ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. 6.1 Clinical Trial Experience Adult In clinical trials, approximately 9,900 patients with type diabetes have been treated with AVANDIA. Short-Term Trials of AVANDIA as Monotherapy and in Combination With Other Hypoglycemic Agents The incidence and types of adverse events reported in short-term clinical trials of AVANDIA as monotherapy are shown in Table 4. Table 4. Adverse Events (>=5% in Any Treatment Group) Reported by Patients in Short-Term Double-Blind Clinical Trials With AVANDIA as MonotherapyPreferred TermAVANDIA Monotherapy = 2,526%Placebo = 601%Metformin = 225%Sulfonylureas+ = 626%Upper respiratory tract infection 9.9 8.7 8.9 7.3 Injury 7.6 43.3 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 weeks to 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 AVANDIA was used in combination with sulfonylurea or metformin were similar to those during monotherapy with AVANDIA. 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 AVANDIA. In double-blind studies, anemia was reported in 1.9% of patients receiving AVANDIA 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 combination of AVANDIA and metformin (7.1%) and with combination of AVANDIA and sulfonylurea plus metformin (6.7%) compared to monotherapy with AVANDIA or in combination with 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 AVANDIA 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 AVANDIA mg in sulfonylurea combinations (12.4%) compared to other combinations, with the exception of insulin. Edema was reported in 14.7% of patients receiving AVANDIA 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 AVANDIA [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 (less than 1%) and few episodes of hypoglycemia were considered to be severe (less than 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 AVANDIA plus insulin and of 203 for insulin alone). Rates of hypoglycemia, confirmed by capillary blood glucose concentration less than or equal to 50 mg/dL, were 6% for insulin alone and 12% (4 mg) and 14% (8 mg) for insulin in combination with AVANDIA. [See Warnings and Precautions (5.10).] Long-Term Trial of AVANDIA as Monotherapy 4- to 6-year study (ADOPT) compared the use of AVANDIA (n 1,456), glyburide (n 1,441), and metformin (n 1,454) as monotherapy in patients recently diagnosed with type diabetes who were not previously treated with antidiabetic medication. Table 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 treatment groups. In ADOPT, fractures were reported in greater number of women treated with AVANDIA (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 treatment groups. Table 5. On-Therapy Adverse Events (Greater Than or Equal To Events/100 Patient-Years [PY]) in Any Treatment Group Reported in 4- to 6-Year Clinical Trial of AVANDIA as Monotherapy (ADOPT)AVANDIAGlyburideMetforminN 1,456N 1,441N 1,454PY 4,954PY 4,244PY 4,906Nasopharyngitis6.36.96.6Back pain5.14.95.3Arthralgia5.04.84.2Hypertension4.46.06.1Upper respiratory tract infection4.35.04.7Hypoglycemia2.913.03.4Diarrhea2.53.26.8 Pediatric AVANDIA has been evaluated for safety in single, active-controlled trial of pediatric patients with type diabetes in which 99 were treated with AVANDIA and 101 were treated with metformin. The most common adverse reactions (greater than 10%) without regard to causality for either AVANDIA 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 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 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 months following initiation of therapy with AVANDIA or following dose increase in AVANDIA. The time course and magnitude of decreases were similar in patients treated with 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 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 AVANDIA in adults [see Clinical Pharmacology (12.2)]. Small changes in serum lipid parameters were reported in children treated with AVANDIA for 24 weeks. Serum Transaminase Levels In pre-approval clinical studies in 4,598 patients treated with AVANDIA (3,600 patient-years of exposure) and in long-term 4- to 6-year study in 1,456 patients treated with AVANDIA (4,954 patient-years exposure), there was no evidence of drug-induced hepatotoxicity. In pre-approval controlled trials, 0.2% of patients treated with AVANDIA had elevations in ALT >3X the upper limit of normal compared to 0.2% on placebo and 0.5% on active comparators. The ALT elevations in patients treated with AVANDIA were reversible. Hyperbilirubinemia was found in 0.3% of patients treated with AVANDIA 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 AVANDIA (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 greater than 3X upper limit of normal (0.3 per 100 patient-years exposure). 6.3 Postmarketing ExperienceIn addition to adverse reactions reported from clinical trials, the events described below have been identified during post-approval use of AVANDIA. Because these events are reported voluntarily from population of unknown size, it is not possible to reliably estimate their frequency or to always establish causal relationship to drug exposure. In patients receiving thiazolidinedione therapy, serious adverse events with or without 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 AVANDIA of hepatitis, hepatic enzyme elevations to or more times the upper limit of normal, and hepatic failure with and without fatal outcome, although causality has not been established. There are postmarketing reports with AVANDIA of rash, pruritus, urticaria, angioedema, anaphylactic reaction, Stevens-Johnson syndrome, and new onset or worsening diabetic macular edema with decreased visual acuity [see Warnings and Precautions (5.7)].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of ActionRosiglitazone, member of the thiazolidinedione class of antidiabetic agents, improves glycemic control by improving insulin sensitivity. Rosiglitazone is highly selective and potent agonist for the peroxisome proliferator-activated receptor-gamma (PPAR). In humans, PPAR receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In addition, PPAR-responsive genes also participate in the regulation of fatty acid metabolism.Insulin resistance is common feature characterizing the pathogenesis of type diabetes. The antidiabetic activity of rosiglitazone has been demonstrated in animal models of type diabetes in which hyperglycemia and/or impaired glucose tolerance is 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 insulins 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 diabetes and/or impaired glucose tolerance.12.2 PharmacodynamicsPatients with lipid abnormalities were not excluded from clinical trials of AVANDIA. In all 26-week controlled trials, across the recommended dose range, AVANDIA 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 to months of therapy with AVANDIA and LDL levels remained elevated above baseline throughout the trials. In contrast, HDL continued to rise over time. As result, the LDL/HDL ratio peaked after 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 AVANDIA mg twice daily. The corresponding values for glyburide were 3.2, 3.1, and 2.9. The differences in change from baseline between AVANDIA and glyburide at week 52 were statistically significant.The pattern of LDL and HDL changes following therapy with AVANDIA in combination with other hypoglycemic agents were generally similar to those seen with AVANDIA in monotherapy.The changes in triglycerides during therapy with AVANDIA 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 StudiesPlacebo-ControlledWeek 26StudiesGlyburide-Studyand ControlledWeek 26Week 52PlaceboAVANDIAAVANDIAGlyburideTitrationAVANDIA8 mg4mg daily mg daily Wk 26 Wk 52 Wk 26 Wk 52 Free Fatty acidsN 207 428 436 181 168 166 145 Baselline (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% LDLN 190 400 374 175 160 161 133 Baselline (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% HDLN 208 429 436 184 170 170 145 Baselline (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 PharmacokineticsMaximum plasma concentration (Cmax) and the area under the curve (AUC) of rosiglitazone increase in dose-proportional manner over the therapeutic dose range (Table 8). The elimination half-life is to hours and is independent of dose. Table 8. Mean (SD) Pharmacokinetic Parameters for Rosiglitazone Following Single Oral Doses (N 32)Parameter1 mgFasting2 mgFasting mgFasting8 mgFedAUC0-inf [ngohr/mL]358(112) 733(184) 2,971(730) 2,890(795) Cmax [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 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 delay in Tmax (1.75 hours). These changes are not likely to be clinically significant; therefore, AVANDIA 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 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 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 Diabetes Population pharmacokinetic analyses from large clinical trials including 642 men and 405 women with type 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 less than 1.7-fold and less than 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 less than 65 years; = 331 greater than or equal to 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, AVANDIA 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, greater therapeutic response was observed in females; however, in more obese patients, gender differences were less evident. For given body mass index (BMI), females tend to have greater fat mass than males. Since the molecular target PPAR is expressed in adipose tissues, this differentiating characteristic may account, at least in part, for the greater response to AVANDIA 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 result, unbound Cmax and AUC0-inf were increased 2- and 3-fold, respectively. Elimination half-life for rosiglitazone was about hours longer in patients with liver disease, compared to healthy subjects. Therapy with AVANDIA should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT greater than 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 population pharmacokinetic analysis with sparse data from 96 pediatric patients in 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 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 AVANDIA. Since metformin is contraindicated in patients with renal impairment, coadministration of metformin with AVANDIA is contraindicated in these patients. Race Results of 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 lesser extent, 2C9. AVANDIA (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 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, decrease in the dose of rosiglitazone may be needed when gemfibrozil is introduced [see Drug Interactions (7.1)]. Rifampin Rifampin administration (600 mg once day), an inducer of CYP2C8, for 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 AVANDIA (2 mg twice daily) taken concomitantly with glyburide (3.75 to 10 mg/day) for days did not alter the mean steady-state 24-hour plasma glucose concentrations in diabetic patients stabilized on glyburide therapy. Repeat doses of AVANDIA (8 mg once daily) for days in healthy adult Caucasian subjects caused decrease in glyburide AUC and Cmax of approximately 30%. In Japanese subjects, glyburide AUC and Cmax slightly increased following coadministration of AVANDIA. Glimepiride Single oral doses of glimepiride in 14 healthy adult subjects had no clinically significant effect on the steady-state pharmacokinetics of AVANDIA. No clinically significant reductions in glimepiride AUC and Cmax were observed after repeat doses of AVANDIA (8 mg once daily) for days in healthy adult subjects. Metformin Concurrent administration of AVANDIA (2 mg twice daily) and metformin (500 mg twice daily) in healthy volunteers for days had no effect on the steady-state pharmacokinetics of either metformin or rosiglitazone. Acarbose Coadministration of acarbose (100 mg three times daily) for days in healthy volunteers had no clinically relevant effect on the pharmacokinetics of single oral dose of AVANDIA. Digoxin Repeat oral dosing of AVANDIA (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 AVANDIA had no clinically relevant effect on the steady-state pharmacokinetics of warfarin enantiomers. Ethanol single administration of moderate amount of alcohol did not increase the risk of acute hypoglycemia in type diabetes mellitus patients treated with AVANDIA. Ranitidine Pretreatment with ranitidine (150 mg twice daily for 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 PregnancyPregnancy Category C.All pregnancies have 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 DataRosiglitazone has been reported to cross the human placenta and be detectable in fetal tissue. The clinical significance of these findings is unknown. There are no adequate and well-controlled studies in pregnant women. AVANDIA should not be used during pregnancy.Animal StudiesThere 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 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 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 mg/kg/day (approximately 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 DeliveryThe effect of rosiglitazone on labor and delivery in humans is not known.8.3 Nursing MothersDrug-related material was detected in milk from lactating rats. It is not known whether AVANDIA is excreted in human milk. Because many drugs are excreted in human milk, AVANDIA should not be administered to nursing woman.8.4 Pediatric UseAfter placebo run-in including diet counseling, children with type diabetes mellitus, aged 10 to 17 years and with baseline mean body mass index (BMI) of 33 kg/m2, were randomized to treatment with mg twice daily of AVANDIA (n 99) or 500 mg twice daily of metformin (n 101) in 24-week, double-blind clinical trial. As expected, FPG decreased in patients naive 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 weeks of treatment, 49% of patients treated with AVANDIA and 55% of metformin-treated patients had their dose doubled if FPG >126 mg/dL. For the overall intent-to-treat population, at week 24, the mean change from baseline in HbA1c was -0.14% with AVANDIA and -0.49% with metformin. There was an insufficient number of patients in this study to establish statistically whether these observed mean treatment effects were similar or different. Treatment effects differed for patients naive 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%NaivePatientsPreviously-Treated PatientsMetforminN 40RosiglitazoneN 45MetforminN 43RosiglitazoneN 32FPG (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 baseline43% 27% 44% 28% HbAlc (%)Baseline (mean) 8.3 8.2 8.8 8.5 Change from baseline (mean)-0.7 -0.5 -0.4 0.1 Adjusted treatment difference (rosiglitazone-metformin)+ (95% CI) 0.2(-0.6, 0.9) 0.5(-0.2, 1.3) of patients with >=0.7% decrease from baseline 63% 52% 54% 31% Change from baseline means are least squares means adjusting for baseline HbA1c, gender, and region.+ Positive values for the difference favor metformin.Treatment differences depended on baseline BMI or weight such that the effects of AVANDIA and metformin appeared more closely comparable among heavier patients. The median weight gain was 2.8 kg with rosiglitazone and 0.2 kg with metformin [see Warnings and Precautions (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 24-Week Study of AVANDIA and Metformin in Pediatric Patients -- Drug-Naive Subgroup8.5 Geriatric UseResults 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 (greater than or equal to 65 years) and younger (less than 65 years) patients were observed.. image of Figure 3.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. 5.1 Cardiac FailureAVANDIA, 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 and II treated with AVANDIA have an increased risk of cardiovascular events. 52-week, double-blind, placebo-controlled echocardiographic study was conducted in 224 patients with type diabetes mellitus and NYHA Class or II CHF (ejection fraction <=45%) on background antidiabetic and CHF therapy. An independent committee conducted 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 AVANDIA compared to placebo during the 52-week study. (See Table 1.) Table 1. Emergent Cardiovascular Adverse Events in Patients With Congestive Heart Failure (NYHA Class and II) Treated With AVANDIA or Placebo (in Addition to Background Antidiabetic and CHF Therapy) Events AVANDIA Placebo = 110n (%)N 114n (%)Adjudicated Cardiovascular deaths (5%) (4%) CHF worsening (6%) (4%) with overnight hospitalization (5%) (4%) without overnight hospitalization (2%) (0%) New or worsening edema 28 (25%) 10 (9%) New or worsening dyspnea 29 (26%) 19 (17%) Increase in CHF medication 36 (33%) 20 (18%) Cardiovascular hospitalization21 (19%) 15 (13%) Investigator-reported, non-adjudicatedIschemic adverse events10 (9%) (4%) Myocardial infarction5 (5%) (2%) Angina6 (5%) (3%) Includes hospitalization for any cardiovascular reason. Initiation of AVANDIA in patients with established NYHA Class III or IV heart failure is contraindicated. AVANDIA is not recommended in patients with symptomatic heart failure. [See Boxed Warning.] Patients experiencing acute coronary syndromes have not been studied in controlled clinical trials. In view of the potential for development of heart failure in patients having an acute coronary event, initiation of AVANDIA is not recommended for patients experiencing an acute coronary event, and discontinuation of AVANDIA during this acute phase should be considered. Patients with NYHA Class III and IV cardiac status (with or without CHF) have not been studied in controlled clinical trials. AVANDIA is not recommended in patients with NYHA Class III and IV cardiac status. 5.2 Myocardial Ischemia Meta-Analysis of Myocardial Ischemia in Group of 42 Clinical Trials meta-analysis was conducted retrospectively to assess cardiovascular adverse events reported across 42 double-blind, randomized, controlled clinical trials (mean duration months).1 These studies had been conducted to assess glucose-lowering efficacy in type 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 AVANDIA versus placebo monotherapy) and add-on trials (AVANDIA or placebo, added to sulfonylurea, metformin, or insulin). Active control studies included monotherapy trials (monotherapy with AVANDIA versus sulfonylurea or metformin monotherapy) and add-on trials (AVANDIA plus sulfonylurea or AVANDIA plus metformin, versus sulfonylurea plus metformin). total of 14,237 patients were included (8,604 in treatment groups containing AVANDIA, 5,633 in comparator groups), with 4,143 patient-years of exposure to AVANDIA and 2,675 patient-years of exposure to comparator. Myocardial ischemic events included angina pectoris, angina pectoris aggravated, unstable angina, cardiac arrest, chest pain, coronary artery occlusion, dyspnea, myocardial infarction, coronary thrombosis, myocardial ischemia, coronary artery disease, and coronary artery disorder. In this analysis, an increased risk of myocardial ischemia with AVANDIA versus pooled comparators was observed (2% AVANDIA versus 1.5% comparators, odds ratio 1.4, 95% confidence interval [CI] 1.1, 1.8). An increased risk of myocardial ischemic events with AVANDIA was observed in the placebo-controlled studies, but not in the active-controlled studies. (See Figure 1.) greater increased risk of myocardial ischemic events was observed in studies where AVANDIA was added to insulin (2.8% for AVANDIA plus insulin versus 1.4% for placebo plus insulin, [OR 2.1, 95% CI 0.9, 5.1]). This increased risk reflects difference of 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 Ratios (95% Confidence Intervals) for Myocardial Ischemic Events in the Meta-Analysis of 42 Clinical Trials greater increased risk of myocardial ischemia was also observed in patients who received AVANDIA and background nitrate therapy. For AVANDIA (N 361) versus control (N 244) in nitrate users, the odds ratio was 2.9 (95% CI 1.4, 5.9), while for non-nitrate users (about 14,000 patients total), the odds ratio was 1.3 (95% CI 0.9, 1.7). This increased risk represents difference of 12 myocardial ischemic events per 100 patient-years (95% CI 3.3, 21.4). Most of the nitrate users had established coronary heart disease. Among patients with known coronary heart disease who were not on nitrate therapy, an increased risk of myocardial ischemic events for AVANDIA versus comparator was not demonstrated. image of Figure 1. Forest Plot of Odds Ratios.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 MonotherapyIn clinical studies, treatment with AVANDIA resulted in an improvement in glycemic control, as measured by FPG and HbA1c, with concurrent reduction in insulin and C-peptide. Postprandial glucose and insulin were also reduced. This is consistent with the mechanism of action of AVANDIA as an insulin sensitizer. The maximum recommended daily dose is mg. Dose-ranging studies suggested that no additional benefit was obtained with total daily dose of 12 mg. Short-Term Clinical Studies total of 2,315 patients with type diabetes, previously treated with diet alone or antidiabetic medication(s), were treated with AVANDIA as monotherapy in double-blind studies, which included two 26-week placebo-controlled studies, one 52-week glyburide-controlled study, and placebo-controlled dose-ranging studies of to 12 weeks duration. Previous antidiabetic medication(s) were withdrawn and patients entered 2 to week placebo run-in period prior to randomization. Two 26-week, double-blind, placebo-controlled trials, in patients with type 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. Table 9. Glycemic Parameters in 26-Week Placebo-Controlled TrialPlaceboAVANDIAAVANDIAAVANDIAAVANDIA4 mg once daily2 mg twice daily8 mg once daily4 mg twice dailyN 173 = 180 = 186 = 181 = 187 FPG (mg/dL)Baseline (mean) 225 229 225 228 228 Change from baseline (mean) -25 -35 -42 -55 Difference from placebo (adjusted mean) -- -31 -43 -49 -62 of patients with >=30 mg/dL decrease from baseline 19% 45% 54% 58% 70% HbAlc (%)Baseline (mean) 8.9 8.9 8.9 8.9 9.0 Change from baseline (mean) 0.8 0.0 -0.1 -0.3 -0.7 Difference from placebo (adjusted mean) -- -0.8 -0.9 -1.1 -1.5 of patients with >=0.7% decrease from baseline 9% 28% 29% 39% 54% less than 0.0001 compared to placebo. When administered at the same total daily dose, AVANDIA 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 mg once daily and mg twice daily doses was not statistically significant. Long-Term Clinical Studies Long-term maintenance of effect was evaluated in 52-week, double-blind, glyburide-controlled trial in patients with type diabetes. Patients were randomized to treatment with AVANDIA mg twice daily (N 195) or AVANDIA 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 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 statistically significant improvement in glycemic control from baseline (Figure 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 AVANDIA mg twice daily; -25.4 mg/dL and -0.27% with AVANDIA mg twice daily; and -30.0 mg/dL and -0.72% with glyburide. For HbA1c, the difference between AVANDIA mg twice daily and glyburide was not statistically significant at week 52. The initial fall in FPG with glyburide was greater than with AVANDIA; however, this effect was less durable over time. The improvement in glycemic control seen with AVANDIA mg twice daily at week 26 was maintained through week 52 of the study. Figure 4. Mean FPG Over Time in 52-Week Glyburide-Controlled Study Figure 5. Mean HbA1c Over Time in 52-Week Glyburide-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 AVANDIA. The improvements in glycemic control were associated with mean weight gain of 1.75 kg and 2.95 kg for patients treated with mg and mg twice daily of AVANDIA, respectively, versus 1.9 kg in glyburide-treated patients. In patients treated with AVANDIA, C-peptide, insulin, pro-insulin, and pro-insulin split products were significantly reduced in dose-ordered fashion, compared to an increase in the glyburide-treated patients. Diabetes Outcome Progression Trial (ADOPT) was multicenter, double-blind, controlled trial (N 4,351) conducted over to years to compare the safety and efficacy of AVANDIA, metformin, and glyburide monotherapy in patients recently diagnosed with type 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 AVANDIA 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 maximum of mg twice daily for AVANDIA, 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 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 years was 15% with AVANDIA, 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 AVANDIA, 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. 14.2 Combination With Metformin or SulfonylureaThe addition of AVANDIA to either metformin or sulfonylurea resulted in significant reductions in hyperglycemia compared to either of these agents alone. These results are consistent with an additive effect on glycemic control when AVANDIA is used as combination therapy. Combination With Metformin total of 670 patients with type diabetes participated in two 26-week, randomized, double-blind, placebo/active-controlled studies designed to assess the efficacy of AVANDIA in combination with metformin. AVANDIA, administered in either once daily or twice daily dosing regimens, was added to the therapy of patients who were inadequately controlled on 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 mg of AVANDIA once daily, mg of AVANDIA once daily, or placebo in addition to metformin. statistically significant improvement in FPG and HbA1c was observed in patients treated with the combinations of metformin and mg of AVANDIA once daily and mg of AVANDIA once daily, versus patients continued on metformin alone (Table 10). Table 10. Glycemic Parameters in 26-Week Combination Study of AVANDIA Plus MetforminMetforminAVANDIAAVANDIA4 mg once daily metformin8 mg once daily metforminN 113 = 116 = 110 FPG (mg/dL)Baseline (mean) 214 215 220 Change from baseline (mean) -33 -48 Difference from metformin alone (adjusted mean) -- -40 -53 of patients with >=30 mg/dL decrease from baseline 20% 45% 61% HbAlc (%)Baseline (mean) 8.6 8.9 8.9 Change from baseline (mean) 0.5 -0.6 -0.8 Difference from metformin alone (adjusted mean) -- -1.0 -1.2 of patients with >=0.7% decrease from baseline11% 45% 52% less than 0.0001 compared to metformin. In second 26-week study, patients with type diabetes inadequately controlled on 2.5 grams/day of metformin who were randomized to receive the combination of AVANDIA mg twice daily and metformin (N 105) showed statistically significant improvement in glycemic control with mean treatment effect for FPG of -56 mg/dL and mean treatment effect for HbA1c of -0.8% over metformin alone. The combination of metformin and AVANDIA resulted in lower levels of FPG and HbA1c than either agent alone. Patients who were inadequately controlled on maximum dose (2.5 grams/day) of metformin and who were switched to monotherapy with AVANDIA 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 total of 3,457 patients with type 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 AVANDIA in combination with sulfonylurea. AVANDIA mg, mg, or mg daily was administered, either once daily (3 studies) or in divided doses twice daily (7 studies), to patients inadequately controlled on submaximal or maximal dose of sulfonylurea. In these studies, the combination of AVANDIA mg or mg daily (administered as single or twice daily divided doses) and sulfonylurea significantly reduced FPG and HbA1c compared to placebo plus sulfonylurea or further up-titration of the sulfonylurea. Table 11 shows pooled data for studies in which AVANDIA added to sulfonylurea was compared to placebo plus sulfonylurea. Table 11. Glycemic Parameters in 24- to 26-Week Combination Studies of AVANDIA Plus SulfonylureaTwice Daily Divided Dosing(5 Studies) Sulfonylurea AVANDIA2 mg twice daily +sulfonylurea Sulfonylurea AVANDIA4 mg twice daily +sulfonylurea = 397 = 497 = 248 = 346 FPG (mg/dL)Baseline (mean) 204 198 188 187 Change from baseline (mean) 11 -29 -43 Difference from sulfonylurea alone (adjusted mean) -- -42 -- -53 of patients with >=30 mg/dL decrease from baseline 17% 49% 15% 61% HbAlc (%)Baseline (mean) 9.4 9.5 9.3 9.6 Change from baseline (mean) 0.2 -1.0 0.0 -1.6 Difference from sulfonylurea alone (adjusted mean) -- -1.1 -- -1.4 of patients with >=0.7% decrease from baseline 21% 60% 23% 75% Once Daily Dosing(3 Studies) Sulfonylurea AVANDIA4 mg once daily +sulfonylurea Sulfonylurea AVANDIA8 mg once daily +sulfonylurea = 172 = 172 = 173 = 176 FPG (mg/dL)Baseline (mean) 198 206 188 192 Change from baseline (mean) 17 -25 17 -43 Difference from sulfonylurea alone (adjusted mean) -- -47 -- -66 of patients with >=30 mg/dL decrease from baseline 17% 48% 19% 55% HbAlc (%)Baseline (mean) 8.6 8.8 8.9 8.9 Change from baseline (mean) 0.4 -0.5 0.1 -1.2 Difference from sulfonylurea alone (adjusted mean) -- -0.9 -- -1.4 of patients with >=0.7% decrease from baseline 11% 36% 20% 68% less than 0.0001 compared to sulfonylurea alone. One of the 24- to 26-week studies included patients who were inadequately controlled on maximal doses of glyburide and switched to mg of AVANDIA daily as monotherapy; in this group, loss of glycemic control was demonstrated, as evidenced by increases in FPG and HbA1c. In 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 AVANDIA (n 115, mg once daily to mg as needed) or to continued up-titration of glipizide (n 110), to maximum of 20 mg twice daily. Mean baseline FPG and HbA1c were 157 mg/dL and 7.72%, respectively, for the AVANDIA 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 significantly lower proportion of patients (2%) on AVANDIA plus glipizide compared to patients in the glipizide up-titration arm (28.7%). About 78% of the patients on combination therapy completed the 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 mean of 132 mg/dL for FPG and mean of 6.98% for HbA1c compared to no change on the glipizide arm. 14.3 Combination With Sulfonylurea Plus MetforminIn two 24- to 26-week, double-blind, placebo-controlled, studies designed to assess the efficacy and safety of AVANDIA in combination with sulfonylurea plus metformin, AVANDIA mg or mg daily, was administered in divided doses twice daily, to patients inadequately controlled on submaximal (10 mg) and maximal (20 mg) doses of glyburide and maximal dose of metformin (2 g/day). statistically significant improvement in FPG and HbA1c was observed in patients treated with the combinations of sulfonylurea plus metformin and mg of AVANDIA and mg of AVANDIA versus patients continued on sulfonylurea plus metformin, as shown in Table 12. Table 12. Glycemic Parameters in 26-Week Combination Study of AVANDIA Plus Sulfonylurea and MetforminSulfonylurea +metformin AVANDIA2 mg twice daily sulfonylurea +metformin AVANDIA4 mg twice daily sulfonylurea +metformin = 273 =276 = 277 FPG (mg/dL)Baseline (mean) 189 190 192 Change from baseline (mean) 14 -19 -40 Difference from sulfonylurea plus metformin(adjusted mean) -- -30 -52 of patients with >=30 mg/dL decrease from baseline16% 46% 62% HbAlc (%)Baseline (mean) 8.7 8.6 8.7 Change from baseline (mean) 0.2 -0.4 -0.9 Difference from sulfonylurea plus metforminadjusted mean) -- -0.6 -1.1 of patients with >=0.7% decrease from baseline16% 39% 63% less than 0.0001 compared to placebo. image of Figure 4. image of Figure 5.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. 17.1 Patient AdvicePatients should be informed of the following: AVANDIA is not recommended for patients with symptoms of heart failure. Patients with more severe heart failure (NYHA Class or 4) cannot start AVANDIA as the risks exceed any potential benefits in such patients. Results of set of clinical studies suggest that treatment with AVANDIA is associated with an increased risk for myocardial ischemic events, such as angina or myocardial infarction (heart attack), especially in patients taking insulin or nitrates. Because this risk has not been confirmed or excluded in different long-term trials, definitive conclusions regarding this risk await completion of an adequately-designed cardiovascular outcome study. AVANDIA is not recommended for patients who are taking nitrates or insulin. There are multiple medications available to treat type diabetes. The benefits and risks of each available diabetes medication should be taken into account when choosing particular diabetes medication for given patient. There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with AVANDIA or any other oral antidiabetic drug. Management of type diabetes should include diet control. Caloric restriction, weight loss, and exercise are essential for the proper treatment of the diabetic patient because they help improve insulin sensitivity. This is important not only in the primary treatment of type diabetes, but in maintaining the efficacy of drug therapy. It is important to adhere to dietary instructions and to regularly have blood glucose and glycosylated hemoglobin tested. It can take weeks to see reduction in blood glucose and to months to see the full effect of AVANDIA. Blood will be drawn to check their liver function prior to the start of therapy and periodically thereafter per the clinical judgment of the healthcare professional. Patients with unexplained symptoms of nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine should immediately report these symptoms to their physician. Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on AVANDIA should immediately report these symptoms to their physician. AVANDIA can be taken with or without meals. When using AVANDIA in combination with other hypoglycemic agents, the risk of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members. Therapy with AVANDIA, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As result, these patients may be at an increased risk for pregnancy while taking AVANDIA. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical studies so the frequency of this occurrence is not known. 17.2 FDA-Approved Medication GuideSee separate leaflet. AVANDIA and TILTAB are registered trademarks of GlaxoSmithKline. GlaxoSmithKline Research Triangle Park, NC 27709 (C)2009, GlaxoSmithKline. All rights reserved. medication guideAVANDIA(R) (ah-VAN-dee-a) rosiglitazone maleate tablets Read this Medication Guide carefully before you start taking AVANDIA and each time you get refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about AVANDIA, ask your doctor or pharmacist. What is the most important information should know about AVANDIA AVANDIA is prescription medicine to treat adults with diabetes. It helps to control high blood sugar. (See What is AVANDIA). It is important that you take AVANDIA exactly how it is prescribed by your doctor to best treat your diabetes. AVANDIA may cause serious side effects, including: New or worse heart failure AVANDIA can cause your body to keep extra fluid (fluid retention), which leads to swelling (edema) and weight gain. Extra body fluid can make some heart problems worse or lead to heart failure. Heart failure means your heart does not pump blood well enough. If you have severe heart failure, you cannot start AVANDIA. If you have heart failure with symptoms (such as shortness of breath or swelling), even if these symptoms are not severe, AVANDIA may not be right for you. Call your doctor right away if you have any of the following: swelling or fluid retention, especially in the ankles or legs shortness of breath or trouble breathing, especially when you lie down an unusually fast increase in weight unusual tiredness Other heart problems AVANDIA may raise the risk of heart problems related to reduced blood flow to the heart. These include possible increases in the risk of heart-related chest pain (angina) or heart attack (myocardial infarction). This risk seemed to be higher in people who took AVANDIA with insulin or with nitrate medicines. Most people who take insulin or nitrate medicines should not also take AVANDIA. If you have chest pain or feeling of chest pressure, get medical help right away, no matter what diabetes medicines you are taking. People with diabetes have greater risk for heart problems. It is important to work with your doctor to manage other conditions, such as high blood pressure or high cholesterol. AVANDIA can have other serious side effects. Be sure to read the section below What are possible side effects of AVANDIA. What is AVANDIA AVANDIA is prescription medicine used with diet and exercise to treat adults with type (adult-onset or non-insulin dependent) diabetes mellitus (high blood sugar). AVANDIA helps to control high blood sugar. AVANDIA may be used alone or with other diabetes medicines. AVANDIA can help your body respond better to insulin made in your body. AVANDIA does not cause your body to make more insulin. For AVANDIA to work best, it is very important to exercise, lose extra weight, and follow the diet recommended by your doctor. AVANDIA has not been studied enough in children under 18 years of age to know if it is safe or effective in children. AVANDIA is not for people with type diabetes mellitus or to treat condition called diabetic ketoacidosis. Who should not take AVANDIA Many people with heart failure should not start taking AVANDIA. See What should tell my doctor before taking AVANDIA. What should tell my doctor before taking AVANDIA Before starting AVANDIA, ask your doctor about what the choices are for diabetes medicines, and what the expected benefits and possible risks are for you in particular. Before taking AVANDIA, tell your doctor about all your medical conditions, including if you: have heart problems or heart failure.have type (juvenile) diabetes or had diabetic ketoacidosis. These conditions should be treated with insulin. have type of diabetic eye disease called macular edema (swelling of the back of the eye). have liver problems. Your doctor should do blood tests to check your liver before you start taking AVANDIA and during treatment as needed. had liver problems while taking REZULIN(R) (troglitazone), another medicine for diabetes.are pregnant or plan to become pregnant. AVANDIA should not be used during pregnancy. It is not known if AVANDIA can harm your unborn baby. You and your doctor should talk about the best way to control your diabetes during pregnancy. If you are premenopausal woman (before the change of life) who does not have regular monthly periods, AVANDIA may increase your chances of becoming pregnant. Talk to your doctor about birth control choices while taking AVANDIA. Tell your doctor right away if you become pregnant while taking AVANDIA. are breast-feeding or planning to breast-feed. It is not known if AVANDIA passes into breast milk. You should not use AVANDIA while breast-feeding. Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins or herbal supplements. AVANDIA and certain other medicines can affect each other and may lead to serious side effects including high or low blood sugar, or heart problems. Especially tell your doctor if you take: insulin.nitrate medicines such as nitroglycerin or isosorbide to treat type of chest pain called angina. any medicines for high blood pressure, high cholesterol or heart failure, or for prevention of heart disease or stroke. Know the medicines you take. Keep list of your medicines and show it to your doctor and pharmacist before you start new medicine. They will tell you if it is alright to take AVANDIA with other medicines. How should take AVANDIA Take AVANDIA exactly as prescribed. Your doctor will tell you how many tablets to take and how often. The usual daily starting dose is mg day taken one time each day or mg taken two times each day. Your doctor may need to adjust your dose until your blood sugar is better controlled. AVANDIA may be prescribed alone or with other diabetes medicines. This will depend on how well your blood sugar is controlled. Take AVANDIA with or without food. It can take weeks for AVANDIA to start lowering blood sugar. It may take to months to see the full effect on your blood sugar level. If you miss dose of AVANDIA, take it as soon as you remember, unless it is time to take your next dose. Take your next dose at the usual time. Do not take double doses to make up for missed dose. If you take too much AVANDIA, call your doctor or poison control center right away. Test your blood sugar regularly as your doctor tells you. Diet and exercise can help your body use its blood sugar better. It is important to stay on your recommended diet, lose extra weight, and get regular exercise while taking AVANDIA. Your doctor should do blood tests to check your liver before you start AVANDIA and during treatment as needed. Your doctor should also do regular blood sugar tests (for example, A1C) to monitor your response to AVANDIA. What are possible side effects of AVANDIA AVANDIA may cause serious side effects including: New or worse heart failure. See What is the most important information should know about AVANDIA. Other heart problems. AVANDIA may increase the risk of heart problems related to reduced blood flow to the heart. These include possible increases in the risk of heart-related chest pain (angina) or heart attack (myocardial infarction). See What is the most important information should know about AVANDIA. Swelling (edema). AVANDIA can cause swelling due to fluid retention. See What is the most important information should know about AVANDIA. Weight gain. AVANDIA can cause weight gain that may be due to fluid retention or extra body fat. Weight gain can be serious problem for people with certain conditions including heart problems. See What is the most important information should know about AVANDIA. Liver problems. It is important for your liver to be working normally when you take AVANDIA. Your doctor should do blood tests to check your liver before you start taking AVANDIA and during treatment as needed. Call your doctor right away if you have unexplained symptoms such as:nausea or vomiting stomach pain unusual or unexplained tiredness loss of appetite dark urine yellowing of your skin or the whites of your eyes. Macular edema (a diabetic eye disease with swelling in the back of the eye). Tell your doctor right away if you have any changes in your vision. Your doctor should check your eyes regularly. Very rarely, some people have experienced vision changes due to swelling in the back of the eye while taking AVANDIA. Fractures (broken bones), usually in the hand, upper arm or foot, in females. Talk to your doctor for advice on how to keep your bones healthy. Low red blood cell count (anemia).Low blood sugar (hypoglycemia). Lightheadedness, dizziness, shakiness or hunger may mean that your blood sugar is too low. This can happen if you skip meals, if you use another medicine that lowers blood sugar, or if you have certain medical problems. Call your doctor if low blood sugar levels are problem for you. Ovulation (release of egg from an ovary in woman) leading to pregnancy. Ovulation may happen in premenopausal women who do not have regular monthly periods. This can increase the chance of pregnancy. See What should tell my doctor before taking AVANDIA. The most common side effects of AVANDIA reported in clinical trials included cold-like symptoms and headache. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store AVANDIA Store AVANDIA at room temperature, 59 to 86F (15 to 30C). Keep AVANDIA in the container it comes in. Safely, throw away AVANDIA that is out of date or no longer needed. Keep AVANDIA and all medicines out of the reach of children. General information about AVANDIA Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use AVANDIA for condition for which it was not prescribed. Do not give AVANDIA to other people, even if they have the same symptoms you have. It may harm them. This Medication Guide summarizes important information about AVANDIA. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about AVANDIA that is written for healthcare professionals. You can also find out more about AVANDIA by calling 1-888-825-5249 or visiting the website www.avandia.com. What are the ingredients in AVANDIA Active Ingredient: Rosiglitazone maleate. Inactive Ingredients: Hypromellose 2910, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 3000, sodium starch glycolate, titanium dioxide, triacetin, and or more of the following: Synthetic red and yellow iron oxides and talc. Always check to make sure that the medicine you are taking is the correct one. AVANDIA tablets are triangles with rounded corners and look like this: mg strength tablets pink with SB on one side and 2 on the other. mg strength tablets orange with SB on one side and 4 on the other. mg strength tablets red-brown with SB on one side and 8 on the other. AVANDIA is registered trademark of GlaxoSmithKline. REZULIN is registered trademark of Parke-Davis Pharmaceuticals Ltd. This Medication Guide has been approved by the U.S. Food and Drug Administration. GlaxoSmithKline Research Triangle Park, NC 27709 (C)2008, GlaxoSmithKline. All rights reserved. October 2008 AVD:4MG AVANDIA is not recommended for patients with symptoms of heart failure. Patients with more severe heart failure (NYHA Class or 4) cannot start AVANDIA as the risks exceed any potential benefits in such patients. Results of set of clinical studies suggest that treatment with AVANDIA is associated with an increased risk for myocardial ischemic events, such as angina or myocardial infarction (heart attack), especially in patients taking insulin or nitrates. Because this risk has not been confirmed or excluded in different long-term trials, definitive conclusions regarding this risk await completion of an adequately-designed cardiovascular outcome study. AVANDIA is not recommended for patients who are taking nitrates or insulin. There are multiple medications available to treat type diabetes. The benefits and risks of each available diabetes medication should be taken into account when choosing particular diabetes medication for given patient. There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with AVANDIA or any other oral antidiabetic drug. Management of type diabetes should include diet control. Caloric restriction, weight loss, and exercise are essential for the proper treatment of the diabetic patient because they help improve insulin sensitivity. This is important not only in the primary treatment of type diabetes, but in maintaining the efficacy of drug therapy. It is important to adhere to dietary instructions and to regularly have blood glucose and glycosylated hemoglobin tested. It can take weeks to see reduction in blood glucose and to months to see the full effect of AVANDIA. Blood will be drawn to check their liver function prior to the start of therapy and periodically thereafter per the clinical judgment of the healthcare professional. Patients with unexplained symptoms of nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine should immediately report these symptoms to their physician. Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on AVANDIA should immediately report these symptoms to their physician. AVANDIA can be taken with or without meals. When using AVANDIA in combination with other hypoglycemic agents, the risk of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members. Therapy with AVANDIA, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As result, these patients may be at an increased risk for pregnancy while taking AVANDIA. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical studies so the frequency of this occurrence is not known. AVANDIA can cause your body to keep extra fluid (fluid retention), which leads to swelling (edema) and weight gain. Extra body fluid can make some heart problems worse or lead to heart failure. Heart failure means your heart does not pump blood well enough. If you have severe heart failure, you cannot start AVANDIA. If you have heart failure with symptoms (such as shortness of breath or swelling), even if these symptoms are not severe, AVANDIA may not be right for you. swelling or fluid retention, especially in the ankles or legs shortness of breath or trouble breathing, especially when you lie down an unusually fast increase in weight unusual tiredness If you have chest pain or feeling of chest pressure, get medical help right away, no matter what diabetes medicines you are taking. People with diabetes have greater risk for heart problems. It is important to work with your doctor to manage other conditions, such as high blood pressure or high cholesterol. For AVANDIA to work best, it is very important to exercise, lose extra weight, and follow the diet recommended by your doctor. AVANDIA has not been studied enough in children under 18 years of age to know if it is safe or effective in children. AVANDIA is not for people with type diabetes mellitus or to treat condition called diabetic ketoacidosis. have heart problems or heart failure.. have type (juvenile) diabetes or had diabetic ketoacidosis. These conditions should be treated with insulin. have type of diabetic eye disease called macular edema (swelling of the back of the eye). have liver problems. Your doctor should do blood tests to check your liver before you start taking AVANDIA and during treatment as needed. had liver problems while taking REZULIN(R) (troglitazone), another medicine for diabetes.. are pregnant or plan to become pregnant. AVANDIA should not be used during pregnancy. It is not known if AVANDIA can harm your unborn baby. You and your doctor should talk about the best way to control your diabetes during pregnancy. If you are premenopausal woman (before the change of life) who does not have regular monthly periods, AVANDIA may increase your chances of becoming pregnant. Talk to your doctor about birth control choices while taking AVANDIA. Tell your doctor right away if you become pregnant while taking AVANDIA. are breast-feeding or planning to breast-feed. It is not known if AVANDIA passes into breast milk. You should not use AVANDIA while breast-feeding. insulin.. nitrate medicines such as nitroglycerin or isosorbide to treat type of chest pain called angina. any medicines for high blood pressure, high cholesterol or heart failure, or for prevention of heart disease or stroke.. Take AVANDIA exactly as prescribed. Your doctor will tell you how many tablets to take and how often. The usual daily starting dose is mg day taken one time each day or mg taken two times each day. Your doctor may need to adjust your dose until your blood sugar is better controlled. AVANDIA may be prescribed alone or with other diabetes medicines. This will depend on how well your blood sugar is controlled. Take AVANDIA with or without food. It can take weeks for AVANDIA to start lowering blood sugar. It may take to months to see the full effect on your blood sugar level. If you miss dose of AVANDIA, take it as soon as you remember, unless it is time to take your next dose. Take your next dose at the usual time. Do not take double doses to make up for missed dose. If you take too much AVANDIA, call your doctor or poison control center right away. Test your blood sugar regularly as your doctor tells you. Diet and exercise can help your body use its blood sugar better. It is important to stay on your recommended diet, lose extra weight, and get regular exercise while taking AVANDIA. Your doctor should do blood tests to check your liver before you start AVANDIA and during treatment as needed. Your doctor should also do regular blood sugar tests (for example, A1C) to monitor your response to AVANDIA. New or worse heart failure. See What is the most important information should know about AVANDIA. Other heart problems. AVANDIA may increase the risk of heart problems related to reduced blood flow to the heart. These include possible increases in the risk of heart-related chest pain (angina) or heart attack (myocardial infarction). See What is the most important information should know about AVANDIA. Swelling (edema). AVANDIA can cause swelling due to fluid retention. See What is the most important information should know about AVANDIA. Weight gain. AVANDIA can cause weight gain that may be due to fluid retention or extra body fat. Weight gain can be serious problem for people with certain conditions including heart problems. See What is the most important information should know about AVANDIA. Liver problems. It is important for your liver to be working normally when you take AVANDIA. Your doctor should do blood tests to check your liver before you start taking AVANDIA and during treatment as needed. Call your doctor right away if you have unexplained symptoms such as:nausea or vomiting stomach pain unusual or unexplained tiredness loss of appetite dark urine yellowing of your skin or the whites of your eyes. nausea or vomiting stomach pain unusual or unexplained tiredness loss of appetite dark urine yellowing of your skin or the whites of your eyes. Macular edema (a diabetic eye disease with swelling in the back of the eye). Tell your doctor right away if you have any changes in your vision. Your doctor should check your eyes regularly. Very rarely, some people have experienced vision changes due to swelling in the back of the eye while taking AVANDIA. Fractures (broken bones), usually in the hand, upper arm or foot, in females. Talk to your doctor for advice on how to keep your bones healthy. Low red blood cell count (anemia).. Low blood sugar (hypoglycemia). Lightheadedness, dizziness, shakiness or hunger may mean that your blood sugar is too low. This can happen if you skip meals, if you use another medicine that lowers blood sugar, or if you have certain medical problems. Call your doctor if low blood sugar levels are problem for you. Ovulation (release of egg from an ovary in woman) leading to pregnancy. Ovulation may happen in premenopausal women who do not have regular monthly periods. This can increase the chance of pregnancy. See What should tell my doctor before taking AVANDIA. Store AVANDIA at room temperature, 59 to 86F (15 to 30C). Keep AVANDIA in the container it comes in. Safely, throw away AVANDIA that is out of date or no longer needed. Keep AVANDIA and all medicines out of the reach of children.