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.

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 )].

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.

Adult

In clinical trials, approximately 9,900 patients with type 2 diabetes have been treated with rosiglitazone maleate.

Pediatric

Rosiglitazone maleate has been evaluated for safety in a single, active-controlled trial of pediatric patients with type 2 diabetes in which 99 were treated with rosiglitazone maleate and 101 were treated with metformin. The most common adverse reactions (>10%) without regard to causality for either rosiglitazone maleate or metformin were headache (17% versus 14%), nausea (4% versus 11%), nasopharyngitis (3% versus 12%), and diarrhea (1% versus 13%). In this study, one case of diabetic ketoacidosis was reported in the metformin group. In addition, there were 3 patients in the rosiglitazone group who had FPG of ∼300 mg/dL, 2+ ketonuria, and an elevated anion gap.

Hematologic

Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with AVANDIA (mean decreases in individual studies as much as 1.0 g/dL hemoglobin and as much as 3.3% hematocrit). The changes occurred primarily during the first 3 months following initiation of therapy with AVANDIA or following a dose increase in AVANDIA. The time course and magnitude of decreases were similar in patients treated with a combination of AVANDIA and other hypoglycemic agents or monotherapy with AVANDIA. Pre-treatment levels of hemoglobin and hematocrit were lower in patients in metformin combination studies and may have contributed to the higher reporting rate of anemia. In a single study in pediatric patients, decreases in hemoglobin and hematocrit (mean decreases of 0.29 g/dL and 0.95%, respectively) were reported. Small decreases in hemoglobin and hematocrit have also been reported in pediatric patients treated with AVANDIA. White blood cell counts also decreased slightly in adult patients treated with AVANDIA. Decreases in hematologic parameters may be related to increased plasma volume observed with treatment with AVANDIA.

Lipids

Changes in serum lipids have been observed following treatment with rosiglitazone maleate in adults [see Clinical Pharmacology (12.2) ]. Small changes in serum lipid parameters were reported in children treated with rosiglitazone maleate for 24 weeks.

Serum Transaminase Levels

In pre-approval clinical studies in 4,598 patients treated with rosiglitazone maleate (3,600 patient-years of exposure) and in a long-term 4- to 6-year study in 1,456 patients treated with rosiglitazone maleate (4,954 patient-years exposure), there was no evidence of drug-induced hepatotoxicity.

In pre-approval controlled trials, 0.2% of patients treated with rosiglitazone maleate 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 rosiglitazone maleate were reversible. Hyperbilirubinemia was found in 0.3% of patients treated with rosiglitazone maleate compared with 0.9% treated with placebo and 1% in patients treated with active comparators. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure. [See Warnings and Precautions (5.6).] 

In the 4- to 6-year ADOPT trial, patients treated with rosiglitazone maleate (4,954 patient-years exposure), glyburide (4,244 patient-years exposure), or metformin (4,906 patient-years exposure), as monotherapy, had the same rate of ALT increase to >3X upper limit of normal (0.3 per 100 patient-years exposure).

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. rosiglitazone maleate 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.

Absorption

The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), but there was an approximately 28% decrease in Cmax and a delay in Tmax (1.75 hours). These changes are not likely to be clinically significant; therefore, rosiglitazone maleate may be administered with or without food.

Distribution

The mean (CV%) oral volume of distribution (Vss/F) of rosiglitazone is approximately 17.6 (30%) liters, based on a population pharmacokinetic analysis. Rosiglitazone is approximately 99.8% bound to plasma proteins, primarily albumin.

Metabolism

Rosiglitazone is extensively metabolized with no unchanged drug excreted in the urine. The major routes of metabolism were N-demethylation and hydroxylation, followed by conjugation with sulfate and glucuronic acid. All the circulating metabolites are considerably less potent than parent and, therefore, are not expected to contribute to the insulin-sensitizing activity of rosiglitazone.

In vitro data demonstrate that rosiglitazone is predominantly metabolized by Cytochrome P450 (CYP) isoenzyme 2C8, with CYP2C9 contributing as a minor pathway.

Excretion

Following oral or intravenous administration of [14C]rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, respectively. The plasma half-life of [14C]related material ranged from 103 to 158 hours.

Population Pharmacokinetics in Patients with Type 2 Diabetes

Population pharmacokinetic analyses from 3 large clinical trials including 642 men and 405 women with type 2 diabetes (aged 35 to 80 years) showed that the pharmacokinetics of rosiglitazone are not influenced by age, race, smoking, or alcohol consumption. Both oral clearance (CL/F) and oral steady-state volume of distribution (Vss/F) were shown to increase with increases in body weight. Over the weight range observed in these analyses (50 to 150 kg), the range of predicted CL/F and Vss/F values varied by <1.7-fold and<2.3-fold, respectively. Additionally, rosiglitazone CL/F was shown to be influenced by both weight and gender, being lower (about 15%) in female patients.

Special Populations

Drugs That Inhibit, Induce, or are Metabolized by Cytochrome P450

In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any of the major P450 enzymes at clinically relevant concentrations. In vitro data demonstrate that rosiglitazone is predominantly metabolized by CYP2C8, and to a lesser extent, 2C9. rosiglitazone maleate (4 mg twice daily) was shown to have no clinically relevant effect on the pharmacokinetics of nifedipine and oral contraceptives (ethinyl estradiol and norethindrone), which are predominantly metabolized by CYP3A4.

Glyburide

Rosiglitazone maleate (2 mg twice daily) taken concomitantly with glyburide (3.75 to 10 mg/day) for 7 days did not alter the mean steady-state 24-hour plasma glucose concentrations in diabetic patients stabilized on glyburide therapy. Repeat doses of rosiglitazone maleate(8 mg once daily) for 8 days in healthy adult Caucasian subjects caused a decrease in glyburide AUC and Cmax of approximately 30%. In Japanese subjects, glyburide AUC and Cmax slightly increased following coadministration of rosiglitazone maleate.

Glimepiride

Single oral doses of glimepiride in 14 healthy adult subjects had no clinically significant effect on the steady-state pharmacokinetics of rosiglitazone maleate. No clinically significant reductions in glimepiride AUC and Cmax were observed after repeat doses of rosiglitazone maleate  (8 mg once daily) for 8 days in healthy adult subjects.

Metformin

Concurrent administration of rosiglitazone maleate (2 mg twice daily) and metformin (500 mg twice daily) in healthy volunteers for 4 days had no effect on the steady-state pharmacokinetics of either metformin or rosiglitazone.

Acarbose

Coadministration of acarbose (100 mg three times daily) for 7 days in healthy volunteers had no clinically relevant effect on the pharmacokinetics of a single oral dose of rosiglitazone maleate.

Digoxin

Repeat oral dosing of rosiglitazone maleate (8 mg once daily) for 14 days did not alter the steady-state pharmacokinetics of digoxin (0.375 mg once daily) in healthy volunteers.

Warfarin

Repeat dosing with rosigllitazone maleate had no clinically relevant effect on the steady-state pharmacokinetics of warfarin enantiomers.

Ethanol

A single administration of a moderate amount of alcohol did not increase the risk of acute hypoglycemia in type 2 diabetes mellitus patients treated with rosiglitazone maleate.

Ranitidine

Pretreatment with ranitidine (150 mg twice daily for 4 days) did not alter the pharmacokinetics of either single oral or intravenous doses of rosiglitazone in healthy volunteers. These results suggest that the absorption of oral rosiglitazone is not altered in conditions accompanied by increases in gastrointestinal pH.

Carcinogenesis

A 2-year carcinogenicity study was conducted in Charles River CD-1 mice at doses of 0.4, 1.5, and 6 mg/kg/day in the diet (highest dose equivalent to approximately 12 times human AUC at the maximum recommended human daily dose). Sprague-Dawley rats were dosed for 2 years by oral gavage at doses of 0.05, 0.3, and 2 mg/kg/day (highest dose equivalent to approximately 10 and 20 times human AUC at the maximum recommended human daily dose for male and female rats, respectively).

Rosiglitazone was not carcinogenic in the mouse. There was an increase in incidence of adipose hyperplasia in the mouse at doses ≥1.5 mg/kg/day (approximately 2 times human AUC at the maximum recommended human daily dose). In rats, there was a significant increase in the incidence of benign adipose tissue tumors (lipomas) at doses ≥0.3 mg/kg/day (approximately 2 times human AUC at the maximum recommended human daily dose). These proliferative changes in both species are considered due to the persistent pharmacological overstimulation of adipose tissue.

Mutagenesis

Rosiglitazone was not mutagenic or clastogenic in the in vitro bacterial assays for gene mutation, the in vitro chromosome aberration test in human lymphocytes, the in vivo mouse micronucleus test, and the in vivo/in vitro rat UDS assay. There was a small (about 2-fold) increase in mutation in the in vitro mouse lymphoma assay in the presence of metabolic activation.

Impairment of Fertility

Rosiglitazone had no effects on mating or fertility of male rats given up to 40 mg/kg/day (approximately 116 times human AUC at the maximum recommended human daily dose). Rosiglitazone altered estrous cyclicity (2 mg/kg/day) and reduced fertility (40 mg/kg/day) of female rats in association with lower plasma levels of progesterone and estradiol (approximately 20 and 200 times human AUC at the maximum recommended human daily dose, respectively). No such effects were noted at 0.2 mg/kg/day (approximately 3 times human AUC at the maximum recommended human daily dose). In juvenile rats dosed from 27 days of age through to sexual maturity (at up to 40 mg/kg/day), there was no effect on male reproductive performance, or on estrous cyclicity, mating performance or pregnancy incidence in females (approximately 68 times human AUC at the maximum recommended human daily dose). In monkeys, rosiglitazone (0.6 and 4.6 mg/kg/day; approximately 3 and 15 times human AUC at the maximum recommended human daily dose, respectively) diminished the follicular phase rise in serum estradiol with consequential reduction in the luteinizing hormone surge, lower luteal phase progesterone levels, and amenorrhea. The mechanism for these effects appears to be direct inhibition of ovarian steroidogenesis.

Short Term Clinical Studies

A total of 2,315 patients with type 2 diabetes, previously treated with diet alone or antidiabetic medication(s), were treated with rosilitazone maleate as monotherapy in 6 double-blind studies, which included two 26-week placebo-controlled studies, one 52-week glyburide-controlled study, and 3 placebo-controlled dose-ranging studies of 8 to 12 weeks duration. Previous antidiabetic medication(s) were withdrawn and patients entered a 2 to 4 week placebo run-in period prior to randomization.

Two 26-week, double-blind, placebo-controlled trials, in patients with type 2 diabetes (n = 1,401) with inadequate glycemic control (mean baseline FPG approximately 228 mg/dL [101 to 425 mg/dL] and mean baseline HbA1c 8.9% [5.2% to 16.2%]), were conducted. Treatment with AVANDIA produced statistically significant improvements in FPG and HbA1c compared to baseline and relative to placebo. Data from one of these studies are summarized in Table 9.

When administered at the same total daily dose, rosiglitazone maleate was generally more effective in reducing FPG and HbA1c when administered in divided doses twice daily compared to once daily doses. However, for HbA1c, the difference between the 4 mg once daily and 2 mg twice daily doses was not statistically significant.

Long Term Clinical Studies

Long-term maintenance of effect was evaluated in a 52-week, double-blind, glyburide-controlled trial in patients with type 2 diabetes. Patients were randomized to treatment with rosiglitazone maleate 2 mg twice daily (N = 195) or rosiglitazone maleate 4 mg twice daily (N = 189) or glyburide (N = 202) for 52 weeks. Patients receiving glyburide were given an initial dosage of either 2.5 mg/day or 5.0 mg/day. The dosage was then titrated in 2.5 mg/day increments over the next 12 weeks, to a maximum dosage of 15.0 mg/day in order to optimize glycemic control. Thereafter the glyburide dose was kept constant.

The median titrated dose of glyburide was 7.5 mg. All treatments resulted in a statistically significant improvement in glycemic control from baseline (Figure 4 and Figure 5). At the end of week 52, the reduction from baseline in FPG and HbA1c was -40.8 mg/dL and -0.53% with rosiglitazone maleate 4 mg twice daily; -25.4 mg/dL and -0.27% with rosiglitazone maleate 2 mg twice daily; and -30.0 mg/dL and -0.72% with glyburide. For HbA1c, the difference between rosiglitazone maleate 4 mg twice daily and glyburide was not statistically significant at week 52. The initial fall in FPG with glyburide was greater than with rosiglitazone maleate; however, this effect was less durable over time. The improvement in glycemic control seen with rosiglitazone maleate 4 mg twice daily at week 26 was maintained through week 52 of the study.

Figure 4 Mean FPG Over Time in a 52-Week Glyburide-Controlled Study

Figure 5 Mean HbA1c Over Time in a 52 Week-Gkyburide-Controlled Study

Hypoglycemia was reported in 12.1% of glyburide-treated patients versus 0.5% (2 mg twice daily) and 1.6% (4 mg twice daily) of patients treated with rosiglitazone maleate. The improvements in glycemic control were associated with a mean weight gain of 1.75 kg and 2.95 kg for patients treated with 2 mg and 4 mg twice daily of rosiglitazone maleate, respectively, versus 1.9 kg in glyburide-treated patients. In patients treated with rosiglitazone maleate, C-peptide, insulin, pro-insulin, and pro-insulin split products were significantly reduced in a dose-ordered fashion, compared to an increase in the glyburide-treated patients.

A Diabetes Outcome Progression Trial (ADOPT) was a multicenter, double-blind, controlled trial (n = 4,351) conducted over 4 to 6 years to compare the safety and efficacy of rosiglitazone maleate, metformin, and glyburide monotherapy in patients recently diagnosed with type 2 diabetes mellitus (≤3 years) inadequately controlled with diet and exercise. The mean age of patients in this trial was 57 years and the majority of patients (83%) had no known history of cardiovascular disease. The mean baseline FPG and HbA1c were 152 mg/dL and 7.4%, respectively. Patients were randomized to receive either rosiglitazone maleate 4 mg once daily, glyburide 2.5 mg once daily, or metformin 500 mg once daily, and doses were titrated to optimal glycemic control up to a maximum of 4 mg twice daily for rosiglitazone maleate, 7.5 mg twice daily for glyburide, and 1,000 mg twice daily for metformin. The primary efficacy outcome was time to consecutive FPG >180 mg/dL after at least 6 weeks of treatment at the maximum tolerated dose of study medication or time to inadequate glycemic control, as determined by an independent adjudication committee.

The cumulative incidence of the primary efficacy outcome at 5 years was 15% with rosiglitazone maleate, 21% with metformin, and 34% with glyburide (hazard ratio 0.68 [95% CI 0.55, 0.85] versus metformin, HR 0.37 [95% CI 0.30, 0.45] versus glyburide).

Cardiovascular and adverse event data (including effects on body weight and bone fracture) from ADOPT for rosiglitazone maleate, metformin, and glyburide are described in Warnings and Precautions (5.2, 5.5, and 5.8) and Adverse Reactions (6.1), respectively. As with all medications, efficacy results must be considered together with safety information to assess the potential benefit and risk for an individual patient.

Combination with Metformin

A total of 670 patients with type 2 diabetes participated in two 26-week, randomized, double-blind, placebo/active-controlled studies designed to assess the efficacy of rosiglitazone maleate in combination with metformin. rosiglitazone maleate, administered in either once daily or twice daily dosing regimens, was added to the therapy of patients who were inadequately controlled on a maximum dose (2.5 grams/day) of metformin.

In one study, patients inadequately controlled on 2.5 grams/day of metformin (mean baseline FPG 216 mg/dL and mean baseline HbA1c 8.8%) were randomized to receive 4 mg of rosiglitazone maleate once daily, 8 mg of rosiglitazone maleate once daily, or placebo in addition to metformin. A statistically significant improvement in FPG and HbA1c was observed in patients treated with the combinations of metformin and 4 mg of rosiglitazone maleate once daily and 8 mg of rosiglitazone maleate once daily, versus patients continued on metformin alone (Table 10).

In a second 26-week study, patients with type 2 diabetes inadequately controlled on 2.5 grams/day of metformin who were randomized to receive the combination of rosiglitazone maleate 4 mg twice daily and metformin (N = 105) showed a statistically significant improvement in glycemic control with a mean treatment effect for FPG of -56 mg/dL and a mean treatment effect for HbA1c of -0.8% over metformin alone. The combination of metformin and rosiglitazone maleate resulted in lower levels of FPG and HbA1c than either agent alone.

Patients who were inadequately controlled on a maximum dose (2.5 grams/day) of metformin and who were switched to monotherapy with rosiglitazone maleate demonstrated loss of glycemic control, as evidenced by increases in FPG and HbA1c. In this group, increases in LDL and VLDL were also seen.

Combination with Sulfonylurea

A total of 3,457 patients with type 2 diabetes participated in ten 24- to 26-week randomized, double-blind, placebo/active-controlled studies and one 2-year double-blind, active-controlled study in elderly patients designed to assess the efficacy and safety of rosiglitazone maleate in combination with a sulfonylurea. rosiglitazone maleate 2 mg, 4 mg, or 8 mg daily, was administered either once daily (3 studies) or in divided doses twice daily (7 studies), to patients inadequately controlled on a submaximal or maximal dose of sulfonylurea.

In these studies, the combination of rosiglitazone maleate 4 mg or 8 mg daily (administered as single or twice daily divided doses) and a sulfonylurea significantly reduced FPG and HbA1c compared to placebo plus sulfonylurea or further up-titrationof the sulfonylurea. Table 11 shows pooled data for 8 studies in which rosiglitazone maleate added to sulfonylurea was compared to placebo plus sulfonylurea.

One of the 24- to 26-week studies included patients who were inadequately controlled on maximal doses of glyburide and switched to 4 mg of rosiglitazone maleate daily as monotherapy; in this group, loss of glycemic control was demonstrated, as evidenced by increases in FPG and HbA1c.

In a 2-year double-blind study, elderly patients (aged 59 to 89 years) on half-maximal sulfonylurea (glipizide 10 mg twice daily) were randomized to the addition of rosiglitazone maleate (n = 115, 4 mg once daily to 8 mg as needed) or to continued up-titration of glipizide (n = 110), to a maximum of 20 mg twice daily. Mean baseline FPG and HbA1c were 157 mg/dL and 7.72%, respectively, for the rosiglitazone maleate plus glipizide arm and 159 mg/dL and 7.65%, respectively, for the glipizide up-titration arm. Loss of glycemic control (FPG ≥180 mg/dL) occurred in a significantly lower proportion of patients (2%) on rosiglitazone maleate plus glipizide compared to patients in the glipizide up-titration arm (28.7%). About 78% of the patients on combination therapy completed the 2 years of therapy while only 51% completed on glipizide monotherapy. The effect of combination therapy on FPG and HbA1c was durable over the 2-year study period, with patients achieving a mean of 132 mg/dL for FPG and a mean of 6.98% for HbA1c compared to no change on the glipizide arm.