Evidence of potential pro‐haemorrhagic drug interactions between CYP3A4 inhibitors and direct oral anticoagulants: Analysis of the FAERS database

Aims There is no consensus on the haemorrhagic risk associated with potential interactions between commonly used CYP3A4 inhibitors and direct oral anticoagulants (DOACs). Methods Macrolide antibiotics and azole antimycotics were investigated in this study. Data from Food and Drug Administration Adverse Event Reporting System were retrieved from July 2010 to September 2021. Haemorrhagic signals were expressed by reporting odds ratios (RORs) and 95% confidence intervals (CIs) based on the interaction/noninteraction methodology as (a/c) / (b/d) and considered significant when the lower limit of 95% CI was >1 and the case number of interaction group was ≥3. Subgroup analyses and logistic regression were conducted by adjusting associated factors in haemorrhagic events. Results From the third quarter of 2010 to the first quarter of 2021, we retrieved 382 853 distinct cases of adverse events associated with DOACs, in which 1128 cases of bleeding were associated with coadministration of CYP3A4 inhibitors and DOACs. The haemorrhagic signal was significant for apixaban when coadministered with clarithromycin (ROR 1.60, 95% CI 1.16–2.20) and posaconazole (ROR 2.69, 95% CI 1.37–5.28). For dabigatran, coadministration with azithromycin (ROR 4.06, 95% CI 2.77–5.95), fluconazole (ROR 2.26, 95% CI 1.52–3.37), itraconazole (ROR 7.52, 95% CI 1.51–37.46) and ketoconazole (ROR 2.06, 95% CI 1.25–3.41) was associated with significantly higher risks of haemorrhages. At the same time, addition of itraconazole to rivaroxaban also indicated significant haemorrhagic signal (ROR 3.58, 95% CI 1.30–9.85). Conclusions Macrolide antibiotics and azole antimycotics have potential but different effects on the bleeding risk of DOACs. Close attention is needed when using these drugs together. Such precautions have already been included in some drug labels.