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Calcium-channel blocker–clarithromycin drug interactions and acute kidney injury

Gandhi S, Fleet JL, Bailey DG, McArthur E, Wald R, Rehman F, Garg AX. JAMA. 2013; 310(23):2544-53.


Importance — Calcium-channel blockers are metabolized by the cytochrome P450 3A4 (CYP3A4; EC 1.14.13.97) enzyme. Blood concentrations of these drugs may rise to harmful levels when CYP3A4 activity is inhibited. Clarithromycin is an inhibitor of CYP3A4 and azithromycin is not, which makes comparisons between these 2 macrolide antibiotics useful in assessing clinically important drug interactions.

Objective — To characterize the risk of acute adverse events following coprescription of clarithromycin compared with azithromycin in older adults taking a calcium-channel blocker.

Design, Setting and Participants — Population-based retrospective cohort study in Ontario, Canada, from 2003 through 2012 of older adults (mean age, 76 years) who were newly coprescribed clarithromycin or azithromycin while taking a calcium-channel blocker (amlodipine, felodipine, nifedipine, diltiazem, or verapamil).

Main Outcomes and Measures — Hospitalization with acute kidney injury (primary outcome) and hospitalization with hypotension and all-cause mortality (secondary outcomes examined separately). Outcomes were assessed within 30 days of a new coprescription.

Results — There were no differences in measured baseline characteristics between the clarithromycin and azithromycin groups. Amlodipine was the most commonly prescribed calcium-channel blocker (more than 50% of patients). Coprescribing clarithromycin vs azithromycin with a calcium-channel blocker was associated with a higher risk of hospitalization with acute kidney injury (420 patients of 96 226 taking clarithromycin [0.44%] vs 208 patients of 94 083 taking azithromycin [0.22%]; absolute risk increase, 0.22% [95% CI, 0.16%-0.27%]; odds ratio [OR], 1.98 [95% CI, 1.68-2.34]). In a subgroup analysis, the risk was highest with dihydropyridines, particularly nifedipine (OR, 5.33 [95% CI, 3.39-8.38]; absolute risk increase, 0.63% [95% CI, 0.49%-0.78%]). Coprescription with clarithromycin was also associated with a higher risk of hospitalization with hypotension (111 patients of 96 226 taking clarithromycin [0.12%] vs 68 patients of 94 083 taking azithromycin [0.07%]; absolute risk increase, 0.04% [95% CI, 0.02%-0.07%]; OR, 1.60 [95% CI, 1.18-2.16]) and all-cause mortality (984 patients of 96 226 taking clarithromycin [1.02%] vs 555 patients of 94 083 taking azithromycin [0.59%]; absolute risk increase, 0.43% [95% CI, 0.35%-0.51%]; OR, 1.74 [95% CI, 1.57-1.93]).

Conclusions and Relevance — Among older adults taking a calcium-channel blocker, concurrent use of clarithromycin compared with azithromycin was associated with a small but statistically significant greater 30-day risk of hospitalization with acute kidney injury. These findings support current safety warnings regarding concurrent use of CYP3A4 inhibitors and calcium-channel blockers.

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Keywords: Drug interactions Drugs (antibiotics) Drugs (cardiovascular)

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