Although the Food and Drug Administration’s decision to keep rosiglitazone on the market with a risk management program in place that preserves some access to the controversial diabetes drug, the plan is expected to squelch most prescribing and therefore, could have an effect that approaches that in Europe, where it will no longer be marketed.
Under a risk evaluation and mitigation strategy (REMS), rosiglitazone will be available only to new patients with type 2 diabetes who are unable to adequately manage their blood glucose on pioglitazone or are unable to take pioglitazone, the only other approved thiazolidinedione (TZD). However, patients who are already taking rosiglitazone may continue if, through the REMS program, they acknowledge their understanding of the drug’s potential cardiac risks, Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, said during a press briefing this week. About 600,000 U.S. patients are taking the drug; Dr. Woodcock said the REMS program will “significantly reduce” that number, while ensuring that those who continue will fully understand its potential risk.
Additionally, the FDA instructed the drug’s manufacturer, GlaxoSmithKline, to commission an independent readjudication of the RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes) trial, which was submitted to the FDA in August 2009 and was undertaken to further explore cardiovascular safety signals seen in earlier trials.
At the same time, the European Medicines Agency announced it was pulling it off the shelves in the European Union, based on the same evidence reviewed by the FDA.
The FDA’s decision reflects the majority opinion of an FDA advisory panel, which in July met to review the cardiovascular safety data of the drug. The majority of the panel members voted to keep the drug on the market but with more warnings and restrictions on its use, but a significant proportion advocated that it should be taken off the market.
Rosiglitazone has been dogged for years by conflicting data on its cardiovascular safety profile and the decision to restrict access came on the heels of an ever-increasing debate about rosiglitazone’s cardiovascular safety. The RECORD trial, sponsored by GlaxoSmithKline, found no increased risk in myocardial infarction, overall death, or cardiovascular death. But several trials came to conflicting conclusions about whether the drug increased the risk of MI; a highly touted 2007 meta-analysis of 42 studies concluded that it increased that risk by up to 43%, and the risk of cardiovascular death by up to 64% (N. Engl. J. Med. 2007;356:2457-71).
The lead author of the meta-analysis, Dr. Steven E. Nissen, a vocal advocate for the withdrawal of rosiglitazone from the market, said in an interview that both the FDA and EMA decisions will result in almost the same outcomes and that rosiglitazone will soon be rarely used.
Even though the FDA did not opt for market withdrawal, the drug in the United States “is essentially off the market,” as long as the REMS is well executed, which he expects it will be. “What you have to actually do in order to prescribe the drug now is you have to say you’ve tried every other diabetes drug, including pioglitazone, and the patient couldn’t tolerate them. There’s nobody that meets that description,” said Dr. Nissen, chairman of the department of cardiovascular medicine, Cleveland Clinic Foundation.
At the July panel meeting, Dr. Nissen told the panel and the FDA that, with another thiazolidinedione available as an alternative (pioglitazone), continued marketing of rosiglitazone could not be medically or ethically justified. But, in the interview, he was positive about the agency’s decision. His message to clinicians is to “stop using the drug, get people on something else, and move on.”
Endocrinologist Clifford Rosen agreed. “This effectively puts an end to rosiglitazone in the United States ... it will be very, very rare to have a patient on rosiglitazone,” said Dr. Rosen, professor of medicine at Tufts University, Boston, and senior scientist at Maine Medical Center, Scarborough. He was among the 10 panel members at the July meeting who voted in favor of allowing continued marketing but with more warnings in the label and restrictions in its use.
The FDA decision “basically puts an end to rosiglitazone prescriptions in the United States,” he said in an interview. “It’s almost impossible for an individual practitioner to write a prescription after spending 20 minutes talking about risk, having the patient sign an informed consent and then filling out forms to send to the FDA. It’s just not going to happen.”
Dr. Rosen added that he expects that most patients who are on the drug now will probably be switched to other drugs. “Maybe a few people who have been on it for a long time, feel great, and have good glucose control might stay on it, but those individuals still need to have full informed consent and have the risks explained to them.”