An Investigational Study Released at ADA Showed that Initial Combination Therapy with JANUVIA(TM) (sitagliptin) and Metformin Led to Improvement in Markers of Beta Cell Function in Patients with Type 2 Diabetes.

* New Study with JANUVIA Suggests that Metformin Acts in a Different Manner than DPP-4 Inhibitors to Increase Total GLP-1 Levels

* Additional Data Suggested that, When Used Together, JANUVIA and Metformin Had a Complementary Effect on Active GLP-1 Levels in Healthy Adults

CHICAGO -- New data from an investigational study released at the American Diabetes Association (ADA) 67th Annual Scientific Sessions showed that initial combination therapy with JANUVIA[TM] (sitagliptin) and metformin demonstrated significant improvement in markers of beta cell function in patients with type 2 diabetes. Pancreatic islet beta cell function determines the ability of the body to produce insulin, a hormone which plays a central role in the regulation of blood sugar levels. New data from a separate pharmacologic study reported today in an oral presentation revealed that, when used in combination in healthy adults, the different mechanisms of action of JANUVIA and metformin had a complementary effect on glucagon-like peptide-1 (GLP-1) levels, another hormone that is an important regulator of blood sugar levels. This aspect of the mechanism of action of metformin used in combination with JANUVIA was previously unknown. GLP-1 acts, in part, by enhancing pancreatic beta cell insulin production and secretion.

JANUVIA is a selective, once-daily dipeptidyl peptidase-4 (DPP-4) inhibitor that enhances a natural body system, called the incretin system, which helps to regulate glucose by affecting the beta cells and alpha cells in the pancreas. JANUVIA is the first and only DPP-4 inhibitor to be approved and marketed in the United States for patients with type 2 diabetes. JANUVIA is indicated, as an adjunct to diet and exercise, to improve glycemic control in patients with type 2 diabetes mellitus. JANUVIA is also indicated to improve glycemic control, in combination with metformin or a thiazolidinedione (TZD), in patients with type 2 diabetes when the single agent alone plus diet and exercise do not provide adequate glycemic control. JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. There are no contraindications for JANUVIA.

Sitagliptin is also a component of JANUMET[TM] (sitagliptin/metformin HCl), the first and only tablet combining a DPP-4 inhibitor and metformin for the treatment of type 2 diabetes. 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. 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.

Investigational use of JANUVIA and metformin as initial combination therapy led to improvement in markers of beta cell function in patients with type 2 diabetes (0533-P; Study #036)

In this investigational study, the effects of JANUVIA and metformin on beta cell function were examined in patients with type 2 diabetes who participated in a 24-week, placebo-controlled study in which 1,091 patients were randomized to one of six treatments: JANUVIA 50 mg/metformin 1000 mg twice daily (n=182); JANUVIA 50 mg/metformin 500 mg twice daily (n=190); metformin 1000 mg twice daily (n=182); metformin 500 mg twice daily (n=182); JANUVIA 100 mg once-daily (n=179); or placebo (n=176). Of these, a subset of 500 patients underwent frequently sampled meal tolerance tests. Beta cell function was measured using a computer model based evaluation. Parameters of beta cell function from this model allowed for the estimation of the insulin secretion rate (ISR) and the characterization of the ISR into static (beta cell responsiveness to above-basal glucose following a meal) and dynamic (beta cell responsiveness to the rate of increase in above-basal glucose following a meal) components.

After 24 weeks, the changes in static and dynamic beta cell responsiveness were increased across all active treatments relative to placebo, and appeared to be increased in an approximately additive fashion with co-administration with JANUVIA and high dose metformin compared to each as monotherapy. The results of the beta cell modeling analysis showed that the addition of JANUVIA to metformin resulted in a 49 percent increase in measured change in static beta cell responsiveness compared with metformin alone (20.1, JANUVIA 50 mg/metformin 1000 mg twice daily vs. 13.5, metformin 1000 mg twice daily). Further, the addition of JANUVIA to metformin resulted in a 114 percent increase in measured change in dynamic beta cell responsiveness compared with metformin alone (151.0, JANUVIA 50 mg/metformin 1000 mg twice daily vs. 70.7, metformin 1000 mg twice daily).

"These data further characterize the effects of DPP-4 inhibition and its role in combination with metformin, the most commonly prescribed drug for type 2 diabetes," said Luciano Rossetti, senior vice president and MRL head, Diabetes & Obesity and Cardiovascular Franchises, Merck & Co., Inc.

JANUVIA and metformin had a complementary effect to increase active GLP-1 concentrations in healthy adults (0286-OR; Study #050)

A randomized, placebo-controlled, double-blind, clinical pharmacology study was conducted in 16 healthy adults to assess the potential complementary effects of JANUVIA and metformin on GLP-1, an important incretin hormone. In each 2-day treatment period, subjects received one of four treatments: JANUVIA, metformin, the co-administration of JANUVIA and metformin, or placebo.

In this study, JANUVIA and metformin, when taken separately, increased overall, post-meal, active concentrations of GLP-1 levels by 1.95- and 1.76-fold, respectively (p<0.001), compared with placebo. When administered together, JANUVIA and metformin increased active concentrations of GLP-1 by 4.12-fold (p<0.001) compared with placebo. In contrast to active GLP-1 levels that were increased by both drugs, the levels of total GLP-1 (which includes both active and inactive GLP-1) were increased by metformin only and not by JANUVIA. These observations are consistent with the effect of JANUVIA to raise active GLP-1 levels by reducing the clearance, but suggest that metformin acts in a different manner to increase active GLP-1 levels. This study provides evidence that the two drugs may have complementary effects on GLP-1.

"This is the first study in humans that showed that metformin increases the concentration of the incretin hormone, GLP-1; thus increasing the total GLP-1 available. When used together with JANUVIA, a DPP-4 inhibitor that blocks the degradation of GLP-1 by inhibiting its breakdown, there was an increase in GLP-1 levels greater than what either agent provided alone," said Nir Barzilai, M.D., professor of Medicine and Molecular Genetics and director of the Institute for Aging Research, Albert Einstein College of Medicine. "It appears as though metformin allows for more total GLP-1 to be available, and JANUVIA helps GLP-1 to remain active thus acting in a complementary way."

GLP-1 plays an important role in regulating the body's blood sugar levels. When food is consumed, GLP-1 is released by the gastrointestinal tract to stimulate the pancreatic beta cells to secrete insulin, a hormone that helps the body to use glucose for energy. GLP-1 also suppresses the release of glucagon from the pancreatic alpha cells, which, in turn, tells the liver to reduce its production of sugar.

Dosing of JANUVIA

The recommended dose of JANUVIA is 100 mg once daily, with or without food, for all approved indications. No dosage adjustment is needed for patients with mild to moderate hepatic insufficiency or in patients with mild renal insufficiency (CrCl [greater than or equal to]50 mL/min). To achieve plasma concentrations of JANUVIA similar to those in patients with normal renal function, lower dosages are recommended in patients with moderate and severe renal insufficiency as well as in end-stage renal disease (ESRD) patients requiring hemodialysis. For patients with moderate renal insufficiency (CrCl [greater than or equal to]30 to <50 mL/min), the dose of JANUVIA is 50 mg once daily. For those with severe renal insufficiency (CrCl <30 mL/min) or with ESRD requiring dialysis, the dose of JANUVIA is 25 mg once daily. Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter.

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.

Selected cautionary information for JANUVIA

Because JANUVIA is renally eliminated, and to achieve plasma concentrations of JANUVIA similar to those in patients with normal renal function, a dosage adjustment is recommended in patients with moderate renal insufficiency and in patients with severe renal insufficiency or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis. Safety and effectiveness of JANUVIA in pediatric patients have not been established. There are no adequate and well-controlled studies in pregnant women. JANUVIA should be used during pregnancy only if clearly needed. Caution should be exercised when JANUVIA is administered to a nursing woman. In clinical trials, JANUVIA demonstrated an overall incidence of side effects comparable to placebo. The most common side effects reported with JANUVIA ([greater than or equal to]5 percent and higher than placebo) were stuffy or runny nose and sore throat, upper respiratory infection, and headache.

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.

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 have been 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.

Merck's Commitment to Type 2 Diabetes

Journey for Control[TM] is Merck's comprehensive educational initiative designed to enlighten, inspire, and empower patients with diabetes by helping them make the necessary lifestyle modifications that lead to improved self-management. The program includes resources for physicians, diabetes educators, patients and health plans; all created with a focus on improving diabetes education. The Merck Journey for Control Program is proud to sponsor the U.S. Diabetes Conversation Maps, an interactive program that combines visual learning techniques and active dialogue between patients and healthcare professional to engage patients in sustainable behavior change.

The U.S. Diabetes Conversation Maps will provide physicians and diabetes educators with a uniquely powerful way to engage patients in conversations to help support behavior changes that can make a critical difference in treatment outcomes. Content for the U.S. Diabetes Conversation Map was developed and reviewed by the ADA and the program was launched in June at the ADA 67th Annual Scientific Sessions in Chicago and will roll out throughout the U.S. in 2007. Every day, more than 4,000 people in the United States are newly diagnosed with diabetes, yet 58 percent of patients will receive no formal education about their disease. Merck is committed to improve patient care in diabetes through its significant pipeline of investigational diabetes compounds, currently marketed diabetes products (JANUVIA[TM] and JANUMET[TM]), and novel resources to support healthcare professionals and patients such as Journey for Control.

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 JANUVIA and JANUMET are attached.

JANUVIA[TM] and JANUMET[TM] are trademarks of Merck & Co., Inc.

JANUVIA(TM)(sitagliptin) Tablets                     9762701

    HIGHLIGHTS OF PRESCRIBING INFORMATION

    These highlights do not include all the information needed to use
JANUVIA safely and effectively. See full prescribing information for
JANUVIA.

    JANUVIA(TM) (sitagliptin) Tablets

    Initial U.S. Approval: 2006

    INDICATIONS AND USAGE

    JANUVIA is indicated as an adjunct to diet and exercise to improve
glycemic control in patients with type 2 diabetes mellitus (type 2
diabetes). JANUVIA is indicated for:

    --  Monotherapy (1.1)

    --  Combination therapy with metformin or a peroxisome
        proliferator-activated receptor gamma (PPAR-gamma) agonist
        (e.g., thiazolidinediones) when the single agent does not
        provide adequate glycemic control. (1.2)

    Important Limitations of Use: JANUVIA should not be used in
patients with type 1 diabetes mellitus (type 1 diabetes) or for the
treatment of diabetic ketoacidosis. (1.3)

    DOSAGE AND ADMINISTRATION

    The recommended dose of JANUVIA is 100 mg once daily as
monotherapy or as combination therapy with metformin or a PPAR-gamma
agonist (e.g., thiazolidinediones). (2.1)

    JANUVIA can be taken with or without food. (2.1)


  Dosage Adjustment in Patients With Moderate, Severe and End Stage
                      Renal Disease (ESRD) (2.2)
----------------------------------------------------------------------
           50 mg once daily                   25 mg once daily
----------------------------------------------------------------------
Moderate                                      Severe and ESRD

CrCl greater than or equal to 30           CrCl less than 30 mL/min
 to less than 50 mL/min

-Serum Cr levels (mg/dL)                  -Serum Cr levels (mg/dL)

Men: greater than 1.7 -                    Men: greater than 3.0;
 less than or equal to 3.0;

Women: greater than 1.5 -                 Women: greater than 2.5;
 less than or equal to 2.5                   or on dialysis
----------------------------------------------------------------------


    DOSAGE FORMS AND STRENGTHS

    Tablets: 100 mg, 50 mg, and 25 mg (3)

    CONTRAINDICATIONS

    None. (4)

    WARNINGS AND PRECAUTIONS

    A dosage adjustment is recommended in patients with moderate renal
insufficiency and in patients with severe renal insufficiency or with
ESRD requiring hemodialysis or peritoneal dialysis. Assessment of
renal function is recommended prior to initiation of JANUVIA and
periodically thereafter. Creatinine clearance can be estimated from
serum creatinine using the Cockcroft-Gault formula. (2.2, 5)

    ADVERSE REACTIONS

    The most common adverse reactions, reported in greater than or
equal to 5% of patients treated with JANUVIA and more commonly than in
patients treated with placebo are: upper respiratory tract infection,
nasopharyngitis, 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.

    USE IN SPECIFIC POPULATIONS

    Safety and effectiveness of JANUVIA in children under 18 years
have not been established. (8.4)

    See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient
labeling.

    Revised: 10/2006

    FULL PRESCRIBING INFORMATION: CONTENTS*

    1 INDICATIONS AND USAGE

    1.1 Monotherapy

    1.2 Combination Therapy

    1.3 Important Limitations of Use

    2 DOSAGE AND ADMINISTRATION

    2.1 Recommended Dosing

    2.2 Patients with Renal Insufficiency

    3 DOSAGE FORMS AND STRENGTHS

    4 CONTRAINDICATIONS

    5 WARNINGS AND PRECAUTIONS

    6 ADVERSE REACTIONS

    6.1 Clinical Trials Experience

    7 DRUG INTERACTIONS

    7.1 Digoxin

    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

    14.1 Monotherapy

    14.2 Combination Therapy

    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

    1 INDICATIONS AND USAGE

    1.1 Monotherapy

    JANUVIA(1) is indicated as an adjunct to diet and exercise to
improve glycemic control in patients with type 2 diabetes mellitus.

    1.2 Combination Therapy

    JANUVIA is indicated in patients with type 2 diabetes mellitus to
improve glycemic control in combination with metformin or a PPAR-gamma
agonist (e.g., thiazolidinediones) when the single agent alone, with
diet and exercise, does not provide adequate glycemic control.

    1.3 Important Limitations of Use

    JANUVIA should not be used in patients with type 1 diabetes or for
the treatment of diabetic ketoacidosis, as it would not be effective
in these settings.

    2 DOSAGE AND ADMINISTRATION

    2.1 Recommended Dosing

    The recommended dose of JANUVIA is 100 mg once daily as
monotherapy or as combination therapy with metformin or a PPAR-gamma
agonist (e.g., thiazolidinediones). JANUVIA can be taken with or
without food.

    2.2 Patients with Renal Insufficiency

    For patients with mild renal insufficiency (creatinine clearance
(CrCl) greater than or equal to 50 mL/min, approximately corresponding
to serum creatinine levels of less than or equal to 1.7 mg/dL in men
and less than or equal to 1.5 mg/dL in women), no dosage adjustment
for JANUVIA is required.

    For patients with moderate renal insufficiency (CrCl greater than
30 to less than 50 mL/min, approximately corresponding to serum
creatinine levels of greater than 1.7 to less than or equal to 3.0
mg/dL in men and greater than 1.5 to less than or equal to 2.5 mg/dL
in women), the dose of JANUVIA is 50 mg once daily.

    For patients with severe renal insufficiency (CrCl less than 30
mL/min, approximately corresponding to serum creatinine levels of
greater than 3.0 mg/dL in men and greater than 2.5 mg/dL in women) or
with end-stage renal disease (ESRD) requiring hemodialysis or
peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA
may be administered without regard to the timing of hemodialysis.

    Because there is a need for dosage adjustment based upon renal
function, assessment of renal function is recommended prior to
initiation of JANUVIA and periodically thereafter. Creatinine
clearance can be estimated from serum creatinine using the
Cockcroft-Gault formula. (See Clinical Pharmacology (12.3).)

    3 DOSAGE FORMS AND STRENGTHS

    -- 100 mg tablets are beige, round, film-coated tablets with "277"
on one side.

    -- 50 mg tablets are light beige, round, film-coated tablets with
"112" on one side.

    -- 25 mg tablets are pink, round, film-coated tablets with "221"
on one side.

    4 CONTRAINDICATIONS

    None.

    5 WARNINGS AND PRECAUTIONS

    Use in Patients with Renal Insufficiency: A dosage adjustment is
recommended in patients with moderate or severe renal insufficiency
and in patients with ESRD requiring hemodialysis or peritoneal
dialysis. (See Dosage and Administration (2.2); Clinical Pharmacology
(12.3).)

    Use with Medications Known to Cause Hypoglycemia: In clinical
trials of JANUVIA as monotherapy and JANUVIA as part of combination
therapy with metformin or pioglitazone, rates of hypoglycemia reported
with JANUVIA were similar to rates in patients taking placebo. The use
of JANUVIA in combination with medications known to cause
hypoglycemia, such as sulfonylureas or insulin, has not been
adequately studied.

    6 ADVERSE REACTIONS

    Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical trials of
a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in practice.

    6.1 Clinical Trials Experience

    In controlled clinical studies as both monotherapy and combination
therapy, the overall incidence of adverse reactions with JANUVIA was
similar to that reported with placebo. Discontinuation of therapy due
to clinical adverse reactions was also similar to placebo.

   Two placebo-controlled monotherapy studies, one of 18- and one of
24-week duration, included patients treated with JANUVIA 100 mg daily,
JANUVIA 200 mg daily, and placebo. Two 24-week, placebo-controlled
combination studies, one with metformin and one with pioglitazone,
were also conducted. In addition to a stable dose of metformin or
pioglitazone, patients whose diabetes was not adequately controlled
were given either JANUVIA 100 mg daily or placebo. The adverse
reactions, reported regardless of investigator assessment of causality
in greater than or equal to 5% of patients treated with JANUVIA 100 mg
daily as monotherapy or in combination with pioglitazone and more
commonly than in patients treated with placebo, are shown in Table 1.


                               Table 1
    Placebo-Controlled Clinical Studies of JANUVIA Monotherapy or
                    Combination with Pioglitazone:

    Adverse Reactions Reported in Greater than or equal to 5% of
Patients and More Commonly than in Patients Given Placebo, Regardless
            of Investigator Assessment of Causality+
----------------------------------------------------------------------
                                           Number of Patients (%)
----------------------------------------------------------------------
Monotherapy                            JANUVIA 100 mg     Placebo
----------------------------------------------------------------------
                                          N = 443         N = 363
----------------------------------------------------------------------
 Nasopharyngitis                              23 (5.2)        12 (3.3)
----------------------------------------------------------------------
Combination with Pioglitazone         JANUVIA 100 mg +   Placebo +
                                        Pioglitazone    Pioglitazone
----------------------------------------------------------------------
                                          N = 175         N = 178
----------------------------------------------------------------------
 Upper Respiratory Tract Infection            11 (6.3)         6 (3.4)
----------------------------------------------------------------------
 Headache                                      9 (5.1)         7 (3.9)
----------------------------------------------------------------------


    + Intent to treat population

    In patients receiving JANUVIA in combination with metformin, 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.

    The overall incidence of hypoglycemia in patients treated with
JANUVIA 100 mg was similar to placebo (1.2% vs 0.9%). The incidence of
selected gastrointestinal adverse reactions in patients treated with
JANUVIA was as follows: abdominal pain (JANUVIA 100 mg, 2.3%; placebo,
2.1%), nausea (1.4%, 0.6%), and diarrhea (3.0%, 2.3%).

    No clinically meaningful changes in vital signs or in ECG
(including in QTc interval) were observed in patients treated with
JANUVIA.

    Laboratory Tests

    The incidence of laboratory adverse reactions in patients treated
with JANUVIA 100 mg was 8.2% compared to 9.8% in patients treated with
placebo. Across clinical 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
an increase in neutrophils. This observation was seen in most but not
all studies. This change in laboratory parameters is not considered to
be clinically relevant. In a 12-week study of 91 patients with chronic
renal insufficiency, 37 patients with moderate renal insufficiency
were randomized to JANUVIA 50 mg daily, while 14 patients with the
same magnitude of renal impairment were randomized to placebo. Mean
(SE) increases in serum creatinine were observed in patients treated
with JANUVIA (0.12 mg/dL (0.04)) and in patients treated with placebo
(0.07 mg/dL (0.07)). The clinical significance of this added increase
in serum creatinine relative to placebo is not known.

    7 DRUG INTERACTIONS

    7.1 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. Patients
receiving digoxin should be monitored appropriately. No dosage
adjustment of digoxin or JANUVIA is recommended.

    8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Pregnancy Category B:

    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 in pregnant women. Because animal reproduction
studies are not always predictive of human response, this drug should
be used during pregnancy only if clearly needed. Merck & Co., Inc.
maintains a registry to monitor the pregnancy outcomes of women
exposed to JANUVIA while pregnant. Health care providers are
encouraged to report any prenatal exposure to JANUVIA by calling the
Pregnancy Registry at [phone].

    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.

    8.3 Nursing Mothers

    Sitagliptin is secreted in the milk of lactating rats at a milk to
plasma ratio of 4:1. It is not known whether sitagliptin is excreted
in human milk. Because many drugs are excreted in human milk, caution
should be exercised when JANUVIA is administered to a nursing woman.

    8.4 Pediatric Use

    Safety and effectiveness of JANUVIA in pediatric patients have not
been established.

    8.5 Geriatric Use

    Of the total number of subjects (N=3884) in clinical safety and
efficacy studies of JANUVIA, 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.

    This drug is known to be substantially excreted by the kidney.
Because elderly patients are more likely to have decreased renal
function, care should be taken in dose selection in the elderly, and
it may be useful to assess renal function in these patients prior to
initiating dosing and periodically thereafter (see Dosage and
Administration (2.2); Clinical Pharmacology (12.3)).

    10 OVERDOSAGE

    During controlled clinical trials in healthy subjects, single
doses of up to 800 mg JANUVIA were administered. Maximal mean
increases in QTc of 8.0 msec were observed in one study at a dose of
800 mg JANUVIA, 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 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
dictated 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.

    11 DESCRIPTION

    JANUVIA Tablets contain sitagliptin phosphate, an orally-active
inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.

    Sitagliptin phosphate 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.

    The empirical formula is C16H15F6N5O-H3PO4-H2O and the molecular
weight is 523.32. The structural formula is:

    (OBJECT OMITTED)

    Sitagliptin phosphate 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.

    Each film-coated tablet of JANUVIA contains 32.13, 64.25, or
128.5 mg of sitagliptin phosphate monohydrate, which is equivalent to
25, 50, or 100 mg, respectively, of free base and the following
inactive ingredients: microcrystalline cellulose, anhydrous dibasic
calcium phosphate, croscarmellose sodium, magnesium stearate, 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 yellow iron oxide.

    12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    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 JANUVIA, 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, JANUVIA 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.

    12.2 Pharmacodynamics

    General

    In patients with type 2 diabetes, administration of JANUVIA 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.

    In studies with healthy subjects, JANUVIA 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 JANUVIA 100 mg,
JANUVIA 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 was observed at 3
hours postdose and 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-fold higher than the peak
concentrations following a 100 mg dose.

    In patients with type 2 diabetes administered JANUVIA 100 mg
(N=81) or JANUVIA 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

    The pharmacokinetics of sitagliptin has been extensively
characterized in healthy subjects and patients with type 2 diabetes.
After oral administration of a 100 mg dose to healthy subjects,
sitagliptin was rapidly absorbed, with peak plasma concentrations
(median Tmax) occurring 1 to 4 hours postdose. Plasma AUC of
sitagliptin increased in a dose-proportional manner. Following a
single oral 100 mg dose to healthy volunteers, mean plasma AUC of
sitagliptin was 8.52 ?M-hr, Cmax was 950 nM, and apparent terminal
half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased
approximately 14% following 100 mg doses at steady-state compared to
the first dose. The intra-subject and inter-subject coefficients of
variation for sitagliptin AUC were small (5.8% and 15.1%). The
pharmacokinetics of sitagliptin was generally similar in healthy
subjects and in patients with type 2 diabetes.

    Absorption

    The absolute bioavailability of sitagliptin is approximately 87%.
Because coadministration of a high-fat meal with JANUVIA had no effect
on the pharmacokinetics, JANUVIA may be administered with or without
food.

    Distribution

    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%).

    Metabolism

    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.

    Excretion

    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.

    Special Populations

    Renal Insufficiency

    A single-dose, open-label study was conducted to evaluate the
pharmacokinetics of JANUVIA (50 mg dose) in patients with varying
degrees of chronic renal insufficiency compared to normal healthy
control subjects. The study included patients with renal insufficiency
classified on the basis of creatinine clearance as mild (50 to less
than 80 mL/min), moderate (30 to less than 50 mL/min), and severe
(less than 30 mL/min), as well as patients with ESRD on hemodialysis.
In addition, the effects of renal insufficiency on sitagliptin
pharmacokinetics in patients with type 2 diabetes and mild or moderate
renal insufficiency were assessed using population pharmacokinetic
analyses. Creatinine clearance was measured by 24-hour urinary
creatinine clearance measurements or estimated from serum creatinine
based on the Cockcroft-Gault formula:


CrCl = (140 - age (years)) x weight (kg) {x 0.85 for female patients}
       ---------------------------------
       (72 x serum creatinine (mg/dL))


    Compared to normal healthy control subjects, an approximate 1.1-
to 1.6-fold increase in plasma AUC of sitagliptin was observed in
patients with mild renal insufficiency. Because increases of this
magnitude are not clinically relevant, dosage adjustment in patients
with mild renal insufficiency is not necessary. Plasma AUC levels of
sitagliptin were increased approximately 2-fold and 4-fold in patients
with moderate renal insufficiency and in patients with severe renal
insufficiency, including patients with ESRD on hemodialysis,
respectively. Sitagliptin was modestly removed by hemodialysis (13.5%
over a 3- to 4-hour hemodialysis session starting 4 hours postdose).
To achieve plasma concentrations of sitagliptin similar to those in
patients with normal renal function, lower dosages are recommended in
patients with moderate and severe renal insufficiency, as well as in
ESRD patients requiring hemodialysis. (See Dosage and Administration
(2.2).)

    Hepatic Insufficiency

    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 JANUVIA. These differences
are not considered to be clinically meaningful. No dosage adjustment
for JANUVIA is necessary for patients with mild or moderate hepatic
insufficiency.

    There is no clinical experience in patients with severe hepatic
insufficiency (Child-Pugh score greater than9).

    Body Mass Index (BMI)

    No dosage adjustment is necessary based on BMI. 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.

    Gender

    No dosage adjustment is necessary based on gender. 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.

    Geriatric

    No dosage adjustment is required based solely on age. 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.

    Pediatric

    Studies characterizing the pharmacokinetics of sitagliptin in
pediatric patients have not been performed.

    Race

    No dosage adjustment is necessary based on race. 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.

    Drug Interactions

    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

    Effects 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 JANUVIA daily for 10 days, the plasma AUC of digoxin
was increased by 11%, and the plasma Cmax by 18%.

    Metformin: Co-administration of multiple twice-daily doses of
sitagliptin with metformin, an OCT substrate, did not meaningfully
alter the pharmacokinetics of metformin in patients with type 2
diabetes. Therefore, sitagliptin is not an inhibitor of OCT-mediated
transport.

    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. However, the risk of hypoglycemia from the co-administration
of sitagliptin and sulfonylureas is unknown.

    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 JANUVIA 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.

    Effects of Other Drugs on Sitagliptin

    Clinical data described below suggest that sitagliptin is not
susceptible to clinically meaningful interactions by co-administered
medications:

    Metformin: Co-administration of multiple twice-daily doses of
metformin with sitagliptin did not meaningfully alter the
pharmacokinetics of sitagliptin in patients with type 2 diabetes.

    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 JANUVIA 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.

    13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    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).

    14 CLINICAL STUDIES

    There were 2316 patients with type 2 diabetes randomized in four
double-blind, placebo-controlled clinical safety and efficacy studies
conducted to evaluate the effects of sitagliptin on glycemic control.
In these studies, the mean age of patients was 54.8 years, and 62% of
patients were white, 18% were Hispanic, 6% were black, 9% were Asian,
and 4% were of other racial groups.

    In patients with type 2 diabetes, treatment with JANUVIA produced
clinically significant improvements in hemoglobin A1C, fasting plasma
glucose (FPG) and 2-hour post-prandial glucose (PPG) compared to
placebo.

    14.1 Monotherapy

    A total of 1262 patients with type 2 diabetes participated in two
double-blind, placebo-controlled studies, one of 18-week and another
of 24-week duration, to evaluate the efficacy and safety of JANUVIA
monotherapy. In both monotherapy studies, patients currently on an
antihyperglycemic agent discontinued the agent, and underwent a diet,
exercise, and drug wash-out period of about 7 weeks. Patients with
inadequate glycemic control (A1C 7% to 10%) after the wash-out period
were randomized after completing a 2-week single-blind placebo run-in
period; patients not currently on antihyperglycemic agents (off
therapy for at least 8 weeks) with inadequate glycemic control (A1C 7%
to 10%) were randomized after completing the 2-week single-blind
placebo run-in period. In the 18-week study, 521 patients were
randomized to placebo, JANUVIA 100 mg, or JANUVIA 200 mg, and in the
24-week study 741 patients were randomized to placebo, JANUVIA 100 mg,
or JANUVIA 200 mg. Patients who failed to meet specific glycemic goals
during the studies were treated with metformin rescue, added on to
placebo or JANUVIA.

    Treatment with JANUVIA at 100 mg daily provided significant
improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table
2). In the 18-week study, 9% of patients receiving JANUVIA 100 mg and
17% who received placebo required rescue therapy. In the 24-week
study, 9% of patients receiving JANUVIA 100 mg and 21% of patients
receiving placebo required rescue therapy. The improvement in A1C was
not affected by gender, age, race, or baseline BMI. As is typical for
trials of agents to treat type 2 diabetes, mean response to JANUVIA in
A1C lowering appears to be related to the degree of A1C elevation at
baseline. Overall, the 200 mg daily dose did not provide greater
glycemic efficacy than the 100 mg daily dose. The effect of JANUVIA on
lipid endpoints was similar to placebo. Body weight did not increase
from baseline with JANUVIA therapy in either study, compared to a
small reduction in patients given placebo.


                               Table 2
Glycemic Parameters in 18- and 24-Week Placebo-Controlled Studies of
               JANUVIA in Patients with Type 2 Diabetes+
----------------------------------------------------------------------
                                     18-Week Study     24-Week Study
                                   ----------------- -----------------
                                   JANUVIA  Placebo  JANUVIA  Placebo
                                    100 mg            100 mg
------------------------------------------- -------- -------- --------
A1C (%)                            N = 193  N = 103  N = 229  N = 244
------------------------------------------- -------- -------- --------
 Baseline (mean)                       8.0      8.1      8.0      8.0
------------------------------------------- -------- -------- --------
 Change from baseline (adjusted
  mean++)                             -0.5      0.1     -0.6      0.2
------------------------------------------- -------- -------- --------
 Difference from placebo (adjusted -0.6ss.           -0.8ss.
  mean++) (95% CI)                 (-0.8,             (-1.0,
                                     -0.4)             -0.6)
------------------------------------------- -------- -------- --------
 Patients (%) achieving A1C less
  than7%                           69 (36%) 16 (16%) 93 (41%) 41 (17%)
------------------------------------------- -------- -------- --------
FPG (mg/dL)                        N = 201  N = 107  N = 234  N = 247
------------------------------------------- -------- -------- --------
 Baseline (mean)                       180      184      170      176
------------------------------------------- -------- -------- --------
 Change from baseline (adjusted
  mean++)                              -13        7      -12        5
------------------------------------------- -------- -------- --------
 Difference from placebo (adjusted  -20ss.            -17ss.
  mean++) (95% CI)                  (-31,             (-24,
                                      -9)              -10)
------------------------------------------- -------- -------- --------
2-hour PPG (mg/dL)                        %        % N = 201  N = 204
------------------------------------------- -------- -------- --------
 Baseline (mean)                                         257      271
------------------------------------------- -------- -------- --------
 Change from baseline (adjusted
  mean++)                                                -49       -2
------------------------------------------- -------- -------- --------
 Difference from placebo (adjusted                    -47ss.
  mean++) (95% CI)                                    (-59,
                                                       -34)
------------------------------------------- -------- -------- --------


    + Intent to Treat Population using last observation on study prior
to metformin rescue therapy.

    ++ Least squares means adjusted for prior antihyperglycemic
therapy status and baseline value.

    ss. pless than0.001 compared to placebo.

    % Data not available.

    Additional Monotherapy Study

    A multinational, randomized, double-blind, placebo-controlled
study was also conducted to assess the safety and tolerability of
JANUVIA in 91 patients with type 2 diabetes and chronic renal
insufficiency (creatinine clearance less than 50 mL/min). Patients
with moderate renal insufficiency received 50 mg daily of JANUVIA and
those with severe renal insufficiency or with ESRD on hemodialysis or
peritoneal dialysis received 25 mg daily. In this study, the safety
and tolerability of JANUVIA were generally similar to placebo. A small
increase in serum creatinine was reported in patients with moderate
renal insufficiency treated with JANUVIA relative to those on placebo.
In addition, the reductions in A1C and FPG with JANUVIA compared to
placebo were generally similar to those observed in other monotherapy
studies. (See Clinical Pharmacology (12.3).)

    14.2 Combination Therapy

    Combination Therapy with Metformin

    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 JANUVIA 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 JANUVIA 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, JANUVIA provided significant
improvements in A1C, FPG, and 2-hour PPG compared to placebo with
metformin (Table 3). Rescue glycemic therapy was used in 5% of
patients treated with JANUVIA 100 mg and 14% of patients treated with
placebo. A similar decrease in body weight was observed for both
treatment groups.


                               Table 3
          Glycemic Parameters at Final Visit (24-Week Study)
              for JANUVIA in Combination with Metformin+
----------------------------------------------------------------------
                                                  JANUVIA    Placebo +
                                                  100 mg +   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    -0.7ss.
  mean++) (95% CI)                                 (-0.8,
                                                    -0.5)
-----------------------------------------------------------  ---------
 Patients (%) achieving A1C less than7%           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     -25ss.
  mean++) (95% CI)                               (-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     -51ss.
  mean++) (95% CI)                               (-61, -41)
-----------------------------------------------------------  ---------


    + Intent to Treat Population using last observation on study prior
to pioglitazone rescue therapy.

    ++ Least squares means adjusted for prior antihyperglycemic
therapy and baseline value.

    ss. pless than0.001 compared to placebo + metformin.

    Combination Therapy with Pioglitazone

    A total of 353 patients with type 2 diabetes participated in a
24-week, randomized, double-blind, placebo-controlled study designed
to assess the efficacy of JANUVIA in combination with pioglitazone.
Patients on any oral antihyperglycemic agent in monotherapy (N=212) or
on a PPAR-gamma agent in combination therapy (N=106) or not on an
antihyperglycemic agent (off therapy for at least 8 weeks, N=34) were
switched to monotherapy with pioglitazone (at a dose of 30-45 mg per
day), and completed a run-in period of approximately 12 weeks in
duration. After the run-in period on pioglitazone monotherapy,
patients were randomized to the addition of either 100 mg of JANUVIA
or placebo, administered once daily. Patients who failed to meet
specific glycemic goals during the studies were treated with metformin
rescue. Glycemic endpoints measured included A1C and fasting glucose.

    In combination with pioglitazone, JANUVIA provided significant
improvements in A1C and FPG compared to placebo with pioglitazone
(Table 4). Rescue therapy was used in 7% of patients treated with
JANUVIA 100 mg and 14% of patients treated with placebo. There was no
significant difference between JANUVIA and placebo in body weight
change.


                               Table 4
          Glycemic Parameters at Final Visit (24-Week Study)
            for JANUVIA in Combination with Pioglitazone+
----------------------------------------------------------------------
                                           JANUVIA 100     Placebo +
                                               mg +       Pioglitazone
                                            Pioglitazone
--------------------------------------------------------  ------------
A1C (%)                                       N = 163       N = 174
--------------------------------------------------------  ------------
 Baseline (mean)                                    8.1           8.0
--------------------------------------------------------  ------------
 Change from baseline (adjusted mean++)            -0.9          -0.2
--------------------------------------------------------  ------------
 Difference from placebo + pioglitazone       -0.7ss.
  (adjusted mean++) (95% CI)               (-0.9, -0.5)
--------------------------------------------------------  ------------
 Patients (%) achieving A1C less than7%         74 (45%)      40 (23%)
--------------------------------------------------------  ------------
FPG (mg/dL)                                   N = 163       N = 174
--------------------------------------------------------  ------------
 Baseline (mean)                                    168           166
--------------------------------------------------------  ------------
 Change from baseline (adjusted mean++)             -17             1
--------------------------------------------------------  ------------
 Difference from placebo + pioglitazone       -18ss.
  (adjusted mean++) (95% CI)                (-24, -11)
--------------------------------------------------------  ------------


    + Intent to Treat Population using last observation on study prior
to metformin rescue therapy.

    ++ Least squares means adjusted for prior antihyperglycemic
therapy status and baseline value.

    ss. pless than0.001 compared to placebo + pioglitazone.

    16 HOW SUPPLIED/STORAGE AND HANDLING

    No. 6737 -- Tablets JANUVIA, 25 mg, are pink, round, film-coated
tablets with "221" on one side. They are supplied as follows:

    NDC 0006-0221-31 unit-of-use bottles of 30

    NDC 0006-0221-54 unit-of-use bottles of 90

    NDC 0006-0221-28 unit dose blister packages of 100.

    No. 6738 -- Tablets JANUVIA, 50 mg, are light beige, round,
film-coated tablets with "112" on one side. They are supplied as
follows:

    NDC 0006-0112-31 unit-of-use bottles of 30

    NDC 0006-0112-54 unit-of-use bottles of 90

    NDC 0006-0112-28 unit dose blister packages of 100.

    No. 6739 -- Tablets JANUVIA, 100 mg, are beige, round, film-coated
tablets with "277" on one side. They are supplied as follows:

    NDC 0006-0277-31 unit-of-use bottles of 30

    NDC 0006-0277-54 unit-of-use bottles of 90

    NDC 0006-0277-28 unit dose blister packages of 100

    NDC 0006-0277-74 bottles of 500

    NDC 0006-0277-82 bottles of 1000.

    Storage

    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
JANUVIA and of alternative modes of therapy. Patients 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.

    Physicians should instruct their patients to read the Patient
Package Insert before starting JANUVIA therapy and to reread each time
the prescription is renewed. Patients should be instructed to inform
their doctor or pharmacist if they develop any unusual symptom, or if
any known symptom persists or worsens.

    17.2 Laboratory Tests

    Patients should be informed that 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. Patients should be informed of the potential need to
adjust dose based on changes in renal function tests over time.

    Manufactured for:

    MERCK & CO., Inc. Whitehouse Station, New Jersey 08889 USA

    Manufactured by:

    Merck Sharp & Dohme (Italia) S.p.A.

    Via Emilia, 21

    27100 - Pavia, Italy

    Printed in USA

    9762701

    US Patent No.: 6,699,871

    17.3 FDA-Approved Patient Labeling

    (1)Trademark of MERCK & CO., Inc., Whitehouse Station, New Jersey
08889 USA

    COPYRIGHT (C) 2006 MERCK & CO., Inc.

    All rights reserved
                                                               9762701
                          Patient Information
                     JANUVIA(TM) (jah-NEW-vee-ah)
                             (sitagliptin)

                                Tablets

    Read the Patient Information that comes with JANUVIA(*) 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 JANUVIA?

    JANUVIA is a prescription medicine used along with diet and
exercise to lower blood sugar in patients with type 2 diabetes
mellitus (type 2 diabetes). JANUVIA may be taken alone or along with
certain other medicines to control blood sugar.

    --  JANUVIA lowers blood sugar when blood sugar is high,
        especially after a meal. JANUVIA also lowers blood sugar
        between meals.

    --  JANUVIA helps to improve the levels of insulin produced by
        your own body after a meal.

    --  JANUVIA decreases the amount of sugar made by the body.
        JANUVIA is unlikely to cause your blood sugar to be lowered to
        a dangerous level (hypoglycemia) because it does not work when
        your blood sugar is low.

    JANUVIA has not been studied in children under 18 years of age.

    JANUVIA has not been studied with medicines known to cause low
blood sugar, such as sulfonylureas or insulin. Ask your doctor if you
are taking a sulfonylurea or other medicine that can cause low blood
sugar.

    Who should not take JANUVIA?

    JANUVIA should not be used to treat patients with:

    --  Type 1 diabetes mellitus

    --  Diabetic ketoacidosis (increased ketones in the blood or
        urine).

    What should I tell my doctor before and during treatment with
JANUVIA? Tell your doctor about all of your medical conditions,
including if you:

    --  have any allergies

    --  have kidney problems

    --  are pregnant or plan to become pregnant, because JANUVIA may
        not be right for you. It is not known if JANUVIA 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 JANUVIA during pregnancy, talk with your
        doctor about how you can be on the JANUVIA registry. The
        toll-free telephone number for the pregnancy registry is:
        1-800-986-8999.

    --  are breast-feeding or plan to breast-feed. JANUVIA may be
        passed in your milk to your baby. Talk with your doctor about
        the best way to feed your baby if you are taking JANUVIA.

    Tell your doctor about all the medicines you take, including
prescription and non-prescription medicines, vitamins, and herbal
supplements.

    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.

    During periods of stress on the body, such as fever, trauma,
infection or surgery, your medication needs may change; contact your
doctor right away.

    How should I take JANUVIA?

    -- Take JANUVIA exactly as your doctor tells you to take it.

    -- Take JANUVIA by mouth once a day.

    -- Take JANUVIA with or without food.

    --  If you have kidney problems, your doctor may prescribe lower
        doses of JANUVIA. Your doctor may perform blood tests on you
        from time to time to measure how well your kidneys are
        working.

    --  Your doctor may prescribe JANUVIA along with certain other
        medicines that lower blood sugar.

    If you miss a dose, take it 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 a double dose of
JANUVIA.

    If you take too much JANUVIA, call your doctor or local Poison
Control Center right away.

    What else should I know about blood sugar control?

    -- Monitor your blood sugar as your doctor tells you to.

    --  Stay on your prescribed diet and exercise program while taking
        JANUVIA.

    --  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.

    What are the possible side effects of JANUVIA? The most common
    side effects of JANUVIA include:

    --  Upper respiratory infection

    --  Stuffy or runny nose and sore throat

    --  Headache

    JANUVIA may occasionally cause stomach discomfort and diarrhea.

    Tell your doctor if you have any side effect that bothers you or
that does not go away. Other side effects may occur when using
JANUVIA. For more information, ask your doctor or pharmacist.

    How should I store JANUVIA?

    --  Store JANUVIA at room temperature, 68 to 77 degrees F (20 to
        25 degrees C).

    Keep JANUVIA and all medicines out of the reach of children.

    General information about the use of JANUVIA

    Medicines are sometimes prescribed for conditions that are not
mentioned in patient information leaflets. Do not use JANUVIA for a
condition for which it was not prescribed. Do not give JANUVIA to
other people, even if they have the same symptoms you have. It may
harm them.

    This leaflet summarizes the most important information about
JANUVIA. If you would like to know more information, talk with your
doctor. You can ask your doctor or pharmacist for additional
information about JANUVIA that is written for health professionals.
For more information go to www.JANUVIA.com OR CALL 1-800-622-4477.

    What are the ingredients in JANUVIA?

    Active ingredient: sitagliptin

    Inactive ingredients: microcrystalline cellulose, anhydrous
dibasic calcium phosphate, croscarmellose sodium, magnesium stearate,
and sodium stearyl fumarate. The tablet film coating contains the
following inactive ingredients: polyvinyl alcohol, polyethylene
glycol, talc, titanium dioxide, red iron oxide, and yellow iron oxide.

    What is type 2 diabetes?

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

    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 disease, kidney
disease, blindness, and amputation.

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

    Issued October 2006

    Manufactured by:
    MERCK & CO., Inc.,
    Whitehouse Station, New Jersey, 08889

    Manufactured by:
    Merck Sharp & Dohme (Italia) S.p.A.
    Via Emilia, 21
    27100 - Pavia, Italy
    9762701

    (*) Trademark of MERCK & CO., Inc., Whitehouse Station, New
Jersey, 08889

    USA COPYRIGHT(c)2006 MERCK & CO., Inc.

    All rights reserved
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 [phone].

    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