These Highlights Do Not Include All The Information Needed To Use Oseni®

Limitations of Use

OSENI is not recommended for use in patients with type 1 diabetes mellitus.

Storage

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed and protect from moisture and humidity.

PRINCIPAL DISPLAY PANEL - 12.5 mg/30 mg Tablet Bottle Label

NDC 64764-123-03

Oseni^®

(alogliptin and

pioglitazone) tablets

12.5 mg/30 mg

Rx Only

Dispense with

Medication Guide

Takeda

30 Tablets

OSENI tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes mellitus: alogliptin and pioglitazone.

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.

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)].

The effectiveness of OSENI has been established based on four adequate and well-controlled Phase 3 trials of alogliptin and pioglitazone as adjunct to diet to improve glycemic control in adult patients with type 2 diabetes mellitus.

In patients with type 2 diabetes mellitus, treatment with alogliptin and pioglitazone produced clinically meaningful and statistically significant improvements in A1C compared to either alogliptin or pioglitazone alone. As is typical for trials of agents to treat type 2 diabetes mellitus, the mean reduction in A1C with alogliptin and pioglitazone appears to be related to the degree of A1C elevation at baseline.

OSENI is contraindicated in patients with:

• Established NYHA Class III or IV heart failure at the time of OSENI initiation [see Boxed Warning].
• A history of serious hypersensitivity reaction to alogliptin, pioglitazone, or any of the excipients in OSENI. Reactions such as anaphylaxis, angioedema and severe cutaneous adverse reactions have been reported [see Warnings and Precautions (5.3), Adverse reactions (6.2)].

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.

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)]

• Strong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone concentrations. Limit the pioglitazone dose to 15 mg daily. (7.2)
• CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations. (7.3)
• Topiramate may decrease pioglitazone concentrations. (7.4)

OSENI is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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.

OSENI combines two antihyperglycemic agents: alogliptin and pioglitazone.

• 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)

• Obtain liver tests prior to initiation.
• OSENI may be taken with or without food. (2.1)
• Individualize the starting dose of OSENI based on the patient’s current regimen and concurrent medical condition but do not exceed a daily dose of alogliptin 25 mg and pioglitazone 45 mg. (2.2)
• The recommended starting dosage in patients with NYHA Class I or II congestive heart failure is 25 mg of alogliptin and 15 mg of pioglitazone (2.4)
• Prior to initiation, assess renal function with creatinine clearance (CrCl) (2.3)
  • Mild renal impairment (creatinine clearance [CrCl] ≥60 mL/min): same as the recommended dosage in patients with normal renal function.
  • Moderate renal impairment (CrCl ≥30 to <60 mL/min): 12.5 mg of alogliptin and 30 mg of pioglitazone once daily.
  • Severe renal impairment (CrCl ≥15 to <30 mL/min) or ESRD (CrCl <15 mL/min or requiring hemodialysis): not recommended.

• 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)

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.

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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

• Thiazolidinediones, including pioglitazone, which is a component of OSENI^®, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.1)].
• After initiation of OSENI and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea and/or edema). If congestive heart failure develops while taking OSENI, consider discontinuation of OSENI or dosage reduction of pioglitazone in OSENI [see Warnings and Precautions (5.1)].
• OSENI is not recommended in patients with symptomatic heart failure [see Warnings and Precautions (5.1)].
• Initiation of OSENI in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1)].

OSENI tablets are available in the following strengths and packages:

25 mg/15 mg tablet: yellow, round, biconvex and film-coated with both “A/P” and “25/15” printed on one side, available in:

25 mg/30 mg tablet: peach, round, biconvex and film-coated with both “A/P” and “25/30” printed on one side, available in:

25 mg/45 mg tablet: red, round, biconvex, film-coated and with both “A/P” and “25/45” printed on one side, available in:

12.5 mg/30 mg tablet: pale peach, round, biconvex and film-coated with both “A/P” and “12.5/30” printed on one side, available in:

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.

Insulin and insulin secretagogues are known to cause hypoglycemia. Coadministration of OSENI with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue and insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.8)].

Recommended Starting Dosage Based on Current Regimen

Individualize the starting dosage of OSENI based on the patient's current regimen and the available strengths of OSENI (see Table 1).

Dosage Titration for Additional Glycemic Control

Titrate the OSENI dosage gradually, as needed, after assessing therapeutic response and tolerability, up to a maximum dosage of 25 mg of alogliptin and 45 mg of pioglitazone once daily.

Discuss the potential for unintended pregnancy with premenopausal women as therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some anovulatory women.

Starting Dosage in Patients with NYHA Class I or II Congestive Heart Failure

For patients with preexisting NYHA Class I or II congestive heart failure, the recommended starting dosage of OSENI is 25 mg of alogliptin and 15 mg of pioglitazone [see Boxed Warning and Warnings and Precautions (5.1)].

Monitoring for Fluid Retention and Dosage Modifications for Congestive Heart Failure

After initiation of OSENI or with dosage increase, monitor patients carefully for adverse reactions related to fluid retention as has been seen with pioglitazone (e.g., weight gain, edema and signs and symptoms of congestive heart failure).

If congestive heart failure develops while taking OSENI, consider discontinuation of OSENI or dosage reduction of pioglitazone in OSENI [see Boxed Warning and Warnings and Precautions (5.1)].

The maximum recommended dosage of OSENI is 25 mg of alogliptin and 15 mg of pioglitazone once daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

• Obtain liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) prior to initiating OSENI [see Warnings and Precautions (5.4)].
• Take OSENI orally once daily. Do not split tablets.
• OSENI may be taken with or without food [see Clinical Pharmacology (12.3)].
• If a dose is missed, do not double the next dose.

• Assess renal function prior to initiation of OSENI and periodically thereafter [see Use in Specific Populations (8.6)].
• The recommended dosage of OSENI in patients with mild renal impairment (creatinine clearance [CrCl] ≥60 mL/min) is the same as the recommended dosage in patients with normal renal function [see Dosage and Administration (2.1)].
• 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) because these patients require a lower dosage of alogliptin than what is available in the fixed dose combination product, OSENI [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

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)].

Limitations of Use

OSENI is not recommended for use in patients with type 1 diabetes mellitus.

Storage

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed and protect from moisture and humidity.

PRINCIPAL DISPLAY PANEL - 12.5 mg/30 mg Tablet Bottle Label

NDC 64764-123-03

Oseni^®

(alogliptin and

pioglitazone) tablets

12.5 mg/30 mg

Rx Only

Dispense with

Medication Guide

Takeda

30 Tablets

OSENI tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes mellitus: alogliptin and pioglitazone.

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.

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)].

The effectiveness of OSENI has been established based on four adequate and well-controlled Phase 3 trials of alogliptin and pioglitazone as adjunct to diet to improve glycemic control in adult patients with type 2 diabetes mellitus.

In patients with type 2 diabetes mellitus, treatment with alogliptin and pioglitazone produced clinically meaningful and statistically significant improvements in A1C compared to either alogliptin or pioglitazone alone. As is typical for trials of agents to treat type 2 diabetes mellitus, the mean reduction in A1C with alogliptin and pioglitazone appears to be related to the degree of A1C elevation at baseline.

OSENI is contraindicated in patients with:

• Established NYHA Class III or IV heart failure at the time of OSENI initiation [see Boxed Warning].
• A history of serious hypersensitivity reaction to alogliptin, pioglitazone, or any of the excipients in OSENI. Reactions such as anaphylaxis, angioedema and severe cutaneous adverse reactions have been reported [see Warnings and Precautions (5.3), Adverse reactions (6.2)].

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.

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)]

• Strong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone concentrations. Limit the pioglitazone dose to 15 mg daily. (7.2)
• CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations. (7.3)
• Topiramate may decrease pioglitazone concentrations. (7.4)

OSENI is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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.

OSENI combines two antihyperglycemic agents: alogliptin and pioglitazone.

• 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)

• Obtain liver tests prior to initiation.
• OSENI may be taken with or without food. (2.1)
• Individualize the starting dose of OSENI based on the patient’s current regimen and concurrent medical condition but do not exceed a daily dose of alogliptin 25 mg and pioglitazone 45 mg. (2.2)
• The recommended starting dosage in patients with NYHA Class I or II congestive heart failure is 25 mg of alogliptin and 15 mg of pioglitazone (2.4)
• Prior to initiation, assess renal function with creatinine clearance (CrCl) (2.3)
  • Mild renal impairment (creatinine clearance [CrCl] ≥60 mL/min): same as the recommended dosage in patients with normal renal function.
  • Moderate renal impairment (CrCl ≥30 to <60 mL/min): 12.5 mg of alogliptin and 30 mg of pioglitazone once daily.
  • Severe renal impairment (CrCl ≥15 to <30 mL/min) or ESRD (CrCl <15 mL/min or requiring hemodialysis): not recommended.

• 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)

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.

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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

• Thiazolidinediones, including pioglitazone, which is a component of OSENI^®, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.1)].
• After initiation of OSENI and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea and/or edema). If congestive heart failure develops while taking OSENI, consider discontinuation of OSENI or dosage reduction of pioglitazone in OSENI [see Warnings and Precautions (5.1)].
• OSENI is not recommended in patients with symptomatic heart failure [see Warnings and Precautions (5.1)].
• Initiation of OSENI in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1)].

OSENI tablets are available in the following strengths and packages:

25 mg/15 mg tablet: yellow, round, biconvex and film-coated with both “A/P” and “25/15” printed on one side, available in:

25 mg/30 mg tablet: peach, round, biconvex and film-coated with both “A/P” and “25/30” printed on one side, available in:

25 mg/45 mg tablet: red, round, biconvex, film-coated and with both “A/P” and “25/45” printed on one side, available in:

12.5 mg/30 mg tablet: pale peach, round, biconvex and film-coated with both “A/P” and “12.5/30” printed on one side, available in:

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.

Insulin and insulin secretagogues are known to cause hypoglycemia. Coadministration of OSENI with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue and insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.8)].

Recommended Starting Dosage Based on Current Regimen

Individualize the starting dosage of OSENI based on the patient's current regimen and the available strengths of OSENI (see Table 1).

Dosage Titration for Additional Glycemic Control

Titrate the OSENI dosage gradually, as needed, after assessing therapeutic response and tolerability, up to a maximum dosage of 25 mg of alogliptin and 45 mg of pioglitazone once daily.

Discuss the potential for unintended pregnancy with premenopausal women as therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some anovulatory women.

Starting Dosage in Patients with NYHA Class I or II Congestive Heart Failure

For patients with preexisting NYHA Class I or II congestive heart failure, the recommended starting dosage of OSENI is 25 mg of alogliptin and 15 mg of pioglitazone [see Boxed Warning and Warnings and Precautions (5.1)].

Monitoring for Fluid Retention and Dosage Modifications for Congestive Heart Failure

After initiation of OSENI or with dosage increase, monitor patients carefully for adverse reactions related to fluid retention as has been seen with pioglitazone (e.g., weight gain, edema and signs and symptoms of congestive heart failure).

If congestive heart failure develops while taking OSENI, consider discontinuation of OSENI or dosage reduction of pioglitazone in OSENI [see Boxed Warning and Warnings and Precautions (5.1)].

The maximum recommended dosage of OSENI is 25 mg of alogliptin and 15 mg of pioglitazone once daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

• Obtain liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) prior to initiating OSENI [see Warnings and Precautions (5.4)].
• Take OSENI orally once daily. Do not split tablets.
• OSENI may be taken with or without food [see Clinical Pharmacology (12.3)].
• If a dose is missed, do not double the next dose.

• Assess renal function prior to initiation of OSENI and periodically thereafter [see Use in Specific Populations (8.6)].
• The recommended dosage of OSENI in patients with mild renal impairment (creatinine clearance [CrCl] ≥60 mL/min) is the same as the recommended dosage in patients with normal renal function [see Dosage and Administration (2.1)].
• 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) because these patients require a lower dosage of alogliptin than what is available in the fixed dose combination product, OSENI [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

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)].