A multicenter study evaluating the effectiveness and safety of single-dose low molecular weight iron dextran vs single-dose ferumoxytol for the treatment of iron deficiency

Abstract

There are multiple intravenous (IV) iron formulations available, of which several may be administered as single-dose infusions such as low-molecular weight iron dextran (LMWID), ferumoxytol, ferric carboxymaltose, and ferric derisomaltose. However, administration of ferumoxytol as a single-dose infusion is off-label as it is approved as a two-dose series. Previous studies of ferumoxytol alone support the effectiveness and safety of the single-dose regimen, but there is a paucity of data directly comparing single-dose ferumoxytol to other single-dose IV iron formulations. This multicenter cohort study sought to affirm the safety and effectiveness of single-dose ferumoxytol compared to single-dose LMWID. Overall, 906 patients who received single-dose LMWID (n = 439) or ferumoxytol (n = 467) were identified, of whom 351 met criteria for the primary effectiveness endpoint defined as median change in hemoglobin (Hb), hematocrit (Hct), and ferritin 8 to 12 weeks from baseline. All 906 patients were included for the secondary analysis evaluating the incidence of adverse events (AE) and requirement of additional IV iron infusions. Median change in Hb (LMWID 0.5 g/dL; ferumoxytol 0.8 g/dL; P = .24), Hct (LMWID 1.1%; ferumoxytol 1.25%; P = .89), and ferritin (LMWID 87 ng/dL; ferumoxytol 71 ng/dL; P = .47) was not significantly different between groups. Both groups experienced similar rates of AEs (LMWID 2.3%; ferumoxytol 2.8%; P = .63). The LMWID patients more frequently required additional IV iron infusions (LMWID 28.5%; ferumoxtyol 16.1%; P < .001). These findings support that single-dose ferumoxytol is effective and safe, and that patients may require fewer additional infusions compared to patients who received LMWID.

1 |. INTRODUCTION

Iron deficiency anemia is the most common cause of anemia and the most common hematologic condition in the world.¹ Treatment options include oral or intravenous (IV) iron supplementation. Although oral iron is commonly prescribed as first-line therapy, many studies suggest IV iron to be better tolerated, more effective, and associated with better quality of life when compared to oral iron.¹ Meta-analyses have noted gastrointestinal side-effects were three times as likely to occur in patients receiving oral iron supplementation (ferrous sulfate) compared to parenteral iron, and twice as likely as those in the placebo group.² Oral iron often does not adequately replete iron stores. Use of IV iron formulations also mitigates concerns related to absorption of oral iron formulations.¹ In clinical practice, there is general consensus of comparative effectiveness and safety among available IV iron formulations, although single-dose administration is less well characterized.³ Although hypersensitivity reactions remain a concern with use of IV iron formulations, this risk stems primarily from historical use of an older formulation of high molecular weight iron dextran, that was associated with a high incidence of acute hypersensitivity infusion reactions.³

Several forms of IV iron are used in clinical practice, including low molecular weight iron dextran (LMWID), ferumoxytol, ferric gluconate, iron sucrose, ferric carboxymaltose and ferric derisomaltose. Ancillary considerations such as costs related to therapy and administration schedule (ie, multi-dose vs single-dose) often drive institutional utilization of “preferred” formulations. Both LMWID and ferumoxytol are commonly used IV iron formulations and while not technically in line with FDA labeling, both treatment courses can be given as a single-dose infusion.⁴ Single-dose ferumoxytol (1020 mg) and LMWID (1000 mg) are off-label administration schedules, as ferumoxytol is FDA approved as a two-dose series only, and LMWID is FDA approved for hemoglobin-based dosing in iron deficiency anemia at a daily recommended dose of 100 mg of iron (2 mL).^5,6 Consequently, single-dose orders may not be covered by insurers that are unwilling to cover off-label uses despite emerging evidence to support single-dose iron is effective, safe, and convenient.^4–9 Furthermore, prior supporting evidence is limited to characterizing single-dose ferumoxytol alone; to the best of our knowledge there is no prior comparative study evaluating single-dose LMWID and ferumoxytol.^7,10

This retrospective cohort study sought to define the safety and effectiveness of single-dose ferumoxytol by comparing institutional outcomes of patients with iron deficiency anemia who received single-dose IV iron supplementation with either ferumoxytol or LMWID.

2 |. METHODS

This study was approved by the Institutional Review Board of the Oregon Health & Science University (OHSU) before initiation (STUDY00019570). Adults with an ICD-10 diagnosis of iron deficiency anemia treated with LMWID or ferumoxytol from 1 January 2017 to 31 October 2019 were identified at six participating outpatient infusion centers utilizing review of a joint electronic medical record (the OHSU and five affiliated outpatient community hematology practices in Beaverton, East Portland, Gresham, Northwest Portland, and Tualatin Oregon). Notably, selection of IV iron formulations was influenced by a shortage of LMWID in 2018 to 2019, although ultimate utilization was also guided by provider preference and insurance authorization. Inclusion criteria stipulated that patients be of age ≥ 18 years and received IV iron doses appropriate for single-dose administration (LMWID = 1000 mg; ferumoxytol = 1020 mg). Patients who received other IV iron formulations for their initial infusion or who received multi-dose IV iron repletion were excluded. Low-molecular weight iron dextran was administered over 1 hour, and test doses were used intermittently prior to removal from institutional protocol in April 2019. Ferumoxytol was administered over 15 minutes. Neither drug required use of routine premedications. Patient demographics were collected for those meeting the inclusion criteria. The primary outcome was median change from baseline in hemoglobin (Hb), hematocrit (Hct), and ferritin levels 8 to 12 weeks post IV iron infusion. A timeframe of 8 to 12 weeks for post-infusion assessment was selected based on prior studies of single-dose LMWID or ferumoxytol that used follow-up labs of 4 to 8 weeks (one study allowed up to 6 months) after IV iron infusions, although greater increments were observed with follow-up greater than 4 weeks.^7,10,11 To be included in the efficacy analysis patients were required to have follow-up labs 8 to 12 weeks from baseline and to have not received additional doses of IV iron prior to follow-up. Secondary outcomes included incidence of infusion-related reactions and the proportion of patients requiring more than one IV iron supplementation. Infusion reactions were identified if medications (hydrocortisone, famotidine, epinephrine, diphenhydramine) were administered on the same day patients received their IV iron infusion. Chart review was conducted for each patient with evidence of an infusion reaction to further characterize patient response and subsequent therapy. Common Terminology Criteria for Adverse Events (CTCAE) 5.0 was used to classify patient’s infusion-related reactions. Effectiveness endpoints of the primary outcome were analyzed using Mann-Whitney U tests and comparison of incidence of secondary endpoints utilizing chi-square tests.

3 |. RESULTS

Overall, 906 patients (LMWID n = 439 and ferumoxytol n = 467) met the study inclusion criteria, of whom 351 had sufficient laboratory data available for inclusion in the effectiveness analysis (LMWID n = 197 and ferumoxytol n = 154). A breakdown of the patients included in the effectiveness analysis is provided in Figure S1. All 906 were included in the safety analysis. Demographics are described in Table 1. The majority (81%) were female. Of the 439 who received LMWID, 109 (24.8%) received a test dose. No test doses were given with ferumoxytol.

TABLE 1.

Patient demographics

Total (n = 906)
Sex	Males	Females
	18.8% (170)	81.2% (736)
Race	Caucasian	Other
	86.2% (781)	13.8% (125)
Age (y)a	53.6 ± 17.7

^aMedian and interquartile range.

3.1 |. Effectiveness

The primary and secondary endpoints are described in Table 2. Of patients included in the primary endpoint, baseline Hb, Hct, and ferritin were similar between groups with a mean follow-up time of 9.7 and 9.8 weeks for patients who received LMWID and ferumoxytol, respectively. Patients who received LMWID experienced a median change from baseline of 0.5 g/dL, 1.1%, and 87 ng/dL for Hb, Hct, and ferritin, respectively. Patients that received ferumoxytol had median change from baseline of 0.8 g/dL, 1.25%, and 71 ng/dL for Hb, Hct, and ferritin, respectively. Subset analysis were also performed in patients with Hb < 11 g/dL as outlined in Table 2. In the total efficacy cohort there was no statistically significant difference between LMWID or ferumoxytol in regards to median change in Hb (P = .24), Hct (P = .89), or ferritin (P = .47) (Figure 1). Of the patients who received LMWID (n = 439), 28.5% were treated with additional IV iron infusions during the 34 month study observation period compared to 16.1% of patients who received ferumoxytol (n = 467) (P < .001). Results were similar when the analysis was performed for the effectiveness cohort only (LMWID 55/197 (27.8%); Ferumoxytol 23/154 (14.9%); P = .004).

TABLE 2.

Summary of primary and secondary outcomes

Primary endpointa
	Baseline Median (IQR) (Range)	Post IV iron Median (IQR) (Range)	Change baseline from Median (IQR)
LMWID (n = 197)
Hgb (g/dL)	11.9 (10.2–13) (5–16.4)	12.5 (11.2–13.5) (5.8–16.9)	0.5 (0–1.3)
Hct (%)	36.3 (32–39.6) (16.5–53.8)	38.1 (34.6–41.2) (21.2–58.3)	1.1 (−0.3 to 3.7)
Ferritin (ng/dL)	34 (14–68.5) (2–709)	143.4 (66.5–221) (3–1163)	87 (15–164.5)
LMWID with existing anemia (Hgb <11 g/dL) (n = 69)
Hgb (g/dL)	9.7 (8.3–10.4) (5–10.9)	11 (9.5–11.7) (5.8–14.9)	1.1 (0.3–2.5)
Hct (%)	30.2 (27.3–32.4) (16.5–35.7)	34 (29.4–36.5) (21.2–45.4)	2.8 (0.3–7.1)
Ferritin (ng/dL)	27 (10–68.5) (2–573)	106 (40–194) (3–1155)	69 (2.5–138)
Ferumoxytol (n = 154)
Hgb (g/dL)	12 (10.3–13.4) (6.1–15.8)	13.0 (11.5–13.8) (5.9–16.4)	0.8 (0–1.6)
Hct (%)	37.2 (32.9–40.7) (21–50.9)	39.1 (35.7–41.5) (20.8–48.9)	1.25 (−0.8–3.8)
Ferritin (ng/dL)	28.5 (16–71.5) (2–1513)	136 (51–244) (2–1495)	71 (0–191.5)
Ferumoxytol with existing anemia (Hgb <11 g/dL) (n = 56)
Hgb (g/dL)	9.9 (8.7–10.4) (6.1–10.9)	11.2 (9.9–12.5) (5.9–16.2)	1.55 (0.1–3.1)
Hct (%)	31.6 (28.5–33.2) (21–36.2)	34.8 (31.3–37.8) (20.8–48.9)	3.8 (0–7.7)
Ferritin (ng/dL)	22 (10.3–67.3) (2–1513)	52.5 (25.8–147) (2–1495)	24.5 (−3–74.5)

Secondary endpoints
	LMWID (n = 439)	Ferumoxytol (n = 467)
Additional IV iron infusions	28.5% (125)	16.1% (75)
	LMWID effectiveness cohorta (n = 197)	Ferumoxytol effectiveness cohorta (n = 154)
	27.8% (55)	14.9% (23)

Abbreviations: Hct, hematocrit; Hgb, hemoglobin; IQR, Interquartile range; LMWID, low molecular weight iron dextran.

^aExcluded patients with additional IV iron infusion prior to week 8 to 12 labs and patients with first post IV iron labs beyond 12 weeks.

FIGURE 1.

Comparison of primary effectiveness outcomes. LMWID, low-molecular weight iron dextran. Baseline and post-infusion hemoglobin, hematocrit, and ferritin were analyzed to assess effectiveness of single-dose LMWID and ferumoxytol. Overall, ferumoxytol was not found to be inferior to LMWID as there was no statistical difference observed for any of the effectiveness outcomes

3.2 |. Safety

The incidence of adverse events (AE) are described in Table 3. Overall AEs were comparable between patients who received LMWID (n = 439; 2.3%) and ferumoxytol (n = 467; 2.8%) (P = .47). Adverse event grade and type are further detailed in Table 3. The majority of reactions were grade 2 for both groups, with resolution of symptoms promptly after receiving appropriate infusion reaction medications (69.6% diphenhydramine [one patient received loratadine instead], 30.4% famotidine, 34.8% steroid; 34.8% received two or more medications) and holding therapy. Overall, three in each group (LMWID 0.7%; ferumoxytol 0.6%) did not receive the full dose of IV iron due to a treatment-related AE. Of the three who discontinued treatment in the ferumoxytol group, two had grade 3 infusion reactions, while one with a grade 2 infusion reaction refused to continue treatment even though medical staff felt it was safe to do so. One of the three with a grade 3 infusion reaction in the LMWID treatment group was sent to the emergency room; however, their symptoms resolved during their evaluation. The remaining two had resolution of their symptoms in clinic after with holding IV iron. Neither group had any severe or life-threatening reactions or grade 4 AEs. Specific symptoms related to the AE are detailed in Table 3.

TABLE 3.

Summary of adverse events

CTCAE Grading	Ferumoxytol (n = 467)	LMWID (n = 439)
All adverse events	2.8% (13)	2.3% (10)
Grade 1	0	0.2% (1)
Grade 2	2.4% (11)	1.4% (6)
Grade 3	0.4% (2)	0.7% (3)
Grade 4	0	0
Specific Adverse Events
Nausea	0.6% (3)	0.5% (2)
Vomiting	0	0.2% (1)
Cold sweats	0.2% (1)	0.2% (1)
Shortness of breath	0.4% (2)	0.2% (1)
Wheezing	0	0.2% (1)
Lightheadedness	0.4% (2)	0.9% (4)
Cough	0	0.2% (1)
Throat swelling	0	0.5% (2)
Pruritis	0.2% (1)	0.9% (4)
Flushing	0.9% (4)	0.5% (2)
Chest discomfort	0.9% (4)	0.5% (2)
Abdominal pain	0	0.2% (1)
Hives	0.4% (2)	0
Congestion	0.2% (1)	0
Momentary loss of speech	0.2% (1)	0
Heart burn	0.2% (1)	0
Low back pain	0.2% (1)	0
Tongue swelling	0	0.2% (1)
Urinary tract infection	0	0.2% (1)

4 |. DISCUSSION

This cohort study of over 900 individuals examined the safety and effectiveness of two IV iron formulations frequently administered as a total dose infusion; LMWID and ferumoxytol for the treatment of iron deficiency. Clinically significant AEs were similarly rare with both drugs suggesting that either may be used safely as a single-dose infusion for the management of iron deficiency. Both single-dose preparations appear equally effective, however in our study fewer patients who received ferumoxytol were treated with additional doses of IV iron during the study period. Unlike previous studies which evaluated single-dose ferumoxytol alone, our study affirms the effectiveness and safety of single-dose ferumoxytol through comparison with single-dose LMWID. Prior studies which evaluated single-dose LMWID or ferumoxytol separately reported average changes in hemoglobin of 1.2–1.9 g/dL.^7,11,12 Notably, our study utilized medians for reporting and analysis in the setting of heterogeneous data. Although the median change in hemoglobin found for both LMWID and ferumoxytol are lower compared to prior studies, our results remain consistent between groups. In a study by Auerbach et al, it was found that an increased response was found in patients with follow-up evaluation 4 or more weeks following IV iron supplementation compared to those prior to 4 weeks.¹¹ Patients were included in this study with follow-up evaluation of effectiveness labs (ie, hemoglobin, hematocrit, and ferritin) between 8 and 12 weeks, possibly contributing to the wider distribution observed. Subset analysis performed in patients with Hb < 11 g/dL also showed a more robust response in red cell indices as compared to the total cohort, possibly explaining some of the discrepancy. Ferritin is thought to be the most accurate measure of iron deficiency.¹ Despite comparable baseline ferritin levels (34 ng/dL(IQR 14–68.5 ng/dL) and 28.5 ng/dL (IQR 16–71.5 ng/dL) for LMWID and ferumoxytol, respectively), patients who received LMWID more frequently required additional IV iron infusions compared to patients who received ferumoxytol (28.5% vs 16.1%, respectively). As baseline iron labs were similar, the degree or severity of iron deficiency does not likely contribute to this difference. In clinical practice, it is generally accepted that there is comparable effectiveness between IV iron formulations.^1,3,4 Since the single-dose administration remains an off-label use of ferumoxytol and LMWID, it is possible that additional IV iron infusions may not have been captured for patients who only received single-dose ferumoxytol (1020 mg) or LMWID (1000 mg) for their initial infusion, and subsequently continued supplementation with a multi-dose regimen which was not evaluated in our study, although this is unlikely.

The true incidence of severe AEs or anaphylactic reactions to IV iron is thought to be less than one in 200 000 (excluding patients who received high molecular weight iron dextran), with incidence of mild infusion-related reactions estimated to be approximately 1%.^1,4,13 Previous studies reported mild reactions of 6.3% and 0.6% to 7.4% for LMWID and ferumoxytol, respectively.^11,12 Minor infusion reactions are thought to be due to labile/free iron or secondary to infusion rate.^4,13,14 This study found comparable rates of mild to moderate AEs between LMWID (2.3%) and ferumoxytol (2.8%) (Table 3), consistent with prior studies. Infusions were well tolerated with the majority of infusion reactions being grade 2 or less, with no severe reactions or other treatment-related AEs in either group. In the event of infusion reactions, rechallenge was thought to be safe, with almost no report of recurring symptoms.⁴ All patients who experienced infusion reactions had complete resolution of symptoms with observation or intervention with IV fluids, antihistamines, and/or corticosteroids. Of patients who discontinued IV iron therapy, decision to withhold further IV iron supplementation was due to patient preference, not due to high risk of subsequent reactions.

Several limitations of this study are worth considering. The occurrence of infusion reactions was identified through concomitant administration of medications for infusion reactions received on the day patients received their IV iron infusion. Thus, patients who did not receive a medication for an infusion reaction or who received normal saline were not accounted for, as normal saline is routinely included as an as needed premedication in our institutional IV iron infusion panel, and consequently was not included in our screening criteria. Institutional practice also changed during the time from which data was collected, in that test doses for LMWID were removed in April 2019 due to lack of clinical utility and inconsistent use in practice. A group of 109 patients treated with LMWID in our study (24.8%) received a test dose. Although inclusion of patients who received test doses could disproportionately account for patients tolerant of LMWID, this likely did not significantly impact safety results as our reported incidence of infusion-related reactions/AEs are similarly infrequent to other studies describing LMWID AEs.^1,4 Furthermore, per institutional policy patients who received IV iron should not be on concomitant oral iron or erythropoietin stimulating agents except for the small proportion of patients with severe chronic kidney disease. Thus, it was assumed that patients included were not receiving concomitant oral iron supplementation or erythropoietin stimulating agents. Other extenuating circumstances may have delineated LMWID being preferred instead of ferumoxytol; namely, if a patient was scheduled to have an MRI.

5 |. CONCLUSION

This study affirms the safety and effectiveness of single-dose IV LMWID and single-dose IV ferumoxytol. In this trial when administered as a single-dose infusion, ferumoxytol offered decreased infusion requirements and appeared to be a safe and convenient option for IV iron supplementation. Expanded coverage should be considered for single-dose ferumoxytol in patients with iron deficiency anemia with intolerance of, or refractory to oral iron supplementation. Future studies are needed to further affirm the safety and effectiveness of other formulations of single-dose IV iron.