Single total dose infusion of ferumoxytol (1020 mg in 30 minutes) is an improved method of administration of intravenous iron
Authors: Nabin R. Karki, Michael Auerbach
Journal: American Journal of Hematology (2019)

To the Editor: In June, 2009, ferumoxytol, a paramagnetic iron formulation originally designed as a magnetic resonance contrast agent, was approved for the treatment of iron deficiency anemia in patients with chronic kidney disease. The labeled method of administration was a single vial consisting of 510 mg in 17 mL, administered as fast as one mL/s or as fast as 17 seconds. As is the case with all formulations of intravenous iron, a varying amount of labile free iron is released upon administration.1 Labile free iron is associated with a host of different infusion reactions consisting of transient flushing and myalgia with or without urticaria, the so called Fishbane reaction, or other minor infusion reactions.2 These reactions are self-limited, resolve without therapy and may be due to complement activation related pseudoallergy.3 Unfortunately, these reactions are often mistaken for severe hypersensitivity with resultant treatment with vasopressors and/or antihistamines, converting the minor infusion reaction to a hemodynamically significant serious adverse event, ostensibly attributable to the intravenous iron. True, severe hypersensitivity reactions due to mast cell activation are extremely rare and occur in fewer than 1:200 000 administrations.4 Given concerns about possible serious adverse events, albeit rare from postmarketing reports, in 2015 the label was modified to include a boxed warning to highlight the potential for serious adverse events and ways to possibly mitigate them. In addition, the approved rate of infusion was changed from the 17 seconds bolus administration to at least a 15 minutes infusion for the 510 mg dose. In our practice we administered the first 90 doses over the approved 17-second interval and observed three episodes of self-limited hypotension.5 The infusion rate was subsequently reduced to ∼three minutes and the next 4000 doses were administered without a hypotensive episode or other clinically significant adverse event. Whether the mechanism involved clearance of labile free iron, or so called "anaphylactoxins" C3a and C5a induced by complement activation, it was apparent fewer adverse reactions occurred with the slower rate of administration.2, 6, 7 From our experience and from published evidence, it became readily apparent that the dose of ferumoxytol was not related to the presence or absence of adverse events. Subsequently in 2012 we performed a prospective study under an investigator IND (112001) to administer a total dose infusion (1020 mg) at a single administration.8 Sixty iron deficient patients 18 years old or greater received 1020 mg of ferumoxytol over 15 minutes. All responded and no serious adverse events were observed. Efficacy data was consistent with reported outcomes seen with 510 mg administered twice. One complained of swelling of the lips which resolved without therapy. The authors concluded that the higher dose demonstrated improved ease of administration and represented an improvement in convenience for both physicians and patients at decreased cost without a decrement in efficacy or safety. To address concerns about serious adverse events, especially true hypersensitivity, which is very rare, AMAG Pharmaceuticals, ferumoxytol's manufacturer initiated a program of studies to assess safety and efficacy. The largest of these was a 2000 patient double blind, randomized comparison of the FDA approved administration of 1020 mg of ferumoxytol (two vials) to 1500 mg of ferric carboxymaltose (two vials), also FDA approved administration.9 Both formulations were administered over two visits 1 week apart. At five weeks no difference in safety or efficacy was observed and in February 2018, a broad label was granted across all conditions associated with iron lack in adults who were intolerant of, or had an inadequate response to oral iron. After thousands of administrations of 510 mg of ferumoxytol in our practice, based on our previously published data,8 we approached the insurance carriers of the bulk of our population. Blue Cross Blue Shield Care First, Cigna, MedStar Family Choice, and Priority Partners all agreed to pay for a single infusion of 1020 mg of ferumoxytol over 20 to 30 minutes. While more convenient for both physician and patient, the well-considered decision was undoubtedly fomented by the savings of ∼$100 per patient per treatment obviating the second, unnecessary visit. To date, we have performed more than 400 of these infusions. Herein we present the data on the first 184. The population for this report consisted of 184 consecutive, nonselected patients who attended our outpatient hematology clinic and infusion center insured by one of the approving carriers, from May 14, 2018 to February 26, 2019. All received 1020 mg of ferumoxytol as a single infusion over ∼30 minutes. Pre-infusion parameters consisted of serum creatinine, complete blood count, and iron studies (serum iron, total iron binding capacity, percent transferrin saturation, and serum ferritin). All parameters were obtained within the preceding four weeks of the infusion. Any reaction to the infusion and action taken was recorded along with any premedication given (intravenous methylprednisolone and ranitidine for those with multiple drug allergies or asthma, known to be at increased risk for infusion reactions). Postinfusion parameters, when available at time of data collection included complete blood count and iron parameters, all at least four weeks and less than six months, after the date of the infusion. The data was extracted from OncoEMR based on review of clinic lab results, outside laboratory reports, clinic visit notes and nursing medication administration notes. Accuracy of data entry was verified by the senior author (MA). The results were tabulated and analyzed using simple quantitative methods. One hundred seventy-six, consecutive, nonselected, iron deficient patients whose insurance carriers (Blue Cross Blue Shield, Care First, Cigna, MedStar Family Choice, Priority Partners) approved a total dose infusion of ferumoxytol, received 184 infusions of 1020 mg of ferumoxytol in 250 mL of normal saline over 20 to 30 minutes. Twelve received multiple infusions, 11 received two and one received three. Premedication with methylprednisolone and/or ranitidine was administered to 29 for a history of multiple drug allergies (>1) or asthma, consistent with our practice standards. The demographic characteristics and baseline laboratory values are shown in Table S1. One hundred sixty-one (91.5%) were female. The most common diagnosis was menorrhagia in 76 (41.3%), followed by 33 in the second and third trimester of pregnancy (17.9%), and 26 after gastric bypass (14.1%). The mean hemoglobin at presentation was 10.7 g/dL (SD 1.7), MCV 80.1 (SD 11.6), TSAT 11.3 (SD 7.6), and serum ferritin 12.0 (Median Interquartile range 12.0 [SD 8.0-25.]). The mean serum creatinine was 0.7 (SD 0.2). Thirteen (7.4%) reported minor infusion reactions, all of which subsided without residua (see Table 1). Following cessation of the infusion, treatment with methylprednisolone and ranitidine was administered and all received the originally planned dose 15 minutes after resolution of symptoms. Only one of the 13 had received premedication. These observations are consistent with our experience with ferumoxytol and published evidence with other intravenous iron formulations. The mean hemoglobin increment was 1.9 g in those individuals in whom follow-up laboratory testing was available. The mean increments in MCV, TSAT, and ferritin were 5.3 femtoliters, 12.4%, and 100.6 ng/mL, respectively. Values for SD and confidence intervals are reported in Table S2. The felicitousness of a total dose infusion of intravenous iron as a single, short infusion adds convenience and decreased cost to the treatment of iron deficiency.10 Based on the preponderance of published evidence, there is neither an increase in toxicity nor decrease in efficacy with single dose iron repletion compared with multiple administrations to achieve the same dose. By administering ferumoxytol in one visit, not only is the chance for an infusion reaction or extravasation of the intravenous line halved, a savings of ∼$100 (cost of visit and infusion) per patient per treatment is enjoyed. Multiple insurers throughout the country now approve this improved method of treating iron deficiency. Appropriate approval will obviate payment denials and add efficiency to infusion centers. Over the conduct of the study period we treated ∼200 Medicare patients with 1020 mg of ferumoxytol administered as two 510 mg infusions. At current reimbursement rates, in this practice alone, 20 000 dollars of additional costs were generated for an unnecessary second visit, in addition to exposing the patient to a second intravenous line insertion with the resultant, albeit small, chance for an infusion reaction and extravasation. Total dose infusion of ferumoxytol is more convenient for patients and providers, likely associated with fewer infusion reactions and extravasations when administered over two visits, is cost saving and represents and improvement in the management of iron deficiency anemia. Dr Karki has no relevant disclosures. Dr Auerbach has received funding for data management from AMAG Pharmaceuticals. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.