FDA label c6998838-0d1a-4822-805e-9b7298e13c77

WARNING: CONGESTIVE HEART FAILURE AND MYOCARDIAL ISCHEMIA ● Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.1)]. After initiation of rosiglitazone maleate, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of rosiglitazone maleate must be considered. ● Rosiglitazone Maleate is not recommended in patients with symptomatic heart failure. Initiation of rosiglitazone maleate in patients with established NYHA Class III or IV heart failure is contraindicated. [See Contraindications (4) and Warnings and Precautions (5.1 ).] ● A meta-analysis of 42 clinical studies (mean duration 6 months; 14,237 total patients), most of which compared rosiglitazone maleate to placebo, showed rosiglitazone maleate to be associated with an increased risk of myocardial ischemic events such as angina or myocardial infarction. Three other studies (mean duration 41 months; 14,067 total patients), comparing rosiglitazone maleate to some other approved oral antidiabetic agents or placebo, have not confirmed or excluded this risk. In their entirety, the available data on the risk of myocardial ischemia are inconclusive. [See Warnings and Precautions (5.2) .] WARNING: CONGESTIVE HEART FAILURE AND MYOCARDIAL ISCHEMIA ● Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure in some patients (5.1). After initiation of rosiglitazone maleate, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of rosiglitazone maleate must be considered. ● Rosiglitazone maleate is not recommended in patients with symptomatic heart failure. Initiation of rosiglitazone maleate in patients with established NYHA Class III or IV heart failure is contraindicated. (4, 5.1) ● A meta-analysis of 42 clinical studies (mean duration 6 months; 14,237 total patients), most of which compared rosiglitazone maleate to placebo, showed rosiglitazone maleate to be associated with an increased risk of myocardial ischemic events such as angina or myocardial infarction. Three other studies (mean duration 41 months; 14,067 total patients), comparing rosiglitazone maleate to some other approved oral antidiabetic agents or placebo, have not confirmed or excluded this risk. In their entirety, the available data on the risk of myocardial ischemia are inconclusive. (5.2)

5 WARNINGS AND PRECAUTIONS Fluid retention, which may exacerbate or lead to heart failure, may occur. Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk of other cardiovascular effects. (5.1, 5.3) Increased risk of myocardial ischemic events has been observed in a meta-analysis of 42 clinical trials (incidence rate 2% versus 1.5%). (5.2) Use of rosiglitazone maleate with nitrates is not recommended. (1.2, 5.2) Coadministration of rosiglitazone maleate and insulin is not recommended. (1.2, 5.3) Dose-related edema (5.4), weight gain (5.5), and anemia (5.9) may occur. Macular edema has been reported. (5.7) Increased incidence of bone fracture in female patients. (5.8) There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with rosiglitazone maleate or any other oral antidiabetic drug (5.2) 5.1 Cardiac Failure 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 [see Boxed Warning ] . Patients with congestive heart failure (CHF) NYHA Class I and II treated with 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 rosiglitazone maleate compared to placebo during the 52-week study. (See Table 1.) Table 1. Emergent Cardiovascular Adverse Events in Patients With Congestive Heart Failure (NYHA Class I and II) Treated With Rosiglitazone Maleate Tablets or Placebo (in Addition to Background Antidiabetic and CHF Therapy) Events Rosiglitazone maleate tablets Placebo N = 110 n (%) N = 114 n (%) Adjudicated Cardiovascular deaths 5 (5%) 4 (4%) CHF worsening 7 (6%) 4 (4%) – with overnight hospitalization 5 (5%) 4 (4%) – without overnight hospitalization 2 (2%) 0 (0%) New or worsening edema 28 (25%) 10 (9%) New or worsening dyspnea 29 (26%) 19 (17%) Increases in CHF medication 36 (33%) 20 (18%) Cardiovascular hospitalization * 21 (19%) 15 (13%) Investigator-reported, non-adjudicated Ischemic adverse events 10 (9%) 5 (4%) – Myocardial infarction 5 (5%) 2 (2%) – Angina 6 (5%) 3 (3%) * Includes hospitalization for any cardiovascular reason. Initiation of rosiglitazone maleate in patients with established NYHA Class III or IV heart failure is contraindicated. Rosiglitazone maleate is not recommended in patients with symptomatic heart failure. [See Boxed Warning .] 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 rosiglitazone maleate is not recommended for patients experiencing an acute coronary event, and discontinuation of 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. Rosiglitazone maleate is not recommended in patients with NYHA Class III and IV cardiac status. 5.2 Myocardial Ischemia Meta-Analysis of Myocardial Ischemia in a Group of 42 Clinical Trials A meta-analysis was conducted retrospectively to assess cardiovascular adverse events reported across 42 double-blind, randomized, controlled clinical trials (mean duration 6 months). 1 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 rosiglitazone maleate versus placebo monotherapy) and add-on trials (rosiglitazone maleate or placebo, added to sulfonylurea, metformin, or insulin). Active control studies included monotherapy trials (monotherapy with rosiglitazone maleate versus sulfonylurea or metformin monotherapy) and add-on trials (rosiglitazone maleate plus sulfonylurea or rosiglitazone maleate plus metformin, versus sulfonylurea plus metformin). A total of 14,237 patients were included (8,604 in treatment groups containing rosiglitazone maleate, 5,633 in comparator groups), with 4,143 patient-years of exposure to 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 rosiglitazone maleate versus pooled comparators was observed (2% 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 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 rosiglitazone maleate was added to insulin (2.8% for 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. [See Warnings and Precautions (5.3) .] Figure 1 - Forest Plot of Odds Rations (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 rosiglitazone maleate and background nitrate therapy. For 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 rosiglitazone maleate versus comparator was not demonstrated. Myocardial Ischemic Adverse Events Myocardial Ischemic Events in Large Long-Term Prospectice Randomized Controlled Trials of rosiglitazone maleate Data from 3 other large, long-term, prospective, randomized, controlled clinical trials of rosiglitazone maleate were assessed separately from the meta-analysis. These 3 trials include a total of 14,067 patients (treatment groups containing rosiglitazone maleate N = 6,311, comparator groups N = 7,756), with patient-year exposure of 21,803 patient-years for rosiglitazone maleate and 25,998 patient-years for comparator. Duration of follow-up exceeded 3 years in each study. ADOPT (A Diabetes Outcomes Progression Trial) was a 4- to 6-year randomized, active-controlled study in recently diagnosed patients with type 2 diabetes naïve to drug therapy. It was an efficacy and general safety trial that was designed to examine the durability of rosiglitazone maleate as monotherapy (N = 1,456) for glycemic control in type 2 diabetes, with comparator arms of sulfonylurea monotherapy (N = 1,441) and metformin monotherapy (N = 1,454). DREAM (Diabetes Reduction Assessment with Rosiglitazone and Ramipril Medication, published report 2 ) was a 3- to 5-year randomized, placebo-controlled study in patients with impaired glucose tolerance and/or impaired fasting glucose. It had a 2x2 factorial design, intended to evaluate the effect of rosiglitazone maleate, and separately of ramipril (an angiotensin converting enzyme inhibitor [ACEI]), on progression to overt diabetes. In DREAM, 2,635 patients were in treatment groups containing rosligtazone maleate, and 2,634 were in treatment groups not containing rosiglitazone maleate. Interim results have been published 3 for RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes), an ongoing open-label, 6-year cardiovascular outcomes study in patients with type 2 diabetes with an average treatment duration of 3.75 years. RECORD includes patients who have failed metformin or sulfonylurea monotherapy; those who have failed metformin are randomized to receive either add-on rosiglitazone maleate or add-on sulfonylurea, and those who have failed sulfonylurea are randomized to receive either add-on rosiglitazone maleate or add-on metformin. In RECORD, a total of 2,220 patients are receiving add-on rosiglitazone maleate, and 2,227 patients are on one of the add-on regimens not containing rosiglitazone maleate. For these 3 trials, analyses were performed using a composite of major adverse cardiovascular events (myocardial infarction, cardiovascular death, or stroke), referred to hereafter as MACE. This endpoint differed from the meta-analysis’ broad endpoint of myocardial ischemic events, more than half of which were angina. Myocardial infarction included adjudicated fatal and nonfatal myocardial infarction plus sudden death. As shown in Figure 2, the results for the 3 endpoints (MACE, MI, and Total Mortality) were not statistically significantly different between rosiglitazone maleate and comparators. Figure 2. Hazard Ratios for the Risk of MACE (Myocardial Infarction, Cardiovascular Death, or Stroke), Myocardial Infarction, and Total Mortality With Rosiglitazone Maleate Compared With a Control Group In preliminary analyses of the DREAM trial, the incidence of cardiovascular events was higher among subjects who received rosiglitazone maleate in combination with ramipril than among subjects who received ramipril alone, as illustrated in Figure 2. This finding was not confirmed in ADOPT and RECORD (active-controlled trials in patients with diabetes) in which 30% and 40% of patients respectively, reported ACE-inhibitor use at baseline. In their entirety, the available data on the risk of myocardial ischemia are inconclusive. Definitive conclusions regarding this risk await completion of an adequately-designed cardiovascular outcome study. There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with AVANDIA or any other oral antidiabetic drug. Figure 2 - Hazard Ratios 5.3 Congestive Heart Failure and Myocardial Ischemia During Coadministration of AVANDIA With Insulin In studies in which rosiglitazone maleate was added to insulin, rosiglitazone maleate increased the risk of congestive heart failure and myocardial ischemia. (See Table 2.) Coadministration of rosiglitazone maleate and insulin is not recommended. [See Indications and Usage (1.2) and Warnings and Precautions (5.1, 5.2) .] In five, 26-week, controlled, randomized, double-blind trials which were included in the meta-analysis [see Warnings and Precautions (5.2) ] , patients with type 2 diabetes mellitus were randomized to coadministration of AVANDIA and insulin (N = 867) or insulin (N = 663). In these 5 trials, rosiglitazone maleate was added to insulin. These trials included patients with long-standing diabetes (median duration of 12 years) and a high prevalence of pre-existing medical conditions, including peripheral neuropathy, retinopathy, ischemic heart disease, vascular disease, and congestive heart failure. The total number of patients with emergent congestive heart failure was 21 (2.4%) and 7 (1.1%) in the rosiglitazone maleate plus insulin and insulin groups, respectively. The total number of patients with emergent myocardial ischemia was 24 (2.8%) and 9 (1.4%) in the rosiglitazone maleate plus insulin and insulin groups, respectively (OR 2.1 [95% CI 0.9, 5.1]). Although the event rate for congestive heart failure and myocardial ischemia was low in the studied population, consistently the event rate was 2-fold or higher with coadministration of rosiglitazone maleate and insulin. These cardiovascular events were noted at both the 4 mg and 8 mg daily doses of rosiglitazone maleate. (See Table 2.) Table 2. Occurrence of Cardiovascular Events in 5 Controlled Trials of Addition of Rosiglitazone Maleate to Established Insulin Treatment Event* Rosiglitazone Maleate + Insulin (n = 867) n (%) Insulin (n = 663) n (%) Congestive heart failure 21 (2.4%) 7 (1.1%) Myocardial ischemia 24 (2.8%) 9 (1.4%) Composite of cardiovascular death, myocardial infarction, or stroke 10 (1.2%) 5 (0.8%) Stroke 5 (0.6%) 4 (0.6%) Myocardial infarction 4 (0.5%) 1 (0.2%) Cardiovascular death 4 (0.5%) 1 (0.2%) All deaths 6 (0.7%) 1 (0.2%) *Events are not exclusive; i.e., a patient with a cardiovascular death due to a myocardial infarction would be counted in 4 event categories (myocardial ischemia; cardiovascular death, myocardial infarction or stroke; myocardial infarction; cardiovascular death). In a sixth, 24-week, controlled, randomized, double-blind trial of rosiglitaszone maleate and insulin coadministration, insulin was added to AVANDAMET ® (rosiglitazone maleate and metformin HCl) (n = 161) and compared to insulin plus placebo (n = 158), after a single-blind 8-week run-in with AVANDAMET. Patients with edema requiring pharmacologic therapy and those with congestive heart failure were excluded at baseline and during the run-in period. In the group receiving AVANDAMET plus insulin, there was one myocardial ischemic event and one sudden death. No myocardial ischemia was observed in the insulin group, and no congestive heart failure was reported in either treatment group. 5.4 Edema Rosiglitazone maleate should be used with caution in patients with edema. In a clinical study in healthy volunteers who received 8 mg of rosiglitazone maleate 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, rosiglitazone maleate should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure [see Boxed Warning , Warnings and Precautions (5.1 ), and Patient Counseling Information (17.1) ] . 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 were more likely to have adverse events associated with edema if started on combination therapy with insulin and rosiglitazone maleate [see Adverse Reactions (6.1)] . 5.5 Weight Gain Dose-related weight gain was seen with rosiglitazone maleate alone and 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, there have been reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure [see Boxed Warning ] . Table 3. Weight Changes (kg) From Baseline at Endpoint During Clinical Trials Control Group Rosiglitazone maleate 4 mg Rosiglitazone maleate 8 mg Monotherapy Duration Median (25 th , 75 th percentile) Median (25 th , 75 th percentile) Median (25 th , 75 th percentile) 26 weeks placebo -0.9 (-2.8, 0.9) n = 210 1.0 (-0.9, 3.6) n = 436 3.1 (1.1, 5.8) n = 439 52 weeks sulfonylurea 2.0 (0, 4.0) n = 173 2.0 (-0.6, 4.0) n = 150 2.6 (0, 5.3) n = 157 Combination therapy Sulfonylurea 24-26 weeks sulfonylurea 0 (-1.0, 1.3) n = 1,155 2.2 (0.5, 4.0) n = 613 3.5 (1.4, 5.9) n = 841 Metformin 26 weeks metformin -1.4 (-3.2, 0.2) n = 175 0.8 (-1.0, 2.6) n = 100 2.1 (0, 4.3) n = 184 Insulin 26 weeks insulin 0.9 (-0.5, 2.7) n = 162 4.1 (1.4, 6.3) n = 164 5.4 (3.4, 7.3) n = 150 Sulfonylurea + metformin 26 weeks sulfonylurea + metformin 0.2 (-1.2, 1.6) n = 272 2.5 (0.8, 4.6) n = 275 4.5 (2.4, 7.3) n = 276 In a 4- to 6-year, monotherapy, comparative trial (ADOPT) in patients recently diagnosed with type 2 diabetes not previously treated with antidiabetic medication [see Clinical Studies (14.1) ] , the median weight change (25 th , 75 th percentiles) from baseline at 4 years was 3.5 kg (0.0, 8.1) for rosiglitazone maleate, 2.0 kg (-1.0, 4.8) for glyburide, and -2.4 kg (-5.4, 0.5) for metformin. In a 24-week study in pediatric patients aged 10 to 17 years treated with rosiglitazone maleate 4 to 8 mg daily, a median weight gain of 2.8 kg (25 th , 75 th percentiles: 0.0, 5.8) was reported. 5.6 Hepatic Effects Liver enzymes should be measured prior to the initiation of therapy with rosiglitazone maleate in all patients and periodically thereafter per the clinical judgment of the healthcare professional. Therapy with rosiglitazone maleate should not be initiated in patients with increased baseline liver enzyme levels (ALT >2.5X upper limit of normal). Patients with mildly elevated liver enzymes (ALT levels ≤−2.5X upper limit of normal) at baseline or during therapy with rosiglitazone maleate should be evaluated to determine the cause of the liver enzyme elevation. Initiation of, or continuation of, therapy with rosiglitazone maleate in patients with mild liver enzyme elevations should proceed with caution and include close clinical follow-up, including liver enzyme monitoring, to determine if the liver enzyme elevations resolve or worsen. If at any time ALT levels increase to >3X the upper limit of normal in patients on therapy with rosiglitazone maleate, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain >3X the upper limit of normal, therapy with rosiglitazone maleate should be discontinued. If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with rosiglitazone maleate should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued. [See Adverse Reactions (6.2, 6.3).] 5.7 Macular Edema Macular edema has been reported in postmarketing experience in some diabetic patients who were taking rosiglitazone maleate or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but some patients appear to have been diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione. Patients with diabetes should have regular eye exams by an ophthalmologist, per the Standards of Care of the American Diabetes Association. Additionally, any diabetic who reports any kind of visual symptom should be promptly referred to an ophthalmologist, regardless of the patient’s underlying medications or other physical findings. [See Adverse Reactions (6.1) .] 5.8 Fractures In a 4- to 6-year comparative study (ADOPT) of glycemic control with monotherapy in drug-naïve patients recently diagnosed with type 2 diabetes mellitus, an increased incidence of bone fracture was noted in female patients taking rosiglitazone maleate. Over the 4- to 6-year period, the incidence of bone fracture in females was 9.3% (60/645) for rosiglitazone maleate versus 3.5% (21/605) for glyburide and 5.1% (30/590) for metformin. This increased incidence was noted after the first year of treatment and persisted during the course of the study. The majority of the fractures in the women who received rosiglitazone maleate occurred in the upper arm, hand, and foot. These sites of fracture are different from those usually associated with postmenopausal osteoporosis (e.g., hip or spine). No increase in fracture rates was observed in men treated with rosiglitazone maleate. The risk of fracture should be considered in the care of patients, especially female patients, treated with rosiglitazone maleate, and attention given to assessing and maintaining bone health according to current standards of care. 5.9 Hematologic Effects Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with rosiglitazone maleate [see Adverse Reactions (6.2)] . The observed changes may be related to the increased plasma volume observed with treatment with rosiglitazonemaleate. 5.10 Diabetes and Blood Glucose Control Patients receiving rosiglitazone maleate in combination with other hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary. Periodic fasting blood glucose and HbA1c measurements should be performed to monitor therapeutic response. 5.11 Ovulation Therapy with rosiglitazone maleate, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking rosiglitazone maleate [see Use in Specific Populations (8.1 )] . Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical studies; therefore, the frequency of this occurrence is not known. Although hormonal imbalance has been seen in preclinical studies [see Nonclinical Toxicology (13.1 )] , the clinical significance of this finding is not known. If unexpected menstrual dysfunction occurs, the benefits of continued therapy with rosiglitazone maleate should be reviewed.

5.1 Cardiac Failure 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 [see Boxed Warning ] . Patients with congestive heart failure (CHF) NYHA Class I and II treated with 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 rosiglitazone maleate compared to placebo during the 52-week study. (See Table 1.) Table 1. Emergent Cardiovascular Adverse Events in Patients With Congestive Heart Failure (NYHA Class I and II) Treated With Rosiglitazone Maleate Tablets or Placebo (in Addition to Background Antidiabetic and CHF Therapy) Events Rosiglitazone maleate tablets Placebo N = 110 n (%) N = 114 n (%) Adjudicated Cardiovascular deaths 5 (5%) 4 (4%) CHF worsening 7 (6%) 4 (4%) – with overnight hospitalization 5 (5%) 4 (4%) – without overnight hospitalization 2 (2%) 0 (0%) New or worsening edema 28 (25%) 10 (9%) New or worsening dyspnea 29 (26%) 19 (17%) Increases in CHF medication 36 (33%) 20 (18%) Cardiovascular hospitalization * 21 (19%) 15 (13%) Investigator-reported, non-adjudicated Ischemic adverse events 10 (9%) 5 (4%) – Myocardial infarction 5 (5%) 2 (2%) – Angina 6 (5%) 3 (3%) * Includes hospitalization for any cardiovascular reason. Initiation of rosiglitazone maleate in patients with established NYHA Class III or IV heart failure is contraindicated. Rosiglitazone maleate is not recommended in patients with symptomatic heart failure. [See Boxed Warning .] 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 rosiglitazone maleate is not recommended for patients experiencing an acute coronary event, and discontinuation of 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. Rosiglitazone maleate is not recommended in patients with NYHA Class III and IV cardiac status.

Meta-Analysis of Myocardial Ischemia in a Group of 42 Clinical Trials A meta-analysis was conducted retrospectively to assess cardiovascular adverse events reported across 42 double-blind, randomized, controlled clinical trials (mean duration 6 months). 1 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 rosiglitazone maleate versus placebo monotherapy) and add-on trials (rosiglitazone maleate or placebo, added to sulfonylurea, metformin, or insulin). Active control studies included monotherapy trials (monotherapy with rosiglitazone maleate versus sulfonylurea or metformin monotherapy) and add-on trials (rosiglitazone maleate plus sulfonylurea or rosiglitazone maleate plus metformin, versus sulfonylurea plus metformin). A total of 14,237 patients were included (8,604 in treatment groups containing rosiglitazone maleate, 5,633 in comparator groups), with 4,143 patient-years of exposure to 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 rosiglitazone maleate versus pooled comparators was observed (2% 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 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 rosiglitazone maleate was added to insulin (2.8% for 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. [See Warnings and Precautions (5.3) .] Figure 1 - Forest Plot of Odds Rations (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 rosiglitazone maleate and background nitrate therapy. For 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 rosiglitazone maleate versus comparator was not demonstrated. Myocardial Ischemic Adverse Events

Myocardial Ischemic Events in Large Long-Term Prospectice Randomized Controlled Trials of rosiglitazone maleate Data from 3 other large, long-term, prospective, randomized, controlled clinical trials of rosiglitazone maleate were assessed separately from the meta-analysis. These 3 trials include a total of 14,067 patients (treatment groups containing rosiglitazone maleate N = 6,311, comparator groups N = 7,756), with patient-year exposure of 21,803 patient-years for rosiglitazone maleate and 25,998 patient-years for comparator. Duration of follow-up exceeded 3 years in each study. ADOPT (A Diabetes Outcomes Progression Trial) was a 4- to 6-year randomized, active-controlled study in recently diagnosed patients with type 2 diabetes naïve to drug therapy. It was an efficacy and general safety trial that was designed to examine the durability of rosiglitazone maleate as monotherapy (N = 1,456) for glycemic control in type 2 diabetes, with comparator arms of sulfonylurea monotherapy (N = 1,441) and metformin monotherapy (N = 1,454). DREAM (Diabetes Reduction Assessment with Rosiglitazone and Ramipril Medication, published report 2 ) was a 3- to 5-year randomized, placebo-controlled study in patients with impaired glucose tolerance and/or impaired fasting glucose. It had a 2x2 factorial design, intended to evaluate the effect of rosiglitazone maleate, and separately of ramipril (an angiotensin converting enzyme inhibitor [ACEI]), on progression to overt diabetes. In DREAM, 2,635 patients were in treatment groups containing rosligtazone maleate, and 2,634 were in treatment groups not containing rosiglitazone maleate. Interim results have been published 3 for RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes), an ongoing open-label, 6-year cardiovascular outcomes study in patients with type 2 diabetes with an average treatment duration of 3.75 years. RECORD includes patients who have failed metformin or sulfonylurea monotherapy; those who have failed metformin are randomized to receive either add-on rosiglitazone maleate or add-on sulfonylurea, and those who have failed sulfonylurea are randomized to receive either add-on rosiglitazone maleate or add-on metformin. In RECORD, a total of 2,220 patients are receiving add-on rosiglitazone maleate, and 2,227 patients are on one of the add-on regimens not containing rosiglitazone maleate. For these 3 trials, analyses were performed using a composite of major adverse cardiovascular events (myocardial infarction, cardiovascular death, or stroke), referred to hereafter as MACE. This endpoint differed from the meta-analysis’ broad endpoint of myocardial ischemic events, more than half of which were angina. Myocardial infarction included adjudicated fatal and nonfatal myocardial infarction plus sudden death. As shown in Figure 2, the results for the 3 endpoints (MACE, MI, and Total Mortality) were not statistically significantly different between rosiglitazone maleate and comparators. Figure 2. Hazard Ratios for the Risk of MACE (Myocardial Infarction, Cardiovascular Death, or Stroke), Myocardial Infarction, and Total Mortality With Rosiglitazone Maleate Compared With a Control Group In preliminary analyses of the DREAM trial, the incidence of cardiovascular events was higher among subjects who received rosiglitazone maleate in combination with ramipril than among subjects who received ramipril alone, as illustrated in Figure 2. This finding was not confirmed in ADOPT and RECORD (active-controlled trials in patients with diabetes) in which 30% and 40% of patients respectively, reported ACE-inhibitor use at baseline. In their entirety, the available data on the risk of myocardial ischemia are inconclusive. Definitive conclusions regarding this risk await completion of an adequately-designed cardiovascular outcome study. There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with AVANDIA or any other oral antidiabetic drug. Figure 2 - Hazard Ratios

6 ADVERSE REACTIONS Common adverse reactions (>5%) reported in clinical trials without regard to causality were upper respiratory tract infection, injury, and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact West-ward Pharmaceutical Corp, at 732-542-1191 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Adult In clinical trials, approximately 9,900 patients with type 2 diabetes have been treated with rosiglitazone maleate. Short-Term Trials of Rosiglitazone Maleate as Monotherapy and in Combination With Other Hypoglycemic Agents The incidence and types of adverse events reported in short-term clinical trials of rosiglitazone maleate as monotherapy are shown in Table 4. Table 4. Adverse Events (≥5% in Any Treatment Group) Reported by Patients in Short-Term * Double-Blind Clinical Trials With Rosiglitazone Maleate as Monotherapy Preferred Term Rosiglitazone maleate Monotherapy Placebo Metformin Sulfonylureas † N = 2,526 N = 601 N = 225 N = 626 % % % % Upper respiratory tract infection 9.9 8.7 8.9 7.3 Injury 7.6 4.3 7.6 6.1 Headache 5.9 5.0 8.9 5.4 Back pain 4.0 3.8 4.0 5.0 Hyperglycemia 3.9 5.7 4.4 8.1 Fatigue 3.6 5.0 4.0 1.9 Sinusitis 3.2 4.5 5.3 3.0 Diarrhea 2.3 3.3 15.6 3.0 Hypoglycemia 0.6 0.2 1.3 5.9 * Short-term trials ranged from 8 weeks to 1 year. † Includes patients receiving glyburide (N = 514), gliclazide (N = 91), or glipizide (N = 21). Overall, the types of adverse reactions without regard to causality reported when rosiglitazone maleate was used in combination with a sulfonylurea or metformin were similar to those during monotherapy with 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 rosiglitazone maleate. In double-blind studies, anemia was reported in 1.9% of patients receiving 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 and metformin (7.1%) and with a combination of AVANDIA and a sulfonylurea plus metformin (6.7%) compared to monotherapy with Arosiglitazone 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 [see Adverse Reactions (6.2)] . In clinical trials, edema was reported in 4.8% of patients receiving 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 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 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 rosiglitazone maleate [see Boxed Warning and Warnings and Precautions (5.3 )] . In controlled combination therapy studies with sulfonylureas, mild to moderate hypoglycemic symptoms, which appear to be dose related, were reported. Few patients were withdrawn for hypoglycemia (<1%) and few episodes of hypoglycemia were considered to be severe (<1%). 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 rosiglitazone maleate plus insulin and 1 of 203 for insulin alone). Rates of hypoglycemia, confirmed by capillary blood glucose concentration ≤50 mg/dL, were 6% for insulin alone and 12% (4 mg) and 14% (8 mg) for insulin in combination with rosiglitazone maleate. [See Warnings and Precautions (5.10) .] Long-Term Trial of Rosiglitazone Maleate as Monotherapy A 4- to 6-year study (ADOPT) compared the use of 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 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. [See Warnings and Precautions (5.7 ).] The observed incidence of fractures for male patients was similar among the 3 treatment groups. Table 5. On-Therapy Adverse Events (≥5 Events/100 Patient-Years [PY]) in Any Treatment Group Reported in a 4- to 6-Year Clinical Trial of Rosiglitazone Maleate as Monotherapy (ADOPT) Rosiglitazone Maleate Glyburide Metformin N = 1,456 N = 1,441 N = 1,454 PY = 4,954 PY = 4,244 PY = 4,906 Nasopharyngitis 6.3 6.9 6.6 Back pain 5.1 4.9 5.3 Arthralgia 5.0 4.8 4.2 Hypertension 4.4 6.0 6.1 Upper respiratory tract infection 4.3 5.0 4.7 Hypoglycemia 2.9 13.0 3.4 Diarrhea 2.5 3.2 6.8 Pediatric 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 rosiglitazone maleate and 101 were treated with metformin. The most common adverse reactions (>10%) without regard to causality for either 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. 6.2 Laboratory Abnormalities Hematologic Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with AVANDIA (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 or following a dose increase in AVANDIA. The time course and magnitude of decreases were similar in patients treated with a combination of AVANDIA and other hypoglycemic agents or monotherapy with AVANDIA. 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. White blood cell counts also decreased slightly in adult patients treated with AVANDIA. Decreases in hematologic parameters may be related to increased plasma volume observed with treatment with AVANDIA. Lipids Changes in serum lipids have been observed following treatment with rosiglitazone maleate in adults [see Clinical Pharmacology (12.2) ] . Small changes in serum lipid parameters were reported in children treated with rosiglitazone maleate for 24 weeks. Serum Transaminase Levels In pre-approval clinical studies in 4,598 patients treated with rosiglitazone maleate (3,600 patient-years of exposure) and in a long-term 4- to 6-year study in 1,456 patients treated with 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 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 rosiglitazone maleate were reversible. Hyperbilirubinemia was found in 0.3% of patients treated with 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. [See Warnings and Precautions (5.6).] In the 4- to 6-year ADOPT trial, patients treated with 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 >3X upper limit of normal (0.3 per 100 patient-years exposure). 6.3 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the events described below have been identified during post-approval use of 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 [see Boxed Warning and Warnings and Precautions (5.1)] . There are postmarketing reports with 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. Rash, pruritus, urticaria, angioedema, anaphylactic reaction, and Stevens-Johnson syndrome have been reported rarely. Reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received [see Warnings and Precautions (5.7)] .

6.1 Clinical Trial Experience Adult In clinical trials, approximately 9,900 patients with type 2 diabetes have been treated with rosiglitazone maleate. Short-Term Trials of Rosiglitazone Maleate as Monotherapy and in Combination With Other Hypoglycemic Agents The incidence and types of adverse events reported in short-term clinical trials of rosiglitazone maleate as monotherapy are shown in Table 4. Table 4. Adverse Events (≥5% in Any Treatment Group) Reported by Patients in Short-Term * Double-Blind Clinical Trials With Rosiglitazone Maleate as Monotherapy Preferred Term Rosiglitazone maleate Monotherapy Placebo Metformin Sulfonylureas † N = 2,526 N = 601 N = 225 N = 626 % % % % Upper respiratory tract infection 9.9 8.7 8.9 7.3 Injury 7.6 4.3 7.6 6.1 Headache 5.9 5.0 8.9 5.4 Back pain 4.0 3.8 4.0 5.0 Hyperglycemia 3.9 5.7 4.4 8.1 Fatigue 3.6 5.0 4.0 1.9 Sinusitis 3.2 4.5 5.3 3.0 Diarrhea 2.3 3.3 15.6 3.0 Hypoglycemia 0.6 0.2 1.3 5.9 * Short-term trials ranged from 8 weeks to 1 year. † Includes patients receiving glyburide (N = 514), gliclazide (N = 91), or glipizide (N = 21). Overall, the types of adverse reactions without regard to causality reported when rosiglitazone maleate was used in combination with a sulfonylurea or metformin were similar to those during monotherapy with 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 rosiglitazone maleate. In double-blind studies, anemia was reported in 1.9% of patients receiving 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 and metformin (7.1%) and with a combination of AVANDIA and a sulfonylurea plus metformin (6.7%) compared to monotherapy with Arosiglitazone 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 [see Adverse Reactions (6.2)] . In clinical trials, edema was reported in 4.8% of patients receiving 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 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 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 rosiglitazone maleate [see Boxed Warning and Warnings and Precautions (5.3 )] . In controlled combination therapy studies with sulfonylureas, mild to moderate hypoglycemic symptoms, which appear to be dose related, were reported. Few patients were withdrawn for hypoglycemia (<1%) and few episodes of hypoglycemia were considered to be severe (<1%). 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 rosiglitazone maleate plus insulin and 1 of 203 for insulin alone). Rates of hypoglycemia, confirmed by capillary blood glucose concentration ≤50 mg/dL, were 6% for insulin alone and 12% (4 mg) and 14% (8 mg) for insulin in combination with rosiglitazone maleate. [See Warnings and Precautions (5.10) .] Long-Term Trial of Rosiglitazone Maleate as Monotherapy A 4- to 6-year study (ADOPT) compared the use of 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 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. [See Warnings and Precautions (5.7 ).] The observed incidence of fractures for male patients was similar among the 3 treatment groups. Table 5. On-Therapy Adverse Events (≥5 Events/100 Patient-Years [PY]) in Any Treatment Group Reported in a 4- to 6-Year Clinical Trial of Rosiglitazone Maleate as Monotherapy (ADOPT) Rosiglitazone Maleate Glyburide Metformin N = 1,456 N = 1,441 N = 1,454 PY = 4,954 PY = 4,244 PY = 4,906 Nasopharyngitis 6.3 6.9 6.6 Back pain 5.1 4.9 5.3 Arthralgia 5.0 4.8 4.2 Hypertension 4.4 6.0 6.1 Upper respiratory tract infection 4.3 5.0 4.7 Hypoglycemia 2.9 13.0 3.4 Diarrhea 2.5 3.2 6.8 Pediatric 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 rosiglitazone maleate and 101 were treated with metformin. The most common adverse reactions (>10%) without regard to causality for either 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.

Adult In clinical trials, approximately 9,900 patients with type 2 diabetes have been treated with rosiglitazone maleate. Short-Term Trials of Rosiglitazone Maleate as Monotherapy and in Combination With Other Hypoglycemic Agents The incidence and types of adverse events reported in short-term clinical trials of rosiglitazone maleate as monotherapy are shown in Table 4. Table 4. Adverse Events (≥5% in Any Treatment Group) Reported by Patients in Short-Term * Double-Blind Clinical Trials With Rosiglitazone Maleate as Monotherapy Preferred Term Rosiglitazone maleate Monotherapy Placebo Metformin Sulfonylureas † N = 2,526 N = 601 N = 225 N = 626 % % % % Upper respiratory tract infection 9.9 8.7 8.9 7.3 Injury 7.6 4.3 7.6 6.1 Headache 5.9 5.0 8.9 5.4 Back pain 4.0 3.8 4.0 5.0 Hyperglycemia 3.9 5.7 4.4 8.1 Fatigue 3.6 5.0 4.0 1.9 Sinusitis 3.2 4.5 5.3 3.0 Diarrhea 2.3 3.3 15.6 3.0 Hypoglycemia 0.6 0.2 1.3 5.9 * Short-term trials ranged from 8 weeks to 1 year. † Includes patients receiving glyburide (N = 514), gliclazide (N = 91), or glipizide (N = 21). Overall, the types of adverse reactions without regard to causality reported when rosiglitazone maleate was used in combination with a sulfonylurea or metformin were similar to those during monotherapy with 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 rosiglitazone maleate. In double-blind studies, anemia was reported in 1.9% of patients receiving 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 and metformin (7.1%) and with a combination of AVANDIA and a sulfonylurea plus metformin (6.7%) compared to monotherapy with Arosiglitazone 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 [see Adverse Reactions (6.2)] . In clinical trials, edema was reported in 4.8% of patients receiving 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 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 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 rosiglitazone maleate [see Boxed Warning and Warnings and Precautions (5.3 )] . In controlled combination therapy studies with sulfonylureas, mild to moderate hypoglycemic symptoms, which appear to be dose related, were reported. Few patients were withdrawn for hypoglycemia (<1%) and few episodes of hypoglycemia were considered to be severe (<1%). 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 rosiglitazone maleate plus insulin and 1 of 203 for insulin alone). Rates of hypoglycemia, confirmed by capillary blood glucose concentration ≤50 mg/dL, were 6% for insulin alone and 12% (4 mg) and 14% (8 mg) for insulin in combination with rosiglitazone maleate. [See Warnings and Precautions (5.10) .] Long-Term Trial of Rosiglitazone Maleate as Monotherapy A 4- to 6-year study (ADOPT) compared the use of 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 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. [See Warnings and Precautions (5.7 ).] The observed incidence of fractures for male patients was similar among the 3 treatment groups. Table 5. On-Therapy Adverse Events (≥5 Events/100 Patient-Years [PY]) in Any Treatment Group Reported in a 4- to 6-Year Clinical Trial of Rosiglitazone Maleate as Monotherapy (ADOPT) Rosiglitazone Maleate Glyburide Metformin N = 1,456 N = 1,441 N = 1,454 PY = 4,954 PY = 4,244 PY = 4,906 Nasopharyngitis 6.3 6.9 6.6 Back pain 5.1 4.9 5.3 Arthralgia 5.0 4.8 4.2 Hypertension 4.4 6.0 6.1 Upper respiratory tract infection 4.3 5.0 4.7 Hypoglycemia 2.9 13.0 3.4 Diarrhea 2.5 3.2 6.8

Short-Term Trials of Rosiglitazone Maleate as Monotherapy and in Combination With Other Hypoglycemic Agents The incidence and types of adverse events reported in short-term clinical trials of rosiglitazone maleate as monotherapy are shown in Table 4. Table 4. Adverse Events (≥5% in Any Treatment Group) Reported by Patients in Short-Term * Double-Blind Clinical Trials With Rosiglitazone Maleate as Monotherapy Preferred Term Rosiglitazone maleate Monotherapy Placebo Metformin Sulfonylureas † N = 2,526 N = 601 N = 225 N = 626 % % % % Upper respiratory tract infection 9.9 8.7 8.9 7.3 Injury 7.6 4.3 7.6 6.1 Headache 5.9 5.0 8.9 5.4 Back pain 4.0 3.8 4.0 5.0 Hyperglycemia 3.9 5.7 4.4 8.1 Fatigue 3.6 5.0 4.0 1.9 Sinusitis 3.2 4.5 5.3 3.0 Diarrhea 2.3 3.3 15.6 3.0 Hypoglycemia 0.6 0.2 1.3 5.9 * Short-term trials ranged from 8 weeks to 1 year. † Includes patients receiving glyburide (N = 514), gliclazide (N = 91), or glipizide (N = 21). Overall, the types of adverse reactions without regard to causality reported when rosiglitazone maleate was used in combination with a sulfonylurea or metformin were similar to those during monotherapy with 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 rosiglitazone maleate. In double-blind studies, anemia was reported in 1.9% of patients receiving 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 and metformin (7.1%) and with a combination of AVANDIA and a sulfonylurea plus metformin (6.7%) compared to monotherapy with Arosiglitazone 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 [see Adverse Reactions (6.2)] . In clinical trials, edema was reported in 4.8% of patients receiving 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 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 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 rosiglitazone maleate [see Boxed Warning and Warnings and Precautions (5.3 )] . In controlled combination therapy studies with sulfonylureas, mild to moderate hypoglycemic symptoms, which appear to be dose related, were reported. Few patients were withdrawn for hypoglycemia (<1%) and few episodes of hypoglycemia were considered to be severe (<1%). 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 rosiglitazone maleate plus insulin and 1 of 203 for insulin alone). Rates of hypoglycemia, confirmed by capillary blood glucose concentration ≤50 mg/dL, were 6% for insulin alone and 12% (4 mg) and 14% (8 mg) for insulin in combination with rosiglitazone maleate. [See Warnings and Precautions (5.10) .]