Rezulin Recall News

Rezulin & Public Citizen

July 27, 1998, Petition to the Food and Drug Administration to ban troglitazone/Rezulin due to its causing several cases of liver failure

March 26, 1999, Statement before the Food and Drug Administration Endocrine and Metabolic Drugs Advisory Committee meeting advising them to withdraw troglitazone from the U.S. Market

March 7, 2000, Patients, Doctors Not Warned of Dangers of New Diabetes
Drugs

March 7, 2000, Petition to the Food and Drug Administration requesting that it immediately require labeling for the diabetes drug troglitizone (Rezulin), rosiglitazone (Avandia) and pioglitazone (Actos)

March 22, 2000, Letter to the Department of Health and Human Services urging that they implement and enforce the Code of Ethics for Government

July 27, 1998, Petition to the Food and Drug Administration to ban troglitazone/Rezulin due to its causing several cases of liver failure.

Michael Friedman, M.D.
Lead Deputy Commissioner,
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857

Dear Dr. Friedman,
        We have obtained information from the FDA that as of June 5, 1998, there had been at least 21 deaths from liver failure and three patients requiring liver transplants caused by the recently-approved diabetes drug, troglitazone (Rezulin-Parke-Davis/Warner Lambert). In addition, there have been more than 100 patients hospitalized with liver toxicity caused by the drug. Since June 5th, there have been at least five additional deaths from liver damage associated with the use of this drug reported to the FDA for a total of at least 26 deaths from liver failure. The total number of reports received by the FDA in which liver toxicity was associated with troglitazone (Rezulin) is more than 560 since March 1997, when the drug was first marketed. Given that it is estimated that only about one in ten adverse reactions that occur are reported to the FDA, it is likely that there may be as many as 200 deaths from liver damage that have actually occurred. Public Citizen's Health Research Group hereby petitions the FDA pursuant to 21 CFR, section 10.30 to initiate action to ban troglitazone (Rezulin) as authorized by 21 U.S.C., section 355 (e) of the Federal Food, Drug and Cosmetic Act because earlier attempts to prevent its liver-damaging toxicity have failed.
        In December 1997, based on 130 worldwide cases of liver damage linked to troglitazone (Rezulin), including six deaths, the British government concluded that "the risks of troglitazone (Rezulin) therapy outweigh the potential benefits" and the drug was withdrawn from the UK. The British government added that "at present, no clear risk factors for the development of hepatic reactions have been identified which might allow the drug to be used safely in some patients." Glaxo-Wellcome, which had been marketing the drug in the UK, also withdrew license applications for troglitazone (Rezulin) under the European Commission's "mutual recognition" process and all other regulatory activity for the drug on Glaxo's part has also been suspended.
        Instead of withdrawing the drug in the United States, the FDA, in December, 1997, increased the amount of monitoring of patients for liver damage (blood tests to detect this) to ten times in the first year of use from the previous five times which had been in effect for a month. Almost all of the deaths from liver toxicity have occurred after the latest (December 1, 1997) label change (which included a boxed warning) was made, reflecting the fact that the warnings are clearly inadequate to prevent the increasing amount of serious, often fatal liver damage occurring in patients using troglitazone (Rezulin). As of now, this drug is only available in the United States and Japan, all other countries and one of its developers, Glaxo-Wellcome, being too concerned to allow such a dangerous drug to be marketed.

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March 26, 1999, Statement before the Food and Drug Administration Endocrine and Metabolic Drugs Advisory Committee meeting advising them to withdraw troglitazone from the U.S. Market.

Statement by Sidney M. Wolfe, M.D., Director, Public Citizen's Health Research Group
FDA Endocrine and Metabolic Drugs Advisory Committee Meeting on Troglitazone

The last time I appeared before this advisory committee to present information about a diabetes drug was 22 years ago. The drug was phenformin, also said to have unique advantages and whose withdrawal from the market was opposed by many diabetes experts. Like troglitazone (Rezulin), it had a unique type of toxicity, in that case lactic acidosis, fatal in about 50% of those patients who developed this metabolic abnormality from the use of phenformin. After a lawsuit against the FDA by Public Citizen, it was banned as an imminent hazard to the public health in 1977.

Because of the incompleteness of the spontaneously reported adverse reaction data currently made available to the public by the FDA, it is quite difficult to accurately count even the reported number of deaths that appear to be caused by Rezulin or any other drug. This is because individual adverse reaction reports do not have a unique numerical patient identifier which would allow several reports to be determined to be just follow-ups on the same patient. In our efforts to sort this out, it is possible to overmatch and undercount or under match and over count. The fault lies with the cumbersome and difficult-to-use format FDA is now using to supply data to the public. Compounding this uncertainty is the widely agreed upon under reporting which may result in as few as 10% or even 1% of cases which actually occur being reported to the FDA.

With these caveats in mind, our estimates of liver deaths from Rezulin up through the beginning of February 1999 are 43 deaths, including American and Japanese cases. Although Warner Lambert has stated that there have been no new liver deaths since the July re-labeling, this statement appears to be false. In addition to the deaths, there are several additional cases of American patients who had liver transplants and survived. This makes an estimated 45 to 50 cases of liver failure apparently caused by Rezulin. An estimated additional 60 or so patients who neither died nor had liver transplants were hospitalized in whom there was evidence of liver damage.

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March 7, 2000, Patients, Doctors Not Warned of Dangers of New Diabetes Drugs
Public Citizen Petitions FDA to Revise Labels for Three Drugs

WASHINGTON, D.C. -- The U.S. Food and Drug Administration (FDA) should immediately revise labels on three new diabetes drugs to warn doctors and patients that the drugs are of questionable effectiveness and can have serious side effects, Public Citizen said in a petition to the FDA.

One of the drugs, Rezulin, was pulled from the market in 1997 by British medical authorities because of 130 cases worldwide of liver damage, including six deaths. According to a recent statement by the FDA s director of the drug review center, 58 deaths attributed to Rezulin have now been reported to the U.S. agency. Public Citizen petitioned the FDA in 1998 to ban Rezulin. According to a knowledgeable FDA physician, a large proportion of physicians at FDA familiar with Rezulin s dangers think the drug should be taken off the market.

The petition states that:

• Results in nine of 10 studies showed that the three drugs were less effective than older drugs. Blood sugar level deteriorated when patients were switched from old drugs to these new drugs;
• The FDA has received reports that patients using Rezulin had higher rates of heart failure than patients on older drugs used to treat diabetes. In just the first 18 months that Rezulin was on the market, the FDA listed 56 cases of heart failure associated with the drug compared to only four cases reported over a period of 13 years for glucotrol (a sulfonylurea), an older diabetes drug.
• One FDA medical officer wrote, "I am concerned that long-term exposure to [Avandia] may give rise to a similar liver problem as with [Rezulin]" -- that is, the liver failure that drove Rezulin from the market in Great Britain. Two published reports have already documented severe liver damage in patients taking Avandia, but none of the information is in the label, Public Citizen s petition says.

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March 7, 2000, Petition to the Food and Drug Administration requesting that it immediately require labeling for the diabetes drug troglitizone (Rezulin), rosiglitazone (Avandia) and pioglitazone (Actos).

March 7, 2000
Jane Henney, M.D., Commissioner
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857

CITIZEN'S PETITION TO IMMEDIATELY REQUIRE CLASS LABELING FOR THE DIABETES DRUGS TROGLITAZONE (REZULIN), ROSIGLITAZONE (AVANDIA) AND PIOGLITAZONE (ACTOS)
Dear Dr. Henney:

Public Citizen, a nationwide consumer organization, with a membership of more than 150,000, hereby petitions the Food and Drug Administration (FDA), pursuant to the Federal Food, Drug and Cosmetic Act 21 U.S.C. Section 355(e)(3), and 21 C.F.R. 10.30 to immediately require revision of the inadequate, misleading, and potentially dangerous professional product labeling for the thiazolidinediones or "glitazone" diabetes drugs: troglitazone (Rezulin), rosiglitazone (Avandia), and pioglitazone (Actos). Safety issues include liver toxicity, effects on heart function, weight gain, edema, anemia, low blood pressure, elevated lipid levels, and possible changes in progesterone levels.

The first member of the group to be approved, troglitazone (Rezulin), is a drug that has been shown to be too dangerous to be used safely because of its liver toxicity. It should be banned, as requested in our July 27, 1998 petition to the FDA (it has already been withdrawn in Great Britain). Although the severity of the risks due to liver failure do not justify the continued marketing of troglitazone, as long as it remains on the market in the U.S., we include it in our requests for changes in the labeling of the other glitazone drugs.

This petition is based on reviews by FDA Medical Officers, Statisticians, and Pharmacologists as well as transcripts of FDA advisory committee meetings, and a review of the scientific literature for troglitazone, rosiglitazone, and pioglitazone. We compared this information to the current professional product labeling and found that much of this information was never included in the label, or seriously understated. As a result, the labeling omits important safety and efficacy information to such an extent that physicians are likely to prescribe these drugs inappropriately.

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March 22, 2000, Letter to the Department of Health and Human Services urging that they implement and enforce the Code of Ethics for Government.

Dear Secretary Shalala:
        It is urgent for you and other leaders in HHS--and all government agencies--to re-read and strongly urge the implementation and enforcement of a 1958 Congressional Resolution entitled The Code of Ethics for Government Service (175 72 Stat B12, 1958) which states that "Any person in Government Service should put loyalty to the highest moral principles and to country above loyalty to persons, party or Government department." In addition, the Code of Federal Regulations governing basic obligations of public service (5 CFR Subpart A section 2635b.101) states that government "employees shall disclose waste, fraud, abuse and corruption to appropriate authorities." These guidelines have not been followed by those FDA officials who have harassed FDA physicians in the context of the recent controversy concerning Rezulin.
         Yesterday, Rezulin, the fourth drug of 39 new drugs approved in 1997--under conditions which many FDA physicians describe as lowered safety standards--was taken off the market. Rezulin has caused at least 63 people to die of liver failure and has been responsible for hundreds of other cases of severe liver toxicity. The number of drugs already pulled off the market (Posicor, Duract, Raxar and Rezulin) from those approved in 1997 is twice as many as in any previous year of approval, that having happened once, wherein two of the 30 drugs approved in 1985 have been taken off the market. In no other year of drug approvals between 1970 and now, has more than one drug eventually had to be removed from the market.

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