Increased risk for aseptic meningitis after amoxicillin or amoxicillin‐clavulanic acid in males: A signal revealed by subset disproportionality analysis within a global database of suspected adverse drug reactions

PURPOSE: Drug‐induced aseptic meningitis (DIAM) is an inflammation of the membranes of the central nervous system caused by certain medications. It is a rare clinical entity whose risk factors are not yet fully elucidated. A local pattern of disproportionality within a global database of suspected adverse drug reactions (ADRs) revealed an increased reporting of aseptic meningitis and amoxicillin‐clavulanic acid (AC) in males. The aim of this report is to explore the clinical probability of a higher risk in males to support the use of statistical methods to identify subgroups at risk for adverse drug reactions. METHODS: Disproportionality analysis was performed for all drug‐adverse event (AE) pairs in the entire database and for the subsets of males and females. AC‐aseptic meningitis was highlighted for an increased disproportionality in the male subgroup in the absence of an elevated disproportionality measure for the database overall. A clinical review was undertaken. RESULTS: Clinical review revealed a similar statistical pattern of gender difference observed for amoxicillin, evidence to suggest a delayed type 4 hypersensitivity reaction with Th1 cells as a mechanism for amoxicillin‐aseptic meningitis, the existence of sex differences in immune responses (Th1/Th2), and an analogous increased risk of drug‐induced liver injury by AC in males. CONCLUSIONS: Subgroup disproportionality analysis has revealed a larger than expected number of reports of aseptic meningitis after amoxicillin and AC in males. Evidence synthesis supports the statistical finding. Further exploration of spontaneous databases with more extensive analyses could usher in a new era of “precision pharmacovigilance.”