Clarithromycin associated with adverse outcomes with non-CYP3A4–metabolized statins
Older adults taking a statin that is not metabolized by cytochrome P450 3A4 were at greater risk for adverse outcomes when taking clarithromycin compared with azithromycin, according to recent study data.
The interaction between macrolides and statins has previously been attributed to the inhibition of cytochrome P450 3A4 (CYP3A4), the mechanism of action for most macrolides.
“For this reason, the [FDA] currently warns against the co-administration of strong CYP3A4 inhibitors, including clarithromycin, with CYP3A4-metabolized statins,” researchers from Western University in London, Ontario, wrote in Canadian Medical Association Journal. “However, the inhibition of CYP3A4 cannot explain the increased risk of statin toxicity observed in our study, because we examined interactions with statins not metabolized by CYP3A4.”
In a population-based cohort, the researchers evaluated outcomes among 104,041 patients taking non-CYP3A4-metabolized rosuvastatin (Crestor, AstraZeneca), pravastatin or fluvastatin, who also recently were prescribed clarithromycin or azithromycin, which does not inhibit CYP3A4, from June 2002 to March 2013. They followed the patients for 30 days after the first antibiotic co-prescription to determine patient outcomes.
Co-prescription of clarithromycin with one of the statins was associated with a greater risk for hospital admission with acute kidney injury (RR=1.46; 95% CI, 1.16-1.84), hospital admission with hyperkalemia (RR=1.87; 95% CI, 1.05-3.32) and all-cause mortality (RR=1.32; 95% CI, 1.04-1.62). There were 13 admissions with rhabdomyolysis for clarithromycin and six for azithromycin, but the increased risk was not significant (RR=2.21; 95% CI, 0.84-5.81). The associations persisted after adjustment for 15 different confounders.
“Although the FDA recommends the use of non-CYP3A4–metabolized statins as a safer alternative when taken concurrently with CYP3A4 inhibitors, our finding indicate that unintended adverse events may still occur, possibly because of additional mechanisms of drug interactions independent of the CYP3A4 pathway,” the researchers wrote. “To prevent toxicity, the use of azithromycin or another antibiotic that does not interact with statins can be considered.”
Disclosure: The researchers report relationships with Astellas, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Hoffman-La Roche, Novartis, Novo Nordisk, Pfizer and Roche.