References: 1. Goldstein BJ, Feinglos MN, Lunceford JK, et al; for Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007;30(8):1979–1987. 2. Reasner C, Olansky L, Seck TL, et al. The effect of initial therapy with the fixed-dose combination of sitagliptin and metformin compared with metformin monotherapy in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2011;13(7):644–652. 3. Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334(9):574–579. 4. Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med. 2002;137(1):25–33. 5. Krentz AJ, Bailey CJ. Oral antidiabetic agents: current role in type 2 diabetes mellitus. Drugs. 2005;65(3):385–411.

Selected Important Risk Information About JANUMET® XR (sitagliptin and metformin HCl extended-release) tablets

WARNING: LACTIC ACIDOSIS

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

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

JANUMET XR is contraindicated in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] below 30 mL/min/1.73 m2); hypersensitivity to metformin hydrochloride; acute or chronic metabolic acidosis, including diabetic ketoacidosis; or history of a serious hypersensitivity reaction to JANUMET XR or sitagliptin, (one of the components of JANUMET XR), such as anaphylaxis or angioedema.

Postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney.

Before initiating JANUMET XR, obtain an eGFR. JANUMET XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2. Discontinue JANUMET XR if the patient’s eGFR later falls below 30 mL/min/1.73 m2. Initiation of JANUMET XR is not recommended in patients with an eGFR between 30 and 45 mL/min/1.73 m2. In patients taking JANUMET XR whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy. Obtain an eGFR at least annually in all patients taking JANUMET XR. In patients at increased risk for the development of renal impairment (eg, the elderly), renal function should be assessed more frequently.

The concomitant use of JANUMET XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation. Consider more frequent monitoring of patients.

The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.

Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop JANUMET XR 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 JANUMET XR if renal function is stable.

Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. JANUMET XR should be temporarily discontinued while patients have restricted food and fluid intake.

Postmarketing cases of metformin-associated lactic acidosis have 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. Discontinue JANUMET XR if this occurs.

Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving JANUMET XR.

Patients with hepatic impairment have developed metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Avoid using JANUMET XR in patients with clinical or laboratory evidence of hepatic disease.

There have been postmarketing reports of acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin with or without metformin. After initiating JANUMET XR, observe patients carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue JANUMET XR and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUMET XR.

There have been postmarketing reports of worsening renal function in patients taking sitagliptin with or without metformin, including acute renal failure, sometimes requiring dialysis. Before initiating JANUMET XR, and at least annually thereafter, renal function should be assessed. In patients in whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should be assessed more frequently and JANUMET XR discontinued if evidence of renal impairment is present.

Use With Medications Known to Cause Hypoglycemia
Sitagliptin

When sitagliptin was used in combination with a sulfonylurea or insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or insulin. Patients also receiving insulin or an insulin secretagogue (eg, sulfonylurea) may require a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia.

The incidence (and rate) of hypoglycemia based on all reports of symptomatic hypoglycemia were: 16.4% (0.82 episodes/patient-year) for sitagliptin 100 mg in combination with metformin and glimepiride, 0.9% (0.02 episodes/patient-year) for placebo in combination with metformin and glimepiride, 8.2% (0.61 episodes/patient-year) for placebo in combination with metformin and insulin, and 15.3% (0.98 episodes/patient-year) for sitagliptin in combination with metformin and insulin.

Metformin hydrochloride

Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects.

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of JANUMET XR, such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiating sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUMET XR, assess for other potential causes for the event, and institute alternative diabetes treatment.

Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUMET XR.

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 1 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 of severe joint pain and discontinue drug if appropriate.

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 JANUMET XR. If bullous pemphigoid is suspected, JANUMET XR should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUMET XR or any other antidiabetic drug.

In clinical studies, the most common adverse reactions reported, regardless of investigator assessment of causality, in ≥5% of patients treated with either sitagliptin in combination with metformin or placebo were as follows: diarrhea (7.5% vs 4.0%), upper respiratory tract infection (6.2% vs 5.1%), and headache (5.9% vs 2.8%). In patients treated with sitagliptin in combination with metformin and sulfonylurea or placebo in combination with metformin and sulfonylurea: hypoglycemia (16.4% vs 0.9%) and headache (6.9% vs 2.7%). In patients treated with sitagliptin in combination with metformin and insulin or placebo in combination with metformin and insulin: hypoglycemia (15.3% vs 8.2%). Other adverse events with an incidence of ≥5% included nasopharyngitis for sitagliptin monotherapy and hypoglycemia (13.7% vs 4.9%), diarrhea (12.5% vs 5.6%), and nausea (6.7% vs 4.2%) for extended-release metformin vs placebo when added to glyburide.

Adverse reactions with sitagliptin in combination with metformin and rosiglitazone through Week 18 were: upper respiratory tract infection (sitagliptin, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%). Through Week 54 they were: upper respiratory tract infection (sitagliptin, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).

Before prescribing JANUMET® XR (sitagliptin and metformin HCl extended-release) tablets, please read the accompanying Prescribing Information, including the Boxed Warning about lactic acidosis. The Medication Guide also is available.

DIAB-1080641-0006 12/14

Please orient your device to the portrait position to return to the site.

Important Information

JANUMET XR is indicated, as an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both sitagliptin and metformin extended-release is appropriate.

JANUMET XR should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

JANUMET XR has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUMET XR.

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Selected Important Risk Information About JANUMET® XR (sitagliptin and metformin HCl extended-release) tablets

WARNING: LACTIC ACIDOSIS

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

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

JANUMET XR is contraindicated in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] below 30 mL/min/1.73 m2); hypersensitivity to metformin hydrochloride; acute or chronic metabolic acidosis, including diabetic ketoacidosis; or history of a serious hypersensitivity reaction to JANUMET XR or sitagliptin, (one of the components of JANUMET XR), such as anaphylaxis or angioedema.

Postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney.

Before initiating JANUMET XR, obtain an eGFR. JANUMET XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2. Discontinue JANUMET XR if the patient’s eGFR later falls below 30 mL/min/1.73 m2. Initiation of JANUMET XR is not recommended in patients with an eGFR between 30 and 45 mL/min/1.73 m2. In patients taking JANUMET XR whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy. Obtain an eGFR at least annually in all patients taking JANUMET XR. In patients at increased risk for the development of renal impairment (eg, the elderly), renal function should be assessed more frequently.

The concomitant use of JANUMET XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation. Consider more frequent monitoring of patients.

The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.

Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop JANUMET XR 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 JANUMET XR if renal function is stable.

Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. JANUMET XR should be temporarily discontinued while patients have restricted food and fluid intake.

Postmarketing cases of metformin-associated lactic acidosis have 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. Discontinue JANUMET XR if this occurs.

Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving JANUMET XR.

Patients with hepatic impairment have developed metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Avoid using JANUMET XR in patients with clinical or laboratory evidence of hepatic disease.

There have been postmarketing reports of acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin with or without metformin. After initiating JANUMET XR, observe patients carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue JANUMET XR and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUMET XR.

There have been postmarketing reports of worsening renal function in patients taking sitagliptin with or without metformin, including acute renal failure, sometimes requiring dialysis. Before initiating JANUMET XR, and at least annually thereafter, renal function should be assessed. In patients in whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should be assessed more frequently and JANUMET XR discontinued if evidence of renal impairment is present.

Use With Medications Known to Cause Hypoglycemia
Sitagliptin

When sitagliptin was used in combination with a sulfonylurea or insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or insulin. Patients also receiving insulin or an insulin secretagogue (eg, sulfonylurea) may require a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia.

The incidence (and rate) of hypoglycemia based on all reports of symptomatic hypoglycemia were: 16.4% (0.82 episodes/patient-year) for sitagliptin 100 mg in combination with metformin and glimepiride, 0.9% (0.02 episodes/patient-year) for placebo in combination with metformin and glimepiride, 8.2% (0.61 episodes/patient-year) for placebo in combination with metformin and insulin, and 15.3% (0.98 episodes/patient-year) for sitagliptin in combination with metformin and insulin.

Metformin hydrochloride

Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects.

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of JANUMET XR, such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiating sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUMET XR, assess for other potential causes for the event, and institute alternative diabetes treatment.

Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUMET XR.

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 1 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 of severe joint pain and discontinue drug if appropriate.

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 JANUMET XR. If bullous pemphigoid is suspected, JANUMET XR should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUMET XR or any other antidiabetic drug.

In clinical studies, the most common adverse reactions reported, regardless of investigator assessment of causality, in ≥5% of patients treated with either sitagliptin in combination with metformin or placebo were as follows: diarrhea (7.5% vs 4.0%), upper respiratory tract infection (6.2% vs 5.1%), and headache (5.9% vs 2.8%). In patients treated with sitagliptin in combination with metformin and sulfonylurea or placebo in combination with metformin and sulfonylurea: hypoglycemia (16.4% vs 0.9%) and headache (6.9% vs 2.7%). In patients treated with sitagliptin in combination with metformin and insulin or placebo in combination with metformin and insulin: hypoglycemia (15.3% vs 8.2%). Other adverse events with an incidence of ≥5% included nasopharyngitis for sitagliptin monotherapy and hypoglycemia (13.7% vs 4.9%), diarrhea (12.5% vs 5.6%), and nausea (6.7% vs 4.2%) for extended-release metformin vs placebo when added to glyburide.

Adverse reactions with sitagliptin in combination with metformin and rosiglitazone through Week 18 were: upper respiratory tract infection (sitagliptin, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%). Through Week 54 they were: upper respiratory tract infection (sitagliptin, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).

Before prescribing JANUMET® XR (sitagliptin and metformin HCl extended-release) tablets, please read the accompanying Prescribing Information, including the Boxed Warning about lactic acidosis. The Medication Guide also is available.