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Original Investigation
November 17, 2015

Comparative Risk of Anaphylactic Reactions Associated With Intravenous Iron Products

Author Affiliations
  • 1Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
  • 2Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
  • 3Dr Kane is now retired.
  • 4Office of Biostatistics, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
  • 5Acumen LLC, Burlingame, California
  • 6Harvard School of Public Health, Boston, Massachusetts
  • 7Genentech Inc, San Francisco, California
  • 8Centers for Medicare & Medicaid Services, Washington, DC
JAMA. 2015;314(19):2062-2068. doi:10.1001/jama.2015.15572

Importance  All intravenous (IV) iron products are associated with anaphylaxis, but the comparative safety of each product has not been well established.

Objective  To compare the risk of anaphylaxis among marketed IV iron products.

Design, Setting, and Participants  Retrospective new user cohort study of IV iron recipients (n = 688 183) enrolled in the US fee-for-service Medicare program from January 2003 to December 2013. Analyses involving ferumoxytol were limited to the period January 2010 to December 2013.

Exposures  Administrations of IV iron dextran, gluconate, sucrose, or ferumoxytol as reported in outpatient Medicare claims data.

Main Outcomes and Measures  Anaphylaxis was identified using a prespecified and validated algorithm defined with standard diagnosis and procedure codes and applied to both inpatient and outpatient Medicare claims. The absolute and relative risks of anaphylaxis were estimated, adjusting for imbalances among treatment groups.

Results  A total of 274 anaphylaxis cases were identified at first exposure, with an additional 170 incident anaphylaxis cases identified during subsequent IV iron administrations. The risk for anaphylaxis at first exposure was 68 per 100 000 persons for iron dextran (95% CI, 57.8-78.7 per 100 000) and 24 per 100 000 persons for all nondextran IV iron products combined (iron sucrose, gluconate, and ferumoxytol) (95% CI, 20.0-29.5 per 100 000) , with an adjusted odds ratio (OR) of 2.6 (95% CI, 2.0-3.3; P < .001). At first exposure, when compared with iron sucrose, the adjusted OR of anaphylaxis for iron dextran was 3.6 (95% CI, 2.4-5.4); for iron gluconate, 2.0 (95% CI 1.2, 3.5); and for ferumoxytol, 2.2 (95% CI, 1.1-4.3). The estimated cumulative anaphylaxis risk following total iron repletion of 1000 mg administered within a 12-week period was highest with iron dextran (82 per 100 000 persons, 95% CI, 70.5- 93.1) and lowest with iron sucrose (21 per 100 000 persons, 95% CI, 15.3- 26.4).

Conclusions and Relevance  Among patients in the US Medicare nondialysis population with first exposure to IV iron, the risk of anaphylaxis was highest for iron dextran and lowest for iron sucrose.