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Avandamet (Rosiglitazone Maleate) - Warnings and Precautions

 
 



WARNINGS

Rosiglitazone maleate: CONGESTIVE HEART FAILURE AND MYOCARDIAL ISCHEMIA

  • Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions]. After initiation of AVANDAMET, 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 AVANDAMET must be considered.
  • AVANDAMET is not recommended in patients with symptomatic heart failure. Initiation of AVANDAMET in patients with established NYHA Class III or IV heart failure is contraindicated. [See Contraindications and Warnings and Precautions .]
  • A meta-analysis of 42 clinical studies (mean duration 6 months; 14,237 total patients), most of which compared rosiglitazone to placebo, showed rosiglitazone to be associated with an increased risk of myocardial ischemic events such as angina or myocardial infarction. Three other studies (mean duration 41 months; 14,067 total patients), comparing rosiglitazone to some other approved oral antidiabetic agents or placebo, have not confirmed or excluded this risk. In their entirety, the available data on the risk of myocardial ischemia are inconclusive. [See Warnings and Precautions .]

Metformin hydrochloride: LACTIC ACIDOSIS

  • Lactic acidosis is a rare, but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart failure. [See Warnings and Precautions .]
  • Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate. [See Warnings and Precautions .]
  • If acidosis is suspected, discontinue AVANDAMET and hospitalize the patient immediately [see Warnings and Precautions].
 

WARNINGS AND PRECAUTIONS

Lactic Acidosis

Incidence and Management: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with AVANDAMET; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5mcg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin is very low (approximately 0.03 cases/1,000 patient years of exposure, with approximately 0.015 fatal cases/1,000 patient years of exposure). Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking AVANDAMET and by use of the minimum effective dose of AVANDAMET. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Treatment with AVANDAMET should not be initiated in patients ≥80years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, AVANDAMET should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, AVANDAMET should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking AVANDAMET, since alcohol potentiates the effects of metformin on lactate metabolism. In addition, AVANDAMET should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure.

The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur. AVANDAMET should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose and, if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of AVANDAMET, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal but less than 5mmol/L in patients taking AVANDAMET do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity or technical problems in sample handling.

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking AVANDAMET, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin is dialyzable (with a clearance of up to 170mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery [see Contraindications (4)].

Factors That May Predispose Patients to Lactic Acidosis: Assessment of Renal Function: Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive AVANDAMET. In patients with advanced age, AVANDAMET should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. [See Dosage and Administration and Use in Specific Populations (8.5).]

Before initiation of therapy with AVANDAMET and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and AVANDAMET discontinued if evidence of renal impairment is present.

Medications That Affect Renal Function: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion [see Drug Interactions and Clinical Pharmacology], should be used with caution.

Hypoxic States: Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients receiving AVANDAMET, the drug should be promptly discontinued.

Radiologic Studies With Intravascular Iodinated Contrast Materials: Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin [see Contraindications (4)]. Therefore, in patients in whom any such study is planned, AVANDAMET should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.

Surgical Procedures: Use of AVANDAMET should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.

Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving AVANDAMET.

Change in Clinical Status of Patients With Previously Controlled Diabetes: A patient with type 2 diabetes previously well-controlled on AVANDAMET who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, AVANDAMET must be stopped immediately and other appropriate corrective measures initiated.

[See also Warnings and Precautions .]

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 study was conducted in 224 patients with type 2 diabetes mellitus and NYHA ClassI 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 study. (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* 21 (19%) 15 (13%)
Investigator-reported, non-adjudicated
Ischemic adverse events 10 (9%) 5 (4%)
– Myocardial infarction 5 (5%) 2 (2%)
– Angina 6 (5%) 3 (3%)

*Includes hospitalization for any cardiovascular reason.

Initiation of 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.

Myocardial Ischemia

Meta-Analysis of Myocardial Ischemia in a Group of 42 Clinical Trials of Rosiglitazone: A meta-analysis was conducted retrospectively to assess cardiovascular adverse events reported across 42 double-blind, randomized, controlled clinical trials (mean duration 6 months).1 These studies had been conducted to assess glucose-lowering efficacy in type 2 diabetes, and prospectively planned adjudication of cardiovascular events had not occurred in the trials. Some trials were placebo-controlled and some used active oral antidiabetic drugs as controls. Placebo-controlled studies included monotherapy trials (monotherapy with rosiglitazone versus placebo monotherapy) and add-on trials (rosiglitazone or placebo, added to sulfonylurea, metformin, or insulin). Active control studies 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 14,237 patients were included (8,604 in treatment groups containing rosiglitazone, 5,633 in comparator groups), with 4,143 patient-years of exposure to rosiglitazone and 2,675 patient-years of exposure to comparator. Myocardial ischemic events included angina pectoris, angina pectoris aggravated, unstable angina, cardiac arrest, chest pain, coronary artery occlusion, dyspnea, myocardial infarction, coronary thrombosis, myocardial ischemia, coronary artery disease, and coronary artery disorder. In this analysis, an increased risk of myocardial ischemia with rosiglitazone versus pooled comparators was observed (2% rosiglitazone versus 1.5% comparators, odds ratio 1.4, 95% confidence interval [CI] 1.1, 1.8). An increased risk of myocardial ischemic events with rosiglitazone was observed in the placebo-controlled studies, but not in the active-controlled studies. (See Figure1.)

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

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

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

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

Myocardial Ischemic Events in Large Long-Term Prospective Randomized Controlled Trials of Rosiglitazone: Data from 3 other large long-term prospective randomized controlled clinical trials of rosiglitazone were assessed separately from the meta-analysis. These 3 trials include a total of 14,067 patients (treatment groups containing rosiglitazone N=6,311, comparator groups N=7,756), with patient-year exposure of 21,803 patient-years for rosiglitazone and 25,998 patient-years for comparator. Duration of follow-up exceeded 3 years in each study. ADOPT (A Diabetes Outcomes Progression Trial) was a 4- to 6-year randomized, active-controlled study in recently diagnosed patients with type 2 diabetes naive to drug therapy. It was an efficacy and general safety trial that was designed to examine the durability of rosiglitazone as monotherapy (N=1,456) for glycemic control in type 2 diabetes, with comparator arms of sulfonylurea monotherapy (N=1,441) and metformin monotherapy (N=1,454). DREAM (Diabetes Reduction Assessment with Rosiglitazone and Ramipril Medication, published report2) was a 3- to 5-year randomized, placebo-controlled study in patients with impaired glucose tolerance and/or impaired fasting glucose. It had a 2x2 factorial design, intended to evaluate the effect of rosiglitazone, and separately of ramipril (an angiotensin converting enzyme inhibitor [ACEI]), on progression to overt diabetes. In DREAM, 2,635 patients were in treatment groups containing rosiglitazone, and 2,634 were in treatment groups not containing rosiglitazone. Interim results have been published3 for RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes), an ongoing open-label, 6-year cardiovascular outcomes study in patients with type 2 diabetes with an average treatment duration of 3.75 years. RECORD includes patients who have failed metformin or sulfonylurea monotherapy; those who have failed metformin are randomized to receive either add-on rosiglitazone or add-on sulfonylurea, and those who have failed sulfonylurea are randomized to receive either add-on rosiglitazone or add-on metformin. In RECORD, a total of 2,220 patients are receiving add-on rosiglitazone, and 2,227 patients are on one of the add-on regimens not containing rosiglitazone.

For these 3 trials, analyses were performed using a composite of major adverse cardiovascular events (myocardial infarction, cardiovascular death, or stroke), referred to hereafter as MACE. This endpoint differed from the meta-analysis’s broad endpoint of myocardial ischemic events, more than half of which were angina. Myocardial infarction included adjudicated fatal and nonfatal myocardial infarction plus sudden death. As shown in Figure 2, the results for the 3 endpoints (MACE, MI, and Total Mortality) were not statistically significantly different between rosiglitazone and comparators.

Figure 2. Hazard Ratios for the Risk of MACE (Myocardial Infarction, Cardiovascular Death, or Stroke), Myocardial Infarction, and Total Mortality With Rosiglitazone Compared With a Control Group

Figure 2. Hazard Ratios for the Risk of MACE (Myocardial Infarction, Cardiovascular Death, or Stroke), Myocardial Infarction, and Total Mortality With Rosiglitazone Compared With a Control Group

In preliminary analyses of the DREAM trial, the incidence of cardiovascular events was higher among subjects who received rosiglitazone in combination with ramipril than among subjects who received ramipril alone, as illustrated in Figure 2. This finding was not confirmed in ADOPT and RECORD (active-controlled trials in patients with diabetes) in which 30% and 40% of patients respectively, reported ACE-inhibitor use at baseline.

In their entirety, the available data on the risk of myocardial ischemia with rosiglitazone use are inconclusive. Definitive conclusions regarding this risk await completion of an adequately-designed cardiovascular outcome study.

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with AVANDAMET or any other antidiabetic drug.

Congestive Heart Failure and Myocardial Ischemia During Coadministration of Rosiglitazone With Insulin

In studies in which rosiglitazone was added to insulin, rosiglitazone increased the risk of congestive heart failure and myocardial ischemia. (See Table 3.) Coadministration of AVANDAMET and insulin is not recommended. [See Indications and Usage and Warnings and Precautions (5.3).]

In five, 26-week, controlled, randomized, double-blind trials which were included in the meta-analysis [see Warnings and Precautions], patients with type 2 diabetes mellitus were randomized to coadministration of rosiglitazone and insulin (N=867) or insulin (N=663). In these 5 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 21 (2.4%) and 7 (1.1%) in the rosiglitazone plus insulin and insulin groups, respectively. The total number of patients with emergent myocardial ischemia was 24 (2.8%) and 9 (1.4%) in the rosiglitazone plus insulin and insulin groups, respectively (OR 2.1 [95% CI 0.9, 5.1]). Although the event rate for congestive heart failure and myocardial ischemia was low in the studied population, consistently the event rate was 2-fold or higher with coadministration of rosiglitazone and insulin. These cardiovascular events were noted at both the 4mg and 8mg daily doses of rosiglitazone. (See Table 3.)

Table 3. Occurrence of Cardiovascular Events in 5 Controlled Trials of Addition of Rosiglitazone to Established Insulin Treatment
Event*

Rosiglitazone + Insulin

(N=867)

n (%)

Insulin

(N=663)

n (%)

Congestive heart failure 21 (2.4%) 7 (1.1%)
Myocardial ischemia 24 (2.8%) 9 (1.4%)
Composite of cardiovascular death, myocardial infarction, or stroke 10 (1.2%) 5 (0.8%)
Stroke 5 (0.6%) 4 (0.6%)
Myocardial infarction 4 (0.5%) 1 (0.2%)
Cardiovascular death 4 (0.5%) 1 (0.2%)
All deaths 6 (0.7%) 1 (0.2%)

*Events are not exclusive; i.e., a patient with a cardiovascular death due to a myocardial infarction would be counted in 4 event categories (myocardial ischemia; cardiovascular death, myocardial infarction or stroke; myocardial infarction; cardiovascular death).

In a sixth, 24-week, controlled, randomized, double-blind trial of rosiglitazone and insulin coadministration, insulin was added to AVANDAMET (N=161) and compared to insulin plus placebo (N=158), after a single-blind 8-week run-in with AVANDAMET. Patients with edema requiring pharmacologic therapy and those with congestive heart failure were excluded at baseline and during the run-in period. In the group receiving AVANDAMET plus insulin, there was one myocardial ischemic event and one sudden death. No myocardial ischemia was observed in the insulin group, and no congestive heart failure was reported in either treatment group.

Edema

AVANDAMET should be used with caution in patients with edema. In a clinical study in healthy volunteers who received rosiglitazone 8mg once daily for 8weeks, 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, 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 and Patient Counseling Information].

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]. The use of AVANDAMET in combination with insulin is not recommended. [See Warnings and Precautions .]

Weight Gain

Dose-related weight gain was seen with rosiglitazone alone and rosiglitazone together with other hypoglycemic agents (see Table 4). No overall change in median weight was observed with AVANDAMET in drug-naive patients. The mechanism of weight gain with rosiglitazone is unclear but probably involves a combination of fluid retention and fat accumulation.

Table 4. Weight Changes (kg) From Baseline at Endpoint During Clinical Trials [Median(25th,75th,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

26weeks Metformin

-1.4 (-3.2, 0.2)

N=175

0.8 (-1.0, 2.6)

N=100

2.1 (0, 4.3)

N=184

26weeks 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)

N = 136

Rosiglitazone

1.7 (-1.2, 4.5)

N=136

AVANDAMET + Insulin
Duration Control Group AVANDAMET + Insulin
24 weeks Insulin

2.6kg (0.3, 4.8)

N = 145

3.3kg (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 (25th, 75th percentiles) from baseline at 4years was 3.5kg (0.0, 8.1) for rosiglitazone, 2.0kg (-1.0, 4.8) for glyburide, and -2.4kg (-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 ].

Hepatic Effects

Metformin: Since impaired hepatic function has been associated with some cases of lactic acidosis, AVANDAMET should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

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.

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 .]

Fractures

In a 4- to 6-year comparative study (ADOPT) of glycemic control with monotherapy in drug-naive 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 study. 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). No increase in fracture rates was observed in men treated with rosiglitazone. The risk of fracture should be considered in the care of patients, especially female patients, treated with rosiglitazone, and attention given to assessing and maintaining bone health according to current standards of care.

Hematologic Effects

Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with rosiglitazone [see Adverse Reactions]. 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 B12 deficiency may contribute to the observed reductions in hemoglobin [see Warnings and Precautions]. 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.

Vitamin B12 Levels

In controlled clinical trials of metformin of 29 weeks' duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3-year intervals may be useful. Vitamin B12 deficiency should be excluded if megaloblastic anemia is suspected. [See Warnings and Precautions .]

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 beta-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.

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]. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical studies; therefore, the frequency of this occurrence is not known.

Although hormonal imbalance has been seen in preclinical studies [see Nonclinical Toxicology], the clinical significance of this finding is not known. If unexpected menstrual dysfunction occurs, the benefits of continued therapy with AVANDAMET should be reviewed.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C.

All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Careful monitoring of glucose control is essential in such patients. Most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible. AVANDAMET should not be used during pregnancy.

Human Data: There are no adequate and well-controlled studies with AVANDAMET or its individual components in pregnant women. Rosiglitazone has been reported to cross the human placenta and be detectable in fetal tissue. The clinical significance of these findings is unknown.

Animal Studies: No animal studies have been conducted with AVANDAMET. The following data are based on findings in studies performed with rosiglitazone or metformin individually.

Rosiglitazone: There was no effect on implantation or the embryo with rosiglitazone treatment during early pregnancy in rats, but treatment during mid-late gestation was associated with fetal death and growth retardation in both rats and rabbits. Teratogenicity was not observed at doses up to 3mg/kg in rats and 100mg/kg in rabbits (approximately 20 and 75 times human AUC at the maximum recommended human daily dose of the rosiglitazone component of AVANDAMET, respectively). Rosiglitazone caused placental pathology in rats (3mg/kg/day). Treatment of rats during gestation through lactation reduced litter size, neonatal viability, and postnatal growth, with growth retardation reversible after puberty. For effects on the placenta, embryo/fetus, and offspring, the no-effect dose was 0.2mg/kg/day in rats and 15mg/kg/day in rabbits. These no-effect levels are approximately 4 times human AUC at the maximum recommended human daily dose of the rosiglitazone component of AVANDAMET. Rosiglitazone reduced the number of uterine implantations and live offspring when juvenile female rats were treated at 40mg/kg/day from 27days of age through to sexual maturity (approximately 68times human AUC at the maximum recommended daily dose). The no-effect level was 2mg/kg/day (approximately 4times human AUC at the maximum recommended daily dose). There was no effect on pre- or post-natal survival or growth.

Metformin: Metformin was not teratogenic in rats and rabbits at doses up to 600mg/kg/day. This represents an exposure of about 2 and 6 times the maximum recommended human daily dose of 2,000mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

Labor and Delivery

The effect of AVANDAMET or its components on labor and delivery in humans is unknown.

Nursing Mothers

No studies have been conducted with AVANDAMET. In studies performed with the individual components, both rosiglitazone-related material and metformin were detectable in milk from lactating rats. It is not known whether rosiglitazone or metformin is excreted in human milk. Because many drugs are excreted in human milk, AVANDAMET should not be administered to a nursing woman.

Pediatric Use

Safety and effectiveness of AVANDAMET in pediatric patients have not been established. AVANDAMET and rosiglitazone are not indicated for use in pediatric patients.

Geriatric Use

Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, AVANDAMET should only be used in patients with normal renal function [see Contraindications (4), Warnings and Precautions and Clinical Pharmacology]. Because reduced renal function is associated with increasing age, AVANDAMET should be used with caution in elderly patients. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of AVANDAMET [see Dosage and Administration and Warnings and Precautions].

Page last updated: 2008-12-02

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