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Important Safety Information for NESINA, KAZANO, and OSENI

WARNING: CONGESTIVE HEART FAILURE—for OSENI

Thiazolidinediones, including pioglitazone, which is a component of OSENI, cause or exacerbate congestive heart failure in some patients.
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 heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone in OSENI must be considered.
OSENI is not recommended in patients with symptomatic heart failure.
Initiation of OSENI in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.

WARNING: CONGESTIVE HEART FAILURE—for OSENI

Thiazolidinediones, including pioglitazone, which is a component of OSENI, cause or exacerbate congestive heart failure in some patients.
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 heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone in OSENI must be considered.
OSENI is not recommended in patients with symptomatic heart failure.
Initiation of OSENI in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.

WARNING: LACTIC ACIDOSIS—for KAZANO

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. 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.
If metformin-associated lactic acidosis is suspected, immediately discontinue KAZANO and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

NESINA, KAZANO, and OSENI are contraindicated in patients with a history of serious hypersensitivity reaction to any of the components of these products, such as anaphylaxis, angioedema, or severe cutaneous adverse reactions.
KAZANO is contraindicated in patients with severe renal impairment (eGFR below 30 mL/min/1.73m²).
KAZANO is contraindicated in patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis.
Do not initiate OSENI in patients with established NYHA Class III or IV heart failure.

Warnings and Precautions—for KAZANO

Lactic acidosis: Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to immediately discontinue KAZANO and report these symptoms to their healthcare provider. Because metformin is substantially excreted by the kidney, obtain an eGFR before initiating KAZANO and at least annually thereafter; assess more frequently in patients at increased risk for the development of renal impairment (e.g., the elderly); KAZANO is not recommended in patients with an eGFR between 30-60 mL/min/1.73m². Discontinue 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 m²; 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; restart KAZANO if renal function is stable. KAZANO should be temporarily discontinued while patients have restricted food and fluid intake. 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. Avoid use of KAZANO in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B12 deficiency: Metformin may lower Vitamin B12 levels. Monitor hematologic parameters annually.

Warnings and Precautions—for OSENI

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. Monitor patients for signs and symptoms.
Edema: Dose-related edema may occur. Use with caution in patients with edema.
Fractures: Increased incidence in female patients. Apply current standards of care for assessing and maintaining bone health.
Bladder cancer: May increase the risk of bladder cancer. Do not use OSENI in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer. Tell patients to promptly report any sign of hematuria or other symptoms such as dysuria or urinary urgency as these may be due to bladder cancer.
Macular edema: Macular edema has been reported in some patients taking pioglitazone. Recommend regular eye exams. Instruct patients to report any visual changes promptly.
Ovulation: Advise premenopausal females of the potential for an unintended pregnancy as therapy with pioglitazone may result in ovulation in some anovulatory women.

Warnings and Precautions—for NESINA, KAZANO, and OSENI

Acute pancreatitis: There have been reports of acute pancreatitis in both the postmarketing setting and randomized clinical trials. If pancreatitis is suspected, promptly discontinue NESINA, KAZANO, or OSENI.
Heart failure: Consider the risks and benefits of NESINA, KAZANO, or 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, 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, KAZANO, or OSENI.
Hypersensitivity: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin such as anaphylaxis, angioedema or severe cutaneous adverse reactions, including Stevens-Johnson syndrome. In such cases, promptly discontinue NESINA, KAZANO, or OSENI, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. Use caution in patients with a history of angioedema with another dipeptidyl peptidase-4 inhibitor (DPP-4i) because it is unknown whether such patients will be predisposed to angioedema.
Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. Baseline liver test panel is recommended for OSENI. If liver injury is detected, promptly interrupt NESINA, KAZANO, or OSENI and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart NESINA, KAZANO, or OSENI if liver injury is confirmed and no alternative etiology can be found. Use with caution in patients with hepatic impairment.
Hypoglycemia: Insulin and insulin secretagogues are known to cause hypoglycemia. A lower dose of the insulin or insulin secretagogue may be required to minimize the risk when used in combination with NESINA, KAZANO, or OSENI.
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.
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, KAZANO, or OSENI.
Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with NESINA, KAZANO, or OSENI.

Adverse Reactions

Most common adverse reactions (≥4% of patients treated with NESINA 25 mg and more frequently than in patients who received placebo) were nasopharyngitis (4.8%), upper respiratory tract infection (4.5%), and headache (4.3%).
Most common adverse reactions (≥4% of patients treated with co-administration of alogliptin and metformin) were upper respiratory tract infection (8.0%), nasopharyngitis (6.8%), diarrhea (5.5%), hypertension (5.5%), headache (5.3%), back pain (4.3%), and urinary tract infection (4.2%).
Most common adverse reactions (≥4% of patients treated with co-administration of alogliptin and pioglitazone) were nasopharyngitis (4.9%), back pain (4.2%), and upper respiratory tract infection (4.1%).

Drug Interactions

Use of OSENI with CYP2C8 strong inhibitors (e.g., gemfibrozil) will, or inducers (e.g., rifampin) may, require dose adjustment.
Use of OSENI with topiramate may decrease pioglitazone concentrations.
Use of KAZANO with carbonic anhydrase inhibitors may increase the risk of lactic acidosis. Consider more frequent monitoring.
Use of KAZANO with drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use.
Use of KAZANO with alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake.

Indication

NESINA (alogliptin), KAZANO (alogliptin and metformin HCl), and OSENI (alogliptin and pioglitazone) are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. NESINA, KAZANO, and OSENI are not for treatment of type 1 diabetes or diabetic ketoacidosis.

Please see the Full Prescribing Information, including Medication Guide, for NESINA.

Please see the Full Prescribing Information, including Medication Guide, for KAZANO.

Please see the Full Prescribing Information, including Medication Guide, for OSENI.

Important Safety Information for NESINA, KAZANO, and OSENI

WARNING: CONGESTIVE HEART FAILURE—for OSENI

Thiazolidinediones, including pioglitazone, which is a component of OSENI, cause or exacerbate congestive heart failure in some patients.
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 heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone in OSENI must be considered.
OSENI is not recommended in patients with symptomatic heart failure.
Initiation of OSENI in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.

WARNING: CONGESTIVE HEART FAILURE—for OSENI

Thiazolidinediones, including pioglitazone, which is a component of OSENI, cause or exacerbate congestive heart failure in some patients.
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 heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone in OSENI must be considered.
OSENI is not recommended in patients with symptomatic heart failure.
Initiation of OSENI in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.

WARNING: LACTIC ACIDOSIS—for KAZANO

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. 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.
If metformin-associated lactic acidosis is suspected, immediately discontinue KAZANO and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

NESINA, KAZANO, and OSENI are contraindicated in patients with a history of serious hypersensitivity reaction to any of the components of these products, such as anaphylaxis, angioedema, or severe cutaneous adverse reactions.
KAZANO is contraindicated in patients with severe renal impairment (eGFR below 30 mL/min/1.73m²).
KAZANO is contraindicated in patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis.
Do not initiate OSENI in patients with established NYHA Class III or IV heart failure.

Warnings and Precautions—for KAZANO

Lactic acidosis: Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to immediately discontinue KAZANO and report these symptoms to their healthcare provider. Because metformin is substantially excreted by the kidney, obtain an eGFR before initiating KAZANO and at least annually thereafter; assess more frequently in patients at increased risk for the development of renal impairment (e.g., the elderly); KAZANO is not recommended in patients with an eGFR between 30-60 mL/min/1.73m². Discontinue 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 m²; 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; restart KAZANO if renal function is stable. KAZANO should be temporarily discontinued while patients have restricted food and fluid intake. 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. Avoid use of KAZANO in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B12 deficiency: Metformin may lower Vitamin B12 levels. Monitor hematologic parameters annually.

Warnings and Precautions—for OSENI

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. Monitor patients for signs and symptoms.
Edema: Dose-related edema may occur. Use with caution in patients with edema.
Fractures: Increased incidence in female patients. Apply current standards of care for assessing and maintaining bone health.
Bladder cancer: May increase the risk of bladder cancer. Do not use OSENI in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer. Tell patients to promptly report any sign of hematuria or other symptoms such as dysuria or urinary urgency as these may be due to bladder cancer.
Macular edema: Macular edema has been reported in some patients taking pioglitazone. Recommend regular eye exams. Instruct patients to report any visual changes promptly.
Ovulation: Advise premenopausal females of the potential for an unintended pregnancy as therapy with pioglitazone may result in ovulation in some anovulatory women.

Warnings and Precautions—for NESINA, KAZANO, and OSENI

Acute pancreatitis: There have been reports of acute pancreatitis in both the postmarketing setting and randomized clinical trials. If pancreatitis is suspected, promptly discontinue NESINA, KAZANO, or OSENI.
Heart failure: Consider the risks and benefits of NESINA, KAZANO, or 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, 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, KAZANO, or OSENI.
Hypersensitivity: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin such as anaphylaxis, angioedema or severe cutaneous adverse reactions, including Stevens-Johnson syndrome. In such cases, promptly discontinue NESINA, KAZANO, or OSENI, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. Use caution in patients with a history of angioedema with another dipeptidyl peptidase-4 inhibitor (DPP-4i) because it is unknown whether such patients will be predisposed to angioedema.
Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. Baseline liver test panel is recommended for OSENI. If liver injury is detected, promptly interrupt NESINA, KAZANO, or OSENI and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart NESINA, KAZANO, or OSENI if liver injury is confirmed and no alternative etiology can be found. Use with caution in patients with hepatic impairment.
Hypoglycemia: Insulin and insulin secretagogues are known to cause hypoglycemia. A lower dose of the insulin or insulin secretagogue may be required to minimize the risk when used in combination with NESINA, KAZANO, or OSENI.
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.
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, KAZANO, or OSENI.
Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with NESINA, KAZANO, or OSENI.

Adverse Reactions

Most common adverse reactions (≥4% of patients treated with NESINA 25 mg and more frequently than in patients who received placebo) were nasopharyngitis (4.8%), upper respiratory tract infection (4.5%), and headache (4.3%).
Most common adverse reactions (≥4% of patients treated with co-administration of alogliptin and metformin) were upper respiratory tract infection (8.0%), nasopharyngitis (6.8%), diarrhea (5.5%), hypertension (5.5%), headache (5.3%), back pain (4.3%), and urinary tract infection (4.2%).
Most common adverse reactions (≥4% of patients treated with co-administration of alogliptin and pioglitazone) were nasopharyngitis (4.9%), back pain (4.2%), and upper respiratory tract infection (4.1%).

Drug Interactions

Use of OSENI with CYP2C8 strong inhibitors (e.g., gemfibrozil) will, or inducers (e.g., rifampin) may, require dose adjustment.
Use of OSENI with topiramate may decrease pioglitazone concentrations.
Use of KAZANO with carbonic anhydrase inhibitors may increase the risk of lactic acidosis. Consider more frequent monitoring.
Use of KAZANO with drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use.
Use of KAZANO with alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake.

Indication

Please see the Full Prescribing Information, including Medication Guide, for NESINA.

Please see the Full Prescribing Information, including Medication Guide, for KAZANO.

Please see the Full Prescribing Information, including Medication Guide, for OSENI.

U.S. Food and Drug Administration. FDA Listing of Authorized Generics. https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm126391.htm. Published March 30, 2017. Accessed May 12, 2017.
NESINA (alogliptin) Prescribing Information. Takeda Pharmaceuticals.
Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q; Alogliptin Study 008 Group. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. Int J Clin Pract. 2009;63:46-55.
DeFronzo RA, Burant CF, Fleck P, Wilson C, Mekki Q, Pratley RE. Efficacy and tolerability of the DPP-4 inhibitor alogliptin combined with pioglitazone, in metformin-treated patients with type 2 diabetes. J Clin Endocrinol Metab. 2012;97:1615-1622.
Rosenstock J, Inzucchi SE, Seufert J, Fleck PR, Wilson CA, Mekki Q. Initial combination therapy with alogliptin and pioglitazone in drug-naïve patients with type 2 diabetes. Diabetes Care. 2010;33:2406-2408.
DeFronzo RA, Fleck PR, Wilson CA, Mekki Q; Alogliptin Study 010 Group. Efficacy and safety of dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study. Diabetes Care. 2008;31:2315-2317.
KAZANO (alogliptin and metformin HCl) Prescribing Information. Takeda Pharmaceuticals.
Pratley RE, Fleck P, Wilson C. Efficacy and safety of initial combination therapy with alogliptin plus metformin versus either as monotherapy in drug-naïve patients with type 2 diabetes: a randomized, double-blind, 6-month study. Diabetes Obes Metab. 2014;16(7):613-621.
OSENI (alogliptin and pioglitazone) Prescribing Information. Takeda Pharmaceuticals.