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Original Investigation |

Calcium-Channel Blocker–Clarithromycin Drug Interactions and Acute Kidney Injury

Sonja Gandhi, BSc1,2; Jamie L. Fleet, BHSc1; David G. Bailey, BScPhm, PhD3; Eric McArthur, MSc1,4; Ron Wald, MD5; Faisal Rehman, MD1; Amit X. Garg, MD, PhD1,2,3,4
[+] Author Affiliations
1Division of Nephrology, Department of Medicine, Western University, London, Canada
2Department of Epidemiology and Biostatistics, Western University, London, Canada
3Lawson Health Research Institute, London Health Sciences Centre, London, Canada
4Institute for Clinical Evaluative Sciences, Ontario, Canada
5Division of Nephrology, Department of Medicine, St Michael’s Hospital and University of Toronto, Toronto, Canada
JAMA. 2013;310(23):2544-2553. doi:10.1001/jama.2013.282426.
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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 (n = 96 226) or azithromycin (n = 94 083) 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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Figure 1.
Clarithromycin With Each Type of Calcium-Channel Blocker and the Risk of Acute Kidney Injury

The outcome was 30-day hospitalization with acute kidney injury assessed by diagnostic codes. The referent group was patients with evidence of azithromycin coprescription. NS indicates nonsignificant; NR, not reportable for reasons of small cell size; NNH, number needed to harm; and OR, odds ratio. Data marker size is proportional to the inverse of the source variance.aCell sizes less than 6 were not reported for reasons of privacy. Accordingly, the NNH is not presented and an OR assuming 5 events in the reference group is presented. This may overestimate the true rate.bNonsignificant NNH not presented due to the difficulty in interpreting a negative value.

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Figure 2.
Chronic Kidney Disease, Statin Use, and the Risk of Acute Kidney Injury From Coprescription

The outcome was 30-day hospitalization with acute kidney injury assessed by diagnostic codes. The referent group was patients with evidence of azithromycin coprescription. Data marker size is proportional to the inverse of the source variance. CKD indicates chronic kidney disease; NNH, number needed to harm; and OR, odds ratio.

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