FDA restricts rosiglitazone use

European Medicines Agency suspends marketing authorization.

The FDA has announced that it will restrict use of rosiglitazone to patients with type 2 diabetes who cannot control their diabetes with other medications.

In a separate announcement, the European Medicines Agency (EMA) has recommended suspending the marketing authorization of all rosiglitazone-containing antidiabetes medicines, including Avandia, Avandamet and Avaglim. Plans to phase out the drug's availability in Europe within the next few months are in place.

These new restrictions are in response to data that suggest an elevated risk of cardiovascular events, such as myocardial infarction and stroke, in patients treated with rosiglitazone (Avandia, GlaxoSmithKline).

"Both the FDA and the EMA have evaluated the same evidence and reached similar conclusions. Our different approaches in part reflect differences in the tools we have available to manage [the] risk and benefits of [the] medication," Margaret A. Hamburg, MD, FDA commissioner, said during a conference call.

Changes for physicians, patients

Rosiglitazone (Avandia, GlaxoSmithKline) will still be available in the United States, but the FDA will require GlaxoSmithKline to develop a restricted access program for the drug under a Risk Evaluation and Mitigation Strategy. Under the strategy, current rosiglitazone users who are benefiting from the drug will be able to continue taking it. Only patients who could not achieve glucose control with other medications and are unable to take pioglitazone (Actos, Takeda) will be able to take rosiglitazone.

As previously reported by Endocrine Today, the FDA announced it would be evaluating preliminary results from a long-term, observational study suggesting patients who were taking pioglitazone may be at increased risk for bladder cancer. As of press time, no association had been confirmed.

“However, because of concerns of cardiovascular ischemia, physicians and health care professionals may want to consider switching patients to a different medication,” Joshua Sharfstein, MD, FDA principal deputy commissioner, said during the call.

In all cases, physicians must attest to and document their patients’ eligibility for taking the drug, and patients must review statements regarding the CV safety of rosiglitazone and acknowledge they understand the risks.

Both agencies’ decisions come in light of reviews that linked the medicines with an elevated risk for adverse CV events. Previous clinical trials, observational studies and meta-analyses of existing research from the past 3 years denoted a potential association between the medications and increased risk for ischemic heart disease, heart failure and fluid retention. Consequently, restrictions for the medications’ use in people with HF or a history of HF were implemented after market approval.

The FDA also ordered GlaxoSmithKline to convene an independent group of scientists to review key aspects of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial, which compared the CV safety of rosiglitazone to other diabetes drugs. An earlier review noted a potential bias in the identification of CV events. In July, the U.S. Senate Committee on Finance accused GlaxoSmithKline of withholding scientific data pertaining to the drug.

Further, the FDA halted the company’s Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) trial, which compared rosiglitazone with pioglitazone and other diabetes drugs, and rescinded all regulatory deadlines for the completion of the trial.

In Europe, the EMA said it could not pinpoint further measures that would reduce CV risk. Unless GlaxoSmithKline can offer solid evidence that identifies a patient population in whom the drugs’ benefits would outweigh the risks, the suspension will hold. The European Commission has also been notified of the committee’s recommendation for the adoption of a legally binding decision. The EMA also advises patients who are currently taking these medications to consult their physicians to find alternative treatments. They should not, however, discontinue treatment before speaking with their doctors.

Organizations weigh in

The American Diabetes Association, Endocrine Society and American Association of Clinical Endocrinologists urge patients who are currently taking rosiglitazone or any combination pill that includes rosiglitazone to contact their diabetes care provider's office for instructions about treatment options. Patients should be aware that stopping a diabetes medication without consulting a doctor can result in higher levels of blood glucose that may cause serious short-term health problems and could increase the risk for long-term diabetes-related complications.

Patients and health care professionals should also be aware that multiple classes of drugs, often with more than one agent per class, are available to achieve and maintain glucose control in type 2 diabetes. In order to limit the risk of long-term complications, optimal glucose control, along with control of other risk factors, such as high blood pressure and cholesterol, is critically important for patients with type 2 diabetes. A number of other medications can be used to control diabetes and should be discussed with a patient's health care team.

Company response

"Our primary concern continues to be patients with type 2 diabetes and we are making every effort to ensure that physicians in Europe and the United States have all the information they need to help them understand how these regulatory decisions affect them and their patients," Ellen Strahlman, chief medical officer of GlaxoSmithKline, said in a press release.

GlaxoSmithKline said it will work closely with other regulatory agencies to comply with any decisions made by them regarding rosiglitazone-containing medicines. The company will voluntarily cease promotion of rosiglitazone in all countries in which it operates and will continue to respond to requests for information and support from health care professionals and patients.

I do not think this is the end of thiazolidinediones, but they will clearly be relegated to third- or fourth-line status. An ongoing trial with rosiglitazone is continuing and, frankly, I think the EMA was too draconian in its decision to suspend rosiglitazone. Although I do not totally agree with the FDA decision, given the political climate I think it was the most fair decision

– George Bakris, MD

Endocrine Today Editorial Board member

Rightly or wrongly, Avandia's day is over; it had already dwindled over the past few years. More worrisome is the demand for absolute proof of CV safety, which will be carried out in diabetic patients at much higher risk than those for whom we truly believe that glycemic control will matter. We will establish lack of harm for coming agents in patients with advanced diabetes and already existing CVD, but we will be distracted from establishing truly innovative approaches to reducing the burden of the disease.

– Zachary T. Bloomgarden, MD

Endocrine Today Editorial Board member

This has been a multi-year battle and I am pleased with the outcome. It comes too late for many patients, however. Over the decade plus that this drug has been available, many patients have been harmed. The reluctance of the agency to act promptly when this issue came up is in many ways tragic, but we did eventually get an outcome that is reasonable. Rosiglitazone is basically dead. It is not available in Europe, many other countries around the world are moving to remove it and the company has announced that it will stop promoting the drug. We are left with a drug that is technically still on the market, but has been so severely curtailed that really patients aren't going to get it - and that's a good thing.

– Steven E. Nissen, MD

Chairman, Department of Cardiovascular Medicine,
Cleveland Clinic Foundation

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