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warnings and cautions
5 WARNINGS AND PRECAUTIONS • One sulfonylurea has been shown to increase cardiovascular mortality; consider this risk when prescribing any sulfonylurea. (5.1) • 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. (5.2) • Increased risk of myocardial infarction has been observed in a meta-analysis of 52 clinical trials of rosiglitazone (incidence rate 0.4% versus 0.3%). (5.3) • Use with insulin is not recommended. (1, 5.2, 5.3) • Severe hypoglycemia may occur. Use particular care in elderly or debilitated patients and those with adrenal, pituitary, renal or hepatic insufficiency. (5.4) • Dose-related edema (5.5), weight gain (5.6), and anemia (5.10) may occur. • Macular edema has been reported. (5.8) • Increased incidence of bone fracture. (5.9) • The glimepiride component may cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Consider a non-sulfonylurea alternative in these patients. (5.11) 5.1 Increased Risk of Cardiovascular Mortality for Sulfonylurea Drugs 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 trial 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 trial involved 823 patients who were randomly assigned to one of four treatment groups ( Diabetes 1970 ;19 [Suppl. 2]:747-830). 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 trial to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP trial provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glimepiride-containing tablets and of alternative modes of therapy. Although only one drug in the sulfonylurea class (tolbutamide) was included in this trial, 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. 5.2 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 to 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. 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) and Warnings and Precautions (5.3).] In 7 controlled, randomized, double-blind trials which had durations from 16 to 26 weeks and which were included in a meta-analysis 1 [see Warnings and Precautions (5.3)] , 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 2-4 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 5 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. 5.3 Major Adverse Cardiovascular Events Cardiovascular adverse events have been evaluated in a meta-analysis of 52 clinical trials, in long-term, prospective, randomized, controlled trials, and in observational studies. Meta-Analysis of Major Adverse Cardiovascular Events in a Group of 52 Clinical Trials: A meta-analysis was conducted retrospectively to assess cardiovascular adverse events reported across 52 double-blind, randomized, controlled clinical trials (mean duration 6 months). 1 These trials had been conducted to assess glucose-lowering efficacy in type 2 diabetes. Prospectively planned adjudication of cardiovascular events did not occur in most of the trials. Some trials were placebo-controlled and some used active oral antidiabetic drugs as controls. Placebo-controlled trials included monotherapy trials (monotherapy with rosiglitazone versus placebo monotherapy) and add-on trials (rosiglitazone or placebo, added to sulfonylurea, metformin, or insulin). Active control trials included monotherapy trials (monotherapy with rosiglitazone versus sulfonylurea or metformin monotherapy) and add-on trials (rosiglitazone plus sulfonylurea or rosiglitazone plus metformin, versus sulfonylurea plus metformin). A total of 16,995 patients were included (10,039 in treatment groups containing rosiglitazone, 6,956 in comparator groups), with 5,167 patient-years of exposure to rosiglitazone and 3,637 patient-years of exposure to comparator. Cardiovascular events occurred more frequently for patients who received rosiglitazone than for patients who received comparators (see Table 2). Table 2. Occurrence of Cardiovascular Events in a Meta-Analysis of 52 Clinical Trials Event a Rosiglitazone (N=10,039) n (%) Comparator (N=6,956) n (%) MACE (a composite of myocardial infarction, cardiovascular death, or stroke) 70 (0.7) 39 (0.6) Myocardial Infarction 45 (0.4) 20 (0.3) Cardiovascular Death 17 (0.2) 9 (0.1) Stroke 18 (0.2) 16 (0.2) All-cause Death 29 (0.3) 17 (0.2) a 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 infarction; myocardial infarction, cardiovascular death, or stroke; cardiovascular death; all-cause death). In this analysis, a statistically significant increased risk of myocardial infarction with rosiglitazone versus pooled comparators was observed. Analyses were performed using a composite of major adverse cardiovascular events (myocardial infarction, stroke, and cardiovascular death), referred to hereafter as MACE. Rosiglitazone had a statistically non-significant increased risk of MACE compared to the pooled comparators. A statistically significant increased risk of myocardial infarction and statistically non-significant increased risk of MACE with rosiglitazone was observed in the placebo-controlled trials. In the active-controlled trials, there was no increased risk of myocardial infarction or MACE. (See Figure 1 and Table 3.) Figure 1. Forest Plot of Odds Ratios (95% Confidence Intervals) for MACE and Myocardial Infarction in the Meta-Analysis of 52 Clinical Trials Table 3. Occurrence of MACE and Myocardial Infarction in a Meta-Analysis of 52 Clinical Trials by Trial Type MACE Myocardial Infarction N n (%) OR (95%CI) n (%) OR (95%CI) Active- Controlled Trials RSG 2,119 16 (0.8%) 1.05 10 (0.5%) 1.00 Control 1,918 14 (0.7%) (0.48, 2.34) 9 (0.5%) (0.36, 2.82) Placebo- Controlled Trials RSG 8,124 54 (0.7%) 1.53 35 (0.4%) 2.23 Placebo 5,636 28 (0.5%) (0.94, 2.54) 13 (0.2%) (1.14, 4.64) Overall RSG 10,039 70 (0.7%) 1.44 45 (0.4%) 1.8 Control 6,956 39 (0.6%) (0.95, 2.20) 20 (0.3%) (1.03, 3.25) RSG = rosiglitazone Of the placebo-controlled trials in the meta-analysis, 7 trials had patients randomized to rosiglitazone plus insulin or insulin. There were more patients in the rosiglitazone plus insulin group compared to the insulin group with myocardial infarctions, MACE, cardiovascular deaths, and all-cause deaths (see Table 4). The total number of patients with stroke was 5 (0.5%) and 4 (0.5%) in the rosiglitazone plus insulin and insulin groups, respectively. The use of rosiglitazone in combination with insulin may increase the risk of myocardial infarction [See Warnings and Precautions (5.1).] Table 4. Occurrence of Cardiovascular Events for Rosiglitazone in Combination With Insulin in a Meta-Analysis of 52 Clinical Trials Event a Rosiglitazone (N=1,018) (%) Insulin (N = 815) (%) OR (95% CI) MACE (a composite of myocardial infarction, cardiovascular death, or stroke) 1.3 0.6 2.14 (0.70, 7.83) Myocardial infarction 0.6 0.1 5.6 (0.67, 262.7) Cardiovascular death 0.4 0.0 ND, (0.47, ∞) All cause death 0.6 0.2 2.19 (0.38, 22.61) ND = not defined a 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 infarction; myocardial infarction, cardiovascular death, or stroke; cardiovascular death; all-cause death). Myocardial Infarction Events in Large, Long-Term, Prospective, Randomized, Controlled Trials of Rosiglitazone: Data from 3 large, long-term, prospective, randomized, controlled clinical trials of rosiglitazone were assessed separately from the meta-analysis. 6-8 These 3 trials included a total of 14,067 patients (treatment groups containing rosiglitazone N = 6,311; comparator groups N = 7,756), with patient-year exposure of 24,534 patient-years for rosiglitazone and 28,882 patient-years for comparator. Patient populations in the trials included patients with impaired glucose tolerance, patients with type 2 diabetes who were initiating oral agent monotherapy, and patients with type 2 diabetes who had failed monotherapy and were initiating dual oral agent therapy . Duration of follow-up exceeded 3 years in each trial. In each of these trials, there was a statistically non-significant increase in the risk of myocardial infarction for rosiglitazone versus comparator medications. In a long-term, randomized, placebo-controlled, 2x2 factorial trial intended to evaluate rosiglitazone, and separately ramipril (an angiotensin converting enzyme inhibitor [ACEI]), on progression to overt diabetes in 5,269 subjects with glucose intolerance, the incidence of myocardial infarction was higher in the subset of subjects who received rosiglitazone in combination with ramipril than among subjects who received ramipril alone but not in the subset of subjects who received rosiglitazone alone compared to placebo. 6 The higher incidence of myocardial infarction among subjects who received rosiglitazone in combination with ramipril was not confirmed in the two other large (total N = 8,798) long-term, randomized, active-controlled clinical trials conducted in patients with type 2 diabetes, in which 30% and 40% of patients in the two trials reported angiotensin-converting enzyme inhibitor use at baseline. 7,8 There have been no adequately designed clinical trials directly comparing rosiglitazone to pioglitazone on cardiovascular risks. However, in a long-term, randomized, placebo-controlled cardiovascular outcomes trial comparing pioglitazone to placebo in patients with type 2 diabetes mellitus and prior macrovascular disease, pioglitazone was not associated with an increased risk of myocardial infarction or total mortality. 9 The increased risk of myocardial infarction observed in the meta-analysis and large, long-term controlled clinical trials, and the increased risk of MACE observed in the meta-analysis described above, have not translated into a consistent finding of excess mortality from controlled clinical trials or observational studies. Clinical trials have not shown any difference between rosiglitazone and comparator medications in overall mortality or CV-related mortality. 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 ACTOS (pioglitazone). 2-4 One observational study 5 in patients with a mean age of 54 years found no difference in all-cause mortality between patients treated with rosiglitazone compared to ACTOS (pioglitazone) and reported similar results in the subpopulation of patients >65 years of age. One additional small, prospective, observational study 10 found no statistically significant differences for CV mortality and all-cause mortality in patients treated with rosiglitazone compared to ACTOS (pioglitazone). Figure 1. Forest Plot of Odds Ratios (95% Confidence Intervals) for MACE and Myocardial Infarction in the Meta-Analysis of 52 Clinical Trials 5.4 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)] . 5.5 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 to 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 (5.2), 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, 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 (5.2, 5.3)] . 5.6 Weight Gain Dose-related weight gain was seen with AVANDARYL, rosiglitazone alone, and rosiglitazone together with other hypoglycemic agents (see Table 5). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. Table 5. Weight Changes (kg) From Baseline at Endpoint During Clinical Trials [Median (25 th , 75 th , Percentile)] 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 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 ] . 5.7 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. 5.8 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).] 5.9 Fractures In a 4- to 6-year comparative trial (ADOPT) of glycemic control with monotherapy in drug-naïve patients recently diagnosed with type 2 diabetes mellitus, an increased incidence of bone fracture was noted in female patients taking rosiglitazone. Over the 4- to 6-year period, the incidence of bone fracture in females was 9.3% (60/645) for rosiglitazone versus 3.5% (21/605) for glyburide and 5.1% (30/590) for metformin. This increased incidence was noted after the first year of treatment and persisted during the course of the 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. 5.10 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 Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because glimepiride, a component of AVANDARYL, belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In post-marketing experience, hemolytic anemia has also been reported in patients receiving sulfonylureas who did not have known G6PD deficiency [see Adverse Reactions (6.1)] . 5.12 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. 5.13 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.