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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Lactic acidosis: See boxed warning. ( 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 ) • 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. ( 5.3 ) • Dose-related edema ( 5.4 ), weight gain ( 5.5 ), and anemia ( 5.9 ) may occur. • Macular edema has been reported. ( 5.7 ) • Increased incidence of bone fracture. ( 5.8 ) • Measure hematologic parameters annually. ( 5.9 ) 5.1 Lactic Acidosis There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension, and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of AVANDAMET. In patients treated with AVANDAMET with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue AVANDAMET and report these symptoms to their healthcare provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)] : • Before initiating AVANDAMET, obtain an eGFR. • AVANDAMET is contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m 2 [see Contraindications (4)] . • Initiation of AVANDAMET is not recommended in patients with eGFR between 30 – 45 mL/minute/1.73 m 2 . • Obtain an eGFR at least annually in all patients taking AVANDAMET. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. • In patients taking AVANDAMET whose eGFR later falls below 45 mL/minute/1.73 m 2 , assess the benefit and risk of continuing therapy. Drug Interactions: The concomitant use of AVANDAMET with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation [see Drug Interactions (7)] . Therefore, consider more frequent monitoring of patients. Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)] . Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop AVANDAMET at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/minute/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart AVANDAMET if renal function is stable. Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. AVANDAMET should be temporarily discontinued while patients have restricted food and fluid intake. Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue AVANDAMET. Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving AVANDAMET. Hepatic Impairment: Patients with hepatic impairment have developed metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of AVANDAMET in patients with clinical or laboratory evidence of hepatic disease. 5.2 Cardiac Failure 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 2.) Table 2. 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 AVANDAMET in patients with established NYHA Class III or IV heart failure is contraindicated. AVANDAMET 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 AVANDAMET is not recommended for patients experiencing an acute coronary event, and discontinuation of AVANDAMET 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. AVANDAMET 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 (5.3).] 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 (5.3)] , 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 with 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 with pioglitazone in the older subgroup. 5.3 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 with 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 with 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 with 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 with pioglitazone. figure 1 5.4 Edema AVANDAMET should be used with caution in patients with edema. In a clinical trial in healthy volunteers who received rosiglitazone 8 mg 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, AVANDAMET should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure [see Boxed Warning, Warnings and Precautions (5.2), 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 AVANDAMET in combination with insulin is not recommended. [See Warnings and Precautions (5.2, 5.3).] 5.5 Weight Gain Dose-related weight gain was seen with rosiglitazone alone and rosiglitazone together with other hypoglycemic agents (see Table 3). No overall change in median weight was observed with AVANDAMET in drug-naïve patients. The mechanism of weight gain with rosiglitazone is unclear but probably involves a combination of fluid retention and fat accumulation. Table 3. 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 Duration Rosiglitazone + Control Therapy 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 AVANDAMET in Patients with Inadequate Control on Diet and Exercise Duration Control Group AVANDAMET 32 weeks Metformin -2.2 (-5.5, -0.5) N = 123 0.05 kg (-3.45, 3.0) Rosiglitazone 1.7 (-1.2, 4.5) N = 136 N = 136 AVANDAMET + Insulin Duration Control Group AVANDAMET + Insulin 24 weeks Insulin 2.6 kg (0.3, 4.8) N = 145 3.3 kg (1.5, 6.0) N = 147 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 Rosiglitazone: Liver enzymes should be measured prior to the initiation of therapy with AVANDAMET in all patients and periodically thereafter per the clinical judgment of the healthcare professional. Therapy with AVANDAMET 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 AVANDAMET should be evaluated to determine the cause of the liver enzyme elevation. Initiation of, or continuation of, therapy with AVANDAMET in patients with mild liver enzyme elevations should proceed with caution and include close clinical follow-up, including more frequent liver enzyme monitoring, to determine if the liver enzyme elevations resolve or worsen. If at any time ALT levels increase to >3X the upper limit of normal in patients on therapy with AVANDAMET, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain >3X the upper limit of normal, therapy with AVANDAMET 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 AVANDAMET should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued. In addition, if the presence of hepatic disease or hepatic dysfunction of sufficient magnitude to predispose to lactic acidosis is confirmed, therapy with AVANDAMET should be discontinued. 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 Hematologic Effects Decreases in mean 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 and may be dose-related. The decrease in hemoglobin was seen more frequently in combination rosiglitazone and metformin therapy than in rosiglitazone therapy alone. Vitamin B 12 deficiency may contribute to the observed reductions in hemoglobin [see Warnings and Precautions (5.10)] . Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) should be performed, at least on an annual basis. 5.10 Vitamin B 12 Levels In controlled clinical trials of metformin of 29 weeks’ duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. In these patients, routine serum vitamin B 12 measurements at 2- to 3-year intervals may be useful. Vitamin B 12 deficiency should be excluded if megaloblastic anemia is suspected. [See Warnings and Precautions (5.9).] 5.11 Diabetes and Blood Glucose Control Periodic fasting blood glucose and HbA1c measurements should be performed to monitor therapeutic response. When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold AVANDAMET and temporarily administer insulin. AVANDAMET may be reinstituted after the acute episode is resolved. Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with hypoglycemic agents (such as sulfonylureas or insulin) or ethanol. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking β-adrenergic blocking drugs. Patients receiving rosiglitazone in combination with other hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary. 5.12 Ovulation Therapy with rosiglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking AVANDAMET [see 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 AVANDAMET should be reviewed.