October 28, 1997

Dear Healthcare Professional:

We are notifying you of a change in prescribing information initiated by Parke-Davis to provide additional information regarding the incidence of idiosyncratic hepatocellular injury in patients with type 2 diabetes being treated with Rezulin (troglitazone) Tablets. The labeling changes are in response to rare reports during marketed use (35 as of October 21, 1997) of such injury. These cases range from mild elevations of serum transaminases to one liver transplant and one death.

Based on this experience during marketed use, Parke-Davis is recommending that serum transaminase levels be checked within the first one to two months and then every three months during the first year of troglitazone therapy, and periodically thereafter. Liver function tests also should be obtained for patients at the first symptoms suggestive of hepatic dysfunction, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine. Rezulin should be discontinued if the patient has jaundice or if laboratory measurements suggest liver injury (e.g., ALT > 3 times the upper limit of normal).

As described in the Rezulin package insert, rare cases of jaundice, which were reversible, were observed in the controlled clinical studies that supported marketing approval. Approximately 650,000 patients (500,000 in the United States and 150,000 in Japan) have been treated with Rezulin since its introduction in early 1997. Of those 650,000 patients, approximately 85,000 in the United States have been on Rezulin therapy for six months or more.

The changes to prescribing information include:

WARNINGS

Hepatic

RARE CASES OF SEVERE IDIOSYNCRATIC HEPATOCELLULAR INJURY HAVE BEEN REPORTED DURING MARKETED USE (SEE ADVERSE REACTIONS, POSTINTRODUCTION REPORTS). THE HEPATIC INJURY IS USUALLY REVERSIBLE, BUT VERY RARE CASES OF HEPATIC FAILURE, INCLUDING DEATH, HAVE BEEN REPORTED. INJURY HAS OCCURRED AFTER BOTH SHORT- AND LONG-TERM TROGLITAZONE TREATMENT.

During all clinical studies in North America, a total of 48 of 2510 (1.9%) Rezulin-treated patients and 3 of 475 (0.6%) placebo-treated patients had ALT levels greater than 3 times the upper limit of normal. Twenty of the Rezulin-treated and one of the placebo-treated patients were withdrawn from treatment. Two of the 20 Rezulin-treated patients developed reversible jaundice; one of these patients had a liver biopsy which was consistent with an idiosyncratic drug reaction. An additional Rezulin-treated patient had a liver biopsy which was also consistent with an idiosyncratic drug reaction. (See ADVERSE REACTIONS, Laboratory Abnormalities)

It is recommended that serum transaminase levels be checked within the first one to two months and then every three months during the first year of troglitazone therapy, and periodically thereafter. Liver function tests also should be obtained for patients at the first symptoms suggestive of hepatic dysfunction, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine. Rezulin should be discontinued if the patient has jaundice or laboratory measurements suggest liver injury (e.g., ALT > 3 times the upper limit of normal).

PRECAUTIONS

Information for Patients

Patients who develop nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine or other symptoms suggestive of hepatic dysfunction or jaundice should immediately report these signs or symptoms to their physician.

ADVERSE REACTIONS

Postintroduction Reports

Adverse Events associated with Rezulin that have been reported since market introduction, that are not listed above, and for which causal relationship to drug has not been established include the following: jaundice, hepatitis, liver transplant, death. Also see WARNINGS.

A full copy of the revised Package Insert is enclosed.

We trust that this information will be helpful to you in continuing to effectively treat your type 2 diabetes patients with this important therapy. For further information, please contact the Parke-Davis Medical and Scientific Affairs Department at 1-800-223-0432.

Health care professionals are encouraged to report any unexpected events suggestive of idiosyncratic hepatocellular injury directly to the Parke-Davis Medical and Scientific Affairs Department or FDA MedWatch program at 1-800-FDA-1088 (FAX 1-800-FDA-0178).

Rezulin is indicated for concomitant use with a sulfonylurea or insulin to improve glycemic control. Rezulin, as monotherapy, is indicated as an adjunct to diet and exercise to lower blood glucose in patients with type 2 diabetes. Rezulin should not be used as monotherapy in patients previously well-controlled on sulfonylurea therapy. For patients inadequately controlled with a sulfonylurea alone, Rezulin should be added to, not substituted for, the sulfonylurea.

Sincerely,

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

Enclosure

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