By; Shelley Wood, Lisa Nainggolan, Sue Hughes
From Heartwire > Alerts. Posted: 09/23/2010
September 23, 2010 (Updated September 24, 2010) (Silver Springs, Maryland and London, United Kingdom) — The US FDA has decided that rosiglitazone (Avandia, GlaxoSmithKline) can remain available, but only under a very stringent restricted-access program. However, the European Medicines Agency (EMA) has recommended the suspension of the marketing authorizations for all rosiglitazone-containing antidiabetes medications licensed in the EU–Avandia, Avandamet, and Avaglim.
“These medicines will stop being available in Europe within the next few months,” the agency said in a statement. “Patients are advised not to stop their treatment without speaking to their doctor. Doctors should stop prescribing rosiglitazone-containing medicines, and patients taking rosiglitazone-containing medicines should be reviewed in a timely manner to amend their treatment.”
As previously reported by heartwire , rosiglitazone has been under mounting scrutiny both in the US and Europe, culminating in an FDA advisory hearing where 12 out of 33 panel members voted to recommend removal of the drug from the US market and an additional 10 panelists voted to recommend that rosiglitazone stay on the market, but with severe restrictions on its use.
In response to both the FDA and EMA statements issued today, GlaxoSmithKline said that the EMA has “stated that the suspension will remain in place unless convincing data are provided that identify a group of patients in whom the benefits of the medicine outweigh its risks.” In the US, all rosiglitazone-containing medicines will remain available with additional safety labeling and restrictions for use, which includes the FDA requiring a risk evaluation and mitigation strategy (REMS) program with additional measures to ensure the safe use of the medicine.
At a telephone press briefing, EMA senior medical officer Prof Hans-Georg Eichler explained that the agency had now concluded that the benefits of rosiglitazone no longer outweighed its risks, so that is why it has decided to suspend the drug. He said the recommendation for suspension would now be passed onto the European Commission, who will make a formal legally binding decision. That would happen in the next couple of weeks. The drug would then not be available anymore. Letters would go out to advise doctors to discuss with patients on a case-by-case basis the best therapeutic alternatives to use.
Eichler noted that a suspension is different from a withdrawal. “Suspension can be a temporary measure. It can be lifted if a company comes up with convincing and robust data that rosiglitazone benefits outweigh its risks in certain populations.”
Asked about the safety profile of pioglitazone, Dunder noted that “there is large probability that the cardiovascular safety of pioglitazone is different from rosiglitazone, and we have biological plausibility to confirm that.” She added that the risk of bladder cancer with pioglitazone has now been raised and is being investigated. “For the time being, there is absolutely no reason to think that bladder cancer is a real risk, but a question has been raised about this, and we are consistently reviewing this with the FDA.”
At an FDA telephone briefing, FDA Commissioner Dr Margaret Hamburg explained that the REMS restriction on rosiglitazone will allow new patients access to the drug only if they are unable to achieve glycemic control using other medications and, in consultation with their healthcare professional, decide not to take pioglitazone for medical reasons. Current users of rosiglitazone will be able to continue using the medication, again through a REMS program, only if they appear to be benefiting from it and they acknowledge that they understand these risks. Doctors will have to attest to and document their patients’ eligibility; patients will have to review statements describing the cardiovascular safety concerns. The FDA’s explanation of its action is also detailed in a “Perspective” published online earlier today in the New England Journal of Medicine.
The agency anticipates that the REMS will limit use of rosiglitazone significantly. Hamburg estimated that about 600 000 patients are currently taking rosiglitazone in the US, but this number is now expected to “fall significantly,” she said. However, the REMS programs will take several months to set up. The rosiglitazone label will also be strengthened to include even stronger warnings of cardiac risk, but Hamburg said that because new label warnings are not always read, the “significant questions” about the drug’s cardiovascular safety justified stronger measures to support good clinical decision making and protect patients–hence the REMS program.
Echoing the EMA’s comments on the different action in Europe, Hamburg said both the FDA and EMA had reached similar conclusions about the safety of rosiglitazone, but the different actions taken reflected different tools available in Europe and the US. She added: “We [the FDA and EMA] are taking somewhat different strategies, but both are trying to ensure the goal of safety.” Dr Janet Woodcock (director, FDA Center for Drug Evaluation and Research) elaborated: “We have a signal of increased cardiovascular risk with rosiglitazone from the meta-analyses, but there is still considerable uncertainty about the existence and magnitude of that risk. Data from randomized studies have not provided enough reassurance that the drug meets the required standard of safety. Therefore, as a matter of prudence, we have decided to restrict access to the drug. But we have heard very clearly from patients and doctors that some patients were unable to tolerate other diabetes medications and this drug was effective for them. Our approach will enable those patients to continue taking rosiglitazone as long as they are fully informed of the risks.”