PIOGLITAZONE- pioglitazone_tablet

Pioglitazone is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARgamma). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle and liver. Activation of PPARgamma nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance. Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin. Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal and improves hepatic sensitivity to insulin. In patients with type 2 diabetes, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin concentrations and lower HbA1c values. In controlled clinical trials, pioglitazone had an additive effect on glycemic control when used in combination with a sulfonylurea, metformin or insulin [see Clinical Studies 14. 2 Patients with lipid abnormalities were included in clinical trials with pioglitazone. Overall, patients treated with pioglitazone had mean decreases in serum triglycerides, mean increases in HDL cholesterol and no consistent mean changes in LDL and total cholesterol. There is no conclusive evidence of macrovascular benefit with pioglitazone [see Warnings and Precautions 5. 8 Adverse Reactions 6. 1 In a 26-week, placebo-controlled, dose-ranging monotherapy study, mean serum triglycerides decreased in the 15 mg, 30 mg and 45 mg pioglitazone dose groups compared to a mean increase in the placebo group. Mean HDL cholesterol increased to a greater extent in patients treated with pioglitazone than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with pioglitazone compared to placebo (see Table 14 Table 14. Lipids in a 26-Week Placebo-Controlled Monotherapy Dose-Ranging Study Placebo Pioglitazone 15 mg Once Daily Pioglitazone 30 mg Once Daily Pioglitazone 45 mg Once Daily Triglycerides (mg/dL) N = 79 N = 79 N = 84 N = 77 Baseline (mean) 263 284 261 260 Percent change from baseline (adjusted mean Adjusted for baseline, pooled center and pooled center by treatment interaction 4. 8% -9% p < 0. 05 versus placebo -9. 3% HDL Cholesterol (mg/dL) N = 79 N = 79 N = 83 N = 77 Baseline (mean) 42 40 41 41 Percent change from baseline (adjusted mean 8. 1% LDL Cholesterol (mg/dL) N = 65 N = 63 N = 74 N = 62 Baseline (mean) 139 132 136 127 Percent change from baseline (adjusted mean 4. 2% 6% Total Cholesterol (mg/dL) N = 79 N = 79 N = 84 N = 77 Baseline (mean) 225 220 223 214 Percent change from baseline (adjusted mean 4. 4% In the two other monotherapy studies (16 weeks and 24 weeks) and in combination therapy studies with sulfonylurea (16 weeks and 24 weeks), metformin (16 weeks and 24 weeks ) or insulin (16 weeks and 24 weeks), the results were generally consistent with the data above. Following once-daily administration of pioglitazone, steady-state serum concentrations of both pioglitazone and its major active metabolites, M-III (keto derivative of pioglitazone) and M-IV (hydroxyl derivative of pioglitazone), are achieved within 7 days. At steady-state, M-III and M-IV reach serum concentrations equal to or greater than that of pioglitazone. At steady-state, in both healthy volunteers and patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the peak total pioglitazone serum concentrations (pioglitazone plus active metabolites) and 20% to 25% of the total AUC. C max min Absorption Following oral administration of pioglitazone, T max max Distribution The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0. 41 (mean +/- SD) L/kg of body weight. Pioglitazone is extensively protein bound (> 99%) in human serum, principally to serum albumin. Pioglitazone also binds to other serum proteins, but with lower affinity. M-III and M-IV are also extensively bound (> 98%) to serum albumin. Metabolism Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-III and M-IV are the major circulating active metabolites in humans. In vitro In vivo Dosage and Administration 2. 3 Drug Interactions 7 Excretion and Elimination Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces. The mean serum half-life (t ½ Renal Impairment The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance [CLcr] 30 to 50 mL/min) and severe (CLcr < 30 mL/min) renal impairment when compared to subjects with normal renal function. Therefore, no dose adjustment in patients with renal impairment is required. Hepatic Impairment Compared with healthy controls, subjects with impaired hepatic function (Child-Turcotte-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone (pioglitazone, M-III, and M-IV) mean C max There are postmarketing reports of liver failure with pioglitazone and clinical trials have generally excluded patients with serum ALT >2. 5 times the upper limit of the reference range. Use caution in patients with liver disease [see Warnings and Precautions ( 5. 3 Geriatric Patients In healthy elderly subjects, C max ½ Pediatric Patients Safety and efficacy of pioglitazone in pediatric patients have not been established. Pioglitazone is not recommended for use in pediatric patients [see Use in Specific Populations ( 8. 4 Gender The mean C max Ethnicity Pharmacokinetic data among various ethnic groups are not available. Drug-Drug Interactions Table 15. Effect of Pioglitazone Coadministration on Systemic Exposure of Other Drugs Coadministered Drug Pioglitazone Dosage Regimen (mg) Daily for 7 days unless otherwise noted Name and Dose Regimens Change in AUC % change (with/without coadministered drug and no change = 0%); symbols of up arrow and down arrow indicate the exposure increase and decrease, respectively Change in Cmax 45 mg (N = 12) Warfarin Pioglitazone had no clinically significant effect on prothrombin time Daily loading then maintenance doses based PT and INR values Quick’s Value = 35 +/- 5% R-Warfarin down arrow 3% R-Warfarin down arrow 2% S-Warfarin down arrow 1% S-Warfarin up arrow 1% 45 mg (N = 12) Digoxin 0. 200 mg twice daily (loading dose) then 0. 250 mg daily (maintenance dose, 7 days) up arrow 15% up arrow 17% 45 mg daily for 21 days ( = 35) Oral Contraceptive [Ethinyl Estradiol (EE) 0. 035 mg plus Norethindrone (NE) 1 mg] for 21 days EE down arrow 11% EE down arrow 13% NE up arrow 3% NE down arrow 7% 45 mg (N = 23) Fexofenadine 60 mg twice daily for 7 days up arrow 30% up arrow 37% 45 mg (N = 14) Glipizide 5 mg daily for 7 days down arrow 3% down arrow 8% 45 mg daily for 8 days (N = 16) Metformin 1000 mg single dose on day 8 down arrow 3% down arrow 5% 45 mg (N = 21) Midazolam 7. 5 mg single dose on day 15 down arrow 26% down arrow 26% 45 mg (N = 24) Ranitidine 150 mg twice daily for 7 days up arrow 1% down arrow 1% 45 mg daily for 4 days (N = 24) Nifedipine ER 30 mg daily for 4 days down arrow 13% down arrow 17% 45 mg (N = 25) Atorvastatin Ca 80 mg daily for 7 days down arrow 14% down arrow 23% 45 mg (N = 22) Theophylline 400 mg twice daily for 7 days up arrow 2% up arrow 5% Table 16. Effect of Coadministered Drugs on Pioglitazone Systemic Exposure Coadministered Drug and Dosage Regimen Pioglitazone Dose Regimen (mg) Daily for 7 days unless otherwise noted Change in AUC Mean ratio (with/without coadministered drug and no change = 1-fold) % change (with/without coadministered drug and no change = 0%); symbols of up arrow and down arrow indicate the exposure increase and decrease, respectively. Change in Cmax Gemfibrozil 600 mg twice daily for 2 days (N = 12) 15 mg single dose up arrow 3. 2-fold The half-life of pioglitazone increased from 8. 3 hours to 22. 7 hours in the presence of gemfibrozil [see Dosage and Administration ( 2. 1 up arrow 6% Ketoconazole 200 mg twice daily for 7 days (N = 28) 45 mg up arrow 34% up arrow 14% Rifampin 600 mg daily for 5 days (N = 10) 30 mg single dose down arrow 54% down arrow 5% Fexofenadine 60 mg twice daily for 7 days (N = 23) 45 mg up arrow 1% 0% Ranitidine 150 mg twice daily for 4 days (N = 23) 45 mg down arrow 13% down arrow 16% Nifedipine ER 30 mg daily for 7 days (N = 23) 45 mg up arrow 5% up arrow 4% Atorvastatin Ca 80 mg daily for 7 days (N = 24) 45 mg down arrow 24% down arrow 31% Theophylline 400 mg twice daily for 7 days (N = 22) 45 mg down arrow 4% down arrow 2% Topiramate 96 mg twice daily for 7 days Indicates duration of concomitant administration with highest twice-daily dose of topiramate from Day 14 onwards over the 22 days of study (N = 26) 30 mg down arrow 15% Additional decrease in active metabolites; 60% for M-III and 16% for M-IV 0%.

Monotherapy and Combination Therapy Pioglitazone tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings [see Clinical Studies 14 Important Limitations of Use Pioglitazone tablets exerts its antihyperglycemic effect only in the presence of endogenous insulin. Pioglitazone tablets should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings. Use caution in patients with liver disease [ see Warnings and Precautions 5. 3 Pioglitazone tablets are a thiazolidinedione and an agonist for peroxisome proliferator-activated receptor (PPAR) gamma indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings. ( 1 14 Important Limitations of Use: 1.

3 Pioglitazone tablets should be taken once daily and can be taken without regard to meals. The recommended starting dose for patients without congestive heart failure is 15 mg or 30 mg once daily. The recommended starting dose for patients with congestive heart failure (NYHA Class I or II) is 15 mg once daily. The dose can be titrated in increments of 15 mg up to a maximum of 45 mg once daily based on glycemic response as determined by HbA1c. After initiation of pioglitazone tablets or with dose increase, monitor patients carefully for adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure [ see Boxed Warning Warnings and Precautions 5. 5 Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating pioglitazone tablets. Routine periodic monitoring of liver tests during treatment with pioglitazone tablets is not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of pioglitazone tablets or who are found to have abnormal liver tests while taking pioglitazone tablets should be managed as described under Warnings and Precautions [see Warnings and Precautions 5. 3 Clinical Pharmacology 12. 3 If hypoglycemia occurs in a patient co-administered pioglitazone tablets and an insulin secretagogue (e. , sulfonylurea), the dose of the insulin secretagogue should be reduced. If hypoglycemia occurs in a patient co-administered pioglitazone tablets and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response. Coadministration of pioglitazone tablets and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of pioglitazone tablets is 15 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Drug Interactions 7. 1 Clinical Pharmacology 12.

The following serious adverse reactions are discussed elsewhere in the labeling: Boxed Warning Warnings and Precautions ( 5. 1 Warnings and Precautions ( 5. 5 )] Warnings and Precautions ( 5. 6 ) Most common adverse reactions (>= 5%) are upper respiratory tract infection, headache, sinusitis, myalgia, and pharyngitis. 1 To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747, or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 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. 2 Headache 6. 1 Sinusitis 4. 3 Myalgia 2. 4 Pharyngitis 0. 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 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. 7 Headache 3. 3 Flatulence 0. 3 Weight Increased 0 2. 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 + Sulfonylurea % of Patients Pioglitazone 30 mg + Sulfonylurea N = 351 Pioglitazone 45 mg + Sulfonylurea N = 351 Hypoglycemia 13. 1 Upper Respiratory Tract Infection 12. 8 Weight Increased 9. 4 Urinary Tract Infection 5. 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 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. 9 Headache 5. 8 Weight Increased 2. 7 Table 4 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. 4 Edema 7 12. 6 Upper Respiratory Tract Infection 9. 9 Headache 3. 9 Weight Increased 0. 4 Back Pain 4. 3 Dizziness 3. 3 Flatulence 1. 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. 8 Edema 22 26. 1 Weight Increased 7. 9 Urinary Tract Infection 4. 7 Diarrhea 5. 8 Back Pain 3. 4 Blood Creatine Phosphokinase Increased 4. 5 Sinusitis 4. 5 Hypertension 4. 5 A summary of the overall incidence and types of common adverse events reported in the PROactive trial is provided in Table 5 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. % of Patients Placebo N = 2,633 Pioglitazone N = 2,605 Hypoglycemia 18. 7 Cardiac Failure 6. 1 Pain in Extremity 5. 4 Back Pain 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 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. 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. 4%) Hospitalized 0 2 (1%) 1 (0. 9%) Patients Treated with Pioglitazone or Placebo Added on to Metformin Number (%) of 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. 2%) Hospitalized 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. 3%) Overnight hospitalization for worsening CHF (adjudicated) 26 (9. 7%) Emergency room visit for CHF (adjudicated) 4 (1. 2%) Patients experiencing CHF progression during study 35 (13. 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. 7%) Fatal 22 (0. 8%) 25 (1%) Hospitalized, nonfatal 86 (3. 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. Mean duration of follow-up was 34. 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, nonfatal 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. 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 Nonfatal 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. 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 antidiabetic medications. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. Tables 10 11 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 th Median (25 th th Median (25 th th Median (25 th th Monotherapy (16 to 26 weeks) -1. 7/0) N = 256 0. 4) N = 79 1 (-0. 4) N = 188 2. 4) N = 79 Combination Therapy (16 to 24 weeks) Sulfonylurea -0. 7) N = 187 2 (0. 2) N = 183 3. 4) N = 528 4. 3) N = 333 Metformin -1. 3) N = 160 N/A 0. 2) N = 567 1. 9/5) N = 407 Insulin 0. 4) N = 182 2. 3) N = 190 3. 3) N = 522 4. 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. Placebo Pioglitazone Median (25 th th Median (25 th th Change from Baseline to Final Visit (kg) -0. 3, 2) N = 2,581 + 3. 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 greater than three 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 greater than three times the upper limit of the reference range and a corresponding total bilirubin greater than two 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. 4%) and in the 24-week add-on to insulin trial (47. 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 Warnings and Precautions 5. 4 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 11400 IU/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. 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. Warnings and Precautions 5. 7 Warnings and Precautions ( 5. 3 Postmarketing 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 postmarketing experience, there have been reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure [see Boxed Warning Warnings and Precautions ( 5.

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. , 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. 1 Pioglitazone tablets are not recommended in patients with symptomatic heart failure. 1 Initiation of pioglitazone tablets in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.
CONTRAINDICATIONS
see Boxed Warning Boxed Warning 4 4.

4 Risk Summary Limited data with pioglitazone in pregnant women are not sufficient to determine a drug- associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations]. In animal reproduction studies, no adverse developmental effects were observed when pioglitazone was administered to pregnant rats and rabbits during organogenesis at exposures up to 5- and 35-times the 45 mg clinical dose, respectively, based on body surface area [see Data]. The estimated background risk of major birth defects is 6 to 10% in women with pre- gestational diabetes with a HbA1c >7 and has been reported to be as high as 20 to 25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity Data Animal Data Pioglitazone administered to pregnant rats during organogenesis did not cause adverse developmental effects at a dose of 20 mg/kg (~5-times the 45 mg clinical dose), but delayed parturition and reduced embryofetal viability at 40 and 80 mg/kg, or >=9-times the 45 mg clinical dose, by body surface area. In pregnant rabbits administered pioglitazone during organogenesis, no adverse developmental effects were observed at 80 mg/kg (~35-times the 45 mg clinical dose), but reduced embryofetal viability at 160 mg/kg, or ~69-times the 45 mg clinical dose, by body surface area. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in offspring at maternal doses of 10 mg/kg and above or >=2 times the 45 mg clinical dose, by body surface area. Risk Summary There is no information regarding the presence of pioglitazone in human milk, the effects on the breastfed infant, or the effects on milk production. Pioglitazone is present in rat milk; however due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for pioglitazone and any potential adverse effects on the breastfed infant from pioglitazone or from the underlying maternal condition. Discuss the potential for unintended pregnancy with premenopausal women as therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some anovulatory women. Safety and effectiveness of pioglitazone in pediatric patients have not been established. Pioglitazone is not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors [see Warnings and Precautions 5. 6 A total of 92 patients (15. 2%) treated with pioglitazone in the three pooled 16- to 26-week double-blind, placebo-controlled, monotherapy trials were >= 65 years old and two patients (0. 3%) were >= 75 years old. In the two pooled 16- to 24-week add-on to sulfonylurea trials, 201 patients (18. 7 %) treated with pioglitazone were >= 65 years old and 19 (1. 8%) were >= 75 years old. In the two pooled 16- to 24-week add-on to metformin trials, 155 patients (15. 5%) treated with pioglitazone were >= 65 years old and 19 (1. 9%) were >= 75 years old. In the two pooled 16- to 24-week add-on to insulin trials, 272 patients (25. 4%) treated with pioglitazone were >= 65 years old and 22 (2. 1%) were >= 75 years old. In PROactive, 1,068 patients (41%) treated with pioglitazone were >= 65 years old and 42 (1. 6%) were >= 75 years old. In pharmacokinetic studies with pioglitazone, no significant differences were observed in pharmacokinetic parameters between elderly and younger patients [see Clinical Pharmacology ( 12. 3 ) Although clinical experiences have not identified differences in effectiveness and safety between the elderly (>= 65 years) and younger patients, these conclusions are limited by small sample sizes for patients >= 75 years old.

2 An inhibitor of CYP2C8 (e. , gemfibrozil) significantly increases the exposure (area under the serum concentration-time curve or AUC) and half-life (t ½ Dosage and Administration 2. 3 and Clinical Pharmacology 12. An inducer of CYP2C8 (e. , rifampin) may significantly decrease the exposure (AUC) of pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during treatment with pioglitazone, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of 45 mg for pioglitazone [see Clinical Pharmacology 12. A decrease in the exposure of pioglitazone and its active metabolites were noted with concomitant administration of pioglitazone and topiramate [ see Clinical Pharmacology (12.

OVERDOSAGE
During controlled clinical trials, one case of overdose with pioglitazone was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms.
NONCLINICAL TOXICOLOGY
A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m 2 2 The relevance to humans of the bladder findings in the male rat cannot be excluded. A two-year carcinogenicity study was also conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m 2 Pioglitazone hydrochloride was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro in vivo No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone hydrochloride daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m 2 Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone hydrochloride (approximately 11, 1 and 2 times the maximum recommended human oral dose for mice, rats and dogs, respectively, based on mg/m 2 2 2 2.
CLINICAL STUDIES
Three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of pioglitazone as monotherapy in patients with type 2 diabetes. These trials examined pioglitazone at doses up to 45 mg or placebo once daily in a total of 865 patients. In a 26-week dose-ranging monotherapy trial, 408 patients with type 2 diabetes were randomized to receive 7. 5 mg, 15 mg, 30 mg or 45 mg of pioglitazone, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 8 weeks prior to the double-blind period. Treatment with 15 mg, 30 mg and 45 mg of pioglitazone produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) at endpoint compared to placebo (see Figure 1 Table 17 Figure 1 shows the time course for changes in HbA1c in this 26-week study. Mean Change from Baseline for HbA1c in a 26-Week Placebo-Controlled Dose-Ranging Study (Observed Values) Table 17. Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Monotherapy Trial Placebo Pioglitazone 15 mg Once Daily Pioglitazone 30 mg Once Daily Pioglitazone 45 mg Once Daily Total Population HbA1c (%) N = 79 N = 79 N = 85 N = 76 Baseline (mean) 10. 3 Change from baseline (adjusted mean Adjusted for baseline, pooled center and pooled center by treatment interaction 0. 9 Difference from placebo (adjusted mean 95% Confidence Interval -1 p <= 0. placebo (-1. 2, -1) Fasting Plasma Glucose (mg/dL) N = 79 N = 79 N= 84 N = 77 Baseline (mean) 268 267 269 276 Change from baseline (adjusted mean 9 -30 -32 -56 Difference from placebo (adjusted mean 95% Confidence Interval -39 (-63, -16) -41 (-64, -18) -65 (-89, -42) In a 24-week placebo-controlled monotherapy trial, 260 patients with type 2 diabetes were randomized to one of two forced-titration pioglitazone treatment groups or a mock-titration placebo group. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. In one pioglitazone treatment group, patients received an initial dose of 7. 5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the trial (16 weeks). In the second pioglitazone treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with pioglitazone, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 18 Table 18. Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Monotherapy Trial Placebo Pioglitazone 30 mg Final dose in forced titration Once Daily Pioglitazone 45 mg Once Daily Total Population HbA1c (%) N = 83 N = 85 N = 85 Baseline (mean) 10. 8 Change from baseline (adjusted mean Adjusted for baseline, pooled center and pooled center by treatment interaction 0. 6 Difference from placebo (adjusted mean 95% Confidence Interval -1. placebo (-2, -1) -1. 5 (-2, -1) Fasting Plasma Glucose (mg/dL) N = 78 N = 82 N = 85 Baseline (mean) 279 268 281 Change from baseline (adjusted mean 18 -44 -50 Difference from placebo (adjusted mean 95% Confidence Interval -62 (-82, -0. 41) -68 (-88, -0. 48) In a 16-week monotherapy trial, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of pioglitazone or placebo once daily. Treatment with 30 mg of pioglitazone produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 19 Table 19. Glycemic Parameters in a 16-Week Placebo-Controlled Monotherapy Trial Placebo Pioglitazone 30 mg Once Daily Total Population HbA1c (%) N = 93 N = 100 Baseline (mean) 10. 5 Change from baseline (adjusted mean Adjusted for baseline, pooled center and pooled center by treatment interaction 0. 9) Fasting Plasma Glucose (mg/dL) N = 91 N = 99 Baseline (mean) 270 273 Change from baseline (adjusted mean 8 -50 Difference from placebo (adjusted mean 95% Confidence Interval -58 (-77, -38) Figure 1 Three 16-week, randomized, double-blind, placebo-controlled clinical trials were conducted to evaluate the effects of pioglitazone (15 mg and/or 30 mg) on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c >= 8%) despite current therapy with a sulfonylurea, metformin or insulin. In addition, three 24-week randomized, double-blind clinical trials were conducted to evaluate the effects of pioglitazone 30 mg vs. pioglitazone 45 mg on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c >= 8%) despite current therapy with a sulfonylurea, metformin or insulin. Previous diabetes treatment may have been monotherapy or combination therapy. Add-on to Sulfonylurea Trials Two clinical trials were conducted with pioglitazone in combination with a sulfonylurea. Both studies included patients with type 2 diabetes on any dose of a sulfonylurea, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn at least 3 weeks prior to starting study treatment. In the first study, 560 patients were randomized to receive 15 mg or 30 mg of pioglitazone or placebo once daily for 16 weeks in addition to their current sulfonylurea regimen. Treatment with pioglitazone as add-on to sulfonylurea produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to sulfonylurea (see Table 20 Table 20. Glycemic Parameters in a 16-Week Placebo-Controlled, Add-on to Sulfonylurea Trial Placebo + Sulfonylurea Pioglitazone 15 mg + Sulfonylurea Pioglitazone 30 mg + Sulfonylurea Total Population HbA1c (%) N = 181 N = 176 N = 182 Baseline (mean) 9. 9 Change from baseline (adjusted mean Adjusted for baseline, pooled center and pooled center by treatment interaction 0. 2 Difference from placebo + sulfonylurea (adjusted mean 95% Confidence Interval -0. placebo + sulfonylurea (-1. 6, -1) Fasting Plasma Glucose (mg/dL) N = 182 N = 179 N = 186 Baseline (mean) 236 247 239 Change from baseline (adjusted mean 6 -34 -52 Difference from placebo + sulfonylurea (adjusted mean 95% Confidence Interval -39 (-52, -27) -58 (-70, -46) In the second trial, 702 patients were randomized to receive 30 mg or 45 mg of pioglitazone once daily for 24 weeks in addition to their current sulfonylurea regimen. The mean reduction from baseline at Week 24 in HbA1c was 1. 6% for the 30 mg dose and 1. 7% for the 45 mg dose (see Table 21 The therapeutic effect of pioglitazone in combination with sulfonylurea was observed in patients regardless of the sulfonylurea dose. Glycemic Parameters in a 24-Week Add-on to Sulfonylurea Trial 95% CI = 95% confidence interval Pioglitazone 30 mg + Sulfonylurea Pioglitazone 45 mg + Sulfonylurea Total Population HbA1c (%) N = 340 N = 332 Baseline (mean) 9. 9 Change from baseline (adjusted mean Adjusted for baseline, pooled center and pooled center by treatment interaction -1. 7 Difference from 30 mg daily pioglitazone + sulfonylurea (adjusted mean -0. 1) Fasting Plasma Glucose (mg/dL) N = 338 N = 329 Baseline (mean) 214 217 Change from baseline (adjusted mean -52 -56 Difference from 30 mg daily pioglitazone + sulfonylurea (adjusted mean -5 (-12, 3) Add-on to Metformin Trials Two clinical trials were conducted with pioglitazone in combination with metformin. Both trials included patients with type 2 diabetes on any dose of metformin, either alone or in combination with another antidiabetic agent. In the first trial, 328 patients were randomized to receive either 30 mg of pioglitazone or placebo once daily for 16 weeks in addition to their current metformin regimen. Treatment with pioglitazone as add-on to metformin produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to metformin (see Table 22 Table 22. Glycemic Parameters in a 16-Week Placebo-Controlled, Add-on to Metformin Trial Placebo + Metformin Pioglitazone 30 mg + Metformin Total Population HbA1c (%) N = 153 N = 161 Baseline (mean) 9. 6 Difference from placebo + metformin (adjusted mean 95% Confidence Interval -0. placebo + metformin (-1. 5) Fasting Plasma Glucose (mg/dL) N = 157 N = 165 Baseline (mean) 260 254 Change from baseline (adjusted mean -5 -43 Difference from placebo + metformin (adjusted mean 95% Confidence Interval -38 (-49, -26) In the second trial, 827 patients were randomized to receive either 30 mg or 45 mg of pioglitazone once daily for 24 weeks in addition to their current metformin regimen. The mean reduction from baseline at Week 24 in HbA1c was 0. 8% for the 30 mg dose and 1% for the 45 mg dose (see Table 23 Table 23. Glycemic Parameters in a 24-Week Add-on to Metformin Study 95% CI = 95% confidence interval Pioglitazone 30 mg + Metformin Pioglitazone 45 mg + Metformin Total Population HbA1c (%) N = 400 N = 398 Baseline (mean) 9. 8 Change from baseline (adjusted mean Adjusted for baseline, pooled center and pooled center by treatment interaction -0. 8 -1 Difference from 30 mg daily pioglitazone + metformin (adjusted mean -0. 1) Fasting Plasma Glucose (mg/dL) N = 398 N = 399 Baseline (mean) 233 232 Change from baseline (adjusted mean -38 -51 Difference from 30 mg daily pioglitazone + metformin (adjusted mean -12 p <= 0. 30 mg daily pioglitazone + metformin (-21, -4) The therapeutic effect of pioglitazone in combination with metformin was observed in patients regardless of the metformin dose. Add-on to Insulin Trials Two clinical trials were conducted with pioglitazone in combination with insulin. Both trials included patients with type 2 diabetes on insulin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first trial, 566 patients were randomized to receive either 15 mg or 30 mg of pioglitazone or placebo once daily for 16 weeks in addition to their insulin regimen. Treatment with pioglitazone as add-on to insulin produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to insulin (see Table 24 Table 24. Glycemic Parameters in a 16-Week Placebo-Controlled, Add-on to Insulin Trial Placebo + Insulin Pioglitazone 15 mg + Insulin Pioglitazone 30 mg + Insulin Total Population HbA1c (%) N = 177 N = 177 N = 185 Baseline (mean) 9. 3 Difference from placebo + insulin (adjusted mean) 95% Confidence Interval -0. placebo + insulin (-1, -0. 7) Fasting Plasma Glucose (mg/dL) N = 179 N = 183 N = 184 Baseline (mean) 221 222 229 Change from baseline (adjusted mean 1 -35 -48 Difference from placebo + insulin (adjusted mean 95% Confidence Interval -35 (-51, -19) -49 (-65, -33) In the second trial, 690 patients receiving a median of 60 units per day of insulin were randomized to receive either 30 mg or 45 mg of pioglitazone once daily for 24 weeks in addition to their current insulin regimen. 2% for the 30 mg dose and 1. 5% for the 45 mg dose. The mean reduction from baseline at Week 24 in FPG was 32 mg/dL for the 30 mg dose and 46 mg/dL for the 45 mg dose (see Table 25 The therapeutic effect of pioglitazone in combination with insulin was observed in patients regardless of the insulin dose. Glycemic Parameters in a 24-Week Add-on to Insulin Trial 95% CI = 95% confidence interval Pioglitazone 30 mg + Insulin Pioglitazone 45 mg + Insulin Total Population HbA1c (%) N = 328 N = 328 Baseline (mean) 9. 7 Change from baseline (adjusted mean Adjusted for baseline, pooled center and pooled center by treatment interaction -1. 5 Difference from 30 mg daily pioglitazone + Insulin (adjusted mean -0. 30 mg daily pioglitazone + insulin (-0. 1) Fasting Plasma Glucose (mg/dL) N = 325 N = 327 Baseline (mean) 202 199 Change from baseline (adjusted mean -32 -46 Difference from 30 mg daily pioglitazone + Insulin (adjusted mean -14 (-25, -3).
MEDICATION GUIDE
Pioglitazone Tablets, USP (pie-oh-GLIT-ah-zohn) Read this Medication Guide carefully before you start taking pioglitazone tablets and each time you get a 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 pioglitazone tablets, ask your doctor or pharmacist. What is the most important information I should know about pioglitazone tablets? Pioglitazone tablets can cause serious side effects, including new or worse heart failure. Call your doctor right away if you have any of the following: Pioglitazone tablets can have other serious side effects. See “What are the possible side effects of pioglitazone tablets?” What are pioglitazone tablets? Pioglitazone tablets are a prescription medicine used with diet and exercise to improve blood sugar (glucose) control in adults with type 2 diabetes. Pioglitazone tablets are a diabetes medicine called pioglitazone that may be taken alone or with other diabetes medicines. It is not known if pioglitazone tablets are safe and effective in children under the age of 18. Pioglitazone tablets are not recommended for use in children. Pioglitazone tablets are not for people with type 1 diabetes. Pioglitazone tablets are not for people with diabetic ketoacidosis (increased ketones in your blood or urine). Who should not take pioglitazone tablets? See “What is the most important information I should know about pioglitazone tablets?” Do not take pioglitazone tablets if you: . Talk to your doctor before taking pioglitazone tablets if you have either of these conditions. What should I tell my doctor before taking pioglitazone tablets? Before you take pioglitazone tablets, tell your doctor if you: have heart failure have type 1 (“juvenile”) diabetes or had diabetic ketoacidosis have a type of diabetic eye disease that causes swelling in the back of the eye (macular edema) have liver problems have or have had cancer of the bladder are pregnant or plan to become pregnant. are a premenopausal woman (before the “change of life”) who does not have periods regularly or at all. are breastfeeding or plan to breastfeed. Tell your doctor about all the medicines you take Pioglitazone tablets and some of your other medicines can affect each other. You may need to have your dose of pioglitazone tablets or certain other medicines changed. Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist before you start a new medicine. They will tell you if it is okay to take pioglitazone tablets with other medicines. How should I take pioglitazone tablets? What are the possible side effects of pioglitazone tablets? Pioglitazone tablets may cause serious side effects including: See “What is the most important information I should know about pioglitazone tablets?” low blood sugar (hypoglycemia). liver problems ∘ ∘ ∘ ∘ ∘ ∘ bladder cancer. ∘ ∘ ∘ broken bones (fractures). diabetic eye disease with swelling in the back of the eye (macular edema) release of an egg from an ovary in a woman (ovulation) leading to pregnancy. The most common side effects of pioglitazone tablets include: Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the side effects of pioglitazone tablets. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store pioglitazone tablets? General information about the safe and effective use of pioglitazone tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use pioglitazone tablets for a condition for which it was not prescribed. Do not give pioglitazone tablets to other people, even if they have the same symptoms you have. It may harm them. This Medication Guide summarizes the most important information about pioglitazone tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about pioglitazone tablets that is written for healthcare professionals. For more information, call Sandoz at 1-800-525-8747. What are the ingredients in pioglitazone tablets? Active Ingredient: pioglitazone hydrochloride Inactive Ingredients: carboxymethyl cellulose calcium, hydroxypropyl cellulose, lactose monohydrate, and magnesium stearate. This Medication Guide has been approved by the U.S. Food and Drug Administration. Finished Drug Product Manufactured by Lek Pharmaceuticals d.d. SI-1526 Ljubljana, Slovenia for Sandoz Inc., Princeton, NJ 08540 Rev. June 2018

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