The agency said the move follows its review of a study by medical researchers as well as a company study assessing the drug's potential for causing abnormal changes in the electrical activity of the heart.
Last May, a study in the New England Journal of Medicine compared the risk of cardiovascular death in patients who took Zithromax with those who took several other antibiotics, including amoxicillin. It found that patients who took Zithromax, made by Pfizer Inc, had higher rates of fatal heart rhythms.
Generic versions of Zithromax are also available.
In its warning, the FDA said the drug can alter the electrical activity of the heart, which may lead to a potentially fatal heart rhythm known as prolonged QT interval, in which the timing of the heart's contractions becomes irregular.
The FDA said doctors should use caution when giving the antibiotic to patients known to have this condition or who have certain risk factors. The at-risk group includes people with low levels of potassium or magnesium, a slower-than-normal heart rate, or people who take certain drugs used to treat abnormal heart rhythms, or arrhythmias. The drug could also cause problems in people with torsades de pointes - a specific, rare heart rhythm abnormality.
The FDA noted that other drugs in the same class as azithromycin known as macrolides also have the potential for causing QT prolongation, as do non-macrolide antibiotics, such as fluoroquinolones, and doctors need to consider all of these risks when choosing an antibiotic.
The FDA said it has updated the drug's labels with information about the risk of QT interval prolongation and torsades de pointes.
Pfizer stressed in an emailed statement that most patients will not be affected by this label change, and that other antibiotics in the same class have similar risks.
"Patients who are currently prescribed Zithromax should talk to their doctors or healthcare providers if they have questions regarding their treatment," the company said.
Zithromax, or Zmax, is a popular choice because patients can take fewer doses over a shorter period than many other antibiotics. U.S. sales of the drug in 2011 exceeded $450 million, according to IMS Health.
"Zithromax has had a well-established benefit risk profile for more than 20 years and continues to be an effective treatment option for patients all over the globe suffering from many types of bacterial infections," Pfizer said in the statement.
Shares of Pfizer were down nearly 1 percent at $27.07 in late trading on the New York Stock Exchange.