Increased risk of adverse events with clarithromycin-statin combinations

Last Updated: 2014-12-22

By Will Boggs MD

NEW YORK (Reuters Health) - Older adults prescribed clarithromycin and statins face an increased risk of adverse events, according to a database study.

"This an uncommon but preventable cause of patient suffering that may be avoided when drugs that have the potential to interact are not prescribed together," Dr. Amit X. Garg from Western University, London, Ontario, Canada told Reuters Health by email.

Previous work has shown that statin toxicity increases with higher blood statin concentrations, which, in turn, have been linked to inhibition of the drug-metabolizing enzyme cytochrome P450 3A4 (CYP3A4).

Recent evidence suggests that reduced drug-transporter mediated hepatic uptake of statins resulting from polymorphisms in OATP1B1 can also increase statin levels, and the macrolide antibiotic clarithromycin has been shown to inhibit OATP1B1.

Dr. Garg and colleagues compared the risk of statin-associated adverse events when rosuvastatin, pravastatin, or fluvastatin is coprescribed with clarithromycin (or azithromycin, which does not affect OATP1B1 or CYP3A4).

Using five large administrative databases, they identified 104,041 individuals, including 51,523 who received clarithromycin and 52,518 who received azithromycin. In each case the antibiotic was given in combination with rosuvastatin (76%), pravastatin (21%), or fluvastatin (3%).

Compared with azithromycin, coprescription of clarithromycin with a study statin was associated with a significant 46% increased risk of hospital admission with acute kidney injury, 87% increased risk of hospital admission with hyperkalemia, and 32% increased risk of all-cause mortality, the authors reported in a paper released December 22 by CMAJ.

These differences persisted after adjustment for potentially confounding factors.

The absolute increases in risk, however, were quite small. Even if the increased incidence were magnified five-fold, the researchers say, the absolute increase in risk for each outcome would remain below 1 percentage point.

"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," the investigators note.

"To prevent toxicity," they say, "the use of azithromycin or another antibiotic that does not interact with statins can be considered."

Dr. Garg suggested that "drug prescribing references and clinical practice guidelines can mention this uncommon but severe side effect when this set of statins is prescribed with an interacting drug such as clarithromycin."

SOURCE: http://bit.ly/1AYiktR

CMAJ 2014.