Carboxyamidotriazole

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.

Granuloma annulare (GA) is a benign, granulomatous skin condition characterized by ring-shaped papules or plaques on the dorsal aspects of the hands and/or feet. It is most frequently seen in children and young adults, with a female predominance. Although many cases are idiopathic, associations with certain diseases include autoimmune disorders, diabetes mellitus, and thyroid disease. Drugs have also been implicated including allopurinol, diclofenac, topiramate, amlodipine, thalidomide, and TNF-α inhibitors. The clinical and morphologic distinction from the interstitial granulomatous drug reaction (IDG) can be challenging. Acetazolamide, a carbonic anhydrase inhibitor (CAI) commonly used for idiopathic intracranial hypertension, has recently been associated with subcutaneous granuloma annulare (SGA). We report a 16-year-old girl who developed multiple firm subcutaneous nodules on her hands shortly after initiation and dose escalation of acetazolamide. Histopathology demonstrated subcutaneous palisading granulomas with central necrobiosis, consistent with SGA. Nodules resolved nearly completely within 2 weeks of drug discontinuation. Pharmacologic inhibition of carbonic anhydrase may promote endothelial cell apoptosis leading to ischemic changes in the connective tissue fiber matrix and also modulate macrophage activation resulting in an influx of histiocytes at the site of anoxia, suggesting a potential immunologic mechanism shared with other weak CAIs, such as topiramate. This case highlights acetazolamide-induced SGA and further explores the spectrum of granulomatous inflammation associated with drugs of the CAI class.