The risk of hypotension following co-prescription of macrolide antibiotics and calcium-channel blockers

Background The macrolide antibiotics clarithromycin and erythromycin may potentiate calcium-channel blockers by inhibiting cytochrome P450 isoenzyme 3A4. However, this potential drug interaction is widely underappreciated and its clinical consequences have not been well characterized. We explored the risk of hypotension or shock requiring hospital admission following the simultaneous use of calcium-channel blockers and macrolide antibiotics.

Methods We conducted a population-based, nested, case-crossover study involving people aged 66 years and older who had been prescribed a calcium-channel blocker between Apr. 1, 1994, and Mar. 31, 2009. Of these patients, we included those who had been admitted to hospital for the treatment of hypotension or shock. For each antibiotic, we estimated the risk of hypotension or shock associated with the use of a calcium blocker using a pair-matched analytic approach to contrast each patient’s exposure to each macrolide antibiotic (erythromycin, clarithromycin or azithromycin) in a seven-day risk interval immediately before admission to hospital and in a seven-day control interval one month earlier.

Results Of the 7100 patients admitted to hospital because of hypotension while receiving a calcium-channel blocker, 176 had been prescribed a macrolide antibiotic during either the risk or control intervals. Erythromycin (the strongest inhibitor of cytochrome P450 3A4) was most strongly associated with hypotension (odds ratio [OR] 5.8, 95% confidence interval [CI] 2.3–15.0), followed by clarithromycin (OR 3.7, 95% CI 2.3–6.1). Azithromycin, which does not inhibit cytochrome P450 3A4, was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8–2.8). We found similar results in a stratified analysis of patients who received only dihydropyridine calcium-channel blockers.

Interpretation In older patients receiving a calcium-channel blocker, use of erythromycin or clarithromycin was associated with an increased risk of hypotension or shock requiring admission to hospital. Preferential use of azithromycin should be considered when a macrolide antibiotic is required for patients already receiving a calcium-channel blocker.