TYPE Original Research PUBLISHED 06 October 2022 DOI 10.3389/fped.2022.967233 Safety and effectiveness of ferric OPEN ACCESS carboxymaltose intravenous therapy in pediatric patients EDITED BY Meredith Atkinson, Johns Hopkins Medicine, United States REVIEWED BY Ben Reynolds, with chronic kidney disease NHS Greater Glasgow and Clyde, United Kingdom Mario Giordano, Patricia Garcia-Ortega1 , Ines Jimenez-Lozano1*, Giovanni XXIII Children’s Hospital, Italy Álejandro Cruz2 , Aurora Fernandez Polo1 , Mercedes Lopez2 *CORRESPONDENCE Ines Jimenez-Lozano and Gema Ariceta2,3 ines.jimenez@vallhebron.cat 1 Department of Pharmacy, Vall d’Hebron University Hospital, Barcelona, Spain, 2 Department of SPECIALTY SECTION Pediatric Nephrology, Vall d’Hebron University Hospital, Barcelona, Spain, 3 Department of This article was submitted to Pediatrics, Autonomous University of Barcelona, Barcelona, Spain Pediatric Nephrology, a section of the journal Frontiers in Pediatrics Iron-deficiency anemia is the most common reason for worsening of RECEIVED 12 June 2022 ACCEPTED 07 September 2022 the anemia characteristically seen in chronic kidney disease (CKD). Ferric PUBLISHED 06 October 2022 carboxymaltose (FCM) is a macromolecular hydroxide ferric carbohydrate CITATION complex that allows high-dose iron to be administered parenterally for gradual, Garcia-Ortega P, Jimenez-Lozano I, controlled release. The aim of this study was to retrospectively evaluate the Cruz Á, Polo AF, Lopez M and Ariceta G (2022) Safety and safety and effectiveness of FCM treatment in pediatric patients with CKD non- effectiveness of ferric carboxymaltose dependent of hemodialysis, seen at a tertiary hospital. Data were collected intravenous therapy in pediatric patients with chronic kidney disease. on demographics, dosage, infusion time, laboratory results, and tolerability of Front. Pediatr. 10:967233. the medicinal product. A total of 79 patients (40.5% girls) were included; the doi: 10.3389/fped.2022.967233 median age [25th percentile (P25) to 75th percentile (P75)] was 9 years (5–13). COPYRIGHT Laboratory results at 15–45 days post-infusion revealed a median increase of © 2022 Garcia-Ortega, Jimenez-Lozano, Cruz, Polo, Lopez 1.4 g/dL (0.9–1.9) in hemoglobin, 224 µg/L (136–378.5) in ferritin, 37 µg/dL and Ariceta. This is an open-access (17.5–71) in serum iron, and 18% (9.3–27.8) in transferrin saturation. All patients article distributed under the terms of tolerated FCM infusions well, and no serious hypersensitivity reactions or the Creative Commons Attribution License (CC BY). The use, distribution anaphylactic reactions were observed. Only one adverse event was identified: or reproduction in other forums is drug extravasation at the end of the infusion in a 16-year-old patient. These permitted, provided the original author(s) and the copyright owner(s) data provide further evidence for the use of FCM as a safe and effective are credited and that the original therapeutic option in pediatric patients with CKD, based on the low incidence publication in this journal is cited, in of adverse effects, minor intervention required, and anemia improvement accordance with accepted academic practice. No use, distribution or based on laboratory results. reproduction is permitted which does not comply with these terms. KEYWORDS pediatrics, kidney disease, intravenous iron, ferric carboxymaltose, iron deficiency, anemia Introduction Iron-deficiency anemia is the most common reason for worsening of the anemia characteristically seen in chronic kidney disease (CKD). In patients with CKD, decreased erythropoiesis is exacerbated by concomitant conditions of chronic inflammation and the resulting increased production of hepcidin, which inhibits intestinal absorption of Frontiers in Pediatrics 01 frontiersin.org Garcia-Ortega et al. 10.3389/fped.2022.967233 iron and mobilization of iron deposits from the use of iron sucrose and has mainly been limited to patients reticuloendothelial system (RES) to circulating transferrin undergoing hemodialysis, due to the need for repeated doses. (1). In addition, children experience circulating iron loss due The availability of FCM made it possible to extend the use repeated blood draws and during therapeutic procedures, in a of parenteral iron to patients who do not visit the hospital larger proportion than adults with similar clinical condition (2). often, as those not on hemodialysis. Therefore, less effective and Consequently, iron deficiency treatment is very common in tolerated oral iron treatment have been replaced and indeed, CKD, and often is associated with epoetin therapy. Selection clinical practice has shifted considerably toward the intravenous of the route used to administer iron depends on deficiency treatment of iron deficiency far more often. The aim of this severity, venous access availability, prior response to oral study was to describe our experience and evaluate the safety and therapy, adverse effects (AEs) observed, patient compliance, hematologic response of FCM treatment in pediatric patients and cost. The Kidney Disease: Improving Global Outcomes with kidney disease. (KDIGO) clinical guidelines for the diagnosis and treatment of anemia in pediatric patients with CKD recommend maintaining transferrin saturation (TS) ≥ 20% and ferritin ≥ 100 ng/mL and Materials and methods starting treatment with oral iron (or intravenous iron during hemodialysis sessions) to maintain these values, even if patients The research was designed as a retrospective, observational, are receiving erythropoiesis-stimulating factors (ESAs) (3, 4). single-center study that included all pediatric patients aged At early stages of CKD, oral iron therapy has been 18 years or younger diagnosed with kidney disease who R traditionally recommended and used because it is less invasive were treated with FCM (Ferinject ; Vifor Pharma, St Gallen, and less expensive, despite issues related to gastrointestinal Switzerland) between during a 19-month period. Our institution tolerance and absorption are common (5). In addition, more protocol approved that pediatric patient younger than 14 years than 2 to 3 weeks are usually needed to detect an increase received FCM as an off-label indication, but after obtaining in hemoglobin (Hb) and up to 6 months to attain adequate a prior written consent from parents or guardians. Elegible iron deposits, resulting in delayed therapeutic response (2, 6–8). patients to receive FCM where those who, according to medical Recently, the advent of new intravenous iron preparations with criteria, could benefit from of FCM treatment either due to a good safety and tolerability profile (9–11) has made it possible anemia or iron deficiency. Anemia was defined according to the to use higher doses at less frequent intervals. As consequence age-based criteria of the KDIGO guidelines: Hb ≤ 11.0 g/dL in IV iron use is, increasing among patients with kidney disease children aged 0.5–5 years, Hb ≤ 11.5 g/dL in children aged 5–12 who are not on hemodialysis as dose administration can fit to years, Hb ≤ 12 g/dL in children aged 12–15 years, and Hb ≤ 12 less frequent hospital visits for regular care. Further, IV iron g/dL or ≤ 13 g/dL in adolescent girls or boys over 15 years old, administration allows epoetin optimization as is not influence respectively; low serum iron deposits was defined as TS ≤ 20% by patient compliance. and/or ferritin ≤ 100 ng/mL (3). Ferric carboxymaltose (FCM) is a macromolecular Patients were identified using our pediatric hospital e- hydroxide ferric carbohydrate complex that allows for gradual, prescription program for inpatients or outpatients treated at controlled release of iron inside RES cells, with uptake by day hospital. In the latter group, FCM infusions coincided with endogenous iron-binding proteins. Because this complex patient scheduled blood draws for lab work and regular follow is highly stable, ionic iron is not released directly into the up visits at the outpatient nephrology clinic of the Nephrology bloodstream, preventing potential cell damage due to oxidative Department. Intravenous administration consisted in diluting stress (12) and thus allowing high doses to be administered FCM in normal saline (50 mL for doses of 100–499 mg; 100 mL each time: 15 mg of iron/kg by intravenous injection or up to for doses of 500–1000 mg) to achieve concentrations equal to 20 mg of iron/kg by intravenous infusion. Based on drug data or> 2 mg/ml, as indicated in the SmPC for the drug and then sheet, the medication is recommended for the treatment of iron infusing the solution over 30 to 60 min. deficiency in pediatric patients older than 14 years or when oral Electronic medical records were reviewed to collect patients’ iron preparations are ineffective or cannot be used. According demographic and clinical data, including age, sex, weight, to the summary of product characteristics (SmPC), the most diagnosis, estimated glomerular filtration rate (eGFR) based common adverse reactions are nausea, injection/infusion site on the updated Schwartz formula (12), iron therapy in the reactions, low blood phosphate levels, headache, erythema, previous 6 months, concomitant treatment with ESAs, and dizziness, and hypertension (12). type of dialysis. Laboratory results were also collected for Hb, Only a few studies have examined the role of FCM for the serum iron, ferritin, TS, and blood phosphate before and after treatment of iron-deficiency anemia in pediatric patients, and FCM infusion. Infusion times and tolerability information were most have included patients with a gastrointestinal condition. collected from the computer records for each dose. At our hospital, treatment with intravenous iron in pediatric All patients who received at least 1 dose of FCM during the patients with kidney disease has traditionally been based on the study period were included in the safety analysis. To evaluate Frontiers in Pediatrics 02 frontiersin.org Garcia-Ortega et al. 10.3389/fped.2022.967233 TABLE 1 Biodemographic data. TABLE 2 Patients CKD stage* . Total, n 79 Glomerular filtration rate Number Sex, n (%) category (mL/min/1.73 m2 ) of patients Male 47 (59.5%) Description Range n = 76** Female 32 (40.5%) Age (years) G1 > 90 28 Median (P25–P75) 9 (5–13) G2 60–89 22 Weight (kg) G3a 45–59 8 Median (P25–P75) 26.4 (18.3–39.5) G3b 30–44 5 Prior treatment with iron, n (%) 52 (65.8%) G4 15–29 10 Oral 21 (40.4%) G5 < 15 3 IV iron sucrose 30 (57.7%) PD – 6 IV ferric carboxymaltose 1 (1.9%) Ethnicity (%) PD, peritoneal dialysis. * According to the chronic kidney failure classification of the KDIGO 2012 guidelines (3). Caucasian 59 (74.7%) ** eGFR data were obtained from 76/79 patients. Arabian 15 (19,0%) African/afroamerican 5 (6,3%) Treatment with ESAs, n (%) 32 (40.5%) change in Hb was taken as the first value after the first dose Total FCM dose (mg) Median (P25–P75) 500 (280–500) compared with baseline. Patients who showed no increase were FCM dose (mg/kg) studied separately. Changes in the other laboratory results were Median (P25–P75) 15.4 (12.7–18.5) also analyzed. Total number of doses 131 This project was approved by the Clinical Research Ethics Number of doses per patient, n (%) 50 (63%) 13 (16%) Committee of our hospital on December 20, 2019 under 1 dose Protocol Code FCM-NEFRO-PED. Due to the retrospective 2 doses 16 (20%) nature of the study, there were no interventional procedures >2 doses 50 (63%) or changes to current practice in patient management, Duration of infusion, min and all therapeutic decisions were made before the study Median (P25–P75) 60 (45–60) was undertaken. Media (SD) 62,1 (23,76) The univariate statistical analysis was descriptive. Diagnoses, N Continuous variables were expressed as the mean and standard Glomerulopathies 28 deviation, or median and interquartile range (25th percentile- CAKUT 14 75th percentile). Categorical variables were listed according to Hereditary cystic KD (ciliopathy) 11 absolute number and the respective relative frequencies. Metabolic nephropathy 10 Tubulopathy 6 Results KD due to vascular causes 6 Thrombotic microangiopathy 4 A total of 79 patients were included; Tables 1, 2 lists the demographic characteristics, treatment administered (number CAKUT, congenital abnormalities of kidney and urinary tract; eGFR, estimated glomerular filtration rate; ESAs, erythropoiesis–stimulating agents; FCM, ferric of doses, absolute dosage in mg, dosage in mg/kg, and carboxymaltose; min, minutes; P25–P75, interquartile range (25th percentile to 75th administration time per dose) and patients CKD stage. percentile); IV, intravenous; KD, kidney disease; n, number of patients. All patients exhibited good tolerability to FCM infusions, and no serious hypersensitivity reactions or anaphylactic reactions were observed. Only one adverse event was identified effectiveness, patients were included if data were available for in a 16-year-old patient, who experienced extravasation at baseline Hb (up to 30 days before FCM administration) and the end of the infusion. At the time it was detected, it was post-administration Hb (at 7–45 days). Changes in Hb were treated with Burow’s solution, local cold, and limb elevation. analyzed in patients with increased Hb, and these patients were The patient developed painless discoloration in the affected stratified according to whether or not they received concomitant area of the anterior side of the forearm, with subsequent treatment with ESAs. In patients who received more than 1 partial improvement. infusion of FCM due to low Hb levels after a satisfactory Pre- and post-infusion Hb data were obtained in 58/79 initial response or pre-programmed dose to complete the (73.4%) patients. A total of 70.7% (41/58) of patients had anemia dosage according to the calculation of Fe requirements, the at the initiation of treatment according to the normal Hb range Frontiers in Pediatrics 03 frontiersin.org Garcia-Ortega et al. 10.3389/fped.2022.967233 for their age. The rest of the patients had adequate Hb levels Compared with other authors, our case series observed a but low serum iron deposits with TS ≤ 20% and/or ferritin very favorable safety and tolerability profile for the medication, ≤ 100 ng/mL. Positive response to FCM was observed in most with extravasation observed in only 1 patient at the end of patients (Table 3). Further, ferritin and TS normalization was FCM infusion. observed after FCM infusion in 35/39 and 21/31 patients for However, the hematologic response showed a median whom data were available. increase in hemoglobin of 1.4 g/dL (0.9–1.9) in most cases Table 3 lists Hb variations for all patients who had an (89.7%) after a median of 1 month, and an increase in ferritin increase in Hb or maintained a stable value (89.7%), and the and TS. We cannot exclude that a longer examination time of stratified data are described according to whether they were the study could have demonstrated a better response. receiving ESAs or not. As observed in other studies, patients who received ESAs Only in 6 (10.3%) patients, FCM administration was not had lower baseline Hb values, and the observed Hb increase associated with anemia improvement during the study period. was larger than in those who did not receive ESAs (19). Two of them, experienced significant intercurrent infections at Patients with kidney disease and iron deficiency are known that time (1 mumps and 1 urologic sepsis, respectively) that to require higher doses of ESAs (19), and the administration required hospitalization and possibly explained lack of response. of IV iron increases sensitivity to ESAs, making it possible Apparently, no specific cause apart from the underlying disease to lower ESA dosages (20, 21). In our study, we did or treatment, was observed in additional four patients who did not evaluate, the impact on the ESA dose prescribed due not present Hb increase, although in all them ferritin and/or TS its retrospective design and the fact that the study aim increased after FCM. was to evaluate tolerance and effectiveness of FCM on the The median baseline phosphate concentration was 4.9 short term. mg/dL (4.3–5.3). Post-infusion phosphate values were obtained Although oral iron is considered the treatment of choice for 43 patients (79.3%), with a median decrease of 0.5 mg/dL in pediatric patients (except for specific cases such as (0.1–1.1) observed in 22 (51.2%) patients. No patients developed hemodialysis) due to its non-invasiveness and lower cost, low blood phosphate levels according to the normal age- it is often poorly tolerated, is accompanied by absorption adjusted values. problems, and requires 2 to 3 weeks to raise hemoglobin Table 3 summarizes laboratory tests variation at baseline and concentrations and up to 6 months to achieve normal iron after treatment. deposits (3). Nausea, abdominal pain, and constipation are AEs that affect adherence to oral iron therapy among the pediatric population. Because the FCM is a stable complex, Discussion this allows a maximum cumulative weekly dose of 1,000 mg of iron to be administered and fewer infusions are needed Most of published retrospective observational studies on the to administer the total iron dosage needed for each patient, use of FCM in children include patients with gastrointestinal compared with other formulations such as iron sucrose. In conditions, followed by metrorrhagia-related anemia (2, 5, 6, 9, addition, the infusion time required (≤ 15 min) is lower than 13–17). Our study is the first to describe the effectiveness and for iron sucrose (30 min to 2 h) (22), reducing day hospital safety of FCM treatment in a series of 79 pediatric patients with occupancy levels. kidney disease non-dependent on hemodialysis. Consequently, because the use of intravenous iron avoids Lass et al. (9) analyzed a population of 72 pediatric intestinal absorption, gastrointestinal tolerance can be improved patients with iron-deficiency anemia who received FCM, and the number of oral treatments these patients often receive observing mild hives and/or edema in three patients. Another can be decreased, making it an option with cost-saving potential series described by Powers et al. (13) with 72 patients for outpatients who only visit the hospital to receive intravenous who had inflammatory bowel disease and anemia reported iron (8). Greater work-life balance might be achieved for patients adverse effects in 7 (9.7%) patients who received FCM: 1 and their families by scheduling infusions at the same time as patient experienced dyspnea requiring respiratory support, blood draws for lab work and hospital visits. corticosteroids, and diphenhydramine that resolved within Good experience in terms of effectiveness and tolerability 5 min, 1 patient experienced tingling at the infusion site, has made it possible to change the therapeutic approach and 1 patient had extravasation of the medication. All other taken with iron-deficient chronic patients eligible for hospital patients had mild hives or pruritus, which were treated laboratory follow-up who require periodic intravenous with antihistamines and/or corticosteroids. Other authors have treatment, an approach that has been well accepted by patients reported itching, hives on the trunk and legs, and low-grade and their families. fever in 2 (2%) of 101 patients after FCM was administered The main limitation of this study was its observational (3) and the appearance of mild rash in 2 (5.7%) of 35 and retrospective nature, making it impossible to obtain all patients (18). laboratory data for the patients included. Frontiers in Pediatrics 04 frontiersin.org Garcia-Ortega et al. 10.3389/fped.2022.967233 TABLE 3 Pre– and post–infusion changes in ferric carboxymaltose (FCM). Laboratory Baseline 30 days (± 15) Overall parameter change* Hemoglobin, g/dL n 58 52 1.4 (0.9–1.9) Median (P25–P75) 10.4 (9.1–11.7) 11.8 (10.5–13.2) without ESAs n 31 28 Median (P25–P75) 11.4 (9.8–12.2) 12.6 (11.4–13.3) 1.3 (0.7–1.7) with ESAs n 27 24 Median (P25–P75) 10.4 (8.8–10.9) 11.4 (10.2–12.3) 1.6 (1.1–2.8) Ferritin (ng/mL) n 57 43 Median (P25–P75) 32.0 (16–68) 285 (169.5–409.5) 224 (136–378.5) TS (%) n 53 40 Median (P25–P75) 11 (7–15) 31 (20.8–38.5) 18 (9.3–27.8) Fe (µg/dL) n 55 44 Median (P25–P75) 28 (21–40) 66 (50.8–101.8) 37 (17.5–71) Fe, serum iron; n, number of patients; P25–P75, interquartile range (25th percentile to 75th percentile). * For each patient, changes in pre–infusion (baseline) and post–infusion laboratory results were based on the highest value of the specific laboratory result if there were multiple values for the same period. Reference range: Hb (anemia if ≤ 11.0 g/dL in children aged 0.5–5 years, ≤ 11.5 g/dL in children aged 5–12 years, ≤ 12 g/dL in children aged 12–15 years, and ≤ 12 g/dL or ≤ 13 g/dL in adolescent girls or boys over 15 years old, respectively; ferritin (25–400 ng/mL); TS (20–55%); Fe (50–150 µg/dL). In conclusion, these data provide evidence that FCM is this study in accordance with the National Legislation and the a safe and effective therapeutic option in children based on Institutional Requirements. the low incidence of adverse effects and the improvement of laboratory results. Author contributions PG-O organized the database and wrote the first draft Data availability statement of the manuscript. IJ-L contributed to design of the study and wrote sections of the manuscript. IJ-L, AP, ÁC, GA, and The raw data supporting the conclusions of this article will ML contributed to manuscript revision. All authors read and be made available by the authors, without undue reservation. approved the submitted version. Ethics statement Funding The studies involving human participants were reviewed Funding was received from Vifor Pharma Spain for and approved by Clinical Research Ethics Committee of our translation of the manuscript and support for an Open Access hospital on December 20, 2019 under Protocol Code FCM- license. This did not influence the results obtained in this study NEFRO-PED. Written informed consent from the participants’ because all data interpretation and manuscript reviews were legal guardian/next of kin was not required to participate in carried out independently from the source of funding. Frontiers in Pediatrics 05 frontiersin.org Garcia-Ortega et al. 10.3389/fped.2022.967233 Acknowledgments that could be construed as a potential conflict of interest. I would like to express my very great appreciation to all the professionals, patients and families who contributed to this study. Publisher’s note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated Conflict of interest organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or The authors declare that the research was conducted in claim that may be made by its manufacturer, is not guaranteed the absence of any commercial or financial relationships or endorsed by the publisher. References 1. Macdougall IC. Intravenous iron therapy in patients with chronic kidney 13. Powers JM, Shamoun M, McCavit TL, Adix L, Buchanan GR. Intravenous disease: recent evidence and future directions. Clin Kidney J. (2017) 10:i16– ferric carboxymaltose in children with iron deficiency anemia who respond poorly 24. doi: 10.1093/ckj/sfx043 to oral iron. J Pediatr. 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