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FDA Issues New Safety Communication on Clarithromycin Use in Patients with Heart DiseasePublished March 1, 2018

On February 22nd, the Food & Drug Administration (FDA) issued a new drug safety communication to health care providers regarding the long-term risks of clarithromycin use in patients with heart disease.  Clarithromycin is a macrolide antibiotic used for treatment of a variety of respiratory tract and skin infections, and infections caused by Helicobacter pylori and non-tuberculous mycobacteria (e.g., Mycobacterium avium complex).

FDA initially issued a safety communication regarding clarithromycin in December 2005 based on results of the CLARICOR Study published in the British Medical Journal.  The original intent of the CLARICOR Study was to determine the effect of a 14-day course of clarithromycin on the composite outcome of all-cause mortality, myocardial infarction, or unstable angina in patients with stable coronary artery disease (CAD) when compared to placebo.

The study investigators found no difference in the composite outcome between the study groups (15.8% in the clarithromycin group vs. 13.8% in the placebo, p = 0.08).  However, the rates of all-cause mortality (9.8% vs. 7.8%, p = 0.03) and cardiovascular mortality (5.1% vs. 3.4%, p = 0.01) after a mean follow-up of 2.6 years were significantly higher in the clarithromycin group compared to the placebo group.  The increased risk of cardiovascular mortality from clarithromycin remained after multivariate analysis [hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.03-1.85, p = 0.03).  The higher risk of death associated with clarithromycin use in this study was unexpected.  Both the study investigators and FDA were unable to determine the mechanism by which clarithromycin caused an increased in mortality in this patient population.  At that time, the FDA did not make any specific recommendations regarding the use of clarithromycin or change the product labeling for this antibiotic.

The more recently released FDA drug safety communication on clarithromycin was prompted by additional data from a 10-year follow-up of the CLARICOR Study published in the International Journal of Cardiology.  The study found that clarithromycin use tended to increase all-cause mortality (HR 1.10, 95% CI 1.00-1.21, p = 0.054) and significantly increased cerebrovascular disease (HR 1.19, 95% CI 1.02-1.38, p = 0.025) over the 10 years.  When stratified by statin use, all-cause mortality was significantly higher for patients who received clarithromycin but was not receiving statin at study entry (HR 1.19, 95% CI 1.04-1.31, = 0.010).  Based on these data, the FDA has added a new warning about the increased risk of death in patients with heart disease and advised prescribers to consider using other antibiotics in this patient population.

For prescribers who are contemplating whether to prescribe clarithromycin, the following questions should be considered:

Does the patient have a history of heart disease?

Does the patient have an infection and that this infection require the use of clarithromycin?

Can an alternative antibiotic be used in place of clarithromycin (e.g., azithromycin)?

If clarithromycin must be used, is the shortest possible duration being prescribed?

Does the patient have impaired renal functions (e.g., creatinine clearance <30 mL/min) that would necessitating dose adjustment of clarithromycin?

Is the patient on another medication that could potentially interact with clarithromycin, resulting in higher systemic concentration of clarithromycin?

For additional details on the FDA drug safety communication and the CLARICOR study and follow-up, click on the links above.

Written by Phil Chung, PharmD, MS, BCPS

Page last reviewed: November 8, 2018