The 2021 practice guidance for the evaluation and management of drug hypersensitivity for specific drugs emphasized that intravenous iron therapy is a critical alternative for treating iron-deficiency anemia, particularly when oral formulations are unsuitable due to side effects or poor absorption. These intravenous preparations consist of iron-carbohydrate nanoparticles that vary by core size and carbohydrate type, with several formulations available in the U.S., including iron dextran, ferric gluconate, iron sucrose, ferumoxytol, iron isomaltoside, and ferric carboxymaltose. High-molecular-weight iron dextrans have been discontinued due to their association with severe adverse effects. Hypersensitivity reactions to intravenous iron are primarily infusion rate-dependent and can manifest as dyspnea, pain, hypotension, tachycardia, nausea, vomiting, and pruritus, with minor reactions often resolving without intervention. Severe reactions, including anaphylaxis, are rare but potentially fatal, with an incidence of serious reactions being less than 1 in 200,000 administrations, excluding high molecular weight iron dextrans. Iron sucrose has uniquely been associated with peripheral edema and renal injury when administered at higher rates. The risk of severe hypersensitivity is higher in individuals with atopy or multiple drug allergies. Diagnosis of iron-related reactions involves documenting the specific product, dose, administration route, and rate, along with the nature and management of the reaction. Graded challenges are recommended only for low-molecular-weight iron dextrans, as skin testing has limited utility, although a protocol exists for ferric gluconate. Switching formulations can be considered for mild reactions, but all parenteral iron should be avoided in cases of severe reactions. Desensitization protocols are reported for some formulations, but more data are needed to establish roles for rapid desensitization following anaphylaxis. Expert consensus advises against premedication with antihistamines due to their ineffectiveness and potential side effects. For a comprehensive overview on treatment of parenteral iron reactions based on severity of incident, please refer to Table 1. [1]
A 2024 expert consensus guideline presented structured, evidence-informed recommendations for the safe and effective administration of intravenous (IV) iron in the management of iron deficiency (ID) and iron deficiency anemia (IDA). Despite the absence of prospective data to support premedication, available data demonstrate that next day arthralgia-myalgia syndrome associated with the total dose is mitigated with premedication. Overall, based on the low quality of data, the panel suggests premediation to be reserved for patients at high risk of infusion reaction (multiple drug allergies, prior reaction to an IV iron formulation, asthma) and hypersensitivity reactions (HSRs), with first-generation antihistamines being associated with an increase in adverse reactions. The protocol for premedication was not discussed in the review. [2], [3]
A 2023 article provided an overview of managing iron infusion reactions. While the reaction differs based on the products, premedication to manage the reactions notably lacked robust data. The authors recommend premedications only in the presence of one or more risk factors: previous infusion-related reactions, multiple drug allergies, severe respiratory/cardiac disease, age > 65 years, severe asthma/eczema, mastocytosis, systemic inflammatory disease, anxiety disorder, or receiving an angiotensin-converting enzyme (ACE) inhibitor/beta-blocker. In these scenarios, premedication with a corticosteroid 30-60 minutes prior to initiation is recommended. [4]
Strategies on re-challenging patients who experienced anaphylaxis to IV iron infusions can be difficult. Proposed ideas include slowing the infusion rate, decreasing the dose, switching to a different IV iron preparation, and using premedications (e.g., corticosteroids, antihistamines, and/or acetaminophen). For example, a 52-year-old female patient, diagnosed two years prior with IDA with a previous hypersensitivity reaction to IV ferric carboxymaltose (FCM), was admitted to the internal medicine clinic due to complaints of symptoms associated with IDA (mild amnesia, fatigue, weakness). Her IDA did not resolve with oral iron supplementation, and thus parenteral iron therapy was suggested to be administered via desensitization. The patient was premedicated with IV methylprednisolone 60 mg and oral levocetirizine 5 mg and montelukast 10 mg, 1 h prior to procedure. A stock concentration of 2 mg iron/mL FCM (1 vial of 500 mg Ferinject®; 250 ml of 0.9% sodium chloride solution) was infused over 15 minutes at a rate of 0.5 mL/h, starting at 0.25 mg and increasing in rate until 250 mL/h was achieved. Then, the next 500 mg FCM in 250 mL 0.9% sodium chloride solution was infused over 1 hour for a total of 4 h infusion and 1,000 mg FCM. No allergic reaction was observed while increasing the dose and the premedication was considered effective. Another case report of 4 patients also utilized premedication 1 hour prior to IV ferric carboxymaltose infusion for IDA using IV methylprednisolone 40 mg, IV ranitidine 50 mg, oral (PO) cetirizine 10 mg, PO acetylsalicylic acid 300 mg, and PO montelukast 10 mg. The patients did not experience breakthrough reactions while following the step-up dosing. Note that it is uncertain whether patients were able to tolerate IV iron due to the premedication, step-up dosing regimen, or a combination of the two strategies. [5], [6], [7]
A 2022 multicenter cohort study analyzed the rates of infusion reactions among 35,737 intravenous (IV) iron infusions administered to 12,237 patients across six centers from 2015 to 2021. The research focused on four commonly used iron formulations: iron sucrose, iron dextran, ferumoxytol, and ferric carboxymaltose. The overall incidence of infusion-related adverse events was found to be 3.9%, with significant variation among the different iron formulations. Iron sucrose had the highest rate of adverse events at 4.3%, followed by iron dextran at 3.8%, ferumoxytol at 1.8%, and ferric carboxymaltose at 1.4%. Severe adverse events requiring epinephrine were extremely rare, with only two instances documented, both linked to iron dextran. The study highlighted that premedication use significantly increased the incidence of adverse events, with a 23-fold higher rate in premedicated patients compared to those who did not receive premedication (38.6% vs. 1.7% p-value <0.001). Additionally, among the 873 patients with a history of infusion reaction who underwent readministration, receiving the same iron formulation was associated with a higher reaction rate, especially if premedication was used. By contrast, switching to an alternate formulation resulted in a lower rate of further reactions. The study challenges the routine practice of using premedications, especially first-generation histamine receptor antagonists, which may inadvertently cause symptoms mistaken for mild hypersensitivity reactions, potentially outweighing their benefits. While additional research is needed to determine the optimal strategy for re-administering iron to patients who experience infusion reactions, the findings indicate that re-challenging these patients with IV iron, possibly using an alternative formulation and omitting sedating antihistamines, can be safe and effective. [8]