Real-World safety evaluation of epinephrine: an adverse event analysis based on the FAERS database

Real-World safety evaluation of epinephrine: an adverse event analysis based on the FAERS database | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 10 April 2025 V1 Latest version Share on Real-World safety evaluation of epinephrine: an adverse event analysis based on the FAERS database Authors : Huihui Bai 0000-0002-8138-731X , Yan Wang [email protected] , Dan Niu , Boling Li , and Yuan Zong Authors Info & Affiliations https://doi.org/10.22541/au.174428287.79536829/v1 263 views 124 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background Epinephrine is widely used for its life-saving properties in acute medical conditions. However, epinephrine is associated with a range of adverse effects due to its broad receptor activation. This study aims to further explore the adverse event profile of epinephrine, providing insights into its safety and optimizing its therapeutic application. Method In this study, we extract all data from the 2004 to 2024 using the FAERS database. We adopted report odds ratio, proportion report ratio, bayesian confidence propagation neural network, and multi-item gamma-poisson shrinkage to analyze the data mining significant AE signals. Besides, we collect the onset times of epinephrine associated with AEs. Result Our study identified a total of 15,865 case reports of epinephrine as the primary suspect drug (PS) from FAERS. After data cleaning and analysis, a total of 2,338 AE signals were identified across 27 SOCs. The top three PTs are: drug hypersensitivity, hypotension, and stress cardiomyopathy. Notably, several undocumented adverse events not mentioned in the instructions including stress cardiomyopathy, systolic anterior motion of mitral valve, left ventricle outflow tract obstruction, kounis syndrome, chondrolysis, horner’s syndrome, compartment syndrome, oral hypoesthesia, and paresthesia. Conclusion When using epinephrine in clinical practice, it is essential to closely monitor the allergic reactions, malignant arrhythmias, and adverse effects on the circulatory system mentioned in the drug labeling. Additionally, vigilance is required for adverse reactions not listed in the labeling, and careful consideration should be given to the selection of epinephrine auto-injectors. Real-World safety evaluation of epinephrine: an adverse event analysis based on the FAERS database Huihui Bai 1 , Dan Niu 1 , Boling Li 1 , Yuan Zong 1 , Yan Wang 1* 1 Department of Intensive Care Unit, Shaanxi Province People’s Hospital, Xi An, China *Correspondence: Yan Wang [email protected] Funding There were no external funding sources for this study. Ethics approval and consent to participate Because the data were publicly available, the study was exempt from the requirements of an ethics approval statement and informed consent. Data availability statement The data examined in this study is available upon reasonable request from the corresponding author.The datasets analysed during the current study are available in the FAERS repository [http://faers.org.cn:30000/drug\%5D. Acknowledgements We express our gratitude to all individuals who contributed to this project. Conflicts of interest The authors declare no competing interests. Abstract Background Epinephrine is widely used for its life-saving properties in acute medical conditions. However, epinephrine is associated with a range of adverse effects due to its broad receptor activation. This study aims to further explore the adverse event profile of epinephrine, providing insights into its safety and optimizing its therapeutic application. Method In this study, we extract all data from the 2004 to 2024 using the FAERS database. Adverse event (AE) reports were standardized and classified according to the Preferred Term (PT) and System Organ Class (SOC) according to the Medical Dictionary for Regulatory Activities (MedDRA). We adopted report odds ratio (ROR), proportion report ratio (PRR), bayesian confidence propagation neural network (BCPNN), and multi-item gamma-poisson shrinkage (MGPS) to analyze the data mining significant AE signals. Besides, we collect the onset times of epinephrine associated with AEs. Result Our study identified a total of 15,865 case reports of epinephrine as the primary suspect drug (PS) from FAERS. After data cleaning and analysis, a total of 2,338 AE signals were identified across 27 SOCs. The top three PTs are: drug hypersensitivity, hypotension, and stress cardiomyopathy. Notably, several undocumented adverse events not mentioned in the instructions including stress cardiomyopathy, systolic anterior motion of mitral valve, left ventricle outflow tract obstruction, kounis syndrome, chondrolysis, horner’s syndrome, compartment syndrome, oral hypoesthesia, and paresthesia. There are 35 Preferred Terms (PTs) associated with adverse events (AEs) related to product quality issues, encompassing 5,545 reported cases. Notably, particular attention should be given to the AEs associated with epinephrine auto-injectors. Conclusion When using epinephrine in clinical practice, it is essential to closely monitor the allergic reactions, malignant arrhythmias, and adverse effects on the circulatory system mentioned in the drug labeling. Additionally, vigilance is required for adverse reactions not listed in the labeling, and careful consideration should be given to the selection of epinephrine auto-injectors. Keyword: FAERS database, epinephrine, adrenaline, adverse event, adrenaline auto-injectors. Background Epinephrine, also known as adrenaline, is a endogenous catecholamine and a critical neurotransmitter and hormone that plays a pivotal role in the body’s ”fight or flight” response. It was first isolated and identified in the early 20th century and has since become a cornerstone in emergency medicine due to its potent physiological effects[1]. Epinephrine exerts its actions through binding to adrenergic receptors, specifically α1, α2, β1, and β2 receptors. Activation of these receptors leads to a cascade of effects, including vasoconstriction (via α1 receptors), bronchodilation (via β2 receptors), increased heart rate and cardiac output (via β1 receptors), and modulation of metabolic processes such as glycogenolysis and lipolysis[2]. Therapeutically, epinephrine is widely used for its life-saving properties in acute medical conditions. Its primary indications include the treatment of anaphylaxis, a severe and potentially fatal allergic reaction, where it rapidly reverses bronchoconstriction, hypotension, and angioedema[3]. Additionally, it is employed in cardiac arrest to enhance coronary perfusion pressure and improve the likelihood of return of spontaneous circulation[4]. Other clinical uses include the management of severe asthma exacerbations[5], as an adjunct in local anesthesia to prolong its effect and reduce bleeding[6], and in the treatment of septic shock to support blood pressure[7-9]. The World Allergy Organization (WAO) recommends adrenaline as the primary treatment for anaphylaxis[10]. Additionally, prominent organizations including the American Academy of Allergy, Asthma & Immunology (AAAAI), the European Resuscitation Council (ERC), and the American Heart Association (AHA) endorse the use of adrenaline in cardiopulmonary resuscitation[11-13]. Furthermore, the Global Initiative for Asthma (GINA) recommends adrenaline for the management of severe bronchospasm and acute asthma attacks[14]. Despite its therapeutic benefits, epinephrine is associated with a range of adverse effects due to its broad receptor activation. Understanding the balance between its life-saving effects and potential risks is crucial for its safe and effective use in clinical practice. This study aims to further explore the adverse event profile of epinephrine, providing insights into its safety and optimizing its therapeutic application. Method Data sources and extraction This retrospective pharmacovigilance study utilized data from the FAERS (Food and Drug Administration Adverse Event Reporting System) database. The FAERS system, which undergoes quarterly updates, contains seven key data components: 1) demographic and administrative records (DEMO), 2) drug information (DRUG), 3)adverse drug reaction information (REAC), 4) patient outcomes information (OUTC), 5) reported sources (RPSR), 6) drug therapy start dates and end dates (THER), and 7) indications for drug administration (INDI). In this study, the generic drug name ”epinephrine” and “adrenaline” ware used as the search keyword to extract all data from 84 quarters, spanning from the first quarter of 2004 to the fourth quarter of 2024. Data preprocessing and cleaning The data were imported into SAS 9.4 software for processing and cleaning. According to the Food and Drug Administration (FDA) recommended method to remove the duplicate reports, subsequently, reports with the epinephrine as the primary suspected (PS) drug were selected. Adverse event (AE) reports were standardized and classified according to the Preferred Term (PT) and System Organ Class (SOC) according to the Medical Dictionary for Regulatory Activities (MedDRA). Reports clearly unrelated to drug-induced AEs or unrelated to the indications of epinephrine were excluded (show in Figure1). Data analysis Currently, the primary method used for drug safety monitoring is basically the disproportionality analysis. To minimize false positive signals in our study, we applied multiple disproportionality analysis approaches including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the bayesian confidence propagation neural network (BCPNN), along with the multi-item gamma poisson shrinker (MGPS).The calculations for the ROR method and MHRA comprehensive criteria are based on the disproportionality measurement using a 2×2 contingency table, with specific formulas and thresholds provided in Table 1. BCPNN and EBGM are Bayesian methods used to account for reporting bias and variability in sample size. The specific calculation formulas and thresholds are provided in Table 2. These methods utilize different statistical models and criteria to identify and evaluate potential associations between drugs and adverse events, thereby providing a scientific basis for drug safety monitoring. The data selected for analysis in our study were AE signals that were significant across all four algorithms. To enhance the reliability of the results, only cases with more than 10 reported instances were included. Finally, the newly identified AE risk signals were cross-checked with the United States FDA prescribing information for epinephrine to identify novel AE risk signals. We also collect the onset times of AEs associated with epinephrine. Result Descriptive analysis Our study identified a total of 15,865 case reports of epinephrine as the PS drug from FAERS. The clinical characteristics of epinephrine-associated AEs were summarized in Table3 and Figure2. The annual reporting trend about epinephrine-associated AEs showed a gradual increase from 2004, peaking in 2017, and subsequently maintaining a relatively stable range of 1,000-1,500 cases per year (show in Figure2). According to the database, the incidence of AEs was reported by 7,316 (46.1%) males and 5,028 (31.7%) by females. The body weight is mainly ranged from 50kg to 100kg, and age distribution predominantly fell within the 18-64.9 years range. The reporting population consisted mainly of accredited healthcare professionals, including health professionals 3,123 (19.7%), other health experts 2,821 (17.8%), physicians 2,378(15.0%), and pharmacists 1,690(10.7%). Geographically, most reports originated from the United States (10,872, 68.5%), followed by Canada (752, 4.7%), France (720, 4.5%), Japan (417, 2.6%), and the United Kingdom (416, 2.6%). Regarding the indications for epinephrine use as reported in the FAERS database, 2,555 (16.1%) cases were reported for unknown indications, followed by 3,318 (20.9%) cases for anaphylactic reactions, 2,560 (16.1%) cases for anesthesia, 1,039 (6.5%) cases for shock, 158 (1.0%) cases for cardiac arrest, 117 (0.7%) cases for angioedema, and 100 (0.6%) for asthma. The outcomes following epinephrine administration included 1,920 (12.1%) cases for life-threatening, 1,598 (10.1%) cases for hospitalizations, 1,065 (6.7%) cases for fatalities, 76 (0.5%) cases for requiring intervention, and 3,556 (22.4%) cases with other serious outcomes. Signal of system organ class There are 27 AEs signals associated with the use of epinephrine from 37,047 reported cases based on system organ class (SOC) (show in Table4). Among these, the ROR algorithm and BCPNN algorithm detected 6 significant signals, including cardiac disorders, general disorders and administration site conditions, vascular disorders, immune system disorders, product issues, injury, poisoning and procedural complications. The PRR algorithm and MGPS algorithm detected 4 significant signals including cardiac disorders, vascular disorders, immune system disorders, product issues, and injury. Signal of preferred terms In the FAERS database, we identified 2,338 AEs signals associated with the use of epinephrine from 37,047 reported cases based on PTs. 939 AEs signals ware remained after excluding signals that were meaningless in all four algorithms (ROR, PRR, MGPS, and BCPNN) . Among these, the ROR algorithm detected 507 significant signals, the PRR algorithm detected 464 significant signals, the MGPS algorithm detected 623 significant signals, and the BCPNN algorithm detected 939 significant signals. To enhance the reliability of the results, we defined strong signals as AEs with more than 10 cases reported and significant results in all four algorithms, after removed adverse events unrelated to the drug itself, ultimately identifying 167 strong adverse events signals. Sort according to the frequency of reported cases, the top 20 AEs associated with drug-induced are as follows: drug hypersensitivity, hypotension, stress cardiomyopathy, tachycardia, hypertension, heart rate increased, tremor, palpitations, cardiac arrest, bradycardia, anaphylactic reaction, loss of consciousness, ventricular tachycardia, injection site haemorrhage, anaphylactic shock, pulmonary oedema, blood pressure decreased, cardiogenic shock, injection site bruising, and acute myocardial infarction (show in Table5). Ranked based on the combined signal strength of four algorithms, the top 20 PTs are: stress cardiomyopathy, chondrolysis, injection site ischaemia, injection site pallor, systolic anterior motion of mitral valve, injection site laceration, left ventricle outflow tract obstruction, injection site hypoaesthesia, myocardial stunning, arteriospasm coronary, dry gangrene, vasoconstriction, peripheral ischaemia, kounis syndrome, extremity necrosis, drug hypersensitivity, injection site coldness, electrocardiogram st segment depression, ventricular tachycardia, and injection site injury (show in Table6). In addition, there are 35 PTs associated with AEs attributed to product quality issues. The number of reported cases reached 5,545, which is substantial. Therefore, we have specifically ranked the PTs related to product quality issues separately for further analysis. The top 20 PTs ranked by frequency of occurrence are: product quality issue, device failure, liquid product physical issue, needle issue, device malfunction, injury associated with device, device issue, device use issue, product colour issue, device leakage, circumstance or information capable of leading to medication error, product packaging issue, product label confusion, product packaging confusion, device defective, product complaint, product label issue, incorrect dose administered by device, product appearance confusion, and expired device used (show in Table7). Onset time of events The database provided information on when epinephrine-related adverse events first manifested. Among the reported AEs, 647 documented time to onset, with a median of 17 days (interquartile range [IQR] 10–24 days). Findings demonstrated a predominance of cases occurring during the first month post-exposure (n=554, 85.65%). Notably, AEs might still occur afer 1 year of epinephrine treatment as illustrated in our data (show in Figure3). Discuss Epinephrine, as a fundamental emergency medication, has been extensively utilized since the early 20th century, boasting a long history of application. It was recommended in multiple international guidelines as a first-line treatment for various medical emergencies. However, previous research on adrenaline has predominantly focused on areas such as pharmacological mechanisms, clinical trials, and literature analysis, with limited attention given to pharmacovigilance studies. This research addresses this gap by analyzing epinephrine-related adverse events through mining the FAERS database. Our data analysis reveals that the majority of adverse event reports were submitted by healthcare professionals, indicating a high level of reliability in the reported outcomes. Since 2004, there has been a progressive increase in the number of reported adverse events, with significant clinical consequences documented. Specifically, the analysis demonstrated that following the use of epinephrine, 12.1% of cases were life-threatening, 10.1% of cases required hospitalizations, 6.7% of cases resulted in fatalities, 0.5% of cases necessitated medical intervention, and 22.4% of cases were associated with other serious outcomes. These findings demonstrate substantial threats to patient safety, underscoring the critical importance of pharmacovigilance analysis for epinephrine in clinical practice. We strongly recommend that clinicians maintain heightened awareness regarding these adverse events and implement appropriate measures to minimize their occurrence. Although the majority of reported cases indicate that epinephrine is primarily used for approved indications, including anaphylactic shock (induced by medications, hypotension, or food allergies), septic shock, asthma, and local anesthesia, a significant proportion of cases (2,555 cases, 16.1%) were reported for unknown indications. We have consulted the relevant literature, Podos, S.M et al. advocate for the use of epinephrine as the first-line treatment for both primary open-angle glaucoma and ocular hypertension[15]. Previous studies have also explored the use of nebulized epinephrine for the treatment of bronchitis[16]. In arthroscopic surgery, an epinephrine irrigation solution is used to improve visualization and enhance the clarity of the surgical field[17]. For these documented clinical applications, healthcare practitioners should exercise caution and maintain vigilance for potential adverse events during administration. In the analysis of SOC and PT signals, the majority of adverse events were consistent with those described in the FDA-approved prescribing information. Notably, while epinephrine remains the first-line treatment for anaphylaxis, our analysis identified 1,028 reported cases of immune system-related adverse events, primarily comprising hypersensitivity reactions and anaphylactic shock. This phenomenon may be attributed to the presence of sodium bisulfite in adrenaline preparations, which can potentially induce mild to severe allergic reactions, including anaphylaxis or asthma episodes, in susceptible individuals[18]. However, it is crucial to emphasize that the presence of bisulfite should not preclude the use of adrenaline in life-threatening anaphylaxis or other critical emergencies, as alternative therapeutic options may prove inadequate in such clinical scenarios[19]. We did not find any literature reporting allergic reactions caused by epinephrine. It is recommended that clinicians monitor for potential allergic reactions following the administration of epinephrine. The cardiovascular effects of adrenaline represent a critical concern for clinicians seeking to minimize adverse events. Our study reveals significant circulatory system impacts beyond fatal arrhythmias, hypotension, and cardiac arrest, including noteworthy cases of arteriospasm coronary, acute myocardial infarction, and coronary artery thrombosis. We hypothesize that these adverse events may be associated with adrenaline’s action on α1, anf α2 adrenergic receptors, potentially leading to coronary constriction, vascular narrowing, and compromised blood flow. In addition, numerous AEs related to the circulatory system are not mentioned in the drug labeling, including systolic anterior motion of mitral valve, myocardial stunning, kounis syndrome, stress cardiomyopathy, left ventricle outflow tract obstruction, and other related conditions. A previous case report documented an instance of penicillin-induced Kounis syndrome, where the administration of epinephrine resulted in severe myocardial ischemia[20]. In addition, case reports have documented the occurrence of stress cardiomyopathy following the administration of high doses of epinephrine[21-24]. Consequently, particular caution is warranted when administering adrenaline to patients with pre-existing coronary artery disease, as they may be at increased risk of secondary coronary injury. Both SOC and PT signal analyses have identified adverse events related to adrenaline product quality issues. Beyond intrinsic product concerns such as packaging and labeling deficiencies, particular attention should be directed to the critical role of adrenaline auto-injectors (AAI) as essential auxiliary devices. Since the introduction of the first AAI in 1983, various branded devices have been developed. The European Academy of Allergy and Clinical Immunology (EAACI) and the British Society of Allergy and Clinical Immunology (BSACI) has provided specific recommendations for AAI use in its latest guidelines for anaphylaxis management[25,26]. Our analysis identified multiple device-related issues, including product quality concerns, device failure, needle problems, and operational errors. Guillaume Pouessel and colleagues investigated AEs related to AAIs using data from the French pharmacovigilance database and the French poison control centers. The results revealed that the sales of AAIs in France have increased year by year over the past decade. Additionally, the team concluded that the reported cases of AAI-related AEs are significantly underestimated[27,28]. Two US surveys conducted by poison control centres identified 15,190 AAI-related adverse drug reactions between 1994 and 2007, followed by an additional 6,806 cases reported from 2013 to 2014[29,30]. Although the incidence of AAI-related adverse drug reactions is relatively high, literature suggests that AAI rarely causes fatal adverse reactions due to the lack of sustained and adequate plasma epinephrine concentrations[31]. However, we still emphasize the importance of vigilance in clinical practice regarding treatment delays caused by device-related issues, which may result in severe consequences for patients. Our analysis has identified several adverse reactions not previously documented in the prescribing information. Notably, within the musculoskeletal and connective tissue disorders SOC, we detected signals for chondrolysis, compartment syndrome, trismus, and chondropathy. While no published literature specifically addresses chondrolysis or chondropathy associated with adrenaline use, literature reports show that all joint tissues express at least one adrenergic receptor subtype, and in the pathogenesis of osteoarthritis, adrenergic receptor-mediated joint cell effects are mainly catabolic, which may explain why adrenergic use causes cartilage dissolution[32-34]. In the gastrointestinal disorders category, we identified cases of oral hypoesthesia and paresthesia. The nervous system disorders SOC revealed signals for paralysis, sensory loss, Horner’s syndrome, and encephalopathy. Horner syndrome is caused by an interruption of the sympathetic nerve pathway (a three-neuron pathway extending from the hypothalamus to the eye), with epinephrine being one of the primary neurotransmitters of the sympathetic nervous system. Case reports have documented instances of Horner syndrome occurring after epidural anesthesia (which may involve anesthetic agents containing epinephrine), potentially related to the drug’s effects on the sympathetic nerve pathway[35,36]. These emerging signals warrant heightened clinical vigilance and necessitate further investigation into these rare but potentially serious adverse reactions. Our study has several inherent limitations that warrant consideration. As the FAERS database relies on a spontaneous reporting system, the identification of adverse reactions may be influenced by both the awareness of specific adverse events and the perceived significance of these reactions, potentially leading to under reporting. Furthermore, the reporting population is predominantly from Western countries, which may limit the generalizability of our findings to other demographic groups, particularly Asian populations. To validate these results across different populations, large-scale randomized controlled trials specifically designed for diverse ethnic groups are necessary. Conclusion Epinephrine, as a widely used clinical emergency medication, is associated with a high incidence of reported adverse events, which have led to severe clinical outcomes. Among the commonly observed adverse reactions, hypersensitivity reactions, anaphylactic shock, and cardiovascular effects warrant particular attention from healthcare professionals. Notably, our analysis has identified several previously undocumented adverse events, including stress cardiomyopathy, systolic anterior motion of mitral valve, left ventricle outflow tract obstruction, kounis syndrome, chondrolysis, horner’s syndrome, compartment syndrome, oral hypoesthesia, and paresthesia, which necessitate heightened clinical vigilance and further investigation. Additionally, the use of adrenaline auto-injectors has been associated with various device-related complications. Therefore, careful selection of reliable manufacturers is crucial to prevent treatment delays caused by device malfunctions, which could potentially compromise patient safety. Abbreviations: Adverse event (AE), Preferred Term (PT), System Organ Class(SOC), Medical Dictionary for Regulatory Activities (MedDRA), report odds ratio (ROR), proportion report ratio (PRR), bayesian confidence propagation neural network (BCPNN), multi-item gamma-poisson shrinkage (MGPS), primary suspect drug (PS), administrative information (DEMO), drug information (DRUG), adverse drug reaction information (REAC), patient outcomes information (OUCT), reported sources (RPSR), drug therapy start dates and end dates (THER), indications for drug administration (INDI), adrenaline auto-injectors (AAI). References 1. Sneader, W. The discovery and synthesis of epinephrine . 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Supplementary Material File (figure.docx) Download 50.33 KB File (table.doc) Download 476.46 KB Information & Authors Information Version history V1 Version 1 10 April 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords adverse drug reactions catecholamines clinical pharmacology critical care drug safety neuropharmacology pharmacovigilance Authors Affiliations Huihui Bai 0000-0002-8138-731X Department of Intensive Care Unit, Shaanxi Province People’s Hospital View all articles by this author Yan Wang [email protected] View all articles by this author Dan Niu View all articles by this author Boling Li 中国 View all articles by this author Yuan Zong View all articles by this author Metrics & Citations Metrics Article Usage 263 views 124 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Huihui Bai, Yan Wang, Dan Niu, et al. Real-World safety evaluation of epinephrine: an adverse event analysis based on the FAERS database. 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