Summary Basis of Decision for Ferinject

As outlined in the What steps led to the approval of Ferinject? section, during the clinical review of the New Drug Submission for Ferinject, reviews completed by other national drug regulatory bodies were used as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. The review of the pediatric studies was conducted as per Method 1.

Clinical Pharmacology

Ferinject is a colloidal dispersion of ferric carboxymaltose. It contains iron in a stable ferric state as a non-dextran iron complex consisting of a polynuclear iron hydroxide core with a carbohydrate ligand. The complex is designed to provide utilisable iron for the iron transport and storage proteins in the body (transferrin and ferritin, respectively).

The clinical pharmacology data included reports on the human pharmacodynamic (PD) and pharmacokinetic (PK) studies.

In adults administered a single dose of Ferinject (100 to 1,000 mg of iron), total serum iron increased, with the mean maximum concentration (C_max) ranging from 37 µg/mL to 331 µg/mL after 15 minutes to 1.21 hours post dose and the mean area under the concentration-time curve from zero to the last measurable concentration (AUC_0‑t) ranging from 426 µg*h/mL to 6,311 µg*h/mL. The C_max was proportional to the dose, while a more-than-proportional increase was observed in the AUC with increasing doses. In all single‑dose studies, serum iron levels declined to baseline in a mono‑exponential fashion, with a half-life of 10 to 20 hours. In a multiple‑dose study, serum iron levels returned to baseline within 4 to 7 days, and no accumulation of serum iron was observed.

The results of a postpartum anemia study showed that 1% or less of iron from the administered Ferinject dose is transferred to human milk.

In pediatric patients with iron deficiency anemia (IDA), serum iron increased proportionally with the dose administered following a single dose of 7.5 mg iron/kg or 15 mg iron/kg of Ferinject.

The population PK model adequately described the pharmacokinetics of Ferinject in pediatric patients with IDA after up to two doses of 15 mg iron/kg (maximum 750 mg/dose) per course of treatment. The PK and PKPD post hoc predictions and simulations showed that the exposure and PD response in pediatric patients receiving the recommended pediatric dose are, in general, within the range of those in reference adults receiving the recommended dose.

Ferinject treatment in patients with IDA led to an increase in PD response that included hemoglobin levels, reticulocyte counts, transferrin saturation, and serum ferritin levels.

Electrocardiogram parameters were assessed in patients with mild IDA who were administered single doses of Ferinject. There was no evidence of QT/corrected QT (QTc) prolongation potential.

The clinical pharmacology data support the use of Ferinject for the recommended indication. For further details, please refer to the Ferinject Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

Treatment of Iron Deficiency Anemia in Adult Patients

The overall support for the use of Ferinject for the treatment of IDA in adults when oral preparations are not tolerated or are ineffective is based on a totality-of-evidence approach. Five pivotal clinical studies provided data to assess the efficacy of Ferinject in adult patients with IDA of various etiologies, specifically in patients with hemodialysis-dependent chronic kidney disease, (HDD-CKD), non-dialysis-dependent CKD (NDD-CKD), or inflammatory bowel disease (IBD), and women in the postpartum period. The pivotal studies had adequate study designs with clinically relevant endpoints for demonstration of benefit in these patients. As the physiological response to iron supplementation is consistent in all patients with IDA, regardless of the underlying cause, it is reasonable to consider the evidence of efficacy demonstrated in the pivotal studies as applicable to a general population of patients with IDA. In these studies, patients were treated with Ferinject at the recommended dose (15 mg iron/kg; 1,000 mg iron maximum).

Patients with Chronic Kidney Disease

The efficacy of Ferinject in the treatment of IDA associated with CKD was evaluated in one study in patients with HDD-CKD (Study VIT-IV-CL-015) and one study in patients with NDD-CKD (Study FER-CKD-01).

Study VIT-IV-CL-015

Study VIT-IV-CL-015 was a Phase III, open-label, randomized, active-controlled study that compared the efficacy of Ferinject and iron sucrose in patients on hemodialysis with IDA associated with chronic renal failure. Patients had hemoglobin (Hb) ≤115 g/L and transferrin saturation (TSAT) <20% or serum ferritin <200 ng/mL, with or without erythropoietin therapy. After randomization, patients were administered Ferinject or iron sucrose two to three times per week in single doses of 200 mg iron directly into the dialyser until the individually calculated cumulative iron dose was reached (mean cumulative dose of iron as Ferinject: 1,700 mg).

The primary efficacy endpoint was the percentage of patients in the per‑protocol population reaching an Hb increase of ≥10 g/L at 4 weeks after baseline. Of the patients treated with Ferinject, 46.4% had an increase in Hb of ≥10 g/L at 4 weeks after baseline, compared to 37.2% of patients treated with iron sucrose (p = 0.210). However, the study was not powered to detect differences between treatment arms, and statistical significance could not be determined.

Study FER-CKD-01

Study FER-CKD-01 was a Phase III, open-label, randomized, active-controlled, dose-ranging study that compared the long-term efficacy of high-dose and low-dose Ferinject to oral iron to delay or reduce additional or alternative anemia management or Hb trigger in NDD-CKD patients.

The study enrolled patients with Hb levels of 90 to 110 g/L and serum ferritin <100 ng/mL or <200 ng/mL with TSAT <20%, without erythropoiesis-stimulating agent therapy. For a period of 52 weeks, patients were administered high-dose Ferinject (≤1,000 mg iron) once per month, targeting higher serum ferritin levels (400 to 600 ng/mL); low-dose Ferinject (≤200 mg iron) once per month, targeting lower serum ferritin levels (100 to 200 ng/mL); or oral iron (100 mg ferrous sulphate, two times daily).

The primary efficacy endpoint was the time to either the initiation of additional or alternative anemia management, or two consecutive Hb values less than 10 g/L (without an Hb increase of 5 g/L or greater between the values).

The results of the study demonstrated that the time to initiation of additional or alternative anemia management or to the Hb trigger was significantly longer for patients in the Ferinject high-dose treatment arm compared to those in the oral iron treatment arm with a hazard ratio (HR) of 0.65 (95% confidence interval [CI]: 0.44, 0.95; p = 0.026). The comparison between the two Ferinject groups was not powered to reach statistical significance.

Patients with Inflammatory Bowel Disease

Study VIT-IV-CL-008

Study VIT-IV-CL-008 was a Phase III, open-label, randomized, active-controlled study conducted to test the non-inferiority of Ferinject compared to oral iron in reducing IDA in patients with chronic IBD (Crohn disease or ulcerative colitis). Enrolled patients had Hb ≤110 g/L, and TSAT <20% or serum ferritin <100 ng/mL, with a calculated iron requirement of at least 1,000 mg. Patients were randomized 2:1 to treatment with Ferinject (maximum 1,000 mg per infusion) at 1-week intervals until the patient’s calculated total iron deficit was reached, or to oral iron (100 mg ferrous sulphate) twice daily for 12 weeks.

The primary endpoint was the change in Hb from baseline to Week 12. The results of the study demonstrated that treatment with Ferinject was non-inferior to oral iron for the change in hemoglobin from baseline to Week 12 as the least squares mean difference of 0.73 was higher than the lower limit of the 95% CI (-5.0, 6.46).

Study FER-IBD-07-COR

Study FER-IBD-07-COR was a Phase III, open-label, randomized, active-controlled study conducted to compare the efficacy of a simplified dosing schedule (based on Hb and body weight) of Ferinject to individually calculated iron sucrose doses in chronic IBD patients. The study included patients with mild IBD (Crohn disease or ulcerative colitis), Hb of 70 to 120 g/L (women) or 70 to 130 g/L (men), and serum ferritin <100 ng/mL. Patients were treated with Ferinject with up to three infusions of 1,000 mg or 500 mg iron, according to their Hb and body weight, with the total weekly dose not exceeding 1,000 mg. Calculated iron sucrose doses of up to 11 infusions of 200 mg iron within 3 weeks following randomization were administered to patients in the control arm.

The primary endpoint was the number of responders, defined as an increase in Hb of 20 g/L or more by Week 12. The results of the study demonstrated that significantly more patients in the Ferinject treatment arm achieved an increase in Hb of 20 g/L or more at Week 12 compared to the IV iron sucrose treatment arm (65.8% versus [vs.] 53.6%, respectively; p = 0.004).

Women in the Postpartum Period

Study 1VIT06011

Study 1VIT06011 was a Phase III, open-label, randomized, active-controlled trial conducted to compare the efficacy of Ferinject to oral iron in women with postpartum IDA less than 10 days after delivery with Hb ≤100 g/L. Patients received either Ferinject ≤1,000 mg (15 mg/kg), repeated weekly to a calculated replacement dose (maximum 2,500 mg), or oral iron (ferrous sulfate 325 mg) three times daily for 6 weeks.

The results of the study demonstrated that patients treated with Ferinject were significantly more likely to achieve Hb >120 g/L by Study Day 42 (primary efficacy endpoint) than those treated with oral iron (91.4% vs. 66.7%; p <0.0001).

Patients with Heart Failure (New York Heart Association [NYHA] Class II/III)

Study FER-CARS-05

Study FER-CARS-05 was a randomized, double-blind, placebo-controlled study conducted in patients with iron deficiency and chronic heart failure (CHF) with left ventricular ejection fraction <45% and NYHA Class II/III to determine the effect of Ferinject on exercise tolerance. Patients were randomized to receive Ferinject or placebo (0.9% saline IV) for 36 weeks, stratified by screening Hb values.

The results of the study demonstrated that patients treated with Ferinject had a significantly prolonged 6-Minute Walk Test distance at Week 24 (primary efficacy endpoint) compared to patients treated with placebo (difference ± standard deviation for Ferinject vs. placebo: 33 ± 11 m [p = 0.002]).

Pediatric Patients with Iron Deficiency Anemia

The pivotal study assessing the treatment of pediatric patients with iron deficiency anemia with Ferinject (Study 1VIT17044) did not meet its primary efficacy endpoint, as superiority of Ferinject over oral iron was not demonstrated in the studied patient population. However, there was no evidence of a detrimental effect in patients treated with Ferinject compared to oral iron, and its use in pediatric patients was supported by evidence from adequate and well-controlled studies of Ferinject in adults, with additional pharmacokinetic and safety data in pediatric patients aged 1 year and older.

Pharmacokinetic analyses demonstrated that serum iron increased proportionally to the dose after a single dose of 7.5 mg iron/kg or 15 mg iron/kg of Ferinject in pediatric patients with IDA. Model predictions and simulations showed that the exposure and pharmacodynamic response in pediatric patients receiving the recommended pediatric dose are within the range of those in reference adults receiving the recommended dose.

Extrapolation from adult patients to pediatric patients is considered reasonable, based on the following evidence-based assumptions. Iron deficiency anemia is sufficiently similar in adults and children, as the clinical and symptom markers are the same for diagnosis for adult and pediatric patients. The response to treatment for patients with IDA is sufficiently similar in adults and children, as the same signs and symptoms are used for diagnosis and response assessment. Adults and children have a sufficiently similar exposure-response relationship.

Indication

The New Drug Submission for Ferinject was filed by the sponsor with the following proposed indication:

Ferinject (ferric carboxymaltose) is indicated:

• for the treatment of iron deficiency in adults, as well as children and adolescents 1 to 17 years old, when oral iron preparations are ineffective or cannot be used.

• when there is a clinical need to deliver iron rapidly.

The diagnosis of iron deficiency must be based on laboratory tests.

Based on the review of the submitted data, revisions were made to the proposed indication to accurately reflect the patients for whom there is a favourable benefit-harm-uncertainty determination. Accordingly, Health Canada approved the following indication:

Ferinject (ferric carboxymaltose) is indicated:

• for the treatment of iron deficiency anemia (IDA) in adult and pediatric patients 1 year of age and older when oral preparations are not tolerated or are ineffective.

• for the treatment of iron deficiency in adult patients with heart failure and New York Heart Association (NYHA) Class II/III to improve exercise capacity.

The diagnosis of iron deficiency must be based on laboratory tests.

Overall Analysis of Efficacy

The overall support for the use of Ferinject for the treatment of IDA in adults is based on the totality of evidence. The physiological response to iron supplementation is the same and consistent in all patients with IDA, regardless of the underlying cause of the anemia. Together, the data demonstrated clinically relevant benefit of the treatment of IDA with Ferinject regardless of the cause.

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

Clinical Safety

The clinical safety of Ferinject was evaluated using analyses of data from the clinical studies including the pivotal studies described in the Clinical Efficacy section and two pivotal safety studies (1VIT07018 and 1VIT07017).

In the overall pooled safety population of patients with IDA treated with Ferinject (2,196 patients), the most commonly reported adverse reactions (occurring in 2% or more of patients) were headache, edema, hypertension, injection/infusion site reactions, rash, arthralgia, urinary tract infections, dizziness, nausea, nasopharyngitis, and diarrhea. Pyrexia, headache, and pulmonary embolism were the only treatment-related serious adverse events (SAEs) reported for Ferinject-treated patients. No SAEs were reported at a rate of more than 1% in the pooled population of patients treated with Ferinject.

Hypophosphatemia and hypersensitivity reactions were identified as clinically significant adverse events in Ferinject-treated patients. Hypersensitivity and anaphylactic reactions are known risks associated with all intravenous (IV) iron products, and serious, life-threatening, and fatal anaphylactic/anaphylactoid reactions have been reported in patients receiving IV iron products, including Ferinject. In clinical studies, a pooled safety analysis showed that hypersensitivity was reported at the same frequency in patients treated with Ferinject as in patients treated with other IV iron products. Anaphylactic reactions were reported less frequently in Ferinject-treated patients than in patients treated with other IV iron products. No deaths due to hypersensitivity or anaphylactic reactions were reported in the Ferinject clinical studies. Serious hypersensitivity reactions, including life-threatening and fatal anaphylaxis/anaphylactoid reactions in Ferinject-treated patients have been reported only in the post-marketing setting in other countries. Mild to moderate hypersensitivity reactions have been reported in both clinical studies and post-marketing studies. Hypersensitivity reactions have been reported after previously uneventful administration of any parenteral iron complexes. The risk is enhanced for patients with known allergies including drug allergies, and patients with a history of severe asthma, eczema, or other atopic allergy. Cases of symptomatic hypophosphatemia with serious outcomes, including hypophosphatemic osteomalacia and fractures that required clinical intervention including surgery, have been reported in the post-marketing setting. Transient decrease of blood phosphorus below 2.5 mg/dL was reported in 45% of Ferinject-treated patients in clinical studies. The decrease in blood phosphorus in most cases was asymptomatic with treatment-emergent adverse events (TEAEs) reported in 3% of Ferinject-treated patients.

Safety data during use in pregnancy (gestation weeks 16 to 33 inclusive) was available from Study FER-ASAP-2009-01 where it showed that TEAEs were reported by a higher proportion of patients administered Ferinject (48.8%) compared to the oral iron group (40.3%). Adverse events were reported in slightly more newborns from mothers treated with Ferinject (9.8%) than in newborns from mothers treated with oral iron (6.4%). The benefit-risk balance for this specific patient population is considered acceptable in the context of a second-line treatment for patients for whom oral iron is ineffective or not tolerated.

Safety data during breastfeeding was available from Study VIT-IV-CL-009 where iron content in the breast milk of Ferinject-treated patients was observed to be higher compared to breast milk of oral iron-treated patients. The highest value measured in the Ferinject group exceeded the recommended iron content for infant formula by less than 15%. Treatment-emergent adverse event profiles were similar in infants breastfed by patients treated with Ferinject (10.5%) or oral iron (12.0%), with the most commonly reported TEAEs occurring in the Gastrointestinal Disorders System Organ Class (SOC).

The safety profile reported in the pediatric population was consistent with that reported in adult patients. There were no new or unexpected TEAEs observed in the pediatric population; the most commonly reported TEAEs were hypophosphatemia, rash, injection/infusion site reaction, headache, and vomiting. The majority of the observed TEAEs were mild and resolved spontaneously or after appropriate therapeutic intervention. In Study 1 VIT17044, the incidence of TEAEs was higher in the Ferinject arm (35.0%) compared to that in the oral iron arm (24.3%). Treatment-emergent adverse events considered related to study treatment occurred in 17.5% and 13.2% of patients in the Ferinject and oral iron arms, respectively. The most frequently reported treatment-related TEAEs in the Ferinject arm were hypophosphatemia and urticaria.

Safety data for patients with heart failure and ID was available from Study FER-CARS-02 where the TEAE profile was as expected for this population, with the highest incidence of TEAEs in the SOC of Cardiac Disorders in both treatment arms (38.2% and 37.5% in the Ferinject and placebo arms, respectively). Overall, the most commonly reported TEAEs in the Ferinject arm were hypertension, headache, dizziness, fatigue, atrial fibrillation, chest pain, and sinus bradycardia.

Overall, the benefits of Ferinject therapy seen in the pivotal studies are positive and are considered to outweigh the potential risks. Ferinject has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through the use of temporary treatment discontinuation and standard medical care, in addition to labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Ferinject Product Monograph to address the identified safety concerns. Consistent with the labelling for other IV iron products authorized in Canada, a Serious Warnings and Precautions Box has been included in the Ferinject Product Monograph highlighting the identified risk of serious, life-threatening, and fatal hypersensitivity associated with IV iron products. Other warnings and precautions emphasize the risk of hypophosphatemia, hypophosphatemic osteomalacia, and infections, and provide monitoring recommendations to reduce the risk of iron accumulation.

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

As outlined in the What steps led to the approval of Ferinject? section, during the review of the non-clinical component of the New Drug Submission for Ferinject, reviews completed by other national drug regulatory bodies were used as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The subchronic toxicity of ferric carboxymaltose was investigated in repeat-dose studies of up to 26 weeks in rats and dogs. Major toxicity in both species was related to iron deposition in organs, of which the liver, spleen, kidney, and lymph nodes were the principal target organs. Adverse effects observed included reduced red cell parameters, increased spleen, liver, and kidney weights, and laboratory findings indicative of impaired liver and kidney function. The no-observed-adverse-effect level (NOAEL) was 3 mg/kg/week (human equivalent dose [HED] of 0.5 mg/kg/week) in rats and 9 mg/kg/week (HED of 5 mg/kg/week) in dogs.

Ferric carboxymaltose did not show potential for genotoxicity in in vitro and in vivo genotoxicity studies, and the omission of carcinogenicity studies was considered acceptable.

No adverse reproductive effects were observed in a fertility and early embryonic development study in rats at a dose of up to 30 mg/kg three times a week (HED of 15 mg/kg/week). In embryo-fetal development studies in rats and rabbits, adverse effects were observed in the presence of maternal toxicity.

Safety pharmacology studies conducted in rats and dogs given ferric carboxymaltose at a dose of up to 90 mg/kg did not show any significant adverse effects on the cardiovascular, central nervous, respiratory, or renal systems.

Pharmacokinetic studies using radiolabelled ferric carboxymaltose showed that iron from an intravenous (IV) dose is rapidly cleared from the plasma in all species tested.

Placental transfer of iron after IV administration of ferric carboxymaltose was observed in pregnant rat studies; 3.1% and 9.2% of the dose was recovered in placenta and fetuses, respectively, 7 days post dose.

Studies in lactating rats showed transfer of iron into the milk following IV injection of ferric carboxymaltose. The concentration of iron in milk was 2% of that in plasma at 1 hour post dose, and the amount of iron recovered in milk samples was less than 1% of the injected dose. A total of 12.2% of the injected dose was recovered in the carcasses of offspring 28 days after injection.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Ferinject Product Monograph. In view of the intended use of Ferinject, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product. For more information, refer to the Ferinject Product Monograph, approved by Health Canada and available through the Drug Product Database.

As outlined in the What steps led to the approval of Ferinject? section, during the review of the quality component of the New Drug Submission for Ferinject, reviews completed by other national drug regulatory bodies were used as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The chemistry and manufacturing information submitted for Ferinject 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 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 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, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.

None of the excipients used in the formulation of Ferinject is of human or animal origin.