Comparative Risk of Anaphylactic Reactions Associated With Intravenous Iron Products

Bo Ri Kim, Mercer University College of Pharmacy.

According to the American Academy of Family Physician (AAFP), global anemia is prevalent in one third of the population, and iron deficiency is the most common cause. The AAFP suggests that oral iron replacement is the primary treatment for iron deficiency anemia, but parenteral iron can be used when oral preparations can be used for patients with intolerance, impaired absorption, and significant ongoing bleeding. [1]

U.S. Pharmacist reported that intravenous (IV) iron can help build red blood cells more quickly by deliver directly to the blood circulation than oral iron. There are currently four major types of iron products in the United States, iron sucrose, iron dextran, sodium ferric gluconate, and ferumoxytol. There are safety concerns relating to the risk of serious and fatal anaphylaxis can occur at both first and subsequent exposures. [2]

Comparative Risk of Anaphylactic Reactions Associated With Intravenous Iron Products [3]
Design Retrospective new user cohort study of IV iron recipients (N = 688,183) enrolled in the United States fee-for-service Medicare program.
Objective To compare the risk of anaphylaxis among marketed IV iron products
Study Groups Patients were included in the study if on their index date, they were not receiving dialysis, were continuously enrolled in Medicare A and B for the previous 12 months, had no IV iron exposure in the preceding 12 months, and were exposed to only one type of IV iron product. There were 247,500 iron dextran and 440,683 nondextran new IV iron
Methods The primary comparison of interest was the use of dextran vs nondextran IV iron products.

A secondary analysis compared anaphylaxis risk between iron dextran and three approved nondextran products individually (iron gluconate, iron sucrose, and ferumoxytol). Analyses involving ferumoxytol were limited to the period January 2010 to December 2013.

Duration January 2003 to December 2013
Primary Outcome Measure Incidence of anaphylaxis
Baseline Characteristics No. (%) of Patients
Baseline Characteristics Iron Dextran Nondextran IV iron
Age, mean 73.2 (11.3) 74.0 (11.4)
Sex 
Men 83,312 (33.7) 167,097 (37.9)
Women 164,188 (66.3) 273,586 (62.1)
Race
White 214,962 (86.9) 274,436 (85.0)
Black 23,683 (9.6) 48,449 (11.0)
Asian 1718 (0.7) 4222 (1.0)
Hispanic 4231 (1.7) 6926 (1.6)
Other/unknown 2906 (1.2) 6650 (1.5)
Regions 
Northeast 25,935 (10.5) 86,661 (19.7)
Midwest 50,782 (20.5) 119,670 (27.2)
South 135,108 (54.6) 169,783 (38.5)
West 35,106 (14.2) 63,529 (14.4)
Other 569 (0.2) 1040 (0.2)
Indications
Anemia
CKD 53,141 (21.5) 233,229 (52.9)
GI/GU bleeding 53,681 (21.7) 63,956 (14.5)
Other 140,678 (56.8) 143,498 (32.6)
Conditions
Asthma 33,179 (21.5) 233,229 (52.9)
COPD 72,391 (13.4) 132,620 (30.1)
Coronary heart disease 101,419 (41.0) 207,127 (47.0)
Depression 41,481 (16.8) 77,570 (17.6)
Drug allergy 16,151 (6.5) 33,355 (7.6)
Food allergy 958 (0.4) 1968 (0.4)
Hypertension 204,701 (82.7) 394,991 (89.0)
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).

Adverse Events Adverse Events: incidence of anaphylaxis or life-threatening reactions
2003-2013 2010-2013
IV iron Non-dextran Iron dextran Iron Sucrose Iron Dextran Iron Gluconate Iron Sucrose Ferumoxytol
# of anaphylaxis 107 167 45 167 34 21 28
·       Percentages are not provided.
Study Author Conclusions 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.

Results of this study demonstrated that iron dextran has higher anaphylaxis risk compared with nondextran formulations at first administration. Among the nondextran products, the risk of anaphylaxis was higher with both iron gluconate and ferumoxytol than with iron sucrose.

The mechanism of action for anaphylactic reaction after IV iron is unclear. Possible reactions can be unbounded iron released into circulations, which cause oxidative stress, hypotension and cardiac failure in addition to the typical anaphylactic reaction.

This study consisted only of United States Medicare beneficiaries who are not receiving dialysis treatment; therefore the results may not cover to dialysis patients or younger population.

Reference:

  1. American Society of Hematology – Anemia. 2015. Available at: http://www.hematology.org/Patients/Anemia/. Acessed November 20, 2015. 11. 20.
  2. Goddard AF, James MW, Mcintyre AS, Scott BB, Guidelines for the management of iron deficiency anemia. British Society of Gastroenterology. 2011 Oct;60(10):1309-16. doi: 10.1136/gut.2010.228874.
  3. Wang C, Graham D, Kane R, et al. Comparative Risk of Anaphylactic Reactions Associated With Intravenous Iron Products. The Journal of the American Medical Association. 2015;314(19):2062-2068.
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