IMPORTANT DRUG WARNING

July 28, 1998

Dear Healthcare Professional:

Importance of Monitoring Liver Function

This letter is to inform healthcare professionals about the modified requirements relating to more stringent liver enzyme monitoring as reflected in the new product labeling for Rezulin. These new liver enzyme monitoring modifications are intended to reduce the risk of rare but serious liver injury, including liver failure leading to transplant or death. The labeling has also been changed to modify the initial period of evaluation in monotherapy. This letter describes these changes and includes new educational materials for your reference and use with patients.

Modifications to Liver Function Monitoring Information

Liver enzyme monitoring recommendations were originally implemented in November 1997. Since that time there have been few new cases of severe hepatocellular events, primarily involving patients who may not have been monitored as recommended in the labeling. Since the introduction of Rezulin in March 1997, the reported rate of death or transplant in patients receiving Rezulin is approximately 1 case in 60,000 patients. Although it appears to be rare, at least one patient has exhibited a rapid elevation of alanine aminotransferase (ALT). Therefore, it is very important to closely monitor patients who exhibit even modest ALT elevations during their treatment with Rezulin.

Accordingly, Parke-Davis, in consultation with the FDA, 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 (greated 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 about 3 times the upper limit of normal, at which point Rezulin should be discontinued.

For your information, during clinical trials with Rezulin in 2510 patient, 1.9% of patients treated with Rezulin have ALT >3 times the upper limit of normal; overall about 5% of patients treated with Rezulin in these clinical trials developed moderate ALT elevations of greater than 1.5 times the upper limit of normal during the course of therapy.

It should be emphasized that although serious hepatic events associated with Rezulin are rare, all patients on Rezulin must be monitored in accordance with the monitoring schedule described in the revised prescribing information in order to reduce the occurrence of these events.

Parke-Davis encourages healthcare providers to report any new cases of severe adverse liver events or other adverse events to Parke-Davis at 1-800-223-0432 or to the FDA MedWatch program at 1-800-FDA-1088 (Fax 1-800-FDA-0178).

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. For patients not responding adequately to 600 mg after one month, Rezulin should be discontinued and alternative therapeutic options should be pursued.

New Educational Materials Available

Since its introduction in March 1997, Rezulin has been prescribed for more than 1.1 million patients with type 2 diabetes. We are commited to keeping you informed of important developments relating to Rezulin so that your patients can achieve better control of their type 2 diabetes. You will find enclosed items that explain the modifications to the monitoring recommendations, as well as the new prescribing information and other information that will help you to communicate the importance of monitoring liver enzymes to your patients. In addition, we will send similar items to pharmacists and diabetes educators so that they can support your efforts in educating patients about their therapy with Rezulin. We hope that this information will help you and your patients.

Your Parke-Davis and Sankyo Parke Davis representatives will be able to supply additional copies of these and other materials as you require, as well as to respond to your questions or concerns.

Sincerely,

William R. Sigmund II, M.D., M.H.S., F.A.C.C.
Vice President, Medical and Scientific Affairs

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