FDA Accepts Two Supplemental New Drug Applications to Expand the U.S. Labeling for Januvia

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Feb 15, 2007 - Merck & Co., Inc. today announced that the U.S. Food and Drug Administration (FDA) has accepted for standard review two supplemental New Drug Applications (sNDAs) for JANUVIA(TM) (sitagliptin), and the Company expects FDA action on both sNDAs by mid-October.

One sNDA is filed in support of a proposed new indication for the use of JANUVIA, as an adjunct to diet and exercise, in combination with metformin as initial therapy to improve glycemic control. The other sNDA is filed in support of two proposed new indications for use of JANUVIA, as an adjunct to diet and exercise, as add-on therapy to a sulfonylurea when the single agent alone does not provide adequate glycemic control and as add-on therapy to the combination of a sulfonylurea plus metformin when dual therapy does not provide adequate glycemic control.

JANUVIA is currently indicated for use as monotherapy and as add-on therapy to either of two other types of oral diabetes medications, metformin or thiazolidinediones (TZDs), to improve blood sugar (glucose) control in patients with type 2 diabetes when diet and exercise are not enough. The recommended dose of JANUVIA is 100 mg once daily. 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. In clinical trials, JANUVIA demonstrated an overall incidence of side effects comparable to placebo. The most common side effects reported with JANUVIA (greater than or equal to 5 percent and higher than placebo) were stuffy or runny nose and sore throat, upper respiratory infection, and headache.

"If these sNDAs are approved, the expanded labeling will include indications for use of JANUVIA as initial therapy with metformin and as add-on to any of the three most commonly prescribed classes of oral antihyperglycemic agents," said John Amatruda, M.D., vice president, clinical research, Merck & Co., Inc. "These data further support the broad utility of JANUVIA as an important treatment option for patients with type 2 diabetes."

Phase III data supporting two sNDAs

The proposed new indication of JANUVIA in combination with metformin as initial therapy is supported by a 24-week, factorial study in 1,091 randomized patients with type 2 diabetes. Results of this study were presented for the first time at the annual meeting of the European Association for the Study of Diabetes in September 2006.

The study showed a significant mean placebo-subtracted reduction in A1C(1) of 2.1 percent from a mean baseline A1C of 8.7 percent (primary analysis of all patients treated, p >0.001) in the patients treated with JANUVIA 50 mg twice daily combined with metformin 1,000 mg twice daily (n=178). In the same study, 66 percent of patients treated with JANUVIA 50 mg twice daily combined with metformin 1,000 mg twice daily achieved goal A1C levels of <7 percent compared to 38 percent of patients treated with metformin 1,000 mg twice daily alone (p <0.01). Even in those patients receiving a lower dose of metformin (JANUVIA 50 mg twice daily and metformin 500 mg twice daily, n=183), significant A1C placebo-subtracted reductions (1.6 percent, p <0.001) and greater goal attainment (43 percent vs. 23 percent with metformin 500 mg twice daily alone, p <0.01) were observed.

In the study, initial therapy of JANUVIA and metformin was generally well tolerated and showed no meaningful differences in tolerability compared to metformin alone. Side effects of JANUVIA 50 mg twice daily and metformin 1,000 mg twice daily compared to metformin 1,000 mg twice daily alone included diarrhea (9 percent vs. 10 percent, respectively), nausea (6 percent vs. 8 percent), abdominal pain/discomfort (3 percent vs. 5 percent) and vomiting (3 percent vs. 1 percent).

The proposed new indications of adding JANUVIA to a sulfonylurea or to a sulfonylurea plus metformin are supported by a 24-week study examining the efficacy and safety of JANUVIA in 441 patients with type 2 diabetes who had inadequate glycemic control on a sulfonylurea alone or a sulfonylurea plus metformin. Results from this Phase III study were submitted to a major medical meeting for presentation later this year.

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 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

JANUVIA should be used during pregnancy only if clearly needed. Caution should be exercised when JANUVIA is administered to a nursing woman. 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. The incidence of selected gastrointestinal adverse reactions in patients treated with JANUVIA was as follows: abdominal pain (JANUVIA, 2.3 percent; placebo, 2.1 percent), nausea (1.4 percent, 0.6 percent) and diarrhea (3.0 percent, 2.3 percent).

Expanding clinical trial program for JANUVIA

Merck's clinical development program for JANUVIA is robust and continues to expand with 43 studies completed or under way, and ten more studies set to begin this year. There are more than 7,600 patients in the Company's clinical studies with about 4,700 of these patients being treated with JANUVIA. Additionally, about 1,100 patients have been treated with JANUVIA for more than a year.

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck 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 cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2005, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.

JANUVIA(TM) is a registered trademark for Merck & Co., Inc.

(1) A1C is a measure of a person's average blood glucose over a two- to three-month period.

Prescribing information and patient product information for JANUVIA are attached. -0-

JANUVIA(TM)(sitagliptin phosphate) Tablets                     9762700


    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 phosphate) Tablets


    Initial U.S. Approval: 2006


    INDICATIONS AND USAGE


    JANUVIA is indicated as an adjunct to diet and exercise to improve

glycemic control in patients with type 2 diabetes mellitus (type 2

diabetes). JANUVIA is indicated for:


    --  Monotherapy (1.1)


    --  Combination therapy with metformin or a peroxisome

        proliferator-activated receptor gamma (PPAR-gamma) agonist

        (e.g., thiazolidinediones) when the single agent does not

        provide adequate glycemic control. (1.2)


    Important Limitations of Use: JANUVIA should not be used in

patients with type 1 diabetes mellitus (type 1 diabetes) or for the

treatment of diabetic ketoacidosis. (1.3)


    DOSAGE AND ADMINISTRATION


    The recommended dose of JANUVIA is 100 mg once daily as

monotherapy or as combination therapy with metformin or a PPAR-gamma

agonist (e.g., thiazolidinediones). (2.1)


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




  Dosage Adjustment in Patients With Moderate, Severe and End Stage

                      Renal Disease (ESRD) (2.2)

----------------------------------------------------------------------

           50 mg once daily                   25 mg once daily

----------------------------------------------------------------------

Moderate                                      Severe and ESRD


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

 to less than 50 mL/min


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


Men: greater than 1.7 -                    Men: greater than 3.0;

 less than or equal to 3.0;


Women: greater than 1.5 -                 Women: greater than 2.5;

 less than or equal to 2.5                   or on dialysis

----------------------------------------------------------------------



    DOSAGE FORMS AND STRENGTHS


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


    CONTRAINDICATIONS


    None. (4)


    WARNINGS AND PRECAUTIONS


    A dosage adjustment is recommended in patients with moderate renal

insufficiency and in patients with severe renal insufficiency or with

ESRD requiring hemodialysis or peritoneal dialysis. Assessment of

renal function is recommended prior to initiation of JANUVIA and

periodically thereafter. Creatinine clearance can be estimated from

serum creatinine using the Cockcroft-Gault formula. (2.2, 5)


    ADVERSE REACTIONS


    The most common adverse reactions, reported in greater than or

equal to 5% of patients treated with JANUVIA and more commonly than in

patients treated with placebo are: upper respiratory tract infection,

nasopharyngitis, and headache. (6.1)


    To report SUSPECTED ADVERSE REACTIONS, contact Merck & Co., Inc.

at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.


    USE IN SPECIFIC POPULATIONS


    Safety and effectiveness of JANUVIA in children under 18 years

have not been established. (8.4)


    See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient

labeling.


    Revised: 10/2006


    FULL PRESCRIBING INFORMATION: CONTENTS*


    1 INDICATIONS AND USAGE


    1.1 Monotherapy


    1.2 Combination Therapy


    1.3 Important Limitations of Use


    2 DOSAGE AND ADMINISTRATION


    2.1 Recommended Dosing


    2.2 Patients with Renal Insufficiency


    3 DOSAGE FORMS AND STRENGTHS


    4 CONTRAINDICATIONS


    5 WARNINGS AND PRECAUTIONS


    6 ADVERSE REACTIONS


    6.1 Clinical Trials Experience


    7 DRUG INTERACTIONS


    7.1 Digoxin


    8 USE IN SPECIFIC POPULATIONS


    8.1 Pregnancy


    8.3 Nursing Mothers


    8.4 Pediatric Use


    8.5 Geriatric Use


    10 OVERDOSAGE


    11 DESCRIPTION


    12 CLINICAL PHARMACOLOGY


    12.1 Mechanism of Action


    12.2 Pharmacodynamics


    12.3 Pharmacokinetics


    13 NONCLINICAL TOXICOLOGY


    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility


    14 CLINICAL STUDIES


    14.1 Monotherapy


    14.2 Combination Therapy


    16 HOW SUPPLIED/STORAGE AND HANDLING


    17 PATIENT COUNSELING INFORMATION


    17.1 Instructions


    17.2 Laboratory Tests


    17.3 FDA-Approved Patient Labeling


    *Sections or subsections omitted from the full prescribing

information are not listed.


    FULL PRESCRIBING INFORMATION


    1 INDICATIONS AND USAGE


    1.1 Monotherapy


    JANUVIA(1) is indicated as an adjunct to diet and exercise to

improve glycemic control in patients with type 2 diabetes mellitus.


    1.2 Combination Therapy


    JANUVIA is indicated in patients with type 2 diabetes mellitus to

improve glycemic control in combination with metformin or a PPAR-gamma

agonist (e.g., thiazolidinediones) when the single agent alone, with

diet and exercise, does not provide adequate glycemic control.


    1.3 Important Limitations of Use


    JANUVIA should not be used in patients with type 1 diabetes or for

the treatment of diabetic ketoacidosis, as it would not be effective

in these settings.


    2 DOSAGE AND ADMINISTRATION


    2.1 Recommended Dosing


    The recommended dose of JANUVIA is 100 mg once daily as

monotherapy or as combination therapy with metformin or a PPAR-gamma

agonist (e.g., thiazolidinediones). JANUVIA can be taken with or

without food.


    2.2 Patients with Renal Insufficiency


    For patients with mild renal insufficiency (creatinine clearance

(CrCl) greater than or equal to 50 mL/min, approximately corresponding

to serum creatinine levels of less than or equal to 1.7 mg/dL in men

and less than or equal to 1.5 mg/dL in women), no dosage adjustment

for JANUVIA is required.


    For patients with moderate renal insufficiency (CrCl greater than

30 to less than 50 mL/min, approximately corresponding to serum

creatinine levels of greater than 1.7 to less than or equal to 3.0

mg/dL in men and greater than 1.5 to less than or equal to 2.5 mg/dL

in women), the dose of JANUVIA is 50 mg once daily.


    For patients with severe renal insufficiency (CrCl less than 30

mL/min, approximately corresponding to serum creatinine levels of

greater than 3.0 mg/dL in men and greater than 2.5 mg/dL in women) or

with end-stage renal disease (ESRD) requiring hemodialysis or

peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA

may be administered without regard to the timing of hemodialysis.


    Because there is a need for dosage adjustment based upon renal

function, assessment of renal function is recommended prior to

initiation of JANUVIA and periodically thereafter. Creatinine

clearance can be estimated from serum creatinine using the

Cockcroft-Gault formula. (See Clinical Pharmacology (12.3).)


    3 DOSAGE FORMS AND STRENGTHS


    -- 100 mg tablets are beige, round, film-coated tablets with "277"

on one side.


    -- 50 mg tablets are light beige, round, film-coated tablets with

"112" on one side.


    -- 25 mg tablets are pink, round, film-coated tablets with "221"

on one side.


    4 CONTRAINDICATIONS


    None.


    5 WARNINGS AND PRECAUTIONS


    Use in Patients with Renal Insufficiency: A dosage adjustment is

recommended in patients with moderate or severe renal insufficiency

and in patients with ESRD requiring hemodialysis or peritoneal

dialysis. (See Dosage and Administration (2.2); Clinical Pharmacology

(12.3).)


    Use with Medications Known to Cause Hypoglycemia: In clinical

trials of JANUVIA as monotherapy and JANUVIA as part of combination

therapy with metformin or pioglitazone, rates of hypoglycemia reported

with JANUVIA were similar to rates in patients taking placebo. The use

of JANUVIA in combination with medications known to cause

hypoglycemia, such as sulfonylureas or insulin, has not been

adequately studied.


    6 ADVERSE REACTIONS


    Because clinical trials are conducted under widely varying

conditions, adverse reaction rates observed in the clinical trials of

a drug cannot be directly compared to rates in the clinical trials of

another drug and may not reflect the rates observed in practice.


    6.1 Clinical Trials Experience


    In controlled clinical studies as both monotherapy and combination

therapy, the overall incidence of adverse reactions with JANUVIA was

similar to that reported with placebo. Discontinuation of therapy due

to clinical adverse reactions was also similar to placebo.


    Two placebo-controlled monotherapy studies, one of 18- and one of

24-week duration, included patients treated with JANUVIA 100 mg daily,

JANUVIA 200 mg daily, and placebo. Two 24-week, placebo-controlled

combination studies, one with metformin and one with pioglitazone,

were also conducted. In addition to a stable dose of metformin or

pioglitazone, patients whose diabetes was not adequately controlled

were given either JANUVIA 100 mg daily or placebo. The adverse

reactions, reported regardless of investigator assessment of causality

in greater than or equal to 5% of patients treated with JANUVIA 100 mg

daily as monotherapy or in combination with pioglitazone and more

commonly than in patients treated with placebo, are shown in Table 1.




                               Table 1

    Placebo-Controlled Clinical Studies of JANUVIA Monotherapy or

                    Combination with Pioglitazone:


    Adverse Reactions Reported in Greater than or equal to 5% of

Patients and More Commonly than in Patients Given Placebo, Regardless

            of Investigator Assessment of Causality+

----------------------------------------------------------------------

                                           Number of Patients (%)

----------------------------------------------------------------------

Monotherapy                           JANUVIA, 100 mg     Placebo

----------------------------------------------------------------------

                                          N = 443         N = 363

----------------------------------------------------------------------

 Nasopharyngitis                              23 (5.2)        12 (3.3)

----------------------------------------------------------------------

Combination with Pioglitazone         JANUVIA 100 mg +   Placebo +

                                        Pioglitazone    Pioglitazone

----------------------------------------------------------------------

                                          N = 175         N = 178

----------------------------------------------------------------------

 Upper Respiratory Tract Infection            11 (6.3)         6 (3.4)

----------------------------------------------------------------------

 Headache                                      9 (5.1)         7 (3.9)

----------------------------------------------------------------------



    + Intent to treat population


    In patients receiving JANUVIA in combination with metformin, there

were no adverse reactions reported regardless of investigator

assessment of causality in greater than or equal to 5% of patients and

more commonly than in patients given placebo.


    The overall incidence of hypoglycemia in patients treated with

JANUVIA 100 mg was similar to placebo (1.2% vs 0.9%). The incidence of

selected gastrointestinal adverse reactions in patients treated with

JANUVIA was as follows: abdominal pain (JANUVIA 100 mg, 2.3%; placebo,

2.1%), nausea (1.4%, 0.6%), and diarrhea (3.0%, 2.3%).


    No clinically meaningful changes in vital signs or in ECG

(including in QTc interval) were observed in patients treated with

JANUVIA.


    Laboratory Tests


    The incidence of laboratory adverse reactions in patients treated

with JANUVIA 100 mg was 8.2% compared to 9.8% in patients treated with

placebo. Across clinical studies, a small increase in white blood cell

count (approximately 200 cells/microL difference in WBC vs placebo;

mean baseline WBC approximately 6600 cells/microL) was observed due to

an increase in neutrophils. This observation was seen in most but not

all studies. This change in laboratory parameters is not considered to

be clinically relevant. In a 12-week study of 91 patients with chronic

renal insufficiency, 37 patients with moderate renal insufficiency

were randomized to JANUVIA 50 mg daily, while 14 patients with the

same magnitude of renal impairment were randomized to placebo. Mean

(SE) increases in serum creatinine were observed in patients treated

with JANUVIA (0.12 mg/dL (0.04)) and in patients treated with placebo

(0.07 mg/dL (0.07)). The clinical significance of this added increase

in serum creatinine relative to placebo is not known.


    7 DRUG INTERACTIONS


    7.1 Digoxin


    There was a slight increase in the area under the curve (AUC, 11%)

and mean peak drug concentration (Cmax, 18%) of digoxin with the

co-administration of 100 mg sitagliptin for 10 days. Patients

receiving digoxin should be monitored appropriately. No dosage

adjustment of digoxin or JANUVIA is recommended.


    8 USE IN SPECIFIC POPULATIONS


    8.1 Pregnancy


    Pregnancy Category B:


    Reproduction studies have been performed in rats and rabbits.

Doses of sitagliptin up to 125 mg/kg (approximately 12 times the human

exposure at the maximum recommended human dose) did not impair

fertility or harm the fetus. There are, however, no adequate and

well-controlled studies in pregnant women. Because animal reproduction

studies are not always predictive of human response, this drug should

be used during pregnancy only if clearly needed. Merck & Co., Inc.

maintains a registry to monitor the pregnancy outcomes of women

exposed to JANUVIA while pregnant. Health care providers are

encouraged to report any prenatal exposure to JANUVIA by calling the

Pregnancy Registry at (800) 986-8999.


    Sitagliptin administered to pregnant female rats and rabbits from

gestation day 6 to 20 (organogenesis) was not teratogenic at oral

doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately

30- and 20-times human exposure at the maximum recommended human dose

(MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased

the incidence of rib malformations in offspring at 1000 mg/kg, or

approximately 100 times human exposure at the MRHD.


    Sitagliptin administered to female rats from gestation day 6 to

lactation day 21 decreased body weight in male and female offspring at

1000 mg/kg. No functional or behavioral toxicity was observed in

offspring of rats.


    Placental transfer of sitagliptin administered to pregnant rats

was approximately 45% at 2 hours and 80% at 24 hours postdose.

Placental transfer of sitagliptin administered to pregnant rabbits was

approximately 66% at 2 hours and 30% at 24 hours.


    8.3 Nursing Mothers


    Sitagliptin is secreted in the milk of lactating rats at a milk to

plasma ratio of 4:1. It is not known whether sitagliptin is excreted

in human milk. Because many drugs are excreted in human milk, caution

should be exercised when JANUVIA is administered to a nursing woman.


    8.4 Pediatric Use


    Safety and effectiveness of JANUVIA in pediatric patients have not

been established.


    8.5 Geriatric Use


    Of the total number of subjects (N=3884) in clinical safety and

efficacy studies of JANUVIA, 725 patients were 65 years and over,

while 61 patients were 75 years and over. No overall differences in

safety or effectiveness were observed between subjects 65 years and

over and younger subjects. While this and other reported clinical

experience have not identified differences in responses between the

elderly and younger patients, greater sensitivity of some older

individuals cannot be ruled out.


    This drug is known to be substantially excreted by the kidney.

Because elderly patients are more likely to have decreased renal

function, care should be taken in dose selection in the elderly, and

it may be useful to assess renal function in these patients prior to

initiating dosing and periodically thereafter (see Dosage and

Administration (2.2); Clinical Pharmacology (12.3)).


    10 OVERDOSAGE


    During controlled clinical trials in healthy subjects, single

doses of up to 800 mg JANUVIA were administered. Maximal mean

increases in QTc of 8.0 msec were observed in one study at a dose of

800 mg JANUVIA, a mean effect that is not considered clinically

important (see Clinical Pharmacology (12.2)). There is no experience

with doses above 800 mg in humans.


    In the event of an overdose, it is reasonable to employ the usual

supportive measures, e.g., remove unabsorbed material from the

gastrointestinal tract, employ clinical monitoring (including

obtaining an electrocardiogram), and institute supportive therapy as

dictated by the patient's clinical status.


    Sitagliptin is modestly dialyzable. In clinical studies,

approximately 13.5% of the dose was removed over a 3- to 4-hour

hemodialysis session. Prolonged hemodialysis may be considered if

clinically appropriate. It is not known if sitagliptin is dialyzable

by peritoneal dialysis.


    11 DESCRIPTION


    JANUVIA Tablets contain sitagliptin phosphate, an orally-active

inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.


    Sitagliptin phosphate is described chemically as

7-((3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl)-5,6,7,8-

tetrahydro-3- (trifluoromethyl)-1,2,4-triazolo(4,3-a)pyrazine

phosphate (1:1) monohydrate.


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

weight is 523.32. The structural formula is:


    (OBJECT OMITTED)


    Sitagliptin phosphate is a white to off-white, crystalline,

non-hygroscopic powder. It is soluble in water and N,N-dimethyl

formamide; slightly soluble in methanol; very slightly soluble in

ethanol, acetone, and acetonitrile; and insoluble in isopropanol and

isopropyl acetate.


    Each film-coated tablet of JANUVIA contains 32.13, 64.25, or

128.5 mg of sitagliptin phosphate monohydrate, which is equivalent to

25, 50, or 100 mg, respectively, of free base and the following

inactive ingredients: microcrystalline cellulose, anhydrous dibasic

calcium phosphate, croscarmellose sodium, magnesium stearate, and

sodium stearyl fumarate. In addition, the film coating contains the

following inactive ingredients: polyvinyl alcohol, polyethylene

glycol, talc, titanium dioxide, red iron oxide, and yellow iron oxide.


    12 CLINICAL PHARMACOLOGY


    12.1 Mechanism of Action


    Sitagliptin is a DPP-4 inhibitor, which is believed to exert its

actions in patients with type 2 diabetes by slowing the inactivation

of incretin hormones. Concentrations of the active intact hormones are

increased by JANUVIA, thereby increasing and prolonging the action of

these hormones. Incretin hormones, including glucagon-like peptide-1

(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are

released by the intestine throughout the day, and levels are increased

in response to a meal. These hormones are rapidly inactivated by the

enzyme, DPP-4. The incretins are part of an endogenous system involved

in the physiologic regulation of glucose homeostasis. When blood

glucose concentrations are normal or elevated, GLP-1 and GIP increase

insulin synthesis and release from pancreatic beta cells by

intracellular signaling pathways involving cyclic AMP. GLP-1 also

lowers glucagon secretion from pancreatic alpha cells, leading to

reduced hepatic glucose production. By increasing and prolonging

active incretin levels, JANUVIA increases insulin release and

decreases glucagon levels in the circulation in a glucose-dependent

manner. Sitagliptin demonstrates selectivity for DPP-4 and does not

inhibit DPP-8 or DPP-9 activity in vitro at concentrations

approximating those from therapeutic doses.


    12.2 Pharmacodynamics


    General


    In patients with type 2 diabetes, administration of JANUVIA led to

inhibition of DPP-4 enzyme activity for a 24-hour period. After an

oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to

3-fold increase in circulating levels of active GLP-1 and GIP,

decreased glucagon concentrations, and increased responsiveness of

insulin release to glucose, resulting in higher C-peptide and insulin

concentrations. The rise in insulin with the decrease in glucagon was

associated with lower fasting glucose concentrations and reduced

glucose excursion following an oral glucose load or a meal.


    In studies with healthy subjects, JANUVIA did not lower blood

glucose or cause hypoglycemia.


    Cardiac Electrophysiology


    In a randomized, placebo-controlled crossover study, 79 healthy

subjects were administered a single oral dose of JANUVIA 100 mg,

JANUVIA 800 mg (8 times the recommended dose), and placebo. At the

recommended dose of 100 mg, there was no effect on the QTc interval

obtained at the peak plasma concentration, or at any other time during

the study. Following the 800 mg dose, the maximum increase in the

placebo-corrected mean change in QTc from baseline was observed at 3

hours postdose and was 8.0 msec. This increase is not considered to be

clinically significant. At the 800 mg dose, peak sitagliptin plasma

concentrations were approximately 11-fold higher than the peak

concentrations following a 100 mg dose.


    In patients with type 2 diabetes administered JANUVIA 100 mg

(N=81) or JANUVIA 200 mg (N=63) daily, there were no meaningful

changes in QTc interval based on ECG data obtained at the time of

expected peak plasma concentration.


    12.3 Pharmacokinetics


    The pharmacokinetics of sitagliptin has been extensively

characterized in healthy subjects and patients with type 2 diabetes.

After oral administration of a 100 mg dose to healthy subjects,

sitagliptin was rapidly absorbed, with peak plasma concentrations

(median Tmax) occurring 1 to 4 hours postdose. Plasma AUC of

sitagliptin increased in a dose-proportional manner. Following a

single oral 100 mg dose to healthy volunteers, mean plasma AUC of

sitagliptin was 8.52 ?M-hr, Cmax was 950 nM, and apparent terminal

half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased

approximately 14% following 100 mg doses at steady-state compared to

the first dose. The intra-subject and inter-subject coefficients of

variation for sitagliptin AUC were small (5.8% and 15.1%). The

pharmacokinetics of sitagliptin was generally similar in healthy

subjects and in patients with type 2 diabetes.


    Absorption


    The absolute bioavailability of sitagliptin is approximately 87%.

Because coadministration of a high-fat meal with JANUVIA had no effect

on the pharmacokinetics, JANUVIA may be administered with or without

food.


    Distribution


    The mean volume of distribution at steady state following a single

100 mg intravenous dose of sitagliptin to healthy subjects is

approximately 198 liters. The fraction of sitagliptin reversibly bound

to plasma proteins is low (38%).


    Metabolism


    Approximately 79% of sitagliptin is excreted unchanged in the

urine with metabolism being a minor pathway of elimination.


    Following a (14C)sitagliptin oral dose, approximately 16% of the

radioactivity was excreted as metabolites of sitagliptin. Six

metabolites were detected at trace levels and are not expected to

contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In

vitro studies indicated that the primary enzyme responsible for the

limited metabolism of sitagliptin was CYP3A4, with contribution from

CYP2C8.


    Excretion


    Following administration of an oral (14C)sitagliptin dose to

healthy subjects, approximately 100% of the administered radioactivity

was eliminated in feces (13%) or urine (87%) within one week of

dosing. The apparent terminal t1/2 following a 100 mg oral dose of

sitagliptin was approximately 12.4 hours and renal clearance was

approximately 350 mL/min.


    Elimination of sitagliptin occurs primarily via renal excretion

and involves active tubular secretion. Sitagliptin is a substrate for

human organic anion transporter-3 (hOAT-3), which may be involved in

the renal elimination of sitagliptin. The clinical relevance of hOAT-3

in sitagliptin transport has not been established. Sitagliptin is also

a substrate of p-glycoprotein, which may also be involved in mediating

the renal elimination of sitagliptin. However, cyclosporine, a

p-glycoprotein inhibitor, did not reduce the renal clearance of

sitagliptin.


    Special Populations


    Renal Insufficiency


    A single-dose, open-label study was conducted to evaluate the

pharmacokinetics of JANUVIA (50 mg dose) in patients with varying

degrees of chronic renal insufficiency compared to normal healthy

control subjects. The study included patients with renal insufficiency

classified on the basis of creatinine clearance as mild (50 to less

than 80 mL/min), moderate (30 to less than 50 mL/min), and severe

(less than 30 mL/min), as well as patients with ESRD on hemodialysis.

In addition, the effects of renal insufficiency on sitagliptin

pharmacokinetics in patients with type 2 diabetes and mild or moderate

renal insufficiency were assessed using population pharmacokinetic

analyses. Creatinine clearance was measured by 24-hour urinary

creatinine clearance measurements or estimated from serum creatinine

based on the Cockcroft-Gault formula:




CrCl = (140 - age (years)) x weight (kg) {x 0.85 for female patients}

       ---------------------------------

       (72 x serum creatinine (mg/dL))



    Compared to normal healthy control subjects, an approximate 1.1-

to 1.6-fold increase in plasma AUC of sitagliptin was observed in

patients with mild renal insufficiency. Because increases of this

magnitude are not clinically relevant, dosage adjustment in patients

with mild renal insufficiency is not necessary. Plasma AUC levels of

sitagliptin were increased approximately 2-fold and 4-fold in patients

with moderate renal insufficiency and in patients with severe renal

insufficiency, including patients with ESRD on hemodialysis,

respectively. Sitagliptin was modestly removed by hemodialysis (13.5%

over a 3- to 4-hour hemodialysis session starting 4 hours postdose).

To achieve plasma concentrations of sitagliptin similar to those in

patients with normal renal function, lower dosages are recommended in

patients with moderate and severe renal insufficiency, as well as in

ESRD patients requiring hemodialysis. (See Dosage and Administration

(2.2).)


    Hepatic Insufficiency


    In patients with moderate hepatic insufficiency (Child-Pugh score

7 to 9), mean AUC and Cmax of sitagliptin increased approximately 21%

and 13%, respectively, compared to healthy matched controls following

administration of a single 100 mg dose of JANUVIA. These differences

are not considered to be clinically meaningful. No dosage adjustment

for JANUVIA is necessary for patients with mild or moderate hepatic

insufficiency.


    There is no clinical experience in patients with severe hepatic

insufficiency (Child-Pugh score greater than9).


    Body Mass Index (BMI)


    No dosage adjustment is necessary based on BMI. Body mass index

had no clinically meaningful effect on the pharmacokinetics of

sitagliptin based on a composite analysis of Phase I pharmacokinetic

data and on a population pharmacokinetic analysis of Phase I and Phase

II data.


    Gender


    No dosage adjustment is necessary based on gender. Gender had no

clinically meaningful effect on the pharmacokinetics of sitagliptin

based on a composite analysis of Phase I pharmacokinetic data and on a

population pharmacokinetic analysis of Phase I and Phase II data.


    Geriatric


    No dosage adjustment is required based solely on age. When the

effects of age on renal function are taken into account, age alone did

not have a clinically meaningful impact on the pharmacokinetics of

sitagliptin based on a population pharmacokinetic analysis. Elderly

subjects (65 to 80 years) had approximately 19% higher plasma

concentrations of sitagliptin compared to younger subjects.


    Pediatric


    Studies characterizing the pharmacokinetics of sitagliptin in

pediatric patients have not been performed.


    Race


    No dosage adjustment is necessary based on race. Race had no

clinically meaningful effect on the pharmacokinetics of sitagliptin

based on a composite analysis of available pharmacokinetic data,

including subjects of white, Hispanic, black, Asian, and other racial

groups.


    Drug Interactions


    In Vitro Assessment of Drug Interactions


    Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9,

2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4. Sitagliptin is

a p-glycoprotein substrate, but does not inhibit p-glycoprotein

mediated transport of digoxin. Based on these results, sitagliptin is

considered unlikely to cause interactions with other drugs that

utilize these pathways.


    Sitagliptin is not extensively bound to plasma proteins.

Therefore, the propensity of sitagliptin to be involved in clinically

meaningful drug-drug interactions mediated by plasma protein binding

displacement is very low.


    In Vivo Assessment of Drug Interactions


    Effects of Sitagliptin on Other Drugs


    In clinical studies, as described below, sitagliptin did not

meaningfully alter the pharmacokinetics of metformin, glyburide,

simvastatin, rosiglitazone, warfarin, or oral contraceptives,

providing in vivo evidence of a low propensity for causing drug

interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic

cationic transporter (OCT).


    Digoxin: Sitagliptin had a minimal effect on the pharmacokinetics

of digoxin. Following administration of 0.25 mg digoxin concomitantly

with 100 mg of JANUVIA daily for 10 days, the plasma AUC of digoxin

was increased by 11%, and the plasma Cmax by 18%.


    Metformin: Co-administration of multiple twice-daily doses of

sitagliptin with metformin, an OCT substrate, did not meaningfully

alter the pharmacokinetics of metformin in patients with type 2

diabetes. Therefore, sitagliptin is not an inhibitor of OCT-mediated

transport.


    Sulfonylureas: Single-dose pharmacokinetics of glyburide, a CYP2C9

substrate, was not meaningfully altered in subjects receiving multiple

doses of sitagliptin. Clinically meaningful interactions would not be

expected with other sulfonylureas (e.g., glipizide, tolbutamide, and

glimepiride) which, like glyburide, are primarily eliminated by

CYP2C9. However, the risk of hypoglycemia from the co-administration

of sitagliptin and sulfonylureas is unknown.


    Simvastatin: Single-dose pharmacokinetics of simvastatin, a CYP3A4

substrate, was not meaningfully altered in subjects receiving multiple

daily doses of sitagliptin. Therefore, sitagliptin is not an inhibitor

of CYP3A4-mediated metabolism.


    Thiazolidinediones: Single-dose pharmacokinetics of rosiglitazone

was not meaningfully altered in subjects receiving multiple daily

doses of sitagliptin, indicating that JANUVIA is not an inhibitor of

CYP2C8-mediated metabolism.


    Warfarin: Multiple daily doses of sitagliptin did not meaningfully

alter the pharmacokinetics, as assessed by measurement of S(-) or R(+)

warfarin enantiomers, or pharmacodynamics (as assessed by measurement

of prothrombin INR) of a single dose of warfarin. Because S(-)

warfarin is primarily metabolized by CYP2C9, these data also support

the conclusion that sitagliptin is not a CYP2C9 inhibitor.


    Oral Contraceptives: Co-administration with sitagliptin did not

meaningfully alter the steady-state pharmacokinetics of norethindrone

or ethinyl estradiol.


    Effects of Other Drugs on Sitagliptin


    Clinical data described below suggest that sitagliptin is not

susceptible to clinically meaningful interactions by co-administered

medications:


    Metformin: Co-administration of multiple twice-daily doses of

metformin with sitagliptin did not meaningfully alter the

pharmacokinetics of sitagliptin in patients with type 2 diabetes.


    Cyclosporine: A study was conducted to assess the effect of

cyclosporine, a potent inhibitor of p-glycoprotein, on the

pharmacokinetics of sitagliptin. Co-administration of a single 100 mg

oral dose of JANUVIA and a single 600 mg oral dose of cyclosporine

increased the AUC and Cmax of sitagliptin by approximately 29% and

68%, respectively. These modest changes in sitagliptin

pharmacokinetics were not considered to be clinically meaningful. The

renal clearance of sitagliptin was also not meaningfully altered.

Therefore, meaningful interactions would not be expected with other

p-glycoprotein inhibitors.


    13 NONCLINICAL TOXICOLOGY


    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility


    A two-year carcinogenicity study was conducted in male and female

rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day.

There was an increased incidence of combined liver adenoma/carcinoma

in males and females and of liver carcinoma in females at 500 mg/kg.

This dose results in exposures approximately 60 times the human

exposure at the maximum recommended daily adult human dose (MRHD) of

100 mg/day based on AUC comparisons. Liver tumors were not observed at

150 mg/kg, approximately 20 times the human exposure at the MRHD. A

two-year carcinogenicity study was conducted in male and female mice

given oral doses of sitagliptin of 50, 125, 250, and 500 mg/kg/day.

There was no increase in the incidence of tumors in any organ up to

500 mg/kg, approximately 70 times human exposure at the MRHD.

Sitagliptin was not mutagenic or clastogenic with or without metabolic

activation in the Ames bacterial mutagenicity assay, a Chinese hamster

ovary (CHO) chromosome aberration assay, an in vitro cytogenetics

assay in CHO, an in vitro rat hepatocyte DNA alkaline elution assay,

and an in vivo micronucleus assay.


    In rat fertility studies with oral gavage doses of 125, 250, and

1000 mg/kg, males were treated for 4 weeks prior to mating, during

mating, up to scheduled termination (approximately 8 weeks total) and

females were treated 2 weeks prior to mating through gestation day 7.

No adverse effect on fertility was observed at 125 mg/kg

(approximately 12 times human exposure at the MRHD of 100 mg/day based

on AUC comparisons). At higher doses, nondose-related increased

resorptions in females were observed (approximately 25 and 100 times

human exposure at the MRHD based on AUC comparison).


    14 CLINICAL STUDIES


    There were 2316 patients with type 2 diabetes randomized in four

double-blind, placebo-controlled clinical safety and efficacy studies

conducted to evaluate the effects of sitagliptin on glycemic control.

In these studies, the mean age of patients was 54.8 years, and 62% of

patients were white, 18% were Hispanic, 6% were black, 9% were Asian,

and 4% were of other racial groups.


    In patients with type 2 diabetes, treatment with JANUVIA produced

clinically significant improvements in hemoglobin A1C, fasting plasma

glucose (FPG) and 2-hour post-prandial glucose (PPG) compared to

placebo.


    14.1 Monotherapy


    A total of 1262 patients with type 2 diabetes participated in two

double-blind, placebo-controlled studies, one of 18-week and another

of 24-week duration, to evaluate the efficacy and safety of JANUVIA

monotherapy. In both monotherapy studies, patients currently on an

antihyperglycemic agent discontinued the agent, and underwent a diet,

exercise, and drug wash-out period of about 7 weeks. Patients with

inadequate glycemic control (A1C 7% to 10%) after the wash-out period

were randomized after completing a 2-week single-blind placebo run-in

period; patients not currently on antihyperglycemic agents (off

therapy for at least 8 weeks) with inadequate glycemic control (A1C 7%

to 10%) were randomized after completing the 2-week single-blind

placebo run-in period. In the 18-week study, 521 patients were

randomized to placebo, JANUVIA 100 mg, or JANUVIA 200 mg, and in the

24-week study 741 patients were randomized to placebo, JANUVIA 100 mg,

or JANUVIA 200 mg. Patients who failed to meet specific glycemic goals

during the studies were treated with metformin rescue, added on to

placebo or JANUVIA.


    Treatment with JANUVIA at 100 mg daily provided significant

improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table

2). In the 18-week study, 9% of patients receiving JANUVIA 100 mg and

17% who received placebo required rescue therapy. In the 24-week

study, 9% of patients receiving JANUVIA 100 mg and 21% of patients

receiving placebo required rescue therapy. The improvement in A1C was

not affected by gender, age, race, or baseline BMI. As is typical for

trials of agents to treat type 2 diabetes, mean response to JANUVIA in

A1C lowering appears to be related to the degree of A1C elevation at

baseline. Overall, the 200 mg daily dose did not provide greater

glycemic efficacy than the 100 mg daily dose. The effect of JANUVIA on

lipid endpoints was similar to placebo. Body weight did not increase

from baseline with JANUVIA therapy in either study, compared to a

small reduction in patients given placebo.




                               Table 2

Glycemic Parameters in 18- and 24-Week Placebo-Controlled Studies of

               JANUVIA in Patients with Type 2 Diabetes+

----------------------------------------------------------------------

                                     18-Week Study     24-Week Study

                                   ----------------- -----------------

                                   JANUVIA  Placebo  JANUVIA  Placebo

                                    100 mg            100 mg

------------------------------------------- -------- -------- --------

A1C (%)                            N = 193  N = 103  N = 229  N = 244

------------------------------------------- -------- -------- --------

 Baseline (mean)                       8.0      8.1      8.0      8.0

------------------------------------------- -------- -------- --------

 Change from baseline (adjusted

  mean++)                             -0.5      0.1     -0.6      0.2

------------------------------------------- -------- -------- --------

 Difference from placebo (adjusted -0.6ss.           -0.8ss.

  mean++) (95% CI)                 (-0.8,             (-1.0,

                                     -0.4)             -0.6)

------------------------------------------- -------- -------- --------

 Patients (%) achieving A1C less

  than7%                           69 (36%) 16 (16%) 93 (41%) 41 (17%)

------------------------------------------- -------- -------- --------

FPG (mg/dL)                        N = 201  N = 107  N = 234  N = 247

------------------------------------------- -------- -------- --------

 Baseline (mean)                       180      184      170      176

------------------------------------------- -------- -------- --------

 Change from baseline (adjusted

  mean++)                              -13        7      -12        5

------------------------------------------- -------- -------- --------

 Difference from placebo (adjusted  -20ss.            -17ss.

  mean++) (95% CI)                  (-31,             (-24,

                                      -9)              -10)

------------------------------------------- -------- -------- --------

2-hour PPG (mg/dL)                        %        % N = 201  N = 204

------------------------------------------- -------- -------- --------

 Baseline (mean)                                         257      271

------------------------------------------- -------- -------- --------

 Change from baseline (adjusted

  mean++)                                                -49       -2

------------------------------------------- -------- -------- --------

 Difference from placebo (adjusted                    -47ss.

  mean++) (95% CI)                                    (-59,

                                                       -34)

------------------------------------------- -------- -------- --------



    + Intent to Treat Population using last observation on study prior

to metformin rescue therapy.


    ++ Least squares means adjusted for prior antihyperglycemic

therapy status and baseline value.


    ss. pless than0.001 compared to placebo.


    % Data not available.


    Additional Monotherapy Study


    A multinational, randomized, double-blind, placebo-controlled

study was also conducted to assess the safety and tolerability of

JANUVIA in 91 patients with type 2 diabetes and chronic renal

insufficiency (creatinine clearance less than 50 mL/min). Patients

with moderate renal insufficiency received 50 mg daily of JANUVIA and

those with severe renal insufficiency or with ESRD on hemodialysis or

peritoneal dialysis received 25 mg daily. In this study, the safety

and tolerability of JANUVIA were generally similar to placebo. A small

increase in serum creatinine was reported in patients with moderate

renal insufficiency treated with JANUVIA relative to those on placebo.

In addition, the reductions in A1C and FPG with JANUVIA compared to

placebo were generally similar to those observed in other monotherapy

studies. (See Clinical Pharmacology (12.3).)


    14.2 Combination Therapy


    Combination Therapy with Metformin


    A total of 701 patients with type 2 diabetes participated in a

24-week, randomized, double-blind, placebo-controlled study designed

to assess the efficacy of JANUVIA in combination with metformin.

Patients already on metformin (N=431) at a dose of at least 1500 mg

per day were randomized after completing a 2-week single-blind placebo

run-in period. Patients on metformin and another antihyperglycemic

agent (N = 229) and patients not on any antihyperglycemic agents (off

therapy for at least 8 weeks, N = 41) were randomized after a run-in

period of approximately 10 weeks on metformin (at a dose of at least

1500 mg per day) in monotherapy. Patients were randomized to the

addition of either 100 mg of JANUVIA or placebo, administered once

daily. Patients who failed to meet specific glycemic goals during the

studies were treated with pioglitazone rescue.


    In combination with metformin, JANUVIA provided significant

improvements in A1C, FPG, and 2-hour PPG compared to placebo with

metformin (Table 3). Rescue glycemic therapy was used in 5% of

patients treated with JANUVIA 100 mg and 14% of patients treated with

placebo. A similar decrease in body weight was observed for both

treatment groups.




                               Table 3

          Glycemic Parameters at Final Visit (24-Week Study)

              for JANUVIA in Combination with Metformin+

----------------------------------------------------------------------

                                                  JANUVIA    Placebo +

                                                  100 mg +   Metformin

                                                  Metformin

-----------------------------------------------------------  ---------

A1C (%)                                           N = 453     N = 224

-----------------------------------------------------------  ---------

 Baseline (mean)                                       8.0        8.0

-----------------------------------------------------------  ---------

 Change from baseline (adjusted mean++)               -0.7       -0.0

-----------------------------------------------------------  ---------

 Difference from placebo + metformin (adjusted    -0.7ss.

  mean++) (95% CI)                                 (-0.8,

                                                    -0.5)

-----------------------------------------------------------  ---------

 Patients (%) achieving A1C less than7%           213 (47%)   41 (18%)

-----------------------------------------------------------  ---------

FPG (mg/dL)                                       N = 454     N = 226

-----------------------------------------------------------  ---------

 Baseline (mean)                                       170        174

-----------------------------------------------------------  ---------

 Change from baseline (adjusted mean++)                -17          9

-----------------------------------------------------------  ---------

 Difference from placebo + metformin (adjusted     -25ss.

  mean++) (95% CI)                               (-31, -20)

-----------------------------------------------------------  ---------

2-hour PPG (mg/dL)                                N = 387     N = 182

-----------------------------------------------------------  ---------

 Baseline (mean)                                       275        272

-----------------------------------------------------------  ---------

 Change from baseline (adjusted mean++)                -62        -11

-----------------------------------------------------------  ---------

 Difference from placebo + metformin (adjusted     -51ss.

  mean++) (95% CI)                               (-61, -41)

-----------------------------------------------------------  ---------



    + Intent to Treat Population using last observation on study prior

to pioglitazone rescue therapy.


    ++ Least squares means adjusted for prior antihyperglycemic

therapy and baseline value.


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


    Combination Therapy with Pioglitazone


    A total of 353 patients with type 2 diabetes participated in a

24-week, randomized, double-blind, placebo-controlled study designed

to assess the efficacy of JANUVIA in combination with pioglitazone.

Patients on any oral antihyperglycemic agent in monotherapy (N=212) or

on a PPAR-gamma agent in combination therapy (N=106) or not on an

antihyperglycemic agent (off therapy for at least 8 weeks, N=34) were

switched to monotherapy with pioglitazone (at a dose of 30-45 mg per

day), and completed a run-in period of approximately 12 weeks in

duration. After the run-in period on pioglitazone monotherapy,

patients were randomized to the addition of either 100 mg of JANUVIA

or placebo, administered once daily. Patients who failed to meet

specific glycemic goals during the studies were treated with metformin

rescue. Glycemic endpoints measured included A1C and fasting glucose.


    In combination with pioglitazone, JANUVIA provided significant

improvements in A1C and FPG compared to placebo with pioglitazone

(Table 4). Rescue therapy was used in 7% of patients treated with

JANUVIA 100 mg and 14% of patients treated with placebo. There was no

significant difference between JANUVIA and placebo in body weight

change.




                               Table 4

          Glycemic Parameters at Final Visit (24-Week Study)

            for JANUVIA in Combination with Pioglitazone+

----------------------------------------------------------------------

                                           JANUVIA 100     Placebo +

                                               mg +       Pioglitazone

                                            Pioglitazone

--------------------------------------------------------  ------------

A1C (%)                                       N = 163       N = 174

--------------------------------------------------------  ------------

 Baseline (mean)                                    8.1           8.0

--------------------------------------------------------  ------------

 Change from baseline (adjusted mean++)            -0.9          -0.2

--------------------------------------------------------  ------------

 Difference from placebo + pioglitazone       -0.7ss.

  (adjusted mean++) (95% CI)               (-0.9, -0.5)

--------------------------------------------------------  ------------

 Patients (%) achieving A1C less than7%         74 (45%)      40 (23%)

--------------------------------------------------------  ------------

FPG (mg/dL)                                   N = 163       N = 174

--------------------------------------------------------  ------------

 Baseline (mean)                                    168           166

--------------------------------------------------------  ------------

 Change from baseline (adjusted mean++)             -17             1

--------------------------------------------------------  ------------

 Difference from placebo + pioglitazone       -18ss.

  (adjusted mean++) (95% CI)                (-24, -11)

--------------------------------------------------------  ------------



    + Intent to Treat Population using last observation on study prior

to metformin rescue therapy.


    ++ Least squares means adjusted for prior antihyperglycemic

therapy status and baseline value.


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


    16 HOW SUPPLIED/STORAGE AND HANDLING


    No. 6737 -- Tablets JANUVIA, 25 mg, are pink, round, film-coated

tablets with "221" on one side. They are supplied as follows:


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


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


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


    No. 6738 -- Tablets JANUVIA, 50 mg, are light beige, round,

film-coated tablets with "112" on one side. They are supplied as

follows:


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


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


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


    No. 6739 -- Tablets JANUVIA, 100 mg, are beige, round, film-coated

tablets with "277" on one side. They are supplied as follows:


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


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


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


    NDC 0006-0277-74 bottles of 500


    NDC 0006-0277-82 bottles of 1000.


    Storage


    Store at 20-25(degree)C (68-77(degree)F), excursions permitted to

15-30(degree)C (59-86(degree)F), (see USP Controlled Room

Temperature).


    17 PATIENT COUNSELING INFORMATION


    (See FDA-Approved Patient Labeling (17.3).)


    17.1 Instructions


    Patients should be informed of the potential risks and benefits of

JANUVIA and of alternative modes of therapy. Patients should also be

informed about the importance of adherence to dietary instructions,

regular physical activity, periodic blood glucose monitoring and A1C

testing, recognition and management of hypoglycemia and hyperglycemia,

and assessment for diabetes complications. During periods of stress

such as fever, trauma, infection, or surgery, medication requirements

may change and patients should be advised to seek medical advice

promptly.


    Physicians should instruct their patients to read the Patient

Package Insert before starting JANUVIA therapy and to reread each time

the prescription is renewed. Patients should be instructed to inform

their doctor or pharmacist if they develop any unusual symptom, or if

any known symptom persists or worsens.


    17.2 Laboratory Tests


    Patients should be informed that response to all diabetic

therapies should be monitored by periodic measurements of blood

glucose and A1C levels, with a goal of decreasing these levels towards

the normal range. A1C is especially useful for evaluating long-term

glycemic control. Patients should be informed of the potential need to

adjust dose based on changes in renal function tests over time.


    Manufactured for:


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


    Manufactured by:


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


    Via Emilia, 21


    27100 - Pavia, Italy


    Printed in USA


    9762700


    US Patent No.: 6,699,871


    17.3 FDA-Approved Patient Labeling


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

08889 USA


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


    All rights reserved

-0-
                                                               9762700

                          Patient Information

                     JANUVIA(TM) (jah-NEW-vee-ah)

                        (sitagliptin phosphate)


                                Tablets


    Read the Patient Information that comes with JANUVIA(*) before you

start taking it and each time you get a refill. There may be new

information. This leaflet does not take the place of talking with your

doctor about your medical condition or treatment.


    What is JANUVIA?


    JANUVIA is a prescription medicine used along with diet and

exercise to lower blood sugar in patients with type 2 diabetes

mellitus (type 2 diabetes). JANUVIA may be taken alone or along with

certain other medicines to control blood sugar.


    --  JANUVIA lowers blood sugar when blood sugar is high,

        especially after a meal. JANUVIA also lowers blood sugar

        between meals.


    --  JANUVIA helps to improve the levels of insulin produced by

        your own body after a meal.


   

Posted: February 2007


View comments

Hide
(web5)