Efficacy and Safety of Intravenous Ferric Carboxymaltose in Children with Iron Deficiency Anemia Unresponsive to Oral Iron Therapy

Abstract

Background The standard first line therapy for iron deficiency anemia (IDA) is oral iron. Yet, many patients fail to respond to oral iron due to poor adherence and/or adverse effects. Intravenous (IV) iron is an effective means of treating IDA in patients with malabsorption of iron or who are non-adherent and/or experience adverse effects with oral iron. Some IV iron preparations carry an FDA-mandated black box warning and/or require a test dose or prolonged infusion. Ferric carboxymaltose (FCM, Injectafer®) is a relatively new IV iron preparation with demonstrated safety and efficacy in adults with IDA. The manufacturer recommended dosing is 15 mg/kg/dose (maximum 750 mg) x2 doses administered at least 7 days apart, and each individual infusion can be administered over 10 to 15 minutes, without the need for a test dose. Limited data exist on its use in children. Our objective was to assess the hematologic response and adverse effects of IV FCM in a diverse population of infants, children and adolescents with IDA who failed oral iron therapy. Method All children with IDA who received FCM at Children's Health from June 1, 2014 through June 10, 2015 were included. Subjects were identified via search of pharmacy records. All patients received at least one dose of FCM 15 mg/kg (maximum 750 mg) administered as a 15-minute IV infusion (without test dose or pre-medications). Patient characteristics, adverse effects and hematologic response were retrospectively collected from the electronic medical record. Results During the study frame, one hundred twenty-five infusions of FCM were administered to 87 patients (71% female) with a median age of 14 years (range 9 months to 20.8 years). The most common racial/ethnic group was Caucasian/White (Latino) at 45% followed by African American/Black and Caucasian/White (Non-Latino), each at 22%. The primary etiologies were heavy menstrual bleeding (38%), nutritional (24%), and GI bleeding and/or malabsorption (20%) with the remaining 18% representing other/mixed causes of IDA (e.g., inflammatory). The median dose administered during a single infusion was 750 mg (range 132 to 750 mg). No adverse effects were noted during or following the infusion in 77 subjects. Two patients had transient tingling, nausea and/or mild abdominal pain. Five others developed generalized pruritis and/or urticaria and received diphenhydramine and/or hydrocortisone, with prompt resolution. Two adolescents had more clinically significant reactions, 1 with nausea/vomiting post-infusion (likely psychogenic) requiring admission, and 1 with dyspnea 2 minutes into the infusion, requiring its immediate termination and administration of diphenhydramine, hydrocortisone and normal saline with prompt symptom resolution. One patient experienced asymptomatic extravasation during the second infusion which resulted in localized iron-staining of the skin. Median pre-infusion hemoglobin concentration for all patients was 9.1 g/dL (range 3.9 to 13.3 g/dL) (Table). A follow-up measurement was available for 76 patients at a median time of 6 weeks (range 1 to 30 weeks) post-initial infusion with a median hemoglobin increase of 3.3 g/dL (range -1.5 to 9.5 g/dL). Conclusion Intravenous FCM, administered in an outpatient infusion setting as one or two short IV infusions and without need for a test dose, was safe and effective in most children and adolescents with IDA refractory to oral iron therapy. Further clinical data are necessary to more fully characterize the extent of adverse effects in young patients. Prospective studies of IV FCM in children are indicated to assess clinical efficacy, including outcomes such as health related quality of life and fatigue. Table. *Hematologic Response to FCM Pre-Infusion **Post-Infusion Hemoglobin concentration (g/dL) All Etiologies, Pre (n=87), Post (n=76) Heavy menstrual bleeding, Pre (n=33), Post (n=26) Nutritional, Pre (n=21), Post (n=20) - 9.1 (3.9 to 13.3) 9.3 (4.2 to 13.3) 8.8 (4.9 to 12.2) - 12.2 (7.1 to 16) 12.7 (8.8 to 16) 12.2 (10.5 to 13.7) Mean corpuscular volume (fl), Pre (n=87), Post (n=76) 71.6 (49.5 to 97.4) 80.9 (53.3 to 102) Serum ferritin (ng/mL), Pre (n=80), Post (n=60) 5.2 (0.6 to 288.6) 115.7 (2.3 to 679.3) *Median laboratory values are reported. **Follow-up laboratory testing occurred at median time of 6 weeks (range 1 to 30 weeks) post-infusion. Disclosures Powers: Gensavis Pharmaceuticals, LLC: Research Funding. McCavit:Pfizer: Research Funding; Gensavis LLC: Research Funding; Novartis: Speakers Bureau. Adix:Gensavis Pharmaceuticals, LLC: Research Funding. Buchanan:Gensavis Pharmaceuticals, LLC: Research Funding.

Is Intravenous Iron Treatment in Pediatric Patients Safe and Effective Enough?

“…Considering the negative effects on neurodevelopment associated with IDA, the repletion of the iron stores of these children safely and immediately is important. Hb increment effect of IV iron formulations was shown in few studies and 1.56 to 4.8 g/dL increase was reported in one to sixteen weeks (21)(22)(23)(24)(25)(26)(27). Similarly, in our study the evaluation which was performed after the first week of IV iron therapy initiation, there was 2.3±1.5 g/dL improvement in Hb levels.…”

“…Although the current pediatric experience with IV iron administration for children with IDA is limited, IV iron is both effective and safe in children (11)(12)(13)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Few side effects were seen during IV iron infusions in our patients.…”

Advances in Pediatric Intravenous Iron Therapy

“…By far, the most common pediatric indications for IV iron in everyday clinical practice are unresponsiveness to oral iron therapy and heavy menstrual bleeding in adolescent females. The current pediatric experience with IV iron administration for children with IDA in these settings is summarized in Table . As shown, IS was the preferred IV iron preparation for the majority of pediatric studies .…”

“…LMWID as a TDI was used in a single study . FCM was used in a study from Dallas published in abstract form . Irrespective of the product used, IV iron therapy was effective and safe in raising the hemoglobin concentration to near normal or normal in all treated patients, within a few weeks of first infusion, with no serious adverse events.…”

Intravenous Ferric Carboxymaltose as Rescue Therapy in Severe Breath Holding Spells: A Case Report and Literature Review

“…In addition, as in our case, there may be many clinical situations where the administration of high concentrations of iron is rapidly required. Despite safety concerns, high costs, and the need for "off-label" use, treatment strategies using parenteral iron in pediatric populations are gradually increasing [7][8][9][10]. Ferric carboxymaltose is a relatively new IV iron preparation with demonstrated safety and efficacy in adults with IDA [7].…”