May 22, 2007

Letter Demonstrating that FDA Knew About Rosiglitazone (Avandia) Dangers

Andrew von Eschenbach, M.D., Commissioner  
U.S. Food and Drug Administration
Food and Drug Administration
5600 Fishers Lane 
Rockville,  MD 20857 

Dear Dr. von Eschenbach:

We have obtained an internal FDA memo dated almost five years ago concerning heart failure from Avandia and Actos (the other widely-prescribed glitazone drug for diabetes). The July 16, 2002 memo from FDA staff in the Division of Drug Risk Evaluation evaluated cases of heart failure reported to the FDA during the first two years of marketing that were serious enough to require hospitalization.[1] Their analysis of these adverse reaction reports found 47 cases in which the use of Avandia (25 cases) and Actos (22 cases) resulted in hospitalization for heart failure. In the majority of these cases, the heart failure improved with the cessation of treatment with these drugs, further evidence of their role in causing heart failure.

In their memo, the FDA scientists recommended that both labels “should include mention of these postmarketing reports.” They also recommended “a Phase IV cohort study to evaluate possible increased risk of incident CHF” [congestive heart failure]. At the time of this memo, the labeling for these drugs merely stated that:

WARNINGS

Cardiac Failure and Other Cardiac Effects: AVANDIA [or ACTOS], like other thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Patients should be observed for signs and symptoms of heart failure. In combination with insulin, thiazolidinediones may also increase the risk of other cardiovascular adverse events. AVANDIA [or ACTOS] should be discontinued if any deterioration in cardiac status occurs.[2]

Despite this 2002 recommendation to mention post-marketing cases of heart failure and the fact that there are now a total of 1182 cases reported to the FDA with these two drugs (689 for Avandia, 493 for Actos; 803 involving hospitalization 415 for Avandia, 388 for Actos)[3], the current labeling for the drugs still starts with the identical warning.[4]

There continues to be no mention of the large and increasing number of post-marketing reports of heart failure, which was the explicit recommendation in the 2002 internal FDA memo.

The importance of the relationship between heart failure and heart attacks (myocardial infarction) is discussed in the New England Journal of Medicine article posted yesterday: “Rosiglitazone and other thiazolidinediones are known to precipitate congestive heart failure in susceptible patients. Congestive heart failure is a physiological state that is associated with an increased intravascular volume…In susceptible patients, an increase in myocardial oxygen demand could theoretically provoke ischemic events [such as myocardial infarctions].”[5]

The failure of the FDA to act on the recommendations made almost five years ago by its Division of Drug Risk Evaluation is yet another example (e.g.,Rezulin, Vioxx) in which the conclusions of employees engaged in post-market drug safety review are not taken seriously enough or addressed soon enough. As a result, millions of people are prescribed drugs, to the detriment of their health, whose risks are dangerously understated. Thus, instead of being prescribed safer, equally or more effective alternative drugs, patients’ lives continue to be put at risk. The magnitude of this problem can be seen in the enormous number of prescriptions for these drugs. The total number of prescriptions filled for Avandia and Actos in 2006 was 22 million (11 million for each).[6]

The current amount of data demonstrating cardiovascular risk of Avandia and Actos is certainly sufficient to at least label the drug as a last choice treatment and require a black box warning about the risks to the heart. Serious consideration should also be given as to why these drugs, which are supposed to decrease the cardiovascular complications of diabetes, are on the market at all since they actually increase these life-threatening problems.

Until this post-marketing drug safety part of CDER is made independent within the FDA of the rest of the Center for Drug Evaluation and Research, these life-taking mistakes will continue to occur. Such legislation was introduced by Senators Dodd and Grassley but is not included in the package of legislative reforms that have passed in the Senate and are likely to pass in the House.

We look forward to a prompt response to this letter.

Sidney M. Wolfe, M.D.
Director

Elizabeth Barbehenn, Ph.D.
Staff Researcher
Health Research Group at Public Citizen

cc: Congressmen Waxman, Dingell and Senators Grassley, Dodd

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[1] Green L, Shaffer D, and Swartz L. Adverse Event Congestive Heart Failure Requiring Hospitalization: Pioglitazone (Actos) , Rosiglitazone (Avandia) July 16, 2002.