Disproportionality Analysis of Urinary Stone Formation With Carbonic Anhydrase Inhibitors: A VigiBase Analysis

While the use of carbonic anhydrase inhibitors (CAIs) rises, studies of urinary stone formation with CAIs are limited. We sought to study the association between CAIs and reports of stone-related adverse drug reactions (ADRs), investigate dose-dependent associations, and identify at-risk clinical subgroups.

We conducted a pharmacovigilance case-noncase study of signals of stone formation reported with CAIs in VigiBase, a WHO global database of case-safety reports. We included all adverse events (1967-2022); only duplicate reports identified by VigiBase were excluded. We conducted disproportionality analysis with a significance threshold of the lower bound 95% Empiric Bayes Estimator > 1 and described the reporting odds ratio (ROR) and 95% CI.

Of 63,448,915 adverse events, we identified 246 reports of stone-related ADRs with CAI use. CAIs were significantly associated with stone-related ADRs (ROR 5.02; 95% CI: 4.43-5.70). Significant disproportionality signals were observed for topiramate (ROR 4.91; 95% CI: 4.27-5.65), zonisamide (ROR 8.00; 95% CI: 5.84-10.96), and acetazolamide (ROR 2.56; 95% CI: 1.42-4.62). Stone-related ADRs were heavily reported in patients aged < 45 (ROR 8.72; 95% CI: 7.06-10.76) and patients taking zonisamide and topiramate for seizure (ROR 9.40; 95% CI: 6.87-12.85). Dose-dependent associations were observed with topiramate (ROR 25-99 mg: 3.20; ROR 100-199 mg: 5.92; ROR 200-400 mg: 6.57) and zonisamide (ROR 100-199 mg: 6.79; ROR 200-399 mg: NS, ROR 400-600 mg: 14.29).

CAIs were significantly associated with dose-dependent reporting of stone-related ADRs. Younger patients and patients with indication of seizure had higher risk of reporting stone-related ADRs. At-risk patients should be counseled on the risk of developing stones when taking CAIs.