Causes of Drug-Induced Severe Cutaneous Adverse Reaction Epidermal Necrolysis (EN): An Analysis Using FDA Adverse Event Reporting System (FAERS) Database

Abstract

Purpose The purpose of the study is to analyze FAERS data to identify drugs associated with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), determine demographics, drug classes involved, most likely resulted in death, and highlight emerging trends in SJS/TEN reactions. Patients and Methods We reviewed the publicly available FAERS database from 2004–2021. Using search terms “Stevens-Johnson syndrome” or “Toxic epidermal necrolysis”, we identified the reports of SJS/TEN or SJS/TEN followed by death that might associated with specific drugs. Then the amounts and trends were counted analyzed. Results During the study period of 2004–2021, the Food and Drug Administration (FDA) received a total of 14,363,139 reports of adverse reactions, among which 24,976 were linked to SJS or TEN. After excluding the cases with incomplete or insufficient information on age, gender, or country of origin, the median median age of patients was 53.82 (IQR = 57.52), the females accounted for 56.59% (12,827 cases) and 8,507 (38.34%) originated in the United States. The top 50 drugs were associated with 15,149 cases (60.65%). The subsequent fatal outcome occurring in 4878 out of 24,976 cases (19.53%). Top 3 drug classes associated with SJS/TEN in FAERS were antiepileptics, non-steroidal anti-inflammatory drugs (NSAIDs) and others. Top drug classes associated with SJS/TEN deaths were antineoplastic agents and cephalosporins. Linear regression showed that the annual percentage of monoclonal antibody-related SJS/TEN reactions increased at an average rate of 0.25% (95% confidence interval: 0.18, 0.32) from 0.00% in 2004 to 4.79% in 2021, faster than any other drug class except antigout drug (allopurinol). Conclusion By using the publicly available FAERS data, we have identified some important themes and trends in drug-related SJS/TEN reactions. Monoclonal antibodies and proton pump inhibitors are drugs with emerging trends causing SJS/TEN. Additionally, cephalosporin antibiotics have a higher mortality rate following SJS/TEN.

Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis: Analysis of the Russian Database of Spontaneous Reports

“…A retrospective analysis of 59 TEN cases reported in Yokohama City University Hospital and Yokohama City University Medical Center between January 2000 and March 2020 revealed a mortality rate of 13.6% ( n = 8) [ 42 ]. Higher rates of SJS/TEN mortality were demonstrated in the USA: for the period from 2004 to 2021 there were 24,976 cases of SJS/TEN in the Food and Drug Administration Adverse Event Reporting System (FAERS) database, and 19.53% were fatal [ 43 ].…”

“…Antiepileptics are well-known causes of SJS and TEN. They accounted for up to 19.37% of all SJS and TEN reports retrieved from the FAERS database from 2004 to 2021 [ 43 ]. There are a lot of studies identifying the high risk of SJS and TEN associated with antiepileptics.…”

“…Published data demonstrated wide involvement of targeted anticancer drugs and immunotherapies in severe CADR development, including SJS and TEN cases [ 58 ]. FAERS database analysis revealed antineoplastic agents among the top drug classes associated with SJS/TEN deaths [ 43 ]. For the Japanese population, anticancer drugs were the more frequent causes of SJS and TEN in patients older than 80 years compared with patients younger than 50 years [ 59 ].…”

“…Ibuprofen revealed the highest association with SJS based on the highest ROR (ROR = 7.06, 95% two-sided CI 6.59–7.56) and was the most frequently reported NSAID in SJS and TEN [ 21 ]. Fei et al (2023) listed valdecoxib and celecoxib among the top 50 drugs associated with more than 60% of the SJS/TEN reactions in the United States, while diclofenac and acetylsalicylic acid were among the drugs associated with a minority of the SJS and TEN cases (less than 10% of the SJS/TEN reactions in the United States) [ 43 ].…”

A Real-World Safety Profile in Neurological, Skin, and Sexual disorders of Antiepileptic Drugs Using Pharmacovigilance Database of the Korea Adverse Event Reporting System (KAERS)

“…Based on data from the FDA Adverse Event Reporting System (FAERS) between 2004 and 2021, AEDs belonged to the major drug classes that cause Stevens-Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN), and 19.37% of all reports were related to AEDs. Specifically, phenytoin was identified as the most frequently reported drug [30]. The study analyzing 2,942 cases of drug eruption from KAERS DB between 2008 to 2017 found that lamotrigine, valproate, carbamazepine, oxcarbazepine, levetiracetam, and phenytoin were the cause of the eruptions [31].…”