The following is the text of a Press Release issued by the manufacturer on March 21, 2000:

MORRIS PLAINS, N.J., March 21, 2000 -- Warner-Lambert Company announced today that it is voluntarily discontinuing the sale of REZULIN (troglitazone) Tablets, its therapy for the treatment of type 2 diabetes, although the Company continues to believe that the benefits of the drug outweigh its associated risks.

Patients taking REZULIN should consult with their physicians as soon as possible to discuss alternative therapies. Warner-Lambert will work closely with the Food and Drug Administration and other constituencies to assure a safe and efficient transition for patients as they switch to alternative therapies.

The Company has always believed that it is essential for patients and physicians to receive accurate and objective information regarding the benefits and risks of REZULIN. It was for this reason that Warner-Lambert requested a public meeting of the FDA's expert Advisory Committee. However, repeated media reports sensationalizing the risks associated with REZULIN therapy have created an environment in which patients and physicians are simply unable to make well-informed decisions regarding the safety and efficacy of REZULIN. Under these circumstances, and after discussions this evening with the FDA, we have decided it is in the best interests of patients to discontinue marketing REZULIN at this time.

In June, 1999, the FDA and Parke-Davis agreed to again tighten the restrictions on the use of troglitazone

1. The previous indication for use as monotherapy (by itself) was withdrawn.
2. Liver testing (ALT) was recommended monthly for a year, then quarterly
3. If ALT's increase to 1.5-2.0 the upper limits of the normal range, they should be repeated immediately and weekly; if the patient develops jaundice or ALT over 3.0 times the upper limits of normal, the drug should be discontinued
4. It was recommended that patients with the following not be started on troglitazone:
   1. Patients with ALT over 1.5 times the upper limit of the normal range
   2. Patients with prior liver disease
   3. Patients with active liver disease
   4. Patients with alcohol abuse

Parke-Davis Announcements July 28, 1998

1. A revised warning about testing for liver abnormalities (see below): "...in consultation with the FDA, [P-D] has modified the prescribing information in the following way:
   • Patients with moderately elevated ALT levels at the start of therapy (greater than 1.5 times the upper limit of normal) should not be initiated on Rezulin therapy.
   • ALT levels should be measured at the start of Rezulin therapy and monthly for eight months, then every two months for the remainder of the first year of therapy and periodically thereafter.
   • Patients whose ALT levels are found to be moderately elevated (greater than 1.5-2 times the upper limit of normal) during Rezulin therapy should have ALT levels retested within a week and then weekly until they either return to normal levels or rise above 3 times the upper limit of normal, at which point Rezulin should be discontinued."
2. Note: In June, 1999, the indication for monotherapy with troglitazone was withdrawn. In the same letter, P-D advised modifications to monotherapy prescribing information: "The recommendation for use as initial therapy has been modified to the following:
   • For patients not responding to 400 mg, the Rezulin dose should be increased to 600 mg after one month [emphasis in original].
   • For patients not responding adequately to 600 mg after one month [emphasis in original], Rezulin should be discontinued and alternative therapeutic options should be pursued."

Tuesday December 2 2:11 AM EST
FDA Strengthens Warnings for Diabetes Drug

It strengthened its recommendations about the drug, known generically as troglitazone, after reports that some people on the drug had suffered liver failure and three had died.

"FDA has concluded that liver enzyme levels should be measured in patients taking Rezulin at the start of therapy, every month for the first six months of treatment, every other month for the next six months, and periodically thereafter," the FDA said in a statement.

Information about possible liver damage should be more prominently displayed on the label of the drug, made by Parke-Davis, a unit of Warner-Lambert Co, the FDA said.

"These actions, taken with the full cooperation of the drug's manufacturer, re-emphasize for health care providers and patients the importance of monitoring patients taking Rezulin to ensure that it is used in the safest manner," the FDA said.

The FDA said about 600,000 patients in the United States and 200,000 in Japan had taken Rezulin, which is prescribed with insulin or older drugs known as sulfonylureas for patients whose blood sugar levels are not being controlled by the other treatment.

The FDA first announced the danger of liver damage on November 3, after getting reports of 35 cases of liver damage, including liver failure that caused one liver transplant and killed another person.

"At that time the FDA asked for reports on additional adverse events associated with the use of Rezulin, and the agency has received a total of approximately 150 adverse event reports, including three deaths fron liver failure linked to the use of Rezulin in Japan," it said.

About two percent of patients taking the drug show an elevation of certain liver enzymes in the blood, a possible indication of liver damage.

"Although FDA will carefully monitor and evaluate reports of liver problems associated with Rezulin, at present the agency continues to find the benefits outweigh the risks for treating appropriately selected and monitored type-2 diabetes patients with Rezulin," it said.

Warner shares fell sharply after the company said it would be changing the labels on the drugs.

Concern was magnified when Glaxo Wellcome Plc, which manufactures and markets the drug in the United Kingdom under the name Romozin, said earlier on Monday it was suspending sales of the drug pending its review of safety data.

Glaxo also announced it had withdrawn its license applications under the European Commission's mutual recognition process to sell the drug in other European countries.

FDA TALK PAPER

PATIENT TESTING AND LABELING STRENGTHENED FOR REZULIN

These actions, taken with the full cooperation of the drug's manufacturer, re-emphasize for health care providers and patients the importance of monitoring patients taking Rezulin to ensure that it is used in the safest manner.

Rezulin is used in combination with insulin or sulfonylurea in patients with type II diabetes (adult-onset diabetes mellitus) whose blood glucose levels are not adequately controlled by these other therapies alone.

On November 3, FDA and the drug's manufacturer announced changes in the prescribing information for Rezulin, including a new warning and recommendations for monitoring liver function. In making these changes, FDA was aware of approximately 35 post-marketing reports of liver injury among U.S. and Japanese patients taking Rezulin, including liver failure leading to one liver transplant and one death.

At that time, FDA asked for reports on additional adverse events associated with the use of Rezulin, and the agency has now received a total of approximately 150 adverse event reports, including three deaths from liver failure linked to the use of Rezulin in Japan. Approximately 600,000 patients in the U.S. and 200,000 in Japan have been treated with this drug. The deaths in Japan occurred in patients treated before the stronger label warning and recommendation for liver enzyme testing took effect there.

FDA has concluded that liver enzyme levels should be measured in patients taking Rezulin at the start of therapy, every month for the first six months of treatment, every other month for the next six months, and periodically thereafter. In addition, liver function tests should be performed on any patient on Rezulin who develops symptoms of liver dysfunction, such as nausea, vomiting, fatigue, loss of appetite, or dark urine and jaundice. The product's current labeling advises that patients with significant elevation of these liver enzymes stop taking the drug. Previously, liver enzyme testing was recommended during the first two months of therapy and then every three months.

The increased monitoring of patients taking Rezulin is designed to detect those few patients in whom use of the drug can lead to serious liver damage. Warner-Lambert, the manufacturer of the drug, will send a letter within the next week to U.S. health care professionals to inform them of these changes.

While Rezulin was being studied in patients before FDA approval, approximately two percent of all patients were found to develop elevation of liver enzymes in the blood. These elevations, which serve as markers of potential liver injury, were mostly mild, unassociated with symptoms, and usually resolved when the drug was discontinued.

Although FDA will carefully monitor and evaluate reports of liver problems associated with Rezulin, at present the agency continues to find the benefits outweigh the risks for treating appropriately selected and monitored type-2 diabetes patients with Rezulin.

Type 2 diabetes is a serious, life-threatening disease that affects 18 million Americans. It is a leading cause of coronary heart disease, blindness, kidney failure, and limb amputation. Adequate control of blood sugar appears to be the most important means of preventing these complications.

On November 3, 1997, the FDA issued the following warning about troglitazone:
Rezulin Labeling Changes

The manufacturer of the diabetes drug Rezulin (troglitazone) is changing prescribing information for the product and adding new warning information to the labeling, in response to reports of liver injury associated with use of the drug.

Rezulin is used in combination with insulin or sulfonylurea in patients with type II diabetes (adult-onset diabetes mellitus) whose blood glucose levels are not adequately controlled by these other therapies alone.

About 500,000 patients in the United States have been treated with Rezulin since it came on the market in January 1997; of those, approximately 85,000 have been taking the drug for six months or more. As of October 21, 1997, 35 post-marketing reports of liver injury of various degrees have been received. These reports ranged from mildly elevated blood levels of the liver transaminase enzymes to liver failure leading to one liver transplant and one death. Whether the drug was solely responsible for all of these reports of liver injury is as yet unknown, due to confounding medical factors in some of the reported cases.

Based on these reports, FDA and the manufacturer are recommending that serum transaminase levels in patients be checked routinely within the first one to two months of Rezulin therapy, every three months thereafter during the first year of treatment, and periodically thereafter. In addition, liver function tests should be performed on any patient on Rezulin who develops symptoms of liver dysfunction, such as nausea, vomiting, abdominal pain, fatigue, loss of appetite, or dark urine. Patients on Rezulin who develop jaundice or whose laboratory results indicate liver injury should stop taking the drug.

Based on clinical trials, approximately two percent of patients on Rezulin can be expected to have to stop taking the drug because of elevated liver enzymes. Few, if any, of these patients will go on to develop permanent liver damage if the drug is stopped.

The new prescribing information and labeling warning are designed to give health care providers and patients the latest available information about possible risks associated with Rezulin and recommendations for safer use of the drug.

Health care providers are urged to report any Rezulin-related adverse events, especially those suggestive of possible liver injury, to the manufacturer, Parke Davis, at 1-800-223-0432, or FDA MedWatch at (phone) 1-800-FDA-1088, (fax) 1-800-FDA-0178 or (mail) FDA, HF-2, 5600 Fishers Lane, Rockville, MD 20857.

SOURCE: Warner-Lambert Company

New Drug Approved For Diabetes

The Food and Drug Administration said Thursday that it had approved Warner-Lambert Co.'s Rezulin tablets for Type II diabetes, the most common kind of diabetes that usually occurs in adults.

The new drug is particularly aimed at patients who take insulin injections but still have abnormal blood sugar levels or hyperglycemia.

The manufacturer said the drug is the first designed to target insulin resistance, the underlying cause of Type II diabetes. In these patients, the body produces insulin but then cannot use it correctly, a condition known as insulin-resistance.

They end up pumping out more and more insulin, but since it is not used correctly, it ends up pushing blood sugar levels to harmfully high levels.

Rezulin, the brand name for troglitazone, is supposed to help those patients whose hyperglycemia is not adequately controlled despite multiple injections of insulin.

Type II diabetes usually starts in adulthood, and is by far the most common kind of diabetes in the United States, accounting for about 90 percent of the 16 million cases.

Type I diabetics, sometimes called juvenile diabetes, cannot produce their own insulin.

Although some mild Type II cases can be controlled mostly through diet, many people do require medication and about three million Type II cases require insulin injections. Rezulin may help the one million people who do not respond to oral medication or insulin.

In two clinical trials involving more than 500 patients, it significantly improved the ability to use insulin produced in the body or through injection.

Many needed fewer injections, and some were able to stop injections altogether.

"This new drug has the potential to change the lives of people with type II diabetes who are inadequately controlled on insulin," said Dr. Jerrold Olefsky, an endocrinologist at University of San Diego School of Medicine.