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Selected Important Risk Information
In clinical studies, the adverse reactions reported, regardless of investigator assessment of causality, in ≥5% of patients treated with JANUVIA as monotherapy and in combination therapy and more commonly than in patients treated with placebo, were upper respiratory tract infection, nasopharyngitis, and headache.

A dosage adjustment is recommended in patients with moderate or severe renal insufficiency or with end-stage renal disease requiring hemodialysis or peritoneal dialysis.

Important Information About JANUMET

JANUMET 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 is appropriate.

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

JANUMET has not been studied in combination with insulin.

Selected Important Risk Information About JANUMET

JANUMET is contraindicated in patients with renal disease or renal dysfunction (serum creatinine levels ≥1.5 mg/dL in males and ≥1.4 mg/dL in females) or abnormal creatinine clearance; acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma; or history of a serious hypersensitivity reaction to JANUMET or sitagliptin (one of the components of JANUMET), such as anaphylaxis or angioedema.

Temporarily discontinue JANUMET in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials.

Measure renal function before initiation of therapy with JANUMET and periodically thereafter. Avoid use in patients with hepatic disease. Temporarily discontinue for intercurrent serious conditions, infection, or surgery.

When lactic acidosis occurs, it is fatal in approximately 50% of cases. The reported incidence of lactic acidosis in patients receiving metformin is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications.

Use With Medications Known to Cause Hypoglycemia
Sitagliptin
As is typical with other antihyperglycemic agents used with a sulfonylurea, when sitagliptin was used in combination with metformin and a sulfonylurea, a medication known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used with metformin and a sulfonylurea. Therefore, patients also receiving an insulin secretagogue (eg, sulfonylurea, meglitinide) may require a lower dose of the insulin secretagogue to reduce the risk of hypoglycemia.

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, such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Onset of these reactions occurred within the first 3 months after initiation of treatment with sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUMET, assess for other potential causes for the event, and institute alternative treatment for diabetes.

In clinical studies, the most common adverse reactions reported, regardless of investigator assessment of causality, in >5% of patients and more commonly than in patients treated with placebo were as follows: diarrhea, upper respiratory tract infection, and headache (for sitagliptin and metformin combination therapy); nasopharyngitis (for sitagliptin monotherapy); and diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache (for metformin therapy).

The incidence of selected gastrointestinal adverse reactions in patients treated with sitagliptin and metformin was similar to those of placebo and metformin: nausea (1.3%, 0.8%), vomiting (1.1%, 0.8%), abdominal pain (2.2%, 3.8%), and diarrhea (2.4%, 2.5%).

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. When such drugs are administered to a patient receiving JANUMET, the patient should be closely observed to maintain adequate glycemic control.

Because impaired hepatic function has been associated with some cases of lactic acidosis, JANUMET should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

Use of JANUMET should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.

Measurement of hematologic parameters on an annual basis is advised in patients on JANUMET, and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B₁₂ levels.

In any intravascular contrast studies with iodinated materials, use of JANUMET should be temporarily discontinued at the time of or before the procedure, withheld for 48 hours subsequent to the procedure, and reinstituted only after renal function has been reevaluated and found to be normal.

Patients should be warned against excessive alcohol intake, either acute or chronic, when taking metformin.

Before initiation of therapy with JANUMET and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should be assessed more frequently and JANUMET discontinued if evidence of renal impairment is present.

Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion, should be used with caution.

Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JANUMET therapy, the drug should be promptly discontinued.

The dosage of antihyperglycemic therapy with JANUMET should be individualized on the basis of the patient’s current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2,000 mg metformin. Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the health care provider. JANUMET should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal side effects due to metformin.

If therapy with a combination tablet containing sitagliptin and metformin is considered appropriate for a patient inadequately controlled on metformin alone, the recommended starting dose of JANUMET is sitagliptin 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin 850 mg twice daily, the recommended starting dose of JANUMET is 50 mg sitagliptin/1,000 mg metformin twice daily.

If therapy with a combination tablet containing sitagliptin and metformin is considered appropriate for a patient inadequately controlled on sitagliptin alone, the recommended starting dose of JANUMET is 50 mg sitagliptin/500 mg metformin twice daily.

Patients with inadequate control on this dose can be titrated up to 50 mg sitagliptin/1,000 mg metformin twice daily. Patients taking sitagliptin monotherapy dose-adjusted for renal insufficiency should not be switched to JANUMET.

USE IN SPECIFIC POPULATIONS
There are no adequate and well-controlled studies in pregnant women. Therefore, JANUMET should be used during pregnancy only if clearly needed.

Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to JANUMET while pregnant. Health care providers are encouraged to report any prenatal exposure to JANUMET by calling the Pregnancy Registry at 1-800-986-8999.

No studies in lactating animals have been conducted with the combined components of JANUMET. Because many drugs are excreted in human milk, caution should be exercised when JANUMET is administered to a nursing woman.

Safety and effectiveness of JANUMET in children under 18 years have not been established.

No dosage adjustment is required based on age; however, because JANUMET is substantially excreted by the kidney, it may be useful to assess renal function in elderly patients before initiation of JANUMET and periodically thereafter.

Metformin treatment should not be initiated in patients >80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function.

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

Before prescribing JANUMET, please read the Prescribing Information, including the Boxed Warning about lactic acidosis.

Important Information About JANUVIA

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

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

JANUVIA has not been studied in combination with insulin.

Selected Important Risk Information About JANUVIA

The recommended dose of JANUVIA is 100 mg once daily.

A dosage adjustment is recommended in patients with moderate or severe renal insufficiency or with end-stage renal disease requiring hemodialysis or peritoneal dialysis.

No dosage adjustment is required for patients with mild renal insufficiency. For patients with moderate renal insufficiency, the dose of JANUVIA is 50 mg once daily. For patients with severe renal insufficiency or with end-stage renal disease requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily.

JANUVIA is contraindicated in patients with a history of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.

As is typical with other antihyperglycemic agents used in combination with a sulfonylurea, when JANUVIA was used in combination with a sulfonylurea, a class of medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo. Therefore, a lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia.

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with JANUVIA, such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Onset of these reactions occurred within the first 3 months after initiation of treatment with JANUVIA, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUVIA, assess for other potential causes for the event, and institute alternative treatment for diabetes.

In clinical studies, the adverse reactions reported, regardless of investigator assessment of causality, in >5% of patients treated with JANUVIA as monotherapy and in combination therapy and more commonly than in patients treated with placebo, were upper respiratory tract infection, nasopharyngitis, and headache.

The incidence of selected gastrointestinal adverse reactions in patients treated with JANUVIA 100 mg vs placebo was as follows: abdominal pain (2.3%, 2.1%), nausea (1.4%, 0.6%), and diarrhea (3.0%, 2.3%).

USE IN SPECIFIC POPULATIONS

There are no adequate and well-controlled studies in pregnant women. Therefore, JANUVIA should be used during pregnancy only if clearly needed.

Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to JANUVIA while pregnant. Health care providers are encouraged to report any prenatal exposure to JANUVIA by calling the Pregnancy Registry at 1-800-986-8999.

It is not known whether sitagliptin is excreted in human milk. Therefore, caution should be exercised when JANUVIA is administered to a nursing woman.

Safety and effectiveness of JANUVIA in children under 18 years have not been established.

No dosage adjustment is required based on age; however, because JANUVIA is substantially excreted by the kidney, it may be useful to assess renal function in elderly patients before initiation and periodically thereafter.

Before prescribing JANUVIA, please read the Prescribing Information.