Adverse events with quetiapine and clarithromycin coprescription: A population‐based retrospective cohort study

BACKGROUND AND AIMS: Quetiapine is an atypical antipsychotic predominantly metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme. We studied the risk of adverse events following coprescription of clarithromycin (a strong CYP3A4 inhibitor) versus azithromycin (not a CYP3A4 inhibitor) in quetiapine users. MATERIALS AND METHODS: This was a population‐based retrospective cohort study from 2004 to 2020 in Ontario, Canada in adult quetiapine users newly co‐prescribed clarithromycin (n = 16,909) or azithromycin (n = 25,267). The primary outcome was the composite of hospital encounters with encephalopathy (defined as a diagnosis of delirium, disorientation, transient alteration of awareness, transient ischemic attack, or unspecified dementia), a fall, or a fracture within 30 days of new coprescription. Secondary outcomes were individual components of the composite outcome, hospital encounter with computed tomography (CT) head scan, and all‐cause mortality. RESULTS: Coprescription of clarithromycin versus azithromycin with quetiapine was associated with a higher risk of the primary composite outcome (365 of 16,909 clarithromycin users [2.2%] vs. 309 of 16,929 azithromycin users [1.8%]; absolute risk increase, 0.34% [95% confidence interval, CI, 0.04–0.63]; relative risk [RR], 1.19 [95% CI, 1.02–1.38]). This was primarily driven by an increase in fragility fractures (78 of 16,909 clarithromycin users [0.5%] vs. 45 of 16,923 azithromycin users [0.3%]; absolute risk increase, 0.20% [95% CI, 0.07–0.32]; RR, 1.74 [95% CI, 1.21–2.52]). Hospital encounters with a CT head scan were higher in clarithromycin users (220 of 16,909 [1.3%] vs. 175 of 16,923 azithromycin users [1.0%]; absolute risk increase, 0.27% [95% CI, 0.04–0.50]; RR, 1.26 [95% CI, 1.04–1.54]), but there was no difference in hospital encounters with encephalopathy, falls, or all‐cause mortality between macrolide groups. CONCLUSION: Among adults taking quetiapine, concurrent use of clarithromycin compared with azithromycin was associated with a small but statistically greater 30‐day risk of a hospital encounter for encephalopathy, falls, or fracture, which was predominantly related to a higher rate of fragility fractures.