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Statin toxicity from macrolide antibiotic coprescription: a population-based study of older adults

Patel AM, Shariff S, Bailey DG, Juurlink DN, Gandhi S, Mamdani M, Gomes T, Fleet J, Hwang YJ, Garg AX. Ann Intern Med. 2013; 158(12):869-76.

Background — Clarithromycin and erythromycin inhibit cytochrome P450 isoenzyme 3A4 (CYP3A4), increasing blood concentrations of statins metabolized by CYP3A4, while azithromycin does not.

Objective — To assess outcomes of statin toxicity after co-prescription of either clarithromycin or erythromycin.

Design — Population-based cohort study using four linked healthcare databases.

Setting — Ontario, Canada, from 2003 to 2010.

Patients — Continuous statin users over the age of 65 (mean 74 years) who were co-prescribed either clarithromycin (n=72,591) or erythromycin (n = 3,267) compared to those co-prescribed azithromycin (n = 68,478).

Measurements — The primary outcome was hospital admission with rhabdomyolysis within 30 days of the antibiotic prescription. Secondary outcomes included hospital admission with acute kidney injury and all-cause mortality.

Results — Atorvastatin was the most common statin (73%) followed by simvastatin and lovastatin. Compared to azithromycin, co-prescription for either clarithromycin or erythromycin was associated with a higher risk of hospital admission with rhabdomyolysis (absolute risk increase 0.02% (95% confidence interval (CI) 0.01-0.03) and relative risk (RR) 2.17 (95% CI 1.04 to 4.53)), acute kidney injury (absolute risk increase 1.26% (95% CI 0.58 to 1.95) and RR 1.78 (95% CI 1.49 to 2.14), and a higher risk of all-cause mortality (absolute risk increase 0.25% (95% CI 0.15 to 0.33) and RR 1.56 (95% CI 1.36 to 1.80)). Results were consistent in adjusted analyses and in a subpopulation with laboratory measurements.

Limitations — The codes used to identify rhabdomyolysis were insensitive and the absolute risk increase may be underestimated up to ten fold. The authors only studied older adults.

Conclusion — In older adults co-prescription of either clarithromycin or erythromycin with a CYP3A4 metabolized statin increases the risk of statin toxicity.

Keywords: Drug interactions