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Avandia (Rosiglitazone Maleate) - Warnings and Precautions

 
 



WARNING: 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 AVANDIA, 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 AVANDIA must be considered.

● AVANDIA is not recommended in patients with symptomatic heart failure. Initiation of AVANDIA 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 AVANDIA to placebo, showed AVANDIA 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 AVANDIA 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 .]

 

WARNINGS AND PRECAUTIONS

Cardiac Failure

AVANDIA, 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 AVANDIA have an increased risk of cardiovascular events. A 52-week, double-blind, placebo-controlled echocardiographic study was conducted in 224 patients with type 2 diabetes mellitus and NYHA Class I or II CHF (ejection fraction ≤45%) on background antidiabetic and CHF therapy. An independent committee conducted a blinded evaluation of fluid-related events (including congestive heart failure) and cardiovascular hospitalizations according to predefined criteria (adjudication). Separate from the adjudication, other cardiovascular adverse events were reported by investigators. Although no treatment difference in change from baseline of ejection fractions was observed, more cardiovascular adverse events were observed with AVANDIA treatment compared to placebo during the 52-week study. (See Table 1.)

Table 1. Emergent Cardiovascular Adverse Events in Patients With Congestive Heart Failure (NYHA Class I and II) Treated With AVANDIA or Placebo (in Addition to Background Antidiabetic and CHF Therapy)

Events

AVANDIA

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 AVANDIA in patients with established NYHA Class III or IV heart failure is contraindicated. AVANDIA 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 AVANDIA is not recommended for patients experiencing an acute coronary event, and discontinuation of AVANDIA 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. AVANDIA 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

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 (AVANDIA monotherapy versus placebo monotherapy) and add-on trials (AVANDIA or placebo, added to sulfonylurea, metformin, or insulin). Active control studies included monotherapy trials (AVANDIA monotherapy versus sulfonylurea or metformin monotherapy) and add-on trials (AVANDIA plus sulfonylurea or AVANDIA plus metformin, versus sulfonylurea plus metformin). A total of 14,237 patients were included (8,604 in treatment groups containing AVANDIA, 5,633 in comparator groups), with 4,143 patient-years of exposure to AVANDIA 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 AVANDIA versus pooled comparators was observed (2% AVANDIA versus 1.5% comparators, odds ratio 1.4, 95% confidence interval [CI] 1.1, 1.8). An increased risk of myocardial ischemic events with AVANDIA was observed in the placebo-controlled studies, but not in the active-controlled studies. (See Figure 1.)

A greater increased risk of myocardial ischemic events was observed in studies where AVANDIA was added to insulin (2.8% for AVANDIA 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

A greater increased risk of myocardial ischemia was also observed in patients who received AVANDIA and background nitrate therapy. For AVANDIA (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 AVANDIA versus comparator was not demonstrated.

Myocardial Ischemic Events in Large Long-Term Prospective Randomized Controlled Trials of AVANDIA

Data from 3 other large long-term prospective randomized controlled clinical trials of AVANDIA were assessed separately from the meta-analysis. These 3 trials include a total of 14,067 patients (treatment groups containing AVANDIA N = 6,311, comparator groups N = 7,756), with patient-year exposure of 21,803 patient-years for AVANDIA and 25,998 patient-years for comparator. Duration of follow-up exceeded 3 years in each study. ADOPT (A Diabetes Outcomes Progression Trial) was a 4- to 6-year randomized, active-controlled study in recently diagnosed patients with type 2 diabetes naïve to drug therapy. It was an efficacy and general safety trial that was designed to examine the durability of AVANDIA 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 AVANDIA, 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 AVANDIA, and 2,634 were in treatment groups not containing AVANDIA. 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 AVANDIA or add-on sulfonylurea, and those who have failed sulfonylurea are randomized to receive either add-on AVANDIA or add-on metformin. In RECORD, a total of 2,220 patients are receiving add-on AVANDIA, and 2,227 patients are on one of the add-on regimens not containing AVANDIA.

For these 3 trials, analyses were performed using a composite of major adverse cardiovascular events (cardiovascular death, myocardial infarction, and 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 three endpoints (MACE, MI, and Total Mortality) were not statistically significantly different between AVANDIA and comparators.

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

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

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

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

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

In studies in which AVANDIA was added to insulin, AVANDIA increased the risk of congestive heart failure and myocardial ischemia. (See Table 2.) Coadministration of AVANDIA and insulin is not recommended. [See Indications and Usage and Warnings and Precautions (5.1, 5.2).]

In five, 26-week, controlled, randomized, double-blind trials which were included in the meta-analysis [see Warnings and Precautions], patients with type 2 diabetes mellitus were randomized to coadministration of AVANDIA and insulin (N = 867) or insulin (N = 663). In these 5 trials, AVANDIA 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 (2.0%) and 7 (0.9%) in the AVANDIA 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 AVANDIA 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 AVANDIA and insulin. These cardiovascular events were noted at both the 4 mg and 8 mg daily doses of AVANDIA. (See Table 2.)

Table 2. Occurrence of Cardiovascular Events in 5 Controlled Trials of Addition of AVANDIA to Established Insulin Treatment

Event*

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

Edema

AVANDIA should be used with caution in patients with edema. In a clinical study in healthy volunteers who received 8 mg of AVANDIA 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, AVANDIA 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 AVANDIA, 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 AVANDIA [see Adverse Reactions].

Weight Gain

Dose-related weight gain was seen with AVANDIA alone and in combination with other hypoglycemic agents (Table 3). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

In postmarketing experience, there have been reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure [see Boxed Warning].

Table 3. Weight Changes (kg) From Baseline at Endpoint During Clinical Trials

Control Group

AVANDIA

4 mg

AVANDIA

8 mg

Monotherapy

Duration

Median

(25th, 75th percentile)

Median

(25th, 75th percentile)

Median

(25th, 75th percentile)

26 weeks

placebo

-0.9 (-2.8, 0.9)

n = 210

1.0 (-0.9, 3.6)

n = 436

3.1 (1.1, 5.8)

n = 439

52 weeks

sulfonylurea

2.0 (0, 4.0)

n = 173

2.0 (-0.6, 4.0)

n = 150

2.6 (0, 5.3)

n = 157

Combination therapy

Sulfonylurea

24-26 weeks

sulfonylurea

0 (-1.0, 1.3)

n = 1,155

2.2 (0.5, 4.0)

n = 613

3.5 (1.4, 5.9)

n = 841

Metformin

26 weeks

metformin

-1.4 (-3.2, 0.2)

n = 175

0.8 (-1.0, 2.6)

n = 100

2.1 (0, 4.3)

n = 184

Insulin

26 weeks

insulin

0.9 (-0.5, 2.7)

n = 162

4.1 (1.4, 6.3)

n = 164

5.4 (3.4, 7.3)

n = 150

Sulfonylurea + metformin

26 weeks

sulfonylurea + metformin

0.2 (-1.2, 1.6)

n = 272

2.5 (0.8, 4.6)

n = 275

4.5 (2.4, 7.3)

n = 276

In a 24-week study in pediatric patients aged 10 to 17 years treated with AVANDIA 4 to 8 mg daily, a median weight gain of 2.8 kg (25th, 75th percentiles: 0.0, 5.8) was reported.

Hepatic Effects

Another drug of the thiazolidinedione class, troglitazone, was associated with idiosyncratic hepatotoxicity, and very rare cases of liver failure, liver transplants, and death were reported during clinical use. In pre-approval controlled clinical trials in patients with type 2 diabetes, troglitazone was more frequently associated with clinically significant elevations in liver enzymes (ALT >3X upper limit of normal) compared to placebo. Very rare cases of reversible jaundice were also reported.

In pre-approval clinical studies in 4,598 patients treated with AVANDIA, encompassing approximately 3,600 patient years of exposure, there was no signal of drug-induced hepatotoxicity or elevation of ALT levels. In the pre-approval controlled trials, 0.2% of patients treated with AVANDIA had elevations in ALT >3X the upper limit of normal compared to 0.2% on placebo and 0.5% on active comparators. The ALT elevations in patients treated with AVANDIA were reversible and were not clearly causally related to therapy with AVANDIA.

In postmarketing experience with AVANDIA, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established. Rosiglitazone is structurally related to troglitazone, a thiazolidinedione no longer marketed in the United States, which was associated with idiosyncratic hepatotoxicity and rare cases of liver failure, liver transplants, and death during clinical use. Pending the availability of the results of additional large, long-term controlled clinical trials and additional postmarketing safety data, it is recommended that patients treated with AVANDIA undergo periodic monitoring of liver enzymes.

Liver enzymes should be checked prior to the initiation of therapy with AVANDIA in all patients and periodically thereafter per the clinical judgment of the healthcare professional. Therapy with AVANDIA 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 AVANDIA should be evaluated to determine the cause of the liver enzyme elevation. Initiation of, or continuation of, therapy with AVANDIA 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 AVANDIA, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain >3X the upper limit of normal, therapy with AVANDIA 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 AVANDIA should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.

There are no data available from clinical trials to evaluate the safety of AVANDIA in patients who experienced liver abnormalities, hepatic dysfunction, or jaundice while on troglitazone. AVANDIA should not be used in patients who experienced jaundice while taking troglitazone.

Macular Edema

Macular edema has been reported in postmarketing experience in some diabetic patients who were taking AVANDIA 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-naïve patients recently diagnosed with type 2 diabetes mellitus, an increased incidence of bone fracture was noted in female patients taking AVANDIA. Over the 4- to 6-year period, the incidence of bone fracture in females was 9.3% (60/645) for AVANDIA 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. An increased incidence of bone fracture has been observed in female patients taking AVANDIA in a long-term trial. The majority of the fractures in the women who received AVANDIA 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 AVANDIA. The risk of fracture should be considered in the care of patients, especially female patients, treated with AVANDIA, 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 AVANDIA [see Adverse Reactions]. The observed changes may be related to the increased plasma volume observed with treatment with AVANDIA.

Diabetes and Blood Glucose Control

Patients receiving AVANDIA in combination with other hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary.

Periodic fasting blood glucose and HbA1c measurements should be performed to monitor therapeutic response.

Ovulation

Therapy with AVANDIA, 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 AVANDIA [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 AVANDIA 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.

Human Data

Rosiglitazone has been reported to cross the human placenta and be detectable in fetal tissue. The clinical significance of these findings is unknown. There are no adequate and well-controlled studies in pregnant women. AVANDIA should not be used during pregnancy.

Animal Studies

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 3 mg/kg in rats and 100 mg/kg in rabbits (approximately 20 and 75 times human AUC at the maximum recommended human daily dose, respectively). Rosiglitazone caused placental pathology in rats (3 mg/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 0.2 mg/kg/day in rats and 15 mg/kg/day in rabbits. These no-effect levels are approximately 4 times human AUC at the maximum recommended human daily dose. Rosiglitazone reduced the number of uterine implantations and live offspring when juvenile female rats were treated at 40 mg/kg/day from 27 days of age through to sexual maturity (approximately 68 times human AUC at the maximum recommended daily dose). The no-effect level was 2 mg/kg/day (approximately 4 times human AUC at the maximum recommended daily dose). There was no effect on pre- or post-natal survival or growth.

Labor and Delivery

The effect of rosiglitazone on labor and delivery in humans is not known.

Nursing Mothers

Drug-related material was detected in milk from lactating rats. It is not known whether AVANDIA is excreted in human milk. Because many drugs are excreted in human milk, AVANDIA should not be administered to a nursing woman.

Pediatric Use

After placebo run-in including diet counseling, children with type 2 diabetes mellitus, aged 10 to 17 years and with a baseline mean body mass index (BMI) of 33 kg/m2, were randomized to treatment with 2 mg twice daily of AVANDIA (n = 99) or 500 mg twice daily of metformin (n = 101) in a 24-week, double-blind clinical trial. As expected, fasting plasma glucose (FPG) decreased in patients naïve to diabetes medication (n = 104) and increased in patients withdrawn from prior medication (usually metformin) (n = 90) during the run-in period. After at least 8 weeks of treatment, 49% of AVANDIA-treated patients and 55% of metformin-treated patients had their dose doubled if FPG >126 mg/dL. For the overall intent-to-treat population, at week 24, the mean change from baseline in HbA1c was -0.14% with AVANDIA and -0.49% with metformin. There was an insufficient number of patients in this study to establish statistically whether these observed mean treatment effects were similar or different. Treatment effects differed for patients naïve to therapy with antidiabetic drugs and for patients previously treated with antidiabetic therapy (Table 5).

Table 5. Week 24 FPG and HbA1c Change From Baseline Last-Observation-Carried Forward in Children With Baseline HbA1c >6.5%

Naïve Patients

Previously-Treated Patients

Metformin

Rosiglitazone

Metformin

Rosiglitazone

N = 40

N = 45

N = 43

N = 32

FPG (mg/dL)

Baseline (mean)

170

165

221

205

Change from baseline (mean)

-21

-11

-33

-5

Adjusted treatment difference* (rosiglitazone–metformin) (95% CI)

8

(-15, 30)

21

(-9, 51)

% of patients with ≥30 mg/dL decrease from baseline

43%

27%

44%

28%

HbA1c (%)

Baseline (mean)

8.3

8.2

8.8

8.5

Change from baseline (mean)

-0.7

-0.5

-0.4

0.1

Adjusted treatment difference* (rosiglitazone– metformin) (95% CI)

0.2

(-0.6, 0.9)

0.5

(-0.2, 1.3)

% of patients with ≥0.7% decrease from baseline

63%

52%

54%

31%

* Change from baseline means are least squares means adjusting for baseline HbA1c, gender, and region.

Positive values for the difference favor metformin.

Treatment differences depended on baseline BMI or weight such that the effects of AVANDIA and metformin appeared more closely comparable among heavier patients. The median weight gain was 2.8 kg with rosiglitazone and 0.2 kg with metformin [see Warnings and Precautions]. Fifty-four percent of patients treated with rosiglitazone and 32% of patients treated with metformin gained ≥2 kg, and 33% of patients treated with rosiglitazone and 7% of patients treated with metformin gained ≥5 kg on study.

Adverse events observed in this study are described in Adverse Reactions .

Figure 3. Mean HbA1c Over Time in a 24-Week Study of AVANDIA and Metformin in Pediatric Patients — Drug-Naïve Subgroup

Geriatric Use

Results of the population pharmacokinetic analysis showed that age does not significantly affect the pharmacokinetics of rosiglitazone [see Clinical Pharmacology]. Therefore, no dosage adjustments are required for the elderly. In controlled clinical trials, no overall differences in safety and effectiveness between older (≥65 years) and younger (<65 years) patients were observed.

Page last updated: 2008-02-26

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