DUETACT

DUETACT tablets are a thiazolidinedione and a sulfonylurea combination product that contains two oral antihyperglycemic agents: pioglitazone and glimepiride. The concomitant use of pioglitazone and a sulfonylurea, the class of drugs that includes glimepiride, has been previously approved based on clinical trials in patients with type 2 diabetes inadequately controlled on a sulfonylurea. Additional efficacy and safety information about pioglitazone and glimepiride monotherapies may be found in the prescribing information for each individual drug. Pioglitazone is an oral antidiabetic medication. Pioglitazone [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo . No differences were found in the pharmacologic activity between the two enantiomers. The structural formula is as shown: Pioglitazone hydrochloride is an odorless, white crystalline powder that has a molecular formula of C 19 H 20 N 2 O 3 S•HCl and a molecular weight of 392.90 daltons. It is soluble in N,N ‑dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether. Glimepiride is an oral sulfonylurea chemically identified as 1-[[ p -[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)-urea (C 24 H 34 N 4 O 5 S) with a molecular weight of 490.62. Glimepiride is a white to yellowish-white, crystalline, odorless to practically odorless powder and is practically insoluble in water. The structural formula is: DUETACT is available as a tablet for oral administration containing 30 mg pioglitazone (as the base) with 2 mg glimepiride (30 mg/2 mg) or 30 mg pioglitazone (as the base) with 4 mg glimepiride (30 mg/4 mg) formulated with the following excipients: croscarmellose sodium NF, lactose monohydrate NF, magnesium stearate NF, hydroxypropyl cellulose NF, polysorbate 80 NF, and microcrystalline cellulose NF. pio-chem structure.jpg glim-chem structure.jpg

DUETACT is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with a thiazolidinedione and sulfonylurea or who have inadequate glycemic control on a thiazolidinedione alone or a sulfonylurea alone [see Clinical Studies ( 14 )] . Important Limitations of Use Pioglitazone exerts its antihyperglycemic effect only in the presence of endogenous insulin. DUETACT 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 ( 5.5 )] . DUETACT is a thiazolidinedione and a sulfonylurea combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both pioglitazone and glimepiride is appropriate. ( 1 ) Important Limitations of Use: • Not for treatment of type 1 diabetes or diabetic ketoacidosis. ( 1 )

• Individualize the starting dose of DUETACT based on the patient's current regimen. ( 2.1 ) • May adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of pioglitazone 45 mg and glimepiride 8 mg. ( 2.1 ) • DUETACT should be given in a single dose once daily with meals. ( 2.1 ) • Obtain liver tests before starting DUETACT. If abnormal, use caution when treating with DUETACT, investigate the probable cause, treat (if possible) and follow appropriately. Monitoring liver tests while on DUETACT is not recommended in patients without liver disease. ( 5.5 ) 2.1 Recommendations for All Patients DUETACT should be taken once daily with the first main meal. DUETACT tablets are available as a 30 mg pioglitazone plus 2 mg glimepiride or a 30 mg pioglitazone plus 4 mg glimepiride tablet. If therapy with a combination tablet containing pioglitazone and glimepiride is considered appropriate the recommended starting dose is: • 30 mg/2 mg or 30 mg/4 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability, • for patients inadequately controlled on glimepiride monotherapy: 30 mg/2 mg or 30 mg/4 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability, • for patients inadequately controlled on pioglitazone monotherapy: 30 mg/2 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability, • for patients who are changing from combination therapy of pioglitazone plus glimepiride as separate tablets: DUETACT should be taken at doses that are as close as possible to the dose of pioglitazone and glimepiride already being taken, • for patients currently on a different sulfonylurea monotherapy or switching from combination therapy of pioglitazone plus a different sulfonylurea (e.g., glyburide, glipizide, chlorpropamide, tolbutamide, acetohexamide): 30 mg/2 mg once daily and adjusted after assessing adequacy of therapeutic response. Observe for hypoglycemia for one to two weeks due to the potential overlapping drug effect. • for patients with systolic dysfunction, the lowest approved dose of DUETACT should be prescribed only after titration from 15 mg to 30 mg of pioglitazone has been safely tolerated. After initiation of DUETACT or with dose increase, monitor patients carefully for hypoglycemia and adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure [see Boxed Warning and Warnings and Precautions ( 5.7 )] . Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating DUETACT. Routine periodic monitoring of liver tests during treatment with DUETACT is not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of DUETACT or who are found to have abnormal liver tests while taking DUETACT should be managed as described under Warnings and Precautions [see Warnings and Precautions ( 5.5 ) and Clinical Pharmacology ( 12.3 )] . 2.2 Concomitant Use with an Insulin Secretagogue or Insulin If hypoglycemia occurs in a patient coadministered DUETACT and an insulin secretagogue, the dose of the insulin secretagogue should be reduced. If hypoglycemia occurs in a patient coadministered DUETACT 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. 2.3 Concomitant Use with Strong CYP2C8 Inhibitors Coadministration of pioglitazone and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of pioglitazone is 15 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors. If gemfibrozil or other CYP2C8 inhibitors need to co-administered, patients should switch to individual components of DUETACT because the minimum dose of pioglitazone in DUETACT exceeds 15 mg [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )] . 2.4 Concomitant Use with Colesevelam When colesevelam is coadministered with glimepiride, maximum plasma concentration and total exposure to glimepiride is reduced. Therefore, DUETACT should be administered at least four hours prior to colesevelam [see Drug Interactions ( 7.7 ) and Clinical Pharmacology ( 12.3 )] .

• Initiation in patients with established NYHA Class III or IV heart failure [see Boxed Warning ] . • Use in patients with known hypersensitivity to pioglitazone, glimepiride or any other component of DUETACT [see Warnings and Precautions ( 5.3 )] . • Use in patients with known history of an allergic reaction to sulfonamide derivatives. Reported hypersensitivity reactions with glimepiride include cutaneous eruptions with or without pruritus as well as more serious reactions (e.g., anaphylaxis, angioedema, Stevens-Johnson Syndrome, dyspnea) [see Warnings and Precautions ( 5.3 ) and Adverse Reactions ( 6.2 )] • Initiation in patients with established New York Heart Association (NYHA) Class III or IV heart failure [see Boxed Warning ] . ( 4 ) • Use in patients with known hypersensitivity to pioglitazone, glimepiride or any other component of DUETACT. ( 4 ) • Hypersensitivity to sulfonamide derivatives. ( 4 )

The following serious adverse reactions are discussed elsewhere in the labeling: • Congestive Heart Failure [see Boxed Warning and Warnings and Precautions ( 5.1 )] • Hypoglycemia [see Warnings and Precautions ( 5.2 )] • Edema [see Warnings and Precautions ( 5.7 )] • Fractures [see Warnings and Precautions ( 5.8 )] • Hemolytic Anemia [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (≥5%) are upper respiratory tract infection, accidental injury, and combined edema/peripheral edema. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals America, Inc. at 1-877-TAKEDA-7 (1-877-825-3327) 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. The adverse events reported in at least 5% of patients in the controlled 16-week clinical studies between placebo plus a sulfonylurea and pioglitazone (15 mg and 30 mg combined) plus sulfonylurea treatment arms were upper respiratory tract infection (15.5% and 16.6%), accidental injury (8.6% and 3.5%), and combined edema/peripheral edema (2.1% and 7.2%), respectively. The incidence and type of adverse events reported in at least 5% of patients in any combined treatment group from the 24-week study comparing pioglitazone 30 mg plus a sulfonylurea and pioglitazone 45 mg plus a sulfonylurea are shown in Table 1 ; the rate of adverse events resulting in study discontinuation between the two treatment groups was 6% and 9.7%, respectively. Table 1. Adverse Events that Occurred in ≥5% of Patients in Any Treatment Group During the 24-Week Study Adverse Event Pioglitazone 30 mg + Sulfonylurea N=351 n (%) Pioglitazone 45 mg + Sulfonylurea N=351 n (%) Hypoglycemia 47 (13.4) 55 (15.7) Upper Respiratory Tract Infection 43 (12.3) 52 (14.8) Weight Increased 32 (9.1) 47 (13.4) Edema Lower Limb 20 (5.7) 43 (12.3) Headache 25 (7.1) 14 (4.0) Urinary Tract Infection 20 (5.7) 24 (6.8) Diarrhea 21 (6.0) 15 (4.3) Nausea 18 (5.1) 14 (4.0) Pain in Limb 19 (5.4) 14 (4.0) In US double-blind studies, anemia was reported in ≤2% of patients treated with pioglitazone plus a sulfonylurea [see Warnings and Precautions ( 5.9 )] . Pioglitazone Over 8500 patients with type 2 diabetes have been treated with pioglitazone in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes and macrovascular disease treated with pioglitazone in the PROactive clinical trial. In these trials, over 6000 patients have been treated with pioglitazone for six months or longer, over 4500 patients have been treated with pioglitazone for one year or longer, and over 3000 patients have been treated with pioglitazone for at least two 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 (3.0%). In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% 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 2 . 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 the pioglitazone dose. Table 2. 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 A summary of the overall incidence and types of common adverse events reported in the PROactive trial is provided in Table 3 . 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. Mean duration of patient follow-up was 34.5 months. Table 3. PROactive Trial: Incidence and Types of Adverse Events Reported in >5% of Patients Treated with Pioglitazone and More Commonly than Placebo % of Patients Placebo N=2633 Pioglitazone N=2605 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 5.0 5.1 Congestive Heart Failure A summary of the incidence of adverse events related to congestive heart failure is provided in Table 4 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 4. 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 (1.0%) 2 (1.1%) 3 (0.9%) 5 (1.4%) Hospitalized 0 2 (1.0%) 1 (0.5%) 1 (0.3%) 3 (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 (0.6%) 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 5. Table 5. 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 6. Table 6. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) in PROactiveTrial Number (%) of Patients Placebo N=2633 Pioglitazone N=2605 At least one hospitalized CHF event 108 (4.1%) 149 (5.7%) Fatal 22 (0.8%) 25 (1%) Hospitalized, nonfatal 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, 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: 0.80, 1.02; p=0.10). Although there was no statistically significant difference between pioglitazone and placebo for the three-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 7. Table 7. PROactive: Number of First and Total Events for Each Component within the Cardiovascular Composite Endpoint Cardiovascular Events Placebo N=2633 Pioglitazone N=2605 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 (4.0) 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 CABG = coronary artery bypass grafting; PCI = percutaneous intervention 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 8 and 9 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 8. 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 (-2.7/0.0) N=256 0.9 (-0.5/3.4) N=79 1.0 (-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 (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 (-0.9/5.0) 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 9. Median Change in Body Weight in Patients Treated with Pioglitazone vs Patients Treated with Placebo During the Double-Blind Treatment Period in the PROactive Trial 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, 2.0) N=2581 +3.6 (0.0, 7.5) N=2560 Note: Median exposure for both Pioglitazone and Placebo was 2.7 years 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 10. Table 10. Adverse Events of Edema in Patients Treated with Pioglitazone Number (%) of 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 (7.0%) N=187 24 (12.6%) N=191 109 (20.5%) N=533 90 (26.1%) N=345 Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of "edema." Table 11. Adverse Events of Edema in Patients in the PROactive Trial Number (%) of Patients Placebo N=2633 Pioglitazone N=2605 419 (15.9%) 712 (27.3%) Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of "edema." Hepatic Effects There has been no evidence of pioglitazone-induced hepatotoxicity 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 three times the upper limit of the reference range, measured every eight 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 (15.7% versus 13.4%) and in the 24-week add-on to insulin trial (47.8% versus 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) ] . During the three year PROactive clinical trial, 14 patients out of 2605 (0.54%) randomized to pioglitazone and 5 out of 2633 (0.19%) randomized to placebo were diagnosed with bladder cancer. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases on pioglitazone and two (0.08%) cases on placebo. After completion of the trial, a large subset of patients was observed for up to 10 additional years, with little additional exposure to pioglitazone. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or placebo (HR =1.00; 95% CI: 0.59-1.72) [see Warnings and Precautions (5.6) ] . Glimepiride Adverse events that occurred in controlled clinical trials with placebo and glimepiride monotherapy, other than hypoglycemia, included: headache (7.8% and 8.2%), accidental injury (3.4% and 5.8%), flu syndrome (4.4% and 5.4%), nausea (3.4% and 5.0%) and dizziness (2.4% and 5.0%), respectively. Hypoglycemia In a randomized, double-blind, placebo-controlled monotherapy trial of 14 weeks duration, patients already on sulfonylurea therapy underwent a 3-week washout period then were randomized to glimepiride 1 mg, 4 mg, 8 mg or placebo. Patients randomized to glimepiride 4 mg or 8 mg underwent forced-titration from an initial dose of 1 mg to these final doses, as tolerated. The overall incidence of possible hypoglycemia (defined by the presence of at least one symptom that the investigator believed might be related to hypoglycemia; a concurrent glucose measurement was not required) was 4% for glimepiride 1 mg, 17% for glimepiride 4 mg, 16% for glimepiride 8 mg and 0% for placebo. All of these events were self-treated. In a randomized, double-blind, placebo-controlled monotherapy trial of 22 weeks duration, patients received a starting dose of either 1 mg glimepiride or placebo daily. The dose of glimepiride was titrated to a target fasting plasma glucose of 90 −150 mg/dL. Final daily doses of glimepiride were 1, 2, 3, 4, 6 or 8 mg. The overall incidence of possible hypoglycemia (as defined above for the 14-week trial) for glimepiride versus placebo was 19.7% vs. 3.2%. All of these events were self-treated. Weight Gain Glimepiride, like all sulfonylureas, can cause weight gain. Allergic Reactions In clinical trials, allergic reactions, such as pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occurred in less than 1% of glimepiride-treated patients. These may resolve despite continued treatment with glimepiride. There are postmarketing reports of more serious allergic reactions (e.g., dyspnea, hypotension, shock) [see Warnings and Precautions ( 5.3 )] . Laboratory Tests Elevated Serum Alanine Aminotransferase (ALT) In 11 pooled placebo-controlled trials of glimepiride, 1.9% of glimepiride-treated patients and 0.8% of placebo-treated patients developed serum ALT greater than two times the upper limit of the reference range. Laboratory Abnormalities Pioglitazone 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 nine (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. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of pioglitazone and glimepiride. 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. Pioglitazone • New onset or worsening diabetic macular edema with decreased visual acuity [see Warnings and Precautions ( 5.10 )] . • Fatal and nonfatal hepatic failure [see Warnings and Precautions ( 5.5 )] . 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 and Warnings and Precautions ( 5.1 )] . Glimepiride • Serious hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson Syndrome [see Warnings and Precautions ( 5.3 )] • Hemolytic anemia in patients with and without G6PD deficiency [see Warnings and Precautions ( 5.9 )] • Impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis, which may progress to liver failure. • Porphyria cutanea tarda, photosensitivity reactions and allergic vasculitis • Leukopenia, agranulocytosis, aplastic anemia, and pancytopenia • Thrombocytopenia (including severe cases with platelet count less than 10,000/mcL) and thrombocytopenic purpura • Hepatic porphyria reactions and disulfiram-like reactions • Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH), most often in patients who are on other medications or who have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone

• Strong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone concentrations. Limit pioglitazone dose to 15 mg daily. ( 2.3 , 7.1 ) • CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations. ( 7.2 ) • Topiramate may decrease pioglitazone concentrations. ( 7.3 ) • Certain medications may affect glucose metabolism, requiring DUETACT dose adjustment and close monitoring of blood glucose ( 7.4 ). • Miconazole: Severe hypoglycemia can occur when DUETACT and oral miconazole are used concomitantly. ( 7.5 ) • CYP2C9 interactions: Inhibitors and inducers may affect glycemic control by altering glimepiride plasma concentrations. ( 7.6 ) • Colesevelam: Coadministration may reduce glimepiride absorption. DUETACT should be administered at least 4 hours prior to colesevelam. ( 2.4 , 7.7 ) 7.1 Strong CYP2C8 Inhibitors Pioglitazone An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the serum concentration-time curve or AUC) and half-life (t ½ ) of pioglitazone. Therefore, the maximum recommended dose of pioglitazone is 15 mg daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors. Since the minimum dose of pioglitazone in DUETACT exceeds 15 mg, patients taking concomitant strong CYP2C8 inhibitors should switch to individual components of DUETACT, unless the prescribing health care provider determines that the benefit of DUETACT clearly outweighs the risk of increased pioglitazone exposure [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 )] . 7.2 CYP2C8 Inducers Pioglitazone An inducer of CYP2C8 (e.g., 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 ( 12.3 )] . 7.3 Topiramate Pioglitazone A decrease in the exposure of pioglitazone and its active metabolites were noted with concomitant administration of pioglitazone and topiramate [see Clinical Pharmacology (12.3) ] . The clinical relevance of this decrease is unknown; however, when DUETACT and topiramate are used concomitantly, monitor patients for adequate glycemic control. 7.4 Drugs Affecting Glucose Metabolism Glimepiride A number of medications affect glucose metabolism and may require DUETACT dose adjustment and particularly close monitoring for hypoglycemia or worsening glycemic control. The following are examples of medications that may increase the glucose-lowering effect of sulfonylureas including glimepiride, a component of DUETACT, increasing the susceptibility to and/or intensity of hypoglycemia: oral anti-diabetic medications, pramlintide acetate, insulin, angiotensin converting enzyme (ACE) inhibitors, H2 receptor antagonists, fibrates, propoxyphene, pentoxifylline, somatostatin analogs, anabolic steroids and androgens, cyclophosphamide, phenyramidol, guanethidine, fluconazole, sulfinpyrazone, tetracyclines, clarithromycin, disopyramide, quinolones, and those drugs that are highly protein-bound, such as fluoxetine, nonsteroidal anti-inflammatory drugs, salicylates, sulfonamides, chloramphenicol, coumarins, probenecid and monoamine oxidase inhibitors. When these medications are administered to a patient receiving DUETACT, monitor the patient closely for hypoglycemia. When these medications are withdrawn from a patient receiving DUETACT, monitor the patient closely for worsening glycemic control. The following are examples of medications that may reduce the glucose-lowering effect of sulfonylureas including glimepiride, leading to worsening glycemic control: danazol, glucagon, somatropin, protease inhibitors, atypical antipsychotic medications (e.g., olanzapine and clozapine), barbiturates, diazoxide, laxatives, rifampin, thiazides and other diuretics, corticosteroids, phenothiazines, thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics (e.g., epinephrine, albuterol, terbutaline), and isoniazid. When these medications are administered to a patient receiving DUETACT, monitor the patient closely for worsening glycemic control. When these medications are withdrawn from a patient receiving DUETACT, monitor the patient closely for hypoglycemia. Beta-blockers, clonidine, and reserpine may lead to either potentiation or weakening of DUETACT's glucose-lowering effect. Both acute and chronic alcohol intake may potentiate or weaken the glucose-lowering action of DUETACT in an unpredictable fashion. The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic drugs such as beta-blockers, clonidine, guanethidine, and reserpine. 7.5 Miconazole Glimepiride A potential interaction between oral miconazole and sulfonylureas leading to severe hypoglycemia has been reported. Whether this interaction also occurs with other dosage forms of miconazole is not known. 7.6 CYP2C9 Interactions Glimepiride There may be an interaction between glimepiride and inhibitors (e.g., fluconazole) and inducers (e.g., rifampin) of CYP2C9. Fluconazole may inhibit the metabolism of glimepiride, causing increased plasma concentrations of glimepiride which may lead to hypoglycemia. Rifampin may induce the metabolism of glimepiride, causing decreased plasma concentrations of glimepiride which may lead to worsening glycemic control. 7.7 Concomitant Administration of Colesevelam Glimepiride Colesevelam can reduce the maximum plasma concentrations and total exposure of glimepiride when the two are coadministered. However, absorption is not reduced when glimepiride is administered four hours prior to colesevelam. Therefore, DUETACT should be administered at least four hours prior to colesevelam [see Clinical Pharmacology ( 12.3 )] .