FDA Approves Supplemental New Drug Applications for JANUVIA(TM) (sitagliptin).

WHITEHOUSE STATION, N.J. -- Merck & Co., Inc. today announced that the U.S. Food and Drug Administration (FDA) has approved expanded labeling for JANUVIA[TM] (sitagliptin), the only DPP-4 inhibitor available in the United States for the treatment of type 2 diabetes. JANUVIA is indicated, as an adjunct to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes. JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. JANUVIA has not been studied in combination with insulin. The new regimens with JANUVIA described in the updated labeling include, as an adjunct to diet and exercise, initial therapy in combination with metformin; add-on therapy to a sulfonylurea (glimepiride) when the single agent alone does not provide adequate glycemic control; and, add-on therapy to the combination of a sulfonylurea (glimepiride) and metformin when dual therapy does not provide adequate glycemic control.

New data contained in three studies support the efficacy and safety of JANUVIA. Initial therapy with the combination of JANUVIA and metformin provided substantial A1C reductions. JANUVIA demonstrated similar efficacy to a sulfonylurea (glipizide) in patients inadequately controlled on metformin. JANUVIA also provided significant placebo-adjusted A1C reductions in patients being treated with a sulfonylurea (glimepiride), with or without metformin.

The expanded labeling for JANUVIA was also updated, within Warnings and Precautions, to include post-marketing reports of hypersensitivity reactions in patients treated with JANUVIA. These reactions include anaphylaxis, angioedema and exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The expanded labeling also includes a contraindication for patients with history of a serious hypersensitivity reaction to sitagliptin, including anaphylaxis and angioedema.

Since its initial approval in October 2006, over two million prescriptions have been written for JANUVIA. In controlled clinical studies as both monotherapy and combination therapy with metformin or pioglitazone, the overall incidence of adverse reactions, hypoglycemia, and discontinuation of therapy due to clinical adverse reactions with JANUVIA were similar to placebo. In these clinical studies, the most common adverse reactions 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. In clinical trials in combination with a sulfonylurea (glimepiride), with or without metformin, JANUVIA demonstrated an overall incidence of adverse reactions higher than that seen with placebo, in part related to a higher incidence of hypoglycemia.

Initial therapy with the combination of JANUVIA and metformin provides significantly greater A1C reductions with a similar GI tolerability profile compared to metformin alone

JANUVIA as initial therapy in combination with metformin is supported by a randomized, double-blind, placebo-controlled factorial study in 1,091 patients with type 2 diabetes who experienced inadequate glycemic control with diet and exercise alone. In this study, the mean reduction of A1C relative to placebo at 24 weeks was 2.1 percent with initial therapy combining JANUVIA 100 mg daily and metformin 2000 mg daily1 (n=178) from a mean baseline A1C of 8.8 percent (p <0.001). The mean placebo-adjusted A1C reductions in the other arms of the study were 1.6 percent with JANUVIA 100 mg daily and metformin 1000 mg daily2 (n=183); 1.3 percent with metformin 2000 mg daily3 (n=177); 1.0 percent with metformin 1000 mg4 daily (n=178); and 0.8 percent with JANUVIA (n=175), (p<0.001 for all treatment groups versus placebo).

At 24 weeks, 66 percent of patients treated with the initial combination of JANUVIA 100 mg daily and metformin 2000 mg daily achieved the American Diabetes Association's (ADA) goal A1C level of <7 percent vs. 38 percent of patients treated with metformin 2000 mg daily alone. In the other arms of the study, 43 percent of patients treated with JANUVIA 100 mg daily and metformin 1000 mg daily, 23 percent of patients treated with metformin 1000 mg daily, and 20 percent of patients treated with JANUVIA achieved the ADA goal A1C level of <7 percent.

This study also included an open label cohort of an additional 117 patients with severely elevated baseline A1C (mean: 11.2 percent). These patients experienced a significant mean A1C reduction from baseline of 2.9 percent at 24 weeks with initial therapy combining JANUVIA 100 mg daily and metformin 2000 mg daily.

This study also compared the efficacy of JANUVIA to two common doses of metformin in a subset of patients not on any anti-hyperglycemic agent at study entry. In this patient population, patients treated with JANUVIA experienced a mean A1C reduction from baseline of 1.1 percent compared to 1.1 percent in patients treated with metformin 1000 mg daily and 1.2 percent in patients treated with metformin 2000 mg daily.

"The substantial A1C reductions that are seen when JANUVIA is used in combination with metformin as first-line therapy in patients with type 2 diabetes are meaningful to me as a clinician. The data show that this approach helped many patients achieve their A1C goal and the rate of gastrointestinal side effects was similar to that seen with metformin alone," said Barry J. Goldstein, M.D., Ph.D., professor of medicine, Biochemistry and Molecular Pharmacology; director, Division of Endocrinology, Diabetes and Metabolic Diseases, Jefferson Medical College, Philadelphia, PA.

Initial combination therapy or maintenance of combination therapy may not be appropriate for all patients. These management options are left to the discretion of the physician.

In the factorial study, initial therapy with JANUVIA and metformin was not associated with an increased risk of gastrointestinal adverse reactions beyond those commonly seen with metformin alone. In a pooled analysis of four other placebo-controlled clinical studies with JANUVIA, not including initial therapy with JANUVIA and metformin, the incidence of selected gastrointestinal adverse reactions in patients treated with JANUVIA was abdominal pain (2.3 percent JANUVIA; 2.1 percent placebo); nausea (1.4 percent JANUVIA; 0.6 percent placebo); and diarrhea (3.0 percent JANUVIA; 2.3 percent placebo).

The incidence of hypoglycemia was similar across treatment groups (0.6 percent in patients on placebo, 0.6 percent in patients given JANUVIA alone, 0.8 percent in patients given metformin alone, and 1.6 percent in patients given JANUVIA in combination with metformin). The most common adverse reactions reported with JANUVIA and metformin as initial therapy (greater than or equal to 5 percent) compared to metformin alone were upper respiratory infection (6.2 percent vs. 5.2 percent) and headache (5.9 percent vs. 3.8 percent).

JANUVIA demonstrated similar efficacy compared to a sulfonylurea (glipizide) with significantly less hypoglycemia, and patients treated with JANUVIA experienced mean weight loss from baseline of 1.5 kg

The efficacy of JANUVIA was also evaluated in a 52-week, double-blind, glipizide-controlled noninferiority trial predominantly in patients with mildly to moderately elevated A1C levels (mean baseline A1C 7.5 percent). Patients were treated with either JANUVIA 100 mg daily or glipizide up to 20 mg daily (mean daily dose 10 mg daily). This study showed that JANUVIA achieved the pre-specified bounds for noninferiority vs. a sulfonylurea (glipizide). After one year, the mean A1C reduction from baseline was 0.5 percent for JANUVIA and 0.6 percent for glipizide in the intent-to-treat patient population5 and 0.7 percent for JANUVIA and 0.7 percent for glipizide in the per protocol analysis6, confirming the similar efficacy of JANUVIA compared to glipizide.

Patients treated with JANUVIA experienced significant weight loss (mean -1.5 kg) from baseline at 52 weeks, while patients treated with glipizide experienced significant weight gain (mean +1.1 kg) from baseline at 52 weeks. Additionally, patients treated with JANUVIA experienced a lower incidence of hypoglycemia than patients treated with glipizide (4.9 percent vs. 32.0 percent, respectively, p <0.001). The noninferiority of JANUVIA to glipizide may be limited to patients with A1C levels comparable to those included in this study (over 70 percent of patients had a baseline A1C <8 percent and over 90 percent had a baseline A1C <9 percent).

JANUVIA provides significant additional A1C reductions, even in patients on triple therapy

The new regimens for adding JANUVIA to a sulfonylurea (glimepiride) with or without metformin are supported by a 24-week, randomized, double-blind, placebo-controlled study examining the efficacy and safety of JANUVIA in 441 patients with type 2 diabetes and inadequate glycemic control (A1C 7.5 percent to 10.5 percent) on a sulfonylurea (glimepiride) and metformin or on a sulfonylurea (glimepiride) alone. In this study, JANUVIA demonstrated a significant mean difference from placebo in A1C of -0.9 percent when added to patients on glimepiride and metformin and -0.6 percent when added to patients on glimepiride alone (p <0.001 for both comparisons versus placebo).

In this study, the overall incidence of clinical adverse reactions with JANUVIA was higher than that seen with placebo, in part related to a higher incidence of hypoglycemia with JANUVIA compared to placebo (12.2 percent vs. 1.8 percent, respectively). The higher rate of hypoglycemia is commonly seen when antihyperglycemic agents are used in combination with sulfonylurea agents. After 24 weeks, patients treated with JANUVIA had a mean increase in body weight of 1.1 kg versus placebo (+0.8 kg vs. -0.4 kg).

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

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.

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

Expanding clinical development program for sitagliptin family

Merck's clinical development program for sitagliptin is robust and continues to expand with 49 studies completed or underway. Five additional studies are set to begin this year. It is estimated that there have been more than 9,400 patients in the Company's clinical studies, with about 6,000 of these patients being treated with sitagliptin. Additionally, about 2,300 patients have been treated with sitagliptin for more than a year and, of these, approximately 400 patients have been treated for at least two years.

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.

JANUVIA[TM] is a trademark of Merck & Co., Inc.

Prescribing information and patient product information for JANUVIA are attached.

1 JANUVIA 100 mg daily and metformin 2000 mg daily was dosed as JANUVIA 50 mg/metformin 1000 mg twice daily as separate tablets.

2 JANUVIA 100 mg daily and metformin 1000 mg daily was dosed as JANUVIA 50 mg/metformin 500 mg twice daily as separate tablets.

3 Metformin 2000 mg daily was dosed as metformin 1000 mg twice daily.

4 Metformin 1000 mg daily was dosed as metformin 500 mg twice daily.

5 The intent-to-treat analysis used the patients' last observation in the study prior to discontinuation.

6 The per protocol analysis generally included patients who had observations at baseline and at Week 52.

JANUVIA(TM)(sitagliptin)Tablets                                9762703

    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

    RECENT MAJOR CHANGES



Indications and Usage
  Monotherapy and Combination Therapy (1.1)                    10/2007
  Important Limitations of Use (1.2)                           10/2007
Dosage and Administration
  Recommended Dosing (2.1)                                     10/2007
  Concomitant Use with a Sulfonylurea (2.3)                    10/2007
Contraindications (4)                                          10/2007
Warnings and Precautions
  Use with Medications Known to Cause Hypoglycemia (5.2)       10/2007
  Hypersensitivity Reactions (5.3)                             10/2007


    INDICATIONS AND USAGE

    JANUVIA is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as
an adjunct to diet and exercise to improve glycemic control in adults
with type 2 diabetes mellitus. (1.1)

    Important Limitations of Use:

    --  JANUVIA should not be used in patients with type 1 diabetes or
        for the treatment of diabetic ketoacidosis. (1.2)

    --  JANUVIA has not been studied in combination with insulin.
        (1.2)

    DOSAGE AND ADMINISTRATION

    The recommended dose of JANUVIA is 100 mg once daily. JANUVIA can
be taken with or without food. (2.1)

    Dosage adjustment is recommended for patients with moderate or
severe renal insufficiency or end-stage renal disease. (2.2)



  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         CrCl less than 30 mL/min
     30 to less than 50 mL/min

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

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

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


    DOSAGE FORMS AND STRENGTHS

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

    CONTRAINDICATIONS

    History of a serious hypersensitivity reaction to sitagliptin,
such as anaphylaxis or angioedema (5.3, 6.2)

    WARNINGS AND PRECAUTIONS

    --  Dosage adjustment is recommended in patients with moderate or
        severe renal insufficiency and in patients with ESRD.
        Assessment of renal function is recommended prior to
        initiating JANUVIA and periodically thereafter. (2.2, 5.1)

    --  When used with a sulfonylurea, a lower dose of sulfonylurea
        may be required to reduce the risk of hypoglycemia. (2.3, 5.2)

    --  There have been postmarketing reports of serious allergic and
        hypersensitivity reactions in patients treated with JANUVIA
        such as anaphylaxis, angioedema, and exfoliative skin
        conditions including Stevens-Johnson syndrome. In such cases,
        promptly stop JANUVIA, assess for other potential causes,
        institute appropriate monitoring and treatment, and initiate
        alternative treatment for diabetes. (5.3, 6.2)

    ADVERSE REACTIONS

    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. Hypoglycemia was also reported more
commonly in patients treated with the combination of JANUVIA and
sulfonylurea, with or without metformin, than in patients given the
combination of placebo and sulfonylurea, with or without metformin.
(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)

    --  There are no adequate and well-controlled studies in pregnant
        women. To report drug exposure during pregnancy call
        1-800-986-8999. (8.1)

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

    Revised: 10/2007

    FULL PRESCRIBING INFORMATION: CONTENTS*

    1 INDICATIONS AND USAGE

    1.1 Monotherapy and Combination Therapy

    1.2 Important Limitations of Use

    2 DOSAGE AND ADMINISTRATION

    2.1 Recommended Dosing

    2.2 Patients with Renal Insufficiency

    2.3 Concomitant Use with a Sulfonylurea

    3 DOSAGE FORMS AND STRENGTHS

    4 CONTRAINDICATIONS

    5 WARNINGS AND PRECAUTIONS

    5.1 Use in Patients with Renal Insufficiency

    5.2 Use with Medications Known to Cause Hypoglycemia

    5.3 Hypersensitivity Reactions

    6 ADVERSE REACTIONS

    6.1 Clinical Trials Experience

    6.2 Postmarketing 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

    *Sections or subsections omitted from the full prescribing
information are not listed.

    FULL PRESCRIBING INFORMATION

    1 INDICATIONS AND USAGE

    1.1 Monotherapy and Combination Therapy

    JANUVIA(1) is indicated as an adjunct to diet and exercise to
improve glycemic control in adults with type 2 diabetes mellitus. (See
Clinical Studies (14).)

    1.2 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.

    JANUVIA has not been studied in combination with insulin.

    2 DOSAGE AND ADMINISTRATION

    2.1 Recommended Dosing

    The recommended dose of JANUVIA is 100 mg once daily. 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
or equal to 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).)

    2.3 Concomitant Use with a Sulfonylurea

    When JANUVIA is used in combination with a sulfonylurea, a lower
dose of sulfonylurea may be required to reduce the risk of
hypoglycemia. (See Warnings and Precautions (5.2).)

    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

    History of a serious hypersensitivity reaction to sitagliptin,
such as anaphylaxis or angioedema. (See Warnings and Precautions (5.3)
and Adverse Reactions (6.2).)

    5 WARNINGS AND PRECAUTIONS

    5.1 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).)

    5.2 Use with Medications Known to Cause Hypoglycemia

    As is typical with other antihyperglycemic agents used in
combination with a sulfonylurea, when JANUVIA was used in combination
with a sulfonylurea, a class of medications known to cause
hypoglycemia, the incidence of hypoglycemia was increased over that of
placebo. (See Adverse Reactions (6.1).) Therefore, a lower dose of
sulfonylurea may be required to reduce the risk of hypoglycemia. (See
Dosage and Administration (2.3).)

    5.3 Hypersensitivity Reactions

    There have been postmarketing reports of serious hypersensitivity
reactions in patients treated with JANUVIA. These reactions include
anaphylaxis, angioedema, and exfoliative skin conditions including
Stevens-Johnson syndrome. Because these reactions are reported
voluntarily from a population of uncertain size, it is generally not
possible to reliably estimate their frequency or establish a causal
relationship to drug exposure. Onset of these reactions occurred
within the first 3 months after initiation of treatment with JANUVIA,
with some reports occurring after the first dose. If a
hypersensitivity reaction is suspected, discontinue JANUVIA, assess
for other potential causes for the event, and institute alternative
treatment for diabetes. (See Adverse Reactions (6.2).)

    6 ADVERSE REACTIONS

    6.1 Clinical Trials Experience

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

    In controlled clinical studies as both monotherapy and combination
therapy with metformin or pioglitazone, the overall incidence of
adverse reactions, hypoglycemia, and discontinuation of therapy due to
clinical adverse reactions with JANUVIA were similar to placebo. In
combination with glimepiride, with or without metformin, the overall
incidence of clinical adverse reactions with JANUVIA was higher than
with placebo, in part related to a higher incidence of hypoglycemia
(see Table 1); the incidence of discontinuation due to clinical
adverse reactions was 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. Three 24-week, placebo-controlled
add-on combination therapy studies, one with metformin, one with
pioglitazone, and one with glimepiride with or without metformin, were
also conducted. In addition to a stable dose of metformin,
pioglitazone, glimepiride, or glimepiride and metformin, 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, JANUVIA in
combination with pioglitazone, or JANUVIA in combination with
glimepiride, with or without metformin, and more commonly than in
patients treated with placebo, are shown in Table 1.



                               Table 1

Placebo-Controlled Clinical Studies of JANUVIA Monotherapy or Add-on
 Combination Therapy with Pioglitazone or Glimepiride +/- Metformin:
 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)
----------------------------------------------------------------------
Combination with Glimepiride           JANUVIA 100 mg      Placebo
(+/- Metformin)                        + Glimepiride    + Glimepiride
                                      (+/- Metformin)  (+/- Metformin)
----------------------------------------------------------------------
                                          N = 222          N = 219
----------------------------------------------------------------------
  Hypoglycemia                           27 (12.2)         4 (1.8)
----------------------------------------------------------------------
  Nasopharyngitis                         14 (6.3)        10 (4.6)
----------------------------------------------------------------------
  Headache                                13 (5.9)         5 (2.3)
----------------------------------------------------------------------


    + Intent to treat population

    In the study of patients receiving JANUVIA as add-on combination
therapy 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.

    In the prespecified pooled analysis of the two monotherapy
studies, the add-on to metformin study, and the add-on to pioglitazone
study, the overall incidence of adverse reactions of hypoglycemia in
patients treated with JANUVIA 100 mg was similar to placebo (1.2% vs
0.9%). 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 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%).

    In an additional, 24-week, placebo-controlled factorial study of
initial therapy with sitagliptin in combination with metformin, the
adverse reactions reported (regardless of investigator assessment of
causality) in greater than or equal to 5% of patients are shown in
Table 2. The incidence of hypoglycemia was 0.6% in patients given
placebo, 0.6% in patients given sitagliptin alone, 0.8% in patients
given metformin alone, and 1.6% in patients given sitagliptin in
combination with metformin.



                               Table 2
    Initial Therapy with Combination of Sitagliptin and Metformin:
Adverse Reactions Reported (Regardless of Investigator Assessment of
   Causality) in greater than or equal to 5% of Patients Receiving
 Combination Therapy (and Greater than in Patients Receiving Metformin
                alone, Sitagliptin alone, and Placebo)+
----------------------------------------------------------------------
                                      Number of Patients (%)
----------------------------------------------------------------------
                                                 Metformin Sitagliptin
                                     Sitagliptin  500 or   50 mg bid +
                             Placebo  (JANUVIA)   1000 mg   Metformin
                                      100 mg QD    bid ++  500 or 1000
                                                            mg bid ++
----------------------------------------------------------------------
                             N = 176   N = 179   N = 364++  N = 372++
----------------------------------------------------------------------
Upper Respiratory Infection  9 (5.1)     8 (4.5)  19 (5.2)    23 (6.2)
----------------------------------------------------------------------
Headache                     5 (2.8)     2 (1.1)  14 (3.8)    22 (5.9)
----------------------------------------------------------------------


    + Intent-to-treat population.

    ++ Data pooled for the patients given the lower and higher doses
of metformin.

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

    Laboratory Tests

    Across clinical studies, the incidence of laboratory adverse
reactions was similar in patients treated with JANUVIA 100 mg compared
to patients treated with placebo. A small increase in white blood cell
count (WBC) was observed due to an increase in neutrophils. This
increase in WBC (of approximately 200 cells/microL vs placebo, in four
pooled placebo-controlled clinical studies, with a mean baseline WBC
count of approximately 6600 cells/microL) 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.

    6.2 Postmarketing Experience

    The following additional adverse reactions have been identified
during postapproval use of JANUVIA. Because these reactions are
reported voluntarily from a population of uncertain size, it is
generally not possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.

    Hypersensitivity reactions include anaphylaxis, angioedema, rash,
urticaria, and exfoliative skin conditions including Stevens-Johnson
syndrome. (See Warnings and Precautions (5.3).)

    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 under 18
years of age have not been established.

    8.5 Geriatric Use

    Of the total number of subjects (N=3884) in pre-approval 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 Phase I multiple-dose studies,
there were no dose-related clinical adverse reactions observed with
JANUVIA with doses of up to 600 mg per day for periods of up to 10
days and 400 mg per day for 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
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 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.

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

    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 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 how these findings
relate to changes in glycemic control in patients with type 2
diabetes.

    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 times 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 (mu)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 than 9).

    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.

    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

    JANUVIA has been studied as monotherapy and in combination with
metformin, pioglitazone, glimepiride, and glimepiride+metformin.

    There were approximately 3800 patients with type 2 diabetes
randomized in six double-blind, placebo-controlled clinical safety and
efficacy studies conducted to evaluate the effects of sitagliptin on
glycemic control. The ethnic/racial distribution in these studies was
approximately 60% white, 20% Hispanic, 8% Asian, 6% black, and 6%
other groups. Patients had an overall mean age of approximately 55
years (range 18 to 87 years). In addition, an active
(glipizide)-controlled study of 52-weeks duration was conducted in
1172 patients with type 2 diabetes who had inadequate glycemic control
on metformin.

    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 washout period of about 7 weeks. Patients with
inadequate glycemic control (A1C 7% to 10%) after the washout 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
3). 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
compared to placebo was not affected by gender, age, race, prior
antihyperglycemic therapy, or baseline BMI. As is typical for trials
of agents to treat type 2 diabetes, the mean reduction in A1C with
JANUVIA appears to be related to the degree of A1C elevation at
baseline. In these 18- and 24-week studies, among patients who were
not on an antihyperglycemic agent at study entry, the reductions from
baseline in A1C were -0.7% and -0.8%, respectively, for those given
JANUVIA, and -0.1% and -0.2%, respectively, for those given placebo.
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 3
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 100 mg Placebo  JANUVIA 100 mg Placebo
----------------------------------------------------------------------
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, -0.4)            (-1.0, -0.6)
----------------------------------------------------------------------
  Patients (%)
   achieving A1C less
   than 7%                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, -9)               (-24, -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 than 0.001 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

    Add-on 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 with inadequate glycemic
control (A1C 7% to 10%) 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 4). 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 4
          Glycemic Parameters at Final Visit (24-Week Study)
      for JANUVIA in Add-on Combination Therapy with Metformin+
----------------------------------------------------------------------
                                            JANUVIA 100 mg + 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           -0.7ss.
   (adjusted mean++) (95% CI)                 (-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            -25ss.
   (adjusted 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            -51ss.
   (adjusted 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. p less than 0.001 compared to placebo + metformin.

    Initial Combination Therapy with Metformin

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

    Initial therapy with the combination of JANUVIA and metformin
provided significant improvements in A1C, FPG, and 2-hour PPG compared
to placebo, to metformin alone, and to JANUVIA alone (Table 5, Figure
1). Mean reductions from baseline in A1C were generally greater for
patients with higher baseline A1C values. For patients not on an
antihyperglycemic agent at study entry, mean reductions from baseline
in A1C were: JANUVIA 100 mg once daily, -1.1%; metformin 500 mg bid,
-1.1%; metformin 1000 mg bid, -1.2%; sitagliptin 50 mg bid with
metformin 500 mg bid, -1.6%; sitagliptin 50 mg bid with metformin
1000 mg bid, -1.9%; and for patients receiving placebo, -0.2%. Lipid
effects were generally neutral. The decrease in body weight in the
groups given sitagliptin in combination with metformin was similar to
that in the groups given metformin alone or placebo.



                               Table 5
Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin and
        Metformin, Alone and in Combination as Initial Therapy+
----------------------------------------------------------------------

                                             Sitagliptin   Metformin
                                     Placebo  (JANUVIA)    500 mg bid
                                              100 mg QD
----------------------------------------------------------------------
A1C (%)                              N = 165   N = 175      N = 178
----------------------------------------------------------------------
  Baseline (mean)                      8.7       8.9          8.9
----------------------------------------------------------------------
  Change from baseline (adjusted
   mean++)                             0.2       -0.7         -0.8
----------------------------------------------------------------------
  Difference from placebo (adjusted            -0.8ss.      -1.0ss.
   mean++) (95% CI)                          (-1.1, -0.6) (-1.2, -0.8)
----------------------------------------------------------------------
  Patients (%) achieving A1C less
   than 7%                           15 (9%)   35 (20%)     41 (23%)
----------------------------------------------------------------------
  % Patients receiving rescue
   medication                          32         21           17
----------------------------------------------------------------------
FPG (mg/dL)                          N = 169   N = 178      N = 179
----------------------------------------------------------------------
  Baseline (mean)                      196       201          205
----------------------------------------------------------------------
  Change from baseline (adjusted
   mean++)                              6        -17          -27
----------------------------------------------------------------------
  Difference from placebo (adjusted             -23ss.       -33ss.
   mean++) (95% CI)                           (-33, -14)   (-43, -24)
----------------------------------------------------------------------
2-hour PPG (mg/dL)                   N = 129   N = 136      N = 141
----------------------------------------------------------------------
Baseline (mean)                        277       285          293
----------------------------------------------------------------------
  Change from baseline (adjusted
   mean++)                              0        -52          -53
----------------------------------------------------------------------
  Difference from placebo (adjusted             -52ss.       -54ss.
   mean++) (95% CI)                           (-67, -37)   (-69, -39)
----------------------------------------------------------------------

                                             Sitagliptin  Sitagliptin
                                 Metformin   50 mg bid +  50 mg bid +
                                1000 mg bid   Metformin    Metformin
                                              500 mg bid  1000 mg bid
----------------------------------------------------------------------
A1C (%)                           N = 177      N = 183      N = 178
----------------------------------------------------------------------
  Baseline (mean)                   8.7          8.8          8.8
----------------------------------------------------------------------
  Change from baseline
   (adjusted mean++)                -1.1         -1.4         -1.9
----------------------------------------------------------------------
  Difference from placebo         -1.3ss.      -1.6ss.      -2.1ss.
   (adjusted mean++) (95% CI)   (-1.5, -1.1) (-1.8, -1.3) (-2.3, -1.8)
----------------------------------------------------------------------
  Patients (%) achieving A1C
   less than 7%                   68 (38%)     79 (43%)    118 (66%)
----------------------------------------------------------------------
  % Patients receiving rescue
   medication                        12           8            2
----------------------------------------------------------------------
FPG (mg/dL)                       N = 179      N = 183      N = 180
----------------------------------------------------------------------
  Baseline (mean)                   197          204          197
----------------------------------------------------------------------
  Change from baseline
   (adjusted mean++)                -29          -47          -64
----------------------------------------------------------------------
  Difference from placebo          -35ss.       -53ss.       -70ss.
   (adjusted mean++) (95% CI)    (-45, -26)   (-62, -43)   (-79, -60)
----------------------------------------------------------------------
2-hour PPG (mg/dL)                N = 138      N = 147      N = 152
----------------------------------------------------------------------
Baseline (mean)                     283          292          287
----------------------------------------------------------------------
  Change from baseline
   (adjusted mean++)                -78          -93          -117
----------------------------------------------------------------------
  Difference from placebo          -78ss.       -93ss.      -117ss.
   (adjusted mean++) (95% CI)    (-93, -63)  (-107, -78)  (-131, -102)
----------------------------------------------------------------------


    + Intent to Treat Population using last observation on study prior
to glyburide (glibenclamide) rescue therapy.

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

    ss. pless than 0.001 compared to placebo.

  Figure 1: Mean Change from Baseline for A1C (%) over 24 Weeks with
Sitagliptin and Metformin, Alone and in Combination as Initial Therapy
                   in Patients with Type 2 Diabetes+

    (OBJECT OMITTED)

    +All Patients Treated Population Least squares means adjusted for
prior antihyperglycemic therapy and baseline value.

    In addition, this study included patients (N=117) with more severe
hyperglycemia (A1C greater than 11% or blood glucose greater than
280 mg/dL) who were treated with twice daily open-label JANUVIA 50 mg
and metformin 1000 mg. In this group of patients, the mean baseline
A1C value was 11.2%, mean FPG was 314 mg/dL, and mean 2-hour PPG was
441 mg/dL. After 24 weeks, mean decreases from baseline of -2.9% for
A1C, -127 mg/dL for FPG, and -208 mg/dL for 2-hour PPG were observed.

    Initial combination therapy or maintenance of combination therapy
may not be appropriate for all patients. These management options are
left to the discretion of the health care provider.

    Active-Controlled Study vs Glipizide in Combination with Metformin

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

    After 52 weeks, JANUVIA and glipizide had similar mean reductions
from baseline in A1C in the intent-to-treat analysis (Table 6). These
results were consistent with the per protocol analysis (Figure 2). A
conclusion in favor of the non-inferiority of JANUVIA to glipizide may
be limited to patients with baseline A1C comparable to those included
in the study (over 70% of patients had baseline A1C less than 8% and
over 90% had A1C less than 9%).



                               Table 6
           Glycemic Parameters in a 52-Week Study Comparing
   JANUVIA to Glipizide as Add-On Therapy in Patients Inadequately
                       Controlled on Metformin
                    (Intent-to-Treat Population)+
----------------------------------------------------------------------
                                              JANUVIA 100 mg Glipizide
----------------------------------------------------------------------
A1C (%)                                          N = 576      N = 559
----------------------------------------------------------------------
  Baseline (mean)                                  7.7          7.6
----------------------------------------------------------------------
  Change from baseline (adjusted mean++)           -0.5        -0.6
----------------------------------------------------------------------
FPG (mg/dL)                                      N = 583      N = 568
----------------------------------------------------------------------
  Baseline (mean)                                  166          164
----------------------------------------------------------------------
  Change from baseline (adjusted mean++)            -8          -8
----------------------------------------------------------------------


    + The Intent to Treat Analysis used the patients' last observation
in the study prior to discontinuation.

    ++ Least squares means adjusted for prior antihyperglycemic
therapy status and baseline A1C value.

  Figure 2: Mean Change from Baseline for A1C (%) Over 52 Weeks in a
  Study Comparing JANUVIA to Glipizide as Add-On Therapy in Patients
    Inadequately Controlled on Metformin (Per Protocol Population)+

    (OBJECT OMITTED)

    + The per protocol population (mean baseline A1C of 7.5%) included
patients without major protocol violations who had observations at
baseline and at Week 52.

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

    Add-on 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 with inadequate glycemic control (A1C 7% to 10%) 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 were A1C and fasting glucose.

    In combination with pioglitazone, JANUVIA provided significant
improvements in A1C and FPG compared to placebo with pioglitazone
(Table 7). 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 7
          Glycemic Parameters at Final Visit (24-Week Study)
     for JANUVIA in Add-on Combination Therapy with Pioglitazone+
----------------------------------------------------------------------
                                         JANUVIA 100 mg +  Placebo +
                                           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 than
   7%                                        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. p less than 0.001 compared to placebo + pioglitazone.

    Add-on Combination Therapy with Glimepiride, with or without
Metformin

    A total of 441 patients with type 2 diabetes participated in a
24-week, randomized, double-blind, placebo-controlled study designed
to assess the efficacy of JANUVIA in combination with glimepiride,
with or without metformin. Patients entered a run-in treatment period
on glimepiride (greater than or equal to 4 mg per day) alone or
glimepiride in combination with metformin (greater than or equal to
1500 mg per day). After a dose-titration and dose-stable run-in period
of up to 16 weeks and a 2-week placebo run-in period, patients with
inadequate glycemic control (A1C 7.5% to 10.5%) were randomized to the
addition of either 100 mg of 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 glimepiride, with or without metformin,
JANUVIA provided significant improvements in A1C and FPG compared to
placebo (Table 8). In the entire study population (patients on JANUVIA
in combination with glimepiride and patients on JANUVIA in combination
with glimepiride and metformin), a mean reduction from baseline
relative to placebo in A1C of -0.7% and in FPG of -20 mg/dL was seen.
Rescue therapy was used in 12% of patients treated with JANUVIA 100 mg
and 27% of patients treated with placebo. In this study, patients
treated with JANUVIA had a mean increase in body weight of 1.1 kg vs.
placebo (+0.8 kg vs. -0.4 kg). In addition, there was an increased
rate of hypoglycemia. (See Warnings and Precautions (5.2); Adverse
Reactions (6.1).)



                               Table 8
  Glycemic Parameters at Final Visit (24-Week Study) for JANUVIA in
       Combination with Glimepiride, with or without Metformin+
----------------------------------------------------------------------
               JANUVIA 100 mg  Placebo +  JANUVIA 100 mg    Placebo
               + Glimepiride  Glimepiride + Glimepiride  + Glimepiride
                                           + Metformin    + Metformin
----------------------------------------------------------------------

----------------------------------------------------------------------
A1C (%)           N = 102       N = 103      N = 115        N = 105
----------------------------------------------------------------------
  Baseline
   (mean)           8.4           8.5          8.3            8.3
----------------------------------------------------------------------
  Change from
   baseline
   (adjusted
   mean++)          -0.3          0.3          -0.6           0.3
----------------------------------------------------------------------
  Difference
   from
   placebo
   (adjusted
   mean++)        -0.6ss.                    -0.9ss.
   (95% CI)     (-0.8, -0.3)               (-1.1, -0.7)
----------------------------------------------------------------------
  Patients (%)
   achieving
   A1C less
   than 7%        11 (11%)      9 (9%)       26 (23%)       1 (1%)
----------------------------------------------------------------------
FPG (mg/dL)       N = 104       N = 104      N = 115        N = 109
----------------------------------------------------------------------
  Baseline
   (mean)           183           185          179            179
----------------------------------------------------------------------
  Change from
   baseline
   (adjusted
   mean++)           -1           18            -8            13
----------------------------------------------------------------------
  Difference
   from
   placebo
   (adjusted
   mean++)          -19%                      -21ss.
   (95% CI)      (-32, -7)                  (-32, -10)
----------------------------------------------------------------------


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

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

    ss. p less than 0.001 compared to placebo.

    % p less than 0.01 compared to placebo.

    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 degrees C (68-77 degrees F), excursions permitted
to 15-30 degrees C (59-86 degrees F), (see USP Controlled Room
Temperature).

    17 PATIENT COUNSELING INFORMATION

    See FDA-Approved Patient Labeling.

    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.

    Patients should be informed that allergic reactions have been
reported during postmarketing use of JANUVIA. If symptoms of allergic
reactions (including rash, hives, and swelling of the face, lips,
tongue, and throat that may cause difficulty in breathing or
swallowing) occur, patients must stop taking JANUVIA and 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, NJ 08889, USA

    Manufactured by:


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

    9762703

    US Patent No.: 6,699,871

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

    COPYRIGHT (C) 2006, 2007 MERCK & CO., Inc.

    All rights reserved
                                                               9762703

                          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 adult patients with 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 insulin, a medicine known to
cause low blood sugar.

    Who should not take JANUVIA?

    Do not take JANUVIA if you:

    --  have had an allergic reaction to JANUVIA.

    JANUVIA should not be used to treat patients with:

    --  Type 1 diabetes.

    --  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 had an allergic reaction to JANUVIA.

    --  have kidney problems.

    --  are pregnant or plan to become pregnant. 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. It is not known if
        JANUVIA will pass into your breast milk. 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.

    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
        two doses of JANUVIA at the same time.

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

    --  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
        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.

    When JANUVIA is used in combination with another type of diabetes
medicine known as a sulfonylurea, low blood sugar (hypoglycemia) due
to the sulfonylurea can occur. Your doctor may prescribe lower doses
of the sulfonylurea medicine.

    The following additional side effects have been reported in
general use with JANUVIA:

    --  Allergic reactions, which may be serious, including rash,
        hives, and swelling of the face, lips, tongue, and throat that
        may cause difficulty in breathing or swallowing. If you have
        an allergic reaction, stop taking JANUVIA and call your doctor
        right away. Your doctor may prescribe a medication to treat
        your allergic reaction and a different medication for your
        diabetes.

    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.

    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 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.

    Revised October 2007

    Manufactured for:

    MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

    Manufactured by:

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

    9762703

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

    USA COPYRIGHT (C) 2006, 2007 MERCK & CO., Inc.

    All rights reserved