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

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

JANUMET (sitagliptin/metformin HCl) provides significantly greater A1C1 reduction than metformin alone and helped more than twice as many patients get to A1C goal

WHITEHOUSE STATION, N.J. — Merck & Co., Inc. announced today that the U.S. Food and Drug Administration (FDA) approved JANUMET[TM], the first and only tablet combining a dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin (also known as JANUVIA[TM]), 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 JANUMET(2) (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 eN5 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[TM] and JANUVIA[TM] 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

COPYRIGHT 2007 Business Wire

COPYRIGHT 2007 Gale Group