Regulatory Decision Summary for Ferinject

The purpose of this New Drug Submission (NDS) was to seek authorization of Ferinject (ferric carboxymaltose) for the treatment of iron deficiency when oral iron preparations are ineffective or cannot be used or when there is a clinical need to deliver iron rapidly.

Upon review, the approved indications were for the treatment of iron deficiency anemia (IDA) in adult and pediatric patients 1 year of age and older when oral iron preparations are not tolerated or are ineffective and for the treatment of iron deficiency (ID) in adult patients with heart failure and New York Heart Association (NYHA) class II/III to improve exercise capacity.

Five pivotal clinical trials were conducted to assess the efficacy of Ferinject (ferric carboxymaltose, FCM) in adult patients with iron deficiency anemia (IDA) across various therapy areas. In patients with hemodialysis-dependent chronic kidney disease (HDD-CKD) and IDA, more patients treated with Ferinject had an increase ≥10 g/L in hemoglobin (Hb) compared to patients treated with iron sucrose. Another study showed that patients with non-dialysis dependent chronic kidney disease (NDD-CKD) and IDA had a significantly longer time to initiation of additional or alternative anemia management compared to patients treated with oral iron. There were two pivotal studies performed in patients with irritable bowel disease (IBD) with IDA; one of which demonstrated non-inferiority of patients treated with FCM compared to those treated with oral iron in the change in Hb from baseline to week 12, while the other demonstrated that significantly higher proportions of FCM-treated patients achieved Hb response compared to those treated with iron sucrose. An additional pivotal trial in postpartum women with IDA demonstrated that patients treated with FCM were significantly more likely to achieve Hb >120 g/L than those treated with oral iron.

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. The pivotal studies had adequate study designs with clinically relevant endpoints for demonstration of benefit in patients with IDA due to various etiologies. As the physiological response to iron supplementation is consistent in all patients with IDA, regardless of the underlying cause of the anemia, it is reasonable to consider the evidence of efficacy demonstrated from the reviewed pivotal studies applicable to a general population of patients with IDA.

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

The efficacy of Ferinject in the treatment of iron deficiency in patients with chronic heart failure and New York Heart Association (NYHA) Class II/III to improve exercise capacity was also evaluated in a study designed to specifically evaluate the effect of Ferinject on exercise intolerance in chronic heart failure patients with iron deficiency. Treatment with Ferinject significantly prolonged 6-minute walk test (6MWT) distance at Week 24 for Ferinject versus placebo.

The primary safety analyses were based on the submitted pivotal clinical safety and efficacy trials in which patients meeting criteria of the target patient population, across therapy areas including nephrology, gastroenterology, cardiology, and women’s health, were treated with Ferinject at the recommended dose (15 mg iron/kg; 1,000 mg iron maximum). In this pooled analysis, the most common adverse reactions (≥2%) were headache, edema, hypertension, injection/infusion site reactions, , rash, arthralgia, urinary tract infections, dizziness, nausea, nasopharyngitis, and diarrhea. Pyrexia, headache, and pulmonary embolism, reported in 1 patient each, were the only treatment-related serious adverse events (SAEs) reported for Ferinject-treated patients. There were no new or unexpected treatment-emergent adverse events (TEAEs) observed in the pediatric population compared to those reported in the adult population.

Safety data during use in pregnancy was available from Study FER-ASAP-2009-01, in which adverse events (AEs) were reported in more newborns from the Ferinject arm (9.8%) compared to those treated with oral iron (6.4%). This increase was driven by the AE ‘meconium stain’; all of which resolved without sequelae. 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, which demonstrated that TEAE profiles were similar in both the Ferinject and oral iron treatment arms, and were most commonly reported in the Gastrointestinal Disorders SOC (3.1% vs 5.1%).

Hypophosphatemia and hypersensitivity reactions were identified as clinically significant AEs in Ferinject-treated patients. Hypersensitivity and anaphylaxis reactions are known risks associated with all IV iron products, and serious, life-threatening, and fatal anaphylaxis/anaphylactoid reactions have been reported in patients receiving IV iron products, including Ferinject. In Ferinject clinical trials, a pooled safety analysis showed that hypersensitivity was reported at the same frequency in patients treated with Ferinject (N = 9,456) as patients treated with other IV iron products (0.9%), and anaphylactic reactions were reported less frequently in Ferinject-treated patients (<0.1%) than in patients treated with other IV irons (0.2%). There were no deaths due to hypersensitivity or anaphylaxis reactions reported in Ferinject clinical trials. Additionally, cases of symptomatic hypophosphatemia with serious outcomes, including hypophosphatemic osteomalacia and fractures that required clinical intervention, were reported in the post-marketing setting.

A Risk Management Plan (RMP) was submitted by the Sponsor and was considered acceptable (with minor revisions to the Canadian-Specific Addendum) by the Marketed Health Products Directorate.

Overall, the safety profile of FCM is considered acceptable, with AEs typically manageable through the use of temporary treatment discontinuation and standard medical care. Appropriate labelling in the final Ferinject Product Monograph, including recommendations regarding AE monitoring and management, is required and sufficient to adequately manage the risks associated with Ferinject therapy. This includes consistent labelling with the other IV iron products authorized in Canada highlighting the identified risk of serious, life-threatening, and fatal hypersensitivity associated with IV iron products that has been included the Serious Warnings and Precautions Box of the Ferinject Product Monograph. Other Warnings and Precautions emphasized in the final Ferinject Product Monograph include labelling regarding the risk of hypophosphatemia and hypophosphatemic osteomalacia, infections, and monitoring recommendations to reduce the risk of iron accumulation.

All inner and outer labels, patient medication information, package inserts and brand name were found acceptable following careful review.

Taken together, the data from the submitted pivotal and supportive studies demonstrated a favourable benefit-risk balance for the treatment of adult and pediatric patients aged 1 year and older with iron deficiency anemia (regardless of etiology for the IDA) when oral iron preparations are not tolerated or are ineffective, as well as for the treatment of adult patients with iron deficiency with heart failure and New York Heart Association Class II/III.

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