DESCRIPTION

Rezulin ™ (troglitazone) is an oral antihyperglycemic agent which acts primarily by decreasing insulin resistance. Rezulin 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 a-glucosidase inhibitors. The molecule contains 2 chiral centers, with each of the 4 stereoisomers having similar pharmacologic effects. The structural formula is as shown:

Troglitazone is a white to yellowish crystalline compound; it may have a faint,characteristic odor. Troglitazone has a molecular formula of C24H27NO5S 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 is available as 200 and 400 mg tablets for oral administration formulatedwith 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.

CLINICAL PHARMACOLOGY

Mechanism of Action

Troglitazone is a thiazolidinedione antidiabetic agent that lowers blood glucose by improving target cell response to insulin. It has a unique mechanismof action that is dependent on the presence of insulin for activity. Troglitazone decreases hepatic glucose output and increases insulin-dependent glucose disposalin skeletal muscle. Its mechanism of action is thought to involve binding to nuclear receptors (PPAR) that regulate the transcription of a number of insulin responsive genes critical for the control of glucose and lipid metabolism. Unlikesulfonylureas, troglitazone is not an insulin secretagogue.

In animal models of diabetes, troglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type II diabetes. Plasma lactate and ketone body formation arealso decreased. The metabolic changes produced by troglitazone result from the increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance. Treatment with troglitazone did not affect pancreatic weight, islet number or glucagon content, but did increase regranulation of the pancreatic beta cells in rodent models of insulin resistance.

Since troglitazone enhances the effects of circulating insulin (by decreasinginsulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.

Pharmacokinetics and Drug Metabolism

Maximum plasma concentration (Cmax) and the area under plasma concentration-timecurve (AUC) of troglitazone increase proportionally with increasing doses over the dose range of 200 to 600 mg/day (Table 1). Following daily drug administration, steady-state plasma concentrations of troglitazone are reached within 3 to 5 days.

Absorption: Troglitazone is absorbed rapidly following oral administration; the time for maximum plasma concentration (tmax) occurs within 2 to 3 hours. Food increases the extent of absorption by 30% to 85%; thus Rezulin should be taken with a meal to enhance systemic drug availability.

Distribution: Mean apparent volume of distribution (V/F) of troglitazone following multiple-dose administration ranges from 10.5 to 26.5 L/kg of body weight.Troglitazone is extensively bound (>99%) to serum albumin. [14C]troglitazone partitions into red blood cells (~5% of whole blood radioactivity).

Metabolism: In 6 healthy male volunteers given a single 400 mg dose of [14C]troglitazone after 14 days of treatment with 400 mg troglitazone tablets, the major metabolites found in the plasma were the sulfate conjugate (Metabolite 1),followed by the quinone metabolite (Metabolite 3). Only 3.1% of the dose was detected in the urine; this was primarily in the form of the glucuronide conjugate (Metabolite 2), which is present in negligible amounts in the plasma. In both normal volunteers and patients with type II diabetes, steady-state levels of Metabolite 1 are 6 to 7 times that of troglitazone and Metabolite 3.

Troglitazone incubated with expressed human P450 1A1, 1A2, 2A6, 2B6, 2D6, 2E1, and 3A4 in the presence and absence of known inhibitors of these enzymes showed no Metabolite 3 formation above levels in control samples. Incubation of Metabolite3 with human liver microsomes suggests that it is not subject to further metabolism.

The inhibitory profile of troglitazone against the 7 major P450 isozymes was characterized using human liver microsomes. Troglitazone was found to inhibit 3A4,2C9, and 2C19 by 40% to 67% at a concentration of 11 µg/mL. Since the highest peak concentrations expected to be achieved on 600 mg once daily is in the range of 1 to3 µg/mL, inhibition may not be clinically important. The results of in vivo drug interaction studies tend to support this observation (see Drug Interactions); caution should be observed when Rezulin is used in combination with drugs known to be metabolized by one of these enzymes. The inhibitory characteristics of Metabolite 3 have not been investigated directly.

Excretion: Following oral administration of [14C]troglitazone, approximately 88% of the radioactivity is recovered in feces (85%) and urine (3%). Unchanged troglitazone is not recovered in urine following oral administration. Mean plasma elimination half-life of troglitazone ranges from 16 to 34 hours.

Special Populations

Renal Insufficiency: In patients with various degrees of renal function, the apparent clearance of total and unbound troglitazone and the plasma eliminationhalf-life of troglitazone, Metabolite 1, and Metabolite 3 do not correlate with creatinine clearance. Thus, dose adjustment in patients with renal dysfunction is not necessary (see DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency: Troglitazone, Metabolite 1, and Metabolite 3 plasma concentrations in patients with chronic liver disease (Childs-Pugh Grade Bor C) were increased by approximately 30%, 400% and 100%, respectively, compared to those in healthy subjects without hepatic dysfunction. There was no change in plasma protein binding. No adverse events were noted in any group that were attributed to drug. Nevertheless, Rezulin should be used with caution in patients with hepatic disease.

Geriatrics: Steady-state pharmacokinetics of troglitazone, Metabolite 1, and Metabolite 3 in healthy elderly subjects are comparable to those seen in young adults.

Pediatrics: Pharmacokinetic data in the pediatric population are not available.

Gender: Plasma concentrations of troglitazone and its metabolites are similar in men and women.

Ethnicity: Pharmacokinetics of troglitazone and its metabolites are similar among various ethnic groups.

Rezulin ™ (Troglitazone) Tablets

Pharmacodynamics and Clinical Effects

Clinical studies demonstrate that Rezulin improves insulin sensitivity ininsulin-resistant patients. Rezulin increases insulin-dependent glucose disposal, reduces hepatic gluconeogenesis, and enhances cellular responsiveness to insulin and thus, improves dysfunctional glucose homeostasis. In patients with type II diabetes, the decreased insulin resistance produced by Rezulin causes decreases in serum glucose, plasma insulin, and hemoglobin A1C. These effects are independentof weight loss and persist with Rezulin treatment.

Following Rezulin treatment, LDL, HDL, and total cholesterol (total-C) increase, although total-C/HDLand LDL/HDL ratios do not change. The increase in total cholesterol is due to the increase in HDL and LDL cholesterol. Despite the observed increase in total and LDL cholesterol, ApoB fraction levels are not increased. Patients treated with Rezulin and concomitant insulin exhibit an initial reduction in triglyceride levels.With the reduction in insulin doses that may occur following Rezulin therapy, some attenuation of the triglyceride reduction may occur.

Pharmacokinetic estimators of systemic troglitazone exposure do not improve the prediction of pharmacodynamic response beyond that obtained based upon knowledge of the administered dose.

Rezulin has only been shown to exert its antihyperglycemic effect in the presence of insulin. Because Rezulin does not stimulate insulin secretion, hypoglycemia in patients treated with Rezulin alone is not to be expected. Because of this insulin-dependent mechanism of action, Rezulin should not be used in patients with type I diabetes.

Clinical Studies

Two clinical studies were conducted to evaluate the effects of Rezulin on glycemic control and insulin dose in patients with type II diabetes who were being treated with insulin.

In one 6-month, double-blind, placebo-controlled study in insulin-treated type II diabetic patients receiving a mean of 73 (range 27-143) units/day of insulin with a mean baseline HbA1C of 9.42 (range 7.04-12.48), Rezulin (200 or 600 mg/day) or placebo was added to the insulin therapy. Investigators were instructed to reduce insulin doses only if two consecutive FSGs were <=100 mg/dL. Rezulin-treated patients showed a significant (p<0.0001) reduction in HbA1C compared with patients who received placebo (see Table 2).

Thirty percent of patients treated with 200 mg Rezulin and 57% of patients treated with 600 mg Rezulin had an HbA1C value below 8% at the end of the study compared with 11% of placebo-treated patients. Accompanying this improvement in glycemic control was a significant (p<0.0001) decrease in exogenous insulin dosage of 15% in the 200 mg Rezulin treatment group and 42% in the 600 mg Rezulin treatment group compared with 1% in the placebo group. HbA1C values and insulin dose as a function of duration of Rezulin treatment are presented in Figures 1 and 2.

A second 6-month, double-blind, placebo-controlled study in insulin-treated type II diabetics who previously were poorly controlled on oral agents receiving 30 to 150 units insulin/day assessed the use of Rezulin in reducing exogenous insulin dosage while improving glycemic control as measured by capillary blood glucose.

Patients treated with 200 mg (N=75) and 400 mg (N=76) Rezulin had their insulin doses decreased by 41% and 58%, respectively, compared to a reduction of insulin dose in the placebo group (N=71) of 14% while maintainingor improving glycemic control. Forty-one percent of the patients in the 400 mg group decreased their insulin injection frequency an average from 3 to 1 injectionsper day; 19% of patients receiving placebo decreased their injection frequency an average from 3 to 2 injections per day. Insulin therapy was discontinued in 15% of patients in the 400 mg Rezulin group compared to 7% in the 200 mg group and 1.5% in the placebo group.

Rezulin ™ (Troglitazone) Tablets

A greater than 50% reduction in insulin dose was achieved by 51% of patients on 200 mg and 70% on 400 mg once daily as compared to 17% on placebo.

An extended open-label study of Rezulin (N=17), has followed insulin-treated type II diabetic patients for up to 9 months. Following 9 months of treatment with400 mg of Rezulin, mean HbA1C levels were decreased by 0.8% compared with baseline values of 11.8% ± 2.0% (mean ± SD). The mean insulin daily dose decreased by 71% (42 units/day) in these seventeen patients.

INDICATIONS AND USAGE

Rezulin is indicated for use in patients with type II diabetes currently on insulin therapy whose hyperglycemia is inadequately controlled (HbA1c >8.5%) despite insulin therapy of over 30 units per day given as multiple injections.

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 therapy, secondary causes of poor glycemic control, eg, infection or poor injection technique, should be investigated and treated.

CONTRAINDICATIONS

Rezulin is contraindicated in patients with known hypersensitivity or allergy to Rezulin or any of its components.

PRECAUTIONS

General

Because of its mechanism of action, Rezulin is active only in the presence of insulin. Therefore, Rezulin should not be used in type I diabetes or for the treatment of diabetic keto-acidosis.

Hepatic: During all clinical studies in North America (N=2510 patients),a total of 20 Rezulin-treated patients were withdrawn from treatment because of liver function test abnormalities. Two of the 20 patients developed reversible jaundice. Both had liver biopsies which were consistent with an idiosyncratic drug reaction (see ADVERSE REACTIONS, Laboratory Abnormalities).

Hypoglycemia: Patients receiving Rezulin in combination with insulin may be at risk for hypoglycemia and a reduction in the dose of insulin may be necessary.Hypoglycemia has not been observed during the administration of Rezulin as monotherapy and would not be expected based on the mechanism of action.

Ovulation: In premenopausal anovulatory patients with insulin resistance, Rezulin 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 been associated with any significant hematologic clinical effects (See ADVERSE REACTIONS, Laboratory Abnormalities).

Information for Patients

Rezulin 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, infection, or surgery, insulin requirements may change and patients should seek the advice of their physician.

When using combination therapy with insulin, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members.

Drug Interactions

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

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

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

Sulfonylureas: Coadministration of Rezulin with glyburide does not appear to alter troglitazone or glyburide pharmacokinetics, but may further decrease fasting plasma glucose. There are insufficient data on the use of Rezulin with sulfonylureas to establish the efficacy of this combination.

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.

Terfenadine: Coadministration of Rezulin with terfenadine decreases plasma concentrations of terfenadine and its active metabolite by 50 to 70% and may reduce the effectiveness of terfenadine.

Oral Contraceptives: Administration of Rezulin with an oral contraceptive containing ethinyl estradiol and norethindrone reduced the plasma concentrations of both by approximately 30%. These changes could result in loss of contraception.
The above interactions with terfenadine and oral contraceptives suggest that troglitazone may induce drug metabolism by CYP3A4. These findings should be considered when prescribing other CYP3A4 substrates such as cyclosporine, tacrolimus and some HMG-CoA reductase inhibitors.

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, 50, or 200 mg/kg. Maximum plasma troglitazone AUC values based on parent compound represent exposures 12- and 47-fold higher for male and female rats, respectively, than human exposure of 400 mg daily. Troglitazone was not carcinogenic in male rats at any dose tested. In female rats, there was a statistically significant increase in sarcomatous tumors at the high dose (47-fold greater than estimated human exposure of parent compound). However, these findings are of unknown clinical relevance as this dose was associated with excessive mortality and is considered to have surpassed the maximum tolerated dose.No tumors of any type were increased in female rats at 25 and 50 mg/kg at exposures of 5- to 14-fold higher than in humans based on AUC of parent compound. 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 with increased tumor incidence (400 mg/kg) was associated with AUC values of parent compound that were at least 16-fold higher than the human exposure. No tumors of any type were increased in mice at 50 mg/kg at exposures 2- to 4-fold higher than in humans based on AUC of parent compound.

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 cell gene 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 at these doses was estimated to be 2-to 8-fold higher than the human exposure.

Pregnancy

Pregnancy Category B. Troglitazone was not teratogenic in rats given up to 2000 mg/kg or rabbits given up to 1000 mg/kg during organogenesis. Compared to human exposure of 400 mg daily, estimated exposures based on AUC at these doses were up to 8-fold higher in rats and up to 6-fold higher in rabbits. Body weights of fetuses and offspring of rats given 2000 mg/kg during gestation were decreased. 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 should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenitalanomalies 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 should not be administered to a breast-feeding woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

0352G040

Rezulin ™ (Troglitazone) Tablets

Geriatric Use

Twenty-two percent of patients in clinical trials of Rezulin were 65 and over. No differences in effectiveness and safety were observed between these patients and younger patients.

Use in Patients With Heart Failure

Heart enlargement without microscopic changes has been observed in rodents at exposures exceeding 14 times the AUC of the 400 mg human dose. Serial echocardiographic evaluations in monkeys treated chronically at maximum achievableexposures (3-5 times the human exposure at the 400 mg dose) did not reveal changes in heart size or function. In a 2-year echocardiographic clinical study using 600 to 800 mg/day of Rezulin 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 plasmavolume 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 (eg, congestive heart failure) have been observed during controlled clinical trials. However, patients with New York Heart Association (NYHA) Class III and IV cardiac status were not studied during clinicaltrials. Therefore, caution is advised during the administration of Rezulin to patients with NYHA Class III or IV cardiac status.

ADVERSE REACTIONS

In general, Rezulin is well-tolerated. Two patients in the clinical studies developed reversible jaundice with findings on liver biopsy consistent with idiosyncratic drug reaction (See PRECAUTIONS, General).

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 3. 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 3. 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 controlled clinical trials, 2.2% of Rezulin-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-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 for LDH were increased slightly (see PRECAUTIONS, General, Hepatic).

DOSAGE AND ADMINISTRATION

The current insulin dose should be continued upon initiation of Rezulin therapy.Rezulin therapy should be initiated at 200 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of Rezulin should be increased after approximately 2 to 4 weeks.The usual dose of Rezulin is 400 mg once daily. The maximum recommended daily dose is 600 mg. It is recommended thatthe insulin dose be decreased by 10% to 25% when fasting plasma glucoseconcentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and Rezulin. Further adjustments should be individualized based on glucose-lowering response. Rezulin should be taken with a meal.

Patients With Renal Insufficiency

Dose adjustment in patients with renal insufficiency is not required (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism).

Patients With Hepatic Impairment

Rezulin should be used with caution in patients with hepatic disease (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism).

HOW SUPPLIED

Rezulin is available in 200 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)

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 Degrees C-25 Degrees C (68 Degrees F-77 Degrees F). Protect from moisture and humidity.
Caution: Federal law prohibits dispensing without prescription.

©1997, Warner-Lambert Co.
January 1997

PARKE-DAVIS
Div of Warne r-Lambert Co
Morris Plains, NJ 07950 USA

Marketed by:
PARKE-DAVIS
Div of Warner-Lambert Co and
SANKYO PARKE DAVIS
Parsippany, NJ 07054 USA