Emerging Causes of Drug-Induced Anaphylaxis: A Review of Anaphylaxis-Associated Reports in the FDA Adverse Event Reporting System (FAERS)

Abstract

Background: Drug-induced anaphylaxis is a well-known adverse drug reaction for some drug classes, but emerging drug causes of anaphylaxis and novel mechanisms may contribute in unrecognized ways.

Objective: We sought to determine the top drugs reported in association with anaphylaxis and anaphylaxis followed by death in the Food and Drug Administration Adverse Event Reporting System (FAERS).

Methods: We reviewed the publicly available FAERS database from 1999 to 2019. Using search terms "anaphylactic shock" or "anaphylactic reaction" and sorting cases by generic drug names, we counted and trended reports to FAERS in which a drug was associated with anaphylaxis or anaphylaxis followed by death.

Results: From 1999 to 2019, there were 17,506,002 adverse drug events reported in FAERS, of which 47,496 (0.27%) were reported as anaphylaxis. Excluding patients without age, sex, or country data, respectively, the median age of patients in reports of anaphylaxis was 52 (interquartile range: 28), 62.71% were female, and 13,899 of 34,381 (40.43%) reports were from the United States. There were 2984 of 47,496 (6.28%) reports of anaphylaxis followed by death. Top drug classes associated with anaphylaxis in FAERS were antibiotics, monoclonal antibodies (mAbs), nonsteroidal anti-inflammatory drugs, and acetaminophen. Top drug classes associated with anaphylaxis deaths were antibiotics, radiocontrast agents, and intraoperative agents. Linear regression demonstrated reports of anaphylaxis to mAbs increasing at an average rate of 0.77% of total anaphylaxis reports per year (95% confidence interval: 0.65, 0.88) from 2.00% in 1999 to 17.37% in 2019, faster than any other drug class.

Conclusion: Antibiotics were highly reported for anaphylaxis overall and anaphylaxis followed by death. Increasing reports were noted for anaphylaxis to mAb therapies.

Keywords: Anaphylaxis; Death; Drug allergy; FAERS; FDA; Fatal.

Figure 1.

Top 50 drugs associated with a report of anaphylactic shock or anaphylactic reaction to the FDA Adverse Event Reporting System (FAERS) from 1999 to 2019, separated further by drugs with reported non-IgE implicated mast cell activation. Relative size of circles correlates with percent of total cases reported.

Figure 2.

A) The percent of anaphylaxis cases reported to the FDA Adverse Event Reporting Systems (FAERS) in association with drug classes. B) Linear regressions on the percent of anaphylaxis cases reported in association with drug classes. Slopes, 95% confident interval, P values, and percentages in 1999 and 2019 are included for each drug class. C) The percent of anaphylaxis death cases reported to the FDA Adverse Event Reporting Systems (FAERS) in association with drug classes. D) Linear regressions on the percent of anaphylaxis death cases reported in association with drug classes. Slopes, 95% confident interval, P values, and percentages in 1999 and 2019 are included for each drug class. Intraoperative agent class was selected a priori to include Propofol, Rocuronium, Fentanyl, Lidocaine, Sufentanil, Cefazolin, Succinylcholine, Midazolam, Vancomycin, Atracurium, and Sevoflurane.