AVANDARYL^®
(rosiglitazone maleate and glimepiride)
Tablets

• Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure in some patients (see WARNINGS, Rosiglitazone). After initiation of AVANDARYL, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of AVANDARYL must be considered.

• AVANDARYL is not recommended in patients with symptomatic heart failure. Initiation of AVANDARYL in patients with established NYHA Class III or IV heart failure is contraindicated. (See CONTRAINDICATIONS and WARNINGS, Rosiglitazone.)

AVANDARYL (rosiglitazone maleate and glimepiride) tablets contain 2 oral antidiabetic drugs used in the management of type 2 diabetes: Rosiglitazone maleate and glimepiride.

Rosiglitazone maleate is an oral antidiabetic agent of the thiazolidinedione class which acts primarily by increasing insulin sensitivity. Rosiglitazone maleate is not chemically or functionally related to the sulfonylureas, the biguanides, or the alpha-glucosidase inhibitors. Chemically, rosiglitazone maleate is (±)-5-[[4-[2-(methyl-2-pyridinylamino) ethoxy]phenyl] methyl]-2,4-thiazolidinedione, (Z)-2-butenedioate (1:1) with a molecular weight of 473.52 (357.44 free base). The molecule has a single chiral center and is present as a racemate. Due to rapid interconversion, the enantiomers are functionally indistinguishable. The molecular formula is C₁₈H₁₉N₃O₃S•C₄H₄O₄. Rosiglitazone maleate is a white to off-white solid with a melting point range of 122° to 123°C. The pK_a values of rosiglitazone maleate are 6.8 and 6.1. It is readily soluble in ethanol and a buffered aqueous solution with pH of 2.3; solubility decreases with increasing pH in the physiological range. The structural formula of rosiglitazone maleate is:

Glimepiride is an oral antidiabetic drug of the sulfonylurea class. Glimepiride is a white to yellowish-white, crystalline, odorless to practically odorless powder. Chemically, glimepiride is 1-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea with a molecular weight of 490.62. The molecular formula for glimepiride is C₂₄H₃₄N₄O₅S. Glimepiride is practically insoluble in water. The structural formula of glimepiride is:

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.

AVANDARYL combines 2 antidiabetic agents with complementary 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 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. 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.

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 studies 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.

In a bioequivalence study 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 1).

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.

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 to the fasted state. There was an increase in both AUC (19%) and C_max (55%) of glimepiride in the fed state compared to the fasted state.

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

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 PRECAUTIONS, Hepatic Effects).

No pharmacokinetic data from studies in pediatric subjects are available for AVANDARYL.

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.

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.

In a 28-week, randomized, double-blind clinical trial, 901 drug-naïve patients with type 2 diabetes inadequately controlled with 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 to either rosiglitazone or glimepiride alone (see Table 2).

^*Least squared means, p<0.0001 compared to monotherapy.

^†Response is related to baseline HbA1c.

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, PRECAUTIONS, and ADVERSE REACTIONS.)

The lipid profiles of rosiglitazone and glimepiride 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 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 studies and one 2-year double-blind, active-controlled study 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 studies) or in divided doses twice daily (7 studies), to patients inadequately controlled on a submaximal or maximal dose of sulfonylurea.

In these studies, 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 to placebo plus sulfonylurea or further up-titration of the sulfonylurea. Table 3 shows pooled data for 8 studies in which rosiglitazone added to sulfonylurea was compared to placebo plus sulfonylurea.

^*p<0.0001 compared to sulfonylurea alone.

One of the 24- to 26-week studies 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 study, 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 to 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 study period, with patients achieving a mean of 132 mg/dL for FPG and a mean of 6.98% for HbA1c compared to no change on the glipizide arm.

The pattern of LDL and HDL changes following therapy with rosiglitazone in combination with sulfonylureas 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.

AVANDARYL is indicated as an adjunct to diet and exercise, to improve glycemic control in patients with type 2 diabetes mellitus when treatment with dual rosiglitazone and glimepiride therapy is appropriate.

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. Prior to initiation of therapy with AVANDARYL, secondary causes of poor glycemic control, e.g., infection, should be investigated and treated.

Initiation of AVANDARYL in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated (see BOXED WARNING).

AVANDARYL is contraindicated in patients with known hypersensitivity to rosiglitazone or glimepiride or any of the components of AVANDARYL.

AVANDARYL is contraindicated in patients with diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.

SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term, prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes 1970;19[Suppl. 2]:747-830). UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glimepiride-containing tablets and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

Rosiglitazone, like other thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Patients should be observed for signs and symptoms of heart failure. If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of rosiglitazone must be considered (see BOXED WARNING). In combination with insulin, thiazolidinediones may also increase the risk of other cardiovascular adverse events. Rosiglitazone should be discontinued if any deterioration in cardiac status occurs.

Patients with congestive heart failure (CHF) NYHA Class I and II treated with rosiglitazone have an increased risk of cardiovascular events. A 52-week, double-blind, placebo-controlled echocardiographic study was conducted in 224 patients with type 2 diabetes mellitus and NYHA Class I or II CHF (ejection fraction ≤45%) on background antidiabetic and CHF therapy. An independent committee conducted a blinded evaluation of fluid-related events (including congestive heart failure) and cardiovascular hospitalizations according to predefined criteria (adjudication). Separate from the adjudication, other cardiovascular adverse events were reported by investigators. Although no treatment difference in change from baseline of ejection fractions was observed, more cardiovascular adverse events were observed with rosiglitazone treatment compared to placebo during the 52-week study. (See Table 4.)

Table 4. Emergent Cardiovascular Adverse Events in Patients with Congestive Heart Failure (NYHA Class I and II) treated with Rosiglitazone or Placebo (in Addition to Background Antidiabetic and CHF Therapy)

^*Includes hospitalization for any cardiovascular reason.

Initiation of AVANDARYL in patients with established NYHA Class III or IV heart failure is contraindicated. AVANDARYL is not recommended in patients with symptomatic heart failure. (See BOXED WARNING.)

Patients with NYHA Class III and IV cardiac status were not studied during the clinical trials. Rosiglitazone is not recommended in patients with NYHA Class III and IV cardiac status.

In three 26-week trials in patients with type 2 diabetes, 216 received 4 mg of rosiglitazone plus insulin, 322 received 8 mg of rosiglitazone plus insulin, and 338 received insulin alone. These trials included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions, including peripheral neuropathy, retinopathy, ischemic heart disease, vascular disease, and congestive heart failure. In these clinical studies an increased incidence of edema, cardiac failure, and other cardiovascular adverse events was seen in patients on rosiglitazone and insulin combination therapy compared to insulin and placebo. Patients who experienced cardiovascular events were on average older and had a longer duration of diabetes. These cardiovascular events were noted at both the 4 mg and 8 mg daily doses of rosiglitazone. In this population, however, it was not possible to determine specific risk factors that could be used to identify all patients at risk of heart failure and other cardiovascular events on combination therapy. Three of 10 patients who developed cardiac failure on combination therapy during the double-blind part of the fixed-dose studies had no known prior evidence of congestive heart failure, or pre-existing cardiac condition.

In a double-blind study in type 2 diabetes patients with chronic renal failure (112 received 4 mg or 8 mg of rosiglitazone plus insulin and 108 received insulin control), there was no difference in cardiovascular adverse events with rosiglitazone in combination with insulin compared to insulin control.

Patientstreated with combination rosiglitazone and insulin should be monitored for cardiovascular adverse events. This combination therapy should be discontinued in patients who do not respond as manifested by a reduction in HbA1c or insulin dose after 4 to 5 months of therapy or who develop any significant adverse events. (See ADVERSE REACTIONS.)

There are no studies that have evaluated the safety or effectiveness of AVANDARYL in combination with insulin. Therefore, the use of AVANDARYL in combination with insulin is not recommended.

Due to the mechanisms of action, rosiglitazone and glimepiride are active only in the presence of endogenous insulin. Therefore, AVANDARYL should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

AVANDARYL is a combination tablet containing rosiglitazone and glimepiride, a sulfonylurea. All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Elderly patients are particularly susceptible to hypoglycemic action of glucose-lowering drugs. Debilitated or malnourished patients, and those with adrenal, pituitary, renal, or hepatic insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. A starting dose of 1 mg glimepiride, as contained in AVANDARYL 4 mg/1 mg, followed by appropriate dose titration is recommended in these patients. (See CLINICAL PHARMACOLOGY, Special Populations, Renal Impairment.) Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used.

Patients receiving rosiglitazone in combination with a sulfonylurea may be at risk for hypoglycemia, and a reduction in the dose of the sulfonylurea may be necessary (see DOSAGE AND ADMINISTRATION, Specific Patient Populations).

When a patient stabilized on any antidiabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold AVANDARYL and temporarily administer insulin. AVANDARYL may be reinstituted after the acute episode is resolved.

AVANDARYL should be used with caution in patients with edema. In a clinical study in healthy volunteers who received 8 mg of rosiglitazone once daily for 8 weeks, there was a statistically significant increase in median plasma volume compared to placebo.

Since thiazolidinediones, including rosiglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, AVANDARYL should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure (see BOXED WARNING, WARNINGS, Rosiglitazone, and PRECAUTIONS).

In controlled clinical trials of patients with type 2 diabetes, mild to moderate edema was reported in patients treated with rosiglitazone, and may be dose related. Patients with ongoing edema are more likely to have adverse events associated with edema if started on combination therapy with insulin and rosiglitazone (see ADVERSE REACTIONS). The use of AVANDARYL in combination with insulin is not recommended (see WARNINGS, Rosiglitazone).

Macular edema has been reported in postmarketing experience in some diabetic patients who were taking rosiglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but some patients appear to have been diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione. Patients with diabetes should have regular eye exams by an ophthalmologist, per the Standards of Care of the American Diabetes Association. Additionally, any diabetic who reports any kind of visual symptom should be promptly referred to an ophthalmologist, regardless of the patient’s underlying medications or other physical findings. (See ADVERSE REACTIONS, Rosiglitazone.)

In a 4- to 6-year comparative study (ADOPT) of glycemic control with monotherapy in drug-naïve patients recently diagnosed with type 2 diabetes mellitus, an increased incidence of bone fracture was noted in female patients taking rosiglitazone. Over the 4- to 6-year period, the incidence of bone fracture in females was 9.3% (60/645) for rosiglitazone versus 3.5% (21/605) for glyburide and 5.1% (30/590) for metformin. This increased incidence was noted after the first year of treatment and persisted during the course of the study. The majority of the fractures in the women who received rosiglitazone occurred in the upper arm, hand, and foot. These sites of fracture are different from those usually associated with postmenopausal osteoporosis (e.g., hip or spine). No increase in fracture rates was observed in men treated with rosiglitazone. The risk of fracture should be considered in the care of patients, especially female patients, treated with rosiglitazone, and attention given to assessing and maintaining bone health according to current standards of care.

Dose-related weight gain was seen with AVANDARYL, rosiglitazone alone, and rosiglitazone together with other hypoglycemic agents (see Table 5). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

In postmarketing experience with rosiglitazone alone or in combination with other hypoglycemic agents, there have been rare reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure (see BOXED WARNING).

Across all controlled clinical studies, decreases in hemoglobin and hematocrit (mean decreases in individual studies≤1.0 gram/dL and ≤3.3%, respectively) were observed for rosiglitazone alone and in combination with other hypoglycemic agents. The changes occurred primarily during the first 3 months following initiation of therapy with rosiglitazone or following a dose increase in rosiglitazone. White blood cell counts also decreased slightly in patients treated with rosiglitazone. The observed changes may be related to the increased plasma volume observed with treatment with rosiglitazone and may be dose related.

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 rosiglitazone (see PRECAUTIONS, Pregnancy, Pregnancy Category C). Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical studies so the frequency of this occurrence is not known.

Although hormonal imbalance has been seen in preclinical studies (see PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility), the clinical significance of this finding is not known. If unexpected menstrual dysfunction occurs, the benefits of continued therapy with AVANDARYL should be reviewed.

Another drug of the thiazolidinedione class, troglitazone, was associated with idiosyncratic hepatotoxicity, and very rare cases of liver failure, liver transplants, and death were reported during clinical use. In pre-approval controlled clinical trials in patients with type 2 diabetes, troglitazone was more frequently associated with clinically significant elevations in liver enzymes (ALT >3X upper limit of normal) compared to placebo. Very rare cases of reversible jaundice were also reported.

In pre-approval clinical studies in 4,598 patients treated with rosiglitazone, encompassing approximately 3,600 patient years of exposure, there was no signal of drug-induced hepatotoxicity or elevation of ALT levels. In the pre-approval controlled trials, 0.2% of patients treated with rosiglitazone had elevations in ALT >3X the upper limit of normal compared to 0.2% on placebo and 0.5% on active comparators. The ALT elevations in patients treated with rosiglitazone were reversible and were not clearly causally related to therapy with rosiglitazone.

In postmarketing experience with rosiglitazone, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established. Rosiglitazone is structurally related to troglitazone, a thiazolidinedione no longer marketed in the United States, which was associated with idiosyncratic hepatotoxicity and rare cases of liver failure, liver transplants, and death during clinical use. Pending the availability of the results of additional large, long-term controlled clinical trials and additional postmarketing safety data, it is recommended that patients treated with AVANDARYL undergo periodic monitoring of liver enzymes.

With sulfonylureas, including glimepiride, there may be an elevation of liver enzyme levels in rare cases. In isolated instances, impairment of liver function (e.g., with cholestasis and jaundice), as well as hepatitis (which may also lead to liver failure) have been reported.

Liver enzymes should be checked prior to the initiation of therapy with AVANDARYL in all patients and periodically thereafter per the clinical judgement of the healthcare professional. Therapy with AVANDARYL should not be initiated in patients with increased baseline liver enzyme levels (ALT >2.5X upper limit of normal). Patients with mildly elevated liver enzymes (ALT levels ≤2.5X upper limit of normal) at baseline or during therapy with AVANDARYL should be evaluated to determine the cause of the liver enzyme elevation. Initiation of, or continuation of, therapy with AVANDARYL in patients with mild liver enzyme elevations should proceed with caution and include close clinical follow-up, including more frequent liver enzyme monitoring, to determine if the liver enzyme elevations resolve or worsen. If at any time ALT levels increase to >3X the upper limit of normal in patients on therapy with AVANDARYL, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain >3X the upper limit of normal, therapy with AVANDARYL should be discontinued.

If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with AVANDARYL should be guided by clinical judgement pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.

There are no data available from clinical trials to evaluate the safety of AVANDARYL in patients who experienced liver abnormalities, hepatic dysfunction, or jaundice while on troglitazone. AVANDARYL should not be used in patients who experienced jaundice while taking troglitazone.

Periodic fasting glucose and HbA1c measurements should be performed to monitor therapeutic response.

Liver enzyme monitoring is recommended prior to initiation of therapy with AVANDARYL in all patients and periodically thereafter (see PRECAUTIONS, Hepatic Effects).

Patients should be informed of the potential risks and advantages of AVANDARYL and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, weight loss, and a regular exercise program because these methods help improve insulin sensitivity. The importance of regular testing of blood glucose and glycosylated hemoglobin (HbA1c) should be emphasized. Patients should be advised that the sulfonylurea effect of AVANDARYL can begin to take effect within days after initiation, however it can take 2 to 3 months to see the full effect of glycemic improvement.

The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members.

Patients should be informed that blood will be drawn to check their liver function prior to the start of therapy and periodically thereafter per the clinical judgement 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 (see PRECAUTIONS, Pregnancy, Pregnancy Category C). Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical studies so the frequency of this occurrence is not known.

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

Pregnancy Category C. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies as well as increased neonatal morbidity and mortality, most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible. AVANDARYL should not be used during pregnancy.

There are no adequate and well-controlled studies with AVANDARYL or its individual components in pregnant women. No animal studies have been conducted with AVANDARYL. The following data are based on findings in studies performed with rosiglitazone or glimepiride individually.

The effect of AVANDARYL or its components on labor and delivery in humans is unknown.

No studies have been conducted with AVANDARYL. It is not known whether rosiglitazone and/or glimepiride is excreted in human milk. Because many drugs are excreted in human milk, AVANDARYL should not be administered to a nursing woman. If AVANDARYL is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered (see PRECAUTIONS, Pregnancy, Pregnancy Category C).

Safety and effectiveness of AVANDARYL in pediatric patients have not been established. AVANDARYL and its components, rosiglitazone and glimepiride, are not indicated for use in pediatric patients.

Adverse events occurring at a frequency of ≥5% in any treatment group in the 28-week double-blind trial of AVANDARYL in drug-naïve patients with type 2 diabetes mellitus are presented in Table 6. Patients in this trial 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 maximum total daily dose of either 4 mg/4 mg or 8 mg/4 mg for AVANDARYL, 8 mg for rosiglitazone monotherapy or 4 mg for glimepiride monotherapy.

Table 6. Adverse Events (≥5% in Any Treatment Group) Reported by Drug-Naïve Patients in a 28-Week Double-Blind Clinical Trial of AVANDARYL

^*As documented by symptoms and a fingerstick blood glucose measurement of <50 mg/dL.

Hypoglycemia was reported to be generally mild to moderate in intensity and none of the reported events of hypoglycemia resulted in withdrawal from the study. Hypoglycemia requiring parenteral treatment (i.e., intravenous glucose or glucagon injection) was observed in 3 (0.7%) patients treated with AVANDARYL.

Edema was reported by 3.2% of patients on AVANDARYL, 3.0% on rosiglitazone alone, and 2.3% on glimepiride alone.

Congestive heart failure was observed in 1 (0.2%) patient treated with AVANDARYL and in 1 (0.4%) patient treated with rosiglitazone monotherapy.

Studies utilizing rosiglitazone in combination with a sulfonylurea provide support for the use of AVANDARYL. Adverse event data from these trials, in addition to adverse events reported with the use of rosiglitazone and glimepiride as monotherapy, are presented below.

The most common adverse experiences with rosiglitazone monotherapy (≥5%) were upper respiratory tract infection, injury, and headache. Overall, the types of adverse experiences reported when rosiglitazone was added to a sulfonylurea were similar to those during monotherapy with rosiglitazone. In controlled combination therapy studies with sulfonylureas, mild to moderate hypoglycemic symptoms, which appear to be dose related, were reported. Few patients were withdrawn for hypoglycemia (<1%) and few episodes of hypoglycemia were considered to be severe (<1%).

Events of anemia and edema tended to be reported more frequently at higher doses, and were generally mild to moderate in severity and usually did not require discontinuation of treatment with rosiglitazone.

Edema was reported by 4.8% of patients receiving rosiglitazone compared to 1.3% on placebo, and 1.0% on sulfonylurea monotherapy. The reporting rate of edema was higher for rosiglitazone 8 mg added to a sulfonylurea (12.4%) compared to other combinations, with the exception of insulin. Anemia was reported by 1.9% of patients receiving rosiglitazone compared to 0.7% on placebo, 0.6% on sulfonylurea monotherapy, and 2.3% on rosiglitazone in combination with a sulfonylurea. Overall, the types of adverse experiences reported when rosiglitazone was added to a sulfonylurea were similar to those during monotherapy with rosiglitazone.

In 26-week double-blind, fixed-dose studies, edema was reported with higher frequency in the rosiglitazone plus insulin combination trials (insulin, 5.4%; and rosiglitazone in combination with insulin, 14.7%). Reports of new onset or exacerbation of congestive heart failure occurred at rates of 1% for insulin alone, and 2% (4 mg) and 3% (8 mg) for insulin in combination with rosiglitazone (see BOXED WARNING and WARNINGS, Rosiglitazone).

In postmarketing experience in patients receiving thiazolidinedione therapy, serious adverse events potentially related to volume expansion (e.g., congestive heart failure, pulmonary edema with or without a fatal outcome, and pleural effusions) have been reported (see BOXED WARNING and WARNINGS, Rosiglitazone).

In postmarketing experience with rosiglitazone, rash, pruritus, urticaria, angioedema and anaphylactic reaction have been reported rarely.

Postmarketing reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received (see PRECAUTIONS, Macular Edema).

Pediatric Use

OVERDOSAGE

Rosiglitazone

Glimepiride

DOSAGE AND ADMINISTRATION

Starting Dose

Dose Titration

Maximum Dose

Specific Patient Populations

HOW SUPPLIED

STORAGE

REFERENCE

Patient Information