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avandamet (rosiglitazone maleate and metformin hydrochloride)  tablet 
[GlaxoSmithKline]

DESCRIPTION

AVANDAMET (rosiglitazone maleate and metformin HCl) tablets contain 2 oral antihyperglycemic drugs used in the management of type 2 diabetes: Rosiglitazone maleate and metformin hydrochloride.

Rosiglitazone maleate is an oral antidiabetic agent, which acts primarily by increasing insulin sensitivity. Rosiglitazone improves glycemic control while reducing circulating insulin levels. Pharmacologic studies in animal models indicate that rosiglitazone improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Rosiglitazone maleate is not chemically or functionally related to the sulfonylureas, the biguanides, or the a-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 pKa 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:

Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C4H11N5•HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula of metformin hydrochloride is:

AVANDAMET is available for oral administration as tablets containing rosiglitazone maleate and metformin hydrochloride equivalent to: 2 mg rosiglitazone with 500 mg metformin hydrochloride (2 mg/500 mg), 4 mg rosiglitazone with 500 mg metformin hydrochloride (4 mg/500 mg), 2 mg rosiglitazone with 1,000 mg metformin hydrochloride (2 mg/1,000 mg), and 4 mg rosiglitazone with 1,000 mg metformin hydrochloride (4 mg/1,000 mg). In addition, each tablet contains the following inactive ingredients: Hypromellose 2910, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, povidone 29-32, sodium starch glycolate, titanium dioxide, and 1 or more of the following: Red and yellow iron oxides.

CLINICAL PHARMACOLOGY

Mechanism of Action

AVANDAMET

AVANDAMET 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 metformin hydrochloride, a member of the biguanide class. Thiazolidinediones are insulin sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas biguanides act primarily by decreasing endogenous hepatic glucose production.

Rosiglitazone maleate

Rosiglitazone, a member of the thiazolidinedione class of antidiabetic agents, improves glycemic control by improving insulin sensitivity while reducing circulating insulin levels. Rosiglitazone is a highly selective and potent agonist for the peroxisome proliferator–activated receptor-gamma (PPAR?). In humans, PPAR receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR? nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In addition, PPAR?-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, rosiglitazone’s antidiabetic activity was shown to be mediated by increased sensitivity to insulin's action in the liver, muscle, and adipose tissue. 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.

Metformin hydrochloride

Metformin hydrochloride is an antihyperglycemic agent, which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and increases peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Pharmacokinetics

Absorption

AVANDAMET

In a bioequivalence and dose proportionality study of AVANDAMET 4 mg/500 mg, both the rosiglitazone component and the metformin component were bioequivalent to coadministered 4 mg rosiglitazone maleate tablet and 500 mg metformin hydrochloride tablet under fasted conditions (see Table 1). In this study, dose proportionality of rosiglitazone in the combination formulations of 1 mg/500 mg and 4 mg/500 mg was demonstrated.

Administration of AVANDAMET 4 mg/500 mg with food resulted in no change in overall exposure (AUC) for either rosiglitazone or metformin. However, there were decreases in Cmax of both components (22% for rosiglitazone and 15% for metformin, respectively) and a delay in Tmax of both components (1.5 hours for rosiglitazone and 0.5 hours for metformin, respectively). These changes are not likely to be clinically significant. The pharmacokinetics of both the rosiglitazone component and the metformin component of AVANDAMET when taken with food were similar to the pharmacokinetics of rosiglitazone and metformin when administered concomitantly as separate tablets with food.

Absorption

Rosiglitazone maleate

The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Maximum plasma concentration (Cmax) and the area under the curve (AUC) of rosiglitazone increase in a dose-proportional manner over the therapeutic dose range. The elimination half-life is 3 to 4 hours and is independent of dose.

Absorption

Metformin hydrochloride

The absolute bioavailability of a 500 mg metformin hydrochloride tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin hydrochloride tablets of 500 mg to 1,500 mg, and 850 mg to 2,550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination.

Distribution

Rosiglitazone maleate

The mean (CV%) oral volume of distribution (Vss/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.

Distribution

Metformin hydrochloride

The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg metformin hydrochloride averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.

Metabolism and Excretion

Rosiglitazone maleate

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 intravenous 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.

Metabolism and Excretion

Metformin hydrochloride

Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance is approximately 3.5 times greater than creatinine clearance which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Special Populations

Renal Impairment

In subjects with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see WARNINGS, also see GLUCOPHAGE® prescribing information, and CLINICAL PHARMACOLOGY, Pharmacokinetics). Since metformin is contraindicated in patients with renal impairment, administration of AVANDAMET is contraindicated in these patients.

Hepatic Impairment

Unbound oral clearance of rosiglitazone was significantly lower in patients with moderate to severe liver disease (Child-Pugh Class B/C) compared to healthy subjects. As a result, unbound Cmax and AUC0-inf were increased 2- and 3-fold, respectively. Elimination half-life for rosiglitazone was about 2 hours longer in patients with liver disease, compared to healthy subjects.

Therapy with AVANDAMET 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 studies of metformin have been conducted in subjects with hepatic insufficiency.

Geriatric

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. However, limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see GLUCOPHAGE prescribing information and CLINICAL PHARMACOLOGY, Pharmacokinetics). Metformin treatment and therefore treatment with AVANDAMET should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced (see WARNINGS and DOSAGE AND ADMINISTRATION).

Gender

Results of the population pharmacokinetics analysis showed that the mean oral clearance of rosiglitazone in female patients (n = 405) was approximately 6% lower compared to male patients of the same body weight (n = 642). In rosiglitazone and metformin combination studies, efficacy was demonstrated with no gender differences in glycemic response.

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin hydrochloride tablets was comparable in males and females.

Race

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.

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin hydrochloride in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n = 249), blacks (n = 51), and Hispanics (n = 24).

Pediatric

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

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/hr 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.

Drug Interactions

Rosiglitazone maleate

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.

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 to 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.

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

Metformin hydrochloride

Furosemide: A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when coadministered chronically.

Nifedipine: A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.

Cationic Drugs: Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics.

Other: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.

In healthy volunteers, the pharmacokinetics of metformin and propranolol and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies.

Metformin is negligibly bound to plasma proteins and is therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid.

CLINICAL STUDIES

Drug-Na?ve Patients with Type 2 Diabetes Mellitus

In a 32-week, randomized, double-blind clinical trial, 468 drug-naïve patients with type 2 diabetes mellitus inadequately controlled with diet and exercise alone (mean baseline FPG 198 mg/dL and mean baseline HbA1c 8.8% ) were randomized to AVANDAMET 2 mg/500 mg, rosiglitazone 4 mg, or metformin 500 mg. Doses were increased at 4-week intervals up to a maximum of 8 mg/2,000 mg for AVANDAMET, 8 mg for rosiglitazone, and 2,000 mg for metformin to reach a target mean daily glucose of ≤110 mg/dL. Following the initial dosage level, AVANDAMET, rosiglitazone, and metformin were all administered as twice daily regimens. Statistically significant improvements in FPG and HbA1c were observed in patients treated with AVANDAMET compared to either rosiglitazone or metformin alone (see Table 2). However, when considering the choice of therapy for drug-naïve patients, the risk-benefit of initiating monotherapy or dual therapy should be considered.

The lipid profiles of AVANDAMET as well as rosiglitazone and metformin monotherapies are shown in Table 3.

Patients screened in the double-blind clinical trial described above with HbA1c >11% or FPG >270 mg/dL were not eligible for blinded treatment but were treated with open-label AVANDAMET (4 mg/1,000 mg up to a maximum dose of 8 mg/2,000 mg). Treatment with AVANDAMET reduced mean HbA1c from a baseline of 11.8% to 7.8% and mean FPG from a baseline of 305 mg/dL to 166 mg/dL. Given the lack of direct comparators in this evaluation, determination of the exact contribution of rosiglitazone and metformin as well as diet and exercise, to the observed improvement in glycemic control is not possible.

AVANDAMET Therapy in Patients with Type 2 Diabetes Mellitus Treated with Metformin Hydrochloride

AVANDAMET was not studied in patients previously treated with metformin monotherapy; however, the combination of rosiglitazone maleate and metformin hydrochloride was compared to rosiglitazone and metformin monotherapies in clinical trials. Bioequivalence between AVANDAMET and coadministered rosiglitazone maleate tablets and metformin hydrochloride tablets has been demonstrated (see CLINICAL PHARMACOLOGY, Pharmacokinetics).

The pattern of LDL, HDL, and total cholesterol changes following therapy with rosiglitazone in combination with metformin was generally similar to those seen with rosiglitazone monotherapy, and a small decrease in mean triglycerides was observed with the combination therapy.

A total of 670 patients with type 2 diabetes participated in two 26-week, randomized, double-blind, placebo/active-controlled studies designed to assess the efficacy of rosiglitazone in combination with metformin. Rosiglitazone maleate, administered in either once-daily or twice-daily dosing regimens, was added to the therapy of patients who were inadequately controlled on 2.5 grams/day of metformin hydrochloride.

In one study, patients inadequately controlled on 2.5 grams/day of metformin hydrochloride (mean baseline FPG 216 mg/dL and mean baseline HbA1c 8.8%) were randomized to receive rosiglitazone 4 mg once daily, rosiglitazone 8 mg once daily, or placebo in addition to metformin. A statistically significant improvement in FPG and HbA1c was observed in patients treated with the combinations of metformin and rosiglitazone 4 mg once daily and rosiglitazone 8 mg once daily, versus patients continued on metformin alone (see Table 4).

In a second 26-week study, patients with type 2 diabetes inadequately controlled on 2.5 grams/day of metformin hydrochloride who were randomized to receive the combination of rosiglitazone 4 mg twice daily and metformin (N = 105) showed a statistically significant improvement in glycemic control with a mean treatment effect for FPG of –56 mg/dL and a mean treatment effect for HbA1c of –0.8% over metformin alone. The combination of metformin and rosiglitazone resulted in lower levels of FPG and HbA1c than either agent alone.

AVANDAMET Combination with Insulin: After an 8-week single-blind AVANDAMET run-in (rosiglitazone 8 mg/metformin 2,000 mg daily), 324 patients with type 2 diabetes mellitus with fasting plasma glucose (FPG) ≥126 mg/dL were randomized to receive AVANDAMET 8 mg/2,000 mg plus insulin (insulin add-on therapy) or placebo plus insulin (switch to insulin monotherapy) in a 24-week, double-blind, multicenter study. Most of the patients had been treated with metformin therapy (∼20% monotherapy and ∼70% combination therapy with a sulfonylurea) before entering the AVANDAMET run-in. Patients with congestive heart failure or who developed edema or whose edema worsened on AVANDAMET therapy during the run-in were not eligible for randomization. Premixed insulin was initiated at 12 units administered twice daily and could be adjusted at a minimum of every 3 to 5 days to achieve target capillary blood glucose values (pre-breakfast and pre-evening meals FPG ≤117.0 mg/dL).

Patients who had insulin added to maximal AVANDAMET therapy had significantly greater reductions in FPG and HbA1c compared to patients who were switched to insulin monotherapy (see Table 5). At Week 24, the mean final total daily insulin dose was significantly lower in the AVANDAMET plus insulin group compared to the insulin monotherapy group (33 U versus 59 U; mean adjusted treatment difference of 25 U, p<0.0001).

INDICATIONS AND USAGE

AVANDAMET 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 metformin therapy is appropriate.

Management of type 2 diabetes mellitus 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 or escalation of oral antidiabetic therapy in patients with type 2 diabetes mellitus, secondary causes of poor glycemic control, e.g., infection, should be investigated and treated.

CONTRAINDICATIONS

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

AVANDAMET is contraindicated in patients with renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females], or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see WARNINGS and PRECAUTIONS).

AVANDAMET is contraindicated in patients with known hypersensitivity to rosiglitazone maleate or metformin hydrochloride.

AVANDAMET is contraindicated in patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

AVANDAMET should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function (see also PRECAUTIONS).

WARNINGS

Rosiglitazone maleate

Cardiac Failure and Other Cardiac Effects: 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). AVANDAMET 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 6.)

Initiation of AVANDAMET in patients with established NYHA Class III or IV heart failure is contraindicated. AVANDAMET 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. AVANDAMET is not recommended in patients with NYHA Class III and IV cardiac status.

In combination with insulin, thiazolidinediones may increase the risk of other cardiovascular adverse events. 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 alone), there was no difference in cardiovascular adverse events with rosiglitazone in combination with insulin compared to insulin alone.

Patients treated with combination AVANDAMET and insulin should be monitored for cardiovascular adverse events. The 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.)

PRECAUTIONS

Metformin hydrochloride

Monitoring of renal function: Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive AVANDAMET. In patients with advanced age, AVANDAMET should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ≥80 years of age, renal function should be monitored regularly and, generally, AVANDAMET should not be titrated to the maximum dose of the metformin component, i.e., 2,000 mg (see WARNINGS and DOSAGE AND ADMINISTRATION).

Before initiation of therapy with AVANDAMET and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and AVANDAMET discontinued if evidence of renal impairment is present.

Use of concomitant medications that may affect renal function or metformin disposition: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion (see PRECAUTIONS, Drug Interactions), should be used with caution.

Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography [CT] scans with contrast materials): Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see CONTRAINDICATIONS). Therefore, in patients in whom any such study is planned, AVANDAMET should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.

Hypoxic states: Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients receiving AVANDAMET, the drug should be promptly discontinued.

Surgical procedures: Use of AVANDAMET should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.

Alcohol intake: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving AVANDAMET.

Impaired hepatic function: Since impaired hepatic function has been associated with some cases of lactic acidosis, AVANDAMET should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

Vitamin B12 levels: In controlled clinical trials of metformin hydrochloride of 29 weeks’ duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on AVANDAMET and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS, Laboratory Tests). Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3-year intervals may be useful.

Change in clinical status of previously controlled diabetic: A patient with type 2 diabetes previously well-controlled on AVANDAMET who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, AVANDAMET must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS).

Hypoglycemia: Hypoglycemia does not occur in patients receiving metformin hydrochloride alone under usual circumstances of use but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with hypoglycemic agents (such as sulfonylureas or insulin) or ethanol. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are takingß-adrenergic blocking drugs.

Loss of control of blood glucose: When a patient stabilized on any diabetic 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 AVANDAMET and temporarily administer insulin. AVANDAMET may be reinstituted after the acute episode is resolved.

Rosiglitazone maleate

General: Due to its mechanism of action, rosiglitazone is active only in the presence of endogenous insulin. Therefore, AVANDAMET should not be used in patients with type 1 diabetes.

Hypoglycemia: Patients receiving rosiglitazone in combination with other hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary.

Edema: AVANDAMET should be used with caution in patients with edema. In a clinical study in healthy volunteers who received rosiglitazone 8 mg 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, AVANDAMET 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 maleate, and PRECAUTIONS).

In controlled clinical trials of patients with type 2 diabetes, mild to moderate edema was reported in patients treated with rosiglitazone maleate, 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).

Macular Edema: 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, Postmarketing Experience.)

Fractures: 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.

Weight Gain: Dose-related weight gain was seen with rosiglitazone alone and rosiglitazone together with other hypoglycemic agents (see Table 7). No overall change in median weight was observed with AVANDAMET in drug-naïve patients. The mechanism of weight gain with rosiglitazone 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).

Hematologic: Across all controlled clinical studies in adults, decreases in hemoglobin and hematocrit (mean decreases in individual studies of approximately ≤1.0 gram/dL and≤3.3%, respectively) were observed for rosiglitazone maleate alone and in combination with other hypoglycemic agents. The changes occurred primarily during the first 3 months following initiation of rosiglitazone therapy or following an increase in rosiglitazone dose. The decrease in hemoglobin was seen more frequently in combination rosiglitazone and metformin therapy than in rosiglitazone therapy alone. Vitamin B12 deficiency may contribute to the observed reductions in hemoglobin (see PRECAUTIONS, Metformin hydrochloride, Vitamin B12 levels). White blood cell counts also decreased slightly in adult patients treated with rosiglitazone. Small decreases in hemoglobin and hematocrit have also been reported in pediatric 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 (see ADVERSE REACTIONS, Laboratory Abnormalities).

Ovulation: 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 AVANDAMET (see PRECAUTIONS, Pregnancy, Pregn