These Highlights Do Not Include All The Information Needed To Use Alogliptin And Metformin Hcl Tablets Safely And Effectively. See Full Prescribing Information For Alogliptin And Metformin Hcl Tablets.

Limitations of Use

Alogliptin and metformin HCl tablets should not be used in patients with type 1 diabetes mellitus.

Alogliptin and metformin HCl tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes: alogliptin and metformin hydrochloride.

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. Such decrease, possibly due to interference with B₁₂ absorption from the B₁₂-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B₁₂ supplementation. Certain individuals (those with inadequate vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B₁₂ levels. Measure hematologic parameters on an annual basis and vitamin B₁₂ at 2 to 3 year intervals in patients on alogliptin with metformin and manage any abnormalities [see Adverse Reactions (6.1)].

Acute pancreatitis has been reported in the postmarketing setting and in randomized clinical trials. In glycemic control trials in patients with type 2 diabetes, 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 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 alogliptin and metformin HCl tablets.

After initiation of alogliptin and metformin HCl tablets, 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.

In the EXAMINE trial which enrolled patients with type 2 diabetes 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 alogliptin and metformin HCl tablets 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 alogliptin and metformin HCl tablets.

Safety and effectiveness of alogliptin and metformin HCl tablets in pediatric patients have not been established.

The coadministration of alogliptin and metformin has been studied in patients with type 2 diabetes inadequately controlled on either diet and exercise alone, on metformin alone or metformin in combination with a thiazolidinedione.

There have been no clinical efficacy studies conducted with alogliptin and metformin HCl tablets; however, bioequivalence of alogliptin and metformin HCl tablets with coadministered alogliptin and metformin tablets was demonstrated, and efficacy of the combination of alogliptin and metformin has been demonstrated in three Phase 3 efficacy studies.

A total of 2095 patients with type 2 diabetes were randomized in three double-blind, placebo- or active-controlled clinical safety and efficacy studies conducted to evaluate the effects of alogliptin and metformin HCl tablets on glycemic control. The racial distribution of patients exposed to study medication was 69.2% white, 16.3% Asian, 6.5% black and 8.0% other racial groups. The ethnic distribution was 24.3% Hispanic. Patients had an overall mean age of approximately 54.4 years (range 22 to 80 years). In patients with type 2 diabetes, treatment with alogliptin and metformin HCl tablets produced clinically meaningful and statistically significant improvements in A1C versus comparator. As is typical for trials of agents to treat type 2 diabetes, the mean reduction in hemoglobin A1c (A1C) with alogliptin and metformin HCl tablets appears to be related to the degree of A1C elevation at baseline.

Alogliptin and metformin HCl tablets are contraindicated in patients with:

• Severe renal impairment (eGFR below 30 mL/min/1.73 m²) [see Warnings and Precautions (5.1)].
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma.
• Serious hypersensitivity reaction to alogliptin or metformin or any of the exciptients, such as anaphylaxis, angioedema and severe cutaneous adverse reactions [see Warnings and Precautions (5.4), Adverse Reactions (6.2)].

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, 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 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, alogliptin and metformin HCl tablets should be interrupted and investigation done to establish the probable cause. Alogliptin and metformin HCl tablets 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:

• 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)]

• Carbionic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. (7)
• 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. (7)
• Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. (7)

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Alogliptin and metformin HCl tablets is contraindicated in severe renal impairment, patients with an eGFR below 30 mL/min/1.73 m² [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

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 alogliptin and metformin HCl tablets. If bullous pemphigoid is suspected, alogliptin and metformin HCl tablets should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Alogliptin and metformin HCl tablets are not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].

Alogliptin and metformin HCl tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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), and Use in Specific Populations (8.6, 8.7)].

If metformin-associated lactic acidosis is suspected, immediately discontinue alogliptin and metformin HCl tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].

• Lactic acidosis: See boxed warning. (5.1)
• Pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue alogliptin and metformin HCl tablets. (5.2)
• Heart failure: Consider the risks and benefits of alogliptin and metformin HCl tablets 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 alogliptin and metformin HCl tablets. (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. In such cases, promptly discontinue alogliptin and metformin HCl tablets, assess for other potential causes, institute appropriate monitoring and treatment and initiate alternative treatment for diabetes. (5.4)
• Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt alogliptin and metformin HCl tablets and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart alogliptin and metformin HCl tablets if liver injury is confirmed and no alternative etiology can be found. (5.5)
• Vitamin B₁₂ deficiency: Metformin may lower vitamin B₁₂ levels. Measure hematologic parameters annually and B₁₂ at 2 to 3 year intervals and manage any abnormalties. (5.6)
• Hypoglycemia with Concomitant Use with Insulin or Insulin Secretaqoques: When used with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia. (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 alogliptin and metformin HCl tablets. (5.9)

• Individualize the starting dose based on the patient's current regimen. (2.1)
• Give twice daily with food. (2.1)
• Adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 25 mg alogliptin and 2000 mg metformin HCl. (2.1)
• Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR). (2.2)
  • Do not use in patients with eGFR below 60 mL/min/1.73 m².
• Alogliptin and metformin HCl tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. (2.3)

• 12.5 mg/500 mg tablets are pale yellow, oblong, film-coated tablets with "12.5/500" debossed on one side and "322M" debossed on the other side
• 12.5 mg/1000 mg tablets are pale yellow, oblong, film-coated tablets with "12.5/1000" debossed on one side and "322M" debossed on the other side

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.

• Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy.(8.3)
• Pediatrics: Safety and effectiveness of alogliptin and metformin HCl tablets in patients below the age of 18 have not been established. (8.4)
• Geriatric Use: Assess renal function more frequently. (8.5)
• Hepatic Impairment: Avoid use in patients with hepatic impairment. (8.7)

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin. These reactions include anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. If a serious hypersensitivity reaction is suspected, discontinue alogliptin and metformin HCl tablets, assess for other potential causes for the event and institute alternative treatment for diabetes [see Adverse Reactions (6.2)]. 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 alogliptin and metformin HCl tablets.

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)

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.

Product: 50090-5993

NDC: 50090-5993-0 90 TABLET, FILM COATED in a BOTTLE

• Healthcare providers should individualize the starting dose of alogliptin and metformin HCl tablets based on the patient's current regimen.
• Alogliptin and metformin HCl tablets should be taken twice daily with food with gradual dose escalation to reduce the gastrointestinal (GI) side effects due to metformin. Do not split tablets.
• Dosing may be adjusted based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 25 mg alogliptin and 2000 mg metformin hydrochloride (HCl).
• The following doses are available:
  •  
    12.5 mg alogliptin and 500 mg metformin HCl
  •  
    12.5 mg alogliptin and 1000 mg metformin HCl

Assess renal function prior to initiation of alogliptin and metformin HCl tablets and periodically thereafter.

Alogliptin and metformin HCl tablets is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m² [see Contraindications (4) and Warnings and Precautions (5.1)].

Alogliptin and metformin HCl tablets are not recommended in patients with an eGFR between 30 and 59 mL/min/1.73 m² because these patients require a lower daily dosage of alogliptin than what is available in the fixed combination alogliptin and metformin HCl tablets product.

Alogliptin and metformin HCl tablets require no dose adjustment in patients with an eGFR of 60 mL/min/1.73 m² or greater.

There is the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some premenopausal anovulatory women.

Discontinue alogliptin and metformin HCl tablets 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 liver disease, 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 alogliptin and metformin HCl tablets if renal function is stable [see Warnings and Precautions (5.1)].

Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with alogliptin and metformin HCl tablets.

Limitations of Use

Alogliptin and metformin HCl tablets should not be used in patients with type 1 diabetes mellitus.

Alogliptin and metformin HCl tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes: alogliptin and metformin hydrochloride.

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. Such decrease, possibly due to interference with B₁₂ absorption from the B₁₂-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B₁₂ supplementation. Certain individuals (those with inadequate vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B₁₂ levels. Measure hematologic parameters on an annual basis and vitamin B₁₂ at 2 to 3 year intervals in patients on alogliptin with metformin and manage any abnormalities [see Adverse Reactions (6.1)].

Acute pancreatitis has been reported in the postmarketing setting and in randomized clinical trials. In glycemic control trials in patients with type 2 diabetes, 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 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 alogliptin and metformin HCl tablets.

After initiation of alogliptin and metformin HCl tablets, 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.

In the EXAMINE trial which enrolled patients with type 2 diabetes 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 alogliptin and metformin HCl tablets 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 alogliptin and metformin HCl tablets.

Safety and effectiveness of alogliptin and metformin HCl tablets in pediatric patients have not been established.

The coadministration of alogliptin and metformin has been studied in patients with type 2 diabetes inadequately controlled on either diet and exercise alone, on metformin alone or metformin in combination with a thiazolidinedione.

There have been no clinical efficacy studies conducted with alogliptin and metformin HCl tablets; however, bioequivalence of alogliptin and metformin HCl tablets with coadministered alogliptin and metformin tablets was demonstrated, and efficacy of the combination of alogliptin and metformin has been demonstrated in three Phase 3 efficacy studies.

A total of 2095 patients with type 2 diabetes were randomized in three double-blind, placebo- or active-controlled clinical safety and efficacy studies conducted to evaluate the effects of alogliptin and metformin HCl tablets on glycemic control. The racial distribution of patients exposed to study medication was 69.2% white, 16.3% Asian, 6.5% black and 8.0% other racial groups. The ethnic distribution was 24.3% Hispanic. Patients had an overall mean age of approximately 54.4 years (range 22 to 80 years). In patients with type 2 diabetes, treatment with alogliptin and metformin HCl tablets produced clinically meaningful and statistically significant improvements in A1C versus comparator. As is typical for trials of agents to treat type 2 diabetes, the mean reduction in hemoglobin A1c (A1C) with alogliptin and metformin HCl tablets appears to be related to the degree of A1C elevation at baseline.

Alogliptin and metformin HCl tablets are contraindicated in patients with:

• Severe renal impairment (eGFR below 30 mL/min/1.73 m²) [see Warnings and Precautions (5.1)].
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma.
• Serious hypersensitivity reaction to alogliptin or metformin or any of the exciptients, such as anaphylaxis, angioedema and severe cutaneous adverse reactions [see Warnings and Precautions (5.4), Adverse Reactions (6.2)].

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, 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 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, alogliptin and metformin HCl tablets should be interrupted and investigation done to establish the probable cause. Alogliptin and metformin HCl tablets 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:

• 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)]

• Carbionic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. (7)
• 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. (7)
• Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. (7)

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Alogliptin and metformin HCl tablets is contraindicated in severe renal impairment, patients with an eGFR below 30 mL/min/1.73 m² [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

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 alogliptin and metformin HCl tablets. If bullous pemphigoid is suspected, alogliptin and metformin HCl tablets should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Alogliptin and metformin HCl tablets are not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].

Alogliptin and metformin HCl tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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), and Use in Specific Populations (8.6, 8.7)].

If metformin-associated lactic acidosis is suspected, immediately discontinue alogliptin and metformin HCl tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].

• Lactic acidosis: See boxed warning. (5.1)
• Pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue alogliptin and metformin HCl tablets. (5.2)
• Heart failure: Consider the risks and benefits of alogliptin and metformin HCl tablets 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 alogliptin and metformin HCl tablets. (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. In such cases, promptly discontinue alogliptin and metformin HCl tablets, assess for other potential causes, institute appropriate monitoring and treatment and initiate alternative treatment for diabetes. (5.4)
• Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt alogliptin and metformin HCl tablets and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart alogliptin and metformin HCl tablets if liver injury is confirmed and no alternative etiology can be found. (5.5)
• Vitamin B₁₂ deficiency: Metformin may lower vitamin B₁₂ levels. Measure hematologic parameters annually and B₁₂ at 2 to 3 year intervals and manage any abnormalties. (5.6)
• Hypoglycemia with Concomitant Use with Insulin or Insulin Secretaqoques: When used with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia. (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 alogliptin and metformin HCl tablets. (5.9)

• Individualize the starting dose based on the patient's current regimen. (2.1)
• Give twice daily with food. (2.1)
• Adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 25 mg alogliptin and 2000 mg metformin HCl. (2.1)
• Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR). (2.2)
  • Do not use in patients with eGFR below 60 mL/min/1.73 m².
• Alogliptin and metformin HCl tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. (2.3)

• 12.5 mg/500 mg tablets are pale yellow, oblong, film-coated tablets with "12.5/500" debossed on one side and "322M" debossed on the other side
• 12.5 mg/1000 mg tablets are pale yellow, oblong, film-coated tablets with "12.5/1000" debossed on one side and "322M" debossed on the other side

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.

• Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy.(8.3)
• Pediatrics: Safety and effectiveness of alogliptin and metformin HCl tablets in patients below the age of 18 have not been established. (8.4)
• Geriatric Use: Assess renal function more frequently. (8.5)
• Hepatic Impairment: Avoid use in patients with hepatic impairment. (8.7)

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin. These reactions include anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. If a serious hypersensitivity reaction is suspected, discontinue alogliptin and metformin HCl tablets, assess for other potential causes for the event and institute alternative treatment for diabetes [see Adverse Reactions (6.2)]. 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 alogliptin and metformin HCl tablets.

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)

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.

Product: 50090-5993

NDC: 50090-5993-0 90 TABLET, FILM COATED in a BOTTLE

• Healthcare providers should individualize the starting dose of alogliptin and metformin HCl tablets based on the patient's current regimen.
• Alogliptin and metformin HCl tablets should be taken twice daily with food with gradual dose escalation to reduce the gastrointestinal (GI) side effects due to metformin. Do not split tablets.
• Dosing may be adjusted based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 25 mg alogliptin and 2000 mg metformin hydrochloride (HCl).
• The following doses are available:
  •  
    12.5 mg alogliptin and 500 mg metformin HCl
  •  
    12.5 mg alogliptin and 1000 mg metformin HCl

Assess renal function prior to initiation of alogliptin and metformin HCl tablets and periodically thereafter.

Alogliptin and metformin HCl tablets is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m² [see Contraindications (4) and Warnings and Precautions (5.1)].

Alogliptin and metformin HCl tablets are not recommended in patients with an eGFR between 30 and 59 mL/min/1.73 m² because these patients require a lower daily dosage of alogliptin than what is available in the fixed combination alogliptin and metformin HCl tablets product.

Alogliptin and metformin HCl tablets require no dose adjustment in patients with an eGFR of 60 mL/min/1.73 m² or greater.

There is the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some premenopausal anovulatory women.

Discontinue alogliptin and metformin HCl tablets 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 liver disease, 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 alogliptin and metformin HCl tablets if renal function is stable [see Warnings and Precautions (5.1)].

Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with alogliptin and metformin HCl tablets.