With the recent Food and Drug Administration (FDA) approval of ferumoxytol, nephrologists have a new option for the treatment of iron-deficiency anemia in adults with chronic kidney disease. Exactly how the agent may be incorporated into clinical practice remains to be seen, though.
“I think as far as efficacy, iron is iron, and Feraheme [ferumoxytol] has advantages of speed and potentially safety, although no head-to-head trials have been performed to date,” said Daniel W. Coyne, MD, a study investigator for the agent and Professor of Medicine in the Division of Renal Diseases at Washington University School of Medicine in St. Louis, in a phone interview. “It will certainly be competitive in the marketplace and in certain instances offer distinct advantages.”
Half a gram of ferumoxytol can be given in under a minute, and the patient should be observed for another 30 minutes after the agent is administered, Dr. Coyne said. “That's substantially shorter than otherwise.”
The benefits of more rapid administration may vary depending on whether or not the patient is receiving dialysis.
“The advantage in non-dialysis patients is more obvious because we lack IV access in these patients to administer iron on a routine basis,” Dr. Coyne said.
“The advantage of a large-dose injection of Feraheme compared with other products that can be given at lower doses is less clear in dialysis patients because we access those patients' vascular access three times a week, so we can give them small repeated doses. I don't think it is as clear that it offers a distinct advantage over what we're doing now.”
Safety and Efficacy
Ferumoxytol was compared with oral iron in Phase 3 safety and efficacy studies and reached the primary endpoint—a statistically significant increase in mean change in hemoglobin at Day 35:
• In a randomized, open-label, controlled, multicenter trial by Provenzano et al (Clin J Am Soc Nephrol 2009;4:386–393), patients on hemodialysis who had anemia and were on a stable erythropoiesis-stimulating agent (ESA) regimen received either two injections of 510 mg of ferumoxytol within 7 days (114 patients) or 200 mg of elemental oral iron daily for 21 days (116 patients).
The mean increase in hemoglobin at Day 35—the primary endpoint— was 1.02 g/dL for those treated with ferumoxytol, compared with 0.46 g/dL for patients treated with oral iron.
Twice as many patients in the ferumoxytol group had a hemoglobin increase of at least 1 g/dL at Day 35; this difference persisted after adjustment for baseline hemoglobin, transferrin saturation, and serum ferritin.
• In another randomized, open-label, controlled, multicenter trial, this one by Spinowitz et al, 304 patients with CKD Stages 1 to 5 were randomized in a three-to-one ratio to two 510-mg doses of intravenous ferumoxytol within 5 ± 3 days or 200 mg of elemental oral iron daily for 21 days.
The overall hemoglobin increase at Day 35 was 0.82 g/dL in ferumoxytol-treated patients versus 0.16 g/dL for patients treated with oral iron (J Am Soc Nephrol 2008;19:1599–1605).
The safety of ferumoxytol was also evaluated in a randomized, double-blind, placebo-controlled, crossover, multicenter study by Singh and colleagues of patients with CKD Stages 1 through 5 and 5D (Am J Kidney Dis 2008;52;907–915).
Patients received an IV injection of 17 mL of ferumoxytol or saline placebo on Day 0 and the alternate agent on Day 7. A total of 713 patients received ferumoxytol and 711 patients placebo.
Ferumoxytol was well tolerated in this patient population, and it had a similar safety profile to placebo.
In all, 420 adverse events were reported: 242 in 152 patients (21.3%) treated with ferumoxytol and 178 in 119 patients (16.7%) treated with placebo. The incidence of related adverse events was 5.2% with ferumoxytol and 4.5% with placebo.
The most common related adverse events after each treatment were injection/ infusion site-related symptoms, dizziness, pruritus, headache, fatigue, and nausea. Serious adverse events occurred in 21 patients (2.9%) treated with ferumoxytol and 13 patients (1.8%) treated with placebo.
“This is a drug that was designed for performance,” said Brian J. G. Pereira, MD, President and CEO of AMAG Pharmaceuticals, the maker of ferumoxytol.
“It has a neutral pH, it is iso-osmolar with plasma, and it's stable at room temperature for very long periods of time,” Dr. Pereira said in a phone interview. “We tried to design what we thought would be the ideal characteristics of an IV iron in terms of safety, efficacy, and convenience.”
Need for Head-to-Head Comparisons
Comparisons of ferumoxytol with other IV irons, as well as demonstrations of optimal repeated use in dialysis patients, would be helpful, Dr. Coyne said.
Other available intravenous iron preparations include high-molecular-weight iron dextran, low-molecular weight iron dextran, ferric gluconate, and iron sucrose.
“The usual dose for repletion of iron stores is 1,000 to 1,500 mg,” noted Michael Auerbach, MD, Clinical Professor of Medicine at Georgetown University School of Medicine and a hematologist/oncologist, in an editorial published in the American Journal of Kidney Diseases (2008;52: 826–829).
“While high- and low-molecular-weight preparations of iron dextran can be given as a total dose infusion (e.g., 1,000 to 1,500 mg) over 60 to 90 minutes, there are concerns about anaphylactic reactions.
“The iron salts ferric gluconate and iron sucrose do not appear to cause anaphylaxis, but higher doses result in other acute reactions, precluding total dose infusions.”
Before ferric gluconate, and then iron sucrose, were introduced to the US market, iron dextran was the most widely used intravenous iron, Dr. Auerbach noted in the editorial.
“Shortly thereafter, the use of iron dextran in dialysis patients plummeted due to the view that iron dextran carried a greater risk of severe reactions.
“Newer information suggests low-molecular-weight iron dextran is much safer than high-molecular-weight iron dextran,” Dr. Auerbach added, pointing to one of the findings of a retrospective analysis by Chertow and colleagues of all parenteral iron-related adverse drug events reported to the Food and Drug Administration via the MedWatch system between 2001 and 2003 (Nephrol Dial Transplantation 2006;21:378–382).
The analysis also reported that total and life-threatening adverse drug events were significantly less frequent among recipients of sodium ferric gluconate complex and iron sucrose compared with recipients of lower-molecular-weight iron dextran.
Still, Dr. Auerbach said that in his opinion low-molecular-weight iron dextran is currently the safest and easiest iron to administer, though not everyone shares that viewpoint, he noted in a phone interview.
Although ferumoxytol will likely be safer at higher doses, that remains to be seen, he added.
“If ferumoxytol proves that it is as facile as low-molecular-weight iron dextran, it will be a clear step forward in iron administration in nephrology, providing commodious pricing becomes a reality.”
Given ferumoxytol's ease of administration, it should be incorporated into clinical practice, said Kamyar Kalantar-Zadeh, MD, MPH, PhD, Associate Professor of Medicine at the David Geffen School of Medicine at UCLA, in a phone interview.
“I think there are several positive implications. One is that it expands the choice of IV iron for the treatment of anemia in CKD patients.
“It further contributes to increased awareness of the importance of iron supplementation in CKD patients, including dialysis patients, as a main part of anemia management.”
Ferumoxytol's investigational use in patients with CKD who were not yet on dialysis highlights the need for a reconsideration of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) guidelines, Dr. Kalantar-Zadeh added.
“The strength of ferumoxytol is its ease of administration. The clinical trials indicate that it can be used in CKD patients not yet on dialysis. This is a major strength and, therefore, I think the guidelines should be reconsidered and revised to put more emphasis on iron administration for anemia management in early CKD patients.”
In terms of the safety of ferumoxytol relative to other IV iron agents, more data is needed, Dr. Kalantar-Zadeh said.
“According to the current Phase III and safety data, its safety profile is comparable with other medications. It's a little too early to make any competitive statements as to which one is less or more safe.”
AMAG is looking to develop ferumoxytol for other iron-deficiency anemia states, such as those associated with heavy menstrual bleeding, cancer, and gastrointestinal bleeds, Dr. Pereira said.
Ferumoxytol also has FDA Fast Track designation for a potential indication as a magnetic resonance angiography agent. It is currently being studied as such in CKD patients.
In terms of other iron products on the horizon, there are studies looking at treating iron deficiency in hemodialysis patients by adding iron to the dialysate, Dr. Coyne noted.
And single-dose total iron replacement would be the wave of the future, Dr. Auerbach said.
“With the advent of three new irons where full replacement doses can be given in short periods of time, I believe that is the future of iron therapy.”
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