Disproportionality of Brugada Syndrome with Expert-Defined High-Risk Medications in the FDA Adverse Event Reporting System (FAERS), 2021–2025
Year: 2026
Type: article
Study design: Observational Study
Abstract: Brugada syndrome is a cardiac channelopathy in which certain medications can unmask the characteristic electrocardiographic phenotype and precipitate malignant ventricular arrhythmias. BrugadaDrugs.org provides expert classifications separating implicated medications into RED (contraindicated or best avoided) and ORANGE (preferably avoided) categories. Whether these expert-defined categories correspond to real-world spontaneous reporting patterns in large postmarketing databases has not been systematically evaluated. This study performed a retrospective case/non-case disproportionality analysis of reports from the US FDA Adverse Event Reporting System (FAERS) submitted from Q1 2021 through Q4 2025. Reports were deduplicated by case identifier, and Brugada syndrome was identified using the MedDRA Preferred Term "Brugada syndrome". Exposure to RED or ORANGE drugs included medications recorded as primary or secondary suspects; the categories were not mutually exclusive. Reporting odds ratios (RORs) with 95% confidence intervals (CIs) were calculated, with Benjamini–Hochberg false discovery rate correction applied to individual-drug analyses, and only drugs with at least three exposed Brugada syndrome cases were retained. Sensitivity analyses examined primary-suspect exposure and stratification by sex and age. Multivariable logistic regression adjusted for age, sex, and number of suspect drugs using complete-case analysis (n = 4,399,497). The deduplicated dataset contained 7,660,722 FAERS cases, including 406 reports of Brugada syndrome. RED exposure was recorded in 106 Brugada cases (ROR 73.54, 95% CI 58.91–91.79); ORANGE exposure was recorded in 153 cases (ROR 28.24, 95% CI 23.10–34.52). Adjusted ORs were 104.12 (95% CI 79.23–136.83) for RED and 23.11 (95% CI 18.23–29.30) for ORANGE. In mutually exclusive exposed reports (72 RED-only and 119 ORANGE-only Brugada cases), RED exposure was associated with higher adjusted odds than ORANGE exposure (OR 5.54, 95% CI 4.06–7.54). Among individual drugs, flecainide had the largest signal (ROR 320.03); among non-cardiac agents the largest were fluvoxamine (190.48), nortriptyline (166.37), and bupropion (70.89). A sex-by-exposure interaction was observed for ORANGE (p = 1.66 × 10⁻⁵) but not RED (p = 0.842). Comparator medications produced smaller but not uniformly null estimates. Both expert-defined categories were associated with marked disproportionate reporting, with a stronger signal for RED than ORANGE drugs. The pattern is directionally consistent with the BrugadaDrugs.org risk hierarchy but does not constitute independent validation of clinical risk. These findings represent pharmacovigilance signals and should not be interpreted as evidence of causality, incidence, or absolute clinical risk.
Language: English
Subfield: Toxicology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7225099446