Is there literature, specifically guidelines, available on how to medically manage adverse reactions associated with intravenous iron?

Introduction
Iron deficiency impacts a large proportion of the population and is the most common cause of anemia.1,2 Untreated iron deficiency will often lead to iron deficiency anemia, which accounts for nearly a million deaths annually globally. Causes of iron deficiency include increased demand for iron within the body, including growth during childhood or adolescence and pregnancy, increased loss of iron, such as blood loss or menses, or decreased iron intake or absorption due to inadequate diet or malabsorption from disease or surgery.

All patients with iron deficiency anemia should receive treatment, regardless of symptoms, as untreated iron deficiency anemia can progress to severe anemia with organ damage.1,2 The usual treatment is repletion of iron, but the severity and cause of the iron deficiency anemia will determine the appropriate treatment. Most patients will be treated with oral iron because it is effective, available, inexpensive, and safe. However, up to 70% of individuals who use oral iron report gastrointestinal side effects.3

Intravenous (IV) iron is commonly used to treat iron deficiency anemia in instances when oral iron replacement is not tolerated or cannot be used.1,2 It may also be preferred in instances of severe blood loss, severe anemia (hemoglobin [Hb] <7 g/dL), or in specific patients depending on their cause of anemia (e.g., abnormal uterine bleeding, second or third trimester pregnancy, gastrointestinal disorders). Rare, but potentially life-threatening hypersensitivity reactions can occur during IV iron administration. This article will focus on literature, specifically guidelines, currently available to assist with the management of adverse reactions associated with intravenous iron.

Intravenous iron
There are 7 IV iron formulations available in the United States: 2 iron salts (ferric gluconate and iron sucrose) and 5 newer formulations.2,4,5 These newer formulations include low molecular weight iron dextran (LMWID), ferumoxytol, ferric carboxymaltose (FCM), ferric derisomaltose (FDI), and ferumoxytol generic. The iron salts have different binding properties than the newer formulations and often lead to infusion reactions at doses above 200 to 250 mg.2,4 Generally, 4 to 7 clinic visits are required for iron replenishment to avoid adverse reactions. In contrast, the newer formulations allow for a total dose infusion within 15 to 60 minutes, without any increased risk in adverse events. All IV iron formulations have equivalent effectiveness and similar safety profiles.

Despite generally being considered safe, severe hypersensitivity reactions can occur very rarely with IV iron administration.1,4,6,7 The frequency of severe adverse reactions is thought to occur at an incidence of less than 1 in 250,000 doses of IV iron.4,6-8 Despite the rarity, providers should know how to manage hypersensitivity issues due to how commonly IV iron agents are used. Knowledge about the type of allergic reaction has evolved over the years, leading to updates in management recommendations of these hypersensitivity reactions. Most hypersensitivity infusion reactions that occur with IV iron are considered complement activation-related pseudo-allergy (CARPA), sometimes referred to as a Fishbane reaction, thought of as a self-limited reaction to labile free iron. Labile free iron is weakly bound iron within the iron carbohydrate particle and is available to bind to transferrin. These reactions are different from immunoglobulin-E (IgE)-mediated anaphylactic reactions and are not classified as IgE-mediated.

Intravenous iron compounds consist of iron suspended in a colloidal gel, which is stabilized by carbohydrates.4,6,7 The rate of release of the active iron is inversely related to the strength of the complex. For example, stronger complexes have a lower potential to release labile free iron, subsequently being associated with lower free iron toxicity. The CARPA reaction is thought to be a complement-mediated reaction to either nanoparticles of free or labile iron that do not bind to transferrin quickly enough. It can occur at any time without prior sensitization and is often non-life threatening but is most frequently encountered at the beginning of the IV infusion. Symptoms of CARPA include flushing, myalgias, back pain, and/or chest pressure. Symptoms of anaphylaxis are not present. The likelihood of developing CARPA is thought to be proportional to the stability of the formulation of IV iron, along with the rapidity of the infusion. With much smaller cores compared to newer formulations, iron salt forms (gluconate and sucrose) release more labile free iron, necessitating lower administered doses and more frequent visits to achieve appropriate iron repletion without adverse events. However, CARPA can occur with any IV iron formulation.

Prevention of hypersensitivity reactions
Reaction prevention consists of 2 options: premedication and the use of low reactogenic administration protocols (LRPs).4,6,7 Historically, premedication regimens consist of corticosteroids and antihistamines, such as diphenhydramine, along with pain and fever reducing agents such as acetaminophen. However, the efficacy of premedication to prevent mild and moderate hypersensitivity reactions has been questioned, with many providers reserving premedication for patients at increased risk of reactions. Patients at increased risk generally include individuals with a history of asthma or more than 1 drug allergy. Additionally, with the newer hypotheses surrounding the mechanism of action of these hypersensitivities, the benefit of antihistamines, specifically diphenhydramine, is questionable. Antihistamine agents may cause hypotension, somnolence, flushing, dizziness, and supraventricular tachycardia when administered, increasing the frequency of adverse drug reactions, and mimicking a hypersensitivity reaction. Updated guidance from professional organizations recommends avoiding first generation antihistamine agents (H1 blockers) for both prevention and treatment of IV iron hypersensitivity reactions because they may exacerbate the reaction.4,6,9

Another proposed option for reaction prevention includes the use of LRPs.6 The use of LRPs has been used successfully to prevent hypersensitivity reactions to many IV drugs, including IV iron in some very high-risk patients. In general, for all LRPs, the infusion is initiated at 0.001 to 0.01% of the full drug dose given over 5 to 15 minutes. This is thought to desensitize the patient to the drug as well as provide insight into the presence of hypersensitivity prior to a full dose being administered. This approach may only be warranted in individuals at high-risk of a reaction, specifically those with a history of life-threatening reactions.

Management and guideline recommendations
Guidance on the management of IV iron hypersensitivity reactions from multiple professional organizations exist.4,8,9 The most relevant and recently updated guidance is an expert consensus 2024 guideline facilitated by the Infusion Nurses Society that includes consensus on management of reactions.4 If acute signs or symptoms of a hypersensitivity reaction occur during infusion of iron, the first recommended step is to stop the infusion and perform a physical assessment of the patient’s symptoms. Close monitoring of vital signs and symptoms should continue until the patient is stable. Normal saline should be initiated via IV infusion at a slow rate to keep the vein open. Recommendations for management of a reaction based on severity are summarized in the Table below.

Table. Consensus recommendations for treatment of IV iron hypersensitivity reactions.4
Severity of HSR Initial management approachIf patient improves after initial management If no improvement, but not worsening after initial management If patient worsens after initial management
Mild:
pruritis, flushing, urticaria, chest tightness, back and joint pain		Monitor for ≥ 15 minutes.
Maintain IV normal saline at a slow rate to keep vein open.		Monitor for return to baseline and resolution of symptoms.

Consider rechallenge:
Discuss re-challenge with patient; if accepted, restart infusion about 15 minutes after resolution of symptoms.
Re-start at a lower infusion rate (50% of initial rate).
If well tolerated, increase rate slowly after 15 minutes.
Stop infusion if symptoms recur.		Start treatment for individual symptoms:
Nausea: 5-HT3 receptor antagonist (ondansetron 4 to 8 mg IV)
Urticaria: second generation antihistamine (loratadine 10 mg by mouth or cetirizine 10 mg by mouth or IV) plus a corticosteroid (hydrocortisone 100 mg by mouth or IV
Mild hypotension: IV normal saline to maintain SBP > 100 mmHg		Re-evaluate and rule out anaphylaxis.
Moderate:
mild reaction plus transient cough, SOB, tachycardia, hypotensiona		Monitor for ≥ 15 minutes.
Consider IV corticosteroid (hydrocortisone 100 to 500 mg IV).

Consider IV H2 antagonist (famotidine 20 mg IV).

If hypotensive:
Recline patient onto back.
Administer normal saline bolus of 1000 to 2000 mL.

If hypoxemic:
Give O2 by mask or nasal cannula.
Severe or life-threatening, including anaphylaxis: sudden onset and rapid intensification of symptoms, loss of consciousness, hypotensiona, angioedema of tongue or airway, involvement of 2 or more organ systems (i.e., cardiovascular, skin, respiratory, gastrointestinal)Monitor for ≥ 15 minutes.
Consider IV corticosteroid (hydrocortisone 100 to 500 mg IV).

Consider IV H2 antagonist (famotidine 20 mg IV).

If hypotensive:
Recline patient onto back.
Administer normal saline bolus of 1000 to 2000 mL.

If hypoxemic:
Give O2 by mask or nasal cannula.

Immediately call emergency services or resuscitation team.
Administer epinephrine (1 mg/mL) 0.3 mg IM into the mid-third portion of the thigh and assess. May repeat x1 if needed.
Consider B2 agonist nebulizer (albuterol 0.083% via nebulizer)		Follow institutional protocols for a medical emergency and continue observation until resolution of symptoms.
Abbreviations: 5-HT3=5-hydroxytryptamine 3; B2=beta, H2=histamine, HSR=hypersensitivity reaction, IM=intramuscular, IV=intravenous, O2=oxygen, SBP=systolic blood pressure, SOB=shortness of breath.
a Decrease in SBP ≥ 30 mmHg from baseline or SBP ≤ 90 mmHg

As described in the Table above, H1 blocker antihistamine agents should be avoided, as they may exacerbate reactions.4 H2 blocker antihistamine agents can be used in some instances, as the signs/symptoms increase in severity, or if the patient has associated symptoms that can be treated with H2 blockers. Other guidelines, including a 2019 Canadian expert consensus and an older expert group recommendation from the Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference in 2016, generally have recommendations that align with the 2024 consensus guideline.8,9 However, since the KDIGO consensus is older, they do include H1 blockers in their algorithm as a treatment option, which is no longer recommended.8

Conclusion
Intravenous iron is commonly used to treat iron deficiency anemia in instances when oral iron replacement is not tolerated or cannot be used. While they are overall considered safe, very rare, but potentially life-threatening hypersensitivity reactions can occur during IV iron administration. Professional guidelines provide recommendations to manage these hypersensitivity reactions depending on severity. Medications commonly used include corticosteroids and second-generation antihistamines. First-generation antihistamine agents should be avoided, as they may exacerbate reactions. In cases of severe hypersensitivity reactions, including anaphylaxis, the reaction should be treated as a medical emergency.

References

  1. Adamson JS. Iron deficiency and other hypoproliferative anemias. In: Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson JL, eds. Harrison’s Principles of Internal Medicine. 21st ed. McGraw Hill; 2022. Accessed January 15, 2025. https://accessmedicine.mhmedical.com/content.aspx?bookid=3095§ionid=263547538
  2. Elstrott B, Khan L, Olson S, Raghunathan V, DeLoughery T, Shatzel JJ. The role of iron repletion in adult iron deficiency anemia and other diseases. Eur J Haematol. 2020;104(3):153-161. doi: 10.1111/ejh.13345
  3. Tolkien Z, Stecher L, Mander AP, Pereira DIA, Powell JJ. Ferrous sulfate supplementation causes significant gastrointestinal side-effects in adults: a systematic review and meta-analysis. PLoS One. 2015;10(2):e0117383. doi: 10.1371/journal.pone.0117383
  4. Van Doren L, Steinheiser M, Boykin K, Taylor KJ, Menendez M, Auerbach M. Expert consensus guidelines: intravenous iron uses, formulations, administration, and manaement of reactions. Am J Hematol. 2024;99(7):1338-1348. doi: 10.1002/ajh.27220
  5. Drugs@FDA: FDA-approved drugs. U.S. Food & Drug Administration. Accessed January 15, 2025. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm
  6. Szebeni J, Fishbane S, Hedenus M, et al. Hypersensitivity to intravenous iron: classification, terminology, mechanisms and management. Br J Pharmacol. 2015;172(21):5025-5036. doi: 10.1111/bph.13268
  7. Caimmi S, Crisafulli G, Franceschini F, et al. Hypersensitivty to intravenous iron preparations. Children (Basel). 2022;9(10):1473. doi: 10.3390/children9101473
  8. Macdougall IC, Bircher AJ, Eckardt KU, et al. Iron management in chronic kidney disease: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int. 2016;89(1):28-39. doi: 10.1016/j.kint.2015.10.002
  9. Lim W, Afif W, Knowles S, et al. Canadian expert consensus: management of hypersensitivity reactions to intravenous iron in adults. Vox Sang. 2019;114(4):363-373. doi: 10.1111/vox.12773

Prepared by:
Rachel Brunner, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

February 2025

The information presented is current as January 15, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.