3

AEGIS 3 enrolled 167 patients (aged 30 to 90 years; 50 males, 117 females) with non-dialysis dependent chronic kidney disease, baseline hemoglobin concentrations between 8 g/dL and 11 g/dL, and ferritin concentrations <25 mcg/L with a transferrin saturation (TSAT) <25%, or ferritin concentrations <500 mcg/L with a TSAT <15%. Compared to AEGIS 1/2, the patients were not required to have failure with oral ferrous preparations to be eligible for participation in this study. The primary objective of this study was to evaluate the efficacy of oral Accrufer compared with the placebo in the treatment of iron deficiency anemia in patients with chronic kidney disease. Patients were randomized 2:1 to receive either 30 mg of Accrufer twice daily or a matched placebo control for 16 weeks. Patients were permitted to continue Accrufer or switch from placebo to Accrufer after 16 weeks for a total of 36 weeks in the open-label phase of the study. The primary efficacy endpoint in AEGIS 3 was the mean change in hemoglobin concentration from baseline to Week 16. At Week 16, the LS mean change in hemoglobin concentration from baseline was 0.50 g/dL in the Accrufer group and ‑0.02 g/dL in the placebo group. A statistically significant increase in hemoglobin concentration from baseline to Week 16 was observed in the Accrufer group compared to the placebo group (the difference between LS mean change for Accrufer compared to placebo was 0.52 g/dL [p = 0.0149]).

The secondary endpoints (not multiplicity controlled) support the primary efficacy results. The responder analysis of hemoglobin concentrations at Week 16 indicated 22 (19.8%) patients had a hemoglobin increase of ≥1 g/dL from baseline in the Accrufer group compared to 5 (8.9%) patients in the placebo group; 7 (6.3%) patients had a hemoglobin increase of ≥2 g/dL from baseline in the Accrufer group compared to none in the placebo group; and 30 (27.0%) patients had hemoglobin concentration measurements ≥11 g/dL in the Accrufer group compared to 7 (12.5%) patients in the placebo group. The results indicated that, numerically, more patients in the Accrufer group than in the placebo group reached a clinically relevant increase in hemoglobin concentration at Week 16. Likewise, numerically, more patients in the Accrufer group than in the placebo group achieved normalization of hemoglobin levels at Week 16. The LS mean change in ferritin concentration from baseline to Week 16 with last observation carried forward was 25.42 mcg/L for the Accrufer group and ‑7.23 mcg/L for the placebo group.

In addition to the pivotal Phase III studies, the sponsor submitted a non-pivotal Phase IIIb study (FERRIC MALTOL-01-304), which was an open-label randomized, controlled, multicentre, non-inferiority study comparing the efficacy of Accrufer with intravenous iron in the treatment and maintenance of iron deficiency anemia in 250 patients with inflammatory bowel disease. The primary efficacy endpoint was the proportion of patients achieving either an increase in hemoglobin concentration of 2 g/dL or normalization of hemoglobin concentration at Week 12 (i.e., ≥12 g/dL for females, ≥13 g/dL for males). The results showed that there was a larger increase in hemoglobin concentration in the patients administered daily intravenous iron compared to those administered 30 mg Accrufer twice daily. The non-inferiority margin was not met; hence, the primary endpoint was not achieved.

Overall, the data from the three pivotal studies demonstrated that treatment with Accrufer was efficacious in patients with a complex multifactorial etiology of iron deficiency anemia (i.e., patients with chronic kidney disease and inflammatory bowel disease). In addition, the data from the studies demonstrated that treatment with Accrufer is efficacious as a second-line treatment in the treatment of iron deficiency anemia in patients who are unresponsive or intolerant to other oral iron preparations. When patients with iron deficiency anemia are not responsive to, or cannot tolerate, other oral iron preparations, the severity of their anemia can become more serious. In patients in whom treatment for iron deficiency anemia is intolerable and/or insufficiently efficacious, a practitioner would determine whether more effective treatments are needed, and intervention from a practitioner would be needed to support the management of failed therapies. Additionally, all of the study populations can be regarded as the worst-case scenario with respect to the treatment of iron deficiency anemia. In patients with inflammatory bowel disease, there is a possibility that absorption of iron in the gastrointestinal tract may be adversely affected as a result of chronic inflammation, leading to the activation of inhibitory iron pathways (e.g., hepcidin). Similarly, patients with chronic kidney disease are also thought to have reduced uptake of oral iron as a result of inflammation.

Although the medicinal ingredient in the Accrufer drug product is ferric maltol, the active moiety is ferric iron. Ferric maltol is not absorbed intactly into the systemic circulation but is a new way of delivering the established active moiety, ferric iron, which is absorbed from the gastrointestinal tract by the same mechanism used to absorb dietary ferric iron. Taking into consideration the pharmacokinetics of ferric maltol and iron metabolism in general, iron absorption in patients with iron deficiency anemia (who are unresponsive or intolerant to other oral iron preparations) but do not have inflammatory bowel disease or chronic kidney disease would therefore be at least equivalent to that established in these Phase III studies. Therefore, by extrapolation, if Accrufer is efficacious in most complex cases of iron deficiency anemia, there is no scientific reason to believe that the product would not be effective in treating iron deficiency anemia in other patient populations who are unresponsive or intolerant to other oral iron preparations.

Thus, the recommended indication is for the treatment of iron deficiency anemia in adult patients who are unresponsive or intolerant to other oral iron preparations.

Indication

Sponsor's proposed indication	Health Canada-approved indication
Accrufer (ferric maltol capsules) is indicated in adults for the treatment of iron deficiency in patients who are inadequately treated with or cannot tolerate other oral iron preparations.	Accrufer (ferric maltol capsules) is indicated for the treatment of iron deficiency anemia in adult patients who are unresponsive or intolerant to other oral iron preparations.

For more information, refer to the Accrufer Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety profile of Accrufer was mainly characterized based on data from 295 patients enrolled in the pivotal Phase III studies (AEGIS 1, AEGIS 2, and AEGIS 3; described in the Clinical Efficacy section), as well as post-marketing experience from 13,948 patient-years of exposure in the European Union, the United States, and other countries.

Study AEGIS 1/2

In AEGIS 1/2, 111 patients were treated with 30 mg of Accrufer twice daily (double-blind and open-label portions of the studies combined). The majority of patients (88.2%) were treated for more than 12 weeks, while 65 patients (58.6%) were treated for 52 weeks or longer.

The majority of patients experienced treatment-emergent adverse events (TEAEs) that were mild or moderate in intensity. No patients died during the study duration. The most commonly reported TEAEs in the double-blind phase were abdominal pain (8 [12.5%] Accrufer-treated patients versus [vs.] 5 [7.8%] placebo-treated patients), diarrhea (6 [9.4%] vs. 4 [6.3%]), constipation (5 [7.8%] vs. 1 [1.6%]), and rectal haemorrhage (3 [4.7%] vs. 1 [1.6]). Flatulence (4 [6.3%]), arthralgia (3 [4.7%]), and abdominal discomfort (3 [4.7%]) were only reported in Accrufer-treated patients. During the open-label phase, gastrointestinal events tended to be more frequent in those who switched from placebo to Accrufer treatment compared to those who had received Accrufer in the double-blind phase. The profile of adverse events observed in the open-label phase was comparable to that of the Accrufer group in the double-blind phase.

During the double-blind phase, the most common study drug-related adverse event of abdominal pain occurred in 5 (7.8%) patients in the Accrufer group and 4 (6.3%) patients in the placebo group. Other more common treatment-related adverse events were constipation (4 [6.3%] vs. 1 [1.6%]) and flatulence (4 [6.3%] vs. 0). All other study drug-related adverse events occurred in 1 (1.6%) or 2 (3.1%) patients in either treatment group.

The most frequently reported severe TEAEs during the double-blind phase were abdominal pain (5 [7.8%] vs. 1 [1.6%]) and diarrhea (3 [4.7%] vs. 1 [1.6%]). Severe TEAEs of abdominal pain were considered drug related in 3 (4.7%) patients in the Accrufer group and 1 (1.6%) patient in the placebo group. Severe diarrhea was considered drug related in 1 (1.6%) patient in the Accrufer group.

During the double-blind phase, TEAEs leading to discontinuation in the Accrufer group were constipation (1 event), rectal hemorrhage (2 events), abdominal pain (1 event), Crohn’s disease (1 event), and diarrhea (1 event). Of these, constipation, diarrhea, and abdominal pain were assessed as drug related. All events of Crohn’s disease were an exacerbation of the existing condition. In the placebo group, TEAEs which led to drug discontinuation were abdominal pain (2 events, both assessed as related to the study drug) and Crohn’s disease (2 events, both assessed as unrelated to the study drug).

During the open-label phase wherein all patients were treated with Accrufer 30 mg twice daily for an additional 52 weeks, there were 12 events leading to treatment discontinuation; 4 events of diarrhea (including 1 event of hemorrhagic diarrhea), all assessed as related to treatment; 3 events of Crohn’s disease exacerbation, all assessed as unrelated to study treatment; 2 events of abdominal pain, all assessed as related to study treatment; 1 unrelated event of rectal hemorrhage; and 1 related event of flatulence.

Overall, the majority of adverse events reported in the study were gastrointestinal, with abdominal pain, constipation, diarrhea, and flatulence being the most common and reported more frequently in the Accrufer group than the placebo group.

Study AEGIS 3

In AEGIS 3, 167 patients received Accrufer (111 patients) or placebo (56 patients) during both treatment periods. The majority of patients (91 [54.5%] patients) were exposed to Accrufer (60 [54.1%]) or placebo (31 [55.4%]) for a duration of 57 to 112 days.

The majority of TEAEs reported in the study were of mild to moderate intensity. Two patients died during the double-blind 16-week treatment period; 1 in the Accrufer group and 1 in a placebo group. These events were assessed as being unrelated to the study drug.

The TEAEs more frequently reported in the Accrufer group compared to the placebo group during the double-blind 16-week treatment period were diarrhea (9.0% vs. 8.9%), constipation (8.1% vs. 3.6%), and discolored feces (7.2% vs. 1.8%).

The drug-related adverse events more frequently reported in the Accrufer group compared to the placebo group during the double-blind 16-week treatment period were diarrhea (6 [5.4%] vs. 2 [3.6%]), discolored feces (7 [6.3%] vs. 1 [1.8%]), flatulence (4 [3.6%] vs. 0), nausea (3 [2.7%] vs. 1 [1.8%]), constipation (3 [2.7%] vs. 0), and vomiting (3 [2.7%] vs. 0).

Serious adverse events (SAEs) were reported in 23 (20.7%) patients in the Accrufer group and 12 (21.4%) patients in the placebo group. No treatment-related SAEs were reported in either treatment group.

During the double-blind 16-week treatment period, study drug was withdrawn in 12 (7.2%) patients: 7 (6.3%) patients in the Accrufer group and 5 (8.9%) patients in the placebo group. Only 3 patients experienced study drug-related adverse events that led to discontinuation: 1 patient in the Accrufer group experienced study drug-related adverse events of nausea and vomiting; 1 patient in the Accrufer group experienced study drug-related adverse events of diarrhea, nausea, and vomiting; and 1 patient in the placebo group experienced study drug-related adverse events of asthenia and dizziness.

In the open-label phase, the most frequently reported severe TEAEs were congestive cardiac failure (3 [2.4%] patients: 1 patient originally from the Accrufer group and 2 patients originally from the placebo group) and acute kidney injury (3 [2.4%] patients: 1 patient originally from the Accrufer group and 2 patients originally from the placebo group).

Similar to AEGIS 1/2, the majority of adverse events reported in AEGIS 3 were gastrointestinal in nature. However, while the most commonly reported adverse event in this study population was constipation/diarrhea, flatulence, and discoloured feces, the most commonly reported adverse event in AEGIS 1/2 was abdominal pain. This is an important distinction which does not support pooling of the safety results from these clinical studies, because of a potential for underreporting of the most important event occurring in different study populations. This distinction is reflected in the Accrufer Product Monograph.

In the combined safety population from the double-blind phases of studies AEGIS 1/2 and AEGIS 3, the most frequently reported TEAEs in patients from the Accrufer group were diarrhea (16 [9.1%] patients), constipation (14 [8.0%] patients), nausea (9 [5.1%] patients), abdominal pain (9 [5.1%] patients), and flatulence (9 [5.1%] patients). The frequency of these events was higher in the Accrufer group compared to that in the combined placebo group. Similarly, the frequency of rectal bleeding was higher in the Accrufer group (4 [2.3%]) compared to the combined placebo group (1 [0.8%]).

It should be noted that the pivotal clinical studies did not include an active-comparator arm. Therefore, the safety profile of Accrufer could not be compared to that of other oral iron preparations.

Overall, the safety profile of Accrufer is acceptable. The majority of adverse events were mild to moderate in severity. Appropriate warnings and precautions are in place in the approved Accrufer Product Monograph to address the identified safety concerns.

For more information, refer to the Accrufer Product Monograph, approved by Health Canada and available through the Drug Product Database.

The non-clinical data included an in vitro pharmacokinetic drug-drug interaction study, toxicological studies for both ferric maltol and maltol, and literature sources.

Overall, the non-clinical studies did not demonstrate that iron released from orally administered ferric maltol differs in pharmacological activity from the iron in existing iron-containing preparations, including ferrous salts. The uptake of iron from ferric maltol and its subsequent metabolism utilize the physiological processes involved in the uptake of both dietary and supplementary iron. There is no new mechanism of action for ferric maltol compared to existing oral ferrous sulphate preparations. The available data indicate that ferric maltol is a soluble, chemically stable complex of ferric iron and maltol acting orally as an iron delivery system to duodenal enterocytes. Overall, the toxicology of iron and maltol can be considered separately from a systemic point of view.

The iron that is released from the ferric maltol complex for delivery to the intestinal enterocytes has well-established pharmacodynamic drug interactions; therefore, it did not strictly require pharmacokinetic drug interaction studies to be completed. Iron-drug interactions of clinical significance have been reported to occur with numerous concomitant therapies due to the formation of iron-drug complexes by means of chelation or binding of iron by the second drug. A drug-drug interaction study was filed that included 11 in vitro binding studies to evaluate the potential for ferric maltol to bind to commonly used concomitant oral medications. Pharmacokinetic drug interactions are adequately presented in the Accrufer Product Monograph. Non-clinical pharmacology, pharmacodynamic, and pharmacokinetic data were not submitted with the non-clinical package or included in the Accrufer Product Monograph.

No acute toxicology studies with ferric maltol were submitted; however, two literature references established the lethal dose (LD₅₀) of maltol to be 550 mg/kg for female mice, 848 mg/kg for male mice, 1,410 mg/kg for male guinea pigs, and 1,440 mg/kg for male rats.

Repeat-dose studies conducted with ferric maltol (dogs only) and maltol (rats, mice, and dogs) did not reveal any safety issues for the proposed dosage and indication of Accrufer in humans when orally administered at maximum doses of 500 mg/kg/day in dogs and 400 mg/kg/day in rodents. The no-observed-adverse-effect level (NOAEL) for ferric maltol in beagle dogs was 125 mg/kg/day, which provided safety margins of approximately 10 times the human equivalent dose based on body surface area, and was 300 mg/kg/day for maltol in beagle dogs, which provided safety margins of approximately 25 times the human equivalent dose. In dogs, intermittent dose-dependent vomiting occurred in the intermediate- and high-dose groups (i.e., 250 and 500 mg/kg/day) between 2.6 to 6 hours post dose, and had the highest incidence in the high-dose group in the absence of other significant gastrointestinal effects. This was associated with a reduction in food consumption and weight gain. Consumption of ferric maltol resulted in increased weights of the liver, kidney, adrenals, thyroid, and spleen. The organ weight increases were different across dose groups and sexes. The mid-dose group (250 mg/kg) had increased liver, kidney, and spleen weights, whereas the low-dose group (125 mg/kg) only had increased liver weights by the end of the study, with no other notable effects. In rats and mice, the NOAEL for maltol was 400 mg/kg/day, with no other notable toxicological effects related to treatment.

Ferric maltol was mutagenic in the in vitro bacterial reverse mutation (Ames) assay in both the absence and presence of metabolic activation. Maltol was also mutagenic in the Ames assay. Both ferric maltol and maltol only induced mutations at the higher test concentrations. Ferric maltol rendered positive responses in both the absence and presence of metabolic activation at concentrations above 1,700 mcg/plate, whereas maltol was only positive for mutagenic activity at >5,000 mcg/plate in the absence of metabolic activation. Maltol also increased micronucleus formation in an in vivo clastogenicity assay in mice when administered via intraperitoneal injection (not orally administered as the intended route of administration in humans) at the high dose (i.e., 774 mg/kg) 24 hours post administration of the test article. There was no evidence of micronucleus induction at Hour 48 or Hour 72 at the high dose or at the other two lower doses tested; however, maltol was not carcinogenic in an 18-month study in mice at doses up to 400 mg/kg (approximately 5 times the human daily dose) or in a 2-year study in rats at doses up to 400 mg/kg (approximately 10 times the human daily dose). Based on the data that are currently available, the carcinogenic potential of ferric maltol when orally administered to treat iron deficiency anemia (30 mg of ferric maltol twice daily) appears to be low. Moreover, absorbed maltol is rapidly conjugated with glucuronic acid and excreted in the urine; therefore, it is unlikely that the mutagenic activity of maltol would be of toxicological concern in humans when administered orally at the dosage recommendations.

Reproductive and developmental studies have not been conducted with ferric maltol. Chronic maltol exposure did not effect the fertility or reproductive capability of rats. Chronic exposure to maltol at doses up to 400 mg/kg/day did not affect copulation rate, mating behaviour, mating index, fertility index, gestation, parturition, or lactation in rats. No juvenile animal studies of ferric maltol or maltol were submitted.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Accrufer Product Monograph. In view of the intended use of Accrufer, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.

For more information, refer to the Accrufer Product Monograph, approved by Health Canada and available through the Drug Product Database.

The quality (chemistry and manufacturing) information submitted for Accrufer has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is 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 at room temperature (15 ºC to 30 ºC).

The proposed drug-related impurity limits are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits and/or qualified from toxicological studies).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy.)

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.

One excipient in the drug product, lactose monohydrate, is of animal origin. Several packaging components may use small amounts of animal derived tallow or other substances of bovine origin during manufacture. All materials of animal origin are in compliance with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products (EMEA/410/01, Revision 3). Certification letters attesting to these claims were provided by the sponsor.