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Late Breaking Data Released at ADA Showed that the Investigational,Use of Januvia and Metformin as Initial Combination Therapy,Provided Significant Glucose Lowering Efficacy over 54 Weeks in,Patients with Type 2 Diabetes

CHICAGO--(BUSINESS WIRE)--Jun 23, 2007 - Late breaking data presented at the American Diabetes Association (ADA) 67th Annual Scientific Sessions showed that, when used investigationally as initial therapy, JANUVIA(TM) (sitagliptin) in combination with metformin provided significant glycemic improvement and was generally well tolerated over 54 weeks in patients with type 2 diabetes. Additional new data from investigational studies presented also showed that JANUVIA significantly improved blood sugar control in patients with type 2 diabetes when added to a sulfonylurea, glimepiride (dual combination therapy), or when added to a sulfonylurea and metformin (triple combination therapy). Additional data were presented at the meeting regarding the efficacy and safety of JANUVIA.

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

Sitagliptin is also a component of JANUMET(TM) (sitagliptin/metformin HCl), the first and only tablet combining a DPP-4 inhibitor and metformin for the treatment of type 2 diabetes. JANUMET is indicated, as an adjunct to m.

Merck forward-looking statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2006, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.

Prescribing information and patient product information for JANUVIA and JANUMET are attached.

JANUVIA(TM) and JANUMET(TM) are trademarks of Merck & Co., Inc. -0-

JANUVIA(TM)(sitagliptin) Tablets                     9762701


    HIGHLIGHTS OF PRESCRIBING INFORMATION


    These highlights do not include all the information needed to use

JANUVIA safely and effectively. See full prescribing information for

JANUVIA.


    JANUVIA(TM) (sitagliptin) Tablets


    Initial U.S. Approval: 2006


    INDICATIONS AND USAGE


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

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

diabetes). JANUVIA is indicated for:


    --  Monotherapy (1.1)


    --  Combination therapy with metformin or a peroxisome

        proliferator-activated receptor ga
mma (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 d
osage 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 m
onotherapy 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

wi
th 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.


 
diet and exercise, to
improve glycemic control in adult patients with type 2 diabetes who
are not adequately controlled on metformin or sitagliptin alone or
in patients already being treated with the combination of
sitagliptin and metformin. Consistent with the labeling for
metformin alone, JANUMET is contraindicated in patients with renal
disease, renal dysfunction, or abnormal creatinine clearance; and
acute or chronic metabolic acidosis, including diabetic
ketoacidosis. JANUMET should not be used in patients with type 1
diabetes. Consistent with the labeling for metformin alone, the
labeling for JANUMET contains a boxed warning for lactic acidosis,
a rare, but serious, metabolic complication that can occur due to
metformin accumulation during treatment with JANUMET.

Initial combination therapy with JANUVIA and metformin significantly improved blood sugar control compared with metformin alone over one year (LB-04; Study #036)

This study demonstrated a mean A1C reduction from baseline of 1.8 percent in patients treated with JANUVIA 50 mg/metformin 1000 mg twice daily for up to 54 weeks (n=153). Additionally, mean A1C reductions from baseline were 1.4 percent in patients treated with JANUVIA 50 mg/metformin 500 mg twice daily (n=147), 1.3 percent in patients treated with metformin 1000 mg twice daily (n=134), 1.0 percent in patients treated with metformin 500 mg twice daily (n=117), and 0.8 percent in patients treated with JANUVIA 100 mg once daily (n=106).

After completing an initial 24-week placebo-controlled phase (n=1091) ("Phase A"), 762 patients with a mean baseline A1C of 8.7 percent continued in a 30-week, double-blind, active-controlled phase ("Phase B") on their previous active treatments: JANUVIA 50 mg/metformin 1000 mg twice daily (n=161); JANUVIA 50 mg/metformin 500 mg twice daily (n=160); metformin 1000 mg twice daily (n=153); metformin 500 mg twice daily (n=147); and JANUVIA 100 mg once-daily (n=141).

Two-thirds (67 percent 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 gluc ose 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 o f 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 sitagl iptin. 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 recommend ed 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 effec t 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 sin gle 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 ------------------------------------------- ------ ) of patients continuing past 24 weeks in this study achieved the ADA target A1C goal of less than seven percent on JANUVIA 50 mg/metformin 1000 mg twice daily (n=153) compared to 44 percent on metformin 1000 mg twice daily alone (n=134). Further, 48 percent of patients treated with JANUVIA 50 mg/metformin 500 mg twice daily (n=147), 25 percent of patients treated with metformin 500 mg twice daily (n=117), and 23 percent of patients treated with JANUVIA 100 mg once daily (n=106) reached the ADA target A1C goal.

Duration of response was demonstrated by data showing that 85 percent of patients treated with JANUVIA 50 mg/metformin 1000 mg twice daily and 70 percent of patients treated with JANUVIA 100 mg once daily who achieved the target A1C goal of less than seven percent at Week 24 had a Week 54 A1C value of less than seven percent (n=96 and 33, respectively). In addition, 80 percent of patients treated with JANUVIA 50 mg/metformin 500 mg twice daily (n=65), 79 percent of patients treated with metformin 1000 mg twice daily (n=63), and 59 percent of patients treated with metformin 500 mg twice daily (n=34) who reached a goal A1C of less than seven percent at Week 24 had a Week 54 A1C value of less than seven percent.

Over the 54 week study, five out of 182 patients (three percent) treated with JANUVIA 50 mg/metformin 1000 mg twice daily and two out of 182 patients (one percent) treated with metformin 1000 mg twice daily had at least one episode of hypoglycemia. Incidences of gastrointestinal adverse experiences were similar to those observed with metformin alone (26 percent vs. 31 percent with metformin 1000 mg twice daily).

"Initial therapy with one agent is often unsuccessful at getting patients to blood sugar goals. Many patients may require initial combination therapy, and this study provides important and useful information about the use of sitagliptin and metformin, in addition to diet and exercise, in order to achieve and maintain blood su -- -------- -------- 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

gar control," said John Amatruda, M.D., vice president, clinical research, Merck & Co., Inc. "This study examines the clinical effect of initial combination therapy with JANUVIA and metformin, the two drugs comprising JANUMET, over one year."

An important predictive factor of the magnitude of A1C reduction in response to anti-hyperglycemic therapy is a patient's starting level of A1C. In a subgroup analysis of patients grouped by severity of starting baseline A1C, treatment with JANUVIA 50 mg/metformin 1000 mg twice daily demonstrated increasing mean A1C reductions from baseline the higher the baseline A1C. A mean reduction of 3.1 percent was seen in patients with baseline A1C of 10 percent or more (n=17), while reductions of 2.2 percent, 1.7 percent, and 1.0 percent were seen with baseline A1C values of nine to 10 percent, eight to nine percent, and less than eight percent, respectively.

Investigational study showed JANUVIA significantly improved blood sugar control when added to sulfonylurea or to sulfonylurea and metformin vs. sulfonylurea or sulfonylurea and metformin alone (Poster #535-P; Study #035)

In this study, which was designed to examine the efficacy and safety of JANUVIA in patients with type 2 diabetes whose blood glucose levels were inadequately controlled (A1C levels of 7.5 percent to 10.5 percent) on a sulfonylurea (glimepiride) alone or on a sulfonylurea (glimepiride) plus metformin, JANUVIA demonstrated a significant mean difference from placebo in A1C of 0.9 percent in patients on glimepiride and metformin and 0.6 percent in patients on glimepiride alone (p less than 0.001 for both comparisons to the addition of placebo).

After a titration/stabilization period on glimepiride (at least 4 mg/day) with or without metformin (at least 1500 mg/day) and a 2-week placebo run-in, 441 patients with a mean baseline A1C of 8.3 percent were randomized to the addition of JANUVIA 100 mg once-daily or placebo for 24 weeks. Of thes e patients, 212 were on glimepiride alone (106 each on JANUVIA or placebo), and 229 on glimepiride and metformin (116 on JANUVIA, 113 on placebo). The primary endpoint was A1C change from baseline for the entire cohort.

The addition of JANUVIA to a sulfonylurea with or without metformin was generally well-tolerated in this study. A higher incidence of overall adverse experiences (60 vs. 47 percent) and drug-related adverse experiences (15 vs. 7 percent) were reported with JANUVIA compared to placebo in patients treated with glimepiride with or without metformin. These higher rates were partly related to a higher incidence of hypoglycemia with JANUVIA compared to placebo (12 vs. 2 percent, respectively). The higher rate of hypoglycemia has commonly been seen when antihyperglycemic agents are used in combination with sulfonylurea agents. After 24 weeks, body weight was increased more with JANUVIA than with placebo (mean change from baseline of +0.8 vs. -0.4 kg, respectively; p less than 0.001).

"These new potential uses of sitagliptin as add-on to sulfonylurea, as add-on to sulfonylurea plus metformin, and as initial therapy in combination with metformin, if approved by the FDA, would provide physicians with additional treatment options for patients with type 2 diabetes," said Mark Kipnes, M.D., associate medical director, Diabetes and Glandular Research Associates, and clinical professor of Medicine, University of Texas Health Science Center at San Antonio.

As Merck announced in February, these data have been submitted to the U.S. Food and Drug Administration (FDA) in support of proposed new indications for the use of JANUVIA. 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. The FDA is reviewing the sNDA for these indications and Merck expects FDA action by mid-October.

A pooled analysis of 5,141 patients showed overall incidence of adverse experiences, incidence of serious adverse experiences, and incidence of discontinuations due to adverse experiences were similar in the JANUVIA and non-exposed groups for up to two years (Poster #534-P)

The safety and tolerability of JANUVIA was assessed by pooling data from nine completed Phase IIB and III studies, including the studies discussed above, ranging from 24 to 104 weeks in duration, and including 5,141 patients treated with either JANUVIA 100 mg daily (n=2,786) or other treatments (placebo or an active comparator) (n=2,355). The studies assessed JANUVIA as monotherapy, initial combination therapy with metformin, or add-on to another oral agent (metformin, pioglitazone, sulfonylurea, or sulfonylurea and metformin).

JANUVIA 100 mg daily was generally well-tolerated as monotherapy, as initial combination therapy, or as add-on therapy. For adverse experiences (either clinical or laboratory), the overall incidence of adverse experiences, the incidence of serious adverse experiences, and the incidence of discontinuations due to adverse experiences were similar in the JANUVIA treated patients and in patients who received other therapies (patients on placebo or active comparator). Drug-related adverse experiences were higher in the non-exposed group due to hypoglycemia reported in sulfonylurea-treated patients (since studies in which a sulfonylurea agent was a treatment in patients not receiving JANUVIA were included in this pooled analysis).

Specific clinical adverse experiences, expressed as a rate of greater than or equal to 1 event per 100 patient-years of exposure, in the JANUVIA population included nasopharyngitis (12 vs. 9), hypoglycemia (9 vs. 58), increased blood glucose (5 vs. 9), osteoarthritis (2 vs. 1), contact dermatitis (1 vs. less than 1), tremor (1 vs. less than 1), nasal congestion (1 vs. less than 1), and reduced blood glucose (1 vs. 3) for JANUVIA and non-exposed patients, respectively.

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 less than 50 mL/min), the dose of JANUVIA is 50 mg once daily. For those with severe renal insufficiency (CrCl less than 30 mL/min) or with ESRD requiring dialysis, the dose of JANUVIA is 25 mg once daily. Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter.

Dosing of JANUMET

JANUMET should be given twice daily with meals, with gradual dose escalation as needed to reduce the gastrointestinal (GI) side effects due to metformin. In this formulation, the dose of sitagliptin remains constant (100 mg daily) and is combined with the two most widely prescribed doses of metformin (1000 mg daily or 2000 mg daily). The recommended starting dose of JANUMET for patients not on prior metformin therapy and for those not adequately controlled on sitagliptin is 50 mg sitagliptin and 500 mg metformin twice-daily with meals. For patients already receiving metformin therapy, the starting dose should be based on the patient's current metformin regimen. The total daily dose should not exceed 100 mg sitagliptin and 2000 mg metformin.

Metformin and sitagliptin are known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive JANUMET. In the elderly, JANUMET should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging can be associated with reduced renal function. Any dose adjustment should be based on a careful assessment of renal function. Before initiation of therapy with JANUMET and at least annually thereafter, renal function should be assessed and verified as normal.

Selected cautionary information for JANUVIA

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

Selected cautionary information for JANUMET

JANUMET should b e avoided in patients with evidence of hepatic disease. Before initiation of therapy with JANUMET and at least annually thereafter, renal function should be assessed and verified as normal. Patients should be warned against excessive alcohol intake while receiving JANUMET. Patients may require discontinuation of JANUMET and temporary use of insulin during periods of stress and decreased intake of fluids and food such as may occur with fever, trauma, infection or surgery. Patients previously controlled on JANUMET who develop laboratory abnormalities or clinical illness should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). When lactic acidosis occurs, it is fatal in approximately 50 percent of cases.

Expanding clinical development program for sitagliptin family

Merck's clinical development program for sitagliptin is robust and continues to expand with 47 studies completed or under way, and nine more studies set to begin this year. There have been more than 7,600 patients in the Company's clinical studies with about 4,700 of these patients, being treated with sitagliptin. Additionally, about 1,900 patients have been treated with sitagliptin for more than a year.

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.co
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