The European Medicines Agency on Sept. 23 moved to suspend the marketing authorizations for Avandia, Avandamet, and Avaglim, antidiabetes medicines that have increasingly been linked to increased adverse cardiovascular events, including heart attacks.
Courtesy of European Association for the Study of Diabetes
Prof. Clifford Bailey, Prof. David Matthews, Dr. David Kendall and Prof. Ulf Smith discuss the FDA and EMA decisions on rosiglitazone during a press conference on Sept. 23.
Upon legislative action by the European Commission, which is expected within the next few weeks, none of the medicines, all of which contain the drug rosiglitazone and are manufactured by GlaxoSmithKline, will be available anywhere in the European Union.
The EMA’s decision was announced simultaneously to a decision by the U.S. Food and Drug Administration to severely restrict the drug in the United States, but not take it off the market altogether. In a news conference about the decision to suspend, EMA officials said that there had been extensive contact between the U.S. and European agencies on rosiglitazone, and the data used to make the decisions were the same, regardless of the different risk-management strategies adopted.
Dr. Kristina Dunder, and the member of the EMA’s human medicines committee in charge of Avandia (rosiglitazone), Avandamet (rosiglitazone and metformin) and Avaglim (rosiglitazone and glimepiride), said that the agency, considering all available data, now estimated that the drugs were associated with 20%-40% increased risk for cardiovascular events, “depending on baselines.”
EMA officials explained that the two agencies’ different decisions on rosiglitazone were based on the legal tools available to each. “We looked at the possibility of further restricting the use of [rosiglitazone],” Dr. Hans-Georg Eichler, EMA’s senior medical officer, told reporters. Its use, however, “was already very much restricted in Europe.” After an EMA investigation revealed that despite restrictive labeling and warnings, the drug was being prescribed off-label in Europe, the agency concluded that “the best way forward was a suspension,” Dr. Eichler said.
Because the EMA stopped short of revoking the marketing authorizations for the three medicines, opting instead for the ostensibly temporary measure of suspension, the possibility that rosiglitazone might be used in clinical trials remains open. Individual European countries will have to decide whether such trials can proceed, Dr. Eichler said.
Rosiglitazone has had EU marketing authorization since 2000, though its indications have gradually been narrowed because of concerns about cardiovascular risks.
“Since its first authorization, rosiglitazone has been recognized to be associated with fluid retention and increased risk of heart failure, and its cardiovascular safety has always been kept under close review. Consequently, the use of rosiglitazone was restricted to a second-line treatment and contraindicated in patients with heart failure or a history of heart failure,” in 2000, EMA said in a news release explaining its suspension decision. “Data from clinical trials, observational studies and meta-analyses of existing studies that have become available over the last three years have suggested a possibly increased risk of ischaemic heart disease associated with the use of rosiglitazone. Further restrictions on the use of these medicines in patients with ischaemic heart disease were introduced.”
Asked why it took 10 years for the EMA to acquire sufficient data to suspend the drug, Dr. Eichler defended his agency’s actions.
“The difficulty in a situation like this is that we’re looking at a very common adverse event,” he said, saying that though the agency had received “signals” about the drug’s cardiovascular risks from the beginning, such signals were common to nearly every drug, and if heeded, “we’d probably not have a single drug for our patients on the market.”
In the case of a diabetes drug, Dr. Eichler said, it was particularly difficult to determine whether adverse cardiovascular events were the result of the drug or the disease itself. “Evidence accumulates over time, and now sufficient evidence seems to have accumulated,” he said about rosiglitazone’s risks. “Are we happy with the fact that it took 10 years? Of course not.”
Simon O’Neill, a director of care at the health charity Diabetes UK, said in a prepared statement Sept. 23 that his organization was urging people taking rosiglitazone to contact their health care providers as soon as possible, but not to stop taking the medication until meeting with them. “Patient safety is paramount, so we welcome that a decision has been made about Avandia so people can now be supported to change onto an alternative treatment,” O’Neill said. “We would urge the EMA to make swifter decisions in the future to ensure patient safety.”
In a statement released immediately after the FDA announced its decision, Dr. Steven Nissen, the author of the meta-analysis published in 2007 that found an increased risk for myocardial infarction and cardiovascular death associated with treatment, said that both the FDA and EMA decisions will result in essentially the same outcome, and predicted that Avandia “will quickly become a rarely used therapy.”