How should iron deficiency be treated? Intravenous (IV) iron can rapidly correct iron-deficiency anemia, but some formulations can result in low phosphate levels (hypophosphatemia). Ferric carboxymaltose results in phosphate levels below 1 mg/dL for 11% of people who are treated more than once and can lead to osteomalacia.
In this edition of Drawing First Blood, ASH Clinical News invited Thomas Deloughery, MD, MACP, of Oregon Health & Science University, and Michael Auerbach, MD, of Auerbach Hematology-Oncology in Baltimore and Georgetown University School of Medicine in Washington, D.C., to debate the benefits and potential risks of IV iron and discuss when IV iron might be preferred over oral iron to treat anemia.
Thomas Deloughery, Michael Auerbach, MD
MD, MACP
What are the most effective formulations for treating iron deficiency?
Dr. Deloughery: It depends on the situation. If somebody’s never tried iron before and it’s not a complicated situation — they’re not pregnant or have major gastrointestinal (GI) pathology — I would say oral iron is the way to go. One pill a day, at most, though there’s emerging data to support taking it every other day. But certainly, if somebody can’t tolerate oral iron — because of constipation, for example, or a condition such as inflammatory bowel disease (IBD), pregnancy, history of GI issues — I go with IV iron.
Dr. Auerbach: My style is a little different, but what Dr. Deloughery said is correct. There are many situations where oral iron should not be tried; for example, in heavy menstrual bleeding where it has no chance of keeping up with the blood losses or in the second and third trimester of pregnancy. I truly hope it becomes contraindicated before I’m dead because it doesn’t get to the baby. The data are solid that it doesn’t, and just a few months ago the OB-GYN literature showed that IV iron, not oral iron, corrected the baby’s ferritin at birth.1
Curiously, for patients with IBD, oral iron worsens symptoms. It’s toxic to the epithelium and causes an incommodious growth of the wrong intestinal bacteria. For patients who have undergone bariatric surgery, I can’t give a simple answer. If you have Roux-en-Y or biliopancreatic diversion, there’s no absorption at all, and giving oral iron only offers toxicity without benefit; for people who have undergone stapling or sleeves, there is a little bit of benefit with oral iron. However, IV iron simplifies care for so many other GI perturbations and, in the case of comorbid conditions, can overcome the block by hepcidin, which oral iron can’t do. For all other conditions, which is almost nothing, oral iron is okay.
What are the advantages and disadvantages of using IV agents compared to oral agents?
Dr. Auerbach: Suppose you walk into my office with heavy periods. You have symptomatic iron deficiency, and your OB-GYN got the heavy periods under control the week before. You can take one iron pill every other day for a year. And if you take it and tolerate it, it’s likely to work, and you will get better. Or I can fix you in 20 minutes with no GI side effects.
A minor infusion reaction will occur 1% to 3% of the time. If it does, it is very important not to overreact, because if you treat it as a minor, self- limited reaction, it will spontaneously resolve. Dr. Deloughery wrote a spectacular paper in the Journal of the American Medical Association2 with one of his colleagues, Asad Arastu, MD, who was the first author. This paper was so important because it showed that serious adverse events (AEs) with IV iron are vanishingly rare, you should not premedicate, and you should not become hysterical when you have a minor infusion reaction.
Dr. Deloughery: Well, thank you. I’d like to emphasize those points. IV iron is quick and simple and gets the problem solved very rapidly. It’s certainly safer than IV penicillin. If you look at the data, in many situations where oral iron won’t work or is crippling the patient’s quality of life, IV iron is faster, superior, and will get the iron stores up.
What are the differences between IV agents currently available in the U.S.?
Dr. Auerbach: Six are commonly prescribed in the U.S. Two of them, iron sucrose and ferric gluconate, work perfectly well but require five to seven visits to do what the other agents can do in one visit. The others include low-molecular-weight iron dextran, ferumoxytol, ferric derisomaltose, and ferric carboxymaltose.
Low-molecular-weight iron dextran speaks for itself. It’s been around for the longest. Studies in oncology and pregnancy were the first to prospectively test it, and it has been used in hundreds of thousands of patients on dialysis. The drug has a rigorous safety record, and they’re all equivalent except one, and that’s ferumoxytol.
There are no public safety data [for ferumoxytol]. It was approved by the U.S. Food and Drug Administration (FDA) based on molecular identity. The FDA made the same tragic error with high-molecular-weight iron dextran in 1996, when they released the compound that resulted in an 1,800% increase in serious AEs based on their own reporting. I’ve been called by at least a dozen medical systems around the U.S. and asked, “Why are there increased reactions with Feraheme?” I said, “You’re giving the generic,” and 100% of the time they were. That’s just an anecdote, but if you take the FDA files by Sandoz, who makes ferumoxytol, they had to submit 60 patients, which is woefully inadequate for safety. The incidence of minor infusion reactions was double the other four, which have equal safety and efficacy records. There is an issue with hypophosphatemia with ferric carboxymaltose, but we don’t really know if it’s clinically significant.
Should you avoid ferric carboxymaltose?
Dr. Deloughery: There are two issues. One, if you look for it, you’ll find it. You should start requesting phosphorous levels after infusions because [patients] are reading about it. I’ve had one patient who was really hypophosphatemic after one use and was noticing fatigue and muscle issues. More worrisome, there are data that with repeated use, people can see bone weakness such as osteomalacia. We are big fans of low-molecular-weight iron dextran, and that’s been our main product. We use the other ones rarely, such as when there are insurance quibbles or occasional shortages. It’s an agent we’re very familiar with and it’s very cost effective. I tend to avoid ferric carboxymaltose because there are agents we are more comfortable with.
Dr. Auerbach: There was just a paper published in Gut3 in which there was a clear difference in fatigue with ferric carboxymaltose compared to ferric derisomaltose, and some of that fatigue was ostensibly related to hypophosphatemia. I don’t feel like I’m qualified to say the drug should not be used. I think it’s more difficult because you have to monitor phosphorus. I use it; it’s about 1% of the iron that I give, but only in rare circumstances where patients have multiple infusion reactions to the others.
Dr. Deloughery: The way I view it is you have multiple products to choose from. You have one with a relatively unique side effect and others that don’t have that side effect. Again, sometimes we have to use it, but I don’t reach for it preferentially either.
What are the alternatives, and do any of them result in serious side effects?
Dr. Auerbach: Take the minor infusion reaction, which is called the Fishbane reaction. I think people believe it is a complement-mediated reaction, and it has a name called CARPA — complement activation-related pseudo allergy. It’s harmless, goes away without treatment. Some people premedicate with a steroid and an H2 blocker; some don’t. It rarely recurs on rechallenge; however, if you are one of those people who believes there is a legitimate risk of anaphylaxis with IV iron — and I agree with Tom, it’s less frequent than with penicillin — and you intervene for that minor reaction with epinephrine and diphenhydramine, which causes hypotension, somnolence, diaphoresis, tachycardia, and shock, then you are going to have a serious AE. What do you think is going to get blamed — the epinephrine and the diphenhydramine, or the iron? It’s very, very important to not overreact to that minor reaction.
Dr. Deloughery: I’d like to amplify that. When I tell people about IV iron, I tell them about this reaction. I explain that they’ll feel funny, but it’s not an allergy. I explain what it is. It’s important to prepare the patient not to freak out when this happens.
Going back to the phosphate issue, should clinicians monitor serum phosphate levels in all patients undergoing IV treatment for iron deficiency?
Dr. Auerbach: No, just with ferric carboxymaltose. Protracted hypophosphatemia and severe hypophosphatemia have never been described with any of the formulations other than ferric carboxymaltose. Ferric derisomaltose does have about an 8% incidence of hypophosphatemia. It’s never protracted and never severe.
Dr. Deloughery: I agree. It’s a peculiar side effect of one of the agents due to its unique pharmacology and interactions. The only thing I monitor with any other iron is the patient’s response to the iron.
References
- Arastu AH, Elstrott BK, Martens KL, et al. Analysis of adverse events and intravenous iron infusion formulations in adults with and without prior infusion reactions. JAMA Netw Open. 2022;5(3):e224488.
- Awomolo AM, McWhirter A, Sadler LC, et al. Neonatal outcomes from a randomized controlled trial of maternal treatment of iron deficiency anemia with intravenous ferumoxytol vs oral ferrous sulfate. Am J Obstet Gynecol MFM. 2023;5(9),101063.
- Zoller H, Wolf M, Blumenstein I, et al. Hypophosphataemia following ferric derisomaltose and ferric carboxymaltose in patients with iron deficiency anaemia due to inflammatory bowel disease (phosphare-IBD): a randomised clinical trial. Gut. 2023;72(4),644–653.
