KAZANO

WARNING: LACTIC ACIDOSIS Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL [see Warnings and Precautions (5.1) ] . Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information [see Dosage and Administration (2.2) , Contraindications (4) , Warnings and Precautions (5.1) , Drug Interactions (7) , Use in Specific Populations (8.6 , 8.7) ] . If metformin-associated lactic acidosis is suspected, immediately discontinue KAZANO ® and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1) ] . WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning. Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL. ( 5.1 ) Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information. ( 5.1 ) If lactic acidosis is suspected, discontinue KAZANO and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. ( 5.1 )

5 WARNINGS AND PRECAUTIONS Lactic acidosis: See boxed warning . ( 5.1 ) Pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue KAZANO. ( 5.2 ) Heart failure: Consider the risks and benefits of KAZANO prior to initiating treatment in patients at risk for heart failure. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of KAZANO. ( 5.3 ) 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. If hypersensitivity reactions occur, discontinue KAZANO, treat promptly, and monitor until signs and symptoms resolve. ( 5.4 ) Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt KAZANO and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart KAZANO if liver injury is confirmed and no alternative etiology can be found. ( 5.5 ) Vitamin B 12 deficiency: Metformin may lower vitamin B 12 levels. Measure hematologic parameters annually and B 12 at 2 to 3 year intervals and manage any abnormalties. ( 5.6 ) Hypoglycemia: Consider lowering the dosage of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating KAZANO. ( 5.7 ) 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 drug if appropriate. ( 5.8 ) 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 KAZANO. ( 5.9 ) 5.1 Lactic Acidosis Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally greater than 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of KAZANO. In KAZANO-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue KAZANO and report these symptoms to their healthcare provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include [see Dosage and Administration (2.2) , Clinical Pharmacology (12.3) ] : Before initiating KAZANO, obtain an eGFR. KAZANO is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 [see Contraindications (4) ] . KAZANO is not recommended in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 because these patients require a lower dosage of alogliptin than what is available in the fixed combination KAZANO product. Obtain an eGFR at least annually in all patients taking KAZANO. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. Drug Interactions The concomitant use of KAZANO with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions (7) ] . Therefore, consider more frequent monitoring of patients. Age 65 or Greater The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5) ] . Radiological Studies with Contrast Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop KAZANO at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart KAZANO if renal function is stable. Surgery and Other Procedures Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. KAZANO should be temporarily discontinued while patients have restricted food and fluid intake. Hypoxic States Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue KAZANO. Excessive Alcohol Intake Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving KAZANO. Hepatic Impairment Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of KAZANO in patients with clinical or laboratory evidence of hepatic disease. 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 KAZANO . After initiation of KAZANO, patients should be observed for signs and symptoms of pancreatitis. If pancreatitis is suspected, alogliptin should promptly be discontinued and appropriate management should be initiated. 5.3 Heart Failure 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. Consider the risks and benefits of KAZANO 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, and observe these patients for signs and symptoms of heart failure during therapy. Patients should be advised of the characteristic symptoms of heart failure and should be instructed to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of KAZANO. 5.4 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 KAZANO, assess for other potential causes for the event and institute alternative treatment for diabetes mellitus. 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 KAZANO. 5.5 Hepatic Effects There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking alogliptin, although some of the reports contain insufficient information necessary to establish the probable cause [see Adverse Reactions (6.2) ] . In glycemic control trials 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. 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 and if abnormal liver tests persist or worsen, KAZANO should be interrupted and investigation done to establish the probable cause. KAZANO should not be restarted in these patients without another explanation for the liver test abnormalities. 5.6 Vitamin B 12 Levels In metformin clinical trials of 29 week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2 to 3 year intervals in patients on KAZANO and manage any abnormalities [see Adverse Reactions (6.1) ] . 5.7 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 KAZANO. 5.8 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. 5.9 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 DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving KAZANO. If bullous pemphigoid is suspected, KAZANO should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: Pancreatitis [see Warnings and Precautions (5.2) ] Heart Failure [see Warnings and Precautions (5.3) ] Hypersensitivity Reactions [see Warnings and Precautions (5.4) ] Hepatic Effects [see Warnings and Precautions (5.5) ] Severe and Disabling Arthralgia [see Warnings and Precautions (5.8) ] Bullous Pemphigoid [see Warnings and Precautions (5.9) ] Most common adverse reactions (incidence ≥4%) are upper respiratory tract infection, nasopharyngitis, diarrhea, hypertension, headache, back pain and urinary 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 Metformin HCl Over 2,700 patients with type 2 diabetes mellitus have received alogliptin coadministered with metformin in four large, randomized, double-blind controlled clinical trials. The racial distribution of patients exposed to trial medication was 65% White, 20% Asian, 7% Black or African American, 4% American Indian or Alaska Native, 0% Native Hawaiian/Other Pacific Islander and 4% Multiracial or other racial groups. The ethnic distribution was 23% Hispanic or Latino and 77% was not Hispanic or Latino. The mean exposure to alogliptin coadministered with metformin was 58 weeks, with more than 1,400 subjects treated for more than one year. These included two 26 week placebo-controlled trials, one 52 week active control trial and an interim analysis of a 104 week active-controlled trial. In the alogliptin co-administered with metformin HCl arm, the mean duration of diabetes mellitus was approximately six years, the mean body mass index (BMI) was 31 kg/m 2 (56% of patients had a BMI ≥30 kg/m 2 ) and the mean age was 55 years (18% of patients ≥65 years of age). In a pooled analysis of these four controlled clinical studies, the overall incidence of adverse reactions was 74% in patients treated with alogliptin co-administered with metformin HCl compared to 75% treated with placebo. Overall discontinuation of therapy due to adverse reactions was 6.2% with alogliptin co-administered with metformin HCl compared to 1.9% in placebo, 6.4% in metformin and 5.0% in alogliptin. Adverse reactions reported in ≥4% of patients treated with alogliptin co-administered with metformin HCl and more frequently than in patients who received alogliptin, metformin or placebo are summarized in Table 1. Table 1. Adverse Reactions Reported in ≥4% of Adults with Type 2 Diabetes Mellitus Treated with Alogliptin Co-administered with Metformin HCl and More Frequently Than in Patients Receiving Either Alogliptin, Metformin or Placebo Number of Patients (%) Alogliptin and Metformin Alogliptin and metformin – includes data pooled for patients receiving alogliptin 25 and 12.5 mg combined with various doses of metformin Alogliptin Alogliptin – includes data pooled for patients receiving alogliptin 25 and 12.5 mg Metformin Metformin – includes data pooled for patients receiving various doses of metformin Placebo N=2794 N=222 N=1592 N=106 Upper respiratory tract infection 224 (8) 6 (3) 105 (7) 3 (3) Nasopharyngitis 191 (7) 7 (3) 93 (6) 2 (2) Diarrhea 155 (6) 4 (2) 105 (7) 3 (3) Hypertension 154 (6) 5 (2) 96 (6) 6 (6) Headache 149 (5) 11 (5) 74 (5) 3 (3) Back pain 119 (4) 1 (1) 72 (5) 1 (1) Urinary tract infection 116 (4) 4 (2) 59 (4) 2 (2) 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 mellitus 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 patients treated with alogliptin 25 mg and more frequently than in patients who received placebo are summarized in Table 2. Table 2. Adverse Reactions Reported in ≥4% Patients Treated with Alogliptin 25 mg and More Frequently Than in Patients Given Placebo in Pooled Studies 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 Alogliptin and Metformin HCl In a 26 week, double-blind, placebo-controlled trial of alogliptin in combination with metformin, the number of patients reporting hypoglycemia was 1.9% in the alogliptin 12.5 mg with metformin HCl 500 mg, 5.3% in the alogliptin 12.5 mg with metformin HCl 1000 mg, 1.8% in the metformin HCl 500 mg and 6.3% in the metformin HCl 1000 mg treatment groups. In a 26 week placebo-controlled trial of alogliptin 25 mg administered once daily as add-on to metformin regimen, the number of patients reporting hypoglycemic events was 0% in the alogliptin co-administered with metformin HCl and 2.9% in the placebo treatment groups. In a 52 week, active-controlled, double-blind trial of alogliptin once daily 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 number of patients 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 with metformin group. In an interim analysis conducted in a 104 week, double-blind, active-controlled trial of alogliptin 25 mg in combination with metformin, the number of patients reporting hypoglycemia was 1.4% in the alogliptin 25 mg with metformin group versus 23.8% in the glipizide with metformin group. Alogliptin 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. Metformin HCl Table 3. Most Common Adverse Reactions (≥5%) in a Placebo-Controlled Clinical Trial of Metformin Monotherapy Reactions that were more common in metformin than placebo-treated patients Adverse Reaction Metformin Monotherapy (n=141) Placebo (n=145) % of Patients Diarrhea 53.2 11.7 Nausea/vomiting 25.5 8.3 Flatulence 12.1 5.5 Asthenia 9.2 5.5 Indigestion 7.1 4.1 Abdominal discomfort 6.4 4.8 Headache 5.7 4.8 Laboratory Abnormalities Alogliptin and Metformin HCl No clinically meaningful differences were observed among treatment groups regarding hematology, serum chemistry or urinalysis results. Metformin HCl In metformin clinical trials of 29 week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing use. 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 Metformin Hepatobiliary Disorders: Cholestatic, hepatocellular, mixed hepatocellular liver injury

<table width="70%"><caption>Table 1. Adverse Reactions Reported in &#x2265;4% of Adults with Type 2 Diabetes Mellitus Treated with Alogliptin Co-administered with Metformin HCl and More Frequently Than in Patients Receiving Either Alogliptin, Metformin or Placebo</caption><col align="left" valign="top" width="32%"/><col align="center" valign="middle" width="17%"/><col align="center" valign="middle" width="17%"/><col align="center" valign="middle" width="17%"/><col align="center" valign="middle" width="17%"/><thead><tr><th styleCode="Lrule Rrule" rowspan="3"/><th styleCode="Botrule Rrule" colspan="4">Number of Patients (%)</th></tr><tr styleCode="Botrule"><th styleCode="Rrule" align="center">Alogliptin and Metformin<footnote>Alogliptin and metformin &#x2013; includes data pooled for patients receiving alogliptin 25 and 12.5 mg combined with various doses of metformin</footnote></th><th styleCode="Rrule">Alogliptin<footnote>Alogliptin &#x2013; includes data pooled for patients receiving alogliptin 25 and 12.5 mg</footnote></th><th styleCode="Rrule">Metformin<footnote>Metformin &#x2013; includes data pooled for patients receiving various doses of metformin</footnote></th><th styleCode="Rrule">Placebo</th></tr><tr><th styleCode="Rrule" align="center">N=2794</th><th styleCode="Rrule">N=222</th><th styleCode="Rrule">N=1592</th><th styleCode="Rrule">N=106</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper respiratory tract infection</td><td styleCode="Rrule">224 (8)</td><td styleCode="Rrule">6 (3)</td><td styleCode="Rrule">105 (7)</td><td styleCode="Rrule">3 (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nasopharyngitis</td><td styleCode="Rrule">191 (7)</td><td styleCode="Rrule">7 (3)</td><td styleCode="Rrule">93 (6)</td><td styleCode="Rrule">2 (2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">155 (6)</td><td styleCode="Rrule">4 (2)</td><td styleCode="Rrule">105 (7)</td><td styleCode="Rrule">3 (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypertension</td><td styleCode="Rrule">154 (6)</td><td styleCode="Rrule">5 (2)</td><td styleCode="Rrule">96 (6)</td><td styleCode="Rrule">6 (6)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">149 (5)</td><td styleCode="Rrule">11 (5)</td><td styleCode="Rrule">74 (5)</td><td styleCode="Rrule">3 (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Back pain</td><td styleCode="Rrule">119 (4)</td><td styleCode="Rrule">1 (1)</td><td styleCode="Rrule">72 (5)</td><td styleCode="Rrule">1 (1)</td></tr><tr><td styleCode="Lrule Rrule">Urinary tract infection</td><td styleCode="Rrule">116 (4)</td><td styleCode="Rrule">4 (2)</td><td styleCode="Rrule">59 (4)</td><td styleCode="Rrule">2 (2)</td></tr></tbody></table>

<table width="70%"><caption>Table 2. Adverse Reactions Reported in &#x2265;4% Patients Treated with Alogliptin 25 mg and More Frequently Than in Patients Given Placebo in Pooled Studies</caption><col align="left" valign="middle" width="40%"/><col align="center" valign="middle" width="20%"/><col align="center" valign="middle" width="20%"/><col align="center" valign="middle" width="20%"/><thead><tr><th styleCode="Lrule Rrule" rowspan="3"/><th styleCode="Rrule Botrule" colspan="3">Number of Patients (%)</th></tr><tr styleCode="Botrule"><th styleCode="Rrule" align="center">Alogliptin 25 mg</th><th styleCode="Rrule">Placebo</th><th styleCode="Rrule">Active Comparator</th></tr><tr><th styleCode="Rrule" align="center">N=6447</th><th styleCode="Rrule">N=3469</th><th styleCode="Rrule">N=2257</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nasopharyngitis</td><td styleCode="Rrule">309 (5)</td><td styleCode="Rrule">152 (4)</td><td styleCode="Rrule">113 (5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper Respiratory Tract Infection</td><td styleCode="Rrule">287 (5)</td><td styleCode="Rrule">121 (4)</td><td styleCode="Rrule">113 (5)</td></tr><tr><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">278 (4)</td><td styleCode="Rrule">101 (3)</td><td styleCode="Rrule">121 (5)</td></tr></tbody></table>

<table width="70%"><caption>Table 3. Most Common Adverse Reactions (&#x2265;5%) in a Placebo-Controlled Clinical Trial of Metformin Monotherapy<footnote>Reactions that were more common in metformin than placebo-treated patients</footnote></caption><col align="left" valign="middle" width="30%"/><col align="center" valign="middle" width="30%"/><col align="center" valign="middle" width="40%"/><thead><tr><th styleCode="Lrule Rrule" rowspan="2">Adverse Reaction</th><th styleCode="Rrule Botrule">Metformin Monotherapy (n=141)</th><th styleCode="Rrule Botrule">Placebo (n=145)</th></tr><tr><th styleCode="Rrule" colspan="2" align="center">% of Patients</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">53.2</td><td styleCode="Rrule">11.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea/vomiting</td><td styleCode="Rrule">25.5</td><td styleCode="Rrule">8.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Flatulence</td><td styleCode="Rrule">12.1</td><td styleCode="Rrule">5.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Asthenia</td><td styleCode="Rrule">9.2</td><td styleCode="Rrule">5.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Indigestion</td><td styleCode="Rrule">7.1</td><td styleCode="Rrule">4.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal discomfort</td><td styleCode="Rrule">6.4</td><td styleCode="Rrule">4.8</td></tr><tr><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">5.7</td><td styleCode="Rrule">4.8</td></tr></tbody></table>