Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION
● Thiazolidinediones, including Rosiglitazone, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.1)]. After initiation of Rosiglitazone maleate, 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 Rosiglitazone maleate must be considered.
● Rosiglitazone Maleate is not recommended in patients with symptomatic heart failure. Initiation of Rosiglitazone maleate in patients with established NYHA Class III or IV heart failure is contraindicated. [See Contraindications (4) and Warnings and Precautions (5.1 ).]
● A meta-analysis of 42 clinical studies (mean duration 6 months; 14,237 total patients), most of which compared Rosiglitazone maleate to placebo, showed Rosiglitazone maleate 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 maleate 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 (5.2) .]
Indications and Usage for Rosiglitazone
Monotherapy and Combination Therapy
Rogislitazone tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Important Limitations of Use
Due to its mechanism of action, Rosiglitazone maleate is active only in the presence of endogenous insulin. Therefore, Rosiglitazone maleate should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
The coadministration of Rosiglitazone maleate and insulin is not recommended.
The use of Rosiglitazone maleate with nitrates is not recommended.
Rosiglitazone Dosage and Administration
The management of antidiabetic therapy should be individualized. All patients should start Rosiglitazone maleate tablets at the lowest recommended dose. Further increases in the dose of Rosiglitazone maleate tablets should be accompanied by careful monitoring for adverse events related to fluid retention [see Boxed Warning and Warnings and Precautions (5.1) ].
Rosiglitazone maleate tablets may be administered at a starting dose of 4 mg either as a single daily dose or in 2 divided doses. For patients who respond inadequately following 8 to 12 weeks of treatment, as determined by reduction in fasting plasma glucose (FPG), the dose may be increased to 8 mg daily as monotherapy or in combination with metformin, sulfonylurea, or sulfonylurea plus metformin. Reductions in glycemic parameters by dose and regimen are described under Clinical Studies (14.1) . Rosiglitazone maleate tablets may be taken with or without food.
The total daily dose of Rosiglitazone maleate tablets should not exceed 8 mg.
Monotherapy
The usual starting dose of Rosiglitazone maleate tablets is 4 mg administered either as a single dose once daily or in divided doses twice daily. In clinical trials, the 4-mg twice-daily regimen resulted in the greatest reduction in FPG and hemoglobin A1c (HbA1c).
Combination With Sulfonylurea or Metformin
When Rosiglitazone maleate tablets is added to existing therapy, the current dose(s) of the agent(s) can be continued upon initiation of therapy with Rosiglitazone maleate tablets.
Sulfonylurea
When used in combination with sulfonylurea, the usual starting dose of Rosiglitazone maleate is 4 mg administered as either a single dose once daily or in divided doses twice daily. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased.
Metformin
The usual starting dose of Rosiglitazone Maleate in combination with metformin is 4 mg administered as either a single dose once daily or in divided doses twice daily. It is unlikely that the dose of metformin will require adjustment due to hypoglycemia during combination therapy with Rosiglitazone Maleate.
Combination With Sulfonylurea Plus Metformin
The usual starting dose of Rosiglitazone maleate tablets in combination with a sulfonylurea plus metformin is 4 mg administered as either a single dose once daily or divided doses twice daily. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased.
Specific Patient Populations
Renal Impairment
No dosage adjustment is necessary when Rosiglitazone maleate is used as monotherapy in patients with renal impairment. Since metformin is contraindicated in such patients, concomitant administration of metformin and Rosiglitazone maleate is also contraindicated in patients with renal impairment.
Hepatic Impairment
Liver enzymes should be measured prior to initiating treatment with Rosiglitazone maleate. Therapy with Rosiglitazone maleateshould not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT >2.5X upper limit of normal at start of therapy). After initiation of Rosiglitazone maleate, liver enzymes should be monitored periodically per the clinical judgment of the healthcare professional. [See Warnings and Precautions (5.6) and Clinical Pharmacology (12.3) .]
Pediatric
Data are insufficient to recommend pediatric use of Rosiglitazone maleate [see Use in Specific Populations (8.4 )].
Dosage Forms and Strengths
Oval film-coated tablet contains Rosiglitazone as the maleate as follows::
2 mg - Pink oval film coated tablets, engraved with W41.
4 mg - Orange oval film coated tablets, engraved with W42.
8 mg - Brick red oval film coated tablets, engraved with W43.
Contraindications
Initiation of Rosiglitazone maleate in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see Boxed Warning ].
Warnings and Precautions
Cardiac Failure
Rosiglitazone maleate, 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 maleate 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 following treatment with Rosiglitazone maleate compared to placebo during the 52-week study. (See Table 1.)
| 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 Rosiglitazone maleate in patients with established NYHA Class III or IV heart failure is contraindicated. Rosiglitazone maleate 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 Rosiglitazone maleate is not recommended for patients experiencing an acute coronary event, and discontinuation of Rosiglitazone maleate 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. Rosiglitazone maleate 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 (Monotherapy with Rosiglitazone maleate versus placebo monotherapy) and add-on trials (Rosiglitazone maleate or placebo, added to sulfonylurea, metformin, or insulin). Active control studies included monotherapy trials (monotherapy with Rosiglitazone maleate versus sulfonylurea or metformin monotherapy) and add-on trials (Rosiglitazone maleate plus sulfonylurea or Rosiglitazone maleate plus metformin, versus sulfonylurea plus metformin). A total of 14,237 patients were included (8,604 in treatment groups containing Rosiglitazone maleate, 5,633 in comparator groups), with 4,143 patient-years of exposure to Rosiglitazone maleate 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 maleate versus pooled comparators was observed (2% Rosiglitazone maleate 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 maleate 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 Rosiglitazone maleate was added to insulin (2.8% for Rosiglitazone maleate 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 (5.3) .]
Figure 1 - Forest Plot of Odds Rations (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 maleate and background nitrate therapy. For Rosiglitazone maleate (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 maleate versus comparator was not demonstrated.
Myocardial Ischemic Events in Large Long-Term Prospectice Randomized Controlled Trials of Rosiglitazone maleate
Data from 3 other large, long-term, prospective, randomized, controlled clinical trials of Rosiglitazone maleate were assessed separately from the meta-analysis. These 3 trials include a total of 14,067 patients (treatment groups containing Rosiglitazone maleate N = 6,311, comparator groups N = 7,756), with patient-year exposure of 21,803 patient-years for Rosiglitazone maleate 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 Rosiglitazone maleate 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 maleate, 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 rosligtazone maleate, and 2,634 were in treatment groups not containing Rosiglitazone maleate. Interim results have been published 3 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 maleate or add-on sulfonylurea, and those who have failed sulfonylurea are randomized to receive either add-on Rosiglitazone maleate or add-on metformin. In RECORD, a total of 2,220 patients are receiving add-on Rosiglitazone maleate, and 2,227 patients are on one of the add-on regimens not containing Rosiglitazone maleate.
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’ 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 maleate and comparators.
Figure 2. Hazard Ratios for the Risk of MACE (Myocardial Infarction, Cardiovascular Death, or Stroke), Myocardial Infarction, and Total Mortality With Rosiglitazone Maleate Compared With a Control Group
In preliminary analyses of the DREAM trial, the incidence of cardiovascular events was higher among subjects who received Rosiglitazone maleate 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 Rosiglitazone maleate was added to insulin, Rosiglitazone maleate increased the risk of congestive heart failure and myocardial ischemia. (See Table 2.) Coadministration of Rosiglitazone maleate and insulin is not recommended. [See Indications and Usage (1.2) 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 (5.2) ], patients with type 2 diabetes mellitus were randomized to coadministration of AVANDIA and insulin (N = 867) or insulin (N = 663). In these 5 trials, Rosiglitazone maleate 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 maleate 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 maleate 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 maleate and insulin. These cardiovascular events were noted at both the 4 mg and 8 mg daily doses of Rosiglitazone maleate. (See Table 2.)
| Event* | Rosiglitazone Maleate + 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 rosiglitaszone maleate 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
Rosiglitazone maleate should be used with caution in patients with edema. In a clinical study in healthy volunteers who received 8 mg of Rosiglitazone maleate 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, Rosiglitazone maleate should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure [see Boxed Warning , Warnings and Precautions (5.1 ), and Patient Counseling Information (17.1) ].
In controlled clinical trials of patients with type 2 diabetes, mild to moderate edema was reported in patients treated with Rosiglitazone maleate, 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 maleate [see Adverse Reactions (6.1)] .
Weight Gain
Dose-related weight gain was seen with Rosiglitazone maleate 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 ].
| Control Group | Rosiglitazone maleate 4 mg | Rosiglitazone 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 4- to 6-year, monotherapy, comparative trial (ADOPT) in patients recently diagnosed with type 2 diabetes not previously treated with antidiabetic medication [see Clinical Studies (14.1) ], the median weight change (25th, 75th percentiles) from baseline at 4 years was 3.5 kg (0.0, 8.1) for Rosiglitazone maleate, 2.0 kg (-1.0, 4.8) for glyburide, and -2.4 kg (-5.4, 0.5) for metformin.
In a 24-week study in pediatric patients aged 10 to 17 years treated with Rosiglitazone maleate 4 to 8 mg daily, a median weight gain of 2.8 kg (25th, 75th percentiles: 0.0, 5.8) was reported.
Hepatic Effects
Liver enzymes should be measured prior to the initiation of therapy with Rosiglitazone maleate in all patients and periodically thereafter per the clinical judgment of the healthcare professional. Therapy with Rosiglitazone maleate 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 Rosiglitazone maleate should be evaluated to determine the cause of the liver enzyme elevation. Initiation of, or continuation of, therapy with Rosiglitazone maleate in patients with mild liver enzyme elevations should proceed with caution and include close clinical follow-up, including 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 Rosiglitazone maleate, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain >3X the upper limit of normal, therapy with Rosiglitazone maleate 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 Rosiglitazone maleate should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued. [See Adverse Reactions (6.2, 6.3).]
Macular Edema
Macular edema has been reported in postmarketing experience in some diabetic patients who were taking Rosiglitazone maleate 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 (6.1) .]
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 Rosiglitazone maleate. Over the 4- to 6-year period, the incidence of bone fracture in females was 9.3% (60/645) for Rosiglitazone maleate 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 maleate 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 maleate. The risk of fracture should be considered in the care of patients, especially female patients, treated with Rosiglitazone maleate, 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 maleate[see Adverse Reactions (6.2)]. The observed changes may be related to the increased plasma volume observed with treatment with Rosiglitazonemaleate.
Diabetes and Blood Glucose Control
Patients receiving Rosiglitazone maleate 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 Rosiglitazone maleate, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking Rosiglitazone maleate [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 studies; 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 Rosiglitazone maleate should be reviewed.
Adverse Reactions
Clinical Trial Experience
Adult
In clinical trials, approximately 9,900 patients with type 2 diabetes have been treated with Rosiglitazone maleate.
Short-Term Trials of Rosiglitazone Maleate as Monotherapy and in Combination With Other Hypoglycemic Agents
The incidence and types of adverse events reported in short-term clinical trials of Rosiglitazone maleate as monotherapy are shown in Table 4.
| Preferred Term | Rosiglitazone maleate Monotherapy | Placebo | Metformin | Sulfonylureas† |
| N = 2,526 | N = 601 | N = 225 | N = 626 | |
| % | % | % | % | |
| Upper respiratory tract infection | 9.9 | 8.7 | 8.9 | 7.3 |
Injury | 7.6 | 4.3 | 7.6 | 6.1 |
| Headache | 5.9 | 5.0 | 8.9 | 5.4 |
Back pain | 4.0 | 3.8 | 4.0 | 5.0 |
Hyperglycemia | 3.9 | 5.7 | 4.4 | 8.1 |
Fatigue | 3.6 | 5.0 | 4.0 | 1.9 |
Sinusitis | 3.2 | 4.5 | 5.3 | 3.0 |
Diarrhea | 2.3 | 3.3 | 15.6 | 3.0 |
| Hypoglycemia | 0.6 | 0.2 | 1.3 | 5.9 |
| * Short-term trials ranged from 8 weeks to 1 year. | ||||
| † Includes patients receiving glyburide (N = 514), gliclazide (N = 91), or glipizide (N = 21). |
Overall, the types of adverse reactions without regard to causality reported when Rosiglitazone maleate was used in combination with a sulfonylurea or metformin were similar to those during monotherapy with Rosiglitazone maleate.
Events of anemia and edema tended to be reported more frequently at higher doses, and were generally mild to moderate in severity and usually did not require discontinuation of treatment with Rosiglitazone maleate.
In double-blind studies, anemia was reported in 1.9% of patients receiving Rosiglitazone maleate as monotherapy compared to 0.7% on placebo, 0.6% on sulfonylureas, and 2.2% on metformin. Reports of anemia were greater in patients treated with a combination of AVANDIA and metformin (7.1%) and with a combination of AVANDIA and a sulfonylurea plus metformin (6.7%) compared to monotherapy with ARosiglitazone maleate or in combination with a sulfonylurea (2.3%). Lower pre-treatment hemoglobin/hematocrit levels in patients enrolled in the metformin combination clinical trials may have contributed to the higher reporting rate of anemia in these studies [see Adverse Reactions (6.2)].
In clinical trials, edema was reported in 4.8% of patients receiving Rosiglitazone maleate as monotherapy compared to 1.3% on placebo, 1.0% on sulfonylureas, and 2.2% on metformin. The reporting rate of edema was higher for Rosiglitazone maleate 8 mg in sulfonylurea combinations (12.4%) compared to other combinations, with the exception of insulin. Edema was reported in 14.7% of patients receiving Rosiglitazone maleate in the insulin combination trials compared to 5.4% on insulin alone. Reports of new onset or exacerbation of congestive heart failure occurred at rates of 1% for insulin alone, and 2% (4 mg) and 3% (8 mg) for insulin in combination with Rosiglitazone maleate [see Boxed Warning and Warnings and Precautions (5.3 )].
In controlled combination therapy studies with sulfonylureas, mild to moderate hypoglycemic symptoms, which appear to be dose related, were reported. Few patients were withdrawn for hypoglycemia (<1%) and few episodes of hypoglycemia were considered to be severe (<1%). Hypoglycemia was the most frequently reported adverse event in the fixed-dose insulin combination trials, although few patients withdrew for hypoglycemia (4 of 408 for Rosiglitazone maleate plus insulin and 1 of 203 for insulin alone). Rates of hypoglycemia, confirmed by capillary blood glucose concentration ≤50 mg/dL, were 6% for insulin alone and 12% (4 mg) and 14% (8 mg) for insulin in combination with Rosiglitazone maleate. [See Warnings and Precautions (5.10) .]
Long-Term Trial of Rosiglitazone Maleate as Monotherapy
A 4- to 6-year study (ADOPT) compared the use of Rosiglitazone maleate (n = 1,456), glyburide (n = 1,441), and metformin (n = 1,454) as monotherapy in patients recently diagnosed with type 2 diabetes who were not previously treated with antidiabetic medication. Table 5 presents adverse reactions without regard to causality; rates are expressed per 100 patient-years (PY) exposure to account for the differences in exposure to study medication across the 3 treatment groups.
In ADOPT, fractures were reported in a greater number of women treated with Rosiglitazone maleate (9.3%, 2.7/100 patient-years) compared to glyburide (3.5%, 1.3/100 patient-years) or metformin (5.1%, 1.5/100 patient-years). The majority of the fractures in the women who received Rosiglitazone were reported in the upper arm, hand, and foot. [See Warnings and Precautions (5.7 ).] The observed incidence of fractures for male patients was similar among the 3 treatment groups.
| Rosiglitazone Maleate | Glyburide | Metformin | |
N = 1,456 | N = 1,441 | N = 1,454 | |
PY = 4,954 | PY = 4,244 | PY = 4,906 | |
| Nasopharyngitis | 6.3 | 6.9 | 6.6 |
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