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    FDA restricts access to Avandia, cites increased cardiovascular risks

    FDA has determined to significantly restrict the use of formulations that contain rosiglitazone (Avandia, Avandamet, and Avandaryl, GlaxoSmithKline [GSK]) to patients with Type 2 diabetes who cannot control their diabetes with other medications. These new restrictions come in response to evidence suggesting an elevated risk of cardiovascular events, such as heart attack and stroke, in patients treated with rosiglitazone.

    "The FDA is taking this [regulatory] action today to protect patients, after a careful effort to weigh benefits and risks," said FDA Commissioner Margaret A. Hamburg, MD, during a press conference in late September. "We are seeking to strike the right balance to support clinical care."

    REMS requirements

    FDA will allow rosiglitazone to remain on the market, under a risk evaluation and mitigation strategy (REMS) with elements to assure safe use. The REMS program, which GSK is required to develop, must include the following:

    • Provision of complete risk information to all patients and documentation in their medical records that the information was received and understood.
    • Documentation from healthcare providers that all patients receiving rosiglitazone are a) currently taking the drug, or b) not taking the drug and unable to achieve glycemic control with other medications, and decide in consultation with their healthcare providers not to take pioglitazone (Actos, Takeda) for medical reasons.
    • Documentation from healthcare providers that the risk information has been shared with all patients.
    • Physician, patient, and pharmacist enrollment in the REMS program.

    Readjudicating RECORD

    FDA is also requiring GSK to commission an independent readjudication of the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycemia in Diabetes) study, with an initial examination of the mortality finding. If the mortality finding is determined to be valid, then the other elements of combined measure of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death should be readjudicated, according to Janet Woodcock, MD, director of the Center for Drug Evaluation and Research.

    During FDA's review of the RECORD study, questions arose about possible bias in the identification of cardiovascular events. An independent examination of data may yield additional knowledge.

    "Considering the time and effort spent by the thousands of volunteers who participated in RECORD, I believe every effort should be made to learn as much as possible from its results," Dr. Woodcock said.

    Committee uncertainty

    At the July 2010 Advisory Committee meeting, detailed analyses of data on the cardiovascular safety of both rosiglitazone and pioglitazone were presented.

    "Many highly experienced clinical trialists and methodologists, both within and external to FDA, who examined these data, find it hard to arrive at definitive conclusions about the cardiovascular ischemic risk of rosiglitazone, yet they agree that pioglitazone's data do not suggest such a signal of risk. This uncertainty about the risk of rosiglitazone is overwhelmingly the most important reason for the differing opinions on what regulatory action should be taken," Dr. Woodcock said.

    "Allowing Avandia to remain on the market, but under restrictions, is an appropriate response, given the significant concerns and the scientific uncertainty still remaining about this drug."

    Approximately 600,000 patients will be affected by this decision.

    In addition, FDA has halted GSK's clinical trial, TIDE (Thiazolidinedione Intervention With Vitamin D Evaluation), and rescinded all regulatory deadlines for trial completion. The TIDE trial compares rosiglitazone to pioglitazone and to standard diabetes drugs.

    While FDA followed the advice of its advisory panel, which voted in July to allow rosiglitazone to remain on the market, most panelists wanted to see tougher warnings on the diabetes drug's label (see "FDA panel votes to keep Avandia available," Up Front, August 2010).

    The label changes and REMS will take several months to complete, Dr. Hamburg said. "Healthcare providers can talk to their patients about possibly transitioning to another therapy or prepare their patients for REMS implementation."

    On ice in Europe

    The European Medicines Agency (EMA) has decided to suspend marketing authorization for all rosiglitazone-containing medicines (Avandia, Avandamet, and Avaglim). In addition, European physicians are being advised to transition all affected patients to alternative treatment options, according to GSK.

    "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," GSK's press release said.

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