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Risk of Stone Formation with Use of Topiramate and Comparator Medications: A VigiBase Analysis
Jonathan J. Song, BA1, James McAndrew Jones, III, MD
2, David S. Wang, MD
2, Daniel A. Wollin, MD MS
3.
1Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA,
2Boston Medical Center, Boston, MA, USA,
3Brigham and Women’s Hospital, Boston, MA, USA.
Background: Large, long-term studies of stone formation with topiramate use are limited. Mechanistically, it is posited that high urinary pH and hypocitraturia are responsible for calcium phosphate stone formation. We sought to study the association between topiramate and stone formation and whether medications with similar urinary biochemical effects would also be associated with stone formation.
Methods: We conducted a pharmacovigilance case-noncase study of signals of stone formation reported with topiramate and other medication use in VigiBase, the World Health Organization’s global database of individual case safety reports. We included all adverse events (1967 to 2022); only reports identified by Vigibase’s internal system as duplicate reports were excluded. Disproportionality analysis was conducted with a significance threshold set by the lower bound 95% Empiric Bayes Estimator (EBE) > 1, with additional description of the reporting odds ratio (ROR) with its 95% confidence interval (CI).
Results: Of 63,448,915 total adverse drug reactions, we identified 203 reports of stone formation with topiramate use. Topiramate was significantly associated with stone formation (ROR 4.89; 95% CI 4.26-5.61). A significant disproportionality signal was observed in subgroup analysis of men and women, and users aged <45 and ≥45. Other carbonic anhydrase inhibitors, acetazolamide (ROR 2.46; 95% CI 1.36-4.44) and zonisamide (ROR 7.68; 95% CI 5.61-10.52), were also associated with stone formation. No signal was found for drugs that predispose to distal RTA such as lithium and amphotericin, K-sparing diuretics which cause alkalization of urine, or enalapril, an ACE inhibitor previously found to cause hypocitraturia by increasing ATP citrate lyase activity.
Conclusions: Like other prototypical carbonic anhydrase inhibitors, topiramate was significantly associated with stone formation. However, no signal was found for medications that increase urine pH or cause hypocitraturia. At-risk patients should be counseled on the risk of developing stones when taking carbonic anhydrase inhibitors.
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