New Study Data: Januvia (sitagliptin) Significantly Reduced Blood Sugar Levels and Was Not Associated with Hypoglycemia in Elderly Patients with Type 2 Diabetes

NATIONAL HARBOR, Md.--(BUSINESS WIRE)--Nov 21, 2008 - New data presented at the 61st Annual Scientific Meeting of the Gerontological Society of America showed JANUVIA (sitagliptin), a diabetes medicine from Merck & Co., Inc., significantly reduced blood sugar levels in elderly patients with type 2 diabetes and was not associated with hypoglycemia (low blood sugar). In this study of 206 patients aged 65 to 96 years, there were no reports of hypoglycemia in either the JANUVIA or the placebo groups. Advanced age contributes to the risk of hypoglycemia.

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 in patients with a history of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis and angioedema. 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.

“The elderly population presents challenges for the treatment of type 2 diabetes, as various factors can affect the ability to lower these patients' blood sugar to target levels,” said lead study investigator Nir Barzilai, M.D., director of the Institute for Aging Research and Animal Physiology Core, Diabetes Research Training Center at the Albert Einstein College of Medicine. "In this study, JANUVIA effectively helped lower blood glucose levels and was not associated with hypoglycemia."

JANUVIA significantly reduced blood sugar levels with no reported cases of hypoglycemia in this study

In this 24-week randomized, double-blind, placebo-controlled trial, 206 patients aged 65 years and older (mean age of 72 years) with baseline A1C1 levels of 7.0 to 10.0 percent (baseline mean of 7.8 percent) received JANUVIA (n=102) or placebo (n=104). In patients treated with JANUVIA, the mean placebo-adjusted A1C reduction from baseline at 24 weeks was 0.7 percent (JANUVIA, -0.5 percent vs. placebo, +0.2 percent; p<0.001). More than twice as many patients treated with JANUVIA had an A1C less than the American Diabetes Association recommended A1C goal of 7.0 percent at 24 weeks compared with patients given placebo (35 percent vs. 15 percent, respectively; p<0.05). Patients aged 75 years and older (n=30) had a similar response to treatment with JANUVIA as those under age 75 (n=71) (mean placebo-adjusted A1C reductions of 0.7 percent in both groups, p=0.988). In patients treated with JANUVIA, the mean placebo-adjusted reductions from baseline in fasting plasma glucose (FPG) and 2-hour post prandial glucose (PPG) were 27 and 61 mg/dL, respectively (p<0.001).

Safety parameters were also assessed in this study. For patients in the JANUVIA or placebo group, respectively, the incidences of overall adverse experiences (AEs), serious AEs and AEs leading to discontinuation were 46 and 53 percent, 7 and 13 percent and 5 and 3 percent.

Clinical AEs of hypoglycemia and selected gastrointestinal (GI) events (nausea, vomiting, abdominal pain and diarrhea) as well as body weight were pre-specified as AEs of interest. No cases of hypoglycemia were reported in patients treated with JANUVIA. The incidence of pre-specified GI events was similar between the JANUVIA and placebo groups. AEs of constipation (ranging from mild to severe in intensity, all non-serious) were reported for five patients (5 percent) in the JANUVIA group and zero patients in the placebo group. Mean weight loss from baseline was 1.1 kg in patients treated with JANUVIA (p=0.079) and 1.7 kg in patients given placebo (p=0.010).

An important predictive factor of the magnitude of A1C reduction in response to anti-hyperglycemic therapy is a patient's starting level of A1C – the higher the starting level of A1C, the greater the expected reduction in A1C following treatment, and this was observed in this study. In a subgroup analysis of patients grouped by severity of starting baseline A1C, the mean placebo-adjusted reduction was 1.6 percent for patients with baseline A1C of 9.0 percent or more (n=13), while placebo-adjusted reductions of 0.9 percent and 0.5 percent were seen with baseline A1C values of 8 to less than 9 percent (n=20) and less than 8 percent (n=68), respectively (p=0.043, for treatment by subgroup interaction).

Type 2 diabetes in the elderly

Type 2 diabetes can be difficult and complicated to treat in older patients. Treatments for elderly patients must be selected with care, in light of the frequent presence of comorbidities or other medication use. Achieving target glycemic goals while avoiding low blood sugar can also be a challenge for aging patients with type 2 diabetes, as advanced age itself can contribute to the risk of hypoglycemia.

Recognition of hypoglycemia may be diminished in the elderly. Symptoms of hypoglycemia may include shakiness, dizziness, sweating, hunger, headache, pale skin color, sudden moodiness or behavior changes, clumsy or jerky movements, seizure, confusion and unconsciousness.

Use of JANUVIA in the elderly

Of the total number of subjects (n=3,884) 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.

Additional Information about JANUVIA

In controlled clinical studies as both monotherapy and combination therapy with metformin or pioglitazone, the overall incidences 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 (‰¥ 5 percent and higher than placebo) were stuffy or runny nose and sore throat, upper respiratory infection and headache. In clinical trials in combination with a sulfonylurea (glimepiride), with or without metformin, JANUVIA demonstrated an overall incidence of adverse reactions higher than that seen with placebo, in part related to a higher incidence of hypoglycemia.

In a pre-specified pooled analysis of two monotherapy studies, an add-on to metformin study, and an 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 percent vs. 0.9 percent). Adverse reactions of hypoglycemia were based on all reports of hypoglycemia; a concurrent glucose measurement was not required. In an additional, 24-week, placebo-controlled factorial study of initial therapy with sitagliptin in combination with metformin, the incidence of hypoglycemia was 0.6 percent in patients given placebo, 0.6 percent in patients given sitagliptin alone, 0.8 percent in patients given metformin alone and 1.6 percent in patients given sitagliptin in combination with metformin.

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

Selected cautionary information for JANUVIA

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

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

Expanding clinical development program for sitagliptin family

Merck's clinical development program for sitagliptin is robust and continues to expand with 55 studies completed or underway. It is estimated that approximately 7,400 patients have been treated with sitagliptin out of about 12,000 patients who have participated in the Company's clinical studies. Additionally, in clinical studies, approximately 2,300 patients have been treated with sitagliptin for more than one year and, of these, approximately 500 patients have been treated for at least two years.

About Merck

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

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.

JANUVIA™

(sitagliptin) Tablets

9762706

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™ (sitagliptin) Tablets

Initial U.S. Approval: 2006

RECENT MAJOR CHANGES

Warnings and Precautions

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 <50 ml> ~Serum Cr levels [mg/dL]
Men: >1.7– <=3.0;
Women: >1.5– <=2.5

 

 

Severe and ESRD

 

CrCl <30 ml> ~Serum Cr levels [mg/dL]
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 www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS

 

  • Safety and effectiveness of JANUVIA in children under 18 years have not been established. (8.4)
  • There are no adequate and well-controlled studies in pregnant women. To report drug exposure during pregnancy call 1-800-986-8999. (8.1)

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

Revised: 10/2008

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 <50 mL/min, approximately corresponding to serum creatinine levels of >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 <30 mL/min, approximately corresponding to serum creatinine levels of >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)]; hepatic enzyme elevations.

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 C16H15F6N5OH3PO4H2O 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 μMhr, 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 <80 mL/min), moderate (30 to <50 mL/min), and severe (<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 >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 subje

Posted: November 2008

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