Does intravenous (IV) iron need to be administered with a steroid, such as hydrocortisone, and an antihistamine, like diphenhydramine (Benadryl)?

IV Iron Administration: Premedication with Steroids and Benadryl Not Routinely Recommended

Routine premedication with steroids and diphenhydramine (Benadryl) is not recommended for intravenous (IV) iron administration and should be limited only to patients with substantial risk factors for infusion reactions.1

Current Evidence on Premedication for IV Iron

• Premedication should be reserved only for patients with substantial risk factors for infusion reactions, such as multiple drug allergies, prior reaction to an IV iron formulation, or asthma 1
• First-generation antihistamines like diphenhydramine (Benadryl) should be avoided as they can potentially convert minor infusion reactions into hemodynamically significant serious adverse events, including exacerbation of hypotension, tachycardia, diaphoresis, sedation, and shock 1
• Routine prophylactic premedication for all patients receiving IV iron is not justified based on current evidence 2
• The risk of hypersensitivity reactions with newer IV iron formulations is low, making universal premedication unnecessary 2, 3

Management of IV Iron Infusion Reactions

For Mild and Moderate Reactions:

• Stop the infusion immediately and switch to hydration fluid to keep the vein open 1
• Most reactions are self-limiting and resolve spontaneously within 15 minutes 1
• If symptoms persist or worsen after 15 minutes, consider administering an IV corticosteroid such as hydrocortisone 200 mg 1
• For urticaria, use second-generation antihistamines (H2) like loratadine 10 mg orally or cetirizine 10 mg IV/oral 1
• For nausea, consider a 5-HT3 antagonist like ondansetron 4-8 mg IV 1
• Mild hypotension can be managed with IV hydration 1

For Severe Reactions (extremely rare):

• Treat as anaphylaxis with immediate epinephrine administration 1
• Call emergency services or resuscitation team 1
• Administer epinephrine (1 mg/mL) 0.3 mg IM into the anterolateral mid-third portion of the thigh 1

Risk Factors for IV Iron Infusion Reactions

• Previous reaction to an iron infusion 4
• Multiple drug allergies 4
• Atopic diseases 4
• High serum tryptase levels 4
• Asthma 1, 4
• Urticaria 4
• Fast iron infusion rate 4

Important Clinical Considerations

• Modern IV iron formulations have a much lower risk of severe reactions compared to older high-molecular-weight iron dextran preparations 2, 3
• Severe adverse events requiring epinephrine are exceedingly rare (documented in only 2 out of 35,737 infusions in one large study) 5
• In patients with a history of infusion reactions, changing to an alternate iron formulation results in significantly lower reaction rates compared to using the same formulation 5
• The historical practice of routine premedication originated with high-molecular-weight iron dextran, which is no longer available 2
• Delayed reactions to IV iron can occur hours to days after infusion, presenting as flu-like symptoms, arthralgias, myalgias, and fever, which can be managed with NSAIDs 1

Contraindications to Consider

• Unlike contrast media reactions, there is no evidence supporting premedication for patients with seafood or shellfish allergies 1
• For patients with prior anaphylactoid reactions to contrast media (not iron), appropriate steroid and antihistamine prophylaxis is recommended before repeat contrast administration 1

In conclusion, the evidence clearly shows that routine premedication with steroids and diphenhydramine before IV iron administration is unnecessary and potentially harmful. Premedication should be individualized and reserved only for patients with significant risk factors for infusion reactions.