Clarithromycin may cause serious adverse events when taken with certain statins

Clarithromycin may cause serious adverse events when taken with rosuvastatin, pravastatin, or fluvastatin, according to a new study.

Researchers used large health care databases to determine whether increased frequency of adverse events was seen when clarithromycin, which inhibits cytochrome P450 3A4 (CYP3A4), was taken with a statin that CYP3A4 does not metabolize. Included patients were from a population-based cohort who were taking rosuvastatin, pravastatin, or fluvastatin and received a new prescription of clarithromycin or azithromycin between 2002 and 2013. Because azithromycin does not inhibit CYP3A4, patients prescribed this drug served as the control group. The study's primary outcomes, all in 30 days after co-prescription, were hospital admission for rhabdomyolysis, acute kidney injury, or hyperkalemia, all based on diagnostic codes, and all-cause mortality. The study results were published early online Dec. 22 by CMAJ.

Overall, 104,041 people were included in the study, 51,523 in the clarithromycin group and 52,518 in the azithromycin group. Seventy-six percent of patients were prescribed rosuvastatin (76%), 21% were prescribed pravastatin, and 3% were prescribed fluvastatin. The median dosage of clarithromycin and azithromycin was 1,000 mg/d for 10 days and 300 mg/d for 5 days, respectively. Patients who were prescribed both clarithromycin and 1 of the 3 studied statins had a higher risk of hospital admission with acute kidney injury (adjusted relative risk, 1.65; 95% CI, 1.31. to 2.09) and hyperkalemia (adjusted relative risk, 2.17; 95% CI, 1.22 to 3.86), as well as all-cause mortality (adjusted relative risk, 1.43; 95% CI, 1.15 to 1.76), compared with patients in the control group. No statistically significant increase in relative risk was seen for hospital admission with rhabdomyolysis (adjusted relative risk, 2.27; 95% CI, 0.86 to 5.96).

The authors noted that the absolute risk increase for each of the primary outcomes was small. In addition, they pointed out that their findings may not have been causal, that some confounding variables may not have been measured, and that their results apply only to older adults. However, they concluded that the combination of clarithromycin and a statin that is not metabolized by CYP3A4 is associated with a modest increase in deaths and hospital admissions due to adverse events. “Although the US FDA recommends the use of non-CYP34-metabolized statins as a safer alternative when taken concurrently with CYP3A4 inhibitors, our findings indicate that unintended adverse events may still occur, possibly because of additional mechanisms of drug interactions independent of the CYP3A4 pathway,” the authors wrote. “To prevent toxicity, the use of azithromycin or another antibiotic that does not interact with statins can be considered.”