Iron allergy

The graded challenge you suggest sounds reasonable; such a ferumoxytol regimen was suggested by Dr. Lieberman in response to a similar Ask the Expert question. Below is the response:

2/2/2012
I have reviewed your responses to questions regarding anaphylactic/anaphylactoid reactions to intravenous iron preparations and the possible solutions to include product changes between dextran and sucrose preparations as well as incremental dosing/'desensitization' suggestions.

Unfortunately, I have been consulted on a patient with severe anemia after mastectomy and chemotherapy who has experienced burning/itching rash (not classic urticaria in the pictures she provided) to ORAL iron (ferrous sulfate?) that began on ankles, generalized within one hour and was accompanied by wheezing within 2 hours of onset. She self-administered 2 doses of 100 mg Benadryl over 3 hours before relief began. A second dose the next day elicited an identical reaction. She describes a similar reaction to an oral iron preparation more than 10 years ago and has steadfastly avoided iron (including in multivitamins) until the aforementioned event. Reconstructive surgery is not possible until her anemia is addressed and she suffers from debilitating fatigue. She states that she suffers from evanescent similar eruptions since being encouraged to eat iron-rich foods. Worth trying other oral preparations? IV preparations more risky? 'Desensitization' an option? Thank you for your thoughts.

A: I believe you have done due diligence in looking through our previous questions in this regard and summarizing briefly the choices outlined in the responses to these questions. However, there are nuances in regards to your patient that perhaps present you with other options.

Since apparently oral iron might be an available option, I think one strategy would be to use published protocols that have successfully dealt with patients who reacted similarly to oral iron and had to receive it. I have copied below abstracts of two approaches to this problem. Both articles should be readily available to you. I believe that following one of these protocols would be my first choice.

The other choice would be a provocative dosing regimen using a new intravenous iron preparation called ferumoxytol. Although ferumoxytol can produce anaphylactic events according to its package insert (a link to the package insert, for your convenience, is copied below), based on studies to date, it seems to have a relatively good safety profile (also see abstract copied below).

Thus I think you have two choices. One is to use one of the two published protocols in the articles, the abstracts of which are copied for you below. The other would be to consider a provocative dosage regimen as described in the literature and mentioned in our previous responses employing ferumoxytol.

J Investig Allergol Clin Immunol. 2008;18(4):305-8.
Anaphylaxis to oral iron salts. desensitization protocol for tolerance induction.
de Barrio M, Fuentes V, Tornero P, Sánchez I, Zubeldia J, Herrero T.
Source
Allergy Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
Abstract
Allergies to iron salts are seldom reported. We studied a patient with iron-deficiency anemia who had suffered anaphylactic reactions caused by oral iron salts. An allergy study was performed using single-blind, placebo-controlled oral challenge and skin tests with various iron salts as well as excipients in commercial formulations. Oral challenges were positive for 2 of the commercial formulations of iron salts. Intradermal tests with ferrous sulphate and ferrous lactate also showed positive results. All of the cutaneous tests using the excipients were negative. A desensitization protocol was designed which enabled us to readminister ferrous sulphate, although antihistamines were necessary to guarantee good tolerance to iron salts. We report a patient with allergy to iron salts, positive skin tests, and positive controlled challenge. We highlight the desensitization protocol designed to complete the therapeutic management of the anemia.

Ann Allergy Asthma Immunol. 2000 Jan;84(1):43-5.
Oral iron cutaneous adverse reaction and successful desensitization.
Ortega N, Castillo R, Blanco C, Alvarez M, Carrillo T.
Source
Department of Allergy, Hospital Ntra Sra del Pino, Las Palmas de G C Spain.
Abstract
Background: The oral administering of iron preparations sometimes produces adverse gastrointestinal effects. In contrast, cutaneous reactions are extremely rare.
Objective: We report a patient with several episodes of generalized pruritus and erythematous maculopapular eruption after receiving oral compounds of iron and on whom desensitization with oral iron was attempted.
Methods: We studied a female with microcytic anemia due to gynecologic blood loss who presented several episodes of cutaneous eruption after receiving oral compounds of iron. Skin prick-test and two simple-blind, placebo-controlled oral challenges were performed with various iron compounds, and finally desensitization with oral iron was carried out.
Results: Skin prick-test and patch-test with iron preparations were negative. Two simple-blind, placebo-controlled oral challenges were performed and the patient began experiencing similar cutaneous symptoms. We started a slow desensitization protocol using increasing doses until the target amount of the drug was tolerated without adverse effects. The chronic administration of oral iron therapy once a day for 9 months sustained the desensitized state and the anemia disappeared.
Conclusion: We present methods to effectively manage iron supply for a microcytic anemia patient with cutaneous reactions due to oral iron compounds, to avoid repeated transfusions, slow desensitization with oral iron was successfully attempted.

Am J Kidney Dis. 2008 Nov;52(5):907-15. Epub 2008 Sep 27.
Safety of ferumoxytol in patients with anemia and CKD.
Singh A, Patel T, Hertel J, Bernardo M, Kausz A, Brenner L.
Source
Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Abstract
Background: Iron deficiency anemia is a common complication in patients with chronic kidney disease (CKD). Currently available intravenous (IV) iron replacement therapies have either inconvenient regimens of administration or adverse event profiles that limit their utility in the outpatient setting. Ferumoxytol is a novel, semisynthetic, carbohydrate-coated, superparamagnetic iron oxide nanoparticle that is administered IV as an injection. The main objective of this study was to assess the safety of ferumoxytol for the treatment of patients with CKD stages 1 to 5 and 5D.
Study Design: Phase 3, randomized, double-blind, placebo-controlled, crossover, multicenter study of a single 510-mg dose of ferumoxytol versus saline as placebo.
Setting & Participants: 750 patients with CKD stages 1 to 5 and 5D.
Intervention: An IV injection of either 17 mL of ferumoxytol or saline placebo over 17 seconds on day 0 and the alternate agent on day 7.
Outcomes & Measurements: Descriptive comparison of adverse events, laboratory tests, and vital signs.
Results: Of 750 randomly assigned patients with CKD, 60% were not on dialysis therapy. 713 patients received ferumoxytol, and 711 received placebo. There were 420 adverse events reported; 242 in 152 patients (21.3%) with ferumoxytol and 178 in 119 patients (16.7%) 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 included symptoms related to the injection/infusion site, dizziness, pruritus, headache, fatigue, and nausea. Serious adverse events occurred in 21 patients (2.9%) after ferumoxytol and 13 patients (1.8%) after placebo. Serious related adverse events were observed in 1 patient (0.1%) after each treatment. There was no meaningful decrease in blood pressure after administration of ferumoxytol or placebo.
Limitations: Follow-up was 7 days after each study treatment.
Conclusions: Ferumoxytol is well tolerated and has a safety profile similar to placebo in anemic patients with CKD stages 1 to 5 and 5D.

Sincerely,
Phil Lieberman, M.D.

The authors in the article cited below by Rampton, et al with treatment recommendations for patients who reacted to IV iron suggest rather than grading the dose you grade the rate, so give the infusion which normally would be administered over 15 minutes at 10% of the usual rate for 15 minutes and then faster as tolerated.

Rampton D, Folkersen J, Fishbane S, et al. Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management. Haematologica. 2014;99(11):1671-1676.

Patricia McNally, MD, FAAAAI