Nesina

5 WARNINGS AND PRECAUTIONS Pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue NESINA. ( 5.1 ) Heart failure: Consider the risks and benefits of NESINA 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 NESINA. ( 5.2 ) Hypersensitivity: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with NESINA such as anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. If hypersensitivity reactions occur, discontinue NESINA, treat promptly, and monitor until signs and symptoms resolve. ( 5.3 ) Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt NESINA and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart NESINA if liver injury is confirmed and no alternative etiology can be found. ( 5.4 ) Hypoglycemia: Consider lowering the dosage of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating NESINA. ( 5.5 ) 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. ( 5.6 ) 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 NESINA. ( 5.7 ) 5.1 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 NESINA 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%) of patients treated with NESINA and in 7 (0.3%) of patients treated with placebo. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using NESINA . After initiation of NESINA, patients should be observed for signs and symptoms of pancreatitis. If pancreatitis is suspected, NESINA should promptly be discontinued and appropriate management should be initiated. 5.2 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 NESINA and 89 (3.3%) of patients treated with placebo were hospitalized for congestive heart failure. Consider the risks and benefits of NESINA 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 NESINA. 5.3 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions in patients treated with NESINA [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 NESINA, 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 NESINA. 5.4 Hepatic Effects There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking NESINA, 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 NESINA 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 NESINA 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, NESINA should be interrupted and investigation done to establish the probable cause. NESINA should not be restarted in these patients without another explanation for the liver test abnormalities. 5.5 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 NESINA. 5.6 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. 5.7 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 NESINA. If bullous pemphigoid is suspected, NESINA 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 (5.1) ] Heart Failure [see Warnings and Precautions (5.2) ] Hypersensitivity Reactions [see Warnings and Precautions (5.3) ] Hepatic Effects [see Warnings and Precautions (5.4) ] Severe and Disabling Arthralgia [see Warnings and Precautions (5.6) ] Bullous Pemphigoid [see Warnings and Precautions (5.7) ] Most common adverse reactions (incidence ≥4%) are nasopharyngitis, headache 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. 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 NESINA, 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 NESINA 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 NESINA 25 mg compared to 75% with placebo and 70% with active comparator. Overall discontinuation of therapy due to adverse reactions was 6.8% with NESINA 25 mg compared to 8.4% with placebo or 6.2% with active comparator. Adverse reactions reported in ≥4% of adult patients treated with NESINA 25 mg and more frequently than in patients who received placebo are summarized in Table 1. Table 1. Adverse Reactions Reported in ≥4% of Adult Patients with Type 2 Diabetes Mellitus Treated with NESINA 25 mg and More Frequently Than in Patients Given Placebo in Pooled Trials Number of Patients (%) NESINA 25 mg Placebo Active Comparator N=6447 N=3469 N=2257 Nasopharyngitis 309 (5) 152 (4) 113 (5) Upper Respiratory Tract Infection 287 (4) 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 NESINA compared to 1.6% with placebo. The use of NESINA as add-on therapy to glyburide or insulin did not increase the incidence of hypoglycemia compared to placebo. In a monotherapy trial comparing NESINA to a sulfonylurea in elderly patients, the incidence of hypoglycemia was 5.4% with NESINA compared to 26% with glipizide (Table 2) . Table 2. Incidence and Rate of Hypoglycemia Adverse reactions of hypoglycemia were based on all reports of symptomatic and asymptomatic hypoglycemia; a concurrent glucose measurement was not required; intent-to-treat population in Placebo and Active-Controlled Trials in Adults with Type 2 Diabetes Mellitus when NESINA Was Used as Add-On Therapy to Glyburide, Insulin, Metformin, Pioglitazone or Compared to Glipizide or Metformin Add-On to Glyburide (26 Weeks) NESINA 25 mg Placebo N=198 N=99 Overall (%) 19 (10) 11 (11) Severe (%) Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level or loss of consciousness or seizure 0 1 (1) Add-On to Insulin (± Metformin) (26 Weeks) NESINA 25 mg Placebo N=129 N=129 Overall (%) 35 (27) 31 (24) Severe (%) 1 (1) 2 (2) Add-On to Metformin (26 Weeks) NESINA 25 mg Placebo N=207 N=104 Overall (%) 0 3 (3) Severe (%) 0 0 Add-On to Pioglitazone (± Metformin or Sulfonylurea) (26 Weeks) NESINA 25 mg Placebo N=199 N=97 Overall (%) 14 (7) 5 (5) Severe (%) 0 1 (1) Compared to Glipizide (52 Weeks) NESINA 25 mg Glipizide N=222 N=219 Overall (%) 12 (5) 57 (26) Severe (%) 0 3 (1) Compared to Metformin (26 Weeks) NESINA 25 mg Metformin 500 mg twice daily N=112 N=109 Overall (%) 2 (2) 2 (2) Severe (%) 0 0 Add-On to Metformin Compared to Glipizide (52 Weeks) NESINA 25 mg Glipizide N=877 N=869 Overall (%) 12 (1) 207 (4) Severe (%) 0 4 (1) In the EXAMINE trial, the incidence of investigator reported hypoglycemia was 6.7% in patients receiving NESINA and 6.5% in patients receiving placebo. Serious adverse reactions of hypoglycemia were reported in 0.8% of patients treated with NESINA 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 NESINA 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 NESINA and 0.1% for active comparators or placebo), decreased creatinine clearance (1.6% for NESINA and 0.5% for active comparators or placebo) and increased blood creatinine (0.5% for NESINA 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 NESINA 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 NESINA and 6.7% for placebo), decreased glomerular filtration rate (4.9% for NESINA and 4.3% for placebo) and decreased renal clearance (2.2% for NESINA 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 NESINA and 18.7% of patients treated with placebo. Worsening of chronic kidney disease stage was seen in 16.8% of patients treated with NESINA and in 15.5% of patients treated with placebo. 6.2 Postmarketing Experience The following adverse reactions have been identified during the postmarketing use of NESINA. 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. 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

<table width="90%"><caption>Table 1. Adverse Reactions Reported in &#x2265;4% of Adult Patients with Type 2 Diabetes Mellitus Treated with NESINA 25 mg and More Frequently Than in Patients Given Placebo in Pooled Trials</caption><col width="40%" align="left" valign="middle"/><col width="20%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><thead><tr><th styleCode="Rrule Lrule"/><th styleCode="Rrule Botrule" colspan="3"><content styleCode="bold">Number of Patients (%)</content></th></tr><tr><th styleCode="Rrule Lrule"/><th styleCode="Rrule Botrule"><content styleCode="bold">NESINA 25 mg</content></th><th styleCode="Rrule Botrule"><content styleCode="bold">Placebo</content></th><th styleCode="Rrule Botrule"><content styleCode="bold">Active Comparator</content></th></tr><tr styleCode="Botrule"><th styleCode="Rrule Lrule"/><th styleCode="Rrule Botrule">N=6447</th><th styleCode="Rrule Botrule">N=3469</th><th styleCode="Rrule Botrule">N=2257</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Rrule Lrule">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="Rrule Lrule">Upper Respiratory Tract Infection</td><td styleCode="Rrule">287 (4)</td><td styleCode="Rrule">121 (4)</td><td styleCode="Rrule">113 (5)</td></tr><tr><td styleCode="Rrule Lrule">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="90%" ID="table2"><caption>Table 2. Incidence and Rate of Hypoglycemia<footnote>Adverse reactions of hypoglycemia were based on all reports of symptomatic and asymptomatic hypoglycemia; a concurrent glucose measurement was not required; intent-to-treat population</footnote> in Placebo and Active-Controlled Trials in Adults with Type 2 Diabetes Mellitus when NESINA Was Used as Add-On Therapy to Glyburide, Insulin, Metformin, Pioglitazone or Compared to Glipizide or Metformin</caption><col width="50%" align="left" valign="middle"/><col width="25%" align="center" valign="middle"/><col width="25%" align="center" valign="middle"/><tbody><tr styleCode="Botrule"><td styleCode="Rrule Lrule"><content styleCode="bold">Add-On to Glyburide (26 Weeks)</content></td><td styleCode="Rrule"><content styleCode="bold">NESINA 25 mg</content></td><td styleCode="Rrule"><content styleCode="bold">Placebo</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"/><td styleCode="Rrule"><content styleCode="bold">N=198</content></td><td styleCode="Rrule"><content styleCode="bold">N=99</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Overall (%)</td><td styleCode="Rrule">19 (10)</td><td styleCode="Rrule">11 (11)</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Severe (%)<footnote ID="ft2ii">Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level or loss of consciousness or seizure</footnote></td><td styleCode="Rrule">0</td><td styleCode="Rrule">1 (1)</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"><content styleCode="bold">Add-On to Insulin (&#xB1; Metformin) (26 Weeks)</content></td><td styleCode="Rrule"><content styleCode="bold">NESINA 25 mg</content></td><td styleCode="Rrule"><content styleCode="bold">Placebo</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"/><td styleCode="Rrule"><content styleCode="bold">N=129</content></td><td styleCode="Rrule"><content styleCode="bold">N=129</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Overall (%)</td><td styleCode="Rrule">35 (27)</td><td styleCode="Rrule">31 (24)</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Severe (%)<footnoteRef IDREF="ft2ii"/></td><td styleCode="Rrule">1 (1)</td><td styleCode="Rrule">2 (2)</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"><content styleCode="bold">Add-On to Metformin (26 Weeks)</content></td><td styleCode="Rrule"><content styleCode="bold">NESINA 25 mg</content></td><td styleCode="Rrule"><content styleCode="bold">Placebo</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"/><td styleCode="Rrule"><content styleCode="bold">N=207</content></td><td styleCode="Rrule"><content styleCode="bold">N=104</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Overall (%)</td><td styleCode="Rrule">0</td><td styleCode="Rrule">3 (3)</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Severe (%)<footnoteRef IDREF="ft2ii"/></td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"><content styleCode="bold">Add-On to Pioglitazone (&#xB1; Metformin or Sulfonylurea) (26 Weeks)</content></td><td styleCode="Rrule"><content styleCode="bold">NESINA 25 mg</content></td><td styleCode="Rrule"><content styleCode="bold">Placebo</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"/><td styleCode="Rrule"><content styleCode="bold">N=199</content></td><td styleCode="Rrule"><content styleCode="bold">N=97</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Overall (%)</td><td styleCode="Rrule">14 (7)</td><td styleCode="Rrule">5 (5)</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Severe (%)<footnoteRef IDREF="ft2ii"/></td><td styleCode="Rrule">0</td><td styleCode="Rrule">1 (1)</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"><content styleCode="bold">Compared to Glipizide (52 Weeks)</content></td><td styleCode="Rrule"><content styleCode="bold">NESINA 25 mg</content></td><td styleCode="Rrule"><content styleCode="bold">Glipizide</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"/><td styleCode="Rrule"><content styleCode="bold">N=222</content></td><td styleCode="Rrule"><content styleCode="bold">N=219</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Overall (%)</td><td styleCode="Rrule">12 (5)</td><td styleCode="Rrule">57 (26)</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Severe (%)<footnoteRef IDREF="ft2ii"/></td><td styleCode="Rrule">0</td><td styleCode="Rrule">3 (1)</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"><content styleCode="bold">Compared to Metformin (26 Weeks)</content></td><td styleCode="Rrule"><content styleCode="bold">NESINA 25 mg</content></td><td styleCode="Rrule"><content styleCode="bold">Metformin 500 mg twice daily</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"/><td styleCode="Rrule"><content styleCode="bold">N=112</content></td><td styleCode="Rrule"><content styleCode="bold">N=109</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Overall (%)</td><td styleCode="Rrule">2 (2)</td><td styleCode="Rrule">2 (2)</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Severe (%)<footnoteRef IDREF="ft2ii"/></td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"><content styleCode="bold">Add-On to Metformin Compared to Glipizide (52 Weeks)</content></td><td styleCode="Rrule"><content styleCode="bold">NESINA 25 mg</content></td><td styleCode="Rrule"><content styleCode="bold">Glipizide</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"/><td styleCode="Rrule"><content styleCode="bold">N=877</content></td><td styleCode="Rrule"><content styleCode="bold">N=869</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Overall (%)</td><td styleCode="Rrule">12 (1)</td><td styleCode="Rrule">207 (4)</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule"> Severe (%)<footnoteRef IDREF="ft2ii"/></td><td styleCode="Rrule">0</td><td styleCode="Rrule">4 (1)</td></tr></tbody></table>