Newer formulations of intravenous iron: a review of their chemistry and key safety aspects – hypersensitivity, hypophosphatemia, and cardiovascular safety

Figures & data

Table 1. Characteristics of FDI, FCM, and FER [5–10]

	Ferric derisomaltose (FDI)^a	Ferric carboxymaltose (FCM)	Ferumoxytol (FER)
Brand name	US: Monoferric® EU: Monofer®	US: Injectafer® EU: Ferinject®	Feraheme®
Date of approval	US: 2020 EU: 2009	US: 2013 EU: 2007	US: 2009 EU: 2012 (withdrawn 2015)
Manufacturer	Pharmacosmos	US: American Regent EU: Vifor Pharma	AMAG Pharmaceuticals
Iron content	100 mg/mL	50 mg/mL	30 mg/mL
Warnings as per label
Hypersensitivity reactions	Precaution for use	Precaution for use	Black box warning
Symptomatic hypophosphatemia	No specific warning	Yes. Requirement to monitor serum phosphate^b	No specific warning
Cardiovascular safety	No specific warning	No specific warning	No specific warning

^aAlso known as iron isomaltoside, ^bUS label: in patients at risk for low serum phosphate who require a repeat course of treatment; EU label: in patients who receive multiple administrations at higher doses or long-term treatment, and in those with existing risk factors for hypophosphatemia

Figure 1. Chemical structures of the carbohydrate moieties in FDI, FCM, and FER, relative to dextran

FCM = ferric carboxymaltose; FDI = ferric derisomaltose; FER = ferumoxytol; LMWID = low molecular weight iron dextran

Figure 2. Bead-NTBI levels following a single dose of FDI, FCM, or iron sucrose [27]

The timeframe was limited to 48 hours as NTBI was not observed after this time point. FCM = ferric carboxymaltose; FDI = ferric derisomaltose; IS = iron sucrose; NTBI = non-transferrin-bound iron. The figure has been adapted from Figure 4 in Garbowski et al. Haematologica 2020. doi: 10.3324/haematol.2020.250803 [27].

Figure 3. Incidence of hypophosphatemia reported during the PHOSPHARE-IDA trials [28,51]

***p < 0.001 between-group comparison; Cochran-Mantel-Haenszel. The left-most columns correspond to the primary outcome of incident hypophosphatemia at any time during the trial. The remaining columns correspond to the proportions of patients with serum phosphate level <2.0 mg/dL at each individual time point in the safety analysis set. The patterned bars correspond to the proportion of patients with serum phosphate level ≤1.0 mg/dL. FCM = ferric carboxymaltose; FDI = ferric derisomaltose. Adapted with permission from JAMA (Wolf et al. 2020;323(5):432–443). Copyright 2020 American Medical Association. All rights reserved [28]. Adapted from Iqbal et al. Poster presented at the British Society of Gastroenterology (BSG) Annual Meeting, Glasgow, 2019 [51].

Figure 4. Biochemical basis for hypophosphatemia and associated clinical consequences [28,48,49,57–67]

1,25-[OH]₂D = 1,25-dihydroxyvitamin D; 25-(OH)D = 25-hydroxyvitamin D; iFGF23 = intact fibroblast growth factor 23; PTH = parathyroid hormone. Magnetic resonance imaging courtesy of Heinz Zoller. The figure has been adapted from Iqbal et al. Poster presented at the British Society of Gastroenterology (BSG) Annual Meeting, Glasgow, 2019 [51].

Table 2. Ongoing clinical studies of IV iron in patients with HF and iron deficiency

Study name	Patient population	Study design	Treatment(s)	Estimated enrollment	Primary outcome measure(s)	Expected follow-up period
IRONMAN [100]	HF and iron deficiency	Randomized, open-label, blinded endpoint adjudication	FDI versus standard of care	1,300	CV mortality or hospitalization for worsening HF	≥2.5 years
FAIR-HF 2 [101]	Systolic HF and iron deficiency	Randomized, double-blind	FCM versus placebo	1,200	Combined rate of recurrent hospitalizations for HF and of CV death	≥12 months
HEART-FID [102]	HF and iron deficiency	Randomized, double-blind	FCM versus placebo	3,014	Incidence of death	1 year
					Incidence of hospitalization for HF	1 year
					Change in 6MWT	6 months

6MWT = 6-minute walk test; CV = cardiovascular; FCM = ferric carboxymaltose; FDI = ferric derisomaltose; HF = heart failure; IV = intravenous

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