FDA Advisers Recommend New Controls on Rosiglitazone Use

[August 15, 2010, AJHP News]

Kate Traynor

GAITHERSBURG, MD 30 July 2010—A majority of advisers to FDA recommended that the agency restrict the use of rosiglitazone or ban the drug altogether to minimize the risk of ischemic cardiovascular adverse events in patients with type 2 diabetes mellitus.

In all, 10 of 32 advisers at the July 13–14 meeting in Gaithersburg, Maryland, agreed that rosiglitazone requires new labeled warnings and restrictions on use, such as allowing only certain physicians to prescribe the antidiabetic drug. An additional 12 advisers recommended that the GlaxoSmithKline product, sold as Avandia, be removed from the U.S. market.

Seven advisers indicated that the addition of new information to the product's labeling, such as contraindications for certain patient populations or an indication for use as second-line therapy, would be sufficient to ensure the safe use of the product. Three advisers recommended that Avandia's current labeling be retained as is.

The advisers, who included members of FDA's Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee, met to discuss safety information about rosiglitazone that has emerged since July 2007.

At that time, the committee members said postmarketing data suggested that rosiglitazone puts patients with type 2 diabetes at increased risk of cardiac adverse events. Nevertheless, the group in 2007 voted overwhelmingly that the drug should remain on the market with a boxed warning about cardiac risks added to the labeling.

Several advisers at the 2010 meeting expressed disappointment in the quality of data presented for their review.

"What do I know now that I didn't in 2007?" asked patient representative Rebecca Killion. "The answer is, not much. I find there's just very little clarity in the two days of analysis that we've been subjected to."

The analyses included an update of GlaxoSmithKline's Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study, a randomized trial comparing rosiglitazone against metformin–sulfonylurea therapy.

GlaxoSmithKline's analysis concluded that rates of cardiovascular-related hospitalization and death were similar whether patients used rosiglitazone or the control therapy. Other interpretations varied, with some advisers and presenters concluding that the data from RECORD are suspect because of the trial's open-label design, issues with patient follow-up, and GlaxoSmithKline's pooling of data for analysis.

In general, said Sanjay Kaul of Cedars-Sinai Heart Institute in Los Angeles, the caliber of evidence presented to the advisers "does not allow reliable causal inference."

"When reasonable people look at the same data and come away with discordant differences, it speaks to the weakness of the data," he said.

Kaul was one of the seven who voted to revise the labeling for rosiglitazone but not subject it to additional risk-management elements.

Former ASHP President Mark Woods of Saint Luke's Hospital in Kansas City, Missouri, said data describing rosiglitazone's cardiovascular risks were imperfect but persuasive. He voted to remove rosiglitazone from the U.S. marketplace rather than revise the boxed warning or implement a risk evaluation and mitigation strategy (REMS) for the drug.

"I'm very skeptical about the REMS and black-box strategies for changing prescribing habits. I just don't know that that really works," he said.

"Many times they create additional paperwork, essentially—and especially for hospital and health-system pharmacists," he explained immediately after the meeting.

Janet Woodcock, director of FDA's Center for Drug Evaluation and Research, said the agency will evaluate the meeting's proceedings and reach a decision on rosiglitazone "as soon as possible."

Pioglitazone. Much of the discussion during the 2010 meeting dealt with comparisons of rosiglitazone and pioglitazone, the only thiazolidinedione drugs marketed in the United States.

Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic in Ohio, presented an analysis of studies comparing ischemic cardiovascular adverse events in patients taking rosiglitazone or pioglitazone. Nissen concluded that pioglitazone's safety profile is consistently favorable compared with rosiglitazone. He strongly urged that rosiglitazone be removed from the U.S. market.

"No matter whose data you want to use...you get a hazard for rosiglitazone and you either get a neutral or protective effect from pioglitazone," Nissen said. "With an alternative in the same class with favorable effects on cardiovascular outcomes, continued marketing of rosiglitazone cannot be medically or ethically justified."

Woods agreed with findings favoring the safety of pioglitazone over rosiglitazone and said that when the choice exists, "we really need to select the agent that's less likely to cause harm."

He said both drugs are currently on the formulary at his hospital, but given what he learned during the meeting, he wants to recommend that rosiglitazone be removed.

In all, 21 advisers agreed that rosiglitazone poses significant safety concerns for ischemic cardiovascular events in patients with type 2 diabetes relative to pioglitazone. Three advisers did not agree that pioglitazone appears safer than rosiglitazone, and the rest said they were unable to reach a conclusion on the issue.

Clinical practice. Jessica Odom, clinical pharmacy specialist in internal medicine at Greenville Hospital in South Carolina, said she became interested in rosiglitazone's cardiovascular risk issues in 2007 and has continued to follow the topic.

"There's not overwhelming evidence of increased myocardial infarctions with rosiglitazone. But there's not overwhelming reassurance that it's safe either," she said.

Odom said it is not unusual for a patient to be taking pioglitazone when admitted to the hospital, and that such patients are closely monitored for heart failure. But she said rosiglitazone use at her hospital is much rarer.

"We have not seen very many people at all on Avandia in the past couple of years," Odom said. "Our endocrinologists, they are really not using it at all."

When a patient reports rosiglitazone use on admission to the hospital, Odom said she recommends that the therapy be stopped and not reinitiated after discharge.

"Other oral diabetic medications are available that have a much better safety profile. So it seems logical to use another medication that has less risk," she said.

Diabetes itself is considered an independent risk factor for cardiovascular disease and death. According to the Centers for Disease Control and Prevention, deaths from cardiovascular disease are two to four times higher in adults with diabetes than in those without the condition.

On the label. The current labeling for rosiglitazone includes a boxed warning stating that the drug and other thiazolidinediones can cause or exacerbate heart failure. This drug class is not recommended for patients with symptomatic heart failure and is contraindicated in patients with severe heart failure.

In addition to the classwide warning, rosiglitazone's boxed warning includes a product-specific statement, added after the 2007 meeting, that the drug may increase the risk of myocardial ischemic events such as angina or myocardial infarction.

According to briefing documents prepared for the 2010 meeting, Glaxo-SmithKline in August 2009 submitted to FDA paperwork describing the RECORD results. The company requested that the boxed warning be edited, on the basis of the study's data, to delete the statements about myocardial ischemia, leaving only the classwide warning on heart failure. The remainder of the label would be altered to "parallel this change," according to the briefing document.

None of the advisers voted to support this recommendation.