JANUMET

Merck Sharp & Dohme Corp.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use JANUMET XR safely and effectively. See full prescribing information for JANUMET XR. JANUMET XR (sitagliptin and metformin HCl extended-release) tablets Initial U.S. Approval: 2012BOXED WARNINGWARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning . Lactic acidosis can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart failure. (5.1) Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate. (5.1) If acidosis is suspected, discontinue JANUMET XR and hospitalize the patient immediately. (5.1) RECENT MAJOR CHANGES Dosage and Administration   Recommended Dosing (2.1) 02/2014 INDICATIONS AND USAGEJANUMET XR is a dipeptidyl peptidase-4 (DPP-4) inhibitor and biguanide combination product 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. (1, 14)Important Limitations of Use: Not for the treatment of type 1 diabetes or diabetic ketoacidosis. (1) Has not been studied in patients with a history of pancreatitis. (1, 5.2) DOSAGE AND ADMINISTRATION Individualize the starting dose of JANUMET XR based on the patient's current regimen. (2.1) May adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin extended-release. (2.1) Administer once daily with a meal preferably in the evening. Gradually escalate the dose to reduce the gastrointestinal side effects due to metformin. (2.1) Maintain the same total daily dose of sitagliptin and metformin when changing between JANUMET and JANUMET XR, without exceeding the maximum recommended daily dose of 2000 mg metformin extended-release. (2.1) DOSAGE FORMS AND STRENGTHSJANUMET XR Tablets: 100 mg sitagliptin/1000 mg metformin HCl extended-release, 50 mg sitagliptin/500 mg metformin HCl extended-release, and 50 mg sitagliptin/1000 mg metformin HCl extended-release. (3)CONTRAINDICATIONS Renal dysfunction, e.g., serum creatinine ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance. (4, 5.1, 5.4) Metabolic acidosis, including diabetic ketoacidosis. (4, 5.1) History of a serious hypersensitivity reaction (e.g., anaphylaxis or angioedema) to JANUMET XR or to one of its components. (5.14, 6.2) WARNINGS AND PRECAUTIONS Lactic acidosis: Warn against excessive alcohol intake. JANUMET XR is not recommended in hepatic impairment and is contraindicated in renal impairment. Ensure normal renal function before initiating and at least annually thereafter. Temporarily discontinue JANUMET XR in patients undergoing radiologic studies with intravascular administration of iodinated contrast materials or any surgical procedures necessitating restricted intake of food or fluids. (5.1, 5.3, 5.4, 5.7) There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis in patients treated with sitagliptin (one of the components of JANUMET XR) with or without metformin. If pancreatitis is suspected, promptly discontinue JANUMET XR. (5.2) There have been postmarketing reports of acute renal failure in patients treated with sitagliptin with or without metformin, sometimes requiring dialysis. Before initiating JANUMET XR and at least annually thereafter, assess renal function and verify as normal. (4, 5.1, 5.4, 5.10, 6.2) Vitamin B12 deficiency: Metformin may lower Vitamin B12 levels. Measure hematologic parameters annually. (5.5, 6.1) 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 minimize the risk of hypoglycemia. (2.1, 5.9) There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin, such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop JANUMET XR, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. (5.14, 6.2) There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUMET XR or any other anti-diabetic drug. (5.15) Side Effects The most common adverse reactions reported in ≥5% of patients simultaneously started on sitagliptin and metformin and more commonly than in patients treated with placebo were diarrhea, upper respiratory tract infection, and headache. (6.1) Adverse reactions reported in ≥5% of patients treated with sitagliptin in combination with sulfonylurea and metformin and more commonly than in patients treated with placebo in combination with sulfonylurea and metformin were hypoglycemia and headache. (6.1) Hypoglycemia was the only adverse reaction reported in ≥5% of patients treated with sitagliptin in combination with insulin and metformin and more commonly than in patients treated with placebo in combination with insulin and metformin. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Cationic drugs eliminated by renal tubular secretion: Use with caution. (5.10, 7.2) USE IN SPECIFIC POPULATIONS Safety and effectiveness of JANUMET XR in children under 18 years have not been established. (8.4) There are no adequate and well-controlled studies in pregnant women. To report drug exposure during pregnancy call 1-800-986-8999. (8.1)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 JANUMET INDICATIONS AND USAGE
• 2 JANUMET DOSAGE AND ADMINISTRATION
  • 2.1 Recommended Dosing
• 3 DOSAGE FORMS AND STRENGTHS
• 4 JANUMET CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Lactic Acidosis
  • 5.2 Pancreatitis
  • 5.3 Impaired Hepatic Function
  • 5.4 Assessment of Renal Function
  • 5.5 Vitamin B Levels
  • 5.6 Alcohol Intake
  • 5.7 Surgical Procedures
  • 5.8 Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes
  • 5.9 Use with Medications Known to Cause Hypoglycemia
  • 5.10 Concomitant Medications Affecting Renal Function or Metformin Disposition
  • 5.11 Radiologic Studies with Intravascular Iodinated Contrast Materials
  • 5.12 Hypoxic States
  • 5.13 Loss of Control of Blood Glucose
  • 5.14 Hypersensitivity Reactions
  • 5.15 Macrovascular Outcomes
• 6 JANUMET ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Carbonic Anhydrase Inhibitors
  • 7.2 Cationic Drugs
  • 7.3 The Use of Metformin with Other Drugs
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
• 10 OVERDOSAGE
• 11 JANUMET DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 Instructions
  • 17.2 Laboratory Tests

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

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. [See Clinical Studies (14).]

Important Limitations of Use

JANUMET XR should not be used in patients with type 1 diabetes mellitus 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 for the development of pancreatitis while using JANUMET XR. [See Warnings and Precautions (5.2).]

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

The dose of JANUMET XR 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 2000 mg metformin. Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the healthcare provider.

• In patients not currently treated with metformin, the recommended total daily starting dose of JANUMET XR is 100 mg sitagliptin and 1000 mg metformin hydrochloride (HCl) extended-release. Patients with inadequate glycemic control on this dose of metformin can be titrated gradually, to reduce gastrointestinal side effects associated with metformin, up to the maximum recommended daily dose.
• In patients already treated with metformin, the recommended total daily starting dose of JANUMET XR is 100 mg sitagliptin and the previously prescribed dose of metformin.
• For patients taking metformin immediate-release 850 mg twice daily or 1000 mg twice daily, the recommended starting dose of JANUMET XR is two 50 mg sitagliptin/1000 mg metformin hydrochloride extended-release tablets taken together once daily.
• Maintain the same total daily dose of sitagliptin and metformin when changing between JANUMET (sitagliptin and metformin HCl immediate-release) and JANUMET XR. Patients with inadequate glycemic control on this dose of metformin can be titrated gradually, to reduce gastrointestinal side effects associated with metformin, up to the maximum recommended daily dose.

JANUMET XR should be administered with food to reduce the gastrointestinal side effects associated with the metformin component. JANUMET XR should be given once daily with a meal preferably in the evening. JANUMET XR should be swallowed whole. The tablets must not be split, crushed, or chewed before swallowing. There have been reports of incompletely dissolved JANUMET XR tablets being eliminated in the feces. It is not known whether this material seen in feces contains active drug. If a patient reports repeatedly seeing tablets in feces, the healthcare provider should assess adequacy of glycemic control [see Patient Counseling Information (17.1)].

The 100 mg sitagliptin/1000 mg metformin hydrochloride extended-release tablet should be taken as a single tablet once daily. Patients using two JANUMET XR tablets (such as two 50 mg sitagliptin/500 mg metformin hydrochloride extended-release tablets or two 50 mg sitagliptin/1000 mg metformin hydrochloride extended-release tablets) should take the two tablets together once daily.

Patients treated with an insulin secretagogue or insulin

Coadministration of JANUMET XR with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.9)].

No studies have been performed specifically examining the safety and efficacy of JANUMET XR in patients previously treated with other oral antihyperglycemic agents and switched to JANUMET XR. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

3 DOSAGE FORMS AND STRENGTHS

• 100 mg/1000 mg tablets are blue, bi-convex oval, film-coated tablets with "81" debossed on one side.
• 50 mg/500 mg tablets are light blue, bi-convex oval, film-coated tablets with "78" debossed on one side.
• 50 mg/1000 mg tablets are light green, bi-convex oval, film-coated tablets with "80" debossed on one side.

4 CONTRAINDICATIONS

JANUMET XR is contraindicated in patients with:

• Renal impairment (e.g., serum creatinine levels greater than or equal to 1.5 mg/dL for men, greater than or equal to 1.4 mg/dL for women or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia [see Warnings and Precautions (5.1)].
• Hypersensitivity to metformin hydrochloride.
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.
• History of a serious hypersensitivity reaction to JANUMET XR or sitagliptin, such as anaphylaxis or angioedema. [See Warnings and Precautions (5.14); Adverse Reactions (6.2). ]

5 WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis

Metformin hydrochloride

Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with JANUMET XR and is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate concentrations (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 μg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years. In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking JANUMET XR. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. JANUMET XR treatment should not be initiated in any patient unless measurement of creatinine clearance demonstrates that renal function is not reduced. In addition, JANUMET XR should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, JANUMET XR should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment. Patients should be cautioned against excessive alcohol intake when taking JANUMET XR, because alcohol potentiates the effects of metformin on lactate metabolism. In addition, JANUMET XR should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids. Use of topiramate, a carbonic anhydrase inhibitor, in epilepsy and migraine prophylaxis may frequently cause dose-dependent metabolic acidosis (in controlled trials, 32% and 67% for adjunctive treatment in adults and pediatric patients, respectively, and 15 to 25% for monotherapy of epilepsy, with decrease in serum bicarbonate to less than 20 mEq/L; 3% and 11% for adjunctive treatment in adults and pediatric patients, respectively, and 1 to 7% for monotherapy of epilepsy, with decrease in serum bicarbonate to less than 17 mEq/L) and may exacerbate the risk of metformin-induced lactic acidosis. [See Drug Interactions (7.1); Clinical Pharmacology (12).] The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis.

Patients should be educated to promptly report these symptoms to their physician should they occur. If present, JANUMET XR should be withdrawn until lactic acidosis is ruled out. Serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful. Once a patient is stabilized on any dose level of JANUMET XR, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to recur. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking JANUMET XR do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly-controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking JANUMET XR, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery. [See Contraindications (4).]

5.2 Pancreatitis

There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin with or without metformin. After initiation of JANUMET XR, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, JANUMET XR should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using JANUMET XR.

5.3 Impaired Hepatic Function

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

5.4 Assessment of Renal Function

Metformin and sitagliptin are substantially excreted by the kidney.

Metformin hydrochloride

The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Therefore, JANUMET XR is contraindicated in patients with renal impairment.

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

Sitagliptin

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 initiation of therapy with JANUMET XR 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 XR discontinued if evidence of renal impairment is present.

5.5 Vitamin B Levels

In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B₁₂ levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B₁₂ absorption from the B₁₂-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B₁₂ supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on JANUMET XR and any apparent abnormalities should be appropriately investigated and managed. [See Adverse Reactions (6.1).]

Certain individuals (those with inadequate Vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B₁₂ levels. In these patients, routine serum Vitamin B₁₂ measurements at two- to three-year intervals may be useful.

5.6 Alcohol Intake

Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving JANUMET XR.

5.7 Surgical Procedures

Use of JANUMET XR 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.

5.8 Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes

A patient with type 2 diabetes previously well controlled on JANUMET XR who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, JANUMET XR must be stopped immediately and other appropriate corrective measures initiated.

5.9 Use with Medications Known to Cause Hypoglycemia

Sitagliptin

When sitagliptin was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin [see Adverse Reactions (6)]. Therefore, patients also receiving an insulin secretagogue (e.g., sulfonylurea) or insulin may require a lower dose of the insulin secretagogue or insulin to reduce the risk of hypoglycemia [see Dosage and Administration (2.1)].

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. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking β-adrenergic blocking drugs.

5.10 Concomitant Medications Affecting Renal Function or Metformin Disposition

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 [see Drug Interactions (7.2)], should be used with caution.

5.11 Radiologic Studies with Intravascular Iodinated Contrast Materials

Intravascular contrast studies with iodinated materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin [see Contraindications (4)]. Therefore, in patients in whom any such study is planned, JANUMET XR should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.

5.12 Hypoxic States

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 XR therapy, the drug should be promptly discontinued.

5.13 Loss of Control of Blood Glucose

When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold JANUMET XR and temporarily administer insulin. JANUMET XR may be reinstituted after the acute episode is resolved.

5.14 Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of JANUMET XR. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. 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 XR, assess for other potential causes for the event, and institute alternative treatment for diabetes. [See Adverse Reactions (6.2).]

Use caution in a patient with a history of angioedema to another dipeptidyl peptidase-4 (DPP4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUMET XR.

5.15 Macrovascular Outcomes

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

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

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.

Sitagliptin and Metformin Immediate-Release Coadministration in Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise

Table 1 summarizes the most common (≥5% of patients) adverse reactions reported (regardless of investigator assessment of causality) in a 24-week placebo-controlled factorial study in which sitagliptin and metformin immediate-release were coadministered to patients with type 2 diabetes inadequately controlled on diet and exercise.

Table 1: Sitagliptin and Metformin Immediate-Release Coadministered to Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise: Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in ≥5% of Patients Receiving Combination Therapy (and Greater than in Patients Receiving Placebo) Intent-to-treat population.

	Number of Patients (%)
	Placebo	Sitagliptin 100 mg once daily	Metformin Immediate- Release 500 mg or 1000 mg twice daily Data pooled for the patients given the lower and higher doses of metformin.	Sitagliptin 50 mg twice daily + Metformin Immediate- Release 500 mg or 1000 mg twice daily Data pooled for the patients given the lower and higher doses of metformin.
	N = 176	N = 179	N = 364Data pooled for the patients given the lower and higher doses of metformin.	N = 372Data pooled for the patients given the lower and higher doses of metformin.
Diarrhea	7 (4.0)	5 (2.8)	28 (7.7)	28 (7.5)
Upper Respiratory Tract Infection	9 (5.1)	8 (4.5)	19 (5.2)	23 (6.2)
Headache	5 (2.8)	2 (1.1)	14 (3.8)	22 (5.9)

Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Immediate-Release Alone

In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once daily added to a twice daily metformin immediate-release regimen, there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo. Discontinuation of therapy due to clinical adverse reactions was similar to the placebo treatment group (sitagliptin and metformin immediate-release, 1.9%; placebo and metformin immediate-release, 2.5%).

Gastrointestinal Adverse Reactions

The incidences of pre-selected gastrointestinal adverse experiences in patients treated with sitagliptin and metformin immediate-release were similar to those reported for patients treated with metformin immediate-release alone. See Table 2.

Table 2: Pre-selected Gastrointestinal Adverse Reactions (Regardless of Investigator Assessment of Causality) Reported in Patients with Type 2 Diabetes Receiving Sitagliptin and Metformin Immediate-Release

	Number of Patients (%)
	Study of Sitagliptin and Metformin Immediate-Release in Patients Inadequately Controlled on Diet and Exercise				Study of Sitagliptin Add-on in Patients Inadequately Controlled on Metformin Immediate-Release Alone
	Placebo	Sitagliptin 100 mg once daily	Metformin Immediate-Release 500 mg or 1000 mg twice daily Data pooled for the patients given the lower and higher doses of metformin.	Sitagliptin 50 mg bid + Metformin Immediate- Release 500 mg or 1000 mg twice daily Data pooled for the patients given the lower and higher doses of metformin.	Placebo and Metformin Immediate- Release ≥1500 mg daily	Sitagliptin 100 mg once daily and Metformin Immediate- Release ≥1500 mg daily
	N = 176	N = 179	N = 364	N = 372	N = 237	N = 464
Diarrhea	7 (4.0)	5 (2.8)	28 (7.7)	28 (7.5)	6 (2.5)	11 (2.4)
Nausea	2 (1.1)	2 (1.1)	20 (5.5)	18 (4.8)	2 (0.8)	6 (1.3)
Vomiting	1 (0.6)	0 (0.0)	2 (0.5)	8 (2.2)	2 (0.8)	5 (1.1)
Abdominal PainAbdominal discomfort was included in the analysis of abdominal pain in the study of initial therapy.	4 (2.3)	6 (3.4)	14 (3.8)	11 (3.0)	9 (3.8)	10 (2.2)

Sitagliptin in Combination with Metformin Immediate-Release and Glimepiride

In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin immediate-release and glimepiride (sitagliptin, N=116; placebo, N=113), the adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: hypoglycemia (Table 3) and headache (6.9%, 2.7%).

Sitagliptin in Combination with Metformin Immediate-Release and Rosiglitazone

In a placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin immediate-release and rosiglitazone (sitagliptin, N=181; placebo, N=97), the adverse reactions reported regardless of investigator assessment of causality through Week 18 in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory tract infection (sitagliptin, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%). Through Week 54, the adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo 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%).

Sitagliptin in Combination with Metformin Immediate-Release and Insulin

In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin immediate-release and insulin (sitagliptin, N=229; placebo, N=233), the only adverse reaction reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo was hypoglycemia (Table 3).

Hypoglycemia

In all (N=5) studies, adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required although most (77%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. When the combination of sitagliptin and metformin immediate-release was coadministered with a sulfonylurea or with insulin, the percentage of patients reporting at least one adverse reaction of hypoglycemia was higher than that observed with placebo and metformin immediate-release coadministered with a sulfonylurea or with insulin (Table 3).

Table 3: Incidence and Rate of HypoglycemiaAdverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required: Intent-to-treat population. (Regardless of Investigator Assessment of Causality) in Placebo-Controlled Clinical Studies of Sitagliptin in Combination with Metformin Immediate-Release Coadministered with Glimepiride or Insulin

Add-On to Glimepiride +   Metformin Immediate-Release   (24 weeks)	Sitagliptin 100 mg + Metformin Immediate-Release + Glimepiride	Placebo + Metformin Immediate-Release + Glimepiride
	N = 116	N = 113
Overall (%)	19 (16.4)	1 (0.9)
Rate (episodes/patient-year) Based on total number of events (i.e., a single patient may have had multiple events).	0.82	0.02
Severe (%)Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss of consciousness or seizure.	0 (0.0)	0 (0.0)
Add-On to Insulin   + Metformin Immediate-Release   (24 weeks)	Sitagliptin 100 mg + Metformin Immediate-Release + Insulin	Placebo + Metformin Immediate-Release + Insulin
	N = 229	N = 233
Overall (%)	35 (15.3)	19 (8.2)
Rate (episodes/patient-year) Based on total number of events (i.e., a single patient may have had multiple events).	0.98	0.61
Severe (%)Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss of consciousness or seizure.	1 (0.4)	1 (0.4)

The overall incidence of reported adverse reactions of hypoglycemia in patients with type 2 diabetes inadequately controlled on diet and exercise was 0.6% in patients given placebo, 0.6% in patients given sitagliptin alone, 0.8% in patients given metformin immediate-release alone, and 1.6% in patients given sitagliptin in combination with metformin immediate-release. In patients with type 2 diabetes inadequately controlled on metformin immediate-release alone, the overall incidence of adverse reactions of hypoglycemia was 1.3% in patients given add-on sitagliptin and 2.1% in patients given add-on placebo.

In the study of sitagliptin and add-on combination therapy with metformin immediate-release and rosiglitazone, the overall incidence of hypoglycemia was 2.2% in patients given add-on sitagliptin and 0.0% in patients given add-on placebo through Week 18. Through Week 54, the overall incidence of hypoglycemia was 3.9% in patients given add-on sitagliptin and 1.0% in patients given add-on placebo.

Vital Signs and Electrocardiograms

With the combination of sitagliptin and metformin immediate-release, no clinically meaningful changes in vital signs or in electrocardiogram parameters (including the QTc interval) were observed.

Pancreatitis

In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients randomized to receive sitagliptin 100 mg/day (N=5429) or corresponding (active or placebo) control (N=4817), the incidence of acute pancreatitis was 0.1 per 100 patient-years in each group (4 patients with an event in 4708 patient-years for sitagliptin and 4 patients with an event in 3942 patient-years for control). [See Warnings and Precautions (5.2).]

Sitagliptin

The most common adverse experience in sitagliptin monotherapy reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo was nasopharyngitis.

Metformin Extended-Release

In a 24-week clinical trial in which extended-release metformin or placebo was added to glyburide therapy, the most common (>5% and greater than placebo) adverse reactions in the combined treatment group were hypoglycemia (13.7% vs. 4.9%), diarrhea (12.5% vs. 5.6%), and nausea (6.7% vs. 4.2%).

Laboratory Tests

Sitagliptin

The incidence of laboratory adverse reactions was similar in patients treated with sitagliptin and metformin immediate-release (7.6%) compared to patients treated with placebo and metformin (8.7%). In most but not all studies, a small increase in white blood cell count (approximately 200 cells/microL difference in WBC vs. placebo; mean baseline WBC approximately 6600 cells/microL) was observed due to a small increase in neutrophils. This change in laboratory parameters is not considered to be clinically relevant.

Metformin hydrochloride

In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B₁₂ levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B₁₂ absorption from the B₁₂-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B₁₂ supplementation. [See Warnings and Precautions (5.5).]

6.2 Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of sitagliptin with or without metformin, and/or in combination with other antidiabetic medications. 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.

Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome [see Warnings and Precautions (5.14)]; upper respiratory tract infection; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis [see Indications and Usage (1); Warnings and Precautions (5.2)]; worsening renal function, including acute renal failure (sometimes requiring dialysis) [see Warnings and Precautions (5.4)]; constipation; vomiting; headache; arthralgia; myalgia; pain in extremity; back pain.

7 DRUG INTERACTIONS

7.1 Carbonic Anhydrase Inhibitors

Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with JANUMET XR, as the risk of lactic acidosis may increase.

7.2 Cationic Drugs

Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of JANUMET XR and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

7.3 The Use of Metformin with Other Drugs

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving JANUMET XR the patient should be closely observed to maintain adequate glycemic control.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B:

JANUMET XR

There are no adequate and well-controlled studies in pregnant women with JANUMET XR or its individual components; therefore, the safety of JANUMET XR in pregnant women is not known. JANUMET XR should be used during pregnancy only if clearly needed.

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

No animal studies have been conducted with the combined products in JANUMET XR to evaluate effects on reproduction. The following data are based on findings in studies performed with sitagliptin or metformin individually.

Sitagliptin

Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies with sitagliptin in pregnant women.

Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately 30 and 20 times human exposure at the maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100 times human exposure at the MRHD.

Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1000 mg/kg. No functional or behavioral toxicity was observed in offspring of rats.

Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours postdose. Placental transfer of sitagliptin administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.

Metformin hydrochloride

Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day, which represent 3 and 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparison for rats and rabbits, respectively. However, because animal reproduction studies are not always predictive of human response, metformin hydrochloride should not be used during pregnancy unless clearly needed.

8.3 Nursing Mothers

No studies in lactating animals have been conducted with the combined components of JANUMET XR. In studies performed with the individual components, both sitagliptin and metformin are secreted in the milk of lactating rats. It is not known whether sitagliptin or metformin are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when JANUMET XR is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of JANUMET XR in pediatric patients under 18 years have not been established.

8.5 Geriatric Use

JANUMET XR

Because sitagliptin and metformin are substantially excreted by the kidney, and because aging can be associated with reduced renal function, JANUMET XR should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. [See Warnings and Precautions (5.1, 5.4); Clinical Pharmacology (12.3).]

Sitagliptin

Of the total number of subjects (N=3884) in premarketing Phase II and III clinical studies of sitagliptin, 725 patients were 65 years and over, while 61 patients were 75 years and over. No overall differences in safety or effectiveness were observed between subjects 65 years and over and younger subjects. While this and other reported clinical experience have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

Metformin hydrochloride

Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. Metformin should only be used in patients with normal renal function. The initial and maintenance dosing of metformin should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function. [See Contraindications (4); Warnings and Precautions (5.4); Clinical Pharmacology (12.3).]

10 OVERDOSAGE

Sitagliptin

During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg sitagliptin, a mean effect that is not considered clinically important [see Clinical Pharmacology (12.2)]. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with sitagliptin with doses of up to 400 mg per day for periods of up to 28 days.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as indicated by the patient's clinical status.

Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Metformin hydrochloride

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1)]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

11 DESCRIPTION

JANUMET XR tablets contain two oral antidiabetic medications used in the management of type 2 diabetes: sitagliptin and metformin hydrochloride extended-release.

Sitagliptin

Sitagliptin is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. Sitagliptin phosphate monohydrate drug substance is used to manufacture JANUMET XR. Sitagliptin phosphate monohydrate is described chemically as 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-α]pyrazine phosphate (1:1) monohydrate with an empirical formula of C₁₆H₁₅F₆N₅O•H₃PO₄•H₂O and a molecular weight of 523.32. The structural formula is:

Sitagliptin phosphate monohydrate is a white to off-white, crystalline, non-hygroscopic powder. It is soluble in water and N,N-dimethyl formamide; slightly soluble in methanol; very slightly soluble in ethanol, acetone, and acetonitrile; and insoluble in isopropanol and isopropyl acetate.

Metformin hydrochloride

Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is a white to off-white crystalline compound with a molecular formula of C₄H₁₁N₅•HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pK_a of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is as shown:

JANUMET XR

JANUMET XR consists of an extended-release metformin core tablet coated with an immediate-release layer of sitagliptin. The sitagliptin layer is coated with a soluble polymeric film. JANUMET XR is available for oral administration as tablets containing 64.25 mg sitagliptin phosphate monohydrate (equivalent to 50 mg sitagliptin as free base) and either 500 mg metformin hydrochloride extended-release (50 mg/500 mg) or 1000 mg metformin hydrochloride extended-release (50 mg/1000 mg). Additionally, JANUMET XR is available for oral administration as tablets containing 128.5 mg sitagliptin phosphate monohydrate (equivalent to 100 mg sitagliptin as free base) and 1000 mg metformin hydrochloride extended-release (100 mg/1000 mg).

All doses of JANUMET XR contain the following inactive ingredients: povidone, hypromellose, colloidal silicon dioxide, sodium stearyl fumarate, propyl gallate, polyethylene glycol, and kaolin. The JANUMET XR 50 mg/500 mg tablet contains the additional inactive ingredient microcrystalline cellulose. In addition, the film coating for all doses contains the following inactive ingredients: hypromellose, hydroxypropyl cellulose, titanium dioxide, FD&C #2/Indigo Carmine Aluminum Lake and carnauba wax. The JANUMET XR 50 mg/1000 mg tablet film coating also contains the inactive ingredient yellow iron oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

JANUMET XR

JANUMET XR tablets combine two antidiabetic medications with complementary mechanisms of action to improve glycemic control in adults with type 2 diabetes: sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin hydrochloride extended-release, a member of the biguanide class.

Sitagliptin

Sitagliptin is a DPP-4 inhibitor, which exerts its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

Metformin hydrochloride

Metformin is a biguanide that improves glycemic control in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in either patients with type 2 diabetes or healthy subjects except in certain circumstances [see Warnings and Precautions (5.9)] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

12.2 Pharmacodynamics

Sitagliptin

In patients with type 2 diabetes, administration of sitagliptin led to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.

Sitagliptin and Metformin hydrochloride Coadministration

In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, whereas metformin alone increased active and total GLP-1 concentrations to similar extents. Coadministration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations. It is unclear what these findings mean for changes in glycemic control in patients with type 2 diabetes.

In studies with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia.

Cardiac Electrophysiology

In a randomized, placebo-controlled crossover study, 79 healthy subjects were administered a single oral dose of sitagliptin 100 mg, sitagliptin 800 mg (8 times the recommended dose), and placebo. At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800-mg dose, the maximum increase in the placebo-corrected mean change in QTc from baseline at 3 hours postdose was 8.0 msec. This increase is not considered to be clinically significant. At the 800-mg dose, peak sitagliptin plasma concentrations were approximately 11 times higher than the peak concentrations following a 100-mg dose.

In patients with type 2 diabetes administered sitagliptin 100 mg (N=81) or sitagliptin 200 mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.

12.3 Pharmacokinetics

JANUMET XR

The results of a study in healthy subjects demonstrated that the JANUMET XR (sitagliptin and metformin HCl extended-release) 50 mg/500 mg and 100 mg/1000 mg tablets are bioequivalent to coadministration of corresponding doses of sitagliptin and metformin hydrochloride extended-release.

Bioequivalence between two JANUMET XR 50 mg/500 mg tablets and one JANUMET XR 100 mg/1000 mg tablet was also demonstrated.

After administration of two JANUMET XR 50 mg/1000 mg tablets once daily with the evening meal for 7 days in healthy adult subjects, steady-state for sitagliptin and metformin is reached by Day 4 and 5, respectively. The median T_max value for sitagliptin and metformin at steady state is approximately 3 and 8 hours postdose, respectively. The median T_max value for sitagliptin and metformin after administration of a single tablet of JANUMET is 3 and 3.5 hours postdose, respectively.

Absorption

JANUMET XR

After administration of JANUMET XR tablets with a high-fat breakfast, the AUC for sitagliptin was not altered. The mean C_max was decreased by 17%, although the median T_max was unchanged relative to the fasted state. After administration of JANUMET XR with a high-fat breakfast, the AUC for metformin increased 62%, the C_max for metformin decreased by 9%, and the median T_max for metformin occurred 2 hours later relative to the fasted state.

Sitagliptin

The absolute bioavailability of sitagliptin is approximately 87%. Coadministration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics of sitagliptin.

Distribution

Sitagliptin

The mean volume of distribution at steady state following a single 100-mg intravenous dose of sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).

Metformin hydrochloride

Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin hydrochloride tablets 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin hydrochloride tablets, steady-state plasma concentrations of metformin are reached within 24-48 hours and are generally <1 mcg/mL. During controlled clinical trials of metformin, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.

Metabolism

Sitagliptin

Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [¹⁴C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

Metformin hydrochloride

Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion. Metabolism studies with extended-release metformin tablets have not been conducted.

Excretion

Sitagliptin

Following administration of an oral [¹⁴C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t_1/2 following a 100-mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

Metformin hydrochloride

Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Specific Populations

Renal Impairment

JANUMET XR

JANUMET XR should not be used in patients with renal impairment [see Contraindications (4); Warnings and Precautions (5.4)].

Sitagliptin

An approximately 2-fold increase in the plasma AUC of sitagliptin was observed in patients with moderate renal impairment, and an approximately 4-fold increase was observed in patients with severe renal impairment including patients with end-stage renal disease (ESRD) on hemodialysis, as compared to normal healthy control subjects.

Metformin hydrochloride

In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance.

Hepatic Impairment

Sitagliptin

In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), mean AUC and C_max of sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched controls following administration of a single 100-mg dose of sitagliptin. These differences are not considered to be clinically meaningful.

There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score >9).

Metformin hydrochloride

No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.

Gender

Sitagliptin

Gender had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.

Metformin hydrochloride

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender. Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.

Geriatric

Sitagliptin

When the effects of age on renal function are taken into account, age alone did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis. Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.

Metformin hydrochloride

Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half life is prolonged, and C_max is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.

As is true for all patients, JANUMET XR treatment should not be initiated in geriatric patients unless measurement of creatinine clearance demonstrates that renal function is normal [see Warnings and Precautions (5.1, 5.4)].

Pediatric

No studies with JANUMET XR have been performed in pediatric patients.

Race

Sitagliptin

Race had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of available pharmacokinetic data, including subjects of white, Hispanic, black, Asian, and other racial groups.

Metformin hydrochloride

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

Body Mass Index (BMI)

Sitagliptin

Body mass index had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.

Drug Interactions

Sitagliptin and Metformin hydrochloride

Coadministration of multiple doses of sitagliptin (50 mg) and metformin (1000 mg) given twice daily did not meaningfully alter the pharmacokinetics of either sitagliptin or metformin in patients with type 2 diabetes.

Pharmacokinetic drug interaction studies with JANUMET XR have not been performed; however, such studies have been conducted with the individual components of JANUMET XR (sitagliptin and metformin hydrochloride extended-release).

Sitagliptin

In Vitro Assessment of Drug Interactions

Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4. Sitagliptin is a p-glycoprotein substrate, but does not inhibit p-glycoprotein mediated transport of digoxin. Based on these results, sitagliptin is considered unlikely to cause interactions with other drugs that utilize these pathways.

Sitagliptin is not extensively bound to plasma proteins. Therefore, the propensity of sitagliptin to be involved in clinically meaningful drug-drug interactions mediated by plasma protein binding displacement is very low.

In Vivo Assessment of Drug Interactions

Table 4: Effect of Sitagliptin on Systemic Exposure of Coadministered Drugs

Coadministered Drug	Dose of Coadministered DrugAll doses administered as single dose unless otherwise specified	Dose of Sitagliptin All doses administered as single dose unless otherwise specified	Geometric Mean Ratio (ratio with/without sitagliptin) No Effect = 1.00
				AUCAUC is reported as AUC0-∞ unless otherwise specified	Cmax
No dosing adjustments required for the following:
Digoxin	0.25 mgMultiple dose once daily for 10 days	100 mgMultiple dose once daily for 10 days	Digoxin	1.11AUC0-24hr	1.18
Glyburide	1.25 mg	200 mgMultiple dose once daily for 6 days	Glyburide	1.09	1.01
Simvastatin	20 mg	200 mgMultiple dose once daily for 5 days	Simvastatin	0.85AUC0-last	0.80
			Simvastatin Acid	1.12N = 26	1.06
Rosiglitazone	4 mg	200 mgMultiple dose once daily for 5 days	Rosiglitazone	0.98	0.99
Warfarin	30 mg single dose on day 5	200 mgMultiple dose once daily for 11 days	S(-) Warfarin	0.95	0.89
			R(+) Warfarin	0.99	0.89
Ethinyl estradiol and norethindrone	21 days once daily of 35 µg ethinyl estradiol with norethindrone 0.5 mg × 7 days, 0.75 mg × 7 days, 1.0 mg × 7 days	200 mgMultiple dose once daily for 21 days	Ethinyl estradiol	0.99	0.97
			Norethindrone	1.03	0.98
Metformin	1000 mgMultiple dose twice daily for 14 days	50 mgMultiple dose twice daily for 7 days	Metformin	1.02AUC0-12hr	0.97

Table 5: Effect of Coadministered Drugs on Systemic Exposure of Sitagliptin

Coadministered Drug	Dose of Coadministered DrugAll doses administered as single dose unless otherwise specified	Dose of SitagliptinAll doses administered as single dose unless otherwise specified	Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00
				AUCAUC is reported as AUC0-∞ unless otherwise specified	Cmax
No dosing adjustments required for the following:
Cyclosporine	600 mg once daily	100 mg once daily	Sitagliptin	1.29	1.68
Metformin	1000 mgMultiple dose twice daily for 14 days	50 mgMultiple dose twice daily for 7 days	Sitagliptin	1.02AUC0-12hr	1.05

Table 6: Effect of Metformin on Systemic Exposure of Coadministered Drugs

Coadministered Drug	Dose of Coadministered DrugAll doses administered as single dose unless otherwise specified	Dose of MetforminAll doses administered as single dose unless otherwise specified	Geometric Mean Ratio (ratio with/without metformin) No Effect = 1.00
				AUC AUC is reported as AUC0-∞ unless otherwise specified	Cmax
No dosing adjustments required for the following:
Cimetidine	400 mg	850 mg	Cimetidine	0.95AUC0-24hr	1.01
Glyburide	5 mg	500 mgGLUMETZA (metformin hydrochloride extended-release tablets) 500 mg	Glyburide	0.78Ratio of arithmetic means, p value of difference < 0.05	0.63Ratio of arithmetic means, p value of difference < 0.05
Furosemide	40 mg	850 mg	Furosemide	0.87Ratio of arithmetic means, p value of difference < 0.05	0.69Ratio of arithmetic means, p value of difference < 0.05
Nifedipine	10 mg	850 mg	Nifedipine	1.10Change from baseline to Week 3 (LOCF)	1.08
Propranolol	40 mg	850 mg	Propranolol	1.01Change from baseline to Week 3 (LOCF)	0.94
Ibuprofen	400 mg	850 mg	Ibuprofen	0.97Ratio of arithmetic means	1.01Ratio of arithmetic means

Table 7: Effect of Coadministered Drugs on Systemic Exposure of Metformin

Coadministered Drug	Dose of Coadministered DrugAll doses administered as single dose unless otherwise specified	Dose of MetforminAll doses administered as single dose unless otherwise specified	Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00
				AUCAUC is reported as AUC0-∞ unless otherwise specified	Cmax
No dosing adjustments required for the following:
Glyburide	5 mg	500 mgGLUMETZA (metformin hydrochloride extended-release tablets) 500 mg	MetforminGLUMETZA (metformin hydrochloride extended-release tablets) 500 mg	0.98Ratio of arithmetic means	0.99Ratio of arithmetic means
Furosemide	40 mg	850 mg	Metformin	1.09Ratio of arithmetic means	1.22Ratio of arithmetic means
Nifedipine	10 mg	850 mg	Metformin	1.16	1.21
Propranolol	40 mg	850 mg	Metformin	0.90	0.94
Ibuprofen	400 mg	850 mg	Metformin	1.05Ratio of arithmetic means	1.07Ratio of arithmetic means
Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination: use with caution. [See Warnings and Precautions (5.10) and Drug Interactions (7.2).]
Cimetidine	400 mg	850 mg	Metformin	1.40	1.61
Carbonic anhydrase inhibitors may cause metabolic acidosis: use with caution. [See Warnings and Precautions (5.1) and Drug Interactions (7.1).]
Topiramate	100 mgSteady state 100 mg Topiramate every 12 hr + metformin 500 mg every 12 hr. AUC = AUC0-12hr	500 mg	Metformin	1.25	1.17

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

JANUMET XR

No animal studies have been conducted with the combined products in JANUMET XR to evaluate carcinogenesis, mutagenesis or impairment of fertility. The following data are based on the findings in studies with sitagliptin and metformin individually.

Sitagliptin

A two-year carcinogenicity study was conducted in male and female rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day. There was an increased incidence of combined liver adenoma/carcinoma in males and females and of liver carcinoma in females at 500 mg/kg. This dose results in exposures approximately 60 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 100 mg/day based on AUC comparisons. Liver tumors were not observed at 150 mg/kg, approximately 20 times the human exposure at the MRHD. A two-year carcinogenicity study was conducted in male and female mice given oral doses of sitagliptin of 50, 125, 250, and 500 mg/kg/day. There was no increase in the incidence of tumors in any organ up to 500 mg/kg, approximately 70 times human exposure at the MRHD. Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a Chinese hamster ovary (CHO) chromosome aberration assay, an in vitro cytogenetics assay in CHO, an in vitro rat hepatocyte DNA alkaline elution assay, and an in vivo micronucleus assay.

In rat fertility studies with oral gavage doses of 125, 250, and 1000 mg/kg, males were treated for 4 weeks prior to mating, during mating, up to scheduled termination (approximately 8 weeks total), and females were treated 2 weeks prior to mating through gestation day 7. No adverse effect on fertility was observed at 125 mg/kg (approximately 12 times human exposure at the MRHD of 100 mg/day based on AUC comparisons). At higher doses, nondose-related increased resorptions in females were observed (approximately 25 and 100 times human exposure at the MRHD based on AUC comparison).

Metformin hydrochloride

Long-term carcinogenicity studies have been performed in Sprague Dawley rats at doses of 150, 300, and 450 mg/kg/day in males and 150, 450, 900, and 1200 mg/kg/day in females. These doses are approximately 2, 4, and 8 times in males, and 3, 7, 12, and 16 times in females of the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female rats. A carcinogenicity study was also performed in Tg.AC transgenic mice at doses up to 2000 mg applied dermally. No evidence of carcinogenicity was observed in male or female mice.

Genotoxicity assessments in the Ames test, gene mutation test (mouse lymphoma cells), chromosomal aberrations test (human lymphocytes) and in vivo mouse micronucleus tests were negative. Fertility of male or female rats was not affected by metformin when administered at doses up to 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparisons.

14 CLINICAL STUDIES

The coadministration of sitagliptin and metformin immediate-release has been studied in patients with type 2 diabetes inadequately controlled on diet and exercise and in combination with other antidiabetic medications.

There have been no clinical efficacy or safety studies conducted with JANUMET XR to characterize its effect on hemoglobin A1c (A1C) reduction. Bioequivalence of JANUMET XR tablets with coadministered sitagliptin and extended-release metformin tablets has been demonstrated for all tablet strengths [see Clinical Pharmacology (12.3)].

Metformin Extended-Release Compared to Metformin Immediate-Release in Patients with Type 2 Diabetes

In a multicenter, randomized, double-blind, active-controlled, dose-ranging, parallel group trial extended-release metformin 1500 mg once daily, extended-release metformin 1500 mg per day in divided doses (500 mg in the morning and 1000 mg in the evening), and extended-release metformin 2000 mg once daily were compared to immediate-release metformin 1500 mg per day in divided doses (500 mg in the morning and 1000 mg in the evening). This trial enrolled patients (n = 338) who were newly diagnosed with diabetes, patients treated only with diet and exercise, patients treated with a single anti-diabetic medication (sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglitinides), and patients (n = 368) receiving metformin up to 1500 mg/day plus a sulfonylurea at a dose equal to or less than one-half the maximum dose. Patients who were enrolled on monotherapy or combination antidiabetic therapy underwent a 6-week washout. Patients randomized to extended-release metformin began titration from 1000 mg/day up to their assigned treatment dose over 3 weeks. Patients randomized to immediate-release metformin initiated 500 mg twice daily for 1 week followed by 500 mg with breakfast and 1000 mg with dinner for the second week. The 3-week treatment period was followed by an additional 21-week period at the randomized dose. For HbA1c and fasting plasma glucose, each of the extended-release metformin regimens was at least as effective as immediate-release metformin. Additionally, once daily dosing of extended-release metformin was as effective as twice daily dosing of the immediate-release metformin formulation.

Sitagliptin and Metformin Immediate-Release Coadministration in Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise

A total of 1091 patients with type 2 diabetes and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind, placebo-controlled factorial study designed to assess the efficacy of sitagliptin and metformin immediate-release coadministration. Patients on an antihyperglycemic agent (N=541) underwent a diet, exercise, and drug washout period of up to 12 weeks duration. After the washout period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized after completing a 2-week single-blind placebo run-in period. Patients not on antihyperglycemic agents at study entry (N=550) with inadequate glycemic control (A1C 7.5% to 11%) immediately entered the 2-week single-blind placebo run-in period and then were randomized. Approximately equal numbers of patients were randomized to receive placebo, 100 mg of sitagliptin once daily, 500 mg or 1000 mg of metformin immediate-release twice daily, or 50 mg of sitagliptin twice daily in combination with 500 mg or 1000 mg of metformin immediate-release twice daily. Patients who failed to meet specific glycemic goals during the study were treated with glyburide (glibenclamide) rescue.

Sitagliptin and metformin immediate-release coadministration provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo, to metformin immediate-release alone, and to sitagliptin alone (Table 8, Figure 1). For patients not on an antihyperglycemic agent at study entry, mean reductions from baseline in A1C were: sitagliptin 100 mg once daily, -1.1%; metformin immediate-release 500 mg bid, -1.1%; metformin immediate-release 1000 mg bid, -1.2%; sitagliptin 50 mg bid with metformin immediate-release 500 mg bid, -1.6%; sitagliptin 50 mg bid with metformin immediate-release 1000 mg bid, -1.9%; and for patients receiving placebo, -0.2%. Lipid effects were generally neutral. The decrease in body weight in the groups given sitagliptin in combination with metformin immediate-release was similar to that in the groups given metformin alone or placebo.

Table 8: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin and Metformin Immediate-Release, Alone and in Combination in Patients with Type 2 Diabetes Inadequately Controlled on Diet and ExerciseIntent-to-treat population using last observation on study prior to glyburide (glibenclamide) rescue therapy.

	Placebo	Sitagliptin 100 mg once daily	Metformin Immediate-Release 500 mg twice daily	Metformin Immediate-Release 1000 mg twice daily	Sitagliptin 50 mg bid + Metformin Immediate-Release 500 mg twice daily	Sitagliptin 50 mg bid + Metformin Immediate-Release 1000 mg twice daily
A1C (%)	N = 165	N = 175	N = 178	N = 177	N = 183	N = 178
Baseline (mean)	8.7	8.9	8.9	8.7	8.8	8.8
Change from baseline   (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)	0.2	-0.7	-0.8	-1.1	-1.4	-1.9
Difference from placebo   (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)     (95% CI)		-0.8p<0.001 compared to placebo. (-1.1, -0.6)	-1.0p<0.001 compared to placebo. (-1.2, -0.8)	-1.3p<0.001 compared to placebo. (-1.5, -1.1)	-1.6p<0.001 compared to placebo. (-1.8, -1.3)	-2.1p<0.001 compared to placebo. (-2.3, -1.8)
Patients (%) achieving   A1C <7%	15 (9%)	35 (20%)	41 (23%)	68 (38%)	79 (43%)	118 (66%)
% Patients receiving   rescue medication	32	21	17	12	8	2
FPG (mg/dL)	N = 169	N = 178	N = 179	N = 179	N = 183	N = 180
Baseline (mean)	196	201	205	197	204	197
Change from baseline   (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)	6	-17	-27	-29	-47	-64
Difference from placebo   (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)     (95% CI)		-23p<0.001 compared to placebo. (-33, -14)	-33p<0.001 compared to placebo. (-43, -24)	-35p<0.001 compared to placebo. (-45, -26)	-53p<0.001 compared to placebo. (-62, -43)	-70p<0.001 compared to placebo. (-79, -60)
2-hour PPG (mg/dL)	N = 129	N = 136	N = 141	N = 138	N = 147	N = 152
Baseline (mean)	277	285	293	283	292	287
Change from baseline   (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)	0	-52	-53	-78	-93	-117
Difference from placebo   (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)     (95% CI)		-52p<0.001 compared to placebo. (-67, -37)	-54p<0.001 compared to placebo. (-69, -39)	-78p<0.001 compared to placebo. (-93, -63)	-93p<0.001 compared to placebo. (-107, -78)	-117p<0.001 compared to placebo. (-131, -102)

Figure 1: Mean Change from Baseline for A1C (%) over 24 Weeks with Sitagliptin and Metformin Immediate-Release, Alone and in Combination in Patients with Type 2 Diabetes Inadequately Controlled with Diet and Exercise The Completers Population: least squares means adjusted for prior antihyperglycemic therapy and baseline value.

Initial combination therapy or maintenance of combination therapy should be individualized and are left to the discretion of the healthcare provider.

Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Immediate-Release Alone

A total of 701 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin in combination with metformin immediate-release. Patients already on metformin immediate-release (N=431) at a dose of at least 1500 mg per day were randomized after completing a 2-week, single-blind placebo run-in period. Patients on metformin immediate-release and another antihyperglycemic agent (N=229) and patients not on any antihyperglycemic agents (off therapy for at least 8 weeks, N=41) were randomized after a run-in period of approximately 10 weeks on metformin immediate-release (at a dose of at least 1500 mg per day) in monotherapy. Patients were randomized to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue.

In combination with metformin immediate-release, sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin immediate-release (Table 9). Rescue glycemic therapy was used in 5% of patients treated with sitagliptin 100 mg and 14% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups.

Table 9: Glycemic Parameters at Final Visit (24-Week Study) of Sitagliptin as Add-on Combination Therapy with Metformin Immediate-Release Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy.

	Sitagliptin 100 mg once daily + Metformin Immediate-Release	Placebo + Metformin Immediate-Release
A1C (%)	N = 453	N = 224
Baseline (mean)	8.0	8.0
Change from baseline (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy and baseline value.)	-0.7	-0.0
Difference from placebo + metformin immediate-     release (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy and baseline value.) (95% CI)	-0.7p<0.001 compared to placebo + metformin. (-0.8, -0.5)
Patients (%) achieving A1C <7%	213 (47%)	41 (18%)
FPG (mg/dL)	N = 454	N = 226
Baseline (mean)	170	174
Change from baseline (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy and baseline value.)	-17	9
Difference from placebo + metformin immediate-     release (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy and baseline value.) (95% CI)	-25p<0.001 compared to placebo + metformin. (-31, -20)
2-hour PPG (mg/dL)	N = 387	N = 182
Baseline (mean)	275	272
Change from baseline (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy and baseline value.)	-62	-11
Difference from placebo + metformin immediate-     release (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy and baseline value.) (95% CI)	-51p<0.001 compared to placebo + metformin. (-61, -41)

Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on the Combination of Metformin Immediate-Release and Glimepiride

A total of 441 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin in combination with glimepiride, with or without metformin immediate-release. Patients entered a run-in treatment period on glimepiride (≥4 mg per day) alone or glimepiride in combination with metformin immediate-release (≥1500 mg per day). After a dose-titration and dose-stable run-in period of up to 16 weeks and a 2-week placebo run-in period, patients with inadequate glycemic control (A1C 7.5% to 10.5%) were randomized to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue.

Patients receiving sitagliptin with metformin immediate-release and glimepiride had significant improvements in A1C and FPG compared to patients receiving placebo with metformin immediate-release and glimepiride (Table 10), with mean reductions from baseline relative to placebo in A1C of -0.9% and in FPG of -21 mg/dL. Rescue therapy was used in 8% of patients treated with add-on sitagliptin 100 mg and 29% of patients treated with add-on placebo. The patients treated with add-on sitagliptin had a mean increase in body weight of 1.1 kg vs. add-on placebo (+0.4 kg vs. -0.7 kg). In addition, add-on sitagliptin resulted in an increased rate of hypoglycemia compared to add-on placebo. [See Warnings and Precautions (5.9); Adverse Reactions (6.1).]

Table 10: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin in Combination with Metformin Immediate-Release and Glimepiride Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy.

	Sitagliptin 100 mg + Metformin Immediate-Release and Glimepiride	Placebo + Metformin Immediate-Release and Glimepiride
A1C (%)	N = 115	N = 105
Baseline (mean)	8.3	8.3
Change from baseline (adjusted mean Least squares means adjusted for prior antihyperglycemic therapy status and baseline value.)	-0.6	0.3
Difference from placebo (adjusted mean Least squares means adjusted for prior antihyperglycemic therapy status and baseline value.)   (95% CI)	-0.9p<0.001 compared to placebo. (-1.1, -0.7)
Patients (%) achieving A1C <7%	26 (23%)	1 (1%)
FPG (mg/dL)	N = 115	N = 109
Baseline (mean)	179	179
Change from baseline (adjusted mean Least squares means adjusted for prior antihyperglycemic therapy status and baseline value.)	-8	13
Difference from placebo (adjusted mean Least squares means adjusted for prior antihyperglycemic therapy status and baseline value.)   (95% CI)	-21p<0.001 compared to placebo. (-32, -10)

Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on the Combination of Metformin Immediate-Release and Rosiglitazone

A total of 278 patients with type 2 diabetes participated in a 54-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin in combination with metformin immediate-release and rosiglitazone. Patients on dual therapy with metformin immediate-release ≥1500 mg/day and rosiglitazone ≥4 mg/day or with metformin immediate-release ≥1500 mg/day and pioglitazone ≥30 mg/day (switched to rosiglitazone ≥4 mg/day) entered a dose-stable run-in period of 6 weeks. Patients on other dual therapy were switched to metformin immediate-release ≥1500 mg/day and rosiglitazone ≥4 mg/day in a dose titration/stabilization run-in period of up to 20 weeks in duration. After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized 2:1 to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with glipizide (or other sulfonylurea) rescue. The primary time point for evaluation of glycemic parameters was Week 18.

In combination with metformin immediate-release and rosiglitazone, sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin immediate-release and rosiglitazone (Table 11) at Week 18. At Week 54, mean reduction in A1C was -1.0% for patients treated with sitagliptin and -0.3% for patients treated with placebo in an analysis based on the intent-to-treat population. Rescue therapy was used in 18% of patients treated with sitagliptin 100 mg and 40% of patients treated with placebo. There was no significant difference between sitagliptin and placebo in body weight change.

Table 11: Glycemic Parameters at Week 18 for Sitagliptin in Add-on Combination Therapy with Metformin Immediate-Release and Rosiglitazone Intent-to-treat population using last observation on study prior to glipizide (or other sulfonylurea) rescue therapy.

	Week 18
	Sitagliptin 100 mg + Metformin Immediate-Release + Rosiglitazone	Placebo + Metformin Immediate-Release + Rosiglitazone
A1C (%)	N = 176	N = 93
Baseline (mean)	8.8	8.7
Change from baseline (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)	-1.0	-0.4
Difference from placebo +   rosiglitazone + metformin   immediate-release (adjusted   meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.) (95% CI)	-0.7p<0.001 compared to placebo + metformin + rosiglitazone. (-0.9, -0.4)
Patients (%) achieving A1C <7%	39 (22%)	9 (10%)
FPG (mg/dL)	N = 179	N = 94
Baseline (mean)	181	182
Change from baseline (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)	-30	-11
Difference from placebo +   rosiglitazone + metformin   immediate-release (adjusted   meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.) (95% CI)	-18p<0.001 compared to placebo + metformin + rosiglitazone. (-26, -10)
2-hour PPG (mg/dL)	N = 152	N = 80
Baseline (mean)	256	248
Change from baseline (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)	-59	-21
Difference from placebo +   rosiglitazone + metformin   immediate-release (adjusted   meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.) (95% CI)	-39p<0.001 compared to placebo + metformin + rosiglitazone. (-51, -26)

Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on the Combination of Metformin Immediate-Release and Insulin

A total of 641 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin as add-on to insulin therapy. Approximately 75% of patients were also taking metformin immediate-release. Patients entered a 2-week, single-blind run-in treatment period on pre-mixed, long-acting, or intermediate-acting insulin, with or without metformin immediate-release (≥1500 mg per day). Patients using short-acting insulins were excluded unless the short-acting insulin was administered as part of a pre-mixed insulin. After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized to the addition of either 100 mg of sitagliptin (N=229) or placebo (N=233), administered once daily. Patients were on a stable dose of insulin prior to enrollment with no changes in insulin dose permitted during the run-in period. Patients who failed to meet specific glycemic goals during the double-blind treatment period were to have uptitration of the background insulin dose as rescue therapy.

Among patients also receiving metformin immediate-release, the median daily insulin (pre-mixed, intermediate or long acting) dose at baseline was 40 units in the sitagliptin-treated patients and 42 units in the placebo-treated patients. The median change from baseline in daily dose of insulin was zero for both groups at the end of the study. Patients receiving sitagliptin with metformin immediate-release and insulin had significant improvements in A1C, FPG and 2-hour PPG compared to patients receiving placebo with metformin immediate-release and insulin (Table 12). The adjusted mean change from baseline in body weight was -0.3 kg in patients receiving sitagliptin with metformin immediate-release and insulin and -0.2 kg in patients receiving placebo with metformin immediate-release and insulin. There was an increased rate of hypoglycemia in patients treated with sitagliptin. [See Warnings and Precautions (5.9); Adverse Reactions (6.1).]

Table 12: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin as Add-on Combination Therapy with Metformin Immediate-Release and Insulin Intent-to-treat population using last observation on study prior to rescue therapy.

	Sitagliptin 100 mg + Metformin Immediate-Release + Insulin	Placebo + Metformin Immediate-Release + Insulin
A1C (%)	N = 223	N = 229
Baseline (mean)	8.7	8.6
Change from baseline (adjusted meanLeast squares mean adjusted for insulin use at the screening visit, type of insulin used at the screening visit (pre-mixed vs. non pre-mixed [intermediate- or long-acting]), and baseline value. , Treatment by insulin stratum interaction was not significant (p>0.10).)	-0.7	-0.1
Difference from placebo (adjusted meanLeast squares mean adjusted for insulin use at the screening visit, type of insulin used at the screening visit (pre-mixed vs. non pre-mixed [intermediate- or long-acting]), and baseline value.)   (95% CI)	-0.5p<0.001 compared to placebo. (-0.7, -0.4)
Patients (%) achieving A1C (%) <7%	32 (14%)	12 (5%)
FPG (mg/dL)	N = 225	N = 229
Baseline (mean)	173	176
Change from baseline (adjusted meanLeast squares mean adjusted for insulin use at the screening visit, type of insulin used at the screening visit (pre-mixed vs. non pre-mixed [intermediate- or long-acting]), and baseline value.)	-22	-4
Difference from placebo (adjusted meanLeast squares mean adjusted for insulin use at the screening visit, type of insulin used at the screening visit (pre-mixed vs. non pre-mixed [intermediate- or long-acting]), and baseline value.)   (95% CI)	-18p<0.001 compared to placebo. (-28, -8.4)
2-hour PPG (mg/dL)	N = 182	N = 189
Baseline (mean)	281	281
Change from baseline (adjusted meanLeast squares mean adjusted for insulin use at the screening visit, type of insulin used at the screening visit (pre-mixed vs. non pre-mixed [intermediate- or long-acting]), and baseline value.)	-39	1
Difference from placebo (adjusted meanLeast squares mean adjusted for insulin use at the screening visit, type of insulin used at the screening visit (pre-mixed vs. non pre-mixed [intermediate- or long-acting]), and baseline value.)   (95% CI)	-40p<0.001 compared to placebo. (-53, -28)

Sitagliptin Add-on Therapy vs. Glipizide Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Immediate-Release

The efficacy of sitagliptin was evaluated in a 52-week, double-blind, glipizide-controlled noninferiority trial in patients with type 2 diabetes. Patients not on treatment or on other antihyperglycemic agents entered a run-in treatment period of up to 12 weeks duration with metformin immediate-release monotherapy (dose of ≥1500 mg per day) which included washout of medications other than metformin immediate-release, if applicable. After the run-in period, those with inadequate glycemic control (A1C 6.5% to 10%) were randomized 1:1 to the addition of sitagliptin 100 mg once daily or glipizide for 52 weeks. Patients receiving glipizide were given an initial dosage of 5 mg/day and then electively titrated over the next 18 weeks to a maximum dosage of 20 mg/day as needed to optimize glycemic control. Thereafter, the glipizide dose was to be kept constant, except for down-titration to prevent hypoglycemia. The mean dose of glipizide after the titration period was 10 mg.

After 52 weeks, sitagliptin and glipizide had similar mean reductions from baseline in A1C in the intent-to-treat analysis (Table 13). These results were consistent with the per protocol analysis (Figure 2). A conclusion in favor of the non-inferiority of sitagliptin to glipizide may be limited to patients with baseline A1C comparable to those included in the study (over 70% of patients had baseline A1C <8% and over 90% had A1C <9%).

Table 13: Glycemic Parameters in a 52-Week Study Comparing Sitagliptin to Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin Immediate-Release (Intent-to-Treat Population) The intent-to-treat analysis used the patients' last observation in the study prior to discontinuation.

	Sitagliptin 100 mg + Metformin Immediate-Release	Glipizide + Metformin Immediate-Release
A1C (%)	N = 576	N = 559
Baseline (mean)	7.7	7.6
Change from baseline (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline A1C value.)	-0.5	-0.6
FPG (mg/dL)	N = 583	N = 568
Baseline (mean)	166	164
Change from baseline (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline A1C value.)	-8	-8

Figure 2: Mean Change from Baseline for A1C (%) Over 52 Weeks in a Study Comparing Sitagliptin to Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin Immediate-Release (Per Protocol Population) The per protocol population (mean baseline A1C of 7.5%) included patients without major protocol violations who had observations at baseline and at Week 52.

The incidence of hypoglycemia in the sitagliptin group (4.9%) was significantly (p<0.001) lower than that in the glipizide group (32.0%). Patients treated with sitagliptin exhibited a significant mean decrease from baseline in body weight compared to a significant weight gain in patients administered glipizide (-1.5 kg vs. +1.1 kg).

16 HOW SUPPLIED/STORAGE AND HANDLING

No. 3961 — Tablets JANUMET XR, 50 mg/500 mg, are light blue, bi-convex oval, film-coated tablets with "78" debossed on one side. They are supplied as follows:

NDC 0006-0078-61 unit-of-use bottles of 60
NDC 0006-0078-62 unit-of-use bottles of 180
NDC 0006-0078-82 bulk bottles of 1000.

No. 3962 — Tablets JANUMET XR, 50 mg/1000 mg, are light green, bi-convex oval, film-coated tablets with "80" debossed on one side. They are supplied as follows:

NDC 0006-0080-61 unit-of-use bottles of 60
NDC 0006-0080-62 unit-of-use bottles of 180
NDC 0006-0080-82 bulk bottles of 1000.

No. 3963 — Tablets JANUMET XR, 100 mg/1000 mg, are blue, bi-convex oval, film-coated tablets with "81" debossed on one side. They are supplied as follows:

NDC 0006-0081-31 unit-of-use bottles of 30
NDC 0006-0081-54 unit-of-use bottles of 90
NDC 0006-0081-82 bulk bottles of 1000.

Store at 20-25°C (68-77°F), excursions permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature.] Store in a dry place with cap tightly closed. When container is subdivided, dispense into a USP tightly closed, moisture-resistant container.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling (Medication Guide).

17.1 Instructions

Patients should be informed of the potential risks and benefits of JANUMET XR and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be advised to seek medical advice promptly.

The risks of lactic acidosis due to the metformin component, its symptoms, and conditions that predispose to its development, as noted in Warnings and Precautions (5.1), should be explained to patients. Patients should be advised to discontinue JANUMET XR immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, dizziness, slow or irregular heart beat, sensation of feeling cold (especially in the extremities) or other nonspecific symptoms occur. Gastrointestinal symptoms are common during initiation of metformin treatment and may occur during initiation of JANUMET XR therapy; however, patients should consult their physician if they develop unexplained symptoms. Although gastrointestinal symptoms that occur after stabilization are unlikely to be drug related, such an occurrence of symptoms should be evaluated to determine if it may be due to lactic acidosis or other serious disease.

Patients should be advised to notify their health practitioner or call the Poison Control Center immediately in case of JANUMET XR overdose.

Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving JANUMET XR.

Patients should be informed about the importance of regular testing of renal function and hematological parameters when receiving treatment with JANUMET XR.

Patients should be informed that acute pancreatitis has been reported during postmarketing use of JANUMET. Patients should be informed that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Patients should be instructed to promptly discontinue JANUMET XR and contact their physician if persistent severe abdominal pain occurs [see Warnings and Precautions (5.2)].

Patients should be informed that the incidence of hypoglycemia is increased when sitagliptin with or without metformin is added to an insulin secretagogue (e.g., sulfonylurea) or insulin therapy and that a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.

Patients should be informed that allergic reactions have been reported during postmarketing use of sitagliptin, one of the components of JANUMET XR. If symptoms of allergic reactions (including rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking JANUMET XR and seek medical advice promptly.

Patients should be informed that the tablets must be swallowed whole and never split, crushed or chewed.

Patients should be informed that incompletely dissolved JANUMET XR tablets may be eliminated in the feces. Tell patients that, if they repeatedly see tablets in feces, they should report this finding to their healthcare provider. If a patient reports repeatedly observing tablets in feces, the healthcare provider should assess adequacy of glycemic control.

Physicians should instruct their patients to read the Medication Guide before starting JANUMET XR therapy and to reread each time the prescription is renewed. Patients should be instructed to inform their doctor if they develop any bothersome or unusual symptom, or if any symptom persists or worsens.

17.2 Laboratory Tests

Response to all diabetic therapies should be monitored by periodic measurements of blood glucose and A1C levels, with a goal of decreasing these levels towards the normal range. A1C is especially useful for evaluating long-term glycemic control.

Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, Vitamin B₁₂ deficiency should be excluded.

Manufactured for: Merck Sharp & Dohme Corp., a subsidiary of
MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

Manufactured by:
Merck Sharp & Dohme Corp., a subsidiary of
Merck & Co., Inc., Whitehouse Station, NJ 08889, USA
OR
Patheon Inc., Whitby, Ontario, Canada L1N 5Z5

For patent information: www.merck.com/product/patent/home.html

Copyright © 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.

uspi-mk0431a-xrt-1402r004

Medication Guide
JANUMET^® XR (JAN-you-met XR)
(sitagliptin and metformin hydrochloride extended-release)
Tablets

Read this Medication Guide carefully before you start taking JANUMET XR and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about JANUMET XR, ask your doctor or pharmacist.

What is the most important information I should know about JANUMET XR?

Serious side effects can happen in people taking JANUMET XR, including:

• 1. Lactic Acidosis. Metformin, one of the medicines in JANUMET XR, can cause a rare but serious condition called lactic acidosis (a build-up of lactic acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in the hospital.
  
  Stop taking JANUMET XR and call your doctor right away if you get any of the following symptoms, which could be signs of lactic acidosis.
  You:
  • feel very weak or tired.
  • have unusual (not normal) muscle pain.
  • have trouble breathing.
  • have unusual sleepiness or sleep longer than usual.
  • have sudden stomach or intestinal problems with nausea and vomiting or diarrhea.
  • feel cold, especially in your arms and legs.
  • feel dizzy or lightheaded.
  • have a slow or irregular heartbeat.
  
  You have a higher chance of getting lactic acidosis if you:
  • have kidney problems. People whose kidneys are not working properly should not take JANUMET XR.
  • have liver problems.
  • have congestive heart failure that requires treatment with medicines.
  • drink alcohol very often, or drink a lot of alcohol in short-term "binge" drinking.
  • get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids.
  • have certain x-ray tests with dyes or contrast agents that are injected into your body.
  • have surgery.
  • have a heart attack, severe infection, or stroke.
  
  
• 2. Pancreatitis (inflammation of the pancreas) which may be severe and lead to death. Certain medical problems make you more likely to get pancreatitis.

Before you start taking JANUMET XR:

Tell your doctor if you have ever had

• pancreatitis
• stones in your gallbladder (gallstones)
• a history of alcoholism
• high blood triglyceride levels

Stop taking JANUMET XR and call your doctor right away if you have pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen through to your back. The pain may happen with or without vomiting. These may be symptoms of pancreatitis.

What is JANUMET XR?

• JANUMET XR is a prescription medicine that contains 2 prescription diabetes medicines, sitagliptin (JANUVIA^®) and extended-release metformin hydrochloride. JANUMET XR can be used along with diet and exercise to lower blood sugar in adults with type 2 diabetes.
• JANUMET XR is not for people with type 1 diabetes.
• JANUMET XR is not for people with diabetic ketoacidosis (increased ketones in your blood or urine).
• If you have had pancreatitis (inflammation of the pancreas) in the past, it is not known if you have a higher chance of getting pancreatitis while you take JANUMET XR.
• It is not known if JANUMET XR is safe and effective when used in children under 18 years of age.

Who should not take JANUMET XR?

Do not take JANUMET XR if:

• your kidneys are not working properly.
• you are allergic to any of the ingredients in JANUMET XR. See the end of this Medication Guide for a complete list of ingredients in JANUMET XR.
  Symptoms of a serious allergic reaction to JANUMET XR may include:
  • rash
  • raised red patches on your skin (hives)
  • swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing
• you have diabetic ketoacidosis. See " What is JANUMET XR? ".

What should I tell my doctor before taking JANUMET XR?

Before you take JANUMET XR, tell your doctor if you:

• have or have had inflammation of your pancreas (pancreatitis).
• have kidney problems.
• have liver problems.
• have heart problems, including congestive heart failure.
• drink alcohol very often, or drink a lot of alcohol in short-term "binge" drinking.
• are going to get an injection of dye or contrast agents for an x-ray procedure; JANUMET XR will need to be stopped for a short time. Talk to your doctor about when you should stop JANUMET XR and when you should start JANUMET XR again. See " What is the most important information I should know about JANUMET XR? ".
• have any other medical conditions.
• are pregnant or plan to become pregnant. It is not known if JANUMET XR will harm your unborn baby. If you are pregnant, talk with your doctor about the best way to control your blood sugar while you are pregnant.
  Pregnancy Registry: If you take JANUMET XR at any time during your pregnancy, talk with your doctor about how you can join the JANUMET XR pregnancy registry. The purpose of this registry is to collect information about the health of you and your baby. You can enroll in this registry by calling 1-800-986-8999.
• are breast-feeding or plan to breast-feed. It is not known if JANUMET XR will pass into your breast milk. Talk with your doctor about the best way to feed your baby if you are taking JANUMET XR.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. JANUMET XR may affect how well other drugs work and some drugs can affect how well JANUMET XR works.

Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.

How should I take JANUMET XR?

• Take JANUMET XR exactly as your doctor tells you. Your doctor will tell you how many JANUMET XR tablets to take and when you should take them.
• Your doctor may change your dose of JANUMET XR if needed.
• Your doctor may tell you to take JANUMET XR along with certain other diabetes medicines. Low blood sugar (hypoglycemia) can happen more often when JANUMET XR is taken with certain other diabetes medicines. See " What are the possible side effects of JANUMET XR? ".
• Take JANUMET XR 1 time each day with a meal to help to lower your chance of having an upset stomach. It is better to take JANUMET XR with your evening meal.
• Take JANUMET XR tablets whole. Do not break, cut, crush, dissolve, or chew JANUMET XR tablets before swallowing. If you cannot swallow JANUMET XR tablets whole, tell your doctor.
• You may see something that looks like the JANUMET XR tablet in your stool (bowel movement). If you see tablets in your stool several times, talk to your doctor. Do not stop taking JANUMET XR without talking to your doctor.
• Continue to take JANUMET XR as long as your doctor tells you.
• If you take too much JANUMET XR, call your doctor or local Poison Control Center right away.
• If you miss a dose, take it with food as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not take 2 doses of JANUMET XR at the same time.
• You may need to stop taking JANUMET XR for a short time. Call your doctor for instructions if you:
  • are dehydrated (have lost too much body fluid). Dehydration can occur if you are sick with severe vomiting, diarrhea or fever, or if you drink a lot less fluid than normal.
  • plan to have surgery.
  • are going to get an injection of dye or contrast agent for an x-ray procedure. See " What is the most important information I should know about JANUMET XR? " and " What should I tell my doctor before taking JANUMET XR?".
• When your body is under some types of stress, such as fever, trauma (such as a car accident), infection or surgery, the amount of diabetes medicine that you need may change. Tell your doctor right away if you have any of these problems and follow your doctor's instructions.
• Check your blood sugar as your doctor tells you to.
• Stay on your prescribed diet and exercise program while taking JANUMET XR.
• Talk to your doctor about how to prevent, recognize and manage low blood sugar (hypoglycemia), high blood sugar (hyperglycemia), and problems you have because of your diabetes.
• Your doctor will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C.
• Your doctor will do blood tests to check how well your kidneys are working before and during your treatment with JANUMET XR.

What are the possible side effects of JANUMET XR?

Serious side effects have happened in people taking JANUMET XR or the individual medicines in JANUMET XR.

• See " What is the most important information I should know about JANUMET XR? ".
• Low blood sugar (hypoglycemia). If you take JANUMET XR with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you use JANUMET XR. Signs and symptoms of low blood sugar may include:
  

  headache drowsiness weakness dizziness confusion

  irritability hunger fast heart beat sweating feeling jittery

• Serious allergic reactions. If you have any symptoms of a serious allergic reaction, stop taking JANUMET XR and call your doctor right away. See " Who should not take JANUMET XR? ". Your doctor may give you a medicine for your allergic reaction and prescribe a different medicine for your diabetes.
• Kidney problems, sometimes requiring dialysis.

The most common side effects of JANUMET XR include:

• stuffy or runny nose and sore throat
• upper respiratory infection
• diarrhea
• nausea and vomiting
• gas, upset stomach, indigestion
• weakness
• headache
• low blood sugar (hypoglycemia) when used in combination with certain medications, such as a sulfonylurea or insulin.

Taking JANUMET XR with meals can help lessen the common stomach side effects of metformin that usually happen at the beginning of treatment. If you have unusual or sudden stomach problems, talk with your doctor. Stomach problems that start later during treatment may be a sign of something more serious.

JANUMET XR may have other side effects, including:

• swelling of the hands or legs. Swelling of the hands and legs can happen if you take JANUMET XR in combination with rosiglitazone (Avandia^®). Rosiglitazone is another type of diabetes medicine.

These are not all the possible side effects of JANUMET XR. For more information, ask your doctor or pharmacist.

Tell your doctor if you have any side effect that bothers you, is unusual, or does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store JANUMET XR?

Store JANUMET XR at 68°F to 77°F (20°C to 25°C). Store in a dry place and keep cap tightly closed.

Keep JANUMET XR and all medicines out of the reach of children.

General information about the use of JANUMET XR.

Medicines are sometimes prescribed for purposes other than those listed in Medication Guides. Do not use JANUMET XR for a condition for which it was not prescribed. Do not give JANUMET XR to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about JANUMET XR. If you would like to know more information, talk with your doctor. You can ask your doctor or pharmacist for additional information about JANUMET XR that is written for health care professionals. For more information go to www.janumetxr.com or call 1-800-622-4477.

What are the ingredients in JANUMET XR?

Active ingredients: sitagliptin and metformin hydrochloride extended-release

Inactive ingredients:

• All doses of JANUMET XR Tablets contain: povidone, hypromellose, colloidal silicon dioxide, sodium stearyl fumarate, propyl gallate, polyethylene glycol, and kaolin. Film coating contains hypromellose, hydroxypropyl cellulose, titanium dioxide, FD&C #2/Indigo Carmine Aluminum Lake and carnauba wax.
• In addition the JANUMET XR 50 mg/500 mg Tablets also contain: microcrystalline cellulose.
• In addition the JANUMET XR 50 mg/1000 mg Tablets also contain: yellow iron oxide.

What is type 2 diabetes?

Type 2 diabetes is a condition in which your body does not make enough insulin, and the insulin that your body produces does not work as well as it should. Your body can also make too much sugar. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems.

High blood sugar can be lowered by diet and exercise, and by certain medicines when necessary.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured for: Merck Sharp & Dohme Corp., a subsidiary of
MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

Manufactured by:
Merck Sharp & Dohme Corp., a subsidiary of
Merck & Co., Inc., Whitehouse Station, NJ 08889, USA
OR
Patheon Inc., Whitby, Ontario, Canada L1N 5Z5

For patent information: www.merck.com/product/patent/home.html

The trademarks depicted herein are owned by their respective companies.

Copyright © 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.

Revised: 02/2014

usmg-mk0431a-xrt-1402r004

PRINCIPAL DISPLAY PANEL - 50 mg/500 mg Bottle Label

NDC 0006-0078-61

Janumet ^® XR

(sitagliptin and metformin HCl
extended-release) tablets

50 mg/500 mg

Dispense the accompanying Medication Guide
to each patient.

Each tablet contains 64.25 mg sitagliptin phosphate
(equivalent to 50 mg sitagliptin) and 500 mg
metformin hydrochloride extended-release.

Rx only

60 Tablets

PRINCIPAL DISPLAY PANEL - 50 mg/1,000 mg Bottle Label

NDC 0006-0080-61

Janumet ^® XR

(sitagliptin and metformin HCl
extended-release) tablets

50 mg/1,000 mg

Dispense the accompanying Medication Guide
to each patient.

Each tablet contains 64.25 mg sitagliptin phosphate
(equivalent to 50 mg sitagliptin) and 1,000 mg
metformin hydrochloride
extended-release.

Rx only

60 Tablets

PRINCIPAL DISPLAY PANEL - 100 mg/1,000 mg Bottle Label

NDC 0006-0081-31

Janumet ^® XR

(sitagliptin and metformin HCl
extended-release) tablets

100 mg/1,000 mg

Dispense the accompanying Medication Guide
to each patient.

Each tablet contains 128.5 mg sitagliptin phosphate
(equivalent to 100 mg sitagliptin) and 1,000 mg
metformin hydrochloride
extended-release.

Rx only

30 Tablets