AVANDARYL

AVANDARYL is available for oral administration as tablets containing rosiglitazone maleate and glimepiride, respectively, in the following strengths (expressed as rosiglitazone maleate/glimepiride): 4 mg/1 mg, 4 mg/2 mg, 4 mg/4 mg, 8 mg/2 mg, and 8 mg/4 mg. Each tablet contains the following inactive ingredients: hypromellose 2910, lactose monohydrate, macrogol (polyethylene glycol), magnesium stearate, microcrystalline cellulose, sodium starch glycolate, titanium dioxide, and 1 or more of the following: yellow, red, or black iron oxides.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

AVANDARYL combines 2 antidiabetic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes: Rosiglitazone maleate, a member of the thiazolidinedione class, and glimepiride, a member of the sulfonylurea class. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas sulfonylureas act primarily by stimulating release of insulin from functioning pancreatic beta cells.

Rosiglitazone: Rosiglitazone improves glycemic control by improving insulin sensitivity. Rosiglitazone is a highly selective and potent agonist for the peroxisome proliferator-activated receptor-gamma (PPARγ). In humans, PPAR receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In addition, PPARγ-responsive genes also participate in the regulation of fatty acid metabolism.

Insulin resistance is a common feature characterizing the pathogenesis of type 2 diabetes. The antidiabetic activity of rosiglitazone has been demonstrated in animal models of type 2 diabetes in which hyperglycemia and/or impaired glucose tolerance is a consequence of insulin resistance in target tissues. Rosiglitazone reduces blood glucose concentrations and reduces hyperinsulinemia in the ob/ob obese mouse, db/db diabetic mouse, and fa/fa fatty Zucker rat.

In animal models, the antidiabetic activity of rosiglitazone was shown to be mediated by increased sensitivity to insulin’s action in the liver, muscle, and adipose tissues. Pharmacologic studies in animal models indicate that rosiglitazone improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. The expression of the insulin-regulated glucose transporter GLUT-4 was increased in adipose tissue. Rosiglitazone did not induce hypoglycemia in animal models of type 2 diabetes and/or impaired glucose tolerance.

Glimepiride: The primary mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extrapancreatic effects may also play a role in the activity of sulfonylureas such as glimepiride. This is supported by both preclinical and clinical trials demonstrating that glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin. These findings are consistent with the results of a long-term, randomized, placebo-controlled trial in which glimepiride therapy improved postprandial insulin/C-peptide responses and overall glycemic control without producing clinically meaningful increases in fasting insulin/C-peptide levels. However, as with other sulfonylureas, the mechanism by which glimepiride lowers blood glucose during long-term administration has not been clearly established.

12.2 Pharmacodynamics

The lipid profiles of rosiglitazone and glimepiride in a clinical trial of patients with inadequate glycemic control on diet and exercise were consistent with the known profile of each monotherapy. AVANDARYL was associated with increases in HDL and LDL (3% to 4% for each) and decreases in triglycerides (-4%), that were not considered to be clinically meaningful.

The pattern of LDL and HDL changes following therapy with rosiglitazone in patients previously treated with a sulfonylurea was generally similar to those seen with rosiglitazone in monotherapy. Rosiglitazone as monotherapy was associated with increases in total cholesterol, LDL, and HDL and decreases in free fatty acids. The changes in triglycerides during therapy with rosiglitazone were variable and were generally not statistically different from placebo or glyburide controls.

12.3 Pharmacokinetics

In a bioequivalence trial of AVANDARYL 4 mg/4 mg, the area under the curve (AUC) and maximum concentration (C_max) of rosiglitazone following a single dose of the combination tablet were bioequivalent to rosiglitazone 4 mg concomitantly administered with glimepiride 4 mg under fasted conditions. The AUC of glimepiride following a single fasted 4 mg/4 mg dose was equivalent to glimepiride concomitantly administered with rosiglitazone, while the C_max was 13% lower when administered as the combination tablet (see Table 6).

AUC = area under the curve; C_max = maximum concentration; T_½ = terminal half-life; T_max = time of maximum concentration.

Regimen A = AVANDARYL 4 mg/4 mg tablet; Regimen B = Concomitant dosing of a rosiglitazone 4-mg tablet AND a glimepiride 4-mg tablet.

Data presented as geometric mean (range), except T_½ which is presented as arithmetic mean (range) and T_max, which is presented as median (range).

The rate and extent of absorption of both the rosiglitazone component and glimepiride component of AVANDARYL when taken with food were equivalent to the rate and extent of absorption of rosiglitazone and glimepiride when administered concomitantly as separate tablets with food.

Absorption: The AUC and C_max of glimepiride increased in a dose-proportional manner following administration of AVANDARYL 4 mg/1 mg, 4 mg/2 mg, and 4 mg/4 mg. Administration of AVANDARYL in the fed state resulted in no change in the overall exposure of rosiglitazone; however, the C_max of rosiglitazone decreased by 32% compared with the fasted state. There was an increase in both AUC (19%) and C_max (55%) of glimepiride in the fed state compared with the fasted state.

Rosiglitazone: The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. The C_max and AUC of rosiglitazone increase in a dose-proportional manner over the therapeutic dose range.

Glimepiride: After oral administration, glimepiride is completely (100%) absorbed from the gastrointestinal tract. Trials with single oral doses in normal subjects and with multiple oral doses in patients with type 2 diabetes have shown significant absorption of glimepiride within 1 hour after administration and C_max at 2 to 3 hours.

Distribution: Rosiglitazone: The mean (CV%) oral volume of distribution (V_ss/F) of rosiglitazone is approximately 17.6 (30%) liters, based on a population pharmacokinetic analysis. Rosiglitazone is approximately 99.8% bound to plasma proteins, primarily albumin.

Glimepiride: After intravenous (IV) dosing in normal subjects, the volume of distribution (Vd) was 8.8 L (113 mL/kg), and the total body clearance (CL) was 47.8 mL/min. Protein binding was greater than 99.5%.

Metabolism and Excretion: Rosiglitazone: Rosiglitazone is extensively metabolized with no unchanged drug excreted in the urine. The major routes of metabolism were N-demethylation and hydroxylation, followed by conjugation with sulfate and glucuronic acid. All the circulating metabolites are considerably less potent than parent and, therefore, are not expected to contribute to the insulin-sensitizing activity of rosiglitazone. In vitro data demonstrate that rosiglitazone is predominantly metabolized by cytochrome P450 (CYP) isoenzyme 2C8, with CYP2C9 contributing as a minor pathway. Following oral or IV administration of [¹⁴C]rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, respectively. The plasma half-life of [¹⁴C]related material ranged from 103 to 158 hours. The elimination half-life is 3 to 4 hours and is independent of dose.

Glimepiride: Glimepiride is completely metabolized by oxidative biotransformation after either an IV or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). Cytochrome P450 2C9 has been shown to be involved in the biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M1, but not M2, possesses about ⅓ of the pharmacological activity as compared with its parent in an animal model; however, whether the glucose-lowering effect of M1 is clinically meaningful is not clear.

When [¹⁴C]glimepiride was given orally, approximately 60% of the total radioactivity was recovered in the urine in 7 days and M1 (predominant) and M2 accounted for 80% to 90% of that recovered in the urine. Approximately 40% of the total radioactivity was recovered in feces and M1 and M2 (predominant) accounted for about 70% of that recovered in feces. No parent drug was recovered from urine or feces. After IV dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite has been observed.

Special Populations: No pharmacokinetic data are available for AVANDARYL in the following special populations. Information is provided for the individual components of AVANDARYL.

Gender: Rosiglitazone: Results of the population pharmacokinetics analysis showed that the mean oral clearance of rosiglitazone in female patients (N = 405) was approximately 6% lower compared with male patients of the same body weight (N = 642). Combination therapy with rosiglitazone and sulfonylureas improved glycemic control in both males and females with a greater therapeutic response observed in females. For a given body mass index (BMI), females tend to have a greater fat mass than males. Since the molecular target of rosiglitazone, PPARγ, is expressed in adipose tissues, this differentiating characteristic may account, at least in part, for the greater response to rosiglitazone in combination with sulfonylureas in females. Since therapy should be individualized, no dose adjustments are necessary based on gender alone.

•   Glimepiride: There were no differences between males and females in the pharmacokinetics of glimepiride when adjustment was made for differences in body weight.

Geriatric: Rosiglitazone: Results of the population pharmacokinetics analysis (N = 716 <65 years; N = 331 ≥65 years) showed that age does not significantly affect the pharmacokinetics of rosiglitazone.

•   Glimepiride: Comparison of glimepiride pharmacokinetics in type 2 diabetes patients 65 years and younger with those older than 65 years was performed in a trial using a dosing regimen of 6 mg daily. There were no significant differences in glimepiride pharmacokinetics between the 2 age groups. The mean AUC at steady state for the older patients was about 13% lower than that for the younger patients; the mean weight-adjusted clearance for the older patients was about 11% higher than that for the younger patients. [See Use in Specific Populations (8.5).]

Hepatic Impairment: Therapy with AVANDARYL should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT >2.5X upper limit of normal) at baseline [see Warnings and Precautions (5.7)].

•   Rosiglitazone: Unbound oral clearance of rosiglitazone was significantly lower in patients with moderate to severe liver disease (Child-Pugh Class B/C) compared with healthy subjects. As a result, unbound C_max and AUC_0-inf were increased 2- and 3-fold, respectively. Elimination half-life for rosiglitazone was about 2 hours longer in patients with liver disease, compared with healthy subjects.
•   Glimepiride: No trials of glimepiride have been conducted in patients with hepatic insufficiency.

Race: Rosiglitazone: Results of a population pharmacokinetic analysis including subjects of white, black, and other ethnic origins indicate that race has no influence on the pharmacokinetics of rosiglitazone.

•   Glimepiride: No pharmacokinetic trials to assess the effects of race have been performed, but in placebo-controlled trials of glimepiride in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (N = 536), blacks (N = 63), and Hispanics (N = 63).

Renal Impairment: Rosiglitazone: There are no clinically relevant differences in the pharmacokinetics of rosiglitazone in patients with mild to severe renal impairment or in hemodialysis-dependent patients compared with subjects with normal renal function.

•   Glimepiride: A single-dose glimepiride, open-label trial was conducted in 15 patients with renal impairment. Glimepiride (3 mg) was administered to 3 groups of patients with different levels of mean creatinine clearance (CL_cr); (Group I, CL_cr = 77.7 mL/min, N = 5), (Group II, CL_cr = 27.7 mL/min, N = 3), and (Group III, CL_cr = 9.4 mL/min, N = 7). Glimepiride was found to be well tolerated in all 3 groups. The results showed that glimepiride serum levels decreased as renal function decreased. However, M1 and M2 serum levels (mean AUC values) increased 2.3 and 8.6 times from Group I to Group III. The apparent terminal half-life (t_½) for glimepiride did not change, while the half-lives for M1 and M2 increased as renal function decreased. Mean urinary excretion of M1 plus M2 as percent of dose, however, decreased (44.4%, 21.9%, and 9.3% for Groups I to III). A multiple-dose titration trial was also conducted in 16 type 2 diabetes patients with renal impairment using doses ranging from 1 to 8 mg daily for 3 months. The results were consistent with those observed after single doses. All patients with a CL_cr less than 22 mL/min had adequate control of their glucose levels with a dosage regimen of only 1 mg daily. The results from this trial suggest that a starting dose of 1 mg glimepiride, as contained in AVANDARYL 4 mg/1 mg, may be given to type 2 diabetes patients with kidney disease, and the dose may be titrated based on fasting glucose levels.

Pediatric: No pharmacokinetic data from trials in pediatric subjects are available for AVANDARYL.

•   Rosiglitazone: Pharmacokinetic parameters of rosiglitazone in pediatric patients were established using a population pharmacokinetic analysis with sparse data from 96 pediatric patients in a single pediatric clinical trial including 33 males and 63 females with ages ranging from 10 to 17 years (weights ranging from 35 to 178.3 kg). Population mean CL/F and V/F of rosiglitazone were 3.15 L/h and 13.5 L, respectively. These estimates of CL/F and V/F were consistent with the typical parameter estimates from a prior adult population analysis.
•   Glimepiride: The pharmacokinetics of glimepiride (1 mg) were evaluated in a single-dose trial conducted in 30 type 2 diabetic patients (male = 7; female = 23) between ages 10 and 17 years. The mean AUC_0-last (338.8 ± 203.1 ng.h/mL), C_max (102.4 ± 47.7 ng/mL), and t_½ (3.1 ± 1.7 hours) were comparable to those previously reported in adults (AUC_0-last 315.2 ± 95.9 ng.h/mL, C_max 103.2 ± 34.3 ng/mL, and t_½ 5.3 ± 4.1 hours).

12.4 Drug-drug Interactions

Single oral doses of glimepiride in 14 healthy adult subjects had no clinically significant effect on the steady-state pharmacokinetics of rosiglitazone. No clinically significant reductions in glimepiride AUC and C_max were observed after repeat doses of rosiglitazone (8 mg once daily) for 8 days in healthy adult subjects.

Rosiglitazone: Drugs That Inhibit, Induce, or are Metabolized by Cytochrome P450: In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any of the major P450 enzymes at clinically relevant concentrations. In vitro data demonstrate that rosiglitazone is predominantly metabolized by CYP2C8, and to a lesser extent, 2C9. [See Drug Interactions (7.1).]

Rosiglitazone (4 mg twice daily) was shown to have no clinically relevant effect on the pharmacokinetics of nifedipine and oral contraceptives (ethinyl estradiol and norethindrone), which are predominantly metabolized by CYP3A4.

Gemfibrozil: Concomitant administration of gemfibrozil (600 mg twice daily), an inhibitor of CYP2C8, and rosiglitazone (4 mg once daily) for 7 days increased rosiglitazone AUC by 127%, compared with the administration of rosiglitazone (4 mg once daily) alone. Given the potential for dose-related adverse events with rosiglitazone, a decrease in the dose of rosiglitazone may be needed when gemfibrozil is introduced [see Drug Interactions (7.1)].

Rifampin: Rifampin administration (600 mg once a day), an inducer of CYP2C8, for 6 days is reported to decrease rosiglitazone AUC by 66%, compared with the administration of rosiglitazone (8 mg) alone [see Drug Interactions (7.1)].¹

Glyburide: Rosiglitazone (2 mg twice daily) taken concomitantly with glyburide (3.75 to 10 mg/day) for 7 days did not alter the mean steady-state 24-hour plasma glucose concentrations in diabetic patients stabilized on glyburide therapy. Repeat doses of rosiglitazone (8 mg once daily) for 8 days in healthy adult Caucasian subjects caused a decrease in glyburide AUC and C_max of approximately 30%. In Japanese subjects, glyburide AUC and C_max slightly increased following coadministration of rosiglitazone.

Digoxin: Repeat oral dosing of rosiglitazone (8 mg once daily) for 14 days did not alter the steady-state pharmacokinetics of digoxin (0.375 mg once daily) in healthy volunteers.

Warfarin: Repeat dosing with rosiglitazone had no clinically relevant effect on the steady-state pharmacokinetics of warfarin enantiomers.

Additional pharmacokinetic trials demonstrated no clinically relevant effect of acarbose, ranitidine, or metformin on the pharmacokinetics of rosiglitazone.

Glimepiride: The hypoglycemic action of sulfonylureas may be potentiated by certain drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs) and other drugs that are highly protein bound, such as salicylates, sulfonamides, chloramphenicol, coumarins, probenecid, monoamine oxidase inhibitors, and beta-adrenergic blocking agents. When these drugs are administered to a patient receiving glimepiride, the patient should be observed closely for hypoglycemia. When these drugs are withdrawn from a patient receiving glimepiride, the patient should be observed closely for loss of glycemic control.

Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, and isoniazid. When these drugs are administered to a patient receiving glimepiride, the patient should be closely observed for loss of control. When these drugs are withdrawn from a patient receiving glimepiride, the patient should be observed closely for hypoglycemia.

Drugs Metabolized by Cytochrome P450: A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the IV, topical, or vaginal preparations of miconazole is not known. There is a potential interaction of glimepiride with inhibitors (e.g., fluconazole) and inducers (e.g., rifampicin) of cytochrome P450 2C9.

Aspirin: Coadministration of aspirin (1 g three times daily) and glimepiride led to a 34% decrease in the mean glimepiride AUC and, therefore, a 34% increase in the mean CL/F. The mean C_max had a decrease of 4%. Blood glucose and serum C-peptide concentrations were unaffected and no hypoglycemic symptoms were reported.

H₂-receptor Antagonists: Coadministration of either cimetidine (800 mg once daily) or ranitidine (150 mg twice daily) with a single 4-mg oral dose of glimepiride did not significantly alter the absorption and disposition of glimepiride, and no differences were seen in hypoglycemic symptomatology.

Beta-Blockers: Concomitant administration of propranolol (40 mg three times daily) and glimepiride significantly increased C_max, AUC, and t_½ of glimepiride by 23%, 22%, and 15%, respectively, and it decreased CL/F by 18%. The recovery of M1 and M2 from urine, however, did not change. The pharmacodynamic responses to glimepiride were nearly identical in normal subjects receiving propranolol and placebo. Pooled data from clinical trials in patients with type 2 diabetes showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of beta-blockers. However, if beta-blockers are used, caution should be exercised and patients should be warned about the potential for hypoglycemia.

Warfarin: Concomitant administration of glimepiride tablets (4 mg once daily) did not alter the pharmacokinetic characteristics of R- and S-warfarin enantiomers following administration of a single dose (25 mg) of racemic warfarin to healthy subjects. No changes were observed in warfarin plasma protein binding. Glimepiride treatment did result in a slight, but statistically significant, decrease in the pharmacodynamic response to warfarin. The reductions in mean area under the prothrombin time (PT) curve and maximum PT values during glimepiride treatment were very small (3.3% and 9.9%, respectively) and are unlikely to be clinically important.

ACE Inhibitors: The responses of serum glucose, insulin, C-peptide, and plasma glucagon to 2 mg glimepiride were unaffected by coadministration of ramipril (an ACE inhibitor) 5 mg once daily in normal subjects. No hypoglycemic symptoms were reported.

Other: Although no specific interaction trials were performed, pooled data from clinical trials showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of aspirin and other salicylates, H₂-receptor antagonists, ACE inhibitors, calcium-channel blockers, estrogens, fibrates, NSAIDs, HMG CoA reductase inhibitors, sulfonamides, or thyroid hormone.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been conducted with AVANDARYL. The following data are based on findings in studies performed with rosiglitazone or glimepiride alone.

Rosiglitazone: Carcinogenesis: A 2-year carcinogenicity study was conducted in Charles River CD-1 mice at doses of 0.4, 1.5, and 6 mg/kg/day in the diet (highest dose equivalent to approximately 12 times human AUC at the maximum recommended human daily dose). Sprague-Dawley rats were dosed for 2 years by oral gavage at doses of 0.05 mg/kg/day, 0.3 mg/kg/day, and 2 mg/kg/day (highest dose equivalent to approximately 10 and 20 times human AUC at the maximum recommended human daily dose for male and female rats, respectively).

Rosiglitazone was not carcinogenic in the mouse. There was an increase in incidence of adipose hyperplasia in the mouse at doses ≥1.5 mg/kg/day (approximately 2 times human AUC at the maximum recommended human daily dose). In rats, there was a significant increase in the incidence of benign adipose tissue tumors (lipomas) at doses ≥0.3 mg/kg/day (approximately 2 times human AUC at the maximum recommended human daily dose). These proliferative changes in both species are considered due to the persistent pharmacological overstimulation of adipose tissue.

Mutagenesis: Rosiglitazone was not mutagenic or clastogenic in the in vitro bacterial assays for gene mutation, the in vitro chromosome aberration test in human lymphocytes, the in vivo mouse micronucleus test, and the in vivo/in vitro rat UDS assay. There was a small (about 2-fold) increase in mutation in the in vitro mouse lymphoma assay in the presence of metabolic activation.

Impairment of Fertility: Rosiglitazone had no effects on mating or fertility of male rats given up to 40 mg/kg/day (approximately 116 times human AUC at the maximum recommended human daily dose). Rosiglitazone altered estrous cyclicity (2 mg/kg/day) and reduced fertility (40 mg/kg/day) of female rats in association with lower plasma levels of progesterone and estradiol (approximately 20 and 200 times human AUC at the maximum recommended human daily dose, respectively). No such effects were noted at 0.2 mg/kg/day (approximately 3 times human AUC at the maximum recommended human daily dose). In juvenile rats dosed from 27 days of age through to sexual maturity (at up to 40 mg/kg/day), there was no effect on male reproductive performance, or on estrous cyclicity, mating performance or pregnancy incidence in females (approximately 68 times human AUC at the maximum recommended daily dose). In monkeys, rosiglitazone (0.6 and 4.6 mg/kg/day; approximately 3 and 15 times human AUC at the maximum recommended human daily dose, respectively) diminished the follicular phase rise in serum estradiol with consequential reduction in the luteinizing hormone surge, lower luteal phase progesterone levels, and amenorrhea. The mechanism for these effects appears to be direct inhibition of ovarian steroidogenesis.

Glimepiride: Carcinogenesis: Studies in rats at doses of up to 5,000 parts per million (ppm) in complete feed (approximately 340 times the maximum recommended human dose, based on surface area) for 30 months showed no evidence of carcinogenesis. In mice, administration of glimepiride for 24 months resulted in an increase in benign pancreatic adenoma formation which was dose-related and is thought to be the result of chronic pancreatic stimulation. The no-effect dose for adenoma formation in mice in this study was 320 ppm in complete feed, or 46 to 54 mg/kg body weight/day. This is about 35 times the maximum human recommended dose based on surface area.

Mutagenesis: Glimepiride was non-mutagenic in a battery of in vitro and in vivo mutagenicity studies (Ames test, somatic cell mutation, chromosomal aberration, unscheduled DNA synthesis, mouse micronucleus test).

Impairment of Fertility: There was no effect of glimepiride on male mouse fertility in animals exposed up to 2,500 mg/kg body weight (>1,700 times the maximum recommended human dose based on surface area). Glimepiride had no effect on the fertility of male and female rats administered up to 4,000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area).

13.2 Animal Toxicology and/or Pharmacology

Rosiglitazone: Heart weights were increased in mice (3 mg/kg/day), rats (5 mg/kg/day), and dogs (2 mg/kg/day) with rosiglitazone treatments (approximately 5, 22, and 2 times human AUC at the maximum recommended human daily dose, respectively). Effects in juvenile rats were consistent with those seen in adults. Morphometric measurement indicated that there was hypertrophy in cardiac ventricular tissues, which may be due to increased heart work as a result of plasma volume expansion.

Glimepiride: Reduced serum glucose values and degranulation of the pancreatic beta cells were observed in beagle dogs exposed to glimepiride 320 mg/kg/day for 12 months (approximately 1,000 times the recommended human dose based on surface area). No evidence of tumor formation was observed in any organ. One female and one male dog developed bilateral subcapsular cataracts. Non-GLP studies indicated that glimepiride was unlikely to exacerbate cataract formation. Evaluation of the co-cataractogenic potential of glimepiride in several diabetic and cataract rat models was negative and there was no adverse effect of glimepiride on bovine ocular lens metabolism in organ culture [see Adverse Reactions (6.1)].

14 CLINICAL STUDIES

14.1 Patients Inadequately Controlled on Diet and Exercise

In a 28-week, randomized, double-blind, clinical trial, 901 patients with type 2 diabetes inadequately controlled on diet and exercise alone (baseline mean fasting plasma glucose [FPG] 211 mg/dL and baseline mean HbA1c 9.1%) were started on AVANDARYL 4 mg/1 mg, rosiglitazone 4 mg, or glimepiride 1 mg. Doses could be increased at 4-week intervals to reach a target mean daily glucose of ≤110 mg/dL. Patients who received AVANDARYL were randomized to 1 of 2 titration schemes differing in the maximum total daily dose (4 mg/4 mg or 8 mg/4 mg). The maximum total daily dose was 8 mg for rosiglitazone monotherapy and 4 mg for glimepiride monotherapy. All treatments were administered as a once-daily regimen. Improvements in FPG and HbA1c were observed in patients treated with AVANDARYL compared with either rosiglitazone or glimepiride alone (see Table 7).

Treatment with AVANDARYL resulted in statistically significant improvements in FPG and HbA1c compared with each of the monotherapies. However, when considering choice of therapy for drug-naïve patients, the risk-benefit of initiating monotherapy or dual therapy should be considered. In particular, the risk of hypoglycemia and weight gain with dual therapy should be taken into account. [See Warnings and Precautions (5.4, 5.6), Adverse Reactions (6.1).]

14.2 Patients Previously Treated With Sulfonylureas

The safety and efficacy of rosiglitazone added to a sulfonylurea have been studied in clinical trials in patients with type 2 diabetes inadequately controlled on sulfonylureas alone. No clinical trials have been conducted with the fixed-dose combination of AVANDARYL in patients inadequately controlled on a sulfonylurea or who have initially responded to rosiglitazone alone and require additional glycemic control.

A total of 3,457 patients with type 2 diabetes participated in ten 24‑ to 26‑week randomized, double‑blind, placebo/active‑controlled trials and one 2-year double-blind, active-controlled trial in elderly patients designed to assess the efficacy and safety of rosiglitazone in combination with a sulfonylurea. Rosiglitazone 2 mg, 4 mg, or 8 mg daily, was administered either once daily (3 trials) or in divided doses twice daily (7 trials), to patients inadequately controlled on a submaximal or maximal dose of sulfonylurea.

In these trials, the combination of rosiglitazone 4 mg or 8 mg daily (administered as single- or twice-daily divided doses) and a sulfonylurea significantly reduced FPG and HbA1c compared with placebo plus sulfonylurea or further up‑titration of the sulfonylurea. Table 8 shows pooled data for 8 trials in which rosiglitazone added to sulfonylurea was compared with placebo plus sulfonylurea.

^a   P <0.0001 compared with sulfonylurea alone.

One of the 24‑ to 26‑week trials included patients who were inadequately controlled on maximal doses of glyburide and switched to 4 mg of rosiglitazone daily as monotherapy; in this group, loss of glycemic control was demonstrated, as evidenced by increases in FPG and HbA1c.

In a 2-year double-blind trial, elderly patients (aged 59 to 89 years) on half-maximal sulfonylurea (glipizide 10 mg twice daily) were randomized to the addition of rosiglitazone (N = 115, 4 mg once daily to 8 mg as needed) or to continued up‑titration of glipizide (N = 110), to a maximum of 20 mg twice daily. Mean baseline FPG and HbA1c were 157 mg/dL and 7.72%, respectively, for the rosiglitazone plus glipizide arm and 159 mg/dL and 7.65%, respectively, for the glipizide up‑titration arm. Loss of glycemic control (FPG ≥180 mg/dL) occurred in a significantly lower proportion of patients (2%) on rosiglitazone plus glipizide compared with patients in the glipizide up‑titration arm (28.7%). About 78% of the patients on combination therapy completed the 2 years of therapy while only 51% completed on glipizide monotherapy. The effect of combination therapy on FPG and HbA1c was durable over the 2‑year trial period, with patients achieving a mean of 132 mg/dL for FPG and a mean of 6.98% for HbA1c compared with no change on the glipizide arm.

15 REFERENCES

• 1.Park JY, Kim KA, Kang MH, et al. Effect of rifampin on the pharmacokinetics of rosiglitazone in healthy subjects. Clin Pharmacol Ther 2004;75:157-162.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each rounded triangular tablet contains rosiglitazone as the maleate and glimepiride as follows:

4 mg/1 mg – yellow, gsk debossed on one side and 4/1 on the other.

4 mg/2 mg – orange, gsk debossed on one side and 4/2 on the other.

4 mg/4 mg – pink, gsk debossed on one side and 4/4 on the other.

8 mg/2 mg – pale pink, gsk debossed on one side and 8/2 on the other.

8 mg/4 mg – red, gsk debossed on one side and 8/4 on the other.

4 mg/1 mg bottles of 30: NDC 0173-0841-13

4 mg/2 mg bottles of 30: NDC 0173-0842-13

4 mg/4 mg bottles of 30: NDC 0173-0843-13

8 mg/2 mg bottles of 30: NDC 0173-0844-13

8 mg/4 mg bottles of 30: NDC 0173-0845-13

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Dispense in a tight, light-resistant container.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

There are multiple medications available to treat type 2 diabetes. The benefits and risks of each available diabetes medication should be taken into account when choosing a particular diabetes medication for a given patient.

Patients should be informed of the following:

• •AVANDARYL is not recommended in patients with symptomatic heart failure.
• •A meta-analysis of mostly short-term trials suggested an increased risk for myocardial infarction with rosiglitazone compared with placebo. Data from long-term clinical trials of rosiglitazone versus other antidiabetes agents (metformin or sulfonylureas), including a cardiovascular outcome trial (RECORD), observed no difference in overall mortality or in major adverse cardiovascular events (MACE) and its components.
• •AVANDARYL is not recommended for patients who are taking insulin.
• • Management of type 2 diabetes should include diet control. Caloric restriction, weight loss, and exercise are essential for the proper treatment of the diabetic patient because they help improve insulin sensitivity. This is important not only in the primary treatment of type 2 diabetes, but also in maintaining the efficacy of drug therapy.
• •It is important to adhere to dietary instructions and to regularly have blood glucose and glycosylated hemoglobin (HbA1c) tested. It can take 2 weeks to see a reduction in blood glucose and 2 to 3 months to see the full effect of AVANDARYL.
• •The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members.
• •Blood will be drawn to check their liver function prior to the start of therapy and periodically thereafter per the clinical judgment of the healthcare professional. Patients with unexplained symptoms of nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine should immediately report these symptoms to their physician.
• •Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on AVANDARYL should immediately report these symptoms to their physician.
• •AVANDARYL should be taken with the first meal of the day.
• •Therapy with rosiglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking AVANDARYL. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical trials so the frequency of this occurrence is not known.

AVANDARYL is a registered trademark of the GSK group of companies.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2014, the GSK group of companies. All rights reserved.

AVR:14PI

MEDICATION GUIDE

AVANDARYL^® (ah-VAN-duh-ril)

(rosiglitazone maleate and glimepiride) tablets

Read this Medication Guide carefully before you start taking AVANDARYL and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about AVANDARYL, ask your doctor or pharmacist.

What is the most important information I should know about AVANDARYL?

AVANDARYL may cause serious side effects, including:

New or worse heart failure

• •The risk of heart failure may be higher in people who take AVANDARYL with insulin. Most people who take insulin should not also take AVANDARYL.
• •Rosiglitazone, one of the two drugs that make up AVANDARYL, can cause your body to keep extra fluid (fluid retention), which leads to swelling (edema) and weight gain. Extra body fluid can make some heart problems worse or lead to heart failure. Heart failure means your heart does not pump blood well enough.
• •If you have severe heart failure, you cannot start AVANDARYL.
• •If you have heart failure with symptoms (such as shortness of breath or swelling), even if these symptoms are not severe, AVANDARYL may not be right for you.

Call your doctor right away if you have any of the following:

• •swelling or fluid retention, especially in the ankles or legs
• •shortness of breath or trouble breathing, especially when you lie down
• •an unusually fast increase in weight
• •unusual tiredness

AVANDARYL can have other serious side effects. Be sure to read the section “What are possible side effects of AVANDARYL?”

What is AVANDARYL?

AVANDARYL contains 2 prescription medicines to treat diabetes, rosiglitazone maleate (AVANDIA^®) and glimepiride. AVANDARYL is used with diet and exercise to treat adults with type 2 (“adult-onset” or “non-insulin dependent”) diabetes mellitus (“high blood sugar”).

Glimepiride can help your body release more of its own insulin. Rosiglitazone can help your body respond better to the insulin made in your body and does not cause your body to make more insulin. These medicines can work together to help control your blood sugar.

AVANDARYL is not for people with type 1 diabetes mellitus or to treat a condition called diabetic ketoacidosis.

It is not known if AVANDARYL is safe and effective in children younger than 18 years old.

Who should not take AVANDARYL?

Many people with heart failure should not start taking AVANDARYL. See “What should I tell my doctor before taking AVANDARYL?”

Do not take AVANDARYL if you are allergic to rosiglitazone or any of the ingredients in AVANDARYL. See the end of this leaflet for a complete list of ingredients in AVANDARYL.

Symptoms of a severe allergic reaction with AVANDARYL may include:

• •swelling of your face, lips, tongue, or throat
• •problems with breathing or swallowing
• •skin rash or itching
• •raised red areas on your skin (hives)
• •blisters on your skin or in your mouth, nose, or eyes
• •peeling of your skin
• •fainting or feeling dizzy
• •very rapid heartbeat

What should I tell my doctor before taking AVANDARYL?

Before starting AVANDARYL, ask your doctor about what the choices are for diabetes medicines and what the expected benefits and possible risks are for you in particular.

Before taking AVANDARYL, tell your doctor about all of your medical conditions, including if you:

• • have heart problems or heart failure.
• • have type 1 (“juvenile”) diabetes or had diabetic ketoacidosis. These conditions should be treated with insulin and should not be treated with AVANDARYL.
• • have a type of diabetic eye disease called macular edema (swelling of the back of the eye).
• • have liver problems. Your doctor should do blood tests to check your liver before you start taking AVANDARYL and during treatment as needed.
• • had liver problems while taking REZULIN^™ (troglitazone), another medicine for diabetes.
• • have kidney problems. If people with kidney problems use AVANDARYL, they may need a lower dose of the medication.
• • have glucose 6-phosphate dehydrogenase (G6PD) deficiency. This condition runs in families. People with G6PD deficiency who take glimepiride (one of the medicines in AVANDARYL) may develop hemolytic anemia (fast breakdown of red blood cells).
• • are pregnant or plan to become pregnant. It is not known if AVANDARYL can harm your unborn baby. You and your doctor should talk about the best way to control your diabetes during pregnancy. If you are a premenopausal woman (before the “change of life”) who does not have regular monthly periods, AVANDARYL may increase your chances of becoming pregnant. Talk to your doctor about birth control choices while taking AVANDARYL. Tell your doctor right away if you become pregnant while taking AVANDARYL.
• • are breastfeeding or planning to breastfeed. It is not known if AVANDARYL passes into breast milk. You and your doctor should decide if you will take AVANDARYL or breastfeed. You should not do both.

Tell your doctor about all of the medicines you take including prescription and non-prescription medicines, vitamins or herbal supplements. AVANDARYL and certain other medicines can affect each other and may lead to serious side effects including high or low blood sugar, or heart problems. Especially tell your doctor if you take:

• • insulin.
• • any medicines for high blood pressure, high cholesterol or heart failure, or for prevention of heart disease or stroke.

Know the medicines you take. Keep a list of all your medicines and show it to your doctor and pharmacist before you start a new medicine. They will tell you if it is alright to take AVANDARYL with other medicines.

How should I take AVANDARYL?

• •Take AVANDARYL exactly as prescribed. Your doctor may need to change your dose until your blood sugar is better controlled.
• •Take AVANDARYL by mouth one time each day with your first main meal.
• •It usually takes a few days for AVANDARYL to start lowering your blood sugar. It may take 2 to 3 months to see the full effect on your blood sugar level.
• •If you miss a dose of AVANDARYL, take it as soon as you remember unless it is time to take your next dose. Take your next dose at the usual time. Do not take double doses to make up for a missed dose.
• •If you take too much AVANDARYL, call your doctor or poison control center right away.
• •Test your blood sugar regularly as your doctor tells you.
• •Your doctor should do blood tests to check your liver before you start AVANDARYL and during treatment as needed. Your doctor should also do regular blood sugar tests (for example, “A1c”) to monitor your response to AVANDARYL.
• •Call your doctor if you get sick, get injured, get an infection, or have surgery. AVANDARYL may not control your blood sugar levels during these times. Your doctor may need to stop AVANDARYL for a short time and give you insulin to control your blood sugar level.
• •Diet and exercise can help your body use its blood sugar better. It is important to stay on your recommended diet, lose extra weight, and get regular exercise while taking AVANDARYL.

What are possible side effects of AVANDARYL?

AVANDARYL may cause serious side effects, including:

• • New or worse heart failure. See “What is the most important information I should know about AVANDARYL?”
• • Heart attack. AVANDARYL may increase the risk of a heart attack. Talk to your doctor about what this means to you.
  Symptoms of a heart attack can include the following:
  • ∘chest discomfort in the center of your chest that lasts for more than a few minutes, or that goes away or comes back
  • ∘chest discomfort that feels like uncomfortable pressure, squeezing, fullness, or pain
  • ∘pain or discomfort in your arms, back, neck, jaw, or stomach
  • ∘shortness of breath with or without chest discomfort
  • ∘breaking out in a cold sweat
  • ∘nausea or vomiting
  • ∘feeling lightheaded
•   Call your doctor or go to the nearest hospital emergency room right away if you think you are having a heart attack.

• • Swelling (edema). AVANDARYL can cause swelling due to fluid retention. See “What is the most important information I should know about AVANDARYL?”
• • Low blood sugar (hypoglycemia). Lightheadedness, dizziness, shakiness, or hunger may mean that your blood sugar is too low. This can happen if you skip meals, drink alcohol, use another medicine that lowers blood sugar, exercise (particularly hard or long), or if you have certain medical problems. Call your doctor if low blood sugar levels are a problem for you.
• • Weight gain. Rosiglitazone, one of the medicines in AVANDARYL, can cause weight gain that may be due to fluid retention or extra body fat. Weight gain can be a serious problem for people with certain conditions including heart problems. See “What is the most important information I should know about AVANDARYL?”
• • Liver problems. It is important for your liver to be working normally when you take AVANDARYL. Your doctor should do blood tests to check your liver before you start taking AVANDARYL and during treatment as needed. Call your doctor right away if you have unexplained symptoms such as:
  • ∘nausea or vomiting
  • ∘stomach pain
  • ∘unusual or unexplained tiredness
  • ∘loss of appetite
  • ∘dark urine
  • ∘yellowing of your skin or the whites of your eyes.
• • Macular edema (a diabetic eye disease with swelling in the back of the eye). Tell your doctor right away if you have any changes in your vision. Your doctor should check your eyes regularly. Very rarely, some people have had vision changes due to swelling in the back of the eye while taking rosiglitazone, one of the medicines in AVANDARYL.
• • Fractures (broken bones), usually in the hand, upper arm, or foot. Talk to your doctor for advice on how to keep your bones healthy.
• • Low red blood cell count (anemia).
• • Ovulation (release of egg from an ovary in women) leading to pregnancy. Ovulation may happen in premenopausal women who do not have regular monthly periods. This can increase the chance of pregnancy. See “What should I tell my doctor before taking AVANDARYL?”

The most common side effects with AVANDARYL include cold-like symptoms and headache.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store AVANDARYL?

• •Store AVANDARYL at room temperature, 59°F to 86°F (15°C to 30°C). Keep AVANDARYL in the container it comes in. Keep the container closed tightly.
• •Safely, throw away AVANDARYL that is out of date or no longer needed.

Keep AVANDARYL and all medicines out of the reach of children.

General information about AVANDARYL

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use AVANDARYL for a condition for which it was not prescribed. Do not give AVANDARYL to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes important information about AVANDARYL. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about AVANDARYL that is written for healthcare professionals. You can also find out more about AVANDARYL by calling 1-888-825-5249.

What are the ingredients in AVANDARYL?

Active Ingredients: rosiglitazone maleate and glimepiride.

Inactive Ingredients: hypromellose 2910, lactose  monohydrate, macrogol (polyethylene glycol), magnesium stearate, microcrystalline cellulose, sodium starch glycolate, titanium dioxide, triacetin, and 1 or more of the following: yellow, red, or black iron oxides.

Always check to make sure that the medicine you are taking is the correct one. AVANDARYL tablets are triangles with rounded corners and look like this:

4 mg/1 mg – yellow with “gsk” on one side and “4/1” on the other.

4 mg/2 mg – orange with “gsk” on one side and “4/2” on the other.

4 mg/4 mg – pink with “gsk” on one side and “4/4” on the other.

8 mg/2 mg – pale pink with “gsk” on one side and “8/2” on the other.

8 mg/4 mg – red with “gsk” on one side and “8/4” on the other.

AVANDARYL and AVANDIA are registered trademarks of the GSK group of companies.

REZULIN is a trademark of its respective owner and is not a trademark of the GSK group of companies. The maker of this brand is not affiliated with and does not endorse the GSK group of companies or its products.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2014, the GSK group of companies. All rights reserved.

May 2014

AVR:5MG

Principal Display Panel

NDC 0173-0841-13

Avandaryl^®

rosiglitazone maleate 4 mg*

andglimepiride 1 mg

Tablets

once daily

30 Tablets

R_x only

once daily

Federal Law requires dispensing of AVANDARYL^® with the Medication Guide provided with this bottle.

Store at 25^oC (77^oF); [see USP].

*Each tablet contains rosiglitazone maleate equivalent to 4 mg of rosiglitazone and 1 mg of glimepiride.

Dispense in a tight, light-resistant container.

Dosage: See accompanying prescribing information.

GlaxoSmithKline

Research Triangle Park, NC 27709

Rev. 12/11

A100756