Prescription Drugs

Rezulin (troglitazone) WARNINGS Hepatic Rare cases of severe idiosyncratic hepatocellular injury have been reported during marketed use (see ADVERSE REACTIONS). The hepatic injury is usually reversible, but very rare cases of hepatic failure, leading to death or liver transplant, 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 (troglitazone removed from the us market 3/21/00) -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of the Rezulin (troglitazone removed from the us market 3/21/00) -treated and one of the placebo-treated patients were withdrawn from treatment. Two of the 20 Rezulin (troglitazone removed from the us market 3/21/00) -treated patients developed reversible jaundice; one of these patients had a liver biopsy which was consistent with an idiosyncratic drug reaction. An additional Rezulin (troglitazone removed from the us market 3/21/00) -treated patient had a liver biospy which was also consistent with an idiosyncratic drug reaction. (See ADVERSE REACTIONS, Laboratory Abnormalities) It is recommended that serum transaminase levels be checked at the start of therapy, monthly for the first six months of therapy, every two months for the remainder of 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 (troglitazone removed from the us market 3/21/00) therapy should not be initiated if the patient exhibits clinical or laboratory evidence of active liver disease (e.g., ALT> 3 times the upper limit of normal) and should be discontinued if the patient has jaundice or laboratory measurements suggest liver injury (e.g., ALT> 3 times the upper limit of normal). DESCRIPTION Rezulin (troglitazone) is an oral antihyperglycemic agent which acts primarily by decreasing insulin resistance. Rezulin (troglitazone removed from the us market 3/21/00) is used in the management of type II diabetes (noninsulin-dependent diabetes mellitus (NIDDM) also known as adult-onset diabetes). It improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Troglitazone (+-5[[4-[(3,4-dihydro-6- hydroxy-2,5.7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy]phenyl]methyl]-2,4- thiazolidinedione) is not chemically or functionally related to either the sulfonylureas, the biguanides, or the (g-glucosidase inhibitors. The molecule contains 2 chiral centers, with each of the 4 stereoisomers having similar pharmacologic effects. Troglitazone is a white to yellowish crystalline compound: it may have a faint. characteristic odor Troglitazone has a molecular formula of C24H2NO5S and a molecular weight of 441.55 daltons. It is soluble in N, N-dimethylformamide or acetone; sparingly soluble in ethyl acetate; slightly soluble in acetonitrile, anhydrous ethanol, or ether; and practically insoluble in water. Rezulin (troglitazone removed from the us market 3/21/00) is available as 200, 300 and 400 mg tablets for oral administration formulated with the following excipients: croscarmellose sodium, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, polysorbate 80, povidone, purified water, silicon dioxide, titanium dioxide, and synthetic iron oxides.

INDICATIONS Rezulin (troglitazone (removed from the us market 3/21/00)) may be used concomitantly with a sulfonylurea or insulin to improve glycemic control. Rezulin (troglitazone (removed from the us market 3/21/00)) , as monotherapy, is indicated as an adjunct to diet and exercise to lower blood glucose in patients with type II diabetes (see DOSAGE AND ADMINISTRATION). Rezulin (troglitazone (removed from the us market 3/21/00)) should not be used as monotherapy in patients previously well-controlled on sulfonylurea therapy. For patients inadequately controlled with a sulfonylurea alone, Rezulin (troglitazone (removed from the us market 3/21/00)) should be added to. not substituted for. the sulfonylurea. Management of type II diabetes should include diet control. Caloric restriction, weight loss, and exercise are essential for the proper treatment of the diabetic patient. This is important not only in the primary treatment of type II diabetes, but in maintaining the efficacy of drug therapy. Prior to initiation of Rezulin (troglitazone (removed from the us market 3/21/00)) therapy secondary causes of p.o. glycemic control, eg, infection or p.o. injection technique, should be investigated and treated. DOSAGE AND ADMINISTRATION Rezulin (troglitazone (removed from the us market 3/21/00)) should be taken with a meal. Combination Therapy Sulfony Iureas: Rezulin (troglitazone (removed from the us market 3/21/00)) in combination with a sulfonylurea should be initiated at 200 mg once daily. The current sulfonylurea dose should be continued upon initiation of Rezulin (troglitazone (removed from the us market 3/21/00)) therapy. For patients not responding adequate1, the Rezulin (troglitazone (removed from the us market 3/21/00)) dose should be increased at 2 to 4 weeks. The maximum recommended dose is 600 mg once daily. The dose of sulfonylurea may require lowering to optimize therapy. Insulin: The current insulin dose should be continued upon initiation of Rezulin (troglitazone (removed from the us market 3/21/00)) therapy Rezulin (troglitazone (removed from the us market 3/21/00)) therapy should be initiated at 200 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of Rezulin (troglitazone (removed from the us market 3/21/00)) should be increased after approximately 2 to 4 weeks. The usual dose of Rezulin (troglitazone (removed from the us market 3/21/00)) is 400 mg once daily. The maximum recommended daily dose IS 600 mg It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomit ant insulin and Rezulin (troglitazone (removed from the us market 3/21/00)) . Further adjustments should be individualized based on glucose lowing response. Monotherapy Rezulin (troglitazone (removed from the us market 3/21/00)) monotherapy in patients not adequately controlled with diet alone should be initiated at 400 or 600 mg once daily. For patients not responding to 400 mg once daily, the Rezulin (troglitazone (removed from the us market 3/21/00)) dose should be increased to 600 m after 6-8 weeks. For patients not responding adequately to 600 mg after 6-8 weeks, 9 Rezulin (troglitazone (removed from the us market 3/21/00)) should be discontinued and alternative therapeutic options should be pursued. See CLINICAL PHARMACOLOGY, Clinical Studies, Monotherapy. Patients With Renal Insufficiency: Dose adjustment in patients with renal insufficiency is not re uired (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism). Out of 2938 patients, 148 (5%) had a serum creatinine 21.5 at baseline. Of these 148 patients, 145 had creatinine levels between 1.5 and 2.0, inclusive; only 3 patients had levels >2. 0. No consistent trend was seen in any of these adverse events, and no worsening of renal insufficiency was observed. Patients With Hepatic Impairment: Rezulin (troglitazone (removed from the us market 3/21/00)) therapy should not be initiated if the patient exhibits clinical or laboratory evidence of active liver disease (eg, ALT> 3 ALT> 3 times the upper limit of normal). See CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency and WARNINGS. HOW SUPPLIEDNote: FDA removed from the US market 3/21/00 Rezulin (troglitazone (removed from the us market 3/21/00)) is available in 200, 300 and 400 mg tablets as follows: 200 mg Tablets: Yellow, oval, non- scored, film- coated tablet with PD 352 debossed on one side, and 200 on the other, available in: N 0071-0352-15 Bottles of 30 N 0071- 0352- 23 Bottles of 90 N 0071-0352-40 (10 x 10 unit-dose blisters) 300 mg Tablets: White, oval, non-scored, film-coated tablet with PD 357 debossed on one side and 300 on the other, available in: N 0071-0357-20 Bottles of 60 N 0071-0357-25 Bottles of 120 400 mg Tablets: Tan, oval, non-scored, film-coated tablet with PD 353 debossed on one side, and 400 on the other, available in: N 0071-0353-15 Bottles of 30 N 0071-0353-23 Bottles of 90 N 0071-0353-40 (10 x 10 unit-dose blisters) Storage Store at controlled room temperature 20° C- 25° C (68° F-77° F). Protect from moisture and humidity. Caution: Federal law prohibits dispensing without prescription

PATIENT INFORMATION Rezulin (troglitazone (removed from the us market 3/21/00)) should be taken with meals. If the dose is missed at the usual meal, it may be taken at the next meal. If the dose is missed on one day, the dose should not be doubled the following day. It is important to adhere to dietary instructions and to regularly have blood glucose and glycosylated hemoglobin tested. During periods of stress such as fever, trauma, glucose and glycosyin jection, or surgery, insulin requirements may change and patients should seek the advice of their physician. 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. When using combination therapy with insulin or oral hypoglycemic agents. the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members. Use of Rezulin (troglitazone (removed from the us market 3/21/00)) can cause resumption of ovulation in women taking oral contraceptives and in patients with polycystic ovary disease. Therefore, a higher dose of an oral contraceptive or an alternative method of contraception should be considered. Rezulin (troglitazone (removed from the us market 3/21/00)) may affect other medications used in diabetic patients. Patients started on Rezulin (troglitazone (removed from the us market 3/21/00)) should ask their physician to review their other medications to make sure that they are not affected by Rezulin. See also WARNINGS, CONTRAINDICATIONS, PRECAUTIONS.

OVERDOSE No information provided. CONTRAINDICATIONS Rezulin (troglitazone (removed from the us market 3/21/00)) is contraindicated in patients with known hypersensitivity or allergy to Rezulin (troglitazone (removed from the us market 3/21/00)) or any of its components.

SIDE EFFECTS 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 (troglitazone (removed from the us market 3/21/00)) - treated patients and placebo- treated patients are shown in Table 6. In patients treated with Rezulin (troglitazone (removed from the us market 3/21/00)) in glyburide- controlled studies (N= 550) or uncontrolled studies (N= 510), the safety profile of Rezulin (troglitazone (removed from the us market 3/21/00)) appeared similar to that displayed in Table 6. The incidence of withdrawals during clinical trials was similar for patients treated with placebo or Rezulin (troglitazone (removed from the us market 3/21/00)) (4%). TABLE 6. North American Placebo- Controlled Clinical Studies: Adverse Events Reported at a Frequency > 5% of Rezulin (troglitazone (removed from the us market 3/21/00)) - Treated Patients % of Patients Placebo N = 492 Rezulin (troglitazone (removed from the us market 3/21/00)) N = 1450 Placebo N = 492 Rezulin (troglitazone (removed from the us market 3/21/00)) N = 1450 Infection 22 18 Nausea 4 6 Headache 11 11 Rhinitis 7 5 Pain 14 10 Diarrhea 6 5 Accidental Injury 6 8 Urinary Tract Infection 6 5 Asthenia 5 6 Peripheral Edema 5 5 Dizziness 5 6 Pharyngitis 4 5 Back Pain 4 6 . . . Types of adverse events seen when Rezulin (troglitazone (removed from the us market 3/21/00)) was used concomitantly with insulin (N= 543) were similar to those during Rezulin (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) -treated than placebo-treated patients and may be related to increased plasma volume observed with Rezulin (troglitazone (removed from the us market 3/21/00)) treatment. Hemoglobin decreases to below the normal range occurred in 5% of Rezulin (troglitazone (removed from the us market 3/21/00)) -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 (troglitazone (removed from the us market 3/21/00)) -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 Rezulin (troglitazone (removed from the us market 3/21/00)) treated 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 (troglitazone (removed from the us market 3/21/00)) -treated patients compared with 1.7% of patients receiving placebo. In the population of patients treated with Rezulin (troglitazone (removed from the us market 3/21/00)) , 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 (troglitazone (removed from the us market 3/21/00)) 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. DRUG INTERACTIONS Oral Contraceptives: Administration of Rezulin (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) is not recommended. Glyburide: Coadministration of Rezulin and glyburide does not appear to alter troglitazone or glyburide pharmacokinetics. Digoxin: Coadministratjon of Rezulin (troglitazone (removed from the us market 3/21/00)) with digoxin does not alter the steady-state pharmacokinetics of digoxin. Warfarin: Rezulin (troglitazone (removed from the us market 3/21/00)) has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy. Acetaminophen: Coadministration of acetaminophen and Rezulin (troglitazone (removed from the us market 3/21/00)) does not alter the pharmacokinetics of either drug. Metformin: No information is available on the use of Rezulin (troglitazone (removed from the us market 3/21/00)) with metformin. Ethanol: A single administration of a moderate amount of alcohol did not increase the risk of acute hypoglycemia in Rezulin (troglitazone (removed from the us market 3/21/00)) -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 (troglitazone (removed from the us market 3/21/00)) is used concomitantly with these drugs. Patients stable on one or more of these agents when Rezulin (troglitazone (removed from the us market 3/21/00)) is started should be closely monitored and their therapy adjusted as necessary.

WARNINGS Hepatic Rare cases of severe idiosyncratic hepatocellular injury have been reported during marketed use (see ADVERSE REACTIONS). The hepatic injury is usually reversible, but very rare cases of hepatic failure, leading to death or liver transplant, 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 (troglitazone (removed from the us market 3/21/00)) -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 (troglitazone (removed from the us market 3/21/00)) -treated and one of the placebo-treated patients were withdrawn from treatment. Two of the 20 Rezulin (troglitazone (removed from the us market 3/21/00)) -treated patients developed reversible jaundice; one of these patients had a liver biopsy which was consistent with an idiosyncratic drug reaction. An additional Rezulin (troglitazone (removed from the us market 3/21/00)) -treated patient had a liver biospy which was also consistent with an idiosyncratic drug reaction. (See ADVERSE REACTIONS, Laboratory Abnormalities) It is recommended that serum transaminase levels be checked at the start of therapy, monthly for the first six months of therapy, every two months for the remainder of 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 (troglitazone (removed from the us market 3/21/00)) therapy should not be initiated if the patient exhibits clinical or laboratory evidence of active liver disease (e.g., ALT> 3 times the upper limit of normal) and 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 General Because of its mechanism of action, Rezulin (troglitazone (removed from the us market 3/21/00)) is active only in the presence of insulin. Therefore Rezulin (troglitazone (removed from the us market 3/21/00)) should not be used in type1 diabetes or for the treatment of diabetic keto-acidosis. Hypoglycemia: Patients receiving Rezulin (troglitazone (removed from the us market 3/21/00)) in combination with insulin or oral hypoglycemic agents may be at risk for hypoglycemia and a reduction in the dose of the concomitant agent may be necessary. Hypoglycemia has not been observed during the administration of Rezulin (troglitazone (removed from the us market 3/21/00)) as monotherapy and would not be expected based on the mechanism of action. Ovulation: In premenopausal anovulatory patients with insulin resistance, Rezulin (troglitazone (removed from the us market 3/21/00)) treatment may result in resumption of ovulation. These patients may be at risk for pregnancy. Hematologic: Across all clinical studies, hemoglobin declined by 3 to 4 % in troglitazone-treated patients compared with 1 to 2% in those treated with placebo. White blood cell counts also declined slightly in troglitazone-treated patients compared to those treated with placebo. These changes occurred within the first four to eight weeks of therapy. Levels stabilized and remained unchanged for up to two years of continuing therapy. These changes may be due to the dilutional effects of increased plasma volume and have not een associated with any significant hematologic clinical effects (see ADVERSE REACTIONS, Laboratory Abnormalities). Use in Patients With Heart Failure Heart enlargement without microscopic changes has been observed in rodents at exposures of parent compound and active rnetabolite exceeding 7 times the AUC of the 400 mg human dose see PRECAUTIONS: Carcinogenesis. Mutagenesis, Impairment of Fertility and Animal Toxicology). Serial echocardiographic evaluations in monkeys treated chronically at exposures at 4-9 times the human exposure to parent compound and active metabolite at the 400 mg dose did not reveal chan nges in heart size or function. In a 2-year echocardiographic clinical study using 600 to 800 mg/day of Rezulin (troglitazone (removed from the us market 3/21/00)) in patients with type II diabetes, no increase in left ventricular mass or decrease in cardiac output was observed. The methodology employed was able to detect a change of about 10% or more in left ventricular mass. In animal studies, troglitazone treatment was associated with increases of 6% to 15% in plasma volume. In a study of 24 normal volunteers, an increase in plasma volume of 6% to 8% compared to placebo was observed following 6 weeks of troglitazone treatment. No increased incidence of adverse events potentially related to volume expansion (e.g., congestive heart failure) have been observed during controled clinical trials. However, patients with New York Heart Association (NYHA) Class III and IV cardiac status were not studied during clinical trials. Therefore, Rezulin (troglitazone (removed from the us market 3/21/00)) is not indicated unless the expected benefit is believed to outweigh the potential risk to patients with NYHA Class III or IV cardiac status. Information for Patients Rezulin (troglitazone (removed from the us market 3/21/00)) should be taken with meals. If the dose is missed at the usual meal, it may be taken at the next meal. If the dose is missed on one day, the dose should not be doubled the following day. It is important to adhere to dietary instructions and to regularly have blood glucose and glycosylated hemoglobin tested. During periods of stress such as fever, trauma, glucose and glycosyin jection, or surgery, insulin requirements may change and patients should seek the advice of their physician. 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. When using combination therapy with insulin or oral hypoglycemic agents. the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members. Use of Rezulin (troglitazone (removed from the us market 3/21/00)) can cause resumption of ovulation in women taking oral contraceptives and in patients with polycystic ovary disease. Therefore, a higher dose of an oral contraceptive or an alternative method of contraception should be considered. Rezulin (troglitazone (removed from the us market 3/21/00)) may affect other medications used in diabetic patients. Patients started on Rezulin (troglitazone (removed from the us market 3/21/00)) should ask their physician to review their other medications to make sure that they are not affected by Rezulin (troglitazone (removed from the us market 3/21/00)) . Drug Interactions Oral Contraceptives: Administration of Rezulin (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) is not recommended. Glyburide: Coadministration of Rezulin and glyburide does not appear to alter troglitazone or glyburide pharmacokinetics. Digoxin: Coadministratjon of Rezulin (troglitazone (removed from the us market 3/21/00)) with digoxin does not alter the steady-state pharmacokinetics of digoxin. Warfarin: Rezulin (troglitazone (removed from the us market 3/21/00)) has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy. Acetaminophen: Coadministration of acetaminophen and Rezulin (troglitazone (removed from the us market 3/21/00)) does not alter the pharmacokinetics of either drug. Metformin: No information is available on the use of Rezulin (troglitazone (removed from the us market 3/21/00)) with metformin. Ethanol: A single administration of a moderate amount of alcohol did not increase the risk of acute hypoglycemia in Rezulin (troglitazone (removed from the us market 3/21/00)) -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 (troglitazone (removed from the us market 3/21/00)) is used concomitantly with these drugs. Patients stable on one or more of these agents when Rezulin (troglitazone (removed from the us market 3/21/00)) is started should be closely monitored and their therapy adjusted as necessary. Carcinogenesis, Mutagenesis, Impairment of Fertility Troglitazone was administered daily for 104 weeks to male rats at 100, 400, or 800 mg/kg and to female rats at 25, 53, or 200 mg/kg. No tumors of any type were increased at the low and mid doses. Plasma drug exposure based on AUC of parent compound and total metabolites at the low and mid doses was up to 24-fold higher than human exposure at 400 mg daily. The highest dose in each sex exceeded the maximum tolerated dose. In a 104-week study in mice given 50, 400, or 800 mg/ kg. incidence of hemangiosarcoma was increased in females at 400 mg/ kg and in both sexes at 800 mg/ kg; incidence of hepatocellular carcinoma was increased in females at 800 mg/ kg The lowest dose associated with increased tumor incidence (400 mg/ kg) was associated with AUC values of parent compound and total metabolites that were at least 2-fold higher than the human exposure at 400 mg daily. No tumors of any type were increased in mice at 50 mg/ kg at exposures up to 40% of that in humans at 400 mg daily, based on AUC of parent compound and total metabolites. Troglitazone was neither mutagenic in bacteria nor clastogenic in bone marrow of mice. Equivocal increases in chromosome aberrations were observed in an in vitro Chinese hamster lung cell assay in mouse lymphoma cellgene mutations assays, results were equivocal when conducted with a microtiter technique and negative with an agar plate technique. A liver unscheduled DNA synthesis assay in rats was negative. No adverse effects on fertility or reproduction were observed in male or female rats given 40, 200, or 1000 mg/ kg daily prior to and throughout mating and gestation. AUC of parent compound at these doses was estimated to be 3- to 9-fold higher than the human exposure. Animal Toxicology Increased heart weight without microscopic changes were observed in mice and rats treated for up to 1 year at exposure (AUC) of parent and active metabolite exceeding 7 times the human AUC at 400 mg/day.These heart weigh increases were reversible in 2- and 13-week studies, were prevented by coadministration of an ACE inhibitor, and 14 days of troglitazone administration to rats did not affect left ventricular performance. In the lifetime carcinogenicity studies, microscopic changes were noted in the hearts of rats but not in mice. In control and treated rats, microscopic changes included myocardial inflammation and fibrosis and karyomegaly of atrial myocytes. The incidence of these changes in drug-treated rats was increased compared to controls at twice the AUC of the 400 mg human dose. Pregnancy Pregnancy Category B. Troglitazone was not teratogenic in rats given up to 2000 mg/ k or rabbits given up to 1000 mg/kg during organogenesis. Compared to human exposure of 4.00 mg daily, estimated exposures in rats (parent compound) and rabbits (parent compound and active metabolite) based on AUC at these doses were up 9-fold and 3-fold higher, respectively. Body weights of fetuses and offspring of rats given 2000mg/kg during gestation were decreased. . Body Delayed postnatal development attributed to decreased body weight, was observed in offspring of rats given 40, 200, or 1000 mg/kg during late gestation and lactation periods; no effects were observed in offspring of rats given 10 or 20 mg/kg. There are no adequate and well-controlled studies in pregnant women. Rezulin (troglitazone (removed from the us market 3/21/00)) should not be used during pregnancy unless the potential benefit justifies the potentia I risk to the fetus. Because current information strongly su gests that abnormal blood glucose levels during pregnancy are associated with a higher incid ence of congenital anomalies as well as increased neonatal morbidity and mortality, most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Nursing Mothers It is not known whether troglitazone is secreted in human milk. Troglitazone is secreted in the milk of lactating rats. Because many drugs are excreted in human milk, Rezulin (troglitazone (removed from the us market 3/21/00)) should not be administered to a breast-feeding woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Twenty-two percent of patients in clinical trials of Rezulin (troglitazone (removed from the us market 3/21/00)) were 65 and over. No differences in effectiveness and safety were observed between these patients and younger patients.