20 Years of FDA Data Reveal Previously Unrecognized Epinephrine Risks

A post-marketing analysis of > 2 decades of US Food & Drug Administration (FDA) adverse event reports suggests that epinephrine, while foundational to anaphylaxis management, may be associated with a broader and partially unrecognized safety profile.1 Using US FDA Adverse Event Reporting System (FAERS) data from 2004 to 2024, investigators identified thousands of epinephrine-related reports, with strong signals for injection-site reactions and perceived drug ineffectiveness, as well as rare cardiovascular and neurologic events not reflected in current labeling.

“To our knowledge, this is the first investigation to assess the relationship between epinephrine usage and associated AEs under real-world conditions,” wrote study investigator Binglin Yan, from the department of emergency medicine at the 971st Hospital of the People’s Liberation Army Navy, in China, and colleagues.1 “It is noteworthy that we identify several novel AE signals, including myocardial stunning, systolic anterior motion of mitral valve, left ventricle outflow tract obstruction, harlequin syndrome, injection site nerve damage, and injection site movement impairment.”

Epinephrine, a non-selective alpha- and beta-adrenergic agonist, raises heart rate and contractility, constricts blood vessels, and relaxes bronchial muscles, making it essential for anaphylaxis, cardiac arrest, severe asthma, and hypotensive shock.1 According to the Cleveland Clinic, known adverse events for epinephrine include anxiety, dizziness, headache, heart palpitations, muscle weakness, nausea, sweating, tremors, vomiting, and loss of color on the eyelid lining, inner mouth, or nails.2 Despite decades of use, epinephrine’s rare adverse events have remained largely undefined.

FAERS serves as a pharmacovigilance database, collecting real-world drug safety data, and allows for a thorough evaluation of epinephrine’s safety by analyzing reported adverse reactions.1 The database includes demographic and administrative information, report sources, drug information, indications for use, drug therapy start and end times, adverse events, and patient outcomes.

The team identified 9262 FAERS reports listing epinephrine as the primary suspected drug, with signals observed across 24 system organ classes and 264 significant preferred terms.1 The reports included more females than males (50.39% vs 32.39%) and individuals aged 18 – 44 years (17.56%). Most reports came from consumers (44.57%), mostly submitted by medical experts (49.73%), and in the United States (61.27%), followed by Canada (4.73%), the UK (2.61%), Japan (2.44%), and Australia (1.75%).

Reports peaked in 2017 (14.05%) and 2021 (10.94). Adverse events were reported most with epinephrine administered intramuscularly (15.17%), followed by intravenous (6.72% and subcutaneous (3.35%). The most common severe outcome was initial or prolonged hospitalization (25.96%), and the most reported indication was an anaphylactic reaction (16.01%).1

The most frequently reported systems were general disorders and administration site conditions (n = 6112), injury, poisoning, and procedural complications (n = 4287), cardiac disorders (n = 2454), nervous system disorders (n = 1609), and investigations (n = 1285). Investigators observed 300 cases of stress cardiomyopathy, 33 cases of vasoconstriction, 14 cases of vasospasm, and 10 cases of hypertension.1

At the preferred-term level, drug ineffectiveness was the most frequently reported (n = 1867), followed by accidental exposure to product (n = 952) and drug hypersensitivity (n = 668). The strongest safety signal was observed for injection-site ischemia (n = 39), injection-site pallor (n = 132), and medical device site laceration (n = 9).1

The study noted several adverse events not listed in the current epinephrine labeling, including myocardial stunning, systolic anterior motion of the mitral valve, left ventricle outflow tract obstruction, harlequin syndrome, injection site nerve damage, and injection site movement impairment. On average, adverse events occurred the same day as epinephrine administration (interquartile range [IQR], 0 – 0 days), with 69.45% experiencing events < 24 hours.1

“Our findings corroborate previously recognized adverse reactions documented on the drug’s labeling information, and notably, we identified several previously unreported adverse event signals,” investigators concluded.1 “These newly discovered signals provide valuable guidance and a solid foundation for future in-depth research.”

References

1. Yan B, Xiao Q, Jiang Y. Post-marketing safety assessment of epinephrine: an analysis of the US FDA adverse event reporting system. Front Med (Lausanne). 2025;12:1727631. Published 2025 Dec 18. doi:10.3389/fmed.2025.1727631

2. Epinephrine Injection. Cleveland Clinic. Accessed January 13, 2026. https://my.clevelandclinic.org/health/drugs/20064-epinephrine-injection