rich person [1%):<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. Table 5. On-Therapy Adverse Events ( 5 Events/100 Patient-Years [PY]) in Any Treatment Group Reported in a 4- to 6-Year Clinical Trial of Rosiglitazone Maleate as Monotherapy (ADOPT) 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 Back pain 5.1 4.9 5.3 Arthralgia 5.0 4.8 4.2 Hypertension 4.4 6.0 6.1 Upper respiratory tract infection 4.3 5.0 4.7 Hypoglycemia 2.9 13.0 3.4 Diarrhea 2.5 3.2 6.8 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. 6.2 Laboratory Abnormalities 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). 6.3 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the events described below have been identified during post-approval use of Rosiglitazone maleate. Because these events are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or to always establish a causal relationship to drug exposure. In patients receiving thiazolidinedione therapy, serious adverse events with or without a fatal outcome, potentially related to volume expansion (e.g., congestive heart failure, pulmonary edema, and pleural effusions) have been reported [see Boxed Warning and Warnings and Precautions (5.1)] . There are postmarketing reports with Rosiglitazone maleate of hepatitis, hepatic enzyme elevations to 3 or more times the upper limit of normal, and hepatic failure with and without fatal outcome, although causality has not been established. Rash, pruritus, urticaria, angioedema, anaphylactic reaction, and Stevens-Johnson syndrome have been reported rarely. Reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received [see Warnings and Precautions (5.7)] . 7 DRUG INTERACTIONS 7.1 CYP2C8 Inhibitors and Inducers An inhibitor of CYP2C8 (e.g., gemfibrozil) may increase the AUC of Rosiglitazone and an inducer of CYP2C8 (e.g., rifampin) may decrease the AUC of Rosiglitazone. Therefore, if an inhibitor or an inducer of CYP2C8 is started or stopped during treatment with Rosiglitazone, changes in diabetes treatment may be needed based upon clinical response. [See Clinical Pharmacology (12.4).] 8 USE IN SPECIFIC POPULATIONS 8.1 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. 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. 8.2 Labor and Delivery The effect of Rosiglitazone on labor and delivery in humans is not known. 8.3 Nursing Mothers Drug-related material was detected in milk from lactating rats. It is not known whether Rosiglitazone maleate is excreted in human milk. Because many drugs are excreted in human milk, Rosiglitazone maleate should not be administered to a nursing woman. 8.4 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/m 2 , were randomized to treatment with 2 mg twice daily of Rosiglitazone maleate (n = 99) or 500 mg twice daily of metformin (n = 101) in a 24-week, double-blind clinical trial. As expected, 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 patients treated with Rosiglitazone maleate 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 Rosiglitazone maleate 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 6). Table 6. 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 Rosiglitazone maleate 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 (5.4) ] . 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 (6.1 ) . Figure 3. Mean HbA1c Over Time in a 24-Week Study of Rosiglitazone Maleate and Metformin in Pediatric Patients Drug-Naïve Subgroup 8.5 Geriatric Use Results of the population pharmacokinetic analysis showed that age does not significantly affect the pharmacokinetics of Rosiglitazone [see Clinical Pharmacology (12.3) ] . 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. 10 OVERDOSAGE Limited data are available with regard to overdosage in humans. In clinical studies in volunteers, Rosiglitazone maleate has been administered at single oral doses of up to 20 mg and was well-tolerated. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient s clinical status. 11 DESCRIPTION Rosiglitazone maleate is an oral antidiabetic agent which acts primarily by increasing iinsulin sensitivity. Rosiglitazone maleate improves glycemic control while reducing circulating insulin levels. Rosiglitazone maleate is not chemically or functionally related to the sulfonylureas, the biguanides, or the alpha-glucosidase inhibitors. Chemically, Rosiglitazone maleate is ( )-5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, ( Z )-2-butenedioate (1:1) with a molecular weight of 473.52 (357.44 free base). The molecule has a single chiral center and is present as a racemate. Due to rapid interconversion, the enantiomers are functionally indistinguishable. The structural formula of Rosiglitazone maleate is: Structural Formula The molecular formula is C 18 H 19 N 3 O 3 S C 4 H 4 O 4 . Rosiglitazone maleate is a white to off-white solid with a melting point range of 122 to 123 C. The pKa values of Rosiglitazone maleate are 6.8 and 6.1. It is readily soluble in ethanol and a buffered aqueous solution with pH of 2.3; solubility decreases with increasing pH in the physiological range. Each film-coated tablet contains Rosiglitazone maleate equivalent to Rosiglitazone, 2 mg, 4 mg or 8 mg, for oral administration. Inactive ingredients are: Lactose monohydrate, lechithinm, magnesium stearate, microcrystalline cellulose, polyethylene glycol 3350, polyvinyl alcohol, red iron oxide, sodium starch glycolate type A, talc, titanium dioxide. The 4 mg tablet also contains FD&C yellow No, 6 aluminum lake and yellow iron oxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Rosiglitazone, a member of the thiazolidinedione class of antidiabetic agents, improves glycemic control by improving insulin sensitivity. Rosiglitazone is a highly selective and potent agonist for the peroxisome proliferator-activated receptor-gamma (PPARγ). In humans, PPAR receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In addition, PPARγ-responsive genes also participate in the regulation of fatty acid metabolism. Insulin resistance is a common feature characterizing the pathogenesis of type 2 diabetes. The antidiabetic activity of Rosiglitazone has been demonstrated in animal models of type 2 diabetes in which hyperglycemia and/or impaired glucose tolerance is a consequence of insulin resistance in target tissues. Rosiglitazone reduces blood glucose concentrations and reduces hyperinsulinemia in the ob/ob obese mouse, db/db diabetic mouse, and fa/fa fatty Zucker rat. In animal models, the antidiabetic activity of Rosiglitazone was shown to be mediated by increased sensitivity to insulin s action in the liver, muscle, and adipose tissues. Pharmacological studies in animal models indicate that Rosiglitazone inhibits hepatic gluconeogenesis. The expression of the insulin-regulated glucose transporter GLUT-4 was increased in adipose tissue. Rosiglitazone did not induce hypoglycemia in animal models of type 2 diabetes and/or impaired glucose tolerance. 12.2 Pharmacodynamics Patients with lipid abnormalities were not excluded from clinical trials of Rosiglitazone maleate. In all 26-week controlled trials, across the recommended dose range, Rosiglitazone maleate as monotherapy was associated with increases in total cholesterol, LDL, and HDL and decreases in free fatty acids. These changes were statistically significantly different from placebo or glyburide controls (Table 7). Increases in LDL occurred primarily during the first 1 to 2 months of therapy with Rosiglitazone maleate and LDL levels remained elevated above baseline throughout the trials. In contrast, HDL continued to rise over time. As a result, the LDL/HDL ratio peaked after 2 months of therapy and then appeared to decrease over time. Because of the temporal nature of lipid changes, the 52-week glyburide-controlled study is most pertinent to assess long-term effects on lipids. At baseline, week 26, and week 52, mean LDL/HDL ratios were 3.1, 3.2, and 3.0, respectively, for Rosiglitazone maleate 4 mg twice daily. The corresponding values for glyburide were 3.2, 3.1, and 2.9. The differences in change from baseline between Rosiglitazone maleate and glyburide at week 52 were statistically significant. The pattern of LDL and HDL changes following therapy with Rosiglitazone maleate in combination with other hypoglycemic agents were generally similar to those seen with Rosiglitazone maleate in monotherapy. The changes in triglycerides during therapy with Rosiglitazone maleate were variable and were generally not statistically different from placebo or glyburide controls. Table 7. Summary of Mean Lipid Changes in 26-Week Placebo-Controlled and 52-Week Glyburide-Controlled Monotherapy Studies Placebo-Controlled Studies Week 26 Glyburide-Controlled Study Week 26 and Week 52 Placebo Rosiglitazone maleate Glyburide Titration Rosiglitazone maleate 8 mg 4 mg daily * 8 mg daily * Wk 26 Wk 52 Wk 26 Wk 52 Free fatty acids N 207 428 436 181 168 166 145 Baseline (mean) 18.1 17.5 17.9 26.4 26.4 26.9 26.6 % Change from baseline (mean) +0.2% -7.8% -14.7% -2.4% -4.7% -20.8% -21.5% LDL N 190 400 374 175 160 161 133 Baseline (mean) 123.7 126.8 125.3 142.7 141.9 142.1 142.1 % Change from baseline (mean) +4.8% +14.1% +18.6% -0.9% -0.5% +11.9% +12.1% HDL N 208 429 436 184 170 170 145 Baseline (mean) 44.1 44.4 43.0 47.2 47.7 48.4 48.3 % Change from baseline (mean) +8.0% +11.4% +14.2% +4.3% +8.7% +14.0% +18.5% * Once daily and twice daily dosing groups were combined. 12.3 Pharmacokinetics Maximum plasma concentration (C max ) and the area under the curve (AUC) of Rosiglitazone increase in a dose-proportional manner over the therapeutic dose range (Table 8). The elimination half-life is 3 to 4 hours and is independent of dose. Table 8. Mean (SD) Pharmacokinetic Parameters for Rosiglitazone Following Single Oral Doses (N = 32) Parameter 1 mg Fasting 2 mg Fasting 8 mg Fasting 8 mg Fed AUC 0-inf [ng hr/mL] 358 (112) 733 (184) 2,971 (730) 2,890 (795) C max [ng/mL] 76 (13) 156 (42) 598 (117) 432 (92) Half-life [hr] 3.16 (0.72) 3.15 (0.39) 3.37 (0.63) 3.59 (0.70) CL/F * [L/hr] 3.03 (0.87) 2.89 (0.71) 2.85 (0.69) 2.97 (0.81) * CL/F = Oral clearance. 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 C max and a delay in T max (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 [ 14 C]Rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, respectively. The plasma half-life of [ 14 C]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 Geriatric Results of the population pharmacokinetic analysis (n = 716> <65 years; n = 331 65 years) showed that age does not significantly affect the pharmacokinetics of Rosiglitazone. Gender Results of the population pharmacokinetics analysis showed that the mean oral clearance of Rosiglitazone in female patients (n = 405) was approximately 6% lower compared to male patients of the same body weight (n = 642). As monotherapy and in combination with metformin, Rosiglitazone maleate improved glycemic control in both males and females. In metformin combination studies, efficacy was demonstrated with no gender differences in glycemic response. In monotherapy studies, a greater therapeutic response was observed in females; however, in more obese patients, gender differences were less evident. For a given body mass index (BMI), females tend to have a greater fat mass than males. Since the molecular target PPARγ is expressed in adipose tissues, this differentiating characteristic may account, at least in part, for the greater response to Rosiglitazone maleate in females. Since therapy should be individualized, no dose adjustments are necessary based on gender alone. Hepatic Impairment Unbound oral clearance of Rosiglitazone was significantly lower in patients with moderate to severe liver disease (Child-Pugh Class B/C) compared to healthy subjects. As a result, unbound C max and AUC 0-inf were increased 2- and 3-fold, respectively. Elimination half-life for Rosiglitazone was about 2 hours longer in patients with liver disease, compared to healthy subjects. Therapy with Rosiglitazone maleate should 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 baseline [see Warnings and Precautions (5.6)] . Pediatric Pharmacokinetic parameters of Rosiglitazone in pediatric patients were established using a population pharmacokinetic analysis with sparse data from 96 pediatric patients in a single pediatric clinical trial including 33 males and 63 females with ages ranging from 10 to 17 years (weights ranging from 35 to 178.3 kg). Population mean CL/F and V/F of Rosiglitazone were 3.15 L/hr and 13.5 L, respectively. These estimates of CL/F and V/F were consistent with the typical parameter estimates from a prior adult population analysis. Renal Impairment There are no clinically relevant differences in the pharmacokinetics of Rosiglitazone in patients with mild to severe renal impairment or in hemodialysis-dependent patients compared to subjects with normal renal function. No dosage adjustment is therefore required in such patients receiving Rosiglitazone maleate. Since metformin is contraindicated in patients with renal impairment, coadministration of metformin with Rosiglitazone maleate is contraindicated in these patients. Race Results of a population pharmacokinetic analysis including subjects of Caucasian, black, and other ethnic origins indicate that race has no influence on the pharmacokinetics of Rosiglitazone. 12.4 Drug-Drug Interactions 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. Gemfibrozil Concomitant administration of gemfibrozil (600 mg twice daily), an inhibitor of CYP2C8, and Rosiglitazone (4 mg once daily) for 7 days increased Rosiglitazone AUC by 127%, compared to the administration of Rosiglitazone (4 mg once daily) alone. Given the potential for dose-related adverse events with Rosiglitazone, a decrease in the dose of Rosiglitazone may be needed when gemfibrozil is introduced [see Drug Interactions (7.1) ] . Rifampin Rifampin administration (600 mg once a day), an inducer of CYP2C8, for 6 days is reported to decrease Rosiglitazone AUC by 66%, compared to the administration of Rosiglitazone (8 mg) alone [see Drug Interactions (7.1)] . 4 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 C max of approximately 30%. In Japanese subjects, glyburide AUC and C max 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 C max 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. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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. 13.2 Animal Toxicology Heart weights were increased in mice (3 mg/kg/day), rats (5 mg/kg/day), and dogs (2 mg/kg/day) with Rosiglitazone treatments (approximately 5, 22, and 2 times human AUC at the maximum recommended human daily dose, respectively). Effects in juvenile rats were consistent with those seen in adults. Morphometric measurement indicated that there was hypertrophy in cardiac ventricular tissues, which may be due to increased heart work as a result of plasma volume expansion. 14 CLINICAL STUDIES 14.1 Monotherapy 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 prod great
spent time Rosiglitazone overlooked
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