This recommendation is based on the FDA's review of 10 years of followup data from the large CLARICOR clinical trial involving short-term clarithromycin use in patients with stable coronary heart disease. It was during that initial placebo-controlled trial that these adverse events were first observed.
"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," said the agency in its safety announcement. "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."
According to the FDA announcement, the original CLARICOR trial saw an unexpected increase in deaths among patients with coronary heart disease who received a two-week course of clarithromycin compared with placebo, which became apparent after patients had been followed for one year or longer. Those findings prompted a safety alert from the agency at the time. No clear reason for why clarithromycin would contribute to more deaths than placebo was identified.
Increases in both cardiovascular and all-cause mortality were seen with clarithromycin use, according to the followup study. "Clarithromycin tended to increase all-cause mortality in all participants over the 10 years, an effect that was significant in patients not on statin treatment at entry but not in those on statin at entry," the researchers reported. Similarly, the risk for cerebrovascular disease was also heightened significantly in patients not using statins at study entry but not in those taking statin drugs.
Agency officials also said mixed results were seen in observational studies that examined this topic, all of which had design limitations. Of the six observational studies in patients with or without coronary artery disease published to date, two studies found evidence of long-term risks from clarithromycin and four didn't.
Overall, the CLARICOR trial provided the strongest evidence of the increase in risk compared with the observational study results, the FDA announcement stated, although causation remains a mystery. "Based on these studies, we were unable to determine why the risk of death is greater for patients with heart disease," the agency said.
No prospective, randomized and controlled trials with prespecified long-term safety outcome measures following clarithromycin treatment in patients without heart disease have been conducted, FDA officials observed.
"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," the safety announcement said.
The FDA said 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."
Furthermore, the agency said clinicians should educate patients with heart disease about how to recognize the signs and symptoms of cardiovascular problems, regardless of the medical condition for which they are being treated with clarithromycin. Patients should seek medical attention immediately if they 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 their body, or slurred speech.
The FDA also reminded patients that it's important to tell their health care professionals whether they have heart disease, especially when they are being prescribed antibiotics for infection.
Additionally, the agency said patients need to understand that they shouldn't stop taking their heart disease medication or any antibiotic prescribed for them without first speaking with their family physician.
Finally, the agency advised health care professionals and patients to report side effects associated with clarithromycin and other drugs to the FDA MedWatch program.