Drug-induced fluorosis: A study based on the national and international pharmacovigilance databases.

Abstract

Objectives: Despite the widespread use of fluorinated medicines - with approximately 20% of the drugs marketed in 2020 containing fluoride compounds - the association between these medications and fluorosis remains under-recognized. This study aimed to identify medications most likely to induce fluorosis in real-world clinical settings using pharmacovigilance databases.

Methods: A descriptive and disproportionality study was conducted using French national (FPVB) and international pharmacovigilance databases (VigiBase®). Cases of fluorosis were extracted from Vigibase® up to July 8, 2024, using the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms "fluorosis", "fluoride increased" and "fluorosis dental". French cases were subsequently extracted from the FPVB. Disproportionality signals were evaluated by calculating the reporting odds ratio (ROR) and corresponding 95% confidence interval (CI).

Results: A total of 72 cases of suspected drug-induced fluorosis were identified in VigiBase®. The most frequently reported adverse effects were musculoskeletal disorders (n=39, 54.2%), dental disorders (n=11, 15.3%), and eyes and visual disorders (n=8, 11.1%). Two-third of the cases (n=52) were classified as serious. In 40% of cases (n=29), the outcome was favorable. Voriconazole, sodium fluoride, fluconazole and ciprofloxacin were identified as single suspects. Disproportionality signals were detected for sodium fluoride (ROR=2305.7; 95% CI [1143.9; 4647.3]), voriconazole (ROR=1415.4; 95% CI [891.5; 2247.3]), fluconazole (ROR=110.4; 95% CI [52.9; 230.3]), fludarabine (ROR=87.3; 95% CI [31.8; 239.3]) and ciprofloxacin (ROR=7.1; 95% CI [2.2; 22.4]). The 16 cases from the FPVB provided more detailed information, including the clinical context - mainly hematological malignancies (37.5%) and organ transplants (12.5%) - the median time to onset (361 days), mean plasma fluoride concentration (1.33mg/L; range 0.006-7.2mg/L), and results imaging explorations.

Conclusion: This study highlights pharmacovigilance signals suggesting a potential association between fluorosis and certain fluorinated compounds, particularly sodium fluoride, voriconazole, fluconazole, fludarabine and ciprofloxacin. Among these, only sodium fluoride and voriconazole include fluorosis in the summary of product characteristics. Clinicians should remain vigilant regarding this potential adverse drug reaction, especially with long-term use of these medications.