News:FDA Requires Stronger Heart Failure Warning for Avandia and Actos
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August 16, 2007 By Erin Lord [1]
Boston, MA, USA: The U.S. Food and Drug Administration announced on Tuesday that it will require the entire thiazolidinedione class of antidiabetic drugs to have stronger warnings on their labels, notifying users of the increased risk of heart failure associated with the drugs. The information will be provided through a black-box warning, which is the strongest label warning required by the FDA.
Drugs included in the thiazolidinedione class of antidiabetic drugs include: Avandia (rosiglitazone), Actos (pioglitazone), Avandamet (rosiglitazone and metformin), Duetact (pioglitazone and glimepiride), and Avandaryl (rosiglitazone and glimepiride). The drugs’ manufacturers, GlaxoSmithKline and Takeda, have agreed to add the warnings.
Since at least 2002, the labels for all products containing rosiglitazone or pioglitazone have instructed medical professionals to monitor patients on these drugs for symptoms of heart failure. The labels also warned about the risk of fluid retention, which can lead to or worsen heart failure.
After FDA reviewed postmarketing adverse event reports, cases of significant weight gain and edema were discovered. In some cases, patients continued with their therapy and experienced negative outcomes, including death. These revelations provoked the agency to conclude that the black-box warnings on the drugs labels are necessary.
“This new boxed warning addresses FDA’s concerns that despite the warnings and information already listed in the drug labels, these drugs are still being prescribed to patients without careful monitoring for signs of heart failure,” the agency said, as cited by the Philadelphia Business Journal. [2]
The black-box warning states that these drugs should not be administered to people with serious heart failure who must limit their activity and who are only comfortable at rest or who are confined to a chair or bed. It also instructs medical professionals to carefully monitor patients for the signs and symptoms of heart failure, which include shortness of breath, edema, and excessive, rapid weight gain. When patients with these symptoms develop heart failure, health care professionals should administer appropriate management of the heart failure and should reevaluate whether the drug should be used.
The warning also informs medical professionals that the existence of New York Heart Association functional class III or IV heart failure is a contraindication to beginning thiazolidinedione therapy.
Despite recent concerns that Avandia may also increase the risk of heart attacks, the black-box warning will not address this issue. This concern was elevated when Cleveland Clinic Cardiologist Steven Nissen published a 42-trial analysis which implied that the use of Avandia carried an increased risk of heart attacks in the June issue of The New England Journal of Medicine.
The article reported that in the rosiglitazone group, when compared with the control group, the odds ratio for myocardial infarction was 1.43 (95% confidence interval [CI], 1.03 to 1.98; P=0.03). Also, the odds ratio for death from cardiovascular causes was 1.64 (95% CI, 0.98 to 2.74; P=0.06) (1).
Despite such findings, the study was limited because of several important reasons. Primarily, a time-to-event analysis could not be performed due to the inability to access original source data. Also, Nissen et al used the results of trials that were not initially intended to investigate cardiovascular outcomes. As a result, the definitions of myocardial infarction were not available, and the majority of trials did not centrally adjudicate cardiovascular outcomes. Many of the trials were small and short-term, which resulted in few adverse cardiovascular events or deaths. Still other trials were excluded due to no events occurring in either treatment group (1).
On July 30, FDA’s Endocrine and Metabolic Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 22-1 to keep Avandia on the market. However, FDA is continuing to investigate Avandia and its possible link to heart attacks.
References
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2. http://www.bizjournals.com/philadelphia/stories/2007/08/13/daily15.html
