FDA's much-anticipated labeling change for Avandia does not draw a distinction between the GlaxoSmithKline drug and other oral anti-diabetics regarding heart attack risk.

FDA announced Nov. 14 that GlaxoSmithKline is expanding the "black box" warning for Avandia (rosiglitazone) to include data on the risk of heart attacks and related events.

But the agency also requires that all oral anti-diabetics now include language in product labeling emphasizing that no oral anti-diabetic drug has been shown to reduce cardiovascular risk.

The expanded Avandia warning notes that a meta-analysis of 42 clinical studies, most of which compared rosiglitazone to placebo, showed it is associated with an increased risk of myocardial ischemic events.

However, data from three large, longer-term trials - RECORD, DREAM, and ADOPT - comparing Avandia to active therapy or placebo have not confirmed or excluded this risk.

The boxed warning for Avandia concludes that: "In their entirety, the available data on the risk of myocardial ischemia are inconclusive."

Statements about the risk of heart attacks join information about congestive heart failure that caused FDA to apply a "black box" warning to the thiazolidinedione class in August (¹ Also see "Avandia and Actos Add Strengthened “Black Box” Warnings On Heart Failure" - Pink Sheet, 14 August, 2007.).

In total, FDA's updated label for Avandia is more in line with the recent European label - that the benefits of Avandia and Takeda's Actos (pioglitazone) outweigh their risks - than the harsher determination by the Canadian health agency restricting rosiglitazone use (² Also see "Avandia Monotherapy Use Curtailed in Canada" - Pink Sheet, 13 November, 2007.).

GSK has signaled that it would be pleased if the FDA's final labeling was similar to the European label. During the firm's Oct. 24 third quarter earnings call, CEO J.P. Garnier commented that, "If the FDA decides to mimic Europe, I think we'll be in good shape."

FDA could have made a harsher determination for Avandia. At the joint advisory committee review of Avandia safety in July, FDAers advocated withdrawing the drug - although the panel voted to keep Avandia on the market.

Following the meeting, FDA held several internal discussions and convened its Drug Safety Oversight Board to address the issue. The board was divided, but ultimately voted to keep the drug on the market, FDA Chief Medical Officer Janet Woodcock said during a same-day conference call with members of the press.

FDA also is asking GSK to conduct a long-term, active comparator study evaluating the cardiovascular risk of Avandia, despite a cardiovascular outcomes study for the drug already underway in RECORD.

Senate Finance Committee Chairman Max Baucus, D-Mont., and ranking member Chuck Grassley, R-Iowa, both issued statements promising continued oversight of FDA and GSK regarding Avandia.

-Brian Marson (b.marson@elsevier.com)

Avandia Expands Black Box With Heart Attack Risk Information

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