Rosiglitazone Maleate and
Metformin Hydrochloride 003571

Categories, Drug Classes, Brand Names & Cost Of Therapy

Categories: Diabetes mellitus; Pregnancy Category C; FDA Approved 2002 October

Drug Classes: Antidiabetic agents; Biguanides; Thiazolidinediones

Brand Names: Avandamet

Description

Avandamet (rosiglitazone maleate and metformin hydrochloride) tablets contains two oral antihyperglycemic drugs used in the management of Type 2 diabetes: rosiglitazone maleate and metformin hydrochloride. The combination of rosiglitazone maleate and metformin hydrochloride has been previously approved based on clinical trials in people with Type 2 diabetes mellitus inadequately controlled on metformin alone. Additional efficacy and safety information about rosiglitazone and metformin monotherapies may be found in the prescribing information for each individual drug.

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 α-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 122-123°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.

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 pK_a of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.

Avandamet is available for oral administration as tablets containing rosiglitazone maleate and metformin hydrochloride equivalent to: 1 mg rosiglitazone with 500 mg metformin hydrochloride (1 mg/500 mg), 2 mg rosiglitazone with 500 mg metformin hydrochloride (2 mg/500 mg), and 4 mg rosiglitazone with 500 mg metformin hydrochloride (4 mg/500 mg). In addition, each tablet contains the following inactive ingredients: hypromellose, 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

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 HCl, 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, 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 (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, 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 HCl 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 and Bioavailability

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 HCl 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 C_max of both components (22% for rosiglitazone and 15% for metformin, respectively) and a delay in T_max 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.

Rosiglitazone Maleate

The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Maximum plasma concentration (C_max) 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 3-4 hours and is independent of dose.

Metformin HCl

The absolute bioavailability of a 500 mg metformin HCl tablet given under fasting conditions is approximately 50-60%. Studies using single oral doses of metformin HCl tablets of 500 and 1500 mg, and 850-2550 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.

Metformin HCl

The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg metformin HCl 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 24-48 hours and are generally <1 µg/ml. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 µg/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 [ ¹⁴ C]related material ranged from 103-158 hours.

Metformin HCl

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, 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 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 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 >2.5× upper limit of normal) at baseline (see PRECAUTIONS, Hepatic Effects).

No pharmacokinetic studies of metformin have been conducted in subjects with hepatic insufficiency.

Geriatrics

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 HCl in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged and C_max 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, 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 HCl 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 HCl in patients with Type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51) and Hispanics (n=24).

Pediatrics

No pharmacokinetic data from studies in pediatric subjects are available for either rosiglitazone or metformin.

Clinical Studies

The addition of rosiglitazone to metformin resulted in significant improvements in glucose concentrations compared to either of these agents alone. These results are consistent with an additive effect on glycemic control when rosiglitazone is used in combination with metformin. No clinical trials have been conducted with combination rosiglitazone and metformin therapy as initial therapy in patients with Type 2 diabetes mellitus. No controlled clinical trials have been conducted in which metformin was added to patients inadequately controlled with rosiglitazone alone.

The pattern of LDL and HDL changes following therapy with rosiglitazone in combination with metformin was generally similar to those seen with rosiglitazone in monotherapy.

Clinical Trials of Rosiglitazone Add-On Therapy in Patients Not Adequately Controlled on Metformin Alone

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 g/day of metformin HCl.

In one study, patients inadequately controlled on 2.5 g/day of metformin HCl (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 (TABLE 2).

In a second 26 week study, patients with Type 2 diabetes inadequately controlled on 2.5 g/day of metformin HCl 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.

Indications And Usage

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.

The safety and efficacy of Avandamet as initial pharmacologic therapy for patients with Type 2 diabetes mellitus after a trial of caloric restriction, weight loss, and exercise has not been established.

Contraindications

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).

Rosiglitazone Maleate

Cardiac Failure and Other Cardiac Effects

Rosiglitazone, like other thiazolidinediones, can cause fluid retention, which may exacerbate or lead to heart failure. Patients should be observed for signs and symptoms of heart failure. Avandamet should be discontinued if any deterioration in cardiac status occurs.

Patients with New York Heart Association (NYHA) Class 3 and 4 cardiac status were not studied during the clinical trials with rosiglitazone maleate. In patients requiring pharmacologic treatment for congestive heart failure, Avandamet should not be used (see CONTRAINDICATIONS).

In two 26 week US trials involving 611 patients with Type 2 diabetes, rosiglitazone maleate plus insulin therapy was compared with insulin therapy alone. These trials included patients with longstanding diabetes and a high prevalence of pre-existing medical conditions, including peripheral neuropathy (34%), retinopathy (19%), ischemic heart disease (14%), vascular disease (9%), and congestive heart failure (2.5%). In these clinical studies, an increased incidence of cardiac failure and other cardiovascular adverse events were seen in patients on rosiglitazone and insulin combination therapy compared to insulin and placebo. Patients who experienced heart failure were on average older, had a longer duration of diabetes, and were mostly on the higher 8 mg daily dose 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 on combination therapy. Three (3) of 10 patients who developed cardiac failure on combination therapy during the double blind part of the studies had no known prior evidence of congestive heart failure, or pre-existing cardiac condition. The use of rosiglitazone maleate in combination therapy with insulin is not indicated (see ADVERSE REACTIONS), therefore, Avandamet is not indicated for use in combination with insulin.

Precautions

Metformin HCl

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., 2000 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 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 HCl 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 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 2-3 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 HCl 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 taking beta-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.

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 WARNINGS, Rosiglitazone Maleate, Cardiac Failure and Other Cardiac Effects and PRECAUTIONS, Information for the Patient).

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).

Weight Gain

Dose-related weight gain was seen with rosiglitazone alone or in combination with other hypoglycemic agents (TABLE 3). 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.

Hematologic

Across all controlled clinical studies, decreases in hemoglobin and hematocrit (mean decreases in individual studies ≤1.0 g/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. 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 (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 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 Carcinogenesis, Mutagenesis, and Impairment of Fertility), the clinical significance of this finding is not known. If unexpected menstrual dysfunction occurs, the benefits of continued therapy with Avandamet should be reviewed.

Hepatic Effects

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 >3× upper limit of normal) compared to placebo. Very rare cases of reversible jaundice were also reported.

In pre-approval clinical studies in 4598 patients treated with rosiglitazone maleate, encompassing approximately 3600 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 >3× 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 maleate, 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 US, 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 Avandamet undergo periodic monitoring of liver enzymes.

Liver enzymes should be checked prior to the initiation of therapy with Avandamet in all patients. Therapy with Avandamet should not be initiated in patients with increased baseline liver enzyme levels (ALT >2.5× upper limit of normal). In patients with normal baseline liver enzymes, following initiation of therapy with Avandamet, it is recommended that liver enzymes be monitored every 2 months for the first 12 months, and periodically thereafter. Patients with mildly elevated liver enzymes (ALT levels ≤2.5× upper limit of normal) at baseline or during therapy with Avandamet should be evaluated to determine the cause of the liver enzyme elevation. Initiation of, or continuation of, therapy with Avandamet 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 >3× the upper limit of normal in patients on therapy with Avandamet, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain >3× the upper limit of normal, therapy with Avandamet should be discontinued.

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

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. If jaundice is observed, drug therapy should be discontinued.

In addition, if the presence of hepatic disease or hepatic dysfunction of sufficient magnitude to predispose to lactic acidosis is confirmed, therapy with Avandamet should be discontinued.

Laboratory Tests

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

Liver enzyme monitoring is recommended prior to initiation of therapy with Avandamet in all patients and periodically thereafter (see Hepatic Effects and ADVERSE REACTIONS, Laboratory Abnormalities, Serum Transaminase Levels).

Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, vitamin B₁₂ deficiency should be excluded.

Information for the Patient

Patients should be informed of the potential risks and advantages of Avandamet 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 they help improve insulin sensitivity. The importance of regular testing of blood glucose, glycosylated hemoglobin (HbA1c), renal function and hematologic parameters should be emphasized. Patients should be advised that Avandamet can begin to take effect 1-2 weeks after initiation, however it can take 2-3 months to see the full effect of glycemic improvement.

The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue Avandamet immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of Avandamet, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Patients should be counselled against excessive alcohol intake, either acute or chronic, while receiving Avandamet.

Patients should be informed that blood will be drawn to check their liver function prior to the start of therapy and every 2 months for the first 12 months, and periodically thereafter. 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 Avandamet should immediately report these symptoms to their physician.

Therapy with Avandamet, 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 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.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

No animal studies have been conducted with the combined products in Avandamet. The following data are based on findings in studies performed with rosiglitazone or metformin individually.

Rosiglitazone Maleate

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 of the rosiglitazone component of Avandamet). Sprague-Dawley rats were dosed for 2 years by oral gavage at doses of 0.05, 0.3, and 2 mg/kg/day (highest dose equivalent to approximately 10 and 20 times human AUC at the maximum recommended human daily dose of the rosiglitazone component of Avandamet 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 of the rosiglitazone component of Avandamet). 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 of the rosiglitazone component of Avandamet). These proliferative changes in both species are considered due to the persistent pharmacological overstimulation of adipose tissue.

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.

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 of the rosiglitazone component of Avandamet). 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 of the rosiglitazone component of Avandamet, respectively). No such effects were noted at 0.2 mg/kg/day (approximately 3 times human AUC at the maximum recommended human daily dose of the rosiglitazone component of Avandamet). 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 of the rosiglitazone component of Avandamet, 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.

Metformin HCl

Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately 4 times the maximum recommended human daily dose of 2000 mg of the metformin component of Avandamet based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

There was no evidence of mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.

Fertility of male or female rats was unaffected by metformin when administrated at doses as high as 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose of the metformin component of Avandamet based on body surface area comparisons.

Animal Toxicology

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 of the rosiglitazone component of Avandamet, respectively). 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.

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. Avandamet should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

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

Rosiglitazone Maleate

There was no effect on implantation or the embryo with rosiglitazone treatment during early pregnancy in rats, but treatment during mid-late gestation was associated with fetal death and growth retardation in both rats and rabbits. Teratogenicity was not observed at doses up to 3 mg/kg in rats and 100 mg/kg in rabbits (approximately 20 and 75 times human AUC at the maximum recommended human daily dose of the rosiglitazone component of Avandamet, respectively). Rosiglitazone caused placental pathology in rats (3 mg/kg/day). Treatment of rats during gestation through lactation reduced litter size, neonatal viability, and postnatal growth, with growth retardation reversible after puberty. For effects on the placenta, embryo/fetus, and offspring, the no-effect dose was 0.2 mg/kg/day in rats and 15 mg/kg/day in rabbits. These no-effect levels are approximately 4 times human AUC at the maximum recommended human daily dose of the rosiglitazone component of Avandamet.

Metformin HCl

Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

Labor and Delivery

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

Nursing Mothers

No studies have been conducted with the combined components of Avandamet. In studies performed with the individual components, both rosiglitazone-related material and metformin were detectable in milk from lactating rats. It is not known whether rosiglitazone and/or metformin is excreted in human milk. Because many drugs are excreted in human milk, Avandamet should not be administered to a nursing woman. If Avandamet is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use

Safety and effectiveness of Avandamet in pediatric patients have not been established.

Geriatric Use

Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, Avandamet should only be used in patients with normal renal function (see CONTRAINDICATIONS, WARNINGS, and CLINICAL PHARMACOLOGY, Pharmacokinetics). Because aging is associated with reduced renal function, Avandamet should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of Avandamet (see also WARNINGS, DOSAGE AND ADMINISTRATION).

Drug Interactions

Drugs 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.

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

Metformin HCl

Furosemide

A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood C_max by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the C_max 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 co-administered chronically.

Nifedipine

A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin C_max and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. T_max 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. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of Avandamet and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

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. When such drugs are administered to a patient receiving Avandamet, the patient should be closely observed to maintain adequate glycemic control.

In healthy volunteers, the pharmacokinetics of metformin and propranolol and metformin and ibuprofen were not affected when co-administered 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.

Adverse Reactions

Reports of hypoglycemia in patients treated with rosiglitazone and maximum metformin combination therapy were more frequent than in patients treated with rosiglitazone or metformin monotherapies. In double-blind studies, hypoglycemia was reported by 3.0% of patients receiving rosiglitazone in combination with maximum doses of metformin, by 1.3% of patients receiving metformin monotherapy, by 0.6% of patients receiving rosiglitazone as monotherapy, and by 0.2% of patients receiving placebo.

There were a small number of patients treated with rosiglitazone who had adverse events of anemia and edema. Overall, these events were generally mild to moderate in severity and usually did not require discontinuation of treatment with rosiglitazone.

Edema was reported in 4.8% of patients receiving rosiglitazone compared to 1.3% on placebo, and 2.2% on metformin monotherapy and 4.4% on rosiglitazone in combination with maximum doses of metformin. Overall, the types of adverse experiences reported when rosiglitazone was used in combination with metformin were similar to those during monotherapy with rosiglitazone. Reports of anemia (7.1%) were greater in patients treated with a combination of rosiglitazone and metformin compared to monotherapy with rosiglitazone.

Lower pre-treatment hemoglobin/hematocrit levels in patients enrolled in the metformin combination clinical trials may have contributed to the higher reporting rate of anemia in these studies (see Laboratory Abnormalities, Hematologic).

In 26 week double-blind 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 WARNINGS, Rosiglitazone Maleate, Cardiac Failure and Other Cardiac Effects).

In postmarketing experience with rosiglitazone maleate, adverse events potentially related to volume expansion (e.g., congestive heart failure, pulmonary edema, and pleural effusions) have been reported.

(See also Glucophage prescribing information, ADVERSE REACTIONS.)

Laboratory Abnormalities

Hematologic

Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in patients treated with rosiglitazone maleate (mean decreases in individual studies up to 1.0 g/dl hemoglobin and up to 3.3% hematocrit). The time course and magnitude of decreases were similar in patients treated with a combination of rosiglitazone and other hypoglycemic agents or rosiglitazone monotherapy. Pre-treatment levels of hemoglobin and hematocrit were lower in patients in metformin combination studies and may have contributed to the higher reporting rate of anemia. White blood cell counts also decreased slightly in patients treated with rosiglitazone. Decreases in hematologic parameters may be related to increased plasma volume observed with rosiglitazone treatment.

In controlled clinical trials of metformin HCl 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.

Lipids

Changes in serum lipids have been observed following treatment with rosiglitazone maleate (see CLINICAL STUDIES).

Serum Transaminase Levels

In clinical studies in 4598 patients treated with rosiglitazone maleate encompassing approximately 3600 patient years of exposure, there was no evidence of drug-induced hepatotoxicity or elevated ALT levels.

In controlled trials, 0.2% of patients treated with rosiglitazone maleate had reversible elevations in ALT >3× the upper limit of normal compared to 0.2% on placebo and 0.5% on active comparators. Hyperbilirubinemia was found in 0.3% of patients treated with rosiglitazone compared with 0.9% treated with placebo and 1% in patients treated with active comparators.

In the clinical program including long-term, open-label experience, the rate per 100 patient years’ exposure of ALT increase to >3× the upper limit of normal was 0.35 for patients treated with rosiglitazone maleate, 0.59 for placebo-treated patients, and 0.78 for patients treated with active comparator agents.

In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure. In postmarketing experience with rosiglitazone maleate, reports of hepatic enzyme elevations 3 or more times the upper limit of normal and hepatitis have been received (see PRECAUTIONS, Hepatic Effects).

Overdosage

Limited data are available with regard to overdosage in humans. In clinical studies in volunteers, rosiglitazone has been administered at single oral doses of up to 20 mg and was well-tolerated. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s clinical status.

Metformin HCl