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May 1, 2000 REZULIN was approved in 1997 to treat Type 2 diabetes which usually comes on in adulthood and is the most common form of the disease. REZULIN, known generically as TROGLITAZONE, is made and marketed by Parke-Davis, a division of Warner-Lambert Company of Morris Plains, New Jersey.

REZULIN was removed from the market by the FDA in March of this year as a result of having been linked to a mounting number of cases of serious liver damage and death. The drug had already been removed from the market in England in December of 1997 where officials have refused to allow its reintroduction. The Merck Manual recognizes troglitazone (in 200-800 mg doses once a day) as capable of causing "serious hepatotoxicity."

REZULIN (troglitazone) is one of several anti-hyperglycemic drugs or "glitazones" which are known as thiazolidinediones. These drugs are insulin-sensitizers that improve insulin sensitivity in skeletal muscle and suppress hepatic glucose output. The only thiazolidinedione available in the United States is troglitazone of which REZULIN is one. The medical literature, however, clearly recognizes that troglitazone "has potentially idiosyncratic hepatotoxicity." (Merck Manual, 17th Edition p. 176).

Drugs have always been known to be "an important cause of liver damage." Some drugs cause direct toxicity with predictable, dose-related injuries characteristic for the particular drug. Other drugs cause damage only in "susceptible" persons. Such reactions are characterized as idiosyncratic. Through the years, the distinction between the two types of reactions has become less clear. Thus, in situations previously thought to be allergic reactions in susceptible patients, there now appears to be damage directly to cell membranes as a result of drug toxicity.

Various drugs can produce what is essentially a cholestatic reaction. Cholestasis (obstructive jaundice) is a clinical and biochemical syndrome that results when bile flow is impaired. Some drug induced liver damage is virtually indistinguishable from chronic hepatitis and may even progress to cirrhosis. Chronic liver injury that histologically mimics alcoholic liver disease is also capable of being produced by certain drugs. NASH (Non-alcoholic Steroidal Hepatitis) is among such injuries.

Only eight months after REZULIN was marketed in the United States, the Food and Drug Administration (FDA) announced that the drug had been linked to illness and death from liver failure. For this reason, the FDA recommended frequent monitoring of liver function in patients taking REZULIN. Significantly, these problems had been apparent while the drug was being tested according to Dr. Anne Peters, an endocrinologist at the University of California at Los Angeles. Dr. Peters noted that the abnormal test results were so extreme they should have been regarded as a "red flag." Dr. Peters, and others, believed that REZULIN should have been marketed from the beginning with strong warnings and the requirement that those taking the drug have frequent tests of liver function. Instead, the drug was marketed without any recommendation for liver monitoring.

Unfortunately, the injuries and deaths continued. Surveys showed that few patients were being properly monitored. Labeling changes ordered by the FDA did nothing to remedy the situation and soon, serious divisions developed within the agency itself. By the beginning of this year, four senior FDA physicians as well as Dr. Robert I. Mishbin, the FDA Medical Officer most closely involved with the government's approval and continued support of REZULIN, were strongly urging its withdrawal from the market. In fact, in a January 24, 2000 E-Mail to his superiors, Dr Mishbin stated: "I see no reason why any well-informed physician would continue to prescribe [REZULIN]." In warning that "additional cases of preventable liver failure" may occur, Dr. Mishbin also stated that he did not see "any reason why FDA should delay in taking steps to remove [REZULIN] from the market." The FDA's response was to threaten Dr. Mishbin with disciplinary action or dismissal from federal service.

Although the director of the FDA's drug review center, Dr. Janet Woodcock claimed in a March, 2000 prepared statement that the FDA still believed the benefits of REZULIN to outweigh its risks, a member of the FDA Advisory Committee stated that he was "not surprised" to hear of the dramatic increase of reported liver-failure cases associated with the drug. Moreover, even long before Dr. Mishbin's change of position, two other FDA physicians had raised serious questions concerning REZULIN. In October, 1996, FDA Medical Officer, Dr. John L. Gueriguian recommended REZULIN not be approved because of potential liver and heart toxicity. That same month, Dr. Gueriguian was stripped of further involvement in reviewing REZULIN and his negative review purged from agency files. In 1999, Dr. David J. Graham, a senior FDA epidemiologist, publicly warned the agency's Advisory Committee that every REZULIN user was at risk for sudden liver failure. In fact, Dr. Graham presented data indicating that, even with monthly monitoring, REZULIN patients still ran the risk of spiraling into sudden liver failure.

Interestingly, the withdrawal of REZULIN in Britain in 1997 was set in motion by GlaxoWellcome, the very company with rights to market the drug in Europe. As a result of the deaths and liver injuries in the United States and Japan, Glaxo officials concluded that they no longer believed the benefits of REZULIN outweighed the risks associated with its use. Glaxo took this position because there was no way to predict which REZULIN patients would be harmed and because the incidence of liver injuries and death, by that time, was unacceptably high.

Due to the rapidly increasing evidence that REZULIN posed a very real risk of serious liver injury and death, REZULIN labeling in the United States was changed four times between November, 1997 and June, 1999. Each change called for more frequent liver function testing, yet each change was followed by an increase in the total number of REZULIN patients suffering liver failure and death. Despite its very questionable history, REZULIN generated sales of over $1.8 billion up to January 2000 and, at its peak, was prescribed 488,000 times in January of 1999.

Presently, two alternatives to REZULIN are being marketed. AVANDIA, known generically as rosiglitazone, (SmithKline Beecham PLC) was approved in May, 1999 and ACTOS (Eli Lilly & Co. and Takeda Chemical Industries) was approved in July, 1999. Although both drugs are chemically similar to REZULIN, they are not believed to pose similar risks of liver damage and death. Nonetheless, careful medical monitoring of these new drugs is strongly recommended.

Whether REZULIN could have been marketed in a way that maximized its benefits while minimizing the risk to those taking the drug will never be known. What we do know is that the poorly monitored and highly suspect way in which REZULIN was rushed to market has left in its wake an unacceptably large number of catastrophically injured and dead people whose only mistake was to believe REZULIN represented a safe and effective way to control their diabetes. Clearly, the "hype" was nothing but that.
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