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FDA Approves Once-Daily JANUVIA(TM), the First and Only DPP-4 Inhibitor Available in the United States for Type 2 Diabetes

Posted on: Tuesday, 17 October 2006, 18:00 CDT

Merck & Co., Inc. announced today that the U.S. Food and Drug Administration (FDA) approved JANUVIA™ (sitagliptin phosphate), the first and only DPP-4 inhibitor available in the United States for the treatment of type 2 diabetes. JANUVIA has been approved as monotherapy and as add-on therapy to either of two other types of oral diabetes medications, metformin or thiazolidinediones (TZDs), to improve blood sugar (glucose) control in patients with type 2 diabetes when diet and exercise is not enough. The recommended dose of JANUVIA is 100 mg once daily. JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

JANUVIA enhances a natural body system to significantly lower elevated blood sugar

JANUVIA belongs to a new breakthrough class of prescription medications called dipeptidyl peptidase-4 (DPP-4) inhibitors that improves blood sugar control in patients with type 2 diabetes. JANUVIA 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. Through DPP-4 inhibition, JANUVIA works only when blood sugar is elevated to address diminished insulin due to beta-cell dysfunction and uncontrolled production of glucose by the liver due to alpha-cell and beta-cell dysfunction.

"Those patients who are unable to adequately manage their type 2 diabetes with lifestyle changes, like healthy eating and increased physical exercise, and who require medications now have a new product to help regulate their blood sugar levels," said Edward S. Horton, M.D., director of clinical research, Joslin Diabetes Center and professor of medicine, Harvard Medical School, Boston.

"JANUVIA underscores Merck's commitment to the field of diabetes, and the benefits we strive to bring to patients and physicians who struggle in the treatment of type 2 diabetes," said Richard T. Clark, president and chief executive officer, Merck. "The approval of JANUVIA is a clear example of Merck's focus on developing innovative therapies to improve human health around the world."

JANUVIA had an overall incidence of side effects comparable to placebo

In clinical trials, JANUVIA demonstrated an overall incidence of side effects comparable to placebo. The most common side effects reported with JANUVIA (≥5 percent and higher than placebo) were stuffy or runny nose and sore throat, upper respiratory infection, and headache.

JANUVIA provides powerful A1C(1) reductions as monotherapy

In two double-blind, placebo-controlled studies of 24 weeks (n=473) and 18 weeks (n=296) in patients with mild to moderate baseline A1C levels (mean 8.0%; enrollment range 7.0% to 10.0%), JANUVIA 100 mg once-daily showed significant mean differences in A1C from placebo of -0.8% and -0.6%, respectively (p<0.001). As is typical in 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. In a pooled analysis of these two monotherapy studies, a pre-specified subgroup analysis showed that when patients were grouped by baseline A1C into those with mildly elevated A1C levels (<8%, n=411), moderately elevated A1C levels (≥8% to <9%, n=239) and the highest elevated A1C levels (≥9%, n=119), mean differences in A1C from placebo after 18 weeks were -0.6%, -0.7% and -1.4%, respectively (p<0.001 for treatment by subgroup interactions).

JANUVIA has a significant and complementary effect when added to metformin or TZDs

JANUVIA addresses two of the three key defects that cause poor glucose control: diminished insulin release due to beta-cell dysfunction and uncontrolled production of glucose by the liver due to alpha-cell and beta-cell dysfunction. By adding JANUVIA to the insulin sensitizers metformin or pioglitazone (a TZD), the three key defects of type 2 diabetes can be addressed: insulin resistance, beta-cell dysfunction (decreased insulin release), and alpha-cell dysfunction (unsuppressed hepatic glucose production).

In separate 24-week studies of patients with type 2 diabetes who were inadequately controlled on either metformin or pioglitazone alone, JANUVIA 100 mg once daily provided a complementary effect. JANUVIA showed significant mean differences in A1C from placebo of -0.7% in the metformin add-on study (p<0.001) and -0.7% in the pioglitazone add-on study (p<0.001). In those same studies, the mean A1C reduction from baseline with JANUVIA was 0.7% from a mean baseline A1C of 8.0% and 0.9% from a mean baseline of 8.1%, respectively.

Approximately twice as many patients got to A1C goal of <7% with JANUVIA

In the metformin add-on study, more than twice as many patients uncontrolled on metformin got to A1C goal of <7% when JANUVIA was added (47 percent with JANUVIA and metformin vs. 18 percent for patients continuing on metformin alone) (p<0.001). Similarly, in the pioglitazone add-on study, 45 percent of patients adding JANUVIA to their regimen reached the A1C goal of <7% compared with 23 percent who continued on pioglitazone alone (p<0.001).

JANUVIA provides powerful A1C lowering through combined reductions of both PPG and FPG throughout the day

JANUVIA has been demonstrated to provide a 24-hour glucose response at mealtime, between meals and overnight. In a 24-week, placebo-controlled study of patients uncontrolled on metformin, adding JANUVIA 100 mg once daily substantially reduced PPG (or post-meal glucose) levels by 51 mg/dL and FPG by 25 mg/dL compared to patients continuing on metformin alone (p<0.001).

Treatment with JANUVIA was not associated with weight gain or increased risk of hypoglycemia

JANUVIA once-daily was weight neutral compared to placebo in clinical trials. Mean body weight decreased 0.2 kg (vs. 1.1 kg decrease for placebo) and 0.7 kg (vs. 0.6 kg), respectively, in two 24-week trials: one in patients taking JANUVIA as monotherapy (n=193) and one in combination with metformin (n=399). The overall incidence of hypoglycemia in patients treated with JANUVIA 100 mg was similar to placebo (1.2 percent vs. 0.9 percent, respectively) across the clinical program. The incidence of selected gastrointestinal adverse reactions in patients treated with JANUVIA was as follows: abdominal pain (JANUVIA, 2.3 percent; placebo, 2.1 percent), nausea (1.4 percent, 0.6 percent), and diarrhea (3.0 percent, 2.3 percent).

Glucose-dependent mechanism of action

The novel mechanism of JANUVIA is glucose-dependent, responding to the presence of elevated glucose and resulting in the release of insulin and decrease of glucagon only when needed, thereby lowering the potential for hypoglycemia. By inhibiting the DPP-4 enzyme, JANUVIA significantly increases the levels of active incretin hormones, increasing the synthesis and release of insulin from the pancreatic beta cells and decreasing the release of glucagon from the pancreatic alpha cells.

Indications and contraindications for JANUVIA

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 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.

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.

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

Pricing and availability of JANUVIA

The price of once-daily JANUVIA will be $4.86 per tablet. JANUVIA will be broadly available in pharmacies in the near future.

About type 2 diabetes

Type 2 diabetes is a condition in which the body has elevated blood sugar or glucose. With type 2 diabetes, the body may not make enough insulin, the insulin that the body produces may not work as well as it should, and/or the liver may release too much glucose.

Nearly 21 million people in the United States (7 percent of the population) have diabetes, with type 2 accounting for 90-95 percent of cases. Approximately half of people diagnosed with type 2 diabetes have not achieved adequate control of their blood sugar levels. Patients with diabetes can develop heart disease, kidney disease, blindness, vascular or neurological problems that can lead to amputation and can suffer increased rates of mortality.

It is estimated that one in three Americans born in 2000 will develop diabetes sometime during their lifetime. There are currently more than 230 million people with diabetes worldwide, and if nothing is done to slow the epidemic, the worldwide number may exceed 350 million by 2025. The American Diabetes Association recommends that patients with type 2 diabetes achieve a target A1C level of <7%, while the American Academy of Clinical Endocrinologists recommends a target A1C level of <6.5%.

Expanding clinical development program for JANUVIA

Merck's clinical development program for JANUVIA is robust and continues to expand with 43 studies completed or under way, and four more studies set to begin this year. There are about 6,700 patients in the Company's clinical studies with about 4,700 of these patients being treated with JANUVIA. Additionally, about 1,100 patients have been treated with JANUVIA for more than a year.

JANUVIA also is being investigated as part of a single tablet combination with metformin (MK-0431A). MK-0431A has been accepted for standard review by the FDA, and an FDA action is expected by the end of March 2007. Regulatory filings in countries outside the United States are moving forward as planned.

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.

Merck forward-looking statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2005, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.

NOTE: The views stated herein are those of Dr. Edward Horton and do not necessarily represent the views of Joslin Diabetes Center. Joslin Diabetes Center does not endorse products, did not participate in any tests for the product JANUVIA and makes no representations as to its quality or efficacy.

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

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

Prescribing information and patient product information for JANUVIA are attached.

JANUVIA(TM)(sitagliptin phosphate) Tablets 9762700

HIGHLIGHTS OF PRESCRIBING INFORMATION

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

JANUVIA(TM) (sitagliptin phosphate) Tablets

Initial U.S. Approval: 2006

INDICATIONS AND USAGE

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

-- Monotherapy (1.1)

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

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

DOSAGE AND ADMINISTRATION

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

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

Dosage Adjustment in Patients With Moderate, Severe and End Stage Renal Disease (ESRD) (2.2) ---------------------------------------------------------------------- 50 mg once daily 25 mg once daily ---------------------------------------------------------------------- Moderate Severe and ESRD CrCl greater than or equal to 30 CrCl less than 30 mL/min to less than 50 mL/min ~Serum Cr levels (mg/dL) ~Serum Cr levels (mg/dL) Men: greater than 1.7 - Men: greater than 3.0; less than or equal to 3.0; Women: greater than 1.5 - Women: greater than 2.5; less than or equal to 2.5 or on dialysis ----------------------------------------------------------------------

DOSAGE FORMS AND STRENGTHS

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

CONTRAINDICATIONS

None. (4)

WARNINGS AND PRECAUTIONS

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

ADVERSE REACTIONS

The most common adverse reactions, reported in greater than or equal to 5% of patients treated with JANUVIA and more commonly than in patients treated with placebo are: upper respiratory tract infection, nasopharyngitis, and headache. (6.1)

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

USE IN SPECIFIC POPULATIONS

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

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

Revised: 10/2006

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Monotherapy

1.2 Combination Therapy

1.3 Important Limitations of Use

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

2.2 Patients with Renal Insufficiency

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

7 DRUG INTERACTIONS

7.1 Digoxin

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Monotherapy

14.2 Combination Therapy

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Instructions

17.2 Laboratory Tests

17.3 FDA-Approved Patient Labeling

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

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Monotherapy

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

1.2 Combination Therapy

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

1.3 Important Limitations of Use

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

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

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

2.2 Patients with Renal Insufficiency

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

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

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

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

3 DOSAGE FORMS AND STRENGTHS

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

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

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

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

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

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

6 ADVERSE REACTIONS

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

6.1 Clinical Trials Experience

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

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

Table 1 Placebo-Controlled Clinical Studies of JANUVIA Monotherapy or Combination with Pioglitazone: Adverse Reactions Reported in Greater than or equal to 5% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality+ ---------------------------------------------------------------------- Number of Patients (%) ---------------------------------------------------------------------- Monotherapy JANUVIA, 100 mg Placebo ---------------------------------------------------------------------- N = 443 N = 363 ---------------------------------------------------------------------- Nasopharyngitis 23 (5.2) 12 (3.3) ---------------------------------------------------------------------- Combination with Pioglitazone JANUVIA 100 mg + Placebo + Pioglitazone Pioglitazone ---------------------------------------------------------------------- N = 175 N = 178 ---------------------------------------------------------------------- Upper Respiratory Tract Infection 11 (6.3) 6 (3.4) ---------------------------------------------------------------------- Headache 9 (5.1) 7 (3.9) ----------------------------------------------------------------------

+ Intent to treat population

In patients receiving JANUVIA in combination with metformin, there were no adverse reactions reported regardless of investigator assessment of causality in greater than or equal to 5% of patients and more commonly than in patients given placebo.

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

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

Laboratory Tests

The incidence of laboratory adverse reactions in patients treated with JANUVIA 100 mg was 8.2% compared to 9.8% in patients treated with placebo. Across clinical studies, a small increase in white blood cell count (approximately 200 cells/microL difference in WBC vs placebo; mean baseline WBC approximately 6600 cells/microL) was observed due to an increase in neutrophils. This observation was seen in most but not all studies. This change in laboratory parameters is not considered to be clinically relevant. In a 12-week study of 91 patients with chronic renal insufficiency, 37 patients with moderate renal insufficiency were randomized to JANUVIA 50 mg daily, while 14 patients with the same magnitude of renal impairment were randomized to placebo. Mean (SE) increases in serum creatinine were observed in patients treated with JANUVIA (0.12 mg/dL (0.04)) and in patients treated with placebo (0.07 mg/dL (0.07)). The clinical significance of this added increase in serum creatinine relative to placebo is not known.

7 DRUG INTERACTIONS

7.1 Digoxin

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B:

Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Merck & Co., Inc. maintains a registry to monitor the pregnancy outcomes of women exposed to JANUVIA while pregnant. Health care providers are encouraged to report any prenatal exposure to JANUVIA by calling the Pregnancy Registry at (800) 986-8999.

Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately 30- and 20-times human exposure at the maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100 times human exposure at the MRHD.

Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1000 mg/kg. No functional or behavioral toxicity was observed in offspring of rats.

Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours postdose. Placental transfer of sitagliptin administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.

8.3 Nursing Mothers

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

8.4 Pediatric Use

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

8.5 Geriatric Use

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

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

10 OVERDOSAGE

During controlled clinical trials in healthy subjects, single doses of up to 800 mg JANUVIA were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg JANUVIA, a mean effect that is not considered clinically important (see Clinical Pharmacology (12.2)). There is no experience with doses above 800 mg in humans.

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

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

11 DESCRIPTION

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

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

The empirical formula is C16H15F6N5O&8226;H2O and the molecular weight is 523.32. The structural formula is:

(OBJECT OMITTED)

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

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

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

General

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

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

Cardiac Electrophysiology

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

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

12.3 Pharmacokinetics

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

Absorption

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

Distribution

The mean volume of distribution at steady state following a single 100 mg intravenous dose of sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).

Metabolism

Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a (14C)sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

Excretion

Following administration of an oral (14C)sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

Special Populations

Renal Insufficiency

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

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

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

Hepatic Insufficiency

In patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), mean AUC and Cmax of sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched controls following administration of a single 100 mg dose of JANUVIA. These differences are not considered to be clinically meaningful. No dosage adjustment for JANUVIA is necessary for patients with mild or moderate hepatic insufficiency.

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

Body Mass Index (BMI)

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

Gender

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

Geriatric

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

Pediatric

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

Race

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

Drug Interactions

In Vitro Assessment of Drug Interactions

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

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

In Vivo Assessment of Drug Interactions

Effects of Sitagliptin on Other Drugs

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

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

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

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

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

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

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

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

Effects of Other Drugs on Sitagliptin

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

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

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

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

14 CLINICAL STUDIES

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

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

14.1 Monotherapy

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

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

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

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

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

ss. pless than0.001 compared to placebo.

% Data not available.

Additional Monotherapy Study

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

14.2 Combination Therapy

Combination Therapy with Metformin

A total of 701 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of JANUVIA in combination with metformin. Patients already on metformin (N=431) at a dose of at least 1500 mg per day were randomized after completing a 2-week single-blind placebo run-in period. Patients on metformin and another antihyperglycemic agent (N = 229) and patients not on any antihyperglycemic agents (off therapy for at least 8 weeks, N = 41) were randomized after a run-in period of approximately 10 weeks on metformin (at a dose of at least 1500 mg per day) in monotherapy. Patients were randomized to the addition of either 100 mg of JANUVIA or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue.

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

Table 3 Glycemic Parameters at Final Visit (24-Week Study) for JANUVIA in Combination with Metformin+ ---------------------------------------------------------------------- JANUVIA Placebo + 100 mg + Metformin Metformin ----------------------------------------------------------- --------- A1C (%) N = 453 N = 224 ----------------------------------------------------------- --------- Baseline (mean) 8.0 8.0 ----------------------------------------------------------- --------- Change from baseline (adjusted mean++) -0.7 -0.0 ----------------------------------------------------------- --------- Difference from placebo + metformin (adjusted -0.7ss. mean++) (95% CI) (-0.8, -0.5) ----------------------------------------------------------- --------- Patients (%) achieving A1C less than7% 213 (47%) 41 (18%) ----------------------------------------------------------- --------- FPG (mg/dL) N = 454 N = 226 ----------------------------------------------------------- --------- Baseline (mean) 170 174 ----------------------------------------------------------- --------- Change from baseline (adjusted mean++) -17 9 ----------------------------------------------------------- --------- Difference from placebo + metformin (adjusted -25ss. mean++) (95% CI) (-31, -20) ----------------------------------------------------------- --------- 2-hour PPG (mg/dL) N = 387 N = 182 ----------------------------------------------------------- --------- Baseline (mean) 275 272 ----------------------------------------------------------- --------- Change from baseline (adjusted mean++) -62 -11 ----------------------------------------------------------- --------- Difference from placebo + metformin (adjusted -51ss. mean++) (95% CI) (-61, -41) ----------------------------------------------------------- ---------

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

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

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

Combination Therapy with Pioglitazone

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

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

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

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

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

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

16 HOW SUPPLIED/STORAGE AND HANDLING

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

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

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

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

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

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

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

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

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

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

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

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

NDC 0006-0277-74 bottles of 500

NDC 0006-0277-82 bottles of 1000.

Storage

Store at 20-25(degree)C (68-77(degree)F), excursions permitted to 15-30(degree)C (59-86(degree)F), (see USP Controlled Room Temperature).

17 PATIENT COUNSELING INFORMATION

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

17.1 Instructions

Patients should be informed of the potential risks and benefits of JANUVIA and of alternative modes of therapy. Patients should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be advised to seek medical advice promptly.

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

17.2 Laboratory Tests

Patients should be informed that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and A1C levels, with a goal of decreasing these levels towards the normal range. A1C is especially useful for evaluating long-term glycemic control. Patients should be informed of the potential need to adjust dose based on changes in renal function tests over time.

Manufactured for:

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

Manufactured by:

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

Via Emilia, 21

27100 - Pavia, Italy

Printed in USA

9762700

US Patent No.: 6,699,871

17.3 FDA-Approved Patient Labeling

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

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

All rights reserved 9762700 Patient Information JANUVIA(TM) (jah-NEW-vee-ah) (sitagliptin phosphate)

Tablets

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

What is JANUVIA?

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

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

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

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

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

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

Who should not take JANUVIA?

JANUVIA should not

Source: Business Wire

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