Iron Dextran (INFeD) and Ferumoxytol (Feraheme) have black box warnings, largely because of past safety signals of serious hypersensitivity and anaphylaxis. The other IV iron formulations don’t carry boxed warnings because their risk profiles (both in clinical trials and postmarketing surveillance) have been more favorable, and no strong enough signal has required that level of regulatory warning. But the difference is not absolute — it reflects regulatory caution, historical risk, and observed reaction rates more than a mechanistic “safe vs unsafe” split.
- Iron Dextran (INFeD / older dextran forms)
- Dextran-based iron formulations historically had a higher rate of true anaphylactic (IgE-mediated) reactions, especially the older high–molecular-weight dextran.
- Because dextran itself is antigenic, even dextran-only infusions (without iron) had documented anaphylaxis cases historically.
- Low–molecular-weight iron dextran (INFeD) inherited the class label, so the warning stays: “Anaphylactic-type reactions, including fatalities, have been reported following parenteral administration of iron dextran.” FDA Access Data
- The black box is thus partly legacy, partly precaution based on historical risk.
- Ferumoxytol (Feraheme)
- After its introduction, a number of serious hypersensitivity and anaphylactic events were reported in postmarketing surveillance. U.S. Food and Drug Administration+2OptumRx Professionals+2
- The FDA responded by mandating a boxed warning indicating the risk of serious hypersensitivity / anaphylaxis and hypotension. FDA Access Data+1
- The label explicitly warns to administer slowly (≥15 minutes), monitor patients for at least 30 minutes after infusion, and have resuscitation equipment available. FDA Access Data+2FDA Access Data+2
Why other formulations don’t (yet) have black box warnings
- Their observed incidence of serious reactions has been much lower in both clinical trials and postmarketing data.
- No regulatory agency has judged that their risk justifies a boxed warning.
- Their formulations (non-dextran, more stable, smaller nanoparticle architectures) are considered inherently safer with lower likelihood of antigenic reaction or complement activation at typical infusion rates.
- For example:
- In a pharmacovigilance study, iron dextran and ferumoxytol had the highest reporting odds ratio (ROR) for hypersensitivity reactions. Iron sucrose and ferric carboxymaltose had lower RORs. PMC
- In comparative clinical use, ferumoxytol did not show a significantly higher rate of hypersensitivity/hypotension vs other compounds in some analyses, suggesting risk is low overall—but the boxed warning remains as a precaution
Key nuance & caveats
- Black box warning ≠ “unsafe” — it means extra caution is warranted, not that the drug must be avoided. Many drugs with serious risk carry boxed warnings yet are used widely under controlled conditions.
- Even in formulations without a black box, hypersensitivity or infusion reactions can still occur (though rarely).
- Regulatory labeling can lag behind mechanistic knowledge and real-world experience; a safe formulation today might acquire stronger warnings later if new signals emerge.
Summary
Iron dextran (INFeD) and ferumoxytol (Feraheme) carry boxed warnings for hypersensitivity and anaphylaxis due to historical and postmarketing safety signals. Other modern IV iron formulations lack boxed warnings because their observed rates of serious reactions have remained very low, though no IV iron is zero-risk. The absence of a black box does not imply absolute safety — rather, it reflects a balance of clinical trial data, postmarket surveillance, and regulatory judgment.