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Storm surrounding rosiglitazone is not over
Prominent physicians discuss the aftermath of the FDA advisory panel meeting on rosiglitazone.
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The FDA review of rosiglitazone and the diabetes drug’s possible increased risk of cardiovascular events are ongoing, but the controversy surrounding rosiglitazone is still at the forefront.
On July 30, the joint FDA Endocrinologic Metabolic Drugs and Drug Safety and Risk Management advisory panels voted 20-3 that rosiglitazone (Avandia, GlaxoSmithKline) is associated with a clearly increased risk of cardiac ischemic events. In a second vote the committee recommended 22-1 that rosiglitazone continue to be marketed.
“There was enough evidence [presented] to suggest there is a signal for ischemic risks related to rosiglitazone,” Clifford J. Rosen, MD, acting chair of the FDA Advisory Committee, told Endocrine Today. “Now, we are really looking for more data to support that this is such a risk that we really need to pull it off the market.”
The controversy started when Steven E. Nissen, MD, and Kathy Wolski, MPH, a statistician at The Cleveland Clinic, conducted a meta-analysis that pointed to a 43% increased risk of myocardial infarction among patients who used rosiglitazone. This information was published in The New England Journal of Medicine in late May.
There was a disconnect of sorts at the FDA meeting, according to Rosen.
“To have a committee vote 20 to 3 that the drug was a risk but vote 22 to 1 that the drug should stay on the market, a lot of people find that a little hard to understand,” Nissen, chairman of the department of cardiovascular medicine, Cleveland Clinic, said in an interview.
Strong opinions
Although he was disappointed that the committee did not recommend rosiglitazone be withdrawn, Nissen said that after the meeting his stand is now stronger.
“All I had was a study-level analysis where I just took limited data that [were] available,” he said. “We now know that a much more fundamental analysis, done rigorously, confirmed our concerns.”
An FDA meta-analysis presented at the advisory committee meeting confirmed a 40% increased cardiovascular risk. Furthermore, a meta-analysis by Glaxo SmithKline verified a 31% increased risk associated with rosiglitazone.
“Patients and providers deserved to know what those findings were,” Nissen said. “It meant we had to take some criticism, which is fine, but I think it is good to know that the FDA got the same answer. I obviously will have an open mind, but I think that the chances that the drug is not harmful to the cardiovascular system are very low.”
GlaxoSmithKline was pleased with the panel’s recommendation to support the continued availability of rosiglitazone.
“This [was] the first opportunity for these scientific experts to review the full data behind Avandia. The committee recognizes the debilitating nature of this disease and the importance of multiple treatment options,” Ronald Krall, MD, chief medical officer, GlaxoSmithKline, said in a release.
New black-box warning
Many panelists suggested the rosiglitazone label contain a black-box warning and special indications for subgroups of patients who may be at even more increased risk – patients with congestive heart failure, who take rosiglitazone and insulin, the elderly and those using nitrates long-term.
Less than one month after the meeting, rosiglitazone and pioglitazone (Actos, Takeda) started including a black-box warning on the label. The FDA determined that the warning was needed for all thiazolidinediones, including glimepiride (Avandaryl), rosiglitazone and metformin (Avandamet) and pioglitazone and glimepiride (Duetact).
“This new boxed warning addresses the 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,” Steven Galson, MD, MPH, director of the FDA’s Center for Drug Evaluation and Research, said in a press release.
The warning advises patients and physicians to be aware of signs of heart failure while using TZDs, such as rapid weight gain, shortness of breath and edema. It also notes that TZDs are not recommended in patients with symptomatic heart failure, and that TZD use in patients with established NYHA Class III or IV heart failure is contraindicated, according to GlaxoSmithKline officials.
Information about congestive heart failure has been included in the prescribing information for rosiglitazone since 1999, when it was first approved by the FDA. Since 2001, the prescribing information has included a warning for “Cardiac Failure and Other Cardiac Effects” with a recommendation that use of rosiglitazone be discontinued in patients if their cardiac status worsened, according to a press release.
The black-box warning is a step in the right direction, according to Nissen; however, he said it is still not enough.
Part of something bigger
“The controversy surrounding rosiglitazone and the difficulty coming to a clear-cut conclusion was really a reflection of the disorganized way in which drug safety is being handled,” Richard Hellman, MD, president of AACE, told Endocrine Today. “This was just one specific example, though a painful example.”
Since the publication of Nissen and Wolski’s meta-analysis, the number of reports of adverse events associated with rosiglitazone has tripled, according to Hellman. The major problem is the shortcomings of the national post-approval drug safety surveillance, he said.
“We have no idea about most events taking place because no one is reporting them,” he said.
Hellman testified during the open public hearing at the meeting and recommended to make drug safety a collective responsibility by increasing FDA funding for post-approval drug safety; increasing the involvement of physician, patient and allied health groups; and increasing the budget and responsibility for research of randomized controlled trials and case-controlled and epidemiologic studies.
Since the FDA meeting, there already have been some changes in behavior by the FDA, according to Nissen. For example, the agency recently issued a concern about increased cardiovascular risk associated with proton pump inhibitors. – by Katie Kalvaitis