Improving FDA Health Communications with Older Women Regarding FDA-Regulated Products (CDER)

FDA Drug Safety Communication
FDA review finds additional data supports the potential for increased long-term risks with
antibiotic clarithromycin (Biaxin) in patients with heart disease
Safety Announcement
[02-22-2018] The U.S. Food and Drug Administration (FDA) is advising caution before
prescribing the antibiotic clarithromycin (Biaxin) to patients with heart disease because of a
potential increased risk of heart problems or death that can occur years later. Our
recommendation is based on our review of the results of a 10-year follow-up study1 of patients
with coronary heart disease from a large clinical trial2 that first observed this safety issue.
As a result, we have added a new warning about this increased risk of death in patients with heart
disease, and advised prescribers to consider using other antibiotics in such patients. We have
also added the study results to the clarithromycin drug labels. As part of FDA’s usual ongoing
safety monitoring of drugs, we are continuing to monitor safety reports in patients taking
clarithromycin.
Health care professionals should be aware of these significant risks and weigh the benefits and
risks of clarithromycin before prescribing it to any patient, particularly in patients with heart
disease and even for short periods, and consider using other available antibiotics. Advise
patients with heart disease of the signs and symptoms of cardiovascular problems, regardless of
the medical condition for which you are treating them with clarithromycin.
Patients should tell your health care professionals if you have heart disease, especially when you
are being prescribed an antibiotic to treat an infection. Talk to them about the benefits and risks
of clarithromycin and any alternative treatments. Do not stop taking your heart disease medicine
or antibiotic without first talking to your health care professionals. Doing so could be harmful
without your health care professionals’ direct supervision. Seek medical attention immediately if
you experience symptoms of a heart attack or stroke, such as chest pain, shortness of breath or
trouble breathing, pain or weakness in one part or side of your body, or slurred speech.
Like other antibiotics, clarithromycin is used to treat many types of infections affecting the skin,
ears, sinuses, lungs, and other parts of the body, including Mycobacterium avium complex
(MAC) infection, a type of lung infection that often affects people with human
immunodeficiency virus (HIV). Clarithromycin is not approved to treat heart disease. The drug
has been used for more than 25 years, and is sold under the brand name Biaxin and as generics
by many different drug companies. It works by stopping the growth of bacteria. Without
treatment, some infections can spread and lead to serious health problems.

The large clinical trial, called the CLARICOR trial2, observed an unexpected increase in deaths
among patients with coronary heart disease who received a two-week course of clarithromycin
that became apparent after patients had been followed for one year or longer. There is no clear
explanation for how clarithromycin would lead to more deaths than placebo. Some observational
studies also found an increase in deaths or other serious heart-related problems, while others did
not. All the studies had limitations in how they were designed. Of the six observational studies
published to date in patients with or without coronary artery disease, two found evidence of longterm risks from clarithromycin3,4, and four did not5,6,7,8. Overall, results from the prospective,
placebo-controlled CLARICOR trial provide the strongest evidence of the increase in risk
compared to the observational study results. Based on these studies, we were unable to
determine why the risk of death is greater for patients with heart disease.
Furthermore, there are no prospective, randomized, and controlled trials with prespecified longterm safety outcome measures following clarithromycin treatment in patients who do not have
heart disease. Because we currently do not have study information in these patients, and
observational studies have shown different results, we cannot determine whether results of the
CLARICOR trial can be applied to patients who do not have heart disease.
We previously communicated about this safety issue in December 2005, before the 10-year
follow-up results were available for CLARICOR.
We urge health care professionals and patients to report side effects involving clarithromycin and
other drugs to the FDA MedWatch program, using the information in the “Contact FDA” box at
the bottom of the page.
References
1. Winkel P, Hilden J, Fischer Hansen J, et al, Clarithromycin for stable coronary heart
disease increases all-cause and cardiovascular mortality and cerebrovascular morbidity
over 10 years in the CLARICOR randomised, blinded clinical trial. International Journal
of Cardiology 2015; 182:459-465.
2. Jespersen CM, Als-Nielsen B, Damgaard M, et al. Randomised placebo controlled
multicenter trial to assess short term clarithromycin for patients with stable coronary
heart disease: CLARICOR trial. BMJ 2006;332:22-7.
3. Schembri S, Williamson PA, Short PM, et al. Cardiovascular events after clarithromycin
use in lower respiratory tract infections: analysis of two prospective cohort studies. BMJ
2013 Mar 20;346:f1235. doi: 10.1136/bmj.f1235.
4. Mosholder AD, Lee JY, Zhou EH, et al. Long-term risk of acute myocardial infarction,
stroke and mortality in adult outpatients treated with clarithromycin: a retrospective
cohort study in the Clinical Practice Research Datalink. Journal of Epidemiology,
kwx319, https://doi.org/10.1093/aje/kwx319.
5. Andersen SS, Hansen ML, Norgaard, ML, et al. Clarithromycin use and risk of death in
patients with ischemic heart disease. Cardiology 2010;116:89-97.
6. Root AA, Wong AY, Ghebremichael-Weldeselassie Y, et al. Evaluation of the risk of
cardiovascular events with clarithromycin using both propensity score and self-controlled
study designs. Br J Clin Pharmacol 2016 Aug;82(2):512-21.

7. Wong AY, Root A, Douglas IJ, et al. Cardiovascular outcomes associated with use of
clarithromycin: population based study. BMJ 2016 Jan 14;352:h6926. doi:
10.1136/bmj.h6926.
8. Inghammar M, Nibell O, Pastemak B, Melbye M, Svanstrӧm H, Hviid A. Long term risk
of cardiovascular death with use of clarithromycin and roxithromycin - a nationwide
cohort study. Am J Epidemiol 2017; Nov 16: doi: 10.1093/aje/kwx359 [Epub ahead of
print].
Related Information
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Clarithromycin (marketed as Biaxin) Information
Clarithromycin (by mouth)
The FDA’s Drug Review Process: Ensuring Drugs are Safe and Effective
Think It Through: Managing the Benefits and Risks of Medicines