title: Calcium-channel blocker-clarithromycin drug interactions and acute kidney injury.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
  
  
  METHODS
  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
  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.
authors.affiliation: Division of Nephrology, Department of Medicine, Western University, London, Canada2Department of Epidemiology and Biostatistics, Western University, London, Canada.
authors.forename: Sonja
authors.initials: S
authors.lastname: Gandhi
authors.affiliation: Division of Nephrology, Department of Medicine, Western University, London, Canada.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Fleet
authors.affiliation: Lawson Health Research Institute, London Health Sciences Centre, London, Canada.
authors.forename: David G
authors.initials: DG
authors.lastname: Bailey
authors.affiliation: Division of Nephrology, Department of Medicine, Western University, London, Canada4Institute for Clinical Evaluative Sciences, Ontario, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: McArthur
authors.affiliation: Division of Nephrology, Department of Medicine, St Michael's Hospital and University of Toronto, Toronto, Canada.
authors.forename: Ron
authors.initials: R
authors.lastname: Wald
authors.affiliation: Division of Nephrology, Department of Medicine, Western University, London, Canada.
authors.forename: Faisal
authors.initials: F
authors.lastname: Rehman
authors.affiliation: Division of Nephrology, Department of Medicine, Western University, London, Canada2Department of Epidemiology and Biostatistics, Western University, London, Canada3Lawson Health Research Institute, London Health Sciences Centre, London, Canada4Institute for Clinical Evaluative Sciences, Ontario, Canada.
authors.forename: Amit X
authors.initials: AX
authors.lastname: Garg
mesh_terms: D000208:Acute Disease; D058186:Acute Kidney Injury / Q000139:chemically induced*; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects*; D017963:Azithromycin / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000627:therapeutic use*; D017291:Clarithromycin / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000097:blood / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D010818:Practice Patterns, Physicians'; D012189:Retrospective Studies; D012306:Risk
chemical_list: D000900:Anti-Bacterial Agents; D002121:Calcium Channel Blockers; D017963:Azithromycin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017291:Clarithromycin