WHITEHOUSE STATION, N.J. (PRWEB) September 9, 2008

WHITEHOUSE STATION, N.J. (Business Wire EON) September 9, 2008 — New data analyses presented at the 44th Annual Meeting of the European Association for the Study of Diabetes (EASD) showed initial combination therapy with the dipeptidyl peptidase-4 (DPP-4) inhibitor, JANUVIA? (sitagliptin), and metformin provided improvements in blood sugar levels (as measured by A1C1) over two years of treatment and was generally well tolerated. Also presented at the meeting was a separate, new pooled analysis of 6,139 patients that showed that JANUVIA was generally well tolerated in clinical trials up to two years in duration.

JANUVIA is indicated, as an adjunct to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes. JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. JANUVIA has not been studied in combination with insulin. JANUVIA is contraindicated for patients with history of a serious hypersensitivity reaction to sitagliptin, including anaphylaxis and angiedema.

More than six million total prescriptions for JANUVIA have been dispensed worldwide since launch. JANUVIA has received approval in 80 countries and is available in every region around the world. The U.S. Food and Drug Administration approved JANUVIA in October 2006 and the European Medicines Agency (EMEA) approved JANUVIA in Europe in April 2007.

Initial combination of JANUVIA and metformin provided glycemic improvements out to two years

In a study of initial combination therapy with JANUVIA and metformin, glucose-lowering was assessed by measuring the mean change from baseline A1C levels at one year and two years. The mean A1C reductions from baseline in this study were 1.8 percent at one year (n=153) in patients treated with JANUVIA 50 mg/metformin 1000 mg twice-daily. In the extension study at two years, the mean A1C reduction was 1.7 percent (n=105; baseline A1C of 8.6 percent) for this group. Additionally, mean A1C reductions from baseline were 1.4 percent (at one year, n=147 and two years, n=96) in patients treated with JANUVIA 50 mg/metformin 500 mg twice daily, 1.3 percent (at one year, n=134 and two years, n=87) in patients treated with metformin 1000 mg twice daily, 1.0 percent (at one year, n=117) and 1.1 percent (at two years, n=64) in patients treated with metformin 500 mg twice daily. For patients treated with JANUVIA, there was a 0.8 percent reduction in A1C levels from baseline at one year (n=106) and a 1.2 percent reduction from baseline at two years (n=50).

Initial combination therapy or maintenance of combination therapy should be individualized and are left to the discretion of the health care provider.

Three additional studies further demonstrated the safety and efficacy profile of JANUVIA as an add-on to other oral diabetes treatments and efficacy when analyzed based on different baseline characteristics

In one 52-week investigational study, addition of JANUVIA to the combination of metformin and rosiglitazone significantly improved glycemic control in patients with type 2 diabetes. In a separate 52-week study of Japanese patients using an investigational dosing regimen, treatment with JANUVIA added to ongoing pioglitazone therapy provided effective glycemic control and was generally well tolerated with a comparable occurrence of hypoglycemia in the placebo and JANUVIA (50 mg, once daily) groups, and without clinically meaningful change in body weight. A mean change in A1C from baseline of 0.7 percent was observed; 62 percent of patients achieved A1C less than seven percent in the JANUVIA population at the end of the 52-week period.

“These data are interesting for physicians treating type 2 diabetes as they provide data regarding the clinical efficacy of JANUVIA both as initial combination therapy with metformin and also as add on therapy to other commonly used oral diabetes medications,” said Professor Bernard Charbonnel, professor of Endocrinology and Metabolic Diseases, University of Nantes and Head of the Internal Medicine, Endocrinology and Diabetes Department, H?tel Dieu (University Hospital of Nantes). “This is important for patients and physicians because type 2 diabetes is characterized by a progressive deterioration in beta cell function over time, resulting in the disease worsening. This progression of disease leads to decreased effectiveness of all known treatments over time, with patients often requiring multiple therapies in order to achieve their glycemic goals.”

An additional analysis presented at the meeting demonstrated that in patients with type 2 diabetes, JANUVIA provided glycemic control regardless of baseline characteristics of age, gender, BMI, HOMA-?, and P/I ratio.

In controlled clinical studies for JANUVIA as both monotherapy and combination therapy with metformin or pioglitazone, the overall incidence of adverse reactions, hypoglycemia, and discontinuation of therapy due to clinical adverse reactions with JANUVIA were similar to placebo. In these clinical studies, the most common adverse reactions reported with JANUVIA (greater than or equal to five percent and higher than placebo) were stuffy or runny nose and sore throat, upper respiratory infection and headache. In clinical trials in combination with a sulfonylurea (glimepiride), with or without metformin, JANUVIA demonstrated an overall incidence of adverse reactions higher than that seen with placebo, in part related to a higher incidence of hypoglycemia.

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

Initial combination of JANUVIA and metformin: study design and results

Initial combination therapy with JANUVIA and metformin significantly improved blood sugar levels compared with either metformin or JANUVIA alone over two years of treatment. After completing the initial, double-blind 54-week base study, 412 patients who received active treatment throughout the study were included in the all-patients-treated analysis of efficacy at two years.

The mean A1C reduction from baseline in the 1-year base study was 1.8 percent (n=153) in patients treated with JANUVIA 50 mg/metformin 1000 mg twice daily. In the extension study at two years, the mean A1C reduction from baseline was 1.7 percent (n=105) in this group of patients. Additionally, mean A1C reductions from baseline were 1.4 percent (at one year, n=147 and two years, n=96) in patients treated with JANUVIA 50 mg/metformin 500 mg twice daily, 1.3 percent (at one year, n=134 and two years, n=87) in patients treated with metformin 1000 mg twice daily, 1.0 percent (at one year, n=117) and 1.1 percent (at two years, n=64) in patients treated with metformin 500 mg twice daily. For patients treated with JANUVIA, there was a 0.8 percent reduction in A1C levels from baseline at one year (n=106) and a 1.2 percent reduction from baseline at two years (n=50).

Pooled analysis of safety and tolerability of JANUVIA: study design and results

In a pooled analysis of clinical studies up to two years in duration, treatment with JANUVIA was found to be generally well tolerated, with generally similar incidence of adverse experiences in patients treated with JANUVIA relative to those not exposed to JANUVIA.

The safety and tolerability of JANUVIA were evaluated by pooling data from 12 large, double-blind, randomized, completed Phase IIb and III studies of 18-weeks to two years duration that included 6,139 patients receiving either JANUVIA once-daily (n=3,415) or placebo or an active comparator (n=2,724; non-exposed group). The studies assessed JANUVIA as monotherapy, initial combination therapy with metformin or add-on therapy to oral antihyperglycemic agents (metformin, pioglitazone, a sulfonylurea, a sulfonylurea plus metformin or metformin plus rosiglitazone). Patients not receiving JANUVIA received a range of treatments, including placebo, pioglitazone, metformin, a sulfonylurea, a sulfonylurea plus metformin, or metformin plus rosiglitazone. This comparison group, patients not receiving JANUVIA, is referred to as the “non-exposed” group.

For clinical adverse experiences (AEs), the incidence of AEs overall, serious AEs and discontinuations due to AEs were similar between the JANUVIA and non-exposed groups. The incidence of drug-related AEs and discontinuations due to drug-related AEs were higher in the non-exposed group primarily due to events of hypoglycemia in sulfonylurea-treated patients.

Clinical AEs that occurred at a higher incidence in the sitagliptin group and for which the 95 percent confidence intervals around the between-group difference excluded zero were as follows: atrial fibrillation, asthenia, chest discomfort, tooth abscess, osteoarthritis, acne and contact dermatitis. Eleven AEs occurred at a higher incidence in the non-exposed group for which the 95 percent confidence intervals around the between-group difference excluded zero and were as follows: bradycardia, goiter, change in bowel habit, blood glucose decreased, blood glucose increased, weight increased, hypoglycemia, sinus headache, prostatitis, balanitis and hyperkeratosis.

Investigational use of combination therapy with JANUVIA, metformin, and rosiglitazone: study design and results

In this study, 262 patients (mean baseline A1C 8.8 percent) taking metformin (greater than or equal to 1500 mg/day) and rosiglitazone (greater than or equal to 4 mg/day) were randomized in a 2:1 ratio to the addition of JANUVIA (n=170) or placebo (n=92). After 18 weeks, the addition of JANUVIA significantly (p

In the continuation of this study out to 54-weeks, the addition of JANUVIA to the combination of metformin and rosiglitazone was generally well tolerated and continued to show significant (p

Treatment with an investigational dosing regimen of JANUVIA (50 mg once daily) added to ongoing pioglitazone therapy in Japanese patients with type 2 diabetes over 52 weeks: study design and results

A 12-week double-blind period where patients (n=134) on a stable dose of pioglitazone were randomized to the addition of JANUVIA 50 mg (n=66) or placebo (n=68) was followed by a 40-week open-label extension period where patients on placebo were reallocated to JANUVIA 50 mg and JANUVIA could be titrated from 50 mg to 100 mg. In the double-blind period, JANUVIA significantly reduced mean A1C from baseline relative to placebo at week 12 by 0.8 percent. In the open-label extension period of 66 patients allocated to JANUVIA treatment, 50 patients completed 52-weeks of treatment. In this patient population, efficacy at week 52 was observed with a sustained change in A1C from baseline of 0.7 percent and with 62 percent of patients at an A1C goal of less than seven percent. Treatment with JANUVIA was generally well tolerated compared to placebo with a low occurrence of hypoglycemia (3.0 percent vs. 2.9 percent) and edema (1.5 percent vs. 0.0 percent) and without clinically meaningful change in body weight.

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 ?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 ?30 to

Selected cautionary information for JANUVIA

Because JANUVIA is renally eliminated, and to achieve plasma concentrations of JANUVIA similar to those in patients with normal renal function, a dosage adjustment is recommended in patients with moderate renal insufficiency and in patients with severe renal insufficiency or with ESRD requiring hemodialysis or peritoneal dialysis. Safety and effectiveness of JANUVIA in pediatric patients have not been established. There are no adequate and well-controlled studies in pregnant women. JANUVIA should be used during pregnancy only if clearly needed. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when JANUVIA is administered to a nursing woman. There have been post-marketing reports of hypersensitivity reactions in patients treated with JANUVIA. These reactions include anaphylaxis, angiedema and exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Onset of these reactions occurred within the first three months after initiation of treatment with JANUVIA, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUVIA, assess for other potential causes for the event and institute alternative treatment for diabetes.

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or any other anti-diabetic drug.

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 programmes 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 http://www.merck.com.

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, 2007, and in any risk factors or cautionary statements contained in the Company’s periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.

JANUVIA? is a trademark of Merck & Co., Inc.

Prescribing information and patient product information for JANUVIA are attached.

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

Patient Information

JANUVIA? (jah-NEW-vee-ah)

(sitagliptin)

Tablets

Read the Patient Information that comes with JANUVIA* before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or treatment.

What is JANUVIA?

JANUVIA is a prescription medicine used along with diet and exercise to lower blood sugar in adults with type 2 diabetes.

JANUVIA lowers blood sugar when blood sugar is high, especially after a meal. JANUVIA also lowers blood sugar between meals. JANUVIA helps to improve the levels of insulin produced by your own body after a meal. JANUVIA decreases the amount of sugar made by the body. JANUVIA is unlikely to cause your blood sugar to be lowered to a dangerous level (hypoglycemia) because it does not work when your blood sugar is low. JANUVIA has not been studied in children under 18 years of age.

JANUVIA has not been studied with insulin, a medicine known to cause low blood sugar.

Who should not take JANUVIA?

Do not take JANUVIA if you:

have had an allergic reaction to JANUVIA. JANUVIA should not be used to treat patients with:

Type 1 diabetes. Diabetic ketoacidosis (increased ketones in the blood or urine). What should I tell my doctor before and during treatment with JANUVIA?

Tell your doctor about all of your medical conditions, including if you:

have had an allergic reaction to JANUVIA. have kidney problems. are pregnant or plan to become pregnant. It is not known if JANUVIA will harm your unborn baby. If you are pregnant, talk with your doctor about the best way to control your blood sugar while you are pregnant. If you use JANUVIA during pregnancy, talk with your doctor about how you can be on the JANUVIA registry. The toll-free telephone number for the pregnancy registry is: 1-800-986-8999. are breast-feeding or plan to breast-feed. It is not known if JANUVIA will pass into your breast milk. Talk with your doctor about the best way to feed your baby if you are taking JANUVIA. Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.

How should I take JANUVIA?

Take JANUVIA exactly as your doctor tells you to take it. Take JANUVIA by mouth once a day. Take JANUVIA with or without food. If you have kidney problems, your doctor may prescribe lower doses of JANUVIA. Your doctor may perform blood tests on you from time to time to measure how well your kidneys are working. Your doctor may prescribe JANUVIA along with certain other medicines that lower blood sugar. If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not take two doses of JANUVIA at the same time. If you take too much JANUVIA, call your doctor or local Poison Control Center right away. When your body is under some types of stress, such as fever, trauma (such as a car accident), infection or surgery, the amount of diabetes medicine that you need may change. Tell your doctor right away if you have any of these conditions and follow your doctor’s instructions. Monitor your blood sugar as your doctor tells you to. Stay on your prescribed diet and exercise program while taking JANUVIA. Talk to your doctor about how to prevent, recognize and manage low blood sugar (hypoglycemia), high blood sugar (hyperglycemia), and complications of diabetes. Your doctor will monitor your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C. What are the possible side effects of JANUVIA?

The most common side effects of JANUVIA include:

Upper respiratory infection Stuffy or runny nose and sore throat Headache JANUVIA may occasionally cause stomach discomfort and diarrhea.

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

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

Allergic reactions, which may be serious, including rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing. If you have an allergic reaction, stop taking JANUVIA and call your doctor right away. Your doctor may prescribe a medication to treat your allergic reaction and a different medication for your diabetes. Tell your doctor if you have any side effect that bothers you or that does not go away.

Other side effects may occur when using JANUVIA. For more information, ask your doctor.

How should I store JANUVIA?

Store JANUVIA at room temperature, 68 to 77?F (20 to 25?C). Keep JANUVIA and all medicines out of the reach of children.

General information about the use of JANUVIA

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

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

What are the ingredients in JANUVIA?

Active ingredient: sitagliptin

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

What is type 2 diabetes?

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

The main goal of treating diabetes is to lower your blood sugar to a normal level. Lowering and controlling blood sugar may help prevent or delay complications of diabetes, such as heart disease, kidney disease, blindness, and amputation.

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

Revised July 2008 ? Manufactured for: ? K MERCK & CO., INC., Whitehouse Station, NJ 08889, USA ? Manufactured by: ? Merck Sharp & Dohme (Italia) S.p.A. Via Emilia, 21 27100 – Pavia, Italy ? 9762705 ? * Trademark of MERCK & CO., Inc., Whitehouse Station, New Jersey, 08889 USA COPYRIGHT (C) 2006, 2007 MERCK & CO., Inc. All rights reserved 9762705

HIGHLIGHTS OF PRESCRIBING INFORMATION

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

? JANUVIA(TM) (sitagliptin) Tablets

Initial U.S. Approval: 2006

? RECENT MAJOR CHANGES

Indications and Usage ? Monotherapy and Combination Therapy (1.1) 10/2007 Important Limitations of Use (1.2) 10/2007 Dosage and Administration Recommended Dosing (2.1) 10/2007 Concomitant Use with a Sulfonylurea (2.3) 10/2007 Contraindications (4) 10/2007 Warnings and Precautions Use with Medications Known to Cause Hypoglycemia (5.2) 10/2007 Hypersensitivity Reactions (5.3) 10/2007 Macrovascular Outcomes (5.4) 07/2008 INDICATIONS AND USAGE

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

Important Limitations of Use:

JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. (1.2) JANUVIA has not been studied in combination with insulin. (1.2) DOSAGE AND ADMINISTRATION

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

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

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

?

CrCl ?30 to

~Serum Cr levels [mg/dL]

Men: >1.7? ?3.0;

Women: >1.5? ?2.5

? Severe and ESRD

?

CrCl

Men: >3.0;

Women: >2.5;

or on dialysis

DOSAGE FORMS AND STRENGTHS

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

CONTRAINDICATIONS

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

WARNINGS AND PRECAUTIONS

Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD. Assessment of renal function is recommended prior to initiating JANUVIA and periodically thereafter. (2.2, 5.1) When used with a sulfonylurea, a lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia. (2.3, 5.2) There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with JANUVIA such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop JANUVIA, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. (5.3, 6.2) There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or any other anti-diabetic drug. (5.4) ADVERSE REACTIONS

Adverse reactions reported in (?)5% of patients treated with JANUVIA and more commonly than in patients treated with placebo are: upper respiratory tract infection, nasopharyngitis and headache. Hypoglycemia was also reported more commonly in patients treated with the combination of JANUVIA and sulfonylurea, with or without metformin, than in patients given the combination of placebo and sulfonylurea, with or without metformin. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Merck & Co., Inc. at 1-877-888-4231 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS

Safety and effectiveness of JANUVIA in children under 18 years have not been established. (8.4) There are no adequate and well-controlled studies in pregnant women. To report drug exposure during pregnancy call 1-800-986-8999. (8.1) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 07/2008

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Monotherapy and Combination Therapy 1.2 Important Limitations of Use 2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing 2.2 Patients with Renal Insufficiency 2.3 Concomitant Use with a Sulfonylurea 3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Use in Patients with Renal Insufficiency 5.2 Use with Medications Known to Cause Hypoglycemia 5.3 Hypersensitivity Reactions 5.4 Macrovascular Outcomes 6 ADVERSE REACTIONS

6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS

7.1 Digoxin 8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES

14.1 Monotherapy 14.2 Combination Therapy 16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Instructions 17.2 Laboratory Tests *Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Monotherapy and Combination Therapy

JANUVIA1 is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. [See Clinical Studies (14).]

1.2 Important Limitations of Use

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

JANUVIA has not been studied in combination with insulin.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

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

2.2 Patients with Renal Insufficiency

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

For patients with moderate renal insufficiency (CrCl ?30 to 1.7 to ?3.0?mg/dL in men and >1.5 to ?2.5?mg/dL in women), the dose of JANUVIA is 50?mg once daily.

For patients with severe renal insufficiency (CrCl 3.0?mg/dL in men and >2.5?mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25?mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

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

2.3 Concomitant Use with a Sulfonylurea

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

3 DOSAGE FORMS AND STRENGTHS

— 100?mg tablets are beige, round, film-coated tablets with “277″ on one side.

— 50?mg tablets are light beige, round, film-coated tablets with “112″ on one side.

— 25?mg tablets are pink, round, film-coated tablets with “221″ on one side.

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 Use in Patients with Renal Insufficiency

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

5.2 Use with Medications Known to Cause Hypoglycemia

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

5.3 Hypersensitivity Reactions

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

5.4 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or any other anti-diabetic drug.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

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

In controlled clinical studies as both monotherapy and combination therapy with metformin or pioglitazone, the overall incidence of adverse reactions, hypoglycemia, and discontinuation of therapy due to clinical adverse reactions with JANUVIA were similar to placebo. In combination with glimepiride, with or without metformin, the overall incidence of clinical adverse reactions with JANUVIA was higher than with placebo, in part related to a higher incidence of hypoglycemia (see Table?1); the incidence of discontinuation due to clinical adverse reactions was similar to placebo.

Two placebo-controlled monotherapy studies, one of 18- and one of 24-week duration, included patients treated with JANUVIA 100?mg daily, JANUVIA 200?mg daily, and placebo. Three 24-week, placebo-controlled add-on combination therapy studies, one with metformin, one with pioglitazone, and one with glimepiride with or without metformin, were also conducted. In addition to a stable dose of metformin, pioglitazone, glimepiride, or glimepiride and metformin, patients whose diabetes was not adequately controlled were given either JANUVIA 100?mg daily or placebo. The adverse reactions, reported regardless of investigator assessment of causality in ?5% of patients treated with JANUVIA 100?mg daily as monotherapy, JANUVIA in combination with pioglitazone, or JANUVIA in combination with glimepiride, with or without metformin, and more commonly than in patients treated with placebo, are shown in Table?1.

Table 1

Placebo-Controlled Clinical Studies of JANUVIA Monotherapy or Add-on Combination Therapy with Pioglitazone or Glimepiride +/- Metformin:

Adverse Reactions Reported in ?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 + Pioglitazone

? Placebo + Pioglitazone

? ? N = 175 ? N = 178 Upper Respiratory Tract Infection ? 11 (6.3) ? 6 (3.4) Headache ? 9 (5.1) ? 7 (3.9) Combination with Glimepiride (+/- Metformin) ? JANUVIA 100 mg + Glimepiride

(+/- Metformin)

? Placebo + Glimepiride

(+/- Metformin)

? ? N = 222 ? N = 219 Hypoglycemia ? 27 (12.2) ? 4 (1.8) Nasopharyngitis ? 14 (6.3) ? 10 (4.6) Headache ? 13 (5.9) ? 5 (2.3) ? Intent to treat population

In the study of patients receiving JANUVIA as add-on combination therapy with metformin, there were no adverse reactions reported regardless of investigator assessment of causality in ?5% of patients and more commonly than in patients given placebo.

In the prespecified pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on to pioglitazone study, the overall incidence of adverse reactions of hypoglycemia in patients treated with JANUVIA 100?mg was similar to placebo (1.2% vs 0.9%). Adverse reactions of hypoglycemia were based on all reports of hypoglycemia; a concurrent glucose measurement was not required. The incidence of selected gastrointestinal adverse reactions in patients treated with JANUVIA was as follows: abdominal pain (JANUVIA 100?mg, 2.3%; placebo, 2.1%), nausea (1.4%, 0.6%), and diarrhea (3.0%, 2.3%).

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

Table 2

Initial Therapy with Combination of Sitagliptin and Metformin:

Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in ?5% of Patients Receiving Combination Therapy (and Greater than in Patients Receiving Metformin alone, Sitagliptin alone, and Placebo)?

? ? Number of Patients (%) ? ? Placebo

? Sitagliptin (JANUVIA)

100 mg QD

? Metformin

500 or 1000 mg bid ??

? Sitagliptin

50 mg bid +

Metformin

500 or 1000 mg bid ??

? ? N = 176 ? N = 179 ? N = 364??

? N = 372??

Upper Respiratory Infection ? 9 (5.1) ? 8 (4.5) ? 19 (5.2) ? 23 (6.2) Headache ? 5 (2.8) ? 2 (1.1) ? 14 (3.8) ? 22 (5.9) ? Intent-to-treat population.

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

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

Laboratory Tests

Across clinical studies, the incidence of laboratory adverse reactions was similar in patients treated with JANUVIA 100?mg compared to patients treated with placebo. A small increase in white blood cell count (WBC) was observed due to an increase in neutrophils. This increase in WBC (of approximately 200 cells/microL vs placebo, in four pooled placebo-controlled clinical studies, with a mean baseline WBC count of approximately 6600 cells/microL) is not considered to be clinically relevant. In a 12-week study of 91 patients with chronic renal insufficiency, 37 patients with moderate renal insufficiency were randomized to JANUVIA 50?mg daily, while 14 patients with the same magnitude of renal impairment were randomized to placebo. Mean (SE) increases in serum creatinine were observed in patients treated with JANUVIA [0.12?mg/dL (0.04)] and in patients treated with placebo [0.07?mg/dL (0.07)]. The clinical significance of this added increase in serum creatinine relative to placebo is not known.

6.2 Postmarketing Experience

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

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

7 DRUG INTERACTIONS

7.1 Digoxin

There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 18%) of digoxin with the co-administration of 100?mg sitagliptin for 10 days. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or JANUVIA is recommended.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category?B:

Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 125?mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Merck & Co., Inc. maintains a registry to monitor the pregnancy outcomes of women exposed to JANUVIA while pregnant. Health care providers are encouraged to report any prenatal exposure to JANUVIA by calling the Pregnancy Registry at (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 under 18 years of age have not been established.

8.5 Geriatric Use

Of the total number of subjects (N=3884) in pre-approval clinical safety and efficacy studies of JANUVIA, 725 patients were 65 years and over, while 61 patients were 75 years and over. No overall differences in safety or effectiveness were observed between subjects 65 years and over and younger subjects. While this and other reported clinical experience have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

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

10 OVERDOSAGE

During controlled clinical trials in healthy subjects, single doses of up to 800?mg JANUVIA were administered. Maximal mean increases in QTc of 8.0?msec were observed in one study at a dose of 800?mg JANUVIA, a mean effect that is not considered clinically important [see Clinical Pharmacology (12.2)]. There is no experience with doses above 800?mg in humans. In Phase?I multiple-dose studies, there were no dose-related clinical adverse reactions observed with JANUVIA with doses of up to 600 mg per day for periods of up to 10 days and 400?mg per day for up to 28 days.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as dictated by the patient’s clinical status.

Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

11 DESCRIPTION

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

Sitagliptin phosphate monohydrate is described chemically as 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl] -5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate.

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

(Graphic Omitted)

Sitagliptin phosphate monohydrate is a white to off-white, crystalline, non-hygroscopic powder. It is soluble in water and N,N-dimethyl formamide; slightly soluble in methanol; very slightly soluble in ethanol, acetone, and acetonitrile; and insoluble in isopropanol and isopropyl acetate.

Each film-coated tablet of JANUVIA contains 32.13, 64.25, or 128.5?mg of sitagliptin phosphate monohydrate, which is equivalent to 25, 50, or 100?mg, respectively, of free base and the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide, and yellow iron oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by JANUVIA, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

12.2 Pharmacodynamics

General

In patients with type 2 diabetes, administration of JANUVIA led to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.

In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, whereas metformin alone increased active and total GLP-1 concentrations to similar extents. Co-administration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations. It is unclear how these findings relate to changes in glycemic control in patients with type 2 diabetes.

In studies with healthy subjects, JANUVIA did not lower blood glucose or cause hypoglycemia.

Cardiac Electrophysiology

In a randomized, placebo-controlled crossover study, 79 healthy subjects were administered a single oral dose of JANUVIA 100?mg, JANUVIA 800?mg (8 times the recommended dose), and placebo. At the recommended dose of 100?mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800?mg dose, the maximum increase in the placebo-corrected mean change in QTc from baseline was observed at 3 hours postdose and was 8.0?msec. This increase is not considered to be clinically significant. At the 800?mg dose, peak sitagliptin plasma concentrations were approximately 11 times higher than the peak concentrations following a 100?mg dose.

In patients with type 2 diabetes administered JANUVIA 100?mg (N=81) or JANUVIA 200?mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.

12.3 Pharmacokinetics

The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100?mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose. Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100?mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 ?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

CrCl =

? [140 - age (years)] x weight (kg)

[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 >9).

Body Mass Index (BMI)

No dosage adjustment is necessary based on BMI. Body mass index had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.

Gender

No dosage adjustment is necessary based on gender. Gender had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.

Geriatric

No dosage adjustment is required based solely on age. When the effects of age on renal function are taken into account, age alone did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis. Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.

Pediatric

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

Race

No dosage adjustment is necessary based on race. Race had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of available pharmacokinetic data, including subjects of white, Hispanic, black, Asian, and other racial groups.

Drug Interactions

In Vitro Assessment of Drug Interactions

Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4. Sitagliptin is a p-glycoprotein substrate, but does not inhibit p-glycoprotein mediated transport of digoxin. Based on these results, sitagliptin is considered unlikely to cause interactions with other drugs that utilize these pathways.

Sitagliptin is not extensively bound to plasma proteins. Therefore, the propensity of sitagliptin to be involved in clinically meaningful drug-drug interactions mediated by plasma protein binding displacement is very low.

In Vivo Assessment of Drug Interactions

Effects of Sitagliptin on Other Drugs

In clinical studies, as described below, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT).

Digoxin: Sitagliptin had a minimal effect on the pharmacokinetics of digoxin. Following administration of 0.25?mg digoxin concomitantly with 100?mg of JANUVIA daily for 10 days, the plasma AUC of digoxin was increased by 11%, and the plasma Cmax by 18%.

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

Sulfonylureas: Single-dose pharmacokinetics of glyburide, a CYP2C9 substrate, was not meaningfully altered in subjects receiving multiple doses of sitagliptin. Clinically meaningful interactions would not be expected with other sulfonylureas (e.g., glipizide, tolbutamide, and glimepiride) which, like glyburide, are primarily eliminated by CYP2C9.

Simvastatin: Single-dose pharmacokinetics of simvastatin, a CYP3A4 substrate, was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin. Therefore, sitagliptin is not an inhibitor of CYP3A4-mediated metabolism.

Thiazolidinediones: Single-dose pharmacokinetics of rosiglitazone was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin, indicating that JANUVIA is not an inhibitor of CYP2C8-mediated metabolism.

Warfarin: Multiple daily doses of sitagliptin did not meaningfully alter the pharmacokinetics, as assessed by measurement of S(-) or R(+) warfarin enantiomers, or pharmacodynamics (as assessed by measurement of prothrombin INR) of a single dose of warfarin. Because S(-) warfarin is primarily metabolized by CYP2C9, these data also support the conclusion that sitagliptin is not a CYP2C9 inhibitor.

Oral Contraceptives: Co-administration with sitagliptin did not meaningfully alter the steady-state pharmacokinetics of norethindrone or ethinyl estradiol.

Effects of Other Drugs on Sitagliptin

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

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

Cyclosporine: A study was conducted to assess the effect of cyclosporine, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Co-administration of a single 100?mg oral dose of JANUVIA and a single 600?mg oral dose of cyclosporine increased the AUC and Cmax of sitagliptin by approximately 29% and 68%, respectively. These modest changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of sitagliptin was also not meaningfully altered. Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment?of?Fertility

A two-year carcinogenicity study was conducted in male and female rats given oral doses of sitagliptin of 50, 150, and 500?mg/kg/day. There was an increased incidence of combined liver adenoma/carcinoma in males and females and of liver carcinoma in females at 500?mg/kg. This dose results in exposures approximately 60 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 100?mg/day based on AUC comparisons. Liver tumors were not observed at 150?mg/kg, approximately 20 times the human exposure at the MRHD. A two-year carcinogenicity study was conducted in male and female mice given oral doses of sitagliptin of 50, 125, 250, and 500?mg/kg/day. There was no increase in the incidence of tumors in any organ up to 500?mg/kg, approximately 70 times human exposure at the MRHD. Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a Chinese hamster ovary (CHO) chromosome aberration assay, an in vitro cytogenetics assay in CHO, an in vitro rat hepatocyte DNA alkaline elution assay, and an in vivo micronucleus assay.

In rat fertility studies with oral gavage doses of 125, 250, and 1000?mg/kg, males were treated for 4 weeks prior to mating, during mating, up to scheduled termination (approximately 8 weeks total) and females were treated 2 weeks prior to mating through gestation day 7. No adverse effect on fertility was observed at 125?mg/kg (approximately 12 times human exposure at the MRHD of 100?mg/day based on AUC comparisons). At higher doses, nondose-related increased resorptions in females were observed (approximately 25 and 100 times human exposure at the MRHD based on AUC comparison).

14 CLINICAL STUDIES

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

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

14.1 Monotherapy

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

Treatment with JANUVIA at 100&#1

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