Alogliptin and Pioglitazone

5 WARNINGS AND PRECAUTIONS Congestive heart failure: Fluid retention may occur and can exacerbate or lead to congestive heart failure. Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk. Consider the risks and benefits of OSENI prior to initiating treatment in patients at risk for heart failure. Monitor patients for signs and symptoms. ( 5.1 ) Pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue OSENI. ( 5.2 ) Hypersensitivity: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin such as anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. In such cases, promptly discontinue OSENI. ( 5.3 ) Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt OSENI and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart OSENI if liver injury is confirmed and no alternative etiology can be found. Use with caution in patients with liver disease. ( 5.4 ) Edema: Dose-related edema may occur. ( 5.5 ) Fractures: Increased incidence in female patients. Apply current standards of care for assessing and maintaining bone health. ( 5.6 ) Urinary bladder tumors: May increase the risk of bladder cancer. Do not use in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer. ( 5.7 ) Hypoglycemia: Consider a lower dose of insulin or insulin secretagogue to reduce risk of hypoglycemia when used in combination with OSENI. ( 5.8 ) Macular edema: Postmarketing reports. Recommend regular eye exams in all patients with diabetes according to current standards of care with prompt evaluation for acute visual changes. ( 5.9 ) Arthralgia: Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue if appropriate. ( 5.10 ) Bullous pemphigoid: There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue OSENI. ( 5.11 )

5.1 Congestive Heart Failure Alogliptin In the EXAMINE trial which enrolled patients with type 2 diabetes mellitus and recent acute coronary syndrome, 106 (3.9%) of patients treated with alogliptin and 89 (3.3%) of patients treated with placebo were hospitalized for congestive heart failure. Pioglitazone Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure [see Boxed Warning , Contraindications (4) and Adverse Reactions (6.1) ] . Consider the risks and benefits of OSENI prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment. Observe these patients for signs and symptoms of congestive heart failure. Advise patients about the symptoms of congestive heart failure and to immediately report such symptoms. If congestive heart failure develops while taking OSENI, consider discontinuation of OSENI or dosage reduction of pioglitazone in OSENI (6.1) ] .

5.2 Pancreatitis Acute pancreatitis has been reported in the postmarketing setting and in randomized clinical trials. In glycemic control trials in patients with type 2 diabetes mellitus, acute pancreatitis was reported in 6 (0.2%) patients treated with alogliptin 25 mg and 2 (<0.1%) patients treated with active comparators or placebo. In the EXAMINE trial (a cardiovascular outcomes trial of patients with type 2 diabetes mellitus and high cardiovascular (CV) risk), acute pancreatitis was reported in 10 (0.4%) patients treated with alogliptin and in 7 (0.3%) patients treated with placebo. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using OSENI . After initiation of OSENI, patients should be observed for signs and symptoms of pancreatitis. If pancreatitis is suspected, OSENI should promptly be discontinued and appropriate management should be initiated.

5.3 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin [see Adverse Reactions (6.2) ]. These reactions include anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. If a serious hypersensitivity reaction is suspected, discontinue OSENI, assess for other potential causes for the event and institute alternative treatment for diabetes. Use caution in patients with a history of angioedema with another dipeptidyl peptidase-4 (DPP-4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with OSENI.

5.4 Hepatic Effects There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking pioglitazone or alogliptin, although some of the reports contain insufficient information necessary to establish the probable cause [see Adverse Reactions (6.2) ] . In glycemic control trials of alogliptin in patients with type 2 diabetes mellitus, serum alanine aminotransferase (ALT) elevations greater than three times the upper limit of normal (ULN) were reported in 1.3% of patients treated with alogliptin 25 mg and 1.7% of patients treated with active comparators or placebo. In the EXAMINE trial (a cardiovascular outcomes trial of patients with type 2 diabetes mellitus and high cardiovascular (CV) risk), increases in serum alanine aminotransferase three times the upper limit of the reference range occurred in 2.4% of patients treated with alogliptin and in 1.8% of patients treated with placebo. Patients with type 2 diabetes mellitus may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel (ALT, aspartate aminotransferase [AST], alkaline phosphatase and total bilirubin) and assessing the patient is recommended before initiating OSENI therapy. In patients with abnormal liver tests, OSENI should be initiated with caution. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have clinically significant liver enzyme elevations (serum ALT greater than three times the ULN) and if abnormal liver tests persist or worsen, OSENI should be interrupted, and an investigation done to establish the probable cause. OSENI should not be restarted in these patients without another explanation for the liver test abnormalities.

5.5 Edema In controlled clinical trials, edema was reported more frequently in patients treated with pioglitazone than in placebo-treated patients and is dose-related [see Adverse Reactions (6.1) ]. In postmarketing experience, reports of new onset or worsening of edema have been received. OSENI should be used with caution in patients with edema. Because thiazolidinediones, including pioglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, OSENI should be used with caution in patients at risk for congestive heart failure. Patients treated with OSENI should be monitored for signs and symptoms of congestive heart failure [see Boxed Warning , Warnings and Precautions (5.1) ] .

5.6 Fractures In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5,238 patients with type 2 diabetes mellitus and a history of macrovascular disease were randomized to pioglitazone (N=2,605), force-titrated up to 45 mg daily or placebo (N=2,633) in addition to standard of care. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for pioglitazone versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and persisted during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in the incidence of fracture was observed in men treated with pioglitazone (1.7%) versus placebo (2.1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with pioglitazone and attention should be given to assessing and maintaining bone health according to current standards of care.

5.7 Urinary Bladder Tumors Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study [see Nonclinical Toxicology (13.1) ] . In addition, during the three year PROactive clinical trial, 14 patients out of 2,605 (0.54%) randomized to pioglitazone and 5 out of 2,633 (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 2 (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 [Hazard Ratio (HR) =1.00; (95% Confidence Interval (CI): 0.59, 1.72)]. Findings regarding the risk of bladder cancer in patients exposed to pioglitazone vary among observational studies; some did not find an increased risk of bladder cancer associated with pioglitazone, while others did. A large prospective 10 year observational cohort study conducted in the United States (U.S.) found no statistically significant increase in the risk of bladder cancer in diabetic patients ever exposed to pioglitazone, compared to those never exposed to pioglitazone [HR = 1.06 (95% CI: 0.89, 1.26)]. A retrospective cohort study conducted with data from the United Kingdom found a statistically significant association between ever exposure to pioglitazone and bladder cancer [HR = 1.63; (95% CI: 1.22, 2.19)]. Associations between cumulative dose or cumulative duration of exposure to pioglitazone and bladder cancer were not detected in some studies including the 10-year observational study in the U.S., but were in others. Inconsistent findings and limitations inherent in these and other studies preclude conclusive interpretations of the observational data. Pioglitazone may be associated with an increase in the risk of urinary bladder tumors. There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, OSENI should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with OSENI should be considered in patients with a prior history of bladder cancer.

5.8 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, a lower dosage of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with OSENI [see Drug Interactions (7.1) ] .

5.9 Macular Edema Macular edema has been reported in postmarketing experience in diabetic patients who were taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione. Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care. Patients with diabetes who report any visual symptoms should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings [see Adverse Reactions (6.1) ].

5.10 Severe and Disabling Arthralgia There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.

5.11 Bullous Pemphigoid Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving OSENI. If bullous pemphigoid is suspected, OSENI should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

The following serious adverse reactions are described below or elsewhere in the prescribing information: Congestive Heart Failure [see Boxed Warning and Warnings and Precautions (5.1) ] Pancreatitis [see Warnings and Precautions (5.2) ] Hypersensitivity Reactions [see Warnings and Precautions (5.3) ] Hepatic Effects [see Warnings and Precautions (5.4) ] Edema [see Warnings and Precautions (5.5) ] Fractures [see Warnings and Precautions (5.6) ] Urinary Bladder Tumors [see Warnings and Precautions (5.7) ] Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.8) ] Macular Edema [see Warnings and Precautions (5.9) ] Severe and Disabling Arthralgia [see Warnings and Precautions (5.10) ] Bullous Pemphigoid [see Warnings and Precautions (5.11) ] The most common adverse reactions (4% or greater incidence) are nasopharyngitis, back pain and upper respiratory tract infection. ( 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. Alogliptin and Pioglitazone Over 1,500 patients with type 2 diabetes mellitus have received alogliptin coadministered with pioglitazone in four large, randomized, double-blind, controlled clinical trials [see Clinical Studies (14) ] . The mean exposure to alogliptin and pioglitazone was 29 weeks with more than 100 subjects treated for more than one year. The studies consisted of two placebo-controlled studies of 16 to 26 weeks in duration and two active-controlled studies of 26 weeks and 52 weeks in duration. In the alogliptin and pioglitazone arm, the mean duration of diabetes was approximately six years, the mean body mass index (BMI) was 31 kg/m 2 (54% of patients had a BMI ≥30 kg/m 2 ), and the mean age was 54 years (16% of patients ≥65 years of age). In a pooled analysis of these four controlled clinical studies, the overall incidence of adverse reactions was 65% in patients treated with alogliptin and pioglitazone compared to 57% treated with placebo. Overall discontinuation of therapy due to adverse reactions was 2.5% with alogliptin and pioglitazone compared to 2.0% with placebo, 3.7% with pioglitazone or 1.3% with alogliptin. Adverse reactions reported in ≥4% of patients treated with alogliptin and pioglitazone and more frequently than in patients who received alogliptin, pioglitazone or placebo are summarized in Table 2 . Table 2. Adverse Reactions Reported in ≥4% of Patients Treated with Alogliptin and Pioglitazone and More Frequently than in Patients Receiving Either Alogliptin, Pioglitazone or Placebo Number of Patients (%) Alogliptin and pioglitazone Alogliptin and pioglitazone – includes data pooled for patients receiving alogliptin 25 mg and 12.5 mg combined with pioglitazone 15 mg, 30 mg and 45 mg Alogliptin Alogliptin – includes data pooled for patients receiving alogliptin 25 mg and 12.5 mg Pioglitazone Pioglitazone – includes data pooled for patients receiving pioglitazone 15 mg, 30 mg and 45 mg Placebo N=1533 N=446 N=949 N=153 Nasopharyngitis 75 (4.9) 21 (4.7) 37 (3.9) 6 (3.9) Back Pain 64 (4.2) 9 (2.0) 32 (3.4) 5 (3.3) Upper Respiratory Tract Infection 63 (4.1) 19 (4.3) 26 (2.7) 5 (3.3) Alogliptin Add-On Therapy to a Thiazolidinedione In a 26 week, placebo-controlled, double-blind study, patients inadequately controlled on a thiazolidinedione alone or in combination with metformin or a sulfonylurea were treated with add-on alogliptin therapy or placebo; the adverse reactions reported in ≥5% of patients and more frequently than in patients who received placebo was influenza (alogliptin, 5.5%; placebo, 4.1%). Hypoglycemia In a 26 week, placebo-controlled factorial study with alogliptin in combination with pioglitazone on background therapy with metformin, the incidence of subjects reporting hypoglycemia was 0.8%, 0% and 3.8% for alogliptin 25 mg with pioglitazone 15 mg, 30 mg or 45 mg, respectively; 2.3% for alogliptin 25 mg; 4.7%, 0.8% and 0.8% for pioglitazone 15 mg, 30 mg or 45 mg, respectively; and 0.8% for placebo. In a 26 week, active-controlled, double-blind study with alogliptin alone, pioglitazone alone or alogliptin coadministered with pioglitazone in patients inadequately controlled on diet and exercise, the incidence of hypoglycemia was 3% on alogliptin 25 mg with pioglitazone 30 mg, 0.6% on alogliptin 25 mg and 1.8% on pioglitazone 30 mg. In a 52 week, active-controlled, double-blind study of alogliptin as add-on therapy to the combination of pioglitazone 30 mg and metformin compared to the titration of pioglitazone 30 mg to 45 mg and metformin, the incidence of subjects reporting hypoglycemia was 4.5% in the alogliptin 25 mg with pioglitazone 30 mg and metformin group versus 1.5% in the pioglitazone 45 mg and metformin group. Alogliptin A total of 14,778 patients with type 2 diabetes mellitus participated in 14 randomized, double-blind, controlled clinical trials of whom 9,052 subjects were treated with alogliptin, 3,469 subjects were treated with placebo and 2,257 were treated with an active comparator. The racial distribution of patients exposed to trial medication was 71% White, 17% Asian, 6% Black or African American, 2% American Indian or Alaska Native, 0% Native Hawaiian/Other Pacific Islander and 5% Multiracial or other racial groups. The ethnic distribution was 30% Hispanic or Latino and 70% was not Hispanic or Latino. The mean duration of diabetes was seven years, the mean body mass index (BMI) was 31 kg/m 2 (49% of patients had a BMI ≥30 kg/m 2 ) and the mean age was 58 years (26% of patients ≥65 years of age). The mean exposure to alogliptin was 49 weeks with 3,348 subjects treated for more than one year. In a pooled analysis of these 14 controlled clinical trials, the overall incidence of adverse reactions was 73% in patients treated with alogliptin 25 mg compared to 75% with placebo and 70% with active comparator. Overall discontinuation of therapy due to adverse reactions was 6.8% with alogliptin 25 mg compared to 8.4% with placebo or 6.2% with active comparator. Adverse reactions reported in ≥4% of adult patients treated with alogliptin 25 mg and more frequently than in patients who received placebo are summarized in Table 3 . Table 3. Adverse Reactions Reported in ≥4% Adult Patients with Type 2 Diabetes Mellitus Treated with Alogliptin 25 mg and More Frequently Than in Patients Given Placebo in Pooled Trials Number of Patients (%) Alogliptin 25 mg Placebo Active Comparator N=6447 N=3469 N=2257 Nasopharyngitis 309 (5) 152 (4) 113 (5) Upper Respiratory Tract Infection 287 (5) 121 (4) 113 (5) Headache 278 (4) 101 (3) 121 (5) Hypoglycemia Hypoglycemic events were documented based upon a blood glucose value and/or clinical signs and symptoms of hypoglycemia. In the monotherapy trial, the incidence of hypoglycemia was 1.5% in patients treated with alogliptin compared to 1.6% with placebo. The use of alogliptin as add-on therapy to glyburide or insulin did not increase the incidence of hypoglycemia compared to placebo. In a monotherapy trial comparing alogliptin to a sulfonylurea in elderly patients, the incidence of hypoglycemia was 5.4% with alogliptin compared to 26% with glipizide. In the EXAMINE trial, the incidence of investigator reported hypoglycemia was 6.7% in patients receiving alogliptin and 6.5% in patients receiving placebo. Serious adverse reactions of hypoglycemia were reported in 0.8% of patients treated with alogliptin and in 0.6% of patients treated with placebo. Renal Impairment In glycemic control trials in patients with type 2 diabetes mellitus, 3.4% of patients treated with alogliptin and 1.3% of patients treated with placebo had renal function adverse reactions. The most commonly reported adverse reactions were renal impairment (0.5% for alogliptin and 0.1% for active comparators or placebo), decreased creatinine clearance (1.6% for alogliptin and 0.5% for active comparators or placebo) and increased blood creatinine (0.5% for alogliptin and 0.3% for active comparators or placebo) [see Use in Specific Populations (8.6) ] . In the EXAMINE trial of high CV risk type 2 diabetes mellitus patients, 23% of patients treated with alogliptin and 21% of patients treated with placebo had an investigator reported renal impairment adverse reaction. The most commonly reported adverse reactions were renal impairment (7.7% for alogliptin and 6.7% for placebo), decreased glomerular filtration rate (4.9% for alogliptin and 4.3% for placebo) and decreased renal clearance (2.2% for alogliptin and 1.8% for placebo). Laboratory measures of renal function were also assessed. Estimated glomerular filtration rate decreased by 25% or more in 21.1% of patients treated with alogliptin and 18.7% of patients treated with placebo. Worsening of chronic kidney disease stage was seen in 16.8% of patients treated with alogliptin and in 15.5% of patients treated with placebo. Pioglitazone Over 8,500 patients with type 2 diabetes mellitus have been treated with pioglitazone in randomized, double-blind, controlled clinical trials, including 2,605 patients with type 2 diabetes mellitus and macrovascular disease treated with pioglitazone in the PROactive clinical trial. In these trials, over 6,000 patients have been treated with pioglitazone for six 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 two years. Common Adverse Reactions: 16 to 26-Week Monotherapy Trials A summary of the incidence and type of common adverse reactions reported in three pooled 16 to 26 week placebo-controlled monotherapy trials of pioglitazone is provided in Table 4 . 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 reactions were related to pioglitazone dose. Table 4. Three Pooled 16 to 26 Week Placebo-Controlled Clinical Trials of Pioglitazone Monotherapy: Adverse Reactions 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 Congestive Heart Failure A summary of the incidence of adverse reactions related to congestive heart failure 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 were (at least one congestive heart failure, 0.2% to 1.7%; hospitalized due to congestive heart failure, 0.2% to 0.9%). None of the reactions were fatal. Patients with type 2 diabetes mellitus 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 reactions related to congestive heart failure reported in this study is provided in Table 5 . Table 5. Treatment-Emergent Adverse Reactions 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 Reactions of Congestive Heart Failure (CHF) in PROactive Trial Number (%) of Patients Placebo N=2,633 Pioglitazone N=2,605 At least one hospitalized congestive heart failure event 108 (4.1%) 149 (5.7%) Fatal 22 (0.8%) 25 (1%) Hospitalized, nonfatal 86 (3.3%) 124 (4.7%) Cardiovascular Safety In the PROactive trial, 5,238 patients with type 2 diabetes mellitus and a history of macrovascular disease were randomized to pioglitazone (N=2,605), force-titrated up to 45 mg daily or placebo (N=2,633) in addition to standard of care. 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 mellitus of 9.5 years and mean A1C 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=2,633 Pioglitazone N=2,605 First Events n (%) Total Events n First Events n (%) Total Events n CABG=coronary artery bypass grafting; PCI=percutaneous intervention 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 (0.6) 28 9 (0.3) 28 Leg Revascularization 57 (2.2) 92 71 (2.7) 115 Weight Gain Dose-related weight gain occurs when pioglitazone is used alone or in combination with other antidiabetic medications. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. 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. Hepatic Effects There has been no evidence of pioglitazone-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date. One randomized, double-blind, three-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 reactions of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with finger stick 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 2,605 (0.54%) randomized to pioglitazone and 5 out of 2,633 (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 2 (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 (5.7) ] . 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 four 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 2,150 to 11,400 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 the postmarketing use of alogliptin or pioglitazone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Alogliptin Gastrointestinal Disorders: acute pancreatitis, diarrhea, constipation, nausea, ileus Hepatobiliary Disorders: fulminant hepatic failure Immune System Disorders: hypersensitivity reactions including anaphylaxis Investigations: hepatic enzyme elevations Musculoskeletal and Connective Tissue Disorders: severe and disabling arthralgia, rhabdomyolysis Renal and Urinary Disorders: tubulointerstitial nephritis Skin and Subcutaneous Tissue Disorders: angioedema, rash, urticaria and severe cutaneous adverse reactions including Stevens-Johnson syndrome, bullous pemphigoid Pioglitazone Cardiac Disorders: rapid increases in weight, edema, congestive heart failure both with and without previously known heart disease or concomitant insulin administration Eye Disorders: New onset or worsening diabetic macular edema with decreased visual acuity Hepatobiliary Disorders: Fatal and nonfatal hepatic failure

Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. ( 8.3 ) Pediatrics: safety and effectiveness have not been established. ( 8.4 )

8.1 Pregnancy Risk Summary Limited data with OSENI in pregnant women are not sufficient to inform 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. No adverse developmental effects were observed when alogliptin was administered to pregnant rats and rabbits during organogenesis at exposures 180 and 149 times the 25 mg clinical dose, respectively, based on plasma drug exposure (AUC) [see Data ] . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, 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, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Data Animal Data Alogliptin and Pioglitazone Co-administration of 100 mg/kg alogliptin and 40 mg/kg pioglitazone (39 and 10 times the 25 mg and 45 mg clinical doses, respectively, based on body surface area) to pregnant rats during organogenesis slightly augmented pioglitazone-related fetal effects of delayed development and reduced fetal weights but did not result in embryofetal mortality or teratogenicity. Alogliptin Alogliptin administered to pregnant rabbits and rats during the period of organogenesis did not cause adverse developmental effects at doses of up to 200 mg/kg and 500 mg/kg, or 149 times and 180 times, the 25 mg clinical dose, respectively, based on plasma drug exposure (AUC). Placental transfer of alogliptin into the fetus was observed following oral dosing to pregnant rats. No adverse developmental outcomes were observed in offspring when alogliptin was administered to pregnant rats during gestation and lactation at doses up to 250 mg/kg (~95 times the 25 mg clinical dose, based on AUC). Pioglitazone 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.

8.2 Lactation Risk Summary There is no information regarding the presence of pioglitazone or alogliptin in human milk, the effects on the breastfed infant, or the effects on milk production. Pioglitazone and alogliptin are present in rat milk; however, due to species-specific differences in lactation physiology, animal lactation 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 OSENI and any potential adverse effects on the breastfed infant from OSENI or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some anovulatory women.

8.4 Pediatric Use Safety and effectiveness of OSENI in pediatric patients have not been established. OSENI 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 (5.1 , 5.5 , 5.6 , 5.7) ] .

8.5 Geriatric Use Alogliptin and Pioglitazone Of the total number of patients (N=1,533) in clinical safety and efficacy studies treated with alogliptin and pioglitazone, 248 (16.2%) patients were 65 years and older and 15 (1%) patients were 75 years and older. No overall differences in safety or effectiveness were observed between patients 65 years of age and older and younger adult patients. Alogliptin Of the total number of patients (N=9,052) in clinical safety and efficacy studies treated with alogliptin, 2,257 (24.9%) patients were ≥65 years old and 386 (4.3%) patients were ≥75 years old. No overall differences in safety or effectiveness were observed between patients 65 years of age and older and younger adult patients. Pioglitazone 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, 1068 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. These clinical experiences have not identified differences in effectiveness and safety between the elderly (≥65 years) and younger patients although small sample sizes for patients ≥75 years old limit conclusions [see Clinical Pharmacology (12.3) ] .

8.6 Renal Impairment Alogliptin A total of 602 patients with moderate renal impairment (eGFR ≥30 and <60 mL/min/1.73 m 2 ) and four patients with severe renal impairment/end-stage renal disease (eGFR <30 mL/min/1.73 m 2 or <15 mL/min/1.73 m 2 , respectively) at baseline were treated with alogliptin in clinical trials in patients with type 2 diabetes mellitus. In the EXAMINE trial of high CV risk type 2 diabetes mellitus patients, 694 patients had moderate renal impairment and 78 patients had severe renal impairment or end-stage renal disease at baseline. The recommended dosage of OSENI for patients with moderate renal impairment (CrCl ≥30 to <60 mL/min) is 12.5 mg of alogliptin and 30 mg of pioglitazone once daily. OSENI is not recommended for patients with severe renal impairment (CrCl ≥15 to <30 mL/min) or ESRD (CrCl <15 mL/min or requiring hemodialysis) [see Dosage and Administration (2.3) ] .

8.7 Hepatic Impairment Alogliptin No dosage adjustments are required in patients with mild to moderate hepatic impairment (Child-Pugh Grade A and B) [see Clinical Pharmacology (12.3) ] . Alogliptin has not been studied in patients with severe hepatic impairment (Child-Pugh Grade C). Use caution when administering alogliptin to patients with liver disease [see Warnings and Precautions (5.4) ]. Pioglitazone No dosage adjustments are required in patients with hepatic impairment (Child-Pugh Grade B and C) based on insignificant change in systemic exposures (e.g., AUC) compared to subjects with normal hepatic function in a pharmacokinetic study. However, use with caution in patients with liver disease [see Warnings and Precautions (5.4) ].

12.1 Mechanism of Action OSENI combines two antihyperglycemic agents: alogliptin and pioglitazone. Alogliptin Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the dipeptidyl peptidase-4 (DPP-4) enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes mellitus, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Alogliptin is a DPP-4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus. Alogliptin selectively binds to and inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures. Pioglitazone 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 (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle and liver. Activation of PPARγ 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 mellitus. 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.

12.2 Pharmacodynamics Alogliptin and Pioglitazone In a 26 week, randomized, active-controlled study, patients with type 2 diabetes mellitus received alogliptin 25 mg coadministered with pioglitazone 30 mg, alogliptin 12.5 mg coadministered with pioglitazone 30 mg, alogliptin 25 mg alone or pioglitazone 30 mg alone. Patients who were randomized to alogliptin 25 mg with pioglitazone 30 mg achieved a 26.2% decrease in triglyceride levels from a mean baseline of 214.2 mg/dL compared to an 11.5% decrease for alogliptin alone and a 21.8% decrease for pioglitazone alone. In addition, a 14.4% increase in HDL cholesterol levels from a mean baseline of 43.2 mg/dL was also observed for alogliptin 25 mg with pioglitazone 30 mg compared to a 1.9% increase for alogliptin alone and a 13.2% increase for pioglitazone alone. The changes in measures of LDL cholesterol and total cholesterol were similar between alogliptin 25 mg with pioglitazone 30 mg versus alogliptin alone and pioglitazone alone. A similar pattern of lipid effects was observed in a 26 week, placebo-controlled factorial study. Alogliptin Single-dose administration of alogliptin to healthy subjects resulted in a peak inhibition of DPP-4 within two to three hours after dosing. The peak inhibition of DPP-4 exceeded 93% across doses of 12.5 mg to 800 mg. Inhibition of DPP-4 remained above 80% at 24 hours for doses greater than or equal to 25 mg. Peak and total exposure over 24 hours to active GLP-1 were three- to four-fold greater with alogliptin (at doses of 25 to 200 mg) than placebo. In a 16 week, double-blind, placebo-controlled study alogliptin 25 mg demonstrated decreases in postprandial glucagon while increasing postprandial active GLP-1 levels compared to placebo over an eight-hour period following a standardized meal. It is unclear how these findings relate to changes in overall glycemic control in patients with type 2 diabetes mellitus. In this study, alogliptin 25 mg demonstrated decreases in two-hour postprandial glucose compared to placebo (-30 mg/dL versus 17 mg/dL respectively). Multiple-dose administration of alogliptin to patients with type 2 diabetes mellitus also resulted in a peak inhibition of DPP-4 within one to two hours and exceeded 93% across all doses (25 mg, 100 mg and 400 mg) after a single dose and after 14 days of once-daily dosing. At these doses of alogliptin, inhibition of DPP-4 remained above 81% at 24 hours after 14 days of dosing. Cardiac Electrophysiology In a randomized, placebo-controlled, four-arm, parallel-group study, 257 subjects were administered either alogliptin 50 mg, alogliptin 400 mg, moxifloxacin 400 mg or placebo once daily for a total of seven days. No increase in corrected QT (QTc) was observed with either dose of alogliptin. At the 400 mg dose, peak alogliptin plasma concentrations were 19-fold higher than the peak concentrations following the maximum recommended clinical dose of 25 mg. Pioglitazone 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 mellitus, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin concentrations and lower A1C 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) ] . 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 (5.12) and Adverse Reactions (6.1) ] . In a 26 week, placebo-controlled, dose-ranging monotherapy study, mean serum triglycerides decreased in the pioglitazone 15 mg, 30 mg and 45 mg 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 (Table 8) . Table 8. 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 -9.6% -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% 14.1% 12.2% 19.1% LDL Cholesterol (mg/dL) N=65 N=63 N=74 N=62 Baseline (mean) 139 132 136 127 Percent change from baseline (adjusted mean ) 4.8% 7.2% 5.2% 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% 4.6% 3.3% 6.4% 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 lipid results were generally consistent with the data above.

12.3 Pharmacokinetics Absorption Alogliptin and Pioglitazone In bioequivalence studies of OSENI, the area under the plasma concentration curve (AUC) and maximum concentration (C max ) of both the alogliptin and the pioglitazone component following a single dose of the combination tablet (12.5 mg/15 mg or 25 mg/45 mg) were bioequivalent to alogliptin (12.5 mg or 25 mg) concomitantly administered with pioglitazone (15 mg or 45 mg respectively) tablets under fasted conditions in healthy subjects. Administration of OSENI 25 mg/45 mg with food resulted in no significant change in overall exposure of alogliptin or pioglitazone. OSENI may therefore be administered with or without food. Alogliptin The absolute bioavailability of alogliptin is approximately 100%. Administration of alogliptin with a high-fat meal results in no significant change in total and peak exposure to alogliptin. Alogliptin may therefore be administered with or without food. Pioglitazone Following oral administration of pioglitazone hydrochloride, peak concentrations of pioglitazone were observed within two hours. Food slightly delays the time to peak serum concentration (T max ) to three to four hours but does not alter the extent of absorption (AUC). Distribution Alogliptin Following a single, 12.5 mg intravenous infusion of alogliptin to healthy subjects, the volume of distribution during the terminal phase was 417 L, indicating that the drug is well distributed into tissues. Alogliptin is 20% bound to plasma proteins. Pioglitazone The mean apparent V d /F of pioglitazone following single-dose administration is 0.63 ± 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. Metabolites M-III and M-IV also are extensively bound (>98%) to serum albumin. Elimination Metabolism Alogliptin Alogliptin does not undergo extensive metabolism and 60% to 71% of the dose is excreted as unchanged drug in the urine. Two minor metabolites were detected following administration of an oral dose of [ 14 C] alogliptin, N -demethylated, M-I (less than 1% of the parent compound), and N -acetylated alogliptin, M-II (less than 6% of the parent compound). M-I is an active metabolite and is an inhibitor of DPP-4 similar to the parent molecule; M-II does not display any inhibitory activity toward DPP-4 or other DPP-related enzymes. In vitro data indicate that CYP2D6 and CYP3A4 contribute to the limited metabolism of alogliptin. Alogliptin exists predominantly as the ( R )-enantiomer (more than 99%) and undergoes little or no chiral conversion in vivo to the ( S )-enantiomer. The ( S )-enantiomer is not detectable at the 25 mg dose. Pioglitazone 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. 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 seven 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 mellitus, 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. Maximum serum concentration (C max ), AUC and trough serum concentrations (C min ) for pioglitazone and M-III and M-IV, increased proportionally with administered doses of 15 mg and 30 mg per day. In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms, including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with gemfibrozil, a strong CYP2C8 inhibitor, showed that pioglitazone is a CYP2C8 substrate [see Dosage and Administration (2.5) and Drug Interactions (7) ] . Urinary 6β-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer. Excretion Alogliptin The primary route of elimination of [ 14 C] alogliptin derived radioactivity occurs via renal excretion (76%) with 13% recovered in the feces, achieving a total recovery of 89% of the administered radioactive dose. The renal clearance of alogliptin (9.6 L/hr) indicates some active renal tubular secretion and systemic clearance was 14.0 L/hr. Pioglitazone 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 of pioglitazone and its metabolites (M-III and M-IV) range from three to seven hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr. Specific Populations Geriatric Patients Alogliptin No dosage adjustment of alogliptin is necessary based on age. Age did not have any clinically meaningful effect on the pharmacokinetics of alogliptin. Pioglitazone In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are approximately 21% higher than those achieved in younger subjects. The mean terminal half-life values of pioglitazone were also longer in elderly subjects (about 10 hours) as compared to younger subjects (about seven hours). These changes are not considered clinically relevant. Pediatric Patients Alogliptin Studies characterizing the pharmacokinetics of alogliptin in pediatric patients have not been performed. Pioglitazone 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) ] . Male and Female Patients Alogliptin No dosage adjustment of alogliptin is necessary based on gender. Gender did not have any clinically meaningful effect on the pharmacokinetics of alogliptin. Pioglitazone The mean C max and AUC values of pioglitazone were increased 20% to 60% in females compared to males. In controlled clinical trials, A1C decreases from baseline were generally greater for females than for males (mean difference in A1C 0.5%). Because therapy should be individualized for each patient to achieve glycemic control, no dosage adjustment is recommended based on gender alone. Race and Ethnic Groups Alogliptin No dosage adjustment of alogliptin is necessary based on race. Race (White, Black or African American, and Asian) did not have any clinically meaningful effect on the pharmacokinetics of alogliptin. Pioglitazone Pharmacokinetic data among various ethnic groups are not available. Patients with Renal Impairment Alogliptin A single-dose, open-label study was conducted to evaluate the pharmacokinetics of alogliptin 50 mg in patients with chronic renal impairment compared with healthy subjects. In patients with mild renal impairment (creatinine clearance [CrCl] ≥60 to <90 mL/min), an approximate 1.2-fold increase in plasma AUC of alogliptin was observed. Because increases of this magnitude are not considered clinically relevant, dosage adjustment for patients with mild renal impairment is not recommended. In patients with moderate renal impairment (CrCl ≥30 to <60 mL/min), an approximate two-fold increase in plasma AUC of alogliptin was observed. To maintain similar systemic exposures of OSENI to those with normal renal function, the recommended dosage of OSENI is 12.5 mg/30 mg once daily in patients with moderate renal impairment. In patients with severe renal impairment (CrCl ≥15 to <30 mL/min) and end-stage renal disease (ESRD) (CrCl <15 mL/min or requiring dialysis), an approximate three- and four-fold increase in plasma AUC of alogliptin were observed, respectively. Dialysis removed approximately 7% of the drug during a three-hour dialysis session. OSENI is not recommended for patients with severe renal impairment or ESRD because these patients require a lower dosage of alogliptin than what is available in the fixed dose combination product, OSENI. Pioglitazone The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 50 mL/min) to severe (creatinine clearance <30 mL/min) renal impairment when compared to subjects with normal renal function. Therefore no dosage adjustment in patients with renal impairment is required. Patients with Hepatic Impairment Alogliptin Total exposure to alogliptin was approximately 10% lower and peak exposure was approximately 8% lower in patients with moderate hepatic impairment (Child-Pugh Grade B) compared to healthy subjects. The magnitude of these reductions is not considered to be clinically meaningful. Patients with severe hepatic impairment (Child-Pugh Grade C) have not been studied. Use caution when administering OSENI to patients with liver disease [see Use in Specific Populations (8.7) and Warnings and Precautions (5.4) ] . Pioglitazone Compared with healthy controls, subjects with impaired hepatic function (Child-Pugh Grade B and C) have an approximate 45% reduction in pioglitazone and total pioglitazone (pioglitazone, M-III and M-IV) mean peak concentrations but no change in the mean AUC values. Therefore, no dosage adjustment in patients with hepatic impairment is required. 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 (5.4) ]. Drug Interaction Studies Coadministration of alogliptin 25 mg once daily with a CYP2C8 substrate, pioglitazone 45 mg once daily for 12 days had no clinically meaningful effects on the pharmacokinetics of pioglitazone and its active metabolites. Specific pharmacokinetic drug interaction studies with OSENI have not been performed, although such studies have been conducted with the individual components of OSENI (alogliptin and pioglitazone). Alogliptin In Vitro Assessment of Drug Interactions In vitro studies indicate that alogliptin is neither an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4, nor an inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP2D6 at clinically relevant concentrations. In Vivo Assessment of Drug Interactions Effects of Alogliptin on the Pharmacokinetics of Other Drugs In clinical studies, alogliptin did not meaningfully increase the systemic exposure to the following drugs that are metabolized by CYP isozymes or excreted unchanged in urine (Figure 1) . No dosage adjustment of alogliptin is recommended based on results of the described pharmacokinetic studies. Figure 1. Effect of Alogliptin on the Pharmacokinetic Exposure to Other Drugs *Warfarin was given once daily at a stable dose in the range of 1 mg to 10 mg. Alogliptin had no significant effect on the prothrombin time (PT) or International Normalized Ratio (INR). **Caffeine (1A2 substrate), tolbutamide (2C9 substrate), dextromethorphan (2D6 substrate), midazolam (3A4 substrate) and fexofenadine (P-gp substrate) were administered as a cocktail. Effects of Other Drugs on the Pharmacokinetics of Alogliptin There are no clinically meaningful changes in the pharmacokinetics of alogliptin when alogliptin is administered concomitantly with the drugs described below (Figure 2). Figure 2. Effect of Other Drugs on the Pharmacokinetic Exposure of Alogliptin Pioglitazone Table 9. Effect of Pioglitazone Coadministration on Systemic Exposure of Other Drugs Coadministered Drug Pioglitazone Dosage Regimen (mg) Daily for seven days unless otherwise noted Name and Dose Regimens Change in AUC % change (with/without coadministered drug and no change=0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively Change in C max 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 ↓3% R-Warfarin ↓2% S-Warfarin ↓1% S-Warfarin ↑1% 45 mg (N=12) Digoxin 0.200 mg twice daily (loading dose) then 0.250 mg daily (maintenance dose, 7 days) ↑15% ↑17% 45 mg daily for 21 days (N=35) Oral Contraceptive [Ethinyl Estradiol (EE) 0.035 mg plus Norethindrone (NE) 1 mg] for 21 days EE ↓11% EE ↓13% NE ↑3% NE ↓7% 45 mg (N=23) Fexofenadine 60 mg twice daily for 7 days ↑30% ↑37% 45 mg (N=14) Glipizide 5 mg daily for 7 days ↓3% ↓8% 45 mg daily for 8 days (N=16) Metformin 1000 mg single dose on 8 days ↓3% ↓5% 45 mg (N=21) Midazolam 7.5 mg single dose on day 15 ↓26% ↓26% 45 mg (N=24) Ranitidine 150 mg twice daily for 7 days ↑1% ↓1% 45 mg daily for 4 days (N=24) Nifedipine ER 30 mg daily for 4 days ↓13% ↓17% 45 mg (N=25) Atorvastatin Calcium 80 mg daily for 7 days ↓14% ↓23% 45 mg (N=22) Theophylline 400 mg twice daily for 7 days ↑2% ↑5% Table 10. Effect of Coadministered Drugs on Pioglitazone Systemic Exposure Coadministered Drug and Dosage Regimen Pioglitazone Dose Regimen (mg) Daily for seven days unless otherwise noted Change in AUC Mean ratio (with/without coadministered drug and no change=one-fold) % change (with/without coadministered drug and no change=0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively Change in C max Gemfibrozil 600 mg twice daily for 2 days (N=12) 30 mg single dose ↑3.4-fold The half-life of pioglitazone increased from 6.5 hours to 15.1 hours in the presence of gemfibrozil [see Dosage and Administration (2.5) and Drug Interactions (7) ] ↑6% Ketoconazole 200 mg twice daily for 7 days (N=28) 45 mg ↑34% ↑14% Rifampin 600 mg daily for 5 days (N=10) 30 mg single dose ↓54% ↓5% Fexofenadine 60 mg twice daily for 7 days (N=23) 45 mg ↑1% 0% Ranitidine 150 mg twice daily for 4 days (N=23) 45 mg ↓13% ↓16% Nifedipine ER 30 mg daily for 7 days (N=23) 45 mg ↑5% ↑4% Atorvastatin Calcium 80 mg daily for 7 days (N=24) 45 mg ↓24% ↓31% Theophylline 400 mg twice daily for 7 days (N=22) 45 mg ↓4% ↓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 ↓15% Additional decrease in active metabolites; 60% for M-III and 16% for M-IV 0% Figure 1 Figure 2

Alogliptin and Pioglitazone In a 26 week, randomized, active-controlled study, patients with type 2 diabetes mellitus received alogliptin 25 mg coadministered with pioglitazone 30 mg, alogliptin 12.5 mg coadministered with pioglitazone 30 mg, alogliptin 25 mg alone or pioglitazone 30 mg alone. Patients who were randomized to alogliptin 25 mg with pioglitazone 30 mg achieved a 26.2% decrease in triglyceride levels from a mean baseline of 214.2 mg/dL compared to an 11.5% decrease for alogliptin alone and a 21.8% decrease for pioglitazone alone. In addition, a 14.4% increase in HDL cholesterol levels from a mean baseline of 43.2 mg/dL was also observed for alogliptin 25 mg with pioglitazone 30 mg compared to a 1.9% increase for alogliptin alone and a 13.2% increase for pioglitazone alone. The changes in measures of LDL cholesterol and total cholesterol were similar between alogliptin 25 mg with pioglitazone 30 mg versus alogliptin alone and pioglitazone alone. A similar pattern of lipid effects was observed in a 26 week, placebo-controlled factorial study. Alogliptin Single-dose administration of alogliptin to healthy subjects resulted in a peak inhibition of DPP-4 within two to three hours after dosing. The peak inhibition of DPP-4 exceeded 93% across doses of 12.5 mg to 800 mg. Inhibition of DPP-4 remained above 80% at 24 hours for doses greater than or equal to 25 mg. Peak and total exposure over 24 hours to active GLP-1 were three- to four-fold greater with alogliptin (at doses of 25 to 200 mg) than placebo. In a 16 week, double-blind, placebo-controlled study alogliptin 25 mg demonstrated decreases in postprandial glucagon while increasing postprandial active GLP-1 levels compared to placebo over an eight-hour period following a standardized meal. It is unclear how these findings relate to changes in overall glycemic control in patients with type 2 diabetes mellitus. In this study, alogliptin 25 mg demonstrated decreases in two-hour postprandial glucose compared to placebo (-30 mg/dL versus 17 mg/dL respectively). Multiple-dose administration of alogliptin to patients with type 2 diabetes mellitus also resulted in a peak inhibition of DPP-4 within one to two hours and exceeded 93% across all doses (25 mg, 100 mg and 400 mg) after a single dose and after 14 days of once-daily dosing. At these doses of alogliptin, inhibition of DPP-4 remained above 81% at 24 hours after 14 days of dosing. Cardiac Electrophysiology In a randomized, placebo-controlled, four-arm, parallel-group study, 257 subjects were administered either alogliptin 50 mg, alogliptin 400 mg, moxifloxacin 400 mg or placebo once daily for a total of seven days. No increase in corrected QT (QTc) was observed with either dose of alogliptin. At the 400 mg dose, peak alogliptin plasma concentrations were 19-fold higher than the peak concentrations following the maximum recommended clinical dose of 25 mg. Pioglitazone 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 mellitus, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin concentrations and lower A1C 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) ] . 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 (5.12) and Adverse Reactions (6.1) ] . In a 26 week, placebo-controlled, dose-ranging monotherapy study, mean serum triglycerides decreased in the pioglitazone 15 mg, 30 mg and 45 mg 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 (Table 8) . Table 8. 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 -9.6% -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% 14.1% 12.2% 19.1% LDL Cholesterol (mg/dL) N=65 N=63 N=74 N=62 Baseline (mean) 139 132 136 127 Percent change from baseline (adjusted mean ) 4.8% 7.2% 5.2% 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% 4.6% 3.3% 6.4% 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 lipid results were generally consistent with the data above.

Absorption Alogliptin and Pioglitazone In bioequivalence studies of OSENI, the area under the plasma concentration curve (AUC) and maximum concentration (C max ) of both the alogliptin and the pioglitazone component following a single dose of the combination tablet (12.5 mg/15 mg or 25 mg/45 mg) were bioequivalent to alogliptin (12.5 mg or 25 mg) concomitantly administered with pioglitazone (15 mg or 45 mg respectively) tablets under fasted conditions in healthy subjects. Administration of OSENI 25 mg/45 mg with food resulted in no significant change in overall exposure of alogliptin or pioglitazone. OSENI may therefore be administered with or without food. Alogliptin The absolute bioavailability of alogliptin is approximately 100%. Administration of alogliptin with a high-fat meal results in no significant change in total and peak exposure to alogliptin. Alogliptin may therefore be administered with or without food. Pioglitazone Following oral administration of pioglitazone hydrochloride, peak concentrations of pioglitazone were observed within two hours. Food slightly delays the time to peak serum concentration (T max ) to three to four hours but does not alter the extent of absorption (AUC). Distribution Alogliptin Following a single, 12.5 mg intravenous infusion of alogliptin to healthy subjects, the volume of distribution during the terminal phase was 417 L, indicating that the drug is well distributed into tissues. Alogliptin is 20% bound to plasma proteins. Pioglitazone The mean apparent V d /F of pioglitazone following single-dose administration is 0.63 ± 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. Metabolites M-III and M-IV also are extensively bound (>98%) to serum albumin. Elimination Metabolism Alogliptin Alogliptin does not undergo extensive metabolism and 60% to 71% of the dose is excreted as unchanged drug in the urine. Two minor metabolites were detected following administration of an oral dose of [ 14 C] alogliptin, N -demethylated, M-I (less than 1% of the parent compound), and N -acetylated alogliptin, M-II (less than 6% of the parent compound). M-I is an active metabolite and is an inhibitor of DPP-4 similar to the parent molecule; M-II does not display any inhibitory activity toward DPP-4 or other DPP-related enzymes. In vitro data indicate that CYP2D6 and CYP3A4 contribute to the limited metabolism of alogliptin. Alogliptin exists predominantly as the ( R )-enantiomer (more than 99%) and undergoes little or no chiral conversion in vivo to the ( S )-enantiomer. The ( S )-enantiomer is not detectable at the 25 mg dose. Pioglitazone 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. 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 seven 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 mellitus, 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. Maximum serum concentration (C max ), AUC and trough serum concentrations (C min ) for pioglitazone and M-III and M-IV, increased proportionally with administered doses of 15 mg and 30 mg per day. In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms, including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with gemfibrozil, a strong CYP2C8 inhibitor, showed that pioglitazone is a CYP2C8 substrate [see Dosage and Administration (2.5) and Drug Interactions (7) ] . Urinary 6β-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer. Excretion Alogliptin The primary route of elimination of [ 14 C] alogliptin derived radioactivity occurs via renal excretion (76%) with 13% recovered in the feces, achieving a total recovery of 89% of the administered radioactive dose. The renal clearance of alogliptin (9.6 L/hr) indicates some active renal tubular secretion and systemic clearance was 14.0 L/hr. Pioglitazone 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 of pioglitazone and its metabolites (M-III and M-IV) range from three to seven hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr. Specific Populations Geriatric Patients Alogliptin No dosage adjustment of alogliptin is necessary based on age. Age did not have any clinically meaningful effect on the pharmacokinetics of alogliptin. Pioglitazone In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are approximately 21% higher than those achieved in younger subjects. The mean terminal half-life values of pioglitazone were also longer in elderly subjects (about 10 hours) as compared to younger subjects (about seven hours). These changes are not considered clinically relevant. Pediatric Patients Alogliptin Studies characterizing the pharmacokinetics of alogliptin in pediatric patients have not been performed. Pioglitazone 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) ] . Male and Female Patients Alogliptin No dosage adjustment of alogliptin is necessary based on gender. Gender did not have any clinically meaningful effect on the pharmacokinetics of alogliptin. Pioglitazone The mean C max and AUC values of pioglitazone were increased 20% to 60% in females compared to males. In controlled clinical trials, A1C decreases from baseline were generally greater for females than for males (mean difference in A1C 0.5%). Because therapy should be individualized for each patient to achieve glycemic control, no dosage adjustment is recommended based on gender alone. Race and Ethnic Groups Alogliptin No dosage adjustment of alogliptin is necessary based on race. Race (White, Black or African American, and Asian) did not have any clinically meaningful effect on the pharmacokinetics of alogliptin. Pioglitazone Pharmacokinetic data among various ethnic groups are not available. Patients with Renal Impairment Alogliptin A single-dose, open-label study was conducted to evaluate the pharmacokinetics of alogliptin 50 mg in patients with chronic renal impairment compared with healthy subjects. In patients with mild renal impairment (creatinine clearance [CrCl] ≥60 to <90 mL/min), an approximate 1.2-fold increase in plasma AUC of alogliptin was observed. Because increases of this magnitude are not considered clinically relevant, dosage adjustment for patients with mild renal impairment is not recommended. In patients with moderate renal impairment (CrCl ≥30 to <60 mL/min), an approximate two-fold increase in plasma AUC of alogliptin was observed. To maintain similar systemic exposures of OSENI to those with normal renal function, the recommended dosage of OSENI is 12.5 mg/30 mg once daily in patients with moderate renal impairment. In patients with severe renal impairment (CrCl ≥15 to <30 mL/min) and end-stage renal disease (ESRD) (CrCl <15 mL/min or requiring dialysis), an approximate three- and four-fold increase in plasma AUC of alogliptin were observed, respectively. Dialysis removed approximately 7% of the drug during a three-hour dialysis session. OSENI is not recommended for patients with severe renal impairment or ESRD because these patients require a lower dosage of alogliptin than what is available in the fixed dose combination product, OSENI. Pioglitazone The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 50 mL/min) to severe (creatinine clearance <30 mL/min) renal impairment when compared to subjects with normal renal function. Therefore no dosage adjustment in patients with renal impairment is required. Patients with Hepatic Impairment Alogliptin Total exposure to alogliptin was approximately 10% lower and peak exposure was approximately 8% lower in patients with moderate hepatic impairment (Child-Pugh Grade B) compared to healthy subjects. The magnitude of these reductions is not considered to be clinically meaningful. Patients with severe hepatic impairment (Child-Pugh Grade C) have not been studied. Use caution when administering OSENI to patients with liver disease [see Use in Specific Populations (8.7) and Warnings and Precautions (5.4) ] . Pioglitazone Compared with healthy controls, subjects with impaired hepatic function (Child-Pugh Grade B and C) have an approximate 45% reduction in pioglitazone and total pioglitazone (pioglitazone, M-III and M-IV) mean peak concentrations but no change in the mean AUC values. Therefore, no dosage adjustment in patients with hepatic impairment is required. 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 (5.4) ]. Drug Interaction Studies Coadministration of alogliptin 25 mg once daily with a CYP2C8 substrate, pioglitazone 45 mg once daily for 12 days had no clinically meaningful effects on the pharmacokinetics of pioglitazone and its active metabolites. Specific pharmacokinetic drug interaction studies with OSENI have not been performed, although such studies have been conducted with the individual components of OSENI (alogliptin and pioglitazone). Alogliptin In Vitro Assessment of Drug Interactions In vitro studies indicate that alogliptin is neither an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4, nor an inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP2D6 at clinically relevant concentrations. In Vivo Assessment of Drug Interactions Effects of Alogliptin on the Pharmacokinetics of Other Drugs In clinical studies, alogliptin did not meaningfully increase the systemic exposure to the following drugs that are metabolized by CYP isozymes or excreted unchanged in urine (Figure 1) . No dosage adjustment of alogliptin is recommended based on results of the described pharmacokinetic studies. Figure 1. Effect of Alogliptin on the Pharmacokinetic Exposure to Other Drugs *Warfarin was given once daily at a stable dose in the range of 1 mg to 10 mg. Alogliptin had no significant effect on the prothrombin time (PT) or International Normalized Ratio (INR). **Caffeine (1A2 substrate), tolbutamide (2C9 substrate), dextromethorphan (2D6 substrate), midazolam (3A4 substrate) and fexofenadine (P-gp substrate) were administered as a cocktail. Effects of Other Drugs on the Pharmacokinetics of Alogliptin There are no clinically meaningful changes in the pharmacokinetics of alogliptin when alogliptin is administered concomitantly with the drugs described below (Figure 2). Figure 2. Effect of Other Drugs on the Pharmacokinetic Exposure of Alogliptin Pioglitazone Table 9. Effect of Pioglitazone Coadministration on Systemic Exposure of Other Drugs Coadministered Drug Pioglitazone Dosage Regimen (mg) Daily for seven days unless otherwise noted Name and Dose Regimens Change in AUC % change (with/without coadministered drug and no change=0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively Change in C max 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 ↓3% R-Warfarin ↓2% S-Warfarin ↓1% S-Warfarin ↑1% 45 mg (N=12) Digoxin 0.200 mg twice daily (loading dose) then 0.250 mg daily (maintenance dose, 7 days) ↑15% ↑17% 45 mg daily for 21 days (N=35) Oral Contraceptive [Ethinyl Estradiol (EE) 0.035 mg plus Norethindrone (NE) 1 mg] for 21 days EE ↓11% EE ↓13% NE ↑3% NE ↓7% 45 mg (N=23) Fexofenadine 60 mg twice daily for 7 days ↑30% ↑37% 45 mg (N=14) Glipizide 5 mg daily for 7 days ↓3% ↓8% 45 mg daily for 8 days (N=16) Metformin 1000 mg single dose on 8 days ↓3% ↓5% 45 mg (N=21) Midazolam 7.5 mg single dose on day 15 ↓26% ↓26% 45 mg (N=24) Ranitidine 150 mg twice daily for 7 days ↑1% ↓1% 45 mg daily for 4 days (N=24) Nifedipine ER 30 mg daily for 4 days ↓13% ↓17% 45 mg (N=25) Atorvastatin Calcium 80 mg daily for 7 days ↓14% ↓23% 45 mg (N=22) Theophylline 400 mg twice daily for 7 days ↑2% ↑5% Table 10. Effect of Coadministered Drugs on Pioglitazone Systemic Exposure Coadministered Drug and Dosage Regimen Pioglitazone Dose Regimen (mg) Daily for seven days unless otherwise noted Change in AUC Mean ratio (with/without coadministered drug and no change=one-fold) % change (with/without coadministered drug and no change=0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively Change in C max Gemfibrozil 600 mg twice daily for 2 days (N=12) 30 mg single dose ↑3.4-fold The half-life of pioglitazone increased from 6.5 hours to 15.1 hours in the presence of gemfibrozil [see Dosage and Administration (2.5) and Drug Interactions (7) ] ↑6% Ketoconazole 200 mg twice daily for 7 days (N=28) 45 mg ↑34% ↑14% Rifampin 600 mg daily for 5 days (N=10) 30 mg single dose ↓54% ↓5% Fexofenadine 60 mg twice daily for 7 days (N=23) 45 mg ↑1% 0% Ranitidine 150 mg twice daily for 4 days (N=23) 45 mg ↓13% ↓16% Nifedipine ER 30 mg daily for 7 days (N=23) 45 mg ↑5% ↑4% Atorvastatin Calcium 80 mg daily for 7 days (N=24) 45 mg ↓24% ↓31% Theophylline 400 mg twice daily for 7 days (N=22) 45 mg ↓4% ↓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 ↓15% Additional decrease in active metabolites; 60% for M-III and 16% for M-IV 0% Figure 1 Figure 2