Opioid Toxicity Following Concomitant Use of Macrolide Antibiotics with Fentanyl, Hydromorphone, or Oxycodone: A Population‐Based Study

Fentanyl, hydromorphone, and oxycodone are metabolized by cytochrome P450 3A4 (CYP3A4). Co-administration with CYP3A4-inhibiting macrolides (clarithromycin or erythromycin) may increase opioid concentrations and overdose risk, but the clinical impact of these interactions is unknown. We conducted three population-based nested case-control studies of Ontario residents aged 15 years or older who were prescribed transdermal fentanyl, oral hydromorphone, or oral oxycodone between 1997 and 2023. We defined cases as individuals who died of or were hospitalized with opioid toxicity and matched each case to up to four controls on age, sex, calendar year, and a disease risk score. We assigned controls random index dates based on the distribution among cases and estimated adjusted odds ratios (aOR) and 95% confidence intervals (CIs) for the association between opioid toxicity and macrolide use in the preceding 14 days. We matched 735 fentanyl-treated (45.3% of eligible cases), 2,506 hydromorphone-treated (64.5%), and 678 oxycodone-treated (50.1%) individuals with opioid toxicity to at least one control. Across all studies, 70 cases and 120 controls were exposed to a macrolide. CYP3A4-inhibiting macrolide exposure was associated with an increased risk of opioid toxicity among patients treated with fentanyl (aOR 3.80, 95% CI: 1.36-11.56), hydromorphone (aOR 3.38, 95% CI: 1.28-8.97), and oxycodone (aOR 3.11, 95% CI: 1.05-9.51). We observed no associations with azithromycin, a non-CYP3A4 inhibiting macrolide. There was no significant effect modification by study period, and findings were robust in bias analyses. These findings likely extend to individuals exposed to clandestinely produced fentanyl and to other CYP3A4 inhibitors.