FDA Approves JANUMET(TM) for Type 2 Diabetes, Offering Powerful Glucose Control of a DPP-4 Inhibitor and Metformin in a Single Tablet

Merck & Co., Inc. announced today that the U.S. Food and Drug Administration (FDA) approved JANUMET™, the first and only tablet combining a dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin (also known as JANUVIA™), and metformin for the treatment of type 2 diabetes. JANUMET has been approved, as an adjunct to diet and exercise, to improve blood sugar (glucose) control in adult patients with type 2 diabetes who are not adequately controlled on metformin or sitagliptin alone, or in patients already being treated with the combination of sitagliptin and metformin. JANUMET should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. The FDA approved JANUMET based upon clinical data including sitagliptin plus metformin as separate tablets. A clinical bioequivalence study has demonstrated the equivalence between JANUMET and sitagliptin plus metformin as separate tablets. "JANUMET is the latest advance in Merck's longstanding commitment to developing effective medicines for type 2 diabetes," said Adam Schechter, president, United States Human Health, Merck & Co., Inc. "With JANUMET and JANUVIA, Merck now has a growing family of products that provides physicians with important treatment options for patients with type 2 diabetes." JANUMET delivers proven efficacy A 24-week, randomized, double-blind, placebo-controlled study with 701 patients with mildly to moderately elevated A1C levels (mean baseline 8.0 percent) inadequately controlled on metformin, showed that patients taking JANUMET2 (n=453) experienced significant additional mean placebo-subtracted reductions in A1C of 0.7 percent beyond that achieved by patients who continued on metformin alone (n=224) (p<0.001). In the study, more than twice as many patients on JANUMET (213 of 453 patients, or 47 percent) reached the American Diabetes Association's A1C goal of <7 percent compared with patients on metformin alone (41 of 224 patients, or 18 percent) (p<0.001). JANUMET combines two agents with proven ability to deliver significant improvements in glycemic control: metformin, a commonly used effective glucose-lowering agent, and sitagliptin, a DPP-4 inhibitor that provides significant A1C lowering as monotherapy and as add-on therapy to metformin or thiazolidinediones (TZDs) based on clinical trials. JANUMET, like metformin, is dosed twice daily with meals. Consistent with the labeling for metformin alone, the labeling for JANUMET contains a boxed warning for lactic acidosis, a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with JANUMET. "Physicians use several different medications in combination to address the multiple defects associated with type 2 diabetes, however, less than half of patients achieve and maintain their goal A1C levels," said Nir Barzilai, M.D., professor of Medicine and Molecular Genetics, director of the Institute for Aging Research, Albert Einstein College of Medicine. "JANUMET is an important new treatment option for many patients who need more than one therapy to control their type 2 diabetes because it addresses all three key defects of type 2 diabetes for improved glycemic control." Patients treated with JANUMET experienced weight loss comparable to metformin alone, with no increased risk of hypoglycemia, edema, or GI disturbances beyond metformin alone As clinicians select agents to add to the treatment regimens of patients with uncontrolled type 2 diabetes, it is important to consider issues such as weight gain, hypoglycemia, edema, and gastrointestinal disturbances. In a 24-week study, mean body weight decreased 1.5 lb (n=399) in patients taking JANUMET, similar to patients taking metformin alone (1.3 lb decrease; n=169). There was no increased risk of hypoglycemia in patients treated with JANUMET (1.3 percent vs. metformin alone, 2.1 percent) and no increased risk of edema in patients treated with JANUMET (0.9 percent vs. metformin alone, 1.3 percent). In addition, there was no significant increase in the risk of overall gastrointestinal adverse reactions in patients treated with JANUMET (11.6 percent vs. metformin alone, 9.7 percent). Specific gastrointestinal adverse reactions included diarrhea (JANUMET, 2.4 percent vs. metformin alone, 2.5 percent), abdominal pain (JANUMET, 2.2 percent vs. metformin alone, 3.8 percent), nausea (JANUMET, 1.3 percent vs. metformin alone, 0.8 percent), and vomiting (JANUMET, 1.1 percent vs. metformin alone, 0.8 percent). The most common adverse experience in sitagliptin monotherapy reported regardless of investigator assessment of causality in =5 percent of patients and more commonly than in patients given placebo was nasopharyngitis. Clinicians should be mindful that hypoglycemia 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. By incorporating the novel mechanism of DPP-4 inhibition, JANUMET uniquely addresses the three key defects of type 2 diabetes With the two active components, sitagliptin and metformin, JANUMET has a comprehensive mechanism of action that targets all three key defects of type 2 diabetes for improved glycemic control: diminished insulin release, uncontrolled production of glucose, and insulin resistance. The sitagliptin component in JANUMET address two of the three key defects that cause poor glucose control: diminished insulin release due to beta-cell dysfunction and uncontrolled production of glucose by the liver due to alpha-cell and beta-cell dysfunction. By inhibiting the DPP-4 enzyme, sitagliptin significantly increases the levels of active incretin hormones, increasing the synthesis and release of insulin from the pancreatic beta cells and decreasing the release of glucagon from the pancreatic alpha cells. JANUMET also contains metformin, which addresses the other key defect: insulin resistance. Metformin improves insulin sensitivity by increasing uptake and utilization of glucose by the muscles and tissues of the body. Metformin also decreases hepatic glucose production in a manner that is complementary to sitagliptin. JANUMET provides powerful A1C lowering through combined reductions of both post-prandial glucose and fasting plasma glucose JANUMET has been demonstrated to provide 24-hour glucose response - at mealtimes, between meals and overnight. In a 24-week, placebo-controlled study of patients with inadequate glycemic control on metformin alone, JANUMET significantly reduced post prandial, or post-meal, glucose (PPG) levels beyond metformin alone by a mean of 51 mg/dL in patients with a mean baseline 2-hour PPG of 275 mg/dL (n=387, p<0.001) and fasting plasma glucose levels (FPG) beyond metformin alone by a mean of 25 mg/dL in patients with a mean baseline FPG of 170 mg/dL (n=454, p<0.001). Indications and contraindications for JANUMET JANUMET is indicated, as an adjunct to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes who are not adequately controlled on metformin or sitagliptin alone or in patients already being treated with the combination of sitagliptin and metformin. Consistent with the labeling for metformin alone, JANUMET is contraindicated in patients with renal disease, renal dysfunction, or abnormal creatinine clearance; and acute or chronic metabolic acidosis, including diabetic ketoacidosis. JANUMET should not be used in patients with type 1 diabetes. Flexible dosing of JANUMET JANUMET should be given twice daily with meals, with gradual dose escalation as needed to reduce the gastrointestinal (GI) side effects due to metformin. In this formulation, the dose of sitagliptin remains constant (100 mg daily) and is combined with the two most widely prescribed doses of metformin (1000 mg daily or 2000 mg daily). The recommended starting dose of JANUMET for patients not on prior metformin therapy and for those not adequately controlled on sitagliptin is 50 mg sitagliptin and 500 mg metformin twice-daily with meals. For patients already receiving metformin therapy, the starting dose should be based on the patient’s current metformin regimen. The total daily dose should not exceed 100 mg sitagliptin and 2000 mg metformin. Metformin and sitagliptin are known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive JANUMET. In the elderly, JANUMET should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging can be associated with reduced renal function. Any dose adjustment should be based on a careful assessment of renal function. Before initiation of therapy with JANUMET and at least annually thereafter, renal function should be assessed and verified as normal. Pricing and availability of JANUMET The price of twice-daily JANUMET will be $4.86 per day. JANUMET will be broadly available in pharmacies in the near future. Selected cautionary information for JANUMET JANUMET should be avoided in patients with evidence of hepatic disease. Before initiation of therapy with JANUMET and at least annually thereafter, renal function should be assessed and verified as normal. Patients should be warned against excessive alcohol intake while receiving JANUMET. Patients may require discontinuation of JANUMET and temporary use of insulin during periods of stress and decreased intake of fluids and food such as may occur with fever, trauma, infection or surgery. Patients previously controlled on JANUMET who develop laboratory abnormalities or clinical illness should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). When lactic acidosis occurs, it is fatal in approximately 50 percent of cases. About type 2 diabetes Type 2 diabetes is a condition in which the body has elevated blood sugar or glucose. With type 2 diabetes, the body may not make enough insulin, the insulin that the body produces may not work as well as it should, and/or the liver may release too much glucose. Nearly 21 million people in the United States (7 percent of the population) have diabetes, with type 2 accounting for 90-95 percent of cases. Approximately half of people diagnosed with type 2 diabetes have not achieved adequate control of their blood sugar levels. Patients with diabetes can develop heart disease, kidney disease, blindness, vascular or neurological problems that can lead to amputation and can suffer increased rates of mortality. JANUMET and JANUVIA are not approved to treat the serious problems that may result from high blood sugar. It is estimated that one in three Americans born in 2000 will develop diabetes sometime during their lifetime. There are currently more than 230 million people with diabetes worldwide, and if nothing is done to slow the epidemic, the worldwide number may exceed 350 million by 2025. The American Diabetes Association recommends that patients with type 2 diabetes achieve a target A1C level of <7 percent, while the American Association of Clinical Endocrinologists recommends a target A1C level of <6.5 percent. Expanding clinical development program for sitagliptin family Merck’s clinical development program for sitagliptin is robust and continues to expand with 47 studies completed or under way, and nine more studies set to begin this year. There are more than 7,600 patients in the Company’s clinical studies with about 4,700 of these patients, being treated with sitagliptin. Additionally, about 1,900 patients have been treated with sitagliptin for more than a year. About Merck Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com. Merck forward-looking statement This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2006, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference. Prescribing information and patient product information for JANUMET are attached. 1 A1C is a measure of a person’s average blood glucose over a two- to three-month period. 2 Clinical data referenced in this press release for JANUMET were from studies including sitagliptin plus metformin as separate tablets. A clinical bioequivalence study has demonstrated the equivalence between JANUMET and sitagliptin plus metformin as separate tablets. JANUMET™ and JANUVIA™ are trademarks of Merck & Co., Inc. JANUMET(TM) (sitagliptin/metformin HCl) Tablets 9794100 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use JANUMET safely and effectively. See full prescribing information for JANUMET. JANUMET(TM) (sitagliptin/metformin HCl) tablets Initial U.S. Approval: 2007 WARNING: 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 and hospitalize the patient immediately. (5.1) INDICATIONS AND USAGE JANUMET is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus who are not adequately controlled on metformin or sitagliptin alone or in patients already being treated with the combination of sitagliptin and metformin. (1) Important Limitation of Use: JANUMET should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. (1) DOSAGE AND ADMINISTRATION -- Individualize the starting dose of JANUMET 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. (2.1) -- JANUMET should be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side effects due to metformin. (2.1) DOSAGE FORMS AND STRENGTHS Tablets: 50 mg sitagliptin/500 mg metformin HCl and 50 mg sitagliptin/1000 mg metformin HCl (3) CONTRAINDICATIONS -- Renal disease or renal dysfunction, e.g., serum creatinine levels greater than or equal to 1.5 mg/dL (males), greater than or equal to 1.4 mg/dL (females) or abnormal creatinine clearance. (4, 5.1, 5.3) -- Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. (4, 5.1) -- Temporarily discontinue JANUMET in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials. (4, 5.1, 5.10) WARNINGS AND PRECAUTIONS -- Avoid JANUMET use in patients with evidence of hepatic disease. (5.1, 5.2) -- Before initiation of therapy with JANUMET and at least annually thereafter, assess renal function and verify as normal. (4, 5.1, 5.3) -- Measure hematologic parameters annually. (5.4, 6.1) -- Warn patients against excessive alcohol intake. (5.1, 5.5) -- May need to discontinue JANUMET and temporarily use insulin during periods of stress and decreased intake of fluids and food as may occur with fever, trauma, infection or surgery. (5.6, 5.7) -- Promptly evaluate patients previously controlled on JANUMET who develop laboratory abnormalities or clinical illness for evidence of ketoacidosis or lactic acidosis. (5.1, 5.7) ADVERSE REACTIONS -- The most common adverse experience in sitagliptin monotherapy reported regardless of investigator assessment of causality in greater than or equal to 5% of patients and more commonly than in patients given placebo was nasopharyngitis. (6.1) -- The most common (greater than 5%) established adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact 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. (5.9, 7.1) USE IN SPECIFIC POPULATIONS -- Safety and effectiveness of JANUMET in children under 18 years have not been established. (8.4) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: Mar 2007 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING - LACTIC ACIDOSIS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Lactic Acidosis 5.2 Impaired Hepatic Function 5.3 Assessment of Renal Function 5.4 Vitamin B12 Levels 5.5 Alcohol Intake 5.6 Surgical Procedures 5.7 Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes 5.8 Use with Medications Known to Cause Hypoglycemia 5.9 Concomitant Medications Affecting Renal Function or Metformin Disposition 5.10 Radiologic Studies with Intravascular Iodinated Contrast Materials 5.11 Hypoxic States 5.12 Loss of Control of Blood Glucose 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Cationic Drugs 7.2 Digoxin 7.3 Glyburide 7.4 Furosemide 7.5 Nifedipine 7.6 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 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 17.3 FDA-Approved Patient Labeling *Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION WARNING: LACTIC ACIDOSIS Lactic acidosis is a rare, but serious complication that 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. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate. If acidosis is suspected, JANUMET(1) should be discontinued and the patient hospitalized immediately. (See Warnings and Precautions (5.1).) 1 INDICATIONS AND USAGE JANUMET is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus who are not adequately controlled on metformin or sitagliptin alone or in patients already being treated with the combination of sitagliptin and metformin. Important Limitations of Use JANUMET should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing The dosage of antihyperglycemic therapy with JANUMET should be individualized on the basis of the patient's current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin. JANUMET should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side effects due to metformin. The starting dose of JANUMET should be based on the patient's current regimen. JANUMET should be given twice daily with meals. The following doses are available: 50 mg sitagliptin/500 mg metformin hydrochloride 50 mg sitagliptin/1000 mg metformin hydrochloride. Patients inadequately controlled on metformin monotherapy For patients not adequately controlled on metformin alone, the usual starting dose of JANUMET should be equal to 100 mg total daily dose (50 mg twice daily) of sitagliptin plus the dose of metformin already being taken. For patients taking metformin 850 mg twice daily, the recommended starting dose of JANUMET is 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily. Patients inadequately controlled on sitagliptin monotherapy For patients not adequately controlled on sitagliptin alone, the usual starting dose of JANUMET is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily. Patients may be titrated up to 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily. Patients taking sitagliptin monotherapy dose-adjusted for renal insufficiency should not be switched to JANUMET (see Contraindications (4)). Patients switching from sitagliptin co-administered with metformin For patients switching from sitagliptin co-administrated with metformin, JANUMET may be initiated at the dose of sitagliptin and metformin already being taken. No studies have been performed specifically examining the safety and efficacy of JANUMET in patients previously treated with other oral antihyperglycemic agents and switched to JANUMET. 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 -- 50 mg/500 mg tablets are light pink, capsule-shaped, film-coated tablets with "575" debossed on one side. -- 50 mg/1000 mg tablets are red, capsule-shaped, film-coated tablets with "577" debossed on one side. 4 CONTRAINDICATIONS JANUMET (sitagliptin/metformin HCl) is contraindicated in patients with: -- Renal disease or renal dysfunction, e.g., as suggested by serum creatinine levels greater than or equal to 1.5 mg/dL (males), greater than or equal to 1.4 mg/dL (females) 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)). -- Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. JANUMET should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function (see Warnings and Precautions (5.10)). 5 WARNINGS AND PRECAUTIONS 5.1 Lactic Acidosis Metformin hydrochloride Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with JANUMET; when it occurs, it 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 levels (greater than 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 greater than 5 (mu)g/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (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 insufficiency, 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 metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in patients greater than or equal to 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, metformin 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, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking metformin, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see Warnings and Precautions (5.3, 5.5, 5.6, 5.10)). 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. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see Warnings and Precautions (5.11)). Metformin should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. 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 metformin 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 (see Warnings and Precautions (5.7, 5.12)). 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 metformin, 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); Warnings and Precautions (5.5, 5.6, 5.9, 5.10, 5.11)). 5.2 Impaired Hepatic Function Since impaired hepatic function has been associated with some cases of lactic acidosis, JANUMET should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. 5.3 Assessment of Renal Function Metformin and sitagliptin are known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive JANUMET. In the elderly, JANUMET should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging can be associated with reduced renal function. (See Warnings and Precautions (5.1) and Use in Specific Populations (8.5).) Before initiation of therapy with JANUMET and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should be assessed more frequently and JANUMET discontinued if evidence of renal impairment is present. 5.4 Vitamin B12 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 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. 5.5 Alcohol Intake Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving JANUMET. 5.6 Surgical Procedures Use of JANUMET should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal. 5.7 Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes A patient with type 2 diabetes previously well controlled on JANUMET 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 must be stopped immediately and other appropriate corrective measures initiated. 5.8 Use with Medications Known to Cause Hypoglycemia Sitagliptin In clinical trials of sitagliptin as monotherapy and sitagliptin as part of combination therapy with metformin or pioglitazone, rates of hypoglycemia reported with sitagliptin were similar to rates in patients taking placebo. The use of sitagliptin in combination with medications known to cause hypoglycemia, such as sulfonylureas or insulin, has not been adequately studied. 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 (beta)-adrenergic blocking drugs. 5.9 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 (7.1)), should be used with caution. 5.10 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 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. 5.11 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 therapy, the drug should be promptly discontinued. 5.12 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 and temporarily administer insulin. JANUMET may be reinstituted after the acute episode is resolved. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience The overall incidence of side effects reported in patients receiving sitagliptin and metformin was similar to that reported with patients receiving placebo and metformin. In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once daily added to a twice daily metformin regimen, there were no adverse reactions reported regardless of investigator assessment of causality in greater than or equal to 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, 1.9%; placebo and metformin, 2.5%). The overall incidence of adverse reactions of hypoglycemia in patients treated with sitagliptin and metformin was similar to patients treated with placebo and metformin (100 mg sitagliptin and metformin, 1.3%; placebo and metformin, 2.1%). Adverse reactions of hypoglycemia were based on all reports of hypoglycemia; a concurrent glucose measurement was not required. The incidence of selected gastrointestinal adverse reactions in patients treated with sitagliptin and metformin was also similar to placebo and metformin: nausea (sitagliptin and metformin, 1.3%; placebo and metformin, 0.8%), vomiting (1.1%, 0.8%), abdominal pain (2.2%, 3.8%), and diarrhea (2.4%, 2.5%). No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed with the combination of sitagliptin and metformin. The most common adverse experience in sitagliptin monotherapy reported regardless of investigator assessment of causality in greater than or equal to 5% of patients and more commonly than in patients given placebo was nasopharyngitis. The most common (greater than 5%) established adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache. Laboratory Tests Sitagliptin The incidence of laboratory adverse reactions was similar in patients treated with sitagliptin and metformin (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 (5.4).) 7 DRUG INTERACTIONS 7.1 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. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of JANUMET and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system. 7.2 Digoxin There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 18%) of digoxin with the co-administration of 100 mg sitagliptin for 10 days. These increases are not considered likely to be clinically meaningful. Digoxin, as a cationic drug, has the potential to compete with metformin for common renal tubular transport systems, thus affecting the serum concentrations of either digoxin, metformin or both. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or JANUMET is recommended. 7.3 Glyburide In a single-dose interaction study in type 2 diabetes patients, co-administration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects make the clinical significance of this interaction uncertain. 7.4 Furosemide A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically. 7.5 Nifedipine A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine. 7.6 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 the patient should be closely observed to maintain adequate glycemic control. In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when co-administered in single-dose interaction studies. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B: JANUMET There are no adequate and well-controlled studies in pregnant women with JANUMET or its individual components; therefore, the safety of JANUMET in pregnant women is not known. JANUMET should be used during pregnancy only if clearly needed. Merck & Co., Inc. maintains a registry to monitor the pregnancy outcomes of women exposed to JANUMET while pregnant. Health care providers are encouraged to report any prenatal exposure to JANUMET by calling the Pregnancy Registry at (800) 986-8999. No animal studies have been conducted with the combined products in JANUMET 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. This represents an exposure of about 2 and 6 times the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin. 8.3 Nursing Mothers No studies in lactating animals have been conducted with the combined components of JANUMET. 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 is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when JANUMET is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of JANUMET in pediatric patients under 18 years have not been established. 8.5 Geriatric Use JANUMET Because sitagliptin and metformin are substantially excreted by the kidney, and because aging can be associated with reduced renal function, JANUMET 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, 5.3); Clinical Pharmacology (12.3).) Sitagliptin Of the total number of subjects (N=3884) in 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 (5.3); and 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 humans. 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 (sitagliptin/metformin HCl) tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes: sitagliptin and metformin hydrochloride. Sitagliptin is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. Sitagliptin is present in JANUMET tablets in the form of sitagliptin phosphate monohydrate. 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-a)pyrazine phosphate (1:1) monohydrate with an empirical formula of C16H15F6N5O-H3PO4-H2O and a molecular weight of 523.32. The structural formula is: (OBJECT OMITTED) 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 not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin 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 pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is as shown: (OBJECT OMITTED) JANUMET JANUMET is available for oral administration as tablets containing 64.25 mg sitagliptin phosphate monohydrate and metformin hydrochloride equivalent to: 50 mg sitagliptin as free base and 500 mg metformin hydrochloride (JANUMET 50 mg/500 mg) or 1000 mg metformin hydrochloride (JANUMET 50 mg/1000 mg). Each film-coated tablet of JANUMET contains the following inactive ingredients: microcrystalline cellulose, polyvinylpyrrolidone, sodium lauryl sulfate, and sodium stearyl fumarate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide, and black iron oxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action JANUMET JANUMET combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin hydrochloride, a member of the biguanide class. Sitagliptin Sitagliptin is a DPP-4 inhibitor, which is believed to exert 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 an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances (see Warnings and Precautions (5.8))) 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 General 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 Co-administration 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. Co-administration 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 The results of a bioequivalence study in healthy subjects demonstrated that the JANUMET (sitagliptin/metformin HCl) 50 mg/500 mg and 50 mg/1000 mg combination tablets are bioequivalent to co-administration of corresponding doses of sitagliptin (JANUVIA(TM)(2)) and metformin hydrochloride as individual tablets. Absorption Sitagliptin The absolute bioavailability of sitagliptin is approximately 87%. Co-administration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics of sitagliptin. Metformin hydrochloride The absolute bioavailability of a metformin hydrochloride 500-mg tablet given under fasting conditions is approximately 50-60%. Studies using single oral doses of metformin hydrochloride tablets 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850-mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown. 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 The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride tablets 850 mg averaged 654 +/- 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. 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 less than 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) nor biliary excretion. 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 t1/2 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. Special Populations Renal Insufficiency JANUMET JANUMET should not be used in patients with renal insufficiency (see Contraindications (4); Warnings and Precautions (5.3)). Sitagliptin An approximately 2-fold increase in the plasma AUC of sitagliptin was observed in patients with moderate renal insufficiency, and an approximately 4-fold increase was observed in patients with severe renal insufficiency including patients with 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 Insufficiency Sitagliptin In patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), mean AUC and Cmax 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 insufficiency (Child-Pugh score greater than 9). Metformin hydrochloride No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency. 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 Cmax 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 (see GLUCOPHAGE(3) prescribing information: CLINICAL PHARMACOLOGY, Special Populations, Geriatrics). JANUMET treatment should not be initiated in patients greater than or equal to 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced (see Warnings and Precautions (5.1, 5.3)). Pediatric No studies with JANUMET 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 Co-administration 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 have not been performed; however, such studies have been conducted with the individual components of JANUMET (sitagliptin and metformin hydrochloride). 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 Effect of Sitagliptin on Other Drugs In clinical studies, as described below, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT). Digoxin: Sitagliptin had a minimal effect on the pharmacokinetics of digoxin. Following administration of 0.25 mg digoxin concomitantly with 100 mg of sitagliptin daily for 10 days, the plasma AUC of digoxin was increased by 11%, and the plasma Cmax by 18%. Sulfonylureas: Single-dose pharmacokinetics of glyburide, a CYP2C9 substrate, was not meaningfully altered in subjects receiving multiple doses of sitagliptin. Clinically meaningful interactions would not be expected with other sulfonylureas (e.g., glipizide, tolbutamide, and glimepiride) which, like glyburide, are primarily eliminated by CYP2C9 (see Warnings and Precautions (5.8)). Simvastatin: Single-dose pharmacokinetics of simvastatin, a CYP3A4 substrate, was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin. Therefore, sitagliptin is not an inhibitor of CYP3A4-mediated metabolism. Thiazolidinediones: Single-dose pharmacokinetics of rosiglitazone was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin, indicating that sitagliptin is not an inhibitor of CYP2C8-mediated metabolism. Warfarin: Multiple daily doses of sitagliptin did not meaningfully alter the pharmacokinetics, as assessed by measurement of S(-) or R(+) warfarin enantiomers, or pharmacodynamics (as assessed by measurement of prothrombin INR) of a single dose of warfarin. Because S(-) warfarin is primarily metabolized by CYP2C9, these data also support the conclusion that sitagliptin is not a CYP2C9 inhibitor. Oral Contraceptives: Co-administration with sitagliptin did not meaningfully alter the steady-state pharmacokinetics of norethindrone or ethinyl estradiol. Effect of Other Drugs on Sitagliptin Clinical data described below suggest that sitagliptin is not susceptible to clinically meaningful interactions by co-administered medications. Cyclosporine: A study was conducted to assess the effect of cyclosporine, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Co-administration of a single 100-mg oral dose of sitagliptin and a single 600-mg oral dose of cyclosporine increased the AUC and Cmax of sitagliptin by approximately 29% and 68%, respectively. These modest changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of sitagliptin was also not meaningfully altered. Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors. Metformin hydrochloride (See Drug Interactions (7.1, 7.3, 7.4, 7.5, 7.6).) 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility JANUMET No animal studies have been conducted with the combined products in JANUMET 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 rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately four times 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 mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons. 14 CLINICAL STUDIES There have been no clinical efficacy studies conducted with JANUMET; however, bioequivalence of JANUMET with co-administered sitagliptin and metformin hydrochloride tablets was demonstrated. Sitagliptin Add-on Therapy in Patients Not Adequately Controlled on Metformin 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. Patients already on metformin (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 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 (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, sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin (Table 1). 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 1: Glycemic Parameters at Final Visit (24-Week Study) of Sitagliptin in Add-on Combination Therapy with Metformin+ ---------------------------------------------------------------------- Sitagliptin 100 mg q.d. + Placebo + Metformin Metformin ------------------------- --------------- A1C (%) N = 453 N = 224 ----------------------- ------------------------- --------------- Baseline (mean) 8.0 8.0 ----------------------- ------------------------- --------------- Change from baseline (adjusted mean++) -0.7 -0.0 ----------------------- ------------------------- --------------- Difference from placebo + metformin (adjusted mean++) (95% CI) -0.7ss. (-0.8, -0.5) ----------------------- ------------------------- --------------- Patients (%) achieving A1C less than 7% 213 (47%) 41 (18%) ----------------------- ------------------------- --------------- FPG (mg/dL) N = 454 N = 226 ----------------------- ------------------------- --------------- Baseline (mean) 170 174 ----------------------- ------------------------- --------------- Change from baseline (adjusted mean++) -17 9 ----------------------- ------------------------- --------------- Difference from placebo + metformin (adjusted mean++) (95% CI) -25ss. (-31, -20) ----------------------- ------------------------- --------------- 2-hour PPG (mg/dL) N = 387 N = 182 ----------------------- ------------------------- --------------- Baseline (mean) 275 272 ----------------------- ------------------------- --------------- Change from baseline (adjusted mean++) -62 -11 ----------------------- ------------------------- --------------- Difference from placebo + metformin (adjusted mean++) (95% CI) -51ss. (-61, -41) ----------------------- ------------------------- --------------- + Intent to Treated Population using last observation on study prior to pioglitazone rescue therapy. ++ Least squares means adjusted for prior antihyperglycemic therapy and baseline value. ss. p less than 0.001 compared to placebo + metformin. 16 HOW SUPPLIED/STORAGE AND HANDLING No. 6747 -- Tablets JANUMET, 50 mg/500 mg, are light pink, capsule-shaped, film-coated tablets with "575" debossed on one side. They are supplied as follows: NDC 0006-0575-61 unit-of-use bottles of 60 NDC 0006-0575-62 unit-of-use bottles of 180 NDC 0006-0575-52 unit dose blister packages of 50 NDC 0006-0575-82 bulk bottles of 1000. No. 6749 -- Tablets JANUMET, 50 mg/1000 mg, are red, capsule-shaped, film-coated tablets with "577" debossed on one side. They are supplied as follows: NDC 0006-0577-61 unit-of-use bottles of 60 NDC 0006-0577-62 unit-of-use bottles of 180 NDC 0006-0577-52 unit dose blister packages of 50 NDC 0006-0577-82 bulk bottles of 1000. Store at 20-25(degree)C (68-77(degree)F), excursions permitted to 15-30(degree)C (59-86(degree)F), (See USP Controlled Room Temperature). 17 PATIENT COUNSELING INFORMATION (See FDA-Approved Patient Labeling (17.3).) 17.1 Instructions Patients should be informed of the potential risks and benefits of JANUMET 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 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 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 counseled against excessive alcohol intake, either acute or chronic, while receiving JANUMET. Patients should be informed about the importance of regular testing of renal function and hematological parameters when receiving treatment with JANUMET. Physicians should instruct their patients to read the Patient Package Insert before starting JANUMET 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 & CO., Inc. Whitehouse Station, NJ 08889, USA By: MOVA Pharmaceutical Corporation Caguas, Puerto Rico 00725 9794100 US Patent No.: 6,699,871 17.3 FDA-Approved Patient Labeling (1) Trademark of MERCK & CO., Inc., Whitehouse Station, New Jersey 08889 USA (2) Trademark of MERCK & CO., Inc., Whitehouse Station, New Jersey 08889 USA (3) GLUCOPHAGE(R) is a registered trademark of Merck Sante S.A.S, an associate of Merck KGaA of Darmstadt, Germany. Licensed to Bristol-Meyers Squibb Company. COPYRIGHT (C) 2007 MERCK & CO., Inc. All rights reserved 9794100 Patient Information JANUMET(TM) (JAN-you-met) (sitagliptin/metformin HCl) Tablets Read the Patient Information that comes with JANUMET(1) before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or treatment. What is the most important information I should know about JANUMET? Metformin hydrochloride, one of the ingredients in JANUMET, can cause a rare but serious side effect 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 a hospital. Stop taking JANUMET and call your doctor right away if you get any of the following symptoms of lactic acidosis: -- You feel very weak and tired. -- You have unusual (not normal) muscle pain. -- You have trouble breathing. -- You have unexplained stomach or intestinal problems with nausea and vomiting, or diarrhea. -- You feel cold, especially in your arms and legs. -- You feel dizzy or lightheaded. -- You have a slow or irregular heart beat. You have a higher chance of getting lactic acidosis if you: -- have kidney problems. -- have liver problems. -- have congestive heart failure that requires treatment with medicines. -- drink a lot of alcohol (very often or 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 don't drink enough fluids. -- have certain x-ray tests with injectable dyes or contrast agents. -- have surgery. -- have a heart attack, severe infection, or stroke. -- are 80 years of age or older and have not had your kidney function tested. What is JANUMET? JANUMET tablets contain two prescription medicines, sitagliptin (JANUVIA(TM)(2)) and metformin. JANUMET is used along with diet and exercise to lower blood sugar in patients with type 2 diabetes who have already been treated with either JANUVIA or metformin and their blood sugar is not controlled well enough, or patients who are currently taking both JANUVIA and metformin as separate medicines. General information about the use of JANUMET: -- helps to improve the levels of insulin after a meal. -- helps the body respond better to the insulin it makes naturally. -- decreases the amount of sugar made by the body. -- is unlikely to cause low blood sugar (hypoglycemia). JANUMET has not been studied in children under 18 years of age. Who should not take JANUMET? Do not take JANUMET if you: -- have type 1 diabetes. -- have certain kidney problems. -- have conditions called metabolic acidosis or diabetic ketoacidosis (increased ketones in the blood or urine). -- are going to receive an injection of dye or contrast agents for an x-ray procedure, JANUMET will need to be stopped for a short time. Talk to your doctor about when to stop JANUMET and when to start again. See "What is the most important information I should know about JANUMET?" What should I tell my doctor before and during treatment with JANUMET? JANUMET may not be right for you. Tell your doctor about all of your medical conditions, including if you: -- have kidney problems. -- have liver problems. -- have heart problems, including congestive heart failure. -- are older than 80 years. Patients over 80 years should not take JANUMET unless their kidney function is checked and it is normal. -- drink alcohol a lot (all the time or short-term "binge" drinking). -- are pregnant or plan to become pregnant. It is not known if JANUMET 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. If you use JANUMET during pregnancy, talk with your doctor about how you can be on the JANUMET registry. The toll-free telephone number for the pregnancy registry is 1-800-986-8999. -- are breast-feeding or plan to breast-feed. It is not known if JANUMET will pass into your breast milk. Talk with your doctor about the best way to feed your baby if you are taking JANUMET. Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. JANUMET may affect how well other drugs work and some drugs can affect how well JANUMET 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. Talk to your doctor before you start any new medicine. How should I take JANUMET? -- Your doctor will tell you how many JANUMET tablets to take and how often you should take them. Take JANUMET exactly as your doctor tells you. -- Your doctor may need to increase your dose to control your blood sugar. -- Take JANUMET with meals to lower your chance of an upset stomach. -- Continue to take JANUMET as long as your doctor tells you. -- If you take too much JANUMET, call your doctor or 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 two doses of JANUMET at the same time. -- You may need to stop taking JANUMET 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 receive an injection of dye or contrast agent for an x-ray procedure. See "What is the most important information I should know about JANUMET?" and "Who should not take JANUMET?" -- 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 conditions and follow your doctor's instructions. -- Monitor your blood sugar as your doctor tells you to. -- Stay on your prescribed diet and exercise program while taking JANUMET. -- Talk to your doctor about how to prevent, recognize and manage low blood sugar (hypoglycemia), high blood sugar (hyperglycemia), and complications of diabetes. -- Your doctor will monitor your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C. -- Your doctor will do blood tests to check your kidney function before and during treatment with JANUMET. What are the possible side effects of JANUMET? JANUMET can cause serious side effects. See "What is the most important information I should know about JANUMET?" Common side effects when taking JANUMET include: -- stuffy or runny nose and sore throat -- diarrhea -- nausea and vomiting -- gas, stomach discomfort, indigestion -- weakness -- headache Taking JANUMET with meals can help reduce the common stomach side effects of metformin that usually occur at the beginning of treatment. If you have unusual or unexpected stomach problems, talk with your doctor. Stomach problems that start up later during treatment may be a sign of something more serious. These are not all the possible side effects of JANUMET. For more information, ask your doctor. Tell your doctor if you have any side effect that bothers you, is unusual, or does not go away. How should I store JANUMET? Store JANUMET at room temperature, 68-77(degree)F (20-25(degree)C). Keep JANUMET and all medicines out of the reach of children. General information about the use of JANUMET Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use JANUMET for a condition for which it was not prescribed. Do not give JANUMET to other people, even if they have the same symptoms you have. It may harm them. This leaflet summarizes the most important information about JANUMET. If you would like to know more information, talk with your doctor. You can ask your doctor or pharmacist for information about JANUMET that is written for health professionals. For more information go to www.JANUMET.com OR CALL 1-800-622-4477. What are the ingredients in JANUMET? Active ingredients: sitagliptin and metformin hydrochloride. Inactive ingredients: microcrystalline cellulose, polyvinylpyrrolidone, sodium lauryl sulfate, and sodium stearyl fumarate. The tablet film coating contains the following inactive ingredients: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide, and black 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. The main goal of treating diabetes is to lower your blood sugar to a normal level. Lowering and controlling blood sugar may help prevent or delay complications of diabetes, such as heart problems, kidney problems, blindness, and amputation. High blood sugar can be lowered by diet and exercise, and by certain medicines when necessary. Issued March 2007 Manufactured for: MERCK & CO., Inc., Whitehouse Station, NJ 08889, USA By: MOVA Pharmaceutical Corporation Caguas, Puerto Rico 00725 9794100 (1) Trademark of MERCK & CO., Inc., Whitehouse Station, New Jersey 08889 USA COPYRIGHT (C) 2007 MERCK & CO., Inc. All rights reserved (2) Trademark of MERCK & CO., Inc., Whitehouse Station, New Jersey 08889 USA