FDA label 6eb0cad1-596d-1562-e053-2991aa0a2fa4

WARNING: CONGESTIVE HEART FAILURE Thiazolidinediones , including pioglitazone tablets, cause or exacerbate congestive heart failure in some patients [see WARNINGS AND PRECAUTIONS (5.1) ]. After initiation of pioglitazone tablets and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea and/or edema). If heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone tablets must be considered. Pioglitazone tablets are not recommended in patients with symptomatic heart failure. Initiation of pioglitazone tablets in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.1) ]. WARNING: CONGESTIVE HEART FAILURE See full prescribing information for complete boxed warning Thiazolidinediones , including pioglitazone tablets, cause or exacerbate congestive heart failure in some patients. ( 5.1 ) After initiation of pioglitazone tablets and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea and/or edema). If heart failure develops, it should be managed according to current standards of care and discontinue or dose reduction of pioglitazone tablets must be considered. ( 5.1 ) Pioglitazone tablets are not recommended in patients with symptomatic heart failure. ( 5.1 ) Initiation of pioglitazone tablets in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated. ( 4 , 5.1 )

5 WARNINGS AND PRECAUTIONS Congestive Heart Failure: Fluid retention may occur and can exacerbate or lead to congestive heart failure. Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk. Monitor patients for signs and symptoms. ( 5.1 ) Hypoglycemia: When used with insulin or an insulin secretagogue, a lower dose of the insulin or insulin secretagogue may be needed to reduce the risk of hypoglycemia. ( 5.2 ) Hepatic Effects: Post-marketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt pioglitazone and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart pioglitazone if liver injury is confirmed and no alternate etiology can be found. ( 5.3 ) Bladder cancer: Preclinical and clinical trial data, and results from an observational study suggest an increased risk of bladder cancer in pioglitazone users. The observational data further suggest that the risk increases with duration of use. Do not use in patients with active bladder cancer. Use caution when using in patients with prior history of bladder cancer. ( 5.4 ) Edema: Dose related edema may occur. ( 5.5 ) Fractures: Increased incidence in female patients. Apply current standards of care for assessing and maintaining bone health. ( 5.6 ) Macular Edema: Post-marketing reports. Recommend regular eye exams in all patients with diabetes according to current standards of care with prompt evaluation for acute visual changes. ( 5.7 ) Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with pioglitazone or any other antidiabetic drug. ( 5.9 ) 5.1 Congestive Heart Failure Pioglitazone, like other thiazolidinediones, can cause dose related fluid retention when used alone or in combination with other antidiabetic medications and is most common when pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone must be considered [see Boxed Warning, CONTRAINDICATIONS (4) and ADVERSE REACTIONS (6.1) ]. 5.2 Hypoglycemia Patients receiving pioglitazone in combination with insulin or other antidiabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia. A reduction in the dose of the concomitant antidiabetic medication may be necessary to reduce the risk of hypoglycemia [see DOSAGE AND ADMINISTRATION (2.2) ] . 5.3 Hepatic Effects There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking pioglitazone, although the reports contain insufficient information necessary to establish the probable cause. There has been no evidence of drug-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date [see Adverse Reactions ( 6.1 )] . Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) and assessing the patient is recommended before initiating pioglitazone therapy. In patients with abnormal liver tests, pioglitazone should be initiated with caution. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than 3 times the upper limit of the reference range), pioglitazone treatment should be interrupted and investigation done to establish the probable cause. Pioglitazone should not be restarted in these patients without another explanation for the liver test abnormalities. Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury, and should not be restarted on pioglitazone. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with pioglitazone can be used with caution. 5.4 Urinary Bladder Tumors Tumors were observed in the urinary bladder of male rats in the 2-year carcinogenicity study [see Nonclinical Toxicology (13.1)]. In two 3-year trials in which pioglitazone was compared to placebo or glyburide, there were 16/3,656 (0.44%) reports of bladder cancer in patients taking pioglitazone compared to 5/3,679 (0.14%) in patients not taking pioglitazone. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on pioglitazone and two (0.05%) cases on placebo. A 5-year interim report of an ongoing 10-year observational cohort study found a non-significant increase in the risk for bladder cancer in subjects ever exposed to pioglitazone, compared to subjects never exposed to pioglitazone (HR 1.2 [95% CI 0.9 to 1.5]). Compared to never exposure, a duration of pioglitazone therapy longer than 12 months was associated with an increase in risk (HR 1.4 [95% CI 0.9 to 2.1]), which reached statistical significance after more than 24 months of pioglitazone use (HR 1.4 [95% CI 1.03 to 2]). Interim results from this study suggested that taking pioglitazone longer than 12 months increased the relative risk of developing bladder cancer in any given year by 40% which equates to an absolute increase of three cases in 10,000 (from approximately 7 in 10,000 [without pioglitazone] to approximately 10 in 10,000 [with pioglitazone]). There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, pioglitazone should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with pioglitazone should be considered in patients with a prior history of bladder cancer. 5.5 Edema In controlled clinical trials, edema was reported more frequently in patients treated with pioglitazone than in placebo-treated patients and is dose related [see ADVERSE REACTIONS (6.1) ]. In post-marketing experience, reports of new onset or worsening edema have been received. Pioglitazone should be used with caution in patients with edema. Because thiazolidinediones, including pioglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, pioglitazone should be used with caution in patients at risk for congestive heart failure. Patients treated with pioglitazone should be monitored for signs and symptoms of congestive heart failure [see Boxed Warning, WARNINGS AND PRECAUTIONS (5.1) and PATIENT COUNSELING INFORMATION (17) ]. 5.6 Fractures In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5,238 patients with type 2 diabetes and a history of macrovascular disease were randomized to pioglitazone (n = 2,605), force-titrated up to 45 mg daily or placebo (n = 2,633) in addition to standard of care. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for pioglitazone versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and persisted during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in the incidence of fracture was observed in men treated with pioglitazone (1.7%) versus placebo (2.1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with pioglitazone and attention should be given to assessing and maintaining bone health according to current standards of care. 5.7 Macular Edema Macular edema has been reported in post-marketing experience in diabetic patients who were taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of the thiazolidinedione. Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care. Patients with diabetes who report any visual symptoms should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings [see ADVERSE REACTIONS (6.1) ]. 5.8 Ovulation Therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking pioglitazone [see USE IN SPECIFIC POPULATIONS (8.1) ]. This effect has not been investigated in clinical trials, so the frequency of this occurrence is not known. Adequate contraception in all premenopausal women treated with pioglitazone is recommended. 5.9 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with pioglitazone or any other antidiabetic drug.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Congestive Heart Failure [see Boxed Warning and WARNINGS AND PRECAUTIONS (5.1) ] Edema [see WARNINGS AND PRECAUTIONS (5.5) ] Fractures [see WARNINGS AND PRECAUTIONS (5.6) ] Most common adverse reactions (≥ 5%) are upper respiratory tract infection, headache, sinusitis, myalgia and pharyngitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Over 8,500 patients with type 2 diabetes have been treated with pioglitazone in randomized, double-blind, controlled clinical trials, including 2,605 patients with type 2 diabetes and macrovascular disease treated with pioglitazone in the PROactive clinical trial. In these trials, over 6,000 patients have been treated with pioglitazone for 6 months or longer, over 4,500 patients have been treated with pioglitazone for one year or longer and over 3,000 patients have been treated with pioglitazone for at least 2 years. In six pooled 16 to 26-week placebo-controlled monotherapy and 16 to 24-week add-on combination therapy trials, the incidence of withdrawals due to adverse events was 4.5% for patients treated with pioglitazone and 5.8% for comparator-treated patients. The most common adverse events leading to withdrawal were related to inadequate glycemic control, although the incidence of these events was lower (1.5%) with pioglitazone than with placebo (3%). In the PROactive trial, the incidence of withdrawals due to adverse events was 9% for patients treated with pioglitazone and 7.7% for placebo-treated patients. Congestive heart failure was the most common serious adverse event leading to withdrawal occurring in 1.3% of patients treated with pioglitazone and 0.6% of patients treated with placebo. Common Adverse Events: 16 to 26-Week Monotherapy Trials A summary of the incidence and type of common adverse events reported in three pooled 16 to 26-week placebo-controlled monotherapy trials of pioglitazone is provided in Table 1 . Terms that are reported represent those that occurred at an incidence of > 5% and more commonly in patients treated with pioglitazone than in patients who received placebo. None of these adverse events were related to pioglitazone dose. Table 1. Three Pooled 16 to 26-Week Placebo-Controlled Clinical Trials of Pioglitazone Monotherapy: Adverse Events Reported at an Incidence > 5% and More Commonly in Patients Treated with Pioglitazone than in Patients Treated with Placebo % of Patients Placebo n = 259 Pioglitazone n = 606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Pharyngitis 0.8 5.1 Common Adverse Events: 16 to 24-Week Add-on Combination Therapy Trials A summary of the overall incidence and types of common adverse events reported in trials of pioglitazone add-on to sulfonylurea is provided in Table 2 . Terms that are reported represent those that occurred at an incidence of > 5% and more commonly with the highest tested dose of pioglitazone. Table 2. 16 to 24-Week Clinical Trials of Pioglitazone Add-on to Sulfonylurea Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of “edema”. 16-Week Placebo-Controlled Trial Adverse Events Reported in > 5% of Patients and More Commonly in Patients Treated with Pioglitazone 30 mg + Sulfonylurea than in Patients Treated with Placebo + Sulfonylurea % of Patients Placebo + Sulfonylurea n = 187 Pioglitazone 15 mg + Sulfonylurea n = 184 Pioglitazone 30 mg + Sulfonylurea n = 189 Edema 2.1 1.6 12.7 Headache 3.7 4.3 5.3 Flatulence 0.5 2.7 6.3 Weight Increased 0 2.7 5.3 24-Week Non-Controlled Double-Blind Trial Adverse Events Reported in > 5% of Patients and More Commonly in Patients Treated with Pioglitazone 45 mg + Sulfonylurea than in Patients Treated with Pioglitazone 30 mg + Slufonylurea % of Patients Pioglitazone 30 mg + Sulfonylurea n = 351 Pioglitazone 45 mg + Sulfonylurea n = 351 Hypoglycemia 13.4 15.7 Edema 10.5 23.1 Upper Respiratory Tract Infection 12.3 14.8 Weight Increased 9.1 13.4 Urinary Tract Infection 5.7 6.8 A summary of the overall incidence and types of common adverse events reported in trials of pioglitazone add-on to metformin is provided in Table 3 . Terms that are reported represent those that occurred at an incidence of > 5% and more commonly with the highest tested dose of pioglitazone. Table 3. 16 to 24-Week Clinical Trials of Pioglitazone Add-on to Metformin Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of “edema”. 16-Week Placebo-Controlled Trial Adverse Events Reported in > 5% of Patients and More Commonly in Patients Treated with Pioglitazone + Metformin than in Patients Treated with Placebo + Metformin % of Patients Placebo + Metformin n = 160 Pioglitazone 30 mg + Metformin n = 168 Edema 2.5 6 Headache 1.9 6 24-Week Non-Controlled Double-Blind Trial Adverse Events Reported in > 5% of Patients and More Commonly in Patients Treated with Pioglitazone 45 mg + Metformin than in Patients Treated with Pioglitazone 30 mg + Metformin % of Patients Pioglitazone 30 mg + Metformin n = 411 Pioglitazone 45 mg + Metformin n = 416 Upper Respiratory Tract Infection 12.4 13.5 Edema 5.8 13.9 Headache 5.4 5.8 Weight Increased 2.9 6.7 Table 4 summarizes the incidence and types of common adverse events reported in trials of pioglitazone add-on to insulin. Terms that are reported represent those that occurred at an incidence of > 5% and more commonly with the highest tested dose of pioglitazone. Table 4. 16 to 24-Week Clinical Trials of Pioglitazone Add-on to Insulin Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of “edema”. 16-Week Placebo-Controlled Trial Adverse Events Reported in > 5% of Patients and More Commonly in Patients Treated with Pioglitazone 30 mg + Insulin than in Patients Treated with Placebo + Insulin % of Patients Placebo + Insulin n = 187 Pioglitazone 15 mg + Insulin n = 191 Pioglitazone 30 mg + Insulin n = 188 Hypoglycemia 4.8 7.9 15.4 Edema 7 12.6 17.6 Upper Respiratory Tract Infection 9.6 8.4 14.9 Headache 3.2 3.1 6.9 Weight Increased 0.5 5.2 6.4 Back Pain 4.3 2.1 5.3 Dizziness 3.7 2.6 5.3 Flatulence 1.6 3.7 5.3 24-Week Non-Controlled Double-Blind Trial Adverse Events Reported in > 5% of Patients and More Commonly in Patients Treated with Pioglitazone 45 mg + Insulin than in Patients Treated with Pioglitazone 30 mg + Insulin % of Patients Pioglitazone 30 mg + Insulin n = 345 Pioglitazone 45 mg + Insulin n = 345 Hypoglycemia 43.5 47.8 Edema 22 26.1 Weight Increased 7.2 13.9 Urinary Tract Infection 4.9 8.7 Diarrhea 5.5 5.8 Back Pain 3.8 6.4 Blood Creatine Phosphokinase Increased 4.6 5.5 Sinusitis 4.6 5.5 Hypertension 4.1 5.5 A summary of the overall incidence and types of common adverse events reported in the PROactive trial is provided in Table 5 . Terms that are reported represent those that occurred at an incidence of > 5% and more commonly in patients treated with pioglitazone than in patients who received placebo. Table 5. PROactive Trial: Incidence and Types of Adverse Events Reported in > 5% of Patients Treated with Pioglitazone and More Commonly than Placebo Mean duration of patient follow-up was 34.5 months. % of Patients Placebo n = 2,633 Pioglitazone n = 2,605 Hypoglycemia 18.8 27.3 Edema 15.3 26.7 Cardiac Failure 6.1 8.1 Pain in Extremity 5.7 6.4 Back Pain 5.1 5.5 Chest Pain 5 5.1 Congestive Heart Failure A summary of the incidence of adverse events related to congestive heart failure is provided in Table 6 for the 16 to 24-week add-on to sulfonylurea trials, for the 16 to 24-week add-on to insulin trials and for the 16 to 24-week add-on to metformin trials. None of the events were fatal. Table 6. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) Patients Treated with Pioglitazone or Placebo Added on to a Sulfonylurea Number (%) of Patients Placebo-Controlled Trial (16 weeks) Non-Controlled Double Blind Trial (24 weeks) Placebo + Sulfonylurea n = 187 Pioglitazone 15 mg + Sulfonylurea n = 184 Pioglitazone 30 mg + Sulfonylurea n = 189 Pioglitazone 30 mg + Sulfonylurea n = 351 Pioglitazone 45 mg + Sulfonylurea n = 351 At least one congestive heart failure event 2 (1.1%) 0 0 1 (0.3%) 6 (1.7%) Hospitalized 2 (1.1%) 0 0 0 2 (0.6%) Patients Treated with Pioglitazone or Placebo added on to Insulin Number (%) of Patients Placebo-Controlled Trial (16 weeks) Non-Controlled Double Blind Trial (24 weeks) Placebo + Insulin n = 187 Pioglitazone 15 mg + Insulin n = 191 Pioglitazone 30 mg + Insulin n = 188 Pioglitazone 30 mg + Insulin n = 345 Pioglitazone 45 mg + Insulin n = 345 At least one congestive heart failure event 0 2 (1%) 2 (1.1%) 3 (0.9%) 5 (1.4%) Hospitalized 0 2 (1%) 1 (0.5%) 1 (0.3%) 3 (0.9%) Patients Treated with Pioglitazone or Placebo Added on to Metformin Number (%) Patients Placebo-Controlled Trial (16 weeks) Non-Controlled Double Blind Trial (24 weeks) Placebo + Metformin n = 160 Pioglitazone 30 mg + Metformin n = 168 Pioglitazone 30 mg + Metformin n = 411 Pioglitazone 45 mg + Metformin n = 416 At least one congestive heart failure event 0 1 (0.6%) 0 1 (0.2%) Hospitalized 0 1 (0.6%) 0 1 (0.2%) Patients with type 2 diabetes and NYHA class II or early class III congestive heart failure were randomized to receive 24 weeks of double-blind treatment with either pioglitazone at daily doses of 30 mg to 45 mg (n = 262) or glyburide at daily doses of 10 mg to 15 mg (n = 256). A summary of the incidence of adverse events related to congestive heart failure reported in this study is provided in Table 7 . Table 7. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) in Patients with NYHA Class II or III Congestive Heart Failure Treated with Pioglitazone or Glyburide Number (%) of Subjects Pioglitazone n = 262 Glyburide n = 256 Death due to cardiovascular causes (adjudicated) 5 (1.9%) 6 (2.3%) Overnight hospitalization for worsening CHF (adjudicated) 26 (9.9%) 12 (4.7%) Emergency room visit for CHF (adjudicated) 4 (1.5%) 3 (1.2%) Patients experiencing CHF progression during study 35 (13.4%) 21 (8.2%) Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are summarized in Table 8 . Table 8. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) in PROactive Trial Number (%) of Patients Placebo n = 2,633 Pioglitazone n = 2,605 At least one hospitalized congestive heart failure event 108 (4.1%) 149 (5.7%) Fatal 22 (0.8%) 25 (1%) Hospitalized, non-fatal 86 (3.3%) 124 (4.7%) Cardiovascular Safety In the PROactive trial, 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to pioglitazone (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. Almost all patients (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, nitrates, diuretics, aspirin, statins and fibrates). At baseline, patients had a mean age of 62 years, mean duration of diabetes of 9.5 years, and mean HbA1c of 8.1%. Mean duration of follow-up was 34.5 months. The primary objective of this trial was to examine the effect of pioglitazone on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in a cardiovascular composite endpoint that included all-cause mortality, non-fatal myocardial infarction (MI) including silent MI, stroke, acute coronary syndrome, cardiac intervention including coronary artery bypass grafting or percutaneous intervention, major leg amputation above the ankle, and bypass surgery or revascularization in the leg. A total of 514 (19.7%) patients treated with pioglitazone and 572 (21.7%) placebo-treated patients experienced at least one event from the primary composite endpoint (hazard ratio 0.90; 95% Confidence Interval: 0.80, 1.02; p=0.10). Although there was no statistically significant difference between pioglitazone and placebo for the 3-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with pioglitazone. The number of first occurrences and total individual events contributing to the primary composite endpoint is shown in Table 9 . Table 9. PROactive: Number of First and Total Events for Each Component within the Cardiovascular Composite Endpoint CABG = coronary artery bypass grafting; PCI = percutaneous intervention Cardiovascular Events Placebo n = 2,633 Pioglitazone n = 2,605 First Events n (%) Total Events n First Events n (%) Total Events n Any event 572 (21.7) 900 514 (19.7) 803 All-cause mortality 122 (4.6) 186 110 (4.2) 177 Non-fatal myocardial infarction (MI) 118 (4.5) 157 105 (4) 131 Stroke 96 (3.6) 119 76 (2.9) 92 Acute coronary syndrome 63 (2.4) 78 42 (1.6) 65 Cardiac intervention (CABG/PCI) 101 (3.8) 240 101 (3.9) 195 Major leg amputation 15 (0.6) 28 9 (0.3) 28 Leg revascularization 57 (2.2) 92 71 (2.7) 115 Weight Gain Dose-related weight gain occurs when pioglitazone is used alone or in combination with other anti-diabetic medications. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. Tables 10 and 11 summarize the changes in body weight with pioglitazone and placebo in the 16 to 26-week randomized, double-blind monotherapy and 16 to 24-week combination add-on therapy trials and in the PROactive trial. Table 10. Weight Changes (kg) from Baseline During Randomized, Double-Blind Clinical Trials Control Group (Placebo) Pioglitazone 15 mg Pioglitazone 30 mg Pioglitazone 45 mg Median (25 th /75 th percentile) Median (25 th /75 th percentile) Median (25 th /75 th percentile) Median (25 th /75 th percentile) Monotherapy (16 to 26 weeks) -1.4 (-2.7/0) n = 256 0.9 (-0.5/3.4) n = 79 1 (-0.9/3.4) n = 188 2.6 (0.2/5.4) n = 79 Combination Therapy (16 to 24 weeks) Sulfonylurea -0.5 (-1.8/0.7) n = 187 2 (0.2/3.2) n = 183 3.1 (1.1/5.4) n = 528 4.1 (1.8/7.3) n = 333 Metformin -1.4 (-3.2/0.3) n = 160 N/A 0.9 (-1.3/3.2) n = 567 1.8 (-0.9/5) n = 407 Insulin 0.2 (-1.4/1.4) n = 182 2.3 (0.5/4.3) n = 190 3.3 (0.9/6.3) n = 522 4.1 (1.4/6.8) n = 338 Table 11. Median Change in Body Weight in Patients Treated with Pioglitazone Versus Patients Treated with Placebo During the Double-Blind Treatment Period in the PROactive Trial Note: median exposure for both pioglitazone and placebo was 2.7 years. Placebo Pioglitazone Median (25 th /75 th percentile) Median (25 th /75 th percentile) Change from Baseline to Final Visit (kg) -0.5 (-3.3, 2) n = 2,581 + 3.6 (0, 7.5) n = 2,560 Edema Edema induced from taking pioglitazone is reversible when pioglitazone is discontinued. The edema usually does not require hospitalization unless there is coexisting congestive heart failure. A summary of the frequency and types of edema adverse events occurring in clinical investigations of pioglitazone is provided in Table 12 . Table 12. Adverse Events of Edema in Patients Treated with Pioglitazone Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of “edema”. Number (%) Patients Placebo Pioglitazone 15 mg Pioglitazone 30 mg Pioglitazone 45 mg Monotherapy (16 to 26 weeks) 3 (1.2%) n = 259 2 (2.5%) n = 81 13 (4.7%) n = 275 11 (6.5%) n = 169 Combined Therapy (16 to 24 weeks) Sulfonylurea 4 (2.1%) n = 187 3 (1.6%) n = 184 61 (11.3%) n = 540 81 (23.1%) n = 351 Metformin 4 (2.5%) n = 160 N/A 34 (5.9%) n = 579 58 (13.9%) n = 416 Insulin 13 (7%) n = 187 24 (12.6%) n = 191 109 (20.5%) n = 533 90 (26.1%) n = 345 Table 13. Adverse Events of Edema in Patients in the PROactive Trial Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of “edema”. Number (%) of Patients Placebo n = 2,633 Pioglitazone n = 2,605 419 (15.9%) 712 (27.3%) Hepatic Effects There has been no evidence of induced hepatotoxicity with pioglitazone in the pioglitazone controlled clinical trial database to date. One randomized, double-blind, 3-year trial comparing pioglitazone to glyburide as add-on to metformin and insulin therapy was specifically designed to evaluate the incidence of serum ALT elevation to greater than 3 times the upper limit of the reference range, measured every 8 weeks for the first 48 weeks of the trial then every 12 weeks thereafter. A total of 3/1051 (0.3%) patients treated with pioglitazone and 9/1046 (0.9%) patients treated with glyburide developed ALT values >3 times the upper limit of the reference range. None of the patients treated with pioglitazone in the pioglitazone controlled clinical trial database to date have had a serum ALT >3 times the upper limit of the reference range and a corresponding total bilirubin >2 times the upper limit of the reference range, a combination predictive of the potential for severe drug-induced liver injury. Hypoglycemia In the pioglitazone clinical trials, adverse events of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with fingerstick glucose testing. In the 16-week add-on to sulfonylurea trial, the incidence of reported hypoglycemia was 3.7% with pioglitazone 30 mg and 0.5% with placebo. In the 16-week add-on to insulin trial, the incidence of reported hypoglycemia was 7.9% with pioglitazone 15 mg, 15.4% with pioglitazone 30 mg, and 4.8% with placebo. The incidence of reported hypoglycemia was higher with pioglitazone 45 mg compared to pioglitazone 30 mg in both the 24-week add-on to sulfonylurea trial (15.7% vs. 13.4%) and in the 24-week add-on to insulin trial (47.8% vs. 43.5%). Three patients in these four trials were hospitalized due to hypoglycemia. All three patients were receiving pioglitazone 30 mg (0.9%) in the 24-week add-on to insulin trial. An additional 14 patients reported severe hypoglycemia (defined as causing considerable interference with patient's usual activities) that did not require hospitalization. These patients were receiving pioglitazone 45 mg in combination with sulfonylurea (n=2) or pioglitazone 30 mg or 45 mg in combination with insulin (n=12). Urinary Bladder Tumors Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study [see Nonclinical Toxicology ( 13.1 )] . In two 3-year trials in which pioglitazone was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking pioglitazone compared to 5/3679 (0.14%) in patients not taking pioglitazone. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on pioglitazone and two (0.05%) cases on placebo. There are too few events of bladder cancer to establish causality. Laboratory Abnormalities Hematologic Effects Pioglitazone may cause decreases in hemoglobin and hematocrit. In placebo-controlled monotherapy trials, mean hemoglobin values declined by 2% to 4% in patients treated with pioglitazone compared with a mean change in hemoglobin of -1% to +1% in placebo-treated patients. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume associated with pioglitazone therapy and are not likely to be associated with any clinically significant hematologic effects. Creatine Phosphokinase During protocol-specified measurement of serum creatine phosphokinase (CPK) in pioglitazone clinical trials, an isolated elevation in CPK to greater than 10 times the upper limit of the reference range was noted in 9 (0.2%) patients treated with pioglitazone (values of 2150 to 11400IU/L) and in no comparator-treated patients. Six of these nine patients continued to receive pioglitazone, two patients were noted to have the CPK elevation on the last day of dosing and one patient discontinued pioglitazone due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to pioglitazone therapy is unknown. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of pioglitazone. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. New onset or worsening diabetic macular edema with decreased visual acuity [see WARNINGS AND PRECAUTIONS (5.7) ]. Fatal and non-fatal hepatic failure [see WARNINGS AND PRECAUTIONS (5.3) ]. Post-marketing reports of congestive heart failure have been reported in patients treated with pioglitazone, both with and without previously known heart disease and both with and without concomitant insulin administration. In post-marketing experience, there have been reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure [see Boxed Warning and WARNINGS AND PRECAUTIONS (5.1) ].

<table> <caption>Table 1. Three Pooled 16 to 26-Week Placebo-Controlled Clinical Trials of Pioglitazone Monotherapy: Adverse Events Reported at an Incidence &gt; 5% and More Commonly in Patients Treated with Pioglitazone than in Patients Treated with Placebo</caption> <col width="36%"/> <col width="23%"/> <col width="25%"/> <tbody> <tr> <td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">% of Patients</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"/> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>Placebo</paragraph> <paragraph>n = 259</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>Pioglitazone </paragraph> <paragraph>n = 606</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Upper Respiratory Tract Infection</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8.5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13.2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Headache</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6.9</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>9.1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Sinusitis</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4.6</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6.3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Myalgia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2.7</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5.4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>Pharyngitis</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0.8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5.1</paragraph> </td> </tr> </tbody> </table>

<table> <caption>Table 2. 16 to 24-Week Clinical Trials of Pioglitazone Add-on to Sulfonylurea</caption> <col width="26%"/> <col width="26%"/> <col width="25%"/> <col width="25%"/> <tfoot> <tr> <td align="left" colspan="7" styleCode="Botrule" valign="top">Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of &#x201C;edema&#x201D;.</td> </tr> </tfoot> <tbody> <tr> <td rowspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <td align="center" colspan="3" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">16-Week Placebo-Controlled Trial Adverse Events Reported in &gt; 5% of Patients and More Commonly in Patients Treated with Pioglitazone 30 mg + Sulfonylurea than in Patients Treated with Placebo + Sulfonylurea</content> </paragraph> </td> </tr> <tr> <td align="center" colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">% of Patients</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Placebo + Sulfonylurea</content> </paragraph> <paragraph> <content styleCode="bold">n = 187</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Pioglitazone 15 mg + Sulfonylurea</content> </paragraph> <paragraph> <content styleCode="bold">n = 184</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Pioglitazone 30 mg + Sulfonylurea</content> </paragraph> <paragraph> <content styleCode="bold">n = 189</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Edema</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2.1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1.6</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12.7</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Headache</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3.7</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4.3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5.3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Flatulence</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0.5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2.7</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6.3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Weight Increased</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2.7</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5.3</paragraph> </td> </tr> <tr> <td rowspan="3" styleCode="Rrule Lrule Botrule " valign="top"/> <td align="center" colspan="3" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">24-Week Non-Controlled Double-Blind Trial Adverse Events Reported in &gt; 5% of Patients and More Commonly in Patients Treated with Pioglitazone 45 mg + Sulfonylurea than in Patients Treated with Pioglitazone 30 mg + </content> <content styleCode="bold">Slufonylurea</content> </paragraph> </td> </tr> <tr> <td align="center" colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">% of Patients</content> </paragraph> </td> </tr> <tr> <td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Pioglitazone 30 mg + </content> </paragraph> <paragraph> <content styleCode="bold">Sulfonylurea</content> </paragraph> <paragraph> <content styleCode="bold">n = 351</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Pioglitazone 45 mg + Sulfonylurea</content> </paragraph> <paragraph> <content styleCode="bold">n = 351</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Hypoglycemia</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule " valign="top"> <paragraph>13.4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>15.7</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Edema</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule " valign="top"> <paragraph>10.5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>23.1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Upper Respiratory Tract Infection</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule " valign="top"> <paragraph>12.3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>14.8</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Weight Increased</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule " valign="top"> <paragraph>9.1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13.4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>Urinary Tract Infection</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule " valign="top"> <paragraph>5.7</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6.8</paragraph> </td> </tr> </tbody> </table>

<table> <caption>Table 3. 16 to 24-Week Clinical Trials of Pioglitazone Add-on to Metformin</caption> <col width="24%"/> <col width="37%"/> <col width="37%"/> <tfoot> <tr> <td align="left" colspan="10" styleCode="Botrule" valign="top">Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of &#x201C;edema&#x201D;.</td> </tr> </tfoot> <tbody> <tr> <td rowspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <td align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">16-Week Placebo-Controlled Trial Adverse Events Reported in &gt; 5% of Patients and More Commonly in Patients Treated with Pioglitazone + Metformin than in Patients Treated with Placebo + Metformin</content> </paragraph> </td> </tr> <tr> <td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">% of Patients</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Placebo + Metformin</content> </paragraph> <paragraph> <content styleCode="bold">n = 160</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Pioglitazone 30 mg + Metformin</content> </paragraph> <paragraph> <content styleCode="bold">n = 168</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Edema</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2.5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Headache</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1.9</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> </tr> <tr> <td rowspan="3" styleCode="Rrule Lrule Botrule " valign="top"/> <td align="center" colspan="2" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">24-Week Non-Controlled Double-Blind Trial Adverse Events Reported in &gt; 5% of Patients and More Commonly in Patients Treated with Pioglitazone 45 mg + Metformin than in Patients Treated with Pioglitazone 30 mg + Metformin</content> </paragraph> </td> </tr> <tr> <td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">% of Patients</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Pioglitazone 30 mg + Metformin</content> </paragraph> <paragraph> <content styleCode="bold">n = 411</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Pioglitazone 45 mg + Metformin</content> </paragraph> <paragraph> <content styleCode="bold">n = 416</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Upper Respiratory Tract Infection</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12.4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13.5</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Edema</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5.8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13.9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Headache</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5.4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5.8</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>Weight Increased</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2.9</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6.7</paragraph> </td> </tr> </tbody> </table>