Avandia (Rosiglitazone maleate) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

The management of antidiabetic therapy should be individualized. All patients should start Avandia (Rosiglitazone maleate) at the lowest recommended dose. Further increases in the dose of Avandia (Rosiglitazone maleate) should be accompanied by careful monitoring for adverse events related to fluid retention .

Avandia (Rosiglitazone maleate) may be administered at a starting dose of 4 mg either as a single daily dose or in 2 divided doses. For patients who respond inadequately following 8 to 12 weeks of treatment, as determined by reduction in fasting plasma glucose (FPG), the dose may be increased to 8 mg daily as monotherapy or in combination with metformin, sulfonylurea, or sulfonylurea plus metformin. Reductions in glycemic parameters by dose and regimen are described under . Avandia (Rosiglitazone maleate) may be taken with or without food.

The total daily dose of Avandia (Rosiglitazone maleate) should not exceed 8 mg.

The usual starting dose of Avandia (Rosiglitazone maleate) is 4 mg administered either as a single dose once daily or in divided doses twice daily. In clinical trials, the 4-mg twice-daily regimen resulted in the greatest reduction in FPG and hemoglobin A1c (HbA1c).

When Avandia (Rosiglitazone maleate) is added to existing therapy, the current dose(s) of the agent(s) can be continued upon initiation of therapy with Avandia (Rosiglitazone maleate) .

When used in combination with sulfonylurea, the usual starting dose of Avandia (Rosiglitazone maleate) is 4 mg administered as either a single dose once daily or in divided doses twice daily. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased.

The usual starting dose of Avandia (Rosiglitazone maleate) in combination with metformin is 4 mg administered as either a single dose once daily or in divided doses twice daily. It is unlikely that the dose of metformin will require adjustment due to hypoglycemia during combination therapy with Avandia (Rosiglitazone maleate) .

The usual starting dose of Avandia (Rosiglitazone maleate) in combination with a sulfonylurea plus metformin is 4 mg administered as either a single dose once daily or divided doses twice daily. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased.

No dosage adjustment is necessary when Avandia (Rosiglitazone maleate) is used as monotherapy in patients with renal impairment. Since metformin is contraindicated in such patients, concomitant administration of metformin and Avandia (Rosiglitazone maleate) is also contraindicated in patients with renal impairment.

Liver enzymes should be measured prior to initiating treatment with Avandia (Rosiglitazone maleate) . Therapy with Avandia (Rosiglitazone maleate) 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 start of therapy). After initiation of Avandia (Rosiglitazone maleate) , liver enzymes should be monitored periodically per the clinical judgment of the healthcare professional.

Data are insufficient to recommend pediatric use of Avandia (Rosiglitazone maleate) .

Pentagonal film-coated TILTAB tablet contains rosiglitazone as the maleate as follows:

Initiation of Avandia (Rosiglitazone maleate) in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated .

Avandia (Rosiglitazone maleate) , 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 .

Patients with congestive heart failure (CHF) NYHA Class I and II treated with Avandia (Rosiglitazone maleate) 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 following treatment with Avandia (Rosiglitazone maleate) compared to placebo during the 52-week study. (See Table 1.)

Initiation of Avandia (Rosiglitazone maleate) in patients with established NYHA Class III or IV heart failure is contraindicated. Avandia (Rosiglitazone maleate) is not recommended in patients with symptomatic heart failure.

Patients experiencing acute coronary syndromes have not been studied in controlled clinical trials. In view of the potential for development of heart failure in patients having an acute coronary event, initiation of Avandia (Rosiglitazone maleate) is not recommended for patients experiencing an acute coronary event, and discontinuation of Avandia (Rosiglitazone maleate) during this acute phase should be considered.

Patients with NYHA Class III and IV cardiac status (with or without CHF) have not been studied in controlled clinical trials. Avandia (Rosiglitazone maleate) is not recommended in patients with NYHA Class III and IV cardiac status.

A meta-analysis was conducted retrospectively to assess cardiovascular adverse events reported across 42 double-blind, randomized, controlled clinical trials (mean duration 6 months). These studies had been conducted to assess glucose-lowering efficacy in type 2 diabetes, and prospectively planned adjudication of cardiovascular events had not occurred in the trials. Some trials were placebo-controlled and some used active oral antidiabetic drugs as controls. Placebo-controlled studies included monotherapy trials (monotherapy with Avandia (Rosiglitazone maleate) versus placebo monotherapy) and add-on trials (Avandia (Rosiglitazone maleate) or placebo, added to sulfonylurea, metformin, or insulin). Active control studies included monotherapy trials (monotherapy with Avandia (Rosiglitazone maleate) versus sulfonylurea or metformin monotherapy) and add-on trials (Avandia (Rosiglitazone maleate) plus sulfonylurea or Avandia (Rosiglitazone maleate) plus metformin, versus sulfonylurea plus metformin). A total of 14,237 patients were included (8,604 in treatment groups containing Avandia (Rosiglitazone maleate) , 5,633 in comparator groups), with 4,143 patient-years of exposure to Avandia (Rosiglitazone maleate) and 2,675 patient-years of exposure to comparator. Myocardial ischemic events included angina pectoris, angina pectoris aggravated, unstable angina, cardiac arrest, chest pain, coronary artery occlusion, dyspnea, myocardial infarction, coronary thrombosis, myocardial ischemia, coronary artery disease, and coronary artery disorder. In this analysis, an increased risk of myocardial ischemia with Avandia (Rosiglitazone maleate) versus pooled comparators was observed (2% Avandia (Rosiglitazone maleate) versus 1.5% comparators, odds ratio 1.4, 95% confidence interval [CI] 1.1, 1.8). An increased risk of myocardial ischemic events with Avandia (Rosiglitazone maleate) was observed in the placebo-controlled studies, but not in the active-controlled studies. (See Figure 1.)

A greater increased risk of myocardial ischemic events was observed in studies where Avandia (Rosiglitazone maleate) was added to insulin (2.8% for Avandia (Rosiglitazone maleate) plus insulin versus 1.4% for placebo plus insulin, [OR 2.1, 95% CI 0.9, 5.1]). This increased risk reflects a difference of 3 events per 100 patient-years (95% CI -0.1, 6.3) between treatment groups.

Figure 1. Forest Plot of Odds Ratios (95% Confidence Intervals) for Myocardial Ischemic Events in the Meta-Analysis of 42 Clinical Trials

A greater increased risk of myocardial ischemia was also observed in patients who received Avandia (Rosiglitazone maleate) and background nitrate therapy. For Avandia (Rosiglitazone maleate) (N = 361) versus control (N = 244) in nitrate users, the odds ratio was 2.9 (95% CI 1.4, 5.9), while for non-nitrate users (about 14,000 patients total), the odds ratio was 1.3 (95% CI 0.9, 1.7). This increased risk represents a difference of 12 myocardial ischemic events per 100 patient-years (95% CI 3.3, 21.4). Most of the nitrate users had established coronary heart disease. Among patients with known coronary heart disease who were not on nitrate therapy, an increased risk of myocardial ischemic events for Avandia (Rosiglitazone maleate) versus comparator was not demonstrated.

In clinical trials, approximately 9,900 patients with type 2 diabetes have been treated with Avandia (Rosiglitazone maleate) .

The incidence and types of adverse events reported in short-term clinical trials of Avandia (Rosiglitazone maleate) as monotherapy are shown in Table 4.

Overall, the types of adverse reactions without regard to causality reported when Avandia (Rosiglitazone maleate) was used in combination with a sulfonylurea or metformin were similar to those during monotherapy with Avandia (Rosiglitazone maleate) .

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

In double-blind studies, anemia was reported in 1.9% of patients receiving Avandia (Rosiglitazone maleate) as monotherapy compared to 0.7% on placebo, 0.6% on sulfonylureas, and 2.2% on metformin. Reports of anemia were greater in patients treated with a combination of Avandia (Rosiglitazone maleate) and metformin (7.1%) and with a combination of Avandia (Rosiglitazone maleate) and a sulfonylurea plus metformin (6.7%) compared to monotherapy with Avandia (Rosiglitazone maleate) or in combination with a sulfonylurea (2.3%). 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 .

In clinical trials, edema was reported in 4.8% of patients receiving Avandia (Rosiglitazone maleate) as monotherapy compared to 1.3% on placebo, 1.0% on sulfonylureas, and 2.2% on metformin. The reporting rate of edema was higher for Avandia (Rosiglitazone maleate) 8 mg in sulfonylurea combinations (12.4%) compared to other combinations, with the exception of insulin. Edema was reported in 14.7% of patients receiving Avandia (Rosiglitazone maleate) in the insulin combination trials compared to 5.4% on insulin alone. 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 Avandia (Rosiglitazone maleate) .

In controlled combination therapy studies with sulfonylureas, mild to moderate hypoglycemic symptoms, which appear to be dose related, were reported. Few patients were withdrawn for hypoglycemia (less than 1%) and few episodes of hypoglycemia were considered to be severe (less than 1%). Hypoglycemia was the most frequently reported adverse event in the fixed-dose insulin combination trials, although few patients withdrew for hypoglycemia (4 of 408 for Avandia (Rosiglitazone maleate) plus insulin and 1 of 203 for insulin alone). Rates of hypoglycemia, confirmed by capillary blood glucose concentration less than or equal to 50 mg/dL, were 6% for insulin alone and 12% (4 mg) and 14% (8 mg) for insulin in combination with Avandia (Rosiglitazone maleate) .

A 4- to 6-year study (ADOPT) compared the use of Avandia (Rosiglitazone maleate) (n = 1,456), glyburide (n = 1,441), and metformin (n = 1,454) as monotherapy in patients recently diagnosed with type 2 diabetes who were not previously treated with antidiabetic medication. Table 5 presents adverse reactions without regard to causality; rates are expressed per 100 patient-years (PY) exposure to account for the differences in exposure to study medication across the 3 treatment groups.

In ADOPT, fractures were reported in a greater number of women treated with Avandia (Rosiglitazone maleate) (9.3%, 2.7/100 patient-years) compared to glyburide (3.5%, 1.3/100 patient-years) or metformin (5.1%, 1.5/100 patient-years). The majority of the fractures in the women who received rosiglitazone were reported in the upper arm, hand, and foot. The observed incidence of fractures for male patients was similar among the 3 treatment groups.

Avandia (Rosiglitazone maleate) has been evaluated for safety in a single, active-controlled trial of pediatric patients with type 2 diabetes in which 99 were treated with Avandia (Rosiglitazone maleate) and 101 were treated with metformin. The most common adverse reactions (greater than 10%) without regard to causality for either Avandia (Rosiglitazone maleate) or metformin were headache (17% versus 14%), nausea (4% versus 11%), nasopharyngitis (3% versus 12%), and diarrhea (1% versus 13%). In this study, one case of diabetic ketoacidosis was reported in the metformin group. In addition, there were 3 patients in the rosiglitazone group who had FPG of ∼300 mg/dL, 2+ ketonuria, and an elevated anion gap.

Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with Avandia (Rosiglitazone maleate) (mean decreases in individual studies as much as 1.0 g/dL hemoglobin and as much as 3.3% hematocrit). The changes occurred primarily during the first 3 months following initiation of therapy with Avandia (Rosiglitazone maleate) or following a dose increase in Avandia (Rosiglitazone maleate) . The time course and magnitude of decreases were similar in patients treated with a combination of Avandia (Rosiglitazone maleate) and other hypoglycemic agents or monotherapy with Avandia (Rosiglitazone maleate) . 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. In a single study in pediatric patients, decreases in hemoglobin and hematocrit (mean decreases of 0.29 g/dL and 0.95%, respectively) were reported. Small decreases in hemoglobin and hematocrit have also been reported in pediatric patients treated with Avandia (Rosiglitazone maleate) . White blood cell counts also decreased slightly in adult patients treated with Avandia (Rosiglitazone maleate) . Decreases in hematologic parameters may be related to increased plasma volume observed with treatment with Avandia (Rosiglitazone maleate) .

Changes in serum lipids have been observed following treatment with Avandia (Rosiglitazone maleate) in adults . Small changes in serum lipid parameters were reported in children treated with Avandia (Rosiglitazone maleate) for 24 weeks.

In pre-approval clinical studies in 4,598 patients treated with Avandia (Rosiglitazone maleate) (3,600 patient-years of exposure) and in a long-term 4- to 6-year study in 1,456 patients treated with Avandia (Rosiglitazone maleate) (4,954 patient-years exposure), there was no evidence of drug-induced hepatotoxicity.

In pre-approval controlled trials, 0.2% of patients treated with Avandia (Rosiglitazone maleate) had elevations in ALT >3X the upper limit of normal compared to 0.2% on placebo and 0.5% on active comparators. The ALT elevations in patients treated with Avandia (Rosiglitazone maleate) were reversible. Hyperbilirubinemia was found in 0.3% of patients treated with Avandia (Rosiglitazone maleate) compared with 0.9% treated with placebo and 1% in patients treated with active comparators. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure.

In the 4- to 6-year ADOPT trial, patients treated with Avandia (Rosiglitazone maleate) (4,954 patient-years exposure), glyburide (4,244 patient-years exposure), or metformin (4,906 patient-years exposure), as monotherapy, had the same rate of ALT increase to greater than 3X upper limit of normal (0.3 per 100 patient-years exposure).

In addition to adverse reactions reported from clinical trials, the events described below have been identified during post-approval use of Avandia (Rosiglitazone maleate) . Because these events are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or to always establish a causal relationship to drug exposure.

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

There are postmarketing reports with Avandia (Rosiglitazone maleate) of hepatitis, hepatic enzyme elevations to 3 or more times the upper limit of normal, and hepatic failure with and without fatal outcome, although causality has not been established.

There are postmarketing reports with Avandia (Rosiglitazone maleate) of rash, pruritus, urticaria, angioedema, anaphylactic reaction, Stevens-Johnson syndrome, and new onset or worsening diabetic macular edema with decreased visual acuity .

An inhibitor of CYP2C8 (e.g., gemfibrozil) may increase the AUC of rosiglitazone and an inducer of CYP2C8 (e.g., rifampin) may decrease the AUC of rosiglitazone. Therefore, if an inhibitor or an inducer of CYP2C8 is started or stopped during treatment with rosiglitazone, changes in diabetes treatment may be needed based upon clinical response.

Pregnancy Category C.

All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Careful monitoring of glucose control is essential in such patients. Most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Rosiglitazone has been reported to cross the human placenta and be detectable in fetal tissue. The clinical significance of these findings is unknown. There are no adequate and well-controlled studies in pregnant women. Avandia (Rosiglitazone maleate) should not be used during pregnancy.

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, 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. Rosiglitazone reduced the number of uterine implantations and live offspring when juvenile female rats were treated at 40 mg/kg/day from 27 days of age through to sexual maturity (approximately 68 times human AUC at the maximum recommended daily dose). The no-effect level was 2 mg/kg/day (approximately 4 times human AUC at the maximum recommended daily dose). There was no effect on pre- or post-natal survival or growth.

The effect of rosiglitazone on labor and delivery in humans is not known.

Drug-related material was detected in milk from lactating rats. It is not known whether Avandia (Rosiglitazone maleate) is excreted in human milk. Because many drugs are excreted in human milk, Avandia (Rosiglitazone maleate) should not be administered to a nursing woman.

After placebo run-in including diet counseling, children with type 2 diabetes mellitus, aged 10 to 17 years and with a baseline mean body mass index (BMI) of 33 kg/m, were randomized to treatment with 2 mg twice daily of Avandia (Rosiglitazone maleate) (n = 99) or 500 mg twice daily of metformin (n = 101) in a 24-week, double-blind clinical trial. As expected, FPG decreased in patients naïve to diabetes medication (n = 104) and increased in patients withdrawn from prior medication (usually metformin) (n = 90) during the run-in period. After at least 8 weeks of treatment, 49% of patients treated with Avandia (Rosiglitazone maleate) and 55% of metformin-treated patients had their dose doubled if FPG >126 mg/dL. For the overall intent-to-treat population, at week 24, the mean change from baseline in HbA1c was -0.14% with Avandia (Rosiglitazone maleate) and -0.49% with metformin. There was an insufficient number of patients in this study to establish statistically whether these observed mean treatment effects were similar or different. Treatment effects differed for patients naïve to therapy with antidiabetic drugs and for patients previously treated with antidiabetic therapy (Table 6).

*  Change from baseline means are least squares means adjusting for baseline HbA1c, gender, and region.

Treatment differences depended on baseline BMI or weight such that the effects of Avandia (Rosiglitazone maleate) and metformin appeared more closely comparable among heavier patients. The median weight gain was 2.8 kg with rosiglitazone and 0.2 kg with metformin . Fifty-four percent of patients treated with rosiglitazone and 32% of patients treated with metformin gained ≥2 kg, and 33% of patients treated with rosiglitazone and 7% of patients treated with metformin gained ≥5 kg on study.

Figure 3. Mean HbA1c Over Time in a 24-Week Study of Avandia (Rosiglitazone maleate) and Metformin in Pediatric Patients — Drug-Naïve Subgroup

Results of the population pharmacokinetic analysis showed that age does not significantly affect the pharmacokinetics of rosiglitazone . Therefore, no dosage adjustments are required for the elderly. In controlled clinical trials, no overall differences in safety and effectiveness between older (greater than or equal to 65 years) and younger (less than 65 years) patients were observed.

Limited data are available with regard to overdosage in humans. In clinical studies in volunteers, Avandia (Rosiglitazone maleate) 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.

Avandia (Rosiglitazone maleate) is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. Avandia (Rosiglitazone maleate) improves glycemic control while reducing circulating insulin levels.

Rosiglitazone maleate is not chemically or functionally related to the sulfonylureas, the biguanides, or the alpha-glucosidase inhibitors.

The molecular formula is CHNOS•CHO. 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.

Each pentagonal film-coated TILTAB tablet contains rosiglitazone maleate equivalent to rosiglitazone, 2 mg, 4 mg, or 8 mg, for oral administration. Inactive ingredients are: Hypromellose 2910, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 3000, sodium starch glycolate, titanium dioxide, triacetin, and 1 or more of the following: Synthetic red and yellow iron oxides and talc.

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

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

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

Patients with lipid abnormalities were not excluded from clinical trials of Avandia (Rosiglitazone maleate) . In all 26-week controlled trials, across the recommended dose range, Avandia (Rosiglitazone maleate) as monotherapy was associated with increases in total cholesterol, LDL, and HDL and decreases in free fatty acids. These changes were statistically significantly different from placebo or glyburide controls (Table 7).

Increases in LDL occurred primarily during the first 1 to 2 months of therapy with Avandia (Rosiglitazone maleate) and LDL levels remained elevated above baseline throughout the trials. In contrast, HDL continued to rise over time. As a result, the LDL/HDL ratio peaked after 2 months of therapy and then appeared to decrease over time. Because of the temporal nature of lipid changes, the 52-week glyburide-controlled study is most pertinent to assess long-term effects on lipids. At baseline, week 26, and week 52, mean LDL/HDL ratios were 3.1, 3.2, and 3.0, respectively, for Avandia (Rosiglitazone maleate) 4 mg twice daily. The corresponding values for glyburide were 3.2, 3.1, and 2.9. The differences in change from baseline between Avandia (Rosiglitazone maleate) and glyburide at week 52 were statistically significant.

The pattern of LDL and HDL changes following therapy with Avandia (Rosiglitazone maleate) in combination with other hypoglycemic agents were generally similar to those seen with Avandia (Rosiglitazone maleate) in monotherapy.

The changes in triglycerides during therapy with Avandia (Rosiglitazone maleate) were variable and were generally not statistically different from placebo or glyburide controls.

Maximum plasma concentration (C) and the area under the curve (AUC) of rosiglitazone increase in a dose-proportional manner over the therapeutic dose range (Table 8). The elimination half-life is 3 to 4 hours and is independent of dose.

The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), but there was an approximately 28% decrease in C and a delay in T (1.75 hours). These changes are not likely to be clinically significant; therefore, Avandia (Rosiglitazone maleate) may be administered with or without food.

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.

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 [C]rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, respectively. The plasma half-life of [C]related material ranged from 103 to 158 hours.

Population pharmacokinetic analyses from 3 large clinical trials including 642 men and 405 women with type 2 diabetes (aged 35 to 80 years) showed that the pharmacokinetics of rosiglitazone are not influenced by age, race, smoking, or alcohol consumption. Both oral clearance (CL/F) and oral steady-state volume of distribution (Vss/F) were shown to increase with increases in body weight. Over the weight range observed in these analyses (50 to 150 kg), the range of predicted CL/F and Vss/F values varied by less than 1.7-fold and less than 2.3-fold, respectively. Additionally, rosiglitazone CL/F was shown to be influenced by both weight and gender, being lower (about 15%) in female patients.

Results of the population pharmacokinetic analysis (n = 716 less than 65 years; n = 331 greater than or equal to 65 years) showed that age does not significantly affect the pharmacokinetics of rosiglitazone.

Results of the population pharmacokinetics analysis showed that the mean oral clearance of rosiglitazone in female patients (n = 405) was approximately 6% lower compared to male patients of the same body weight (n = 642).

As monotherapy and in combination with metformin, Avandia (Rosiglitazone maleate) improved glycemic control in both males and females. In metformin combination studies, efficacy was demonstrated with no gender differences in glycemic response.

In monotherapy studies, a greater therapeutic response was observed in females; however, in more obese patients, gender differences were less evident. For a given body mass index (BMI), females tend to have a greater fat mass than males. Since the molecular target PPARγ is expressed in adipose tissues, this differentiating characteristic may account, at least in part, for the greater response to Avandia (Rosiglitazone maleate) in females. Since therapy should be individualized, no dose adjustments are necessary based on gender alone.

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 and AUC 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 Avandia (Rosiglitazone maleate) should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5X upper limit of normal) at baseline .

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.

There are no clinically relevant differences in the pharmacokinetics of rosiglitazone in patients with mild to severe renal impairment or in hemodialysis-dependent patients compared to subjects with normal renal function. No dosage adjustment is therefore required in such patients receiving Avandia (Rosiglitazone maleate) . Since metformin is contraindicated in patients with renal impairment, coadministration of metformin with Avandia (Rosiglitazone maleate) is contraindicated in these patients.

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

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. Avandia (Rosiglitazone maleate) (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.

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 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 .

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

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

Concurrent administration of Avandia (Rosiglitazone maleate) (2 mg twice daily) and metformin (500 mg twice daily) in healthy volunteers for 4 days had no effect on the steady-state pharmacokinetics of either metformin or rosiglitazone.

Coadministration of acarbose (100 mg three times daily) for 7 days in healthy volunteers had no clinically relevant effect on the pharmacokinetics of a single oral dose of Avandia (Rosiglitazone maleate) .

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

Repeat dosing with Avandia (Rosiglitazone maleate) had no clinically relevant effect on the steady-state pharmacokinetics of warfarin enantiomers.

A single administration of a moderate amount of alcohol did not increase the risk of acute hypoglycemia in type 2 diabetes mellitus patients treated with Avandia (Rosiglitazone maleate) .

Pretreatment with ranitidine (150 mg twice daily for 4 days) did not alter the pharmacokinetics of either single oral or intravenous doses of rosiglitazone in healthy volunteers. These results suggest that the absorption of oral rosiglitazone is not altered in conditions accompanied by increases in gastrointestinal pH.

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

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

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

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

In clinical studies, treatment with Avandia (Rosiglitazone maleate) resulted in an improvement in glycemic control, as measured by FPG and HbA1c, with a concurrent reduction in insulin and C-peptide. Postprandial glucose and insulin were also reduced. This is consistent with the mechanism of action of Avandia (Rosiglitazone maleate) as an insulin sensitizer.

The maximum recommended daily dose is 8 mg. Dose-ranging studies suggested that no additional benefit was obtained with a total daily dose of 12 mg.

A total of 2,315 patients with type 2 diabetes, previously treated with diet alone or antidiabetic medication(s), were treated with Avandia (Rosiglitazone maleate) as monotherapy in 6 double-blind studies, which included two 26-week placebo-controlled studies, one 52-week glyburide-controlled study, and 3 placebo-controlled dose-ranging studies of 8 to 12 weeks duration. Previous antidiabetic medication(s) were withdrawn and patients entered a 2 to 4 week placebo run-in period prior to randomization.

Two 26-week, double-blind, placebo-controlled trials, in patients with type 2 diabetes (n = 1,401) with inadequate glycemic control (mean baseline FPG approximately 228 mg/dL [101 to 425 mg/dL] and mean baseline HbA1c 8.9% [5.2% to 16.2%]), were conducted. Treatment with Avandia (Rosiglitazone maleate) produced statistically significant improvements in FPG and HbA1c compared to baseline and relative to placebo. Data from one of these studies are summarized in Table 9.

When administered at the same total daily dose, Avandia (Rosiglitazone maleate) was generally more effective in reducing FPG and HbA1c when administered in divided doses twice daily compared to once daily doses. However, for HbA1c, the difference between the 4 mg once daily and 2 mg twice daily doses was not statistically significant.

Long-term maintenance of effect was evaluated in a 52-week, double-blind, glyburide-controlled trial in patients with type 2 diabetes. Patients were randomized to treatment with Avandia (Rosiglitazone maleate) 2 mg twice daily (N = 195) or Avandia (Rosiglitazone maleate) 4 mg twice daily (N = 189) or glyburide (N = 202) for 52 weeks. Patients receiving glyburide were given an initial dosage of either 2.5 mg/day or 5.0 mg/day. The dosage was then titrated in 2.5 mg/day increments over the next 12 weeks, to a maximum dosage of 15.0 mg/day in order to optimize glycemic control. Thereafter, the glyburide dose was kept constant.

Figure 5. Mean HbA1c Over Time in a 52-Week Glyburide-Controlled Study

Hypoglycemia was reported in 12.1% of glyburide-treated patients versus 0.5% (2 mg twice daily) and 1.6% (4 mg twice daily) of patients treated with Avandia (Rosiglitazone maleate) . The improvements in glycemic control were associated with a mean weight gain of 1.75 kg and 2.95 kg for patients treated with 2 mg and 4 mg twice daily of Avandia (Rosiglitazone maleate) , respectively, versus 1.9 kg in glyburide-treated patients. In patients treated with Avandia (Rosiglitazone maleate) , C-peptide, insulin, pro-insulin, and pro-insulin split products were significantly reduced in a dose-ordered fashion, compared to an increase in the glyburide-treated patients.

A Diabetes Outcome Progression Trial (ADOPT) was a multicenter, double-blind, controlled trial (N = 4,351) conducted over 4 to 6 years to compare the safety and efficacy of Avandia (Rosiglitazone maleate) , metformin, and glyburide monotherapy in patients recently diagnosed with type 2 diabetes mellitus (≤3 years) inadequately controlled with diet and exercise. The mean age of patients in this trial was 57 years and the majority of patients (83%) had no known history of cardiovascular disease. The mean baseline FPG and HbA1c were 152 mg/dL and 7.4%, respectively. Patients were randomized to receive either Avandia (Rosiglitazone maleate) 4 mg once daily, glyburide 2.5 mg once daily, or metformin 500 mg once daily, and doses were titrated to optimal glycemic control up to a maximum of 4 mg twice daily for Avandia (Rosiglitazone maleate) , 7.5 mg twice daily for glyburide, and 1,000 mg twice daily for metformin. The primary efficacy outcome was time to consecutive FPG >180 mg/dL after at least 6 weeks of treatment at the maximum tolerated dose of study medication or time to inadequate glycemic control, as determined by an independent adjudication committee.

The cumulative incidence of the primary efficacy outcome at 5 years was 15% with Avandia (Rosiglitazone maleate) , 21% with metformin, and 34% with glyburide (hazard ratio 0.68 [95% CI 0.55, 0.85] versus metformin, HR 0.37 [95% CI 0.30, 0.45] versus glyburide).

Cardiovascular and adverse event data (including effects on body weight and bone fracture) from ADOPT for Avandia (Rosiglitazone maleate) , metformin, and glyburide are described in and , respectively. As with all medications, efficacy results must be considered together with safety information to assess the potential benefit and risk for an individual patient.

The addition of Avandia (Rosiglitazone maleate) to either metformin or sulfonylurea resulted in significant reductions in hyperglycemia compared to either of these agents alone. These results are consistent with an additive effect on glycemic control when Avandia (Rosiglitazone maleate) is used as 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 Avandia (Rosiglitazone maleate) in combination with metformin. Avandia (Rosiglitazone maleate) , administered in either once daily or twice daily dosing regimens, was added to the therapy of patients who were inadequately controlled on a maximum dose (2.5 grams/day) of metformin.

In one study, patients inadequately controlled on 2.5 grams/day of metformin (mean baseline FPG 216 mg/dL and mean baseline HbA1c 8.8%) were randomized to receive 4 mg of Avandia (Rosiglitazone maleate) once daily, 8 mg of Avandia (Rosiglitazone maleate) 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 4 mg of Avandia (Rosiglitazone maleate) once daily and 8 mg of Avandia (Rosiglitazone maleate) once daily, versus patients continued on metformin alone (Table 10).

In a second 26-week study, patients with type 2 diabetes inadequately controlled on 2.5 grams/day of metformin who were randomized to receive the combination of Avandia (Rosiglitazone maleate) 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 Avandia (Rosiglitazone maleate) resulted in lower levels of FPG and HbA1c than either agent alone.

Patients who were inadequately controlled on a maximum dose (2.5 grams/day) of metformin and who were switched to monotherapy with Avandia (Rosiglitazone maleate) demonstrated loss of glycemic control, as evidenced by increases in FPG and HbA1c. In this group, increases in LDL and VLDL were also seen.

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

In these studies, the combination of Avandia (Rosiglitazone maleate) 4 mg or 8 mg daily (administered as single or twice daily divided doses) and a sulfonylurea significantly reduced FPG and HbA1c compared to placebo plus sulfonylurea or further up-titration of the sulfonylurea. Table 11 shows pooled data for 8 studies in which Avandia (Rosiglitazone maleate) added to sulfonylurea was compared to placebo plus sulfonylurea.

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

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

In two 24- to 26-week, double-blind, placebo-controlled, studies designed to assess the efficacy and safety of Avandia (Rosiglitazone maleate) in combination with sulfonylurea plus metformin, Avandia (Rosiglitazone maleate) 4 mg or 8 mg daily, was administered in divided doses twice daily, to patients inadequately controlled on submaximal (10 mg) and maximal (20 mg) doses of glyburide and maximal dose of metformin (2 g/day). A statistically significant improvement in FPG and HbA1c was observed in patients treated with the combinations of sulfonylurea plus metformin and 4 mg of Avandia (Rosiglitazone maleate) and 8 mg of Avandia (Rosiglitazone maleate) versus patients continued on sulfonylurea plus metformin, as shown in Table 12.

Each pentagonal film-coated TILTAB tablet contains rosiglitazone as the maleate as follows: 2 mg–pink, debossed with SB on one side and 2 on the other; 4 mg–orange, debossed with SB on one side and 4 on the other; 8 mg–red-brown, debossed with SB on one side and 8 on the other.

2 mg bottles of 30: NDC 54868-5249-02 mg bottles of 60: NDC 54868-5249-1

4 mg bottles of 30: NDC 54868-4198-04 mg bottles of 60: NDC 54868-4198-1

8 mg bottles of 30: NDC 54868-4221-0

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

Patients should be informed of the following:

See separate leaflet.

Avandia (Rosiglitazone maleate) and TILTAB are registered trademarks of GlaxoSmithKline.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2009, GlaxoSmithKline. All rights reserved.

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

Avandia (Rosiglitazone maleate) is a prescription medicine to treat adults with diabetes. It helps to control high blood sugar. (See “What is Avandia (Rosiglitazone maleate) ?”). It is important that you take Avandia (Rosiglitazone maleate) exactly how it is prescribed by your doctor to best treat your diabetes.

Avandia (Rosiglitazone maleate) may cause serious side effects, including:

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

Avandia (Rosiglitazone maleate) may raise the risk of heart problems related to reduced blood flow to the heart. These include possible increases in the risk of heart-related chest pain (angina) or "heart attack" (myocardial infarction). This risk seemed to be higher in people who took Avandia (Rosiglitazone maleate) with insulin or with nitrate medicines. Most people who take insulin or nitrate medicines should not also take Avandia (Rosiglitazone maleate) .

Avandia (Rosiglitazone maleate) can have other serious side effects. Be sure to read the section below “What are possible side effects of Avandia (Rosiglitazone maleate) ?”.

Avandia (Rosiglitazone maleate) is a prescription medicine used with diet and exercise to treat adults with type 2 (“adult-onset” or “non-insulin dependent”) diabetes mellitus (“high blood sugar”). Avandia (Rosiglitazone maleate) helps to control high blood sugar. Avandia (Rosiglitazone maleate) may be used alone or with other diabetes medicines. Avandia (Rosiglitazone maleate) can help your body respond better to insulin made in your body. Avandia (Rosiglitazone maleate) does not cause your body to make more insulin.

Many people with heart failure should not start taking Avandia (Rosiglitazone maleate) . See “What should I tell my doctor before taking Avandia (Rosiglitazone maleate) ?”.

Before starting Avandia (Rosiglitazone maleate) , ask your doctor about what the choices are for diabetes medicines, and what the expected benefits and possible risks are for you in particular.

Before taking Avandia (Rosiglitazone maleate) , tell your doctor about all your medical conditions, including if you:

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

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

The most common side effects of Avandia (Rosiglitazone maleate) reported in clinical trials included cold-like symptoms and headache.

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

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

This Medication Guide summarizes important information about Avandia (Rosiglitazone maleate) . If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Avandia (Rosiglitazone maleate) that is written for healthcare professionals. You can also find out more about Avandia (Rosiglitazone maleate) by calling 1-888-825-5249 or visiting the website www.Avandia (Rosiglitazone maleate) .com.

Active Ingredient:  Rosiglitazone maleate.

Inactive Ingredients: Hypromellose 2910, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 3000, sodium starch glycolate, titanium dioxide, triacetin, and 1 or more of the following: Synthetic red and yellow iron oxides and talc.

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

2 mg strength tablets – pink with “SB” on one side and “2” on the other.

4 mg strength tablets – orange with “SB” on one side and “4” on the other.

8 mg strength tablets – red-brown with “SB” on one side and “8” on the other.

Avandia (Rosiglitazone maleate) is a registered trademark of GlaxoSmithKline.

REZULIN is a registered trademark of Parke-Davis Pharmaceuticals Ltd.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2008, GlaxoSmithKline. All rights reserved.

October 2008

AVD:4MG

Avandia (Rosiglitazone maleate)

ROSIGLITAZONE MALEATE TABLETS

Avandia (Rosiglitazone maleate)

ROSIGLITAZONE MALEATE TABLETS

Avandia (Rosiglitazone maleate)

ROSIGLITAZONE MALEATE TABLETS