FDA label 65a39528-3e4c-4eed-90de-c7245ef80b3c

WARNING: CONGESTIVE HEART FAILURE • Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.1)] . After initiation of AVANDARYL ® , and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of AVANDARYL must be considered. • AVANDARYL is not recommended in patients with symptomatic heart failure. Initiation of AVANDARYL in patients with established NYHA Class III or IV heart failure is contraindicated. [See Contraindications (4), Warnings and Precautions (5.1).] WARNING: CONGESTIVE HEART FAILURE See full prescribing information for complete boxed warning. • Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure in some patients ( 5.1 ). After initiation of AVANDARYL, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of AVANDARYL must be considered. • AVANDARYL is not recommended in patients with symptomatic heart failure. Initiation of AVANDARYL in patients with established NYHA Class III or IV heart failure is contraindicated. ( 4 , 5.1 )

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 ) • Meta-analysis of 52 mostly short-term trials suggested a potential risk of ischemic cardiovascular (CV) events relative to placebo, not confirmed in a long-term CV outcome trial versus metformin or sulfonylurea. ( 5.2 ) • Severe hypoglycemia may occur. Use particular care in elderly or debilitated patients and those with adrenal, pituitary, renal, or hepatic insufficiency. ( 5.3 ) • Dose-related edema ( 5.4 ), weight gain ( 5.5 ), and anemia ( 5.10 ) may occur. • Macular edema has been reported. ( 5.7 ) • Increased incidence of bone fracture. ( 5.8 ) • Postmarketing reports for glimepiride include anaphylaxis, angioedema, and Stevens-Johnson syndrome. Promptly discontinue AVANDARYL, assess for other causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. ( 5.9 ) • Hemolytic anemia can occur if glucose 6-phosphate dehydrogenase (G6PD) deficient. Consider a non-sulfonylurea alternative. ( 5.11 ) • Potential increased risk of cardiovascular mortality with sulfonylureas: Inform patients of risks, benefits and treatment alternatives. ( 5.12 ) 5.1 Cardiac Failure With Rosiglitazone Rosiglitazone, like other thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Patients should be observed for signs and symptoms of heart failure. If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of rosiglitazone must be considered [see Boxed Warning] . Patients with congestive heart failure (CHF) NYHA Class I and II treated with rosiglitazone have an increased risk of cardiovascular events. A 52-week, double-blind, placebo-controlled, echocardiographic trial was conducted in 224 patients with type 2 diabetes mellitus and NYHA Class I or II CHF (ejection fraction ≤45%) on background antidiabetic and CHF therapy. An independent committee conducted a blinded evaluation of fluid-related events (including congestive heart failure) and cardiovascular hospitalizations according to predefined criteria (adjudication). Separate from the adjudication, other cardiovascular adverse events were reported by investigators. Although no treatment difference in change from baseline of ejection fractions was observed, more cardiovascular adverse events were observed with rosiglitazone treatment compared with placebo during the 52-week trial. (See Table 1.) Table 1. Emergent Cardiovascular Adverse Events in Patients With Congestive Heart Failure (NYHA Class I and II) Treated With Rosiglitazone or Placebo (in Addition to Background Antidiabetic and CHF Therapy) Events Rosiglitazone 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 a 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%) a Includes hospitalization for any cardiovascular reason. In a long-term, cardiovascular outcome trial (RECORD) in patients with type 2 diabetes [see Adverse Reactions (6.1)] , the incidence of heart failure was higher in patients treated with rosiglitazone [2.7% (61/2,220) compared with active control 1.3% (29/2,227), HR 2.10 (95% CI: 1.35, 3.27)]. Initiation of AVANDARYL in patients with established NYHA Class III or IV heart failure is contraindicated. AVANDARYL is not recommended in patients with symptomatic heart failure. [See Boxed Warning.] Patients 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 AVANDARYL is not recommended for patients experiencing an acute coronary event, and discontinuation of AVANDARYL 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. AVANDARYL is not recommended in patients with NYHA Class III and IV cardiac status. Congestive Heart Failure During Coadministration of Rosiglitazone With Insulin: In trials in which rosiglitazone was added to insulin, rosiglitazone increased the risk of congestive heart failure. Coadministration of rosiglitazone and insulin is not recommended. [See Indications and Usage (1), Warnings and Precautions (5.2).] In 7 controlled, randomized, double-blind trials which had durations from 16 to 26 weeks and which were included in a meta-analysis [see Warnings and Precautions (5.2)] , patients with type 2 diabetes mellitus were randomized to coadministration of rosiglitazone and insulin (N = 1,018) or insulin (N = 815). In these 7 trials, rosiglitazone 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 23 (2.3%) and 8 (1.0%) in the rosiglitazone plus insulin and insulin groups, respectively. Heart Failure in Observational Studies of Elderly Diabetic Patients Comparing Rosiglitazone to Pioglitazone: Three observational studies in elderly diabetic patients (age 65 years and older) found that rosiglitazone statistically significantly increased the risk of hospitalized heart failure compared to use of pioglitazone. One other observational study in patients with a mean age of 54 years, which also included an analysis in a subpopulation of patients >65 years of age, found no statistically significant increase in emergency department visits or hospitalization for heart failure in patients treated with rosiglitazone compared to pioglitazone in the older subgroup. 5.2 Major Adverse Cardiovascular Events Data from long-term, prospective, randomized, controlled clinical trials of rosiglitazone versus metformin or sulfonylureas, particularly a cardiovascular outcome trial (RECORD), observed no difference in overall mortality or in major adverse cardiovascular events (MACE) and its components. A meta-analysis of mostly short-term trials suggested an increased risk for myocardial infarction with rosiglitazone compared with placebo. Cardiovascular Events in Large, Long-term, Prospective, Randomized, Controlled Trials of Rosiglitazone: RECORD, a prospectively designed cardiovascular outcome trial (mean follow-up 5.5 years; 4,447 patients), compared the addition of rosiglitazone to metformin or a sulfonylurea (N = 2,220) with a control group of metformin plus sulfonylurea (N = 2,227) in patients with type 2 diabetes [see Adverse Reactions (6.1)] . Non-inferiority was demonstrated for the primary endpoint, cardiovascular hospitalization or cardiovascular death, for rosiglitazone compared with control [HR 0.99 (95% CI: 0.85, 1.16)] demonstrating no overall increased risk in cardiovascular morbidity or mortality. The hazard ratios for total mortality and MACE were consistent with the primary endpoint and the 95% CI similarly excluded a 20% increase in risk for rosiglitazone. The hazard ratios for the components of MACE were 0.72 (95% CI: 0.49, 1.06) for stroke, 1.14 (95% CI: 0.80, 1.63) for myocardial infarction, and 0.84 (95% CI: 0.59, 1.18) for cardiovascular death. The results of RECORD are consistent with the findings of 2 earlier long-term, prospective, randomized, controlled clinical trials (each trial >3 years’ duration; total of 9,620 patients) (see Figure 1). In patients with impaired glucose tolerance (DREAM trial), although the incidence of cardiovascular events was higher among subjects who were randomized to rosiglitazone in combination with ramipril than among subjects randomized to ramipril alone, no statistically significant differences were observed for MACE and its components between rosiglitazone and placebo. In type 2 diabetes patients who were initiating oral agent monotherapy (ADOPT trial), no statistically significant differences were observed for MACE and its components between rosiglitazone and metformin or a sulfonylurea. Figure 1. Hazard Ratios for the Risk of MACE, Myocardial Infarction, and Total Mortality With Rosiglitazone Compared With a Control Group in Long-term Trials Cardiovascular Events in a Group of 52 Clinical Trials: In a meta-analysis of 52 double-blind, randomized, controlled clinical trials designed to assess glucose-lowering efficacy in type 2 diabetes (mean duration 6 months), a statistically significant increased risk of myocardial infarction with rosiglitazone versus pooled comparators was observed [0.4% versus 0.3%; OR 1.8, (95% CI: 1.03, 3.25)]. A statistically non-significant increased risk of MACE was observed with rosiglitazone versus pooled comparators (OR 1.44, 95% CI: 0.95, 2.20). In the placebo-controlled trials, a statistically significant increased risk of myocardial infarction [0.4% versus 0.2%, OR 2.23 (95% CI: 1.14, 4.64)] and statistically non-significant increased risk of MACE [0.7% versus 0.5%, OR 1.53 (95% CI: 0.94, 2.54)] with rosiglitazone were observed. In the active-controlled trials, there was no increased risk of myocardial infarction or MACE. Mortality in Observational Studies of Rosiglitazone Compared to Pioglitazone: Three observational studies in elderly diabetic patients (age 65 years and older) found that rosiglitazone statistically significantly increased the risk of all-cause mortality compared to use of pioglitazone. One observational study in patients with a mean age of 54 years found no difference in all-cause mortality between patients treated with rosiglitazone compared to pioglitazone and reported similar results in the subpopulation of patients >65 years of age. One additional small, prospective, observational study found no statistically significant differences for CV mortality and all-cause mortality in patients treated with rosiglitazone compared to pioglitazone. Figure 1 5.3 Hypoglycemia AVANDARYL is a combination tablet containing rosiglitazone and glimepiride, a sulfonylurea. All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Elderly patients are particularly susceptible to hypoglycemic action of glucose-lowering drugs. Debilitated or malnourished patients, and those with adrenal, pituitary, renal, or hepatic insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. A starting dose of 1 mg glimepiride, as contained in AVANDARYL 4 mg/1 mg, followed by appropriate dose titration is recommended in these patients. [See Clinical Pharmacology (12.3).] Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used. Patients receiving rosiglitazone in combination with a sulfonylurea may be at risk for hypoglycemia, and a reduction in the dose of the sulfonylurea may be necessary [see Dosage and Administration (2.2)] . 5.4 Edema AVANDARYL should be used with caution in patients with edema. In a clinical trial in healthy volunteers who received 8 mg of rosiglitazone once daily for 8 weeks, there was a statistically significant increase in median plasma volume compared with placebo. Since thiazolidinediones, including rosiglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, AVANDARYL should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure [see Boxed Warning, Warnings and Precautions (5.1), Patient Counseling Information (17)] . In controlled clinical trials of patients with type 2 diabetes, mild to moderate edema was reported in patients treated with rosiglitazone, and may be dose-related. Patients with ongoing edema were more likely to have adverse events associated with edema if started on combination therapy with insulin and rosiglitazone [see Adverse Reactions (6.1)] . The use of AVANDARYL in combination with insulin is not recommended [see Warnings and Precautions (5.1, 5.2)] . 5.5 Weight Gain Dose-related weight gain was seen with AVANDARYL, rosiglitazone alone, and rosiglitazone together with other hypoglycemic agents (see Table 2). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. Table 2. Weight Changes (kg) From Baseline at Endpoint During Clinical Trials [Median (25 th , 75 th Percentiles)] Monotherapy Duration Control Group Rosiglitazone 4 mg Rosiglitazone 8 mg 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 Rosiglitazone +Control Therapy Duration Control Group Rosiglitazone 4 mg Rosiglitazone 8 mg 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 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 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 AVANDARYL in Patients With Inadequate Control on Diet and Exercise Duration Control Group AVANDARYL 4 mg/4 mg AVANDARYL 8 mg/4 mg 28 weeks Glimepiride 1.1 (-1.1, 3.2) N = 222 2.2 (0, 4.5) N = 221 2.9 (0, 5.8) N = 217 Rosiglitazone 0.9 (-1.4, 3.2) N = 228 In a 4- to 6-year, monotherapy, comparative trial (ADOPT) in patients recently diagnosed with type 2 diabetes not previously treated with antidiabetic medication, the median weight change (25 th , 75 th percentiles) from baseline at 4 years was 3.5 kg (0.0, 8.1) for rosiglitazone, 2.0 kg (-1.0, 4.8) for glyburide, and -2.4 kg (-5.4, 0.5) for metformin. In postmarketing experience with rosiglitazone alone or in combination with other hypoglycemic agents, there have been rare reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure [see Boxed Warning] . 5.6 Hepatic Effects With sulfonylureas, including glimepiride, there may be an elevation of liver enzyme levels in rare cases. In isolated instances, impairment of liver function (e.g., with cholestasis and jaundice), as well as hepatitis (which may also lead to liver failure) have been reported. Liver enzymes should be measured prior to the initiation of therapy with AVANDARYL in all patients and periodically thereafter per the clinical judgment of the healthcare professional. Therapy with AVANDARYL should not be initiated in patients with increased baseline liver enzyme levels (ALT >2.5X upper limit of normal). Patients with mildly elevated liver enzymes (ALT levels ≤2.5X upper limit of normal) at baseline or during therapy with AVANDARYL should be evaluated to determine the cause of the liver enzyme elevation. Initiation of, or continuation of, therapy with AVANDARYL in patients with mild liver enzyme elevations should proceed with caution and include close clinical follow-up, including more frequent liver enzyme monitoring, to determine if the liver enzyme elevations resolve or worsen. If at any time ALT levels increase to >3X the upper limit of normal in patients on therapy with AVANDARYL, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain >3X the upper limit of normal, therapy with AVANDARYL should be discontinued. If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with AVANDARYL should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued. 5.7 Macular Edema Macular edema has been reported in postmarketing experience in some diabetic patients who were taking rosiglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but some patients appear to have been diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione. Patients with diabetes should have regular eye exams by an ophthalmologist, per the Standards of Care of the American Diabetes Association. Additionally, any diabetic who reports any kind of visual symptom should be promptly referred to an ophthalmologist, regardless of the patient’s underlying medications or other physical findings. [See Adverse Reactions (6.3).] 5.8 Fractures Long-term trials (ADOPT and RECORD) show an increased incidence of bone fracture in patients, particularly female patients, taking rosiglitazone [see Adverse Reactions (6.1)]. This increased incidence was noted after the first year of treatment and persisted during the course of the trial. The majority of the fractures in the women who received rosiglitazone occurred in the upper arm, hand, and foot. These sites of fracture are different from those usually associated with postmenopausal osteoporosis (e.g., hip or spine). Other trials suggest that this risk may also apply to men, although the risk of fracture among women appears higher than that among men. The risk of fracture should be considered in the care of patients treated with rosiglitazone, and attention given to assessing and maintaining bone health according to current standards of care. 5.9 Hypersensitivity Reactions There have been postmarketing reports of hypersensitivity reactions in patients treated with glimepiride, including serious reactions such as anaphylaxis, angioedema, and Stevens-Johnson syndrome. If a hypersensitivity reaction is suspected, promptly discontinue AVANDARYL, assess for other potential causes for the reaction, and institute alternative treatment for diabetes. 5.10 Hematologic Effects Decreases in hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with rosiglitazone [see Adverse Reactions (6.2)] . The observed changes may be related to the increased plasma volume observed with treatment with rosiglitazone. 5.11 Hemolytic Anemia Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Because glimepiride, a component of AVANDARYL, is a sulfonylurea, use caution in patients with G6PD deficiency and consider the use of a non-sulfonylurea alternative. There are also postmarketing reports of hemolytic anemia in patients receiving glimepiride who did not have known G6PD deficiency [see Adverse Reactions (6.3)] . 5.12 Increased Risk of Cardiovascular Mortality With Sulfonylureas The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term, prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups. UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glimepiride and of alternative modes of therapy. Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure. 5.13 Diabetes and Blood Glucose Control When a patient stabilized on any antidiabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold AVANDARYL and temporarily administer insulin. AVANDARYL may be reinstituted after the acute episode is resolved. Periodic fasting glucose and HbA1c measurements should be performed to monitor therapeutic response. 5.14 Ovulation Therapy with rosiglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking rosiglitazone [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 trials; 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 AVANDARYL should be reviewed.

<table ID="_Refid_c6b9f288-5579-4543-be92-1fa945775" width="100%"> <caption>Table 1. Emergent Cardiovascular Adverse Events in Patients With Congestive Heart Failure (NYHA Class I and II) Treated With Rosiglitazone or Placebo (in Addition to Background Antidiabetic and CHF Therapy)</caption> <col width="61%"/> <col width="23%"/> <col width="16%"/> <tbody> <tr> <td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">Events</content> </paragraph> </td> <td align="center" styleCode="Rrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">Rosiglitazone</content> </paragraph> </td> <td align="center" styleCode="Rrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">Placebo</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">N = 110</content> </paragraph> <paragraph> <content styleCode="bold">n (%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">N = 114</content> </paragraph> <paragraph> <content styleCode="bold">n (%)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Adjudicated</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Cardiovascular deaths</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5 (5%)</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4 (4%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> CHF worsening</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7 (6%)</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4 (4%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> &#x2013; with overnight hospitalization</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5 (5%)</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4 (4%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> &#x2013; without overnight hospitalization</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2 (2%)</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0 (0%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> New or worsening edema</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>28 (25%)</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>10 (9%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> New or worsening dyspnea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>29 (26%)</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>19 (17%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Increases in CHF medication</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>36 (33%)</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>20 (18%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Cardiovascular hospitalization^a </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>21 (19%)</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>15 (13%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Investigator-reported, non-adjudicated</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Ischemic adverse events </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>10 (9%)</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5 (4%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> &#x2013; Myocardial infarction</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5 (5%)</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2 (2%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph> &#x2013; Angina</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6 (5%)</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3 (3%)</paragraph> </td> </tr> </tbody> </table>

<table ID="_Refid_f2fdff87-7302-48f8-b0bc-617dc0c50" width="100%"> <caption>Table 2. Weight Changes (kg) From Baseline at Endpoint During Clinical Trials [Median (25^th, 75^th Percentiles)]</caption> <col width="20%"/> <col width="14%"/> <col width="15%"/> <col width="26%"/> <col width="26%"/> <tbody> <tr> <td align="center" colspan="5" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">Monotherapy</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">Duration</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">Control Group</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Rosiglitazone 4 mg</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Rosiglitazone 8 mg</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption> </caption> 26 weeks</item> </list> </td> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Placebo</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>-0.9 (-2.8, 0.9)</paragraph> <paragraph>N = 210</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.0 (-0.9, 3.6)</paragraph> <paragraph>N = 436</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>3.1 (1.1, 5.8)</paragraph> <paragraph>N = 439</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption> </caption> 52 weeks</item> </list> </td> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Sulfonylurea</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>2.0 (0, 4.0)</paragraph> <paragraph>N = 173</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>2.0 (-0.6, 4.0)</paragraph> <paragraph>N = 150</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>2.6 (0, 5.3)</paragraph> <paragraph>N = 157</paragraph> </td> </tr> <tr> <td align="center" colspan="5" styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">Combination Therapy</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="bottom"/> <td colspan="2" valign="top"/> <td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Rosiglitazone +Control Therapy</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">Duration</content> </paragraph> </td> <td align="center" colspan="2" valign="bottom"> <paragraph> <content styleCode="bold">Control Group</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Rosiglitazone 4 mg</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Rosiglitazone 8 mg</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption> </caption> 24-26 weeks</item> </list> </td> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Sulfonylurea</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0 (-1.0, 1.3)</paragraph> <paragraph>N = 1,155</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>2.2 (0.5, 4.0)</paragraph> <paragraph>N = 613</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>3.5 (1.4, 5.9)</paragraph> <paragraph>N = 841</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption> </caption> 26 weeks</item> </list> </td> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Metformin</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>-1.4 (-3.2, 0.2)</paragraph> <paragraph>N = 175</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.8 (-1.0, 2.6)</paragraph> <paragraph>N = 100</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>2.1 (0, 4.3)</paragraph> <paragraph>N = 184</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption> </caption> 26 weeks</item> </list> </td> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Insulin</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.9 (-0.5, 2.7)</paragraph> <paragraph>N = 162</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>4.1 (1.4, 6.3)</paragraph> <paragraph>N = 164</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>5.4 (3.4, 7.3)</paragraph> <paragraph>N = 150</paragraph> </td> </tr> <tr> <td align="center" colspan="5" styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="xmChange"> <content styleCode="bold">AVANDARYL in Patients With Inadequate Control on Diet and Exercise</content> </content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="xmChange"> <content styleCode="bold">Duration</content> </content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="xmChange"> <content styleCode="bold">Control Group</content> </content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="xmChange"> <content styleCode="bold">AVANDARYL 4 mg/4 mg</content> </content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="xmChange"> <content styleCode="bold">AVANDARYL 8 mg/4 mg</content> </content> </paragraph> </td> </tr> <tr> <td rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"> <list listType="unordered"> <item> <caption> </caption> <content styleCode="xmChange"> 28 weeks</content> </item> </list> </td> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="xmChange">Glimepiride</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="xmChange">1.1 (-1.1, 3.2)</content> </paragraph> <paragraph> <content styleCode="xmChange">N = 222</content> </paragraph> </td> <td align="center" rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="xmChange">2.2 (0, 4.5)</content> </paragraph> <paragraph> <content styleCode="xmChange">N = 221</content> </paragraph> </td> <td align="center" rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="xmChange">2.9 (0, 5.8)</content> </paragraph> <paragraph> <content styleCode="xmChange">N = 217</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph> <content styleCode="xmChange">Rosiglitazone</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph> <content styleCode="xmChange">0.9 (-1.4, 3.2)</content> </paragraph> <paragraph> <content styleCode="xmChange">N = 228</content> </paragraph> </td> </tr> </tbody> </table>

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail elsewhere in the labeling: • Cardiac Failure With Rosiglitazone [see Warnings and Precautions (5.1)] • Major Adverse Cardiovascular Events [see Warnings and Precautions (5.2)] • Hypoglycemia [see Warnings and Precautions (5.3)] • Edema [see Warnings and Precautions (5.4)] • Weight Gain [see Warnings and Precautions (5.5)] • Hepatic Effects [see Warnings and Precautions (5.6)] • Macular Edema [see Warnings and Precautions (5.7)] • Fractures [see Warnings and Precautions (5.8)] • Hypersensitivity Reactions [see Warnings and Precautions (5.9)] • Hematologic Effects [see Warnings and Precautions (5.10)] • Hemolytic Anemia [see Warnings and Precautions (5.11)] • Increased Risk of Cardiovascular Mortality for Sulfonylurea Drugs [see Warnings and Precautions (5.12)] • Ovulation [see Warnings and Precautions (5.14)] Common adverse reactions (≥5%) reported in clinical trials for AVANDARYL without regard to causality were headache, hypoglycemia, and nasopharyngitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Patients With Inadequate Glycemic Control on Diet and Exercise: Table 3 summarizes adverse events occurring at a frequency of ≥5% in any treatment group in the 28‑week, double-blind trial of AVANDARYL in patients with type 2 diabetes mellitus inadequately controlled on diet and exercise. Patients in this trial were started on AVANDARYL 4 mg/1 mg, rosiglitazone 4 mg, or glimepiride 1 mg. Doses could be increased at 4-week intervals to reach a maximum total daily dose of either 4 mg/4 mg or 8 mg/4 mg for AVANDARYL, 8 mg for rosiglitazone monotherapy, or 4 mg for glimepiride monotherapy. Table 3. Adverse Events (≥5% in any Treatment Group) Reported by Patients With Inadequate Glycemic Control on Diet and Exercise in a 28‑Week, Double‑blind Clinical Trial of AVANDARYL Preferred Term Glimepiride Monotherapy Rosiglitazone Monotherapy AVANDARYL 4 mg/4 mg AVANDARYL 8 mg/4 mg N = 222 N = 230 N = 224 N = 218 % % % % Headache 2.3 6.1 3.1 6.0 Nasopharyngitis 3.6 5.2 4.0 4.6 Hypertension 3.6 5.2 3.1 2.3 Hypoglycemia a 4.1 0.4 3.6 5.5 a As documented by symptoms and a fingerstick blood glucose measurement of <50 mg/dL. Hypoglycemia was reported to be generally mild to moderate in intensity and none of the reported events of hypoglycemia resulted in withdrawal from the trial. Hypoglycemia requiring parenteral treatment (i.e., intravenous glucose or glucagon injection) was observed in 3 (0.7%) patients treated with AVANDARYL. Edema was reported by 3.2% of patients on AVANDARYL, 3.0% on rosiglitazone alone, and 2.3% on glimepiride alone. Congestive heart failure was observed in 1 (0.2%) patient treated with AVANDARYL and in 1 (0.4%) patient treated with rosiglitazone monotherapy. Patients Treated With Rosiglitazone Added to Sulfonylurea Monotherapy and Other Experience With Rosiglitazone or Glimepiride: Trials utilizing rosiglitazone in combination with a sulfonylurea provide support for the use of AVANDARYL. Adverse event data from these trials, in addition to adverse events reported with the use of rosiglitazone and glimepiride therapy, are presented below. Rosiglitazone: The most common adverse experiences with rosiglitazone monotherapy (≥5%) were upper respiratory tract infection, injury, and headache. Overall, the types of adverse experiences reported when rosiglitazone was added to a sulfonylurea were similar to those during monotherapy with rosiglitazone. In controlled combination therapy trials with sulfonylureas, mild to moderate hypoglycemic symptoms, which appear to be dose-related, were reported. Few patients were withdrawn for hypoglycemia (<1%) and few episodes of hypoglycemia were considered to be severe (<1%). Events of anemia and edema tended to be reported more frequently at higher doses, and were generally mild to moderate in severity and usually did not require discontinuation of treatment with rosiglitazone. Edema was reported by 4.8% of patients receiving rosiglitazone compared with 1.3% on placebo, and 1.0% on sulfonylurea monotherapy. The reporting rate of edema was higher for rosiglitazone 8 mg added to a sulfonylurea (12.4%) compared with other combinations, with the exception of insulin. Anemia was reported by 1.9% of patients receiving rosiglitazone compared with 0.7% on placebo, 0.6% on sulfonylurea monotherapy, and 2.3% on rosiglitazone in combination with a sulfonylurea. Overall, the types of adverse experiences reported when rosiglitazone was added to a sulfonylurea were similar to those during monotherapy with rosiglitazone. In 26-week, double-blind, fixed-dose trials, edema was reported with higher frequency in the rosiglitazone plus insulin combination trials (insulin, 5.4%; and rosiglitazone in combination with insulin, 14.7%). Reports of new onset or exacerbation of congestive heart failure occurred at rates of 1% for insulin alone, and 2% (4 mg) and 3% (8 mg) for insulin in combination with rosiglitazone [see Boxed Warning, Warnings and Precautions (5.1)] . Long-term Trial of Rosiglitazone as Monotherapy: A 4- to 6-year trial (ADOPT) compared the use of rosiglitazone (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 4 presents adverse reactions without regard to causality; rates are expressed per 100 patient-years (PY) exposure to account for the differences in exposure to trial medication across the 3 treatment groups. In ADOPT, fractures were reported in a greater number of women treated with rosiglitazone (9.3%, 2.7/100 patient-years) compared with 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 (5.8).] The observed incidence of fractures for male patients was similar among the 3 treatment groups. Table 4. 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 as Monotherapy (ADOPT) Preferred Term Rosiglitazone 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 Long-term Trial of Rosiglitazone as Combination Therapy (RECORD): RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) was a multicenter, randomized, open-label, non-inferiority trial in subjects with type 2 diabetes inadequately controlled on maximum doses of metformin or sulfonylurea (glyburide, gliclazide, or glimepiride) to compare the time to reach the combined cardiovascular endpoint of cardiovascular death or cardiovascular hospitalization between patients randomized to the addition of rosiglitazone versus metformin or sulfonylurea. The trial included patients who have failed metformin or sulfonylurea monotherapy; those who failed metformin (n = 2,222) were randomized to receive either add-on rosiglitazone (n = 1,117) or add-on sulfonylurea (n = 1,105), and those who failed sulfonylurea (n = 2,225) were randomized to receive either add-on rosiglitazone (n = 1,103) or add-on metformin (n = 1,122). Patients were treated to target HbA1c ≤7% throughout the trial. The mean age of patients in this trial was 58 years, 52% were male, and the mean duration of follow-up was 5.5 years. Rosiglitazone demonstrated non-inferiority to active control for the primary endpoint of cardiovascular hospitalization or cardiovascular death (HR 0.99, 95% CI: 0.85-1.16). There were no significant differences between groups for secondary endpoints with the exception of congestive heart failure (see Table 5). The incidence of congestive heart failure was significantly greater among patients randomized to rosiglitazone. Table 5. Cardiovascular (CV) Outcomes for the RECORD Trial Primary Endpoint Rosiglitazone N = 2,220 Active Control N = 2,227 Hazard Ratio 95% CI CV death or CV hospitalization 321 323 0.99 0.85-1.16 Secondary Endpoint All-cause death 136 157 0.86 0.68-1.08 CV death 60 71 0.84 0.59-1.18 Myocardial infarction 64 56 1.14 0.80-1.63 Stroke 46 63 0.72 0.49-1.06 CV death, myocardial infarction, or stroke 154 165 0.93 0.74-1.15 Heart failure 61 29 2.10 1.35-3.27 There was an increased incidence of bone fracture for subjects randomized to rosiglitazone in addition to metformin or sulfonylurea compared with those randomized to metformin plus sulfonylurea (8.3% versus 5.3%) [see Warnings and Precautions (5.8)] . The majority of fractures were reported in the upper limbs and distal lower limbs. The risk of fracture appeared to be higher in females relative to control (11.5% versus 6.3%), than in males relative to control (5.3% versus 4.3%). Additional data are necessary to determine whether there is an increased risk of fracture in males after a longer period of follow-up. Glimepiride: Approximately 2,800 patients with type 2 diabetes have been treated with glimepiride in the controlled clinical trials. In these trials, approximately 1,700 patients were treated with glimepiride for at least 1 year. Table 6 summarizes adverse events, other than hypoglycemia, that were reported in 11 pooled placebo-controlled trials, whether or not considered to be possibly or probably related to study medication. Treatment duration ranged from 13 weeks to 12 months. Terms that are reported represent those that occurred at an incidence of≥5% among glimepiride-treated patients and more commonly than in patients who received placebo. Table 6. Eleven Pooled Placebo-Controlled Trials Ranging From 13 Weeks to 12 Months: Adverse Events (Excluding Hypoglycemia) Occurring in ≥5% of Glimepiride-Treated Patients and at a Greater Incidence Than With Placebo a Glimepiride Placebo N = 745 N = 294 Preferred Term % % Headache 8.2 7.8 Accidental injury b 5.8 3.4 Flu syndrome 5.4 4.4 Nausea 5.0 3.4 Dizziness 5.0 2.4 a Glimepiride doses ranges from 1 to 16 mg administered daily. b Insufficient information to determine whether any of the accidental injury events were associated with hypoglycemia. Hypoglycemia: In a randomized, double-blind, placebo-controlled monotherapy trial of 14 weeks duration, patients already on sulfonylurea therapy underwent a 3-week washout period then were randomized to glimepiride 1 mg, 4 mg, 8 mg or placebo. Patients randomized to glimepiride 4 mg or 8 mg underwent forced-titration from an initial dose of 1 mg to these final doses, as tolerated. The overall incidence of possible hypoglycemia (defined by the presence of at least one symptom that the investigator believed might be related to hypoglycemia; a concurrent glucose measurement was not required) was 4% for glimepiride 1 mg, 17% for glimepiride 4 mg, 16% for glimepiride 8 mg, and 0% for placebo. All of these events were self-treated. In a randomized, double-blind, placebo-controlled monotherapy trial of 22 weeks duration, patients received a starting dose of either 1 mg glimepiride or placebo daily. The dose of glimepiride was titrated to a target fasting plasma glucose of 90 to 150 mg/dL. Final daily doses of glimepiride were 1, 2, 3, 4, 6, or 8 mg. The overall incidence of possible hypoglycemia (as defined above for the 14-week trial) for glimepiride versus placebo was 19.7% versus 3.2%. All of these events were self-treated. Weight Gain: Glimepiride, like all sulfonylureas, can cause weight gain. Allergic Reactions: In clinical trials, allergic reactions, such as pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occurred in less than 1% of glimepiride-treated patients. These may resolve despite continued treatment with glimepiride. There are postmarketing reports of more serious allergic reactions (e.g., dyspnea, hypotension, shock) [see Warnings and Precautions (5.9)] . 6.2 Laboratory Abnormalities Rosiglitazone: Hematologic: Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with rosiglitazone (mean decreases in individual trials 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 rosiglitazone or following a dose increase in rosiglitazone. The time course and magnitude of decreases were similar in patients treated with a combination of rosiglitazone and other hypoglycemic agents or monotherapy with rosiglitazone. White blood cell counts also decreased slightly in adult patients treated with rosiglitazone. Decreases in hematologic parameters may be related to increased plasma volume observed with treatment with rosiglitazone. Lipids: Changes in serum lipids have been observed following treatment with rosiglitazone in adults [see Clinical Pharmacology (12.2)] . Serum Transaminase Levels: In pre-approval clinical trials in 4,598 patients treated with rosiglitazone encompassing approximately 3,600 patient-years of exposure, there was no evidence of drug-induced hepatotoxicity. In pre-approval controlled trials, 0.2% of patients treated with rosiglitazone had reversible elevations in ALT >3X the upper limit of normal compared with 0.2% on placebo and 0.5% on active comparators. The ALT elevations in patients treated with rosiglitazone were reversible. Hyperbilirubinemia was found in 0.3% of patients treated with rosiglitazone compared with 0.9% treated with placebo and 1% in patients treated with active comparators. In 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 (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). In the RECORD trial, patients randomized to rosiglitazone in addition to metformin or sulfonylurea (10,849 patient-years exposure) and to metformin plus sulfonylurea (10,209 patient-years exposure) had a rate of ALT increase to ≥3X upper limit of normal of approximately 0.2 and 0.3 per 100 patient-years exposure, respectively. Glimepiride: Serum Transaminase Levels: In 11 pooled, placebo-controlled trials of glimepiride, 1.9% of glimepiride-treated patients and 0.8% of placebo-treated patients developed serum ALT >2X the upper limit of the reference range. 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 AVANDARYL or its individual components. 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. Rosiglitazone: 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, Warnings and Precautions (5.1)] . There are postmarketing reports with rosiglitazone 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 rosiglitazone of rash, pruritus, urticaria, angioedema, anaphylactic reaction, Stevens-Johnson syndrome [see Contraindications (4)] , and new onset or worsening diabetic macular edema with decreased visual acuity [see Warnings and Precautions (5.7)] . Glimepiride: • Serious hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson syndrome [see Warnings and Precautions (5.9)] • Hemolytic anemia in patients with and without G6PD deficiency [see Warnings and Precautions (5.11)] • Impairment of liver function (e.g., with cholestasis and jaundice), as well as hepatitis, which may progress to liver failure • Porphyria cutanea tarda, photosensitivity reactions, and allergic vasculitis • Leukopenia, agranulocytosis, aplastic anemia, and pancytopenia • Thrombocytopenia (including severe cases with platelet count less than 10,000/µL) and thrombocytopenic purpura • Hepatic porphyria reactions and disulfiram-like reactions • Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH), most often in patients who are on other medications or who have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone

<table ID="_RefID0EPMBG" width="100%"> <caption>Table 3. Adverse Events (&#x2265;5% in any Treatment Group) Reported by Patients With Inadequate Glycemic Control on Diet and Exercise in a 28&#x2011;Week, Double&#x2011;blind Clinical Trial of AVANDARYL</caption> <col width="21%"/> <col width="19%"/> <col width="19%"/> <col width="20%"/> <col width="20%"/> <tbody> <tr> <td align="center" rowspan="3" styleCode="Rrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">Preferred Term</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">Glimepiride</content> </paragraph> <paragraph> <content styleCode="bold">Monotherapy</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">Rosiglitazone</content> </paragraph> <paragraph> <content styleCode="bold">Monotherapy</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">AVANDARYL</content> </paragraph> <paragraph> <content styleCode="bold">4 mg/4 mg</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">AVANDARYL</content> </paragraph> <paragraph> <content styleCode="bold">8 mg/4 mg</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule " valign="bottom"> <paragraph> <content styleCode="bold">N = 222</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule " valign="bottom"> <paragraph> <content styleCode="bold">N = 230</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule " valign="bottom"> <paragraph> <content styleCode="bold">N = 224</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule " valign="bottom"> <paragraph> <content styleCode="bold">N = 218</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">%</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">%</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">%</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">%</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Headache</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>2.3</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>6.1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>3.1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>6.0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Nasopharyngitis</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>3.6</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>5.2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>4.0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>4.6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Hypertension</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>3.6</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>5.2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>3.1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>2.3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>Hypoglycemia^a </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>4.1</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>0.4</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>3.6</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>5.5</paragraph> </td> </tr> </tbody> </table>

<table ID="_Refid_69bd741f-71f9-49ce-b797-36edbd1d3" width="100%"> <caption>Table 4. On-therapy Adverse Events [&#x2265;5 Events/100 Patient-Years (PY)] in any Treatment Group Reported in a 4- to 6-Year Clinical Trial of Rosiglitazone as Monotherapy (ADOPT)</caption> <col width="44%"/> <col width="21%"/> <col width="18%"/> <col width="18%"/> <tbody> <tr> <td align="center" rowspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">Preferred Term</content> </paragraph> </td> <td align="center" styleCode="Rrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Rosiglitazone</content> </paragraph> </td> <td align="center" styleCode="Rrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Glyburide</content> </paragraph> </td> <td align="center" styleCode="Rrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Metformin</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule " valign="top"> <paragraph> <content styleCode="bold">N = 1,456</content> </paragraph> </td> <td align="center" styleCode="Rrule " valign="top"> <paragraph> <content styleCode="bold">N = 1,441</content> </paragraph> </td> <td align="center" styleCode="Rrule " valign="top"> <paragraph> <content styleCode="bold">N = 1,454</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">PY = 4,954</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">PY = 4,244</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">PY = 4,906</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Nasopharyngitis</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6.3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6.9</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6.6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Back pain</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5.1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4.9</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5.3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Arthralgia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5.0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4.8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4.2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Hypertension</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4.4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6.0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6.1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Upper respiratory tract infection</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4.3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5.0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4.7</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Hypoglycemia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2.9</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13.0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3.4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2.5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3.2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6.8</paragraph> </td> </tr> </tbody> </table>

<table ID="_RefID0EB1BG" width="100%"> <caption>Table 5. Cardiovascular (CV) Outcomes for the RECORD Trial</caption> <col width="41%"/> <col width="15%"/> <col width="17%"/> <col width="16%"/> <col width="11%"/> <tbody> <tr> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">Primary Endpoint</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Rosiglitazone</content> </paragraph> <paragraph> <content styleCode="bold">N = 2,220</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Active Control</content> </paragraph> <paragraph> <content styleCode="bold">N = 2,227</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Hazard Ratio</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">95% CI</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>CV death or CV hospitalization</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>321</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>323</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.99</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.85-1.16</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">Secondary Endpoint</content> </paragraph> </td> <td styleCode="Rrule Lrule Botrule " valign="top"/> <td styleCode="Rrule Lrule Botrule " valign="top"/> <td styleCode="Rrule Lrule Botrule " valign="top"/> <td styleCode="Rrule Lrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>All-cause death</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>136</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>157</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.86</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.68-1.08</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>CV death</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>60</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>71</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.84</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.59-1.18</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Myocardial infarction</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>64</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>56</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.14</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.80-1.63</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Stroke</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>46</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>63</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.72</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.49-1.06</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>CV death, myocardial infarction, or stroke</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>154</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>165</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.93</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.74-1.15</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>Heart failure</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>61</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>29</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>2.10</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>1.35-3.27</paragraph> </td> </tr> </tbody> </table>