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Co\u2010administration with CYP3A4\u2010inhibiting macrolides (clarithromycin or erythromycin) may increase opioid concentrations and overdose risk, but the clinical impact of these interactions is unknown. We conducted three population\u2010based nested case\u2010control studies of Ontario residents aged 15\u2009years 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\u2009days. We matched 735 fentanyl\u2010treated (45.3% of eligible cases), 2,506 hydromorphone\u2010treated (64.5%), and 678 oxycodone\u2010treated (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\u2010inhibiting macrolide exposure was associated with an increased risk of opioid toxicity among patients treated with fentanyl (aOR 3.80, 95% CI: 1.36\u201311.56), hydromorphone (aOR 3.38, 95% CI: 1.28\u20138.97), and oxycodone (aOR 3.11, 95% CI: 1.05\u20139.51). We observed no associations with azithromycin, a non\u2010CYP3A4 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.<\/jats:p>","DOI":"10.1002\/cpt.70267","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T11:39:46Z","timestamp":1775561986000},"page":"122-138","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Opioid Toxicity Following Concomitant Use of Macrolide Antibiotics with Fentanyl, Hydromorphone, or Oxycodone: A Population\u2010Based Study"],"prefix":"10.1002","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6984-8953","authenticated-orcid":false,"given":"Tony","family":"Antoniou","sequence":"first","affiliation":[{"name":"Department of Family and Community Medicine University of Toronto  Toronto Ontario Canada"},{"name":"ICES  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Yang","sequence":"additional","affiliation":[{"name":"ICES  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0368-4212","authenticated-orcid":false,"given":"David N.","family":"Juurlink","sequence":"additional","affiliation":[{"name":"ICES  Toronto Ontario Canada"},{"name":"Department of Pediatrics University of Toronto  Toronto Ontario Canada"},{"name":"Department of Medicine University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8252-2034","authenticated-orcid":false,"given":"Joanne M.\u2010W.","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Medicine McMaster University  Hamilton Ontario Canada"},{"name":"Schlegel Research Institute for Aging  Waterloo Ontario Canada"},{"name":"GeriMedRisk  Waterloo Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5199-6344","authenticated-orcid":false,"given":"Muhammad","family":"Mamdani","sequence":"additional","affiliation":[{"name":"ICES  Toronto Ontario Canada"},{"name":"Leslie Dan Faculty of Pharmacy University of Toronto  Toronto Ontario Canada"},{"name":"Temerty Faculty of Medicine University of Toronto  Toronto Ontario Canada"},{"name":"Dalla Lana Faculty of Public Health University of Toronto  Toronto Ontario Canada"},{"name":"Vector Institute  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4311-3337","authenticated-orcid":false,"given":"Fangyun","family":"Wu","sequence":"additional","affiliation":[{"name":"ICES  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1911-6129","authenticated-orcid":false,"given":"Mina","family":"Tadrous","sequence":"additional","affiliation":[{"name":"ICES  Toronto Ontario Canada"},{"name":"Leslie Dan Faculty of Pharmacy University of Toronto  Toronto Ontario Canada"},{"name":"Women's College Research Institute  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1468-1965","authenticated-orcid":false,"given":"Tara","family":"Gomes","sequence":"additional","affiliation":[{"name":"ICES  Toronto Ontario Canada"},{"name":"Leslie Dan Faculty of Pharmacy University of Toronto  Toronto Ontario Canada"},{"name":"Li Ka Shing Knowledge Institute Unity Health Toronto  Toronto Ontario Canada"},{"name":"Institute for Health Policy, Management and Evaluation University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"e_1_2_11_1_1","volume-title":"Opioid\u2010 and Stimulant\u2010Related Harms in Canada","author":"Substance\u2010related Overdose and Mortality Surveillance Task Group on behalf of the Council of Chief Medical Officers of Health","year":"2025"},{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1503\/cmaj.231339"},{"key":"e_1_2_11_3_1","unstructured":"National Institute on Drug Abuse.Drug Overdose Deaths: Facts and Figures<https:\/\/nida.nih.gov\/research\u2010topics\/trends\u2010statistics\/overdose\u2010death\u2010rates#Fig3>. 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