Ferumoxytol: a silver lining in the treatment of anemia of chronic kidney disease or another dark cloud?

Figures & data

Table 1 Comparison of properties of ferumoxytol and those of other intravenous iron formulations

Properties	FMX	FCM	IMc	IDd	IS	FG
Molecular weight (Da)a	731,000	150,000b	150,000‡	410,000	252,000e	200,000
Carbohydrate shellb	Polyglucose sorbitol carboxymethyl ether*	Carboxymaltose	Isomaltoside	Dextran polysaccharide	Sucrose	Gluconate, loosely associated sucrose
Median shell/particle diameter (nm)c	26.3	23.1	20.5	12.2	8.3	8.6
Relative catalytic iron releasea,c,f	+	+§	+	++	+++	+++
Relative stability of elemental iron within the carbohydrate shella	High	High	High	High	Medium	Low
Relative osmolalitiesa,g	Isotonic	Isotonic	N/A	Isotonic†	Hypertonic	Hypertonic
Administration (intravenous push) ratesb	30 mg/sec	Bolus push	50 mg/min	50 mg (1 mL)/min	About 20 mg/min	12.5 mg/min
Maximum single doseb,c	510 mg	15 mg/kg	20 mg/kg	20 mg/kg	200 mg	125 mg
Half-life (hours)b	About 15	7–12	5–20	5–20	6	~about 1

Notes:

a Balakrishnan et al,²¹ release of catalytic Fe measured by bleomycin-detectable iron assay in a nonclinical model (5 minutes post injection);

b from USP package insert/prescribing information;

c Jahn et al,²³ shell particle diameter was measured by dynamic light scattering;

d data listed are for low molecular weight iron dextran, unless stated otherwise;

e package insert/prescribing information states the molecular weight of iron sucrose (Venofer^®) to be 34,000–60,000 Da;

f Pai et al⁴³ showed that nontransferrin bound iron levels were significantly higher in patients on iron sucrose and FG versus ID;

g Funk et al⁵¹ compared physical and pharmacological properties of FCM with other intravenous iron products [+ (Fe ≤ 0.02 μg/mL); ++ (Fe > 0.02 to ≤0.04 μg/mL), +++ (>0.04 μg/mL)].

* A modified dextran shell;⁴⁷

† Balakrishnan et al,²¹ low molecular weight iron dextran had a slightly hypertonic osmolality (500 mOsmol/kg);

§ free (dialyzable) iron was 0.002% in buffered solution but was elevated by 100× in normal saline (Jahn et al²³);

‡ apparent molecular weight as measured by gel permeation chromatography (Jahn et al²³).

Abbreviations: FMX, ferumoxytol; FCM, ferric carboxymaltose; IM, iron isomaltoside 1000; ID, iron dextran; FG, ferric gluconate; Fe, iron; IS, iron sucrose; IV, intravenous.

Table 2 Summary of safety and efficacy data from key clinical trials

Authors	Study type	Patient characteristics	Treatment groups	Outcome at follow-up	P valuea	Reported adverse events
Spinowitz et al^Citation20	Phase II	CKD patients with Hgb ≤ 12.5 g/dL and TSAT ≤ 35%	4 doses of 255 mg FMX (each dose 2–3 days apart) n = 10 or	Hemoglobin: 10.4 ± 1.3 g/dL increased to 11.4 ± 1.2 g/dL	P < 0.05b	All ADRs were described as mildc: constipation Delayed pruritic edematous rash Pain at injection site
		(n = 21)	2 doses of 510 mg (each dose one week apart) n = 11	TSAT: 21.3% ± 10% increased to 37.2% ± 22.1%	<0.05b
Spinowitz et al^Citation29	Phase III	Patients with CKD with Hgb ≤ 11 g/dL, ferritin ≤ 600 ng/mL, and TSAT ≤ 30%	2 doses of FMX 510 mg IV (about a week apart) n = 228 or	Hgb: increase by 0.82 ± 1.24 g/dL (FMX) versus 0.16 ± 1.02 g/dL (oral iron)	<0.0001	292 patients were included in the safety analysis Treatment-related ADRs: 10.6% (FMX) versus 24% (oral iron)
		(n = 304)	200 mg oral iron daily for 21 days n = 76	Ferritin: increase by 381.7 ± 278.6 ng/dL (FMX) versus 6.9 ± 60.1 ng/dL (oral iron)	<0.0001	The most common ADRs in the FMX group: Nausea (1.8%)
				TSAT: increase by 9.8% ± 9.2% (FMX) versus 1.3% ± 6.4% (oral iron)	<0.0001	Dizziness (1.8%) Diarrhea (1.4%) Injection site swelling (0.9%)
Provenzano et al^Citation30	Phase III	CKD stage 5 patients on HD ≥ 90 days, hemoglobin ≤ 11.5 g/dL, ferritin ≤ 600 ng/mL,	2 doses of FMX 510 mg iv (about a week apart) n = 114 or	Hgb: increased by 1.02 ± 1.13 g/dL (FMX) versus 0.46 ± 1.06 g/dL (oral iron)	0.0002	110 patients were included in the safety analysisd Treatment-related ADRs: 8.2% (FMX) versus 15.9% (oral iron)
		TSAT ≤ 30%, and at stable ESA doses for at least 10 days prior to study	200 mg oral iron daily for 21 days n = 116	Ferritin: increase by 233.9 ± 206.9 ng/dL (FMX) versus −59.23 ± 106.22 ng/dL (oral iron)	<0.0001	Serious ADRs in the FMX group (n = 54): Hypotension (3.7%) Cellulitis (3.7%)
		(n = 230)		TSAT: increase by 6.44% ± 12.59% (FMX) versus 0.55% ± 8.34% (oral iron)	<0.0001	COPD exacerbation (3.7%)

Notes:

a Significant changes from baseline at follow-up on day-35;

b significant difference in cumulative Hgb and TSAT of both groups at day 14;

c this study did not provide the frequency of ADRs;

d represents only safety data from the randomized phase of this study.

Abbreviations: ADR, adverse drug reaction; COPD, chronic obstructive pulmonary disease; HD, hemodialysis; Hgb, hemoglobin; ESA, erythropoiesis-stimulating agents; FMX, ferumoxytol; IV, intravenous; TSAT, transferrin saturation.

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