Antibiotic Clarithromycin May Increase Risk of Death, FDA Warns

On Feb. 22, the Food and Drug Administration (FDA) warned that use of the commonly prescribed antibiotic clarithromycin (BIAXIN, PREVPAC) may increase the risk of heart problems or death years later in patients with heart disease.[1] As a result, the FDA has added a new warning about this risk to the drug’s product labeling and advised health care professionals to consider prescribing other antibiotics for their patients.

Overview of clarithromycin

Initially approved by the FDA in 1991, clarithromycin is a macrolide antibiotic,[2] which belongs to a family of drugs that also includes azithromycin (ZITHROMAX, ZMAX) and erythromycin (E.E.S., E.E.S. 400, ERY-TAB, ERYC, ERYPED, PCE). It is approved for treating a variety of mild-to-moderate acute bacterial infections, including acute bacterial exacerbations of chronic bronchitis in adults, community-acquired pneumonia, ear infections in children, maxillary sinusitis, skin infections and tonsillitis. It also is used in combination with other drugs to treat peptic ulcer disease caused by Helicobacter pylori bacteria.

Clarithromycin is available only in oral formulations. Depending on the infection being treated, the drug is prescribed at doses ranging from 500 to 1500 milligrams (mg) daily for seven to 14 days.

The most frequent adverse reactions of clarithromycin that were seen in clinical trials testing the drug were abdominal pain, diarrhea, nausea, vomiting and abnormal sense of taste. The drug also can cause liver damage, severe allergic reactions, vaginal fungal infections, headache, insomnia and rash.

Clarithromycin, like other macrolide antibiotics, has been linked to an increased risk of QT prolongation, a change in the electrical activity of the heart that can lead to a fatal heart rhythm disturbance called torsades de pointes, resulting in sudden death.[3] Importantly, this heart toxicity occurs in the short term while taking the drug and is evidently not related to the long-term heart risk that is addressed in the FDA’s recent warning.

The FDA warning

The FDA warning is based on a large randomized clinical trial called the CLARICOR trial.[4],[5] The trial was based on the theory that inflammation due to a certain type of bacteria known as Chlamydia pneumoniae may play a role in the development of coronary artery disease.

The CLARICOR trial was conducted in Denmark and involved 4,373 subjects with stable coronary artery disease who previously had been diagnosed with a heart attack or angina (chest pain due to narrowed coronary arteries).[6] The subjects — who were enrolled from 1999 to 2000 — were randomly assigned to a two-week course of either clarithromycin, at a dose of 500 mg, or a placebo once daily. The researchers then obtained data on subjects’ deaths and hospitalizations for cardiovascular disease (such as heart attacks and strokes) for the next consecutive 10 years.

Rather than showing that a twoweek course of clarithromycin was beneficial for patients with coronary artery disease, the trial unexpectedly revealed higher rates of death from any cause and death from cardiovascular disease in subjects who had received clarithromycin than in those who received a placebo.[7] This increased death rate became apparent after the subjects had been followed for one year or longer after their twoweek course of the antibiotic. The FDA observed that “there is no clear explanation for how clarithromycin would lead to more deaths than placebo.”

The FDA also reported that among six published observational studies in patients with or without coronary artery disease, two revealed evidence of an increased long-term risk of death or other serious heartrelated problems associated with clarithromycin use, whereas four did not. The FDA noted, however, that all of the observational studies had limitations and that the randomized CLARICOR trial provided the strongest evidence of an increased risk of death. It is unknown whether this risk with clarithromycin extends to patients without heart disease.

What You Can Do

Tell your health care professionals if you have heart disease, especially when you are being prescribed an antibiotic to treat an infection. If you have heart disease and develop a bacterial infection that requires antibiotic treatment, you should avoid using clarithromycin unless no other suitable antibiotic is available. You should seek medical attention immediately if you ever 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.

References

[1] Food and Drug Administration. 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. February 22, 2018. https://www.fda.gov/Drugs/DrugSafety/ucm597289.htm. Accessed April 5, 2018.

[2] AbbVie. Label: clarithromycin (BIAXIN). June 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/050662s058,050698s038,050775s026lbl.pdf. Accessed April 5, 2018.

[3] Worst Pills, Best Pills. Drug profile: azithromycin (ZITHROMAX, ZMAX); clarithromycin (BIAXIN, BIAXIN-XL, PREVPAC). /monographs/view/250. Accessed April 5, 2018.

[4] Food and Drug Administration. 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. February 22, 2018. https://www.fda.gov/Drugs/DrugSafety/ucm597289.htm. Accessed April 5, 2018.

[5] Winkel P, Hilden J, Hansen JF, 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. Int J Cardiol. 2015 Mar 1;182:459-465.

[6] 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(7532):22-27.

[7] Food and Drug Administration. 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. February 22, 2018. https://www.fda.gov/Drugs/DrugSafety/ucm597289.htm. Accessed April 5, 2018.