Two patients in the clinical studies developed reversible jaundice: one of these patients had a liver biopsy which was consistent with an idiosyncraticdrug reaction. An additional patient had a liver biopsy associated which was also consistent with an Idiosyncratic drug reaction. Symptoms that are with hepatic dysfunction have been reported, including: nausea, vomitin abdominal pain, fatigue, anorexia, dark urine, abnormal liver function tests (including increased ALT, AST, LDH, alkaline phosphatase, bilirubin). Also see WARNINGS.

The overall incidence and types of adverse reactions reported in placebo- controlled clinical trials for Rezulin- treated patients and placebo- treated patients are shown in Table 6. In patients treated with Rezulin in glyburide- controlled studies (N= 550) or uncontrolled studies (N= 510), the safety profile of Rezulin appeared similar to that displayed in Table 6. The incidence of withdrawals during clinical trials was similar for patients treated with placebo or Rezulin (4%).

Types of adverse events seen when Rezulin was used concomitantly with insulin (N= 543) were similar to those during Rezulin monotherapy (N= 1731), although hypoglycemia occurred on insulin combination therapy (see PRECAUTIONS).

Laboratory Abnormalities

Hematologic: Small decreases in hemoglobin, hematocrit, and neutrophil counts (within the normal range) were more common in Rezulin-treated than placebo-treated patients and may be related to increased plasma volume observed with Rezulin treatment. Hemoglobin decreases to below the normal range occurred in 5% of Rezulin-treated and 4 % of placebo-treated patients.

Lipids: Small changes in serum lipids have been observed (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical effects).

Serum Transaminase Levels: 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 upp er limit of normal. During controlled clinical trials. 2.2% of Rezulintreated patients had reversible elevations in AST or ALT greater than 3 times the upper limit of normal, compared with 0.6% of patients receiving placebo. Hyperbilirubinemia (> 1.25 upper limit of normal) was found in 0.7% of Rezulin-treated patients compared with 1.7% of patients receiving placebo. In the population of patients treated with Rezulin, mean and median values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline, while values or LDH were increased slightly (see WARNINGS).

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 congestive heart failure, weight gain, edema, fever, abnormal lab tests including increased CPK and creatinine, hyperglycemia, syncope, anemia, malaise.

Oral Contraceptives: Administration of Rezulin with an oral contraceptive containing ethinyl estradiol and norethindrone reduced the plasma concentrations of both by approximately 30% which could result in loss of contraception. Therefore, a higher dose of oral contraceptive or an alternative method of contraception should be considered.

Terfenadine: Coadministration of Rezulin with terfenadine decreases the plasma concentration of both terfenadine and its active metabolite by 50-70% and may result in decreased efficacy of terfenadine.

Cholestyramine: Concomitant administration of cholestyramine with Rezulin reduces the absorption of troglitazone by 70%; thus, coadministration of cholestyramine and Rezulin is not recommended.

Glyburide: Coadministration of Rezulin and glyburide does not appear to alter troglitazone or glyburide pharmacokinetics.

Digoxin: Coadministratjon of Rezulin with digoxin does not alter the steady-state pharmacokinetics of digoxin.

Warfarin: Rezulin has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy.

Acetaminophen: Coadministration of acetaminophen and Rezulin does not alter the pharmacokinetics of either drug.

Metformin: No information is available on the use of Rezulin with metformin.

Ethanol: A single administration of a moderate amount of alcohol did not increase the risk of acute hypoglycemia in Rezulin-treated patients with type II diabetes mellitus.

The above interactions with terfenadine and oral contraceptives suggest that troglitazone may induce drug metabolism by CYP3A4. Studies have not been performed with other drugs metabolized by this enzyme such as: astemizole, calcium channel blockers, cisapride, corticosteroids cyclosporine. HMG-CoA reductase inhibitors, tacrolimus, triazolam, and trimetrexate. The possi bility of altered safety and efficacy should be considered when Rezulin is used concomitantly with these drugs.

Patients stable on one or more of these agents when Rezulin is started should be closely monitored and their therapy adjusted as necessary.

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