PURPOSE: Azole antimycotics and nystatin oral solution are used to treat oral candidiasis. Azoles inhibit cytochrome (CYP) P450-dependent metabolism of warfarin, which could increase the anticoagulant effect of warfarin. Nystatin is not expected to interfere with warfarin metabolism, but current data are conflicting. With this study, we aimed to explore the potential drug-drug interactions between warfarin and azole anti-mycotics used in the treatment of oral candidiasis, that is, systemic fluconazole, miconazole oral gel, and nystatin oral solution.

METHODS: By linking clinical data on international normalized ratio (INR) measurements with administra-tive data on filled prescriptions of warfarin and antimycotics during 2000-2015, we explored INR changes in warfarin users relative to initiation of systemic fluconazole (n = 413), miconazole oral gel (n = 330), and nystatin oral solution (n = 399).

RESULTS: We found a significant increase in mean INR of 0.83 (95% confidence interval [CI] 0.61-1.04) and 1.27 (95% CI 0.94-1.59) following initiation of systemic fluconazole and miconazole oral gel, respec-tively. Also, the proportion of patients experiencing an INR-value above 5 was increased after initiation of fluconazole (from 4.3% to 15.3%) and miconazole (from 5.5% to 30.1%). INR was unaffected by initiation of nystatin oral solution (mean change 0.08; 95% CI-0.10 to 0.25).

CONCLUSION: Initiation of systemic fluconazole and miconazole oral gel was associated with increased INR in warfarin users. A similar association was not found for nystatin oral solution, which thus appears to be the safest alternative when treating oral candidiasis in warfarin users. (C) 2020 Elsevier Inc. All rights reserved.