In a Post-Hoc Analysis, Januvia (sitagliptin), Merck's Diabetes Medicine, Compared with a Sulfonylurea (Glipizide) on Composite Endpoint of Lower Blood Sugar, No Hypoglycemia and No Weight Gain

New Data Presented at the American Diabetes Association 70th Annual Scientific Sessions

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Jun 28, 2010 - In a new post-hoc analysis presented for the first time at the American Diabetes Association (ADA) 70th Annual Scientific Sessions, significantly more patients treated with the DPP-4 inhibitor JANUVIA (sitagliptin) for one year achieved a composite endpoint of A1C1 reduction (greater than 0.5 percent), no hypoglycemia and no weight gain compared with patients treated with glipizide, a commonly used sulfonylurea.

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 patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using JANUVIA.

“Managing the risks of hypoglycemia and weight gain are important considerations when physicians choose among type 2 diabetes medicines for patients, so it is important to have data about these effects in different treatment regimens,” said Barry J. Goldstein, M.D., Ph.D., vice president of Clinical Research, Merck Research Laboratories. “In the original study, JANUVIA lowered blood sugar levels to a similar extent as a sulfonylurea, and was associated with less hypoglycemia and weight gain compared with the sulfonylurea.”

In a population with a mean baseline A1C of 7.5 percent, this post-hoc analysis was conducted using data from the previously published study. A composite endpoint was defined as reduction in A1C of greater than 0.5 percent, no hypoglycemia and no weight gain. In the analysis, significantly more patients taking JANUVIA experienced the composite endpoint of A1C reduction without weight gain or hypoglycemia (38.1 percent of 388 patients), compared with patients treated with glipizide (11.8 percent of 415 patients) over one year (a between-group difference of 26.3 percent [95 percent CI: 20.5, 32.0]).

Hypoglycemia, or low blood sugar, occurs when the level of glucose in the blood drops too low for the body's needs. Hypoglycemia can occur in patients with type 2 diabetes and is usually associated with certain medications. Symptoms of hypoglycemia can range from mild to severe, and may include headache, drowsiness, weakness, dizziness, confusion, irritability, hunger, fast heart beat, sweating and feeling jittery.

JANUVIA is a selective, once-daily DPP-4 inhibitor that enhances a natural body system called the incretin system to help regulate blood sugar by increasing levels of active GLP-1 and GIP hormones. JANUVIA inhibits DPP-4 over 24 hours. JANUVIA is the first approved compound in the DPP-4 inhibitor class of oral treatments. JANUVIA has been approved in more than 90 countries, and to date, more than 22 million prescriptions have been dispensed for sitagliptin in the U.S. alone.

JANUVIA is contraindicated in patients with a history of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema. As is typical with other antihyperglycemic agents used in combination with a sulfonylurea or insulin, when sitagliptin is used in combination with a sulfonylurea or insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo. Therefore, a lower dose of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia. 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. Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to the initiation of JANUVIA and periodically thereafter.

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 postmarketing reports of acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUVIA. After initiating JANUVIA, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, JANUVIA should be promptly discontinued and appropriate management initiated. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUVIA.

About the Study and Post-Hoc Analysis

For this post-hoc analysis, data from a clinical trial in patients with inadequate glycemic control at baseline with mildly to moderately elevated A1C (mean baseline A1C of 7.5 percent) on metformin monotherapy were used. Patients were originally randomized in a double-blind manner to the addition of JANUVIA 100 mg once daily (n=588) or glipizide 5 mg/day (up-titrated up to 20 mg/d based on glycemic criteria; mean daily dose 10 mg daily; n=584) for 104 weeks. The original study showed that JANUVIA achieved the pre-specified bounds for non-inferiority vs. a sulfonylurea (glipizide). After one year, the mean A1C reduction from baseline was 0.5 percent for JANUVIA and 0.6 percent for glipizide in the intent-to-treat patient population and 0.7 percent for JANUVIA and 0.7 percent for glipizide in the per protocol analysis, confirming the similar efficacy of JANUVIA compared to glipizide. The non-inferiority of JANUVIA to glipizide may be limited to patients with A1C levels comparable to those included in this study (more than 70 percent of patients had a baseline A1C of less than 8 percent and more than 90 percent had a baseline A1C of less than 9 percent). At 52 weeks, mean body weight decreased with sitagliptin (-1.5 kg) and increased with glipizide (1.1 kg), a significant difference of 2.5 kg (-3.1, -2.0; p<0.001) or 5.5 pounds. Additionally, patients treated with JANUVIA experienced a lower incidence of hypoglycemia than patients treated with glipizide (4.9 percent vs. 32.0 percent, respectively, p<0.001).

In this post-hoc analysis, only patients with A1C and body weight measurements at week 52 were included (n=790). The odds ratio for achieving the composite endpoint was greater with JANUVIA compared with glipizide (5.43 [95 percent CI: 3.70, 7.96]). The analysis also compared JANUVIA and glipizide by baseline A1C. Among patients with a baseline A1C of greater than or equal to 8.0 percent, significantly more patients achieved the composite endpoint in the JANUVIA group (n=58) compared with those in the glipizide group (n=24) (55.8 percent vs. 20.9 percent, respectively). In addition, significantly more patients with a baseline A1C of less than 8.0 percent achieved the composite endpoint in the JANUVIA group (n=90) compared with those in the glipizide group (n=25) (31.7 percent vs. 8.3 percent, respectively).

Selected risk information for JANUVIA

JANUVIA is contraindicated in patients with a history of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.

A dosage adjustment is recommended in patients with moderate or severe renal insufficiency or with end-stage renal disease requiring hemodialysis or peritoneal dialysis.

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

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with JANUVIA, such as 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, JANUVIA should be discontinued, other potential causes for the event assessed, and an alternative treatment for diabetes instituted.

In clinical studies, the adverse reactions reported, regardless of investigator assessment of causality, in ‰¥5% of patients treated with JANUVIA as monotherapy and in combination therapy and more commonly than in patients treated with placebo, were upper respiratory tract infection, nasopharyngitis, and headache.

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Prescribing Information and Medication Guide for JANUVIA® are attached and are also available at www.JANUVIA.com.

JANUVIA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

1 JANUVIA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. A1C is a measure of a person's blood average blood glucose over a two- to three-month period.

JANUVIA®

(sitagliptin) Tablets

9984400

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

Indications and Usage

Important Limitations of Use (1.2) 02/2010

Dosage and Administration

Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin (2.3) 02/2010

Warnings and Precautions

Pancreatitis (5.1) 12/2009

Use with Medications Known to Cause Hypoglycemia (5.3) 02/2010

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 patients with a history of pancreatitis. (1.2, 5.1)

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   Severe and ESRD
     
CrCl ‰¥30 to 50 mL/min   CrCl 30 mL/min
~Serum Cr levels [mg/dL]   ~Serum Cr levels [mg/dL]
Men: >1.7– ‰¤3.0;   Men: >3.0;
Women: >1.5– ‰¤2.5   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 (5.4, 6.2)

WARNINGS AND PRECAUTIONS

 

  • There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue JANUVIA. (5.1)
  • 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, 5.2)
  • There is an increased risk of hypoglycemia when JANUVIA is added to an insulin secretagogue (e.g., sulfonylurea) or insulin therapy. Consider lowering the dose of the sulfonylurea or insulin to reduce the risk of hypoglycemia. (2.3, 5.3)
  • 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. (5.4, 6.2)
  • There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or any other anti-diabetic drug. (5.5)

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. In the add-on to sulfonylurea and add-on to insulin studies, hypoglycemia was also more commonly reported in patients treated with JANUVIA compared to placebo. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of 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 Medication Guide.

Revised: 02/2010

________________________________________________________________________________________

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 an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Pancreatitis

5.2 Use in Patients with Renal Insufficiency

5.3 Use with Medications Known to Cause Hypoglycemia

5.4 Hypersensitivity Reactions

5.5 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 patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using JANUVIA. [See Warnings and Precautions (5.1).]

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 an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin

When JANUVIA is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia. [See Warnings and Precautions (5.3).]

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

History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema. [See Warnings and Precautions (5.4); Adverse Reactions (6.2).]

5 WARNINGS AND PRECAUTIONS

5.1 Pancreatitis

There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUVIA. After initiation of JANUVIA, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, JANUVIA should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using JANUVIA.

5.2 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).]

5.3 Use with Medications Known to Cause Hypoglycemia

When JANUVIA was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin. [See Adverse Reactions (6.1).] Therefore, a lower dose of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia. [See Dosage and Administration (2.3).]

5.4 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).]

5.5 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, pioglitazone, or rosiglitazone and metformin, 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 3); 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. Five placebo-controlled add-on combination therapy studies were also conducted: one with metformin; one with pioglitazone; one with metformin and rosiglitazone; one with glimepiride (with or without metformin); and one with insulin (with or without metformin). In these trials, patients with inadequate glycemic control on a stable dose of the background therapy were randomized to add-on therapy with JANUVIA 100 mg daily or placebo. The adverse reactions, excluding hypoglycemia, reported regardless of investigator assessment of causality in ‰¥5% of patients treated with JANUVIA 100 mg daily and more commonly than in patients treated with placebo, are shown in Table 1 for the clinical trials of at least 18 weeks duration. Incidences of hypoglycemia are shown in Table 3.

Table 1
Placebo-Controlled Clinical Studies of JANUVIA Monotherapy or Add-on Combination Therapy with
Pioglitazone, Metformin + Rosiglitazone, or Glimepiride +/- Metformin: Adverse Reactions (Excluding
Hypoglycemia) Reported in ‰¥5% of Patients and More Commonly than in Patients Given Placebo,
Regardless of Investigator Assessment of Causality( )

 

    Number of Patients (%)
Monotherapy (18 or 24 weeks)   JANUVIA 100 mg   Placebo
    N = 443   N = 363
Nasopharyngitis   23 (5.2)   12 (3.3)
Combination with Pioglitazone (24 weeks)   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 Metformin + Rosiglitazone (18 weeks)   JANUVIA 100 mg + Metformin

+ Rosiglitazone

 

  Placebo + Metformin

+ Rosiglitazone

 

    N = 181   N = 97
Upper Respiratory Tract Infection   10 (5.5)   5 (5.2)
Nasopharyngitis   11 (6.1)   4 (4.1)
Combination with Glimepiride
(+/- Metformin) (24 weeks)
  JANUVIA 100 mg + Glimepiride

(+/- Metformin)

 

  Placebo + Glimepiride

(+/- Metformin)

 

    N = 222   N = 219
Nasopharyngitis   14 (6.3)   10 (4.6)
Headache   13 (5.9)   5 (2.3)
  Intent to treat population

 

       
In the 24-week 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 24-week study of patients receiving JANUVIA as add-on therapy to insulin (with or without 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, except for hypoglycemia (see Table 3).

In the study of JANUVIA as add-on combination therapy with metformin and rosiglitazone (Table 1), through Week 54 the adverse reactions reported regardless of investigator assessment of causality in ‰¥5% of patients treated with JANUVIA and more commonly than in patients treated with placebo were: upper respiratory tract infection (JANUVIA, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).

In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on to pioglitazone study, 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.

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.
In a 24-week study of initial therapy with JANUVIA in combination with pioglitazone, there were no adverse reactions reported (regardless of investigator assessment of causality) in ‰¥5% of patients and more commonly than in patients given pioglitazone alone.

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

Hypoglycemia

In all (N=9) studies, adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia. A concurrent blood glucose measurement was not required although most (74%) reports of hypoglycemia were accompanied by a blood glucose measurement ‰¤70 mg/dL. When JANUVIA was co-administered with a sulfonylurea or with insulin, the percentage of patients with at least one adverse reaction of hypoglycemia was higher than in the corresponding placebo group (Table 3).

Table 3

Incidence and Rate of Hypoglycemia  in Placebo-Controlled Clinical Studies when JANUVIA was used
as Add-On Therapy to Glimepiride (with or without Metformin) or Insulin (with or without Metformin),
Regardless of Investigator Assessment of Causality

 

  JANUVIA 100 mg Placebo
Add-On to Glimepiride + Glimepiride + Glimepiride
(+/- Metformin) (24 weeks) (+/- Metformin) (+/- Metformin)
  N = 222 N = 219
Overall (%) 27 (12.2) 4 (1.8)
Rate (episodes/patient-year)¡ 0.59 0.24
Severe (%)§ 0 (0.0) 0 (0.0)
Add-On to Insulin JANUVIA 100 mg Placebo
(+/- Metformin) (24 weeks) + Insulin + Insulin
  (+/- Metformin) (+/- Metformin)
  N = 322 N = 319
Overall (%) 50 (15.5) 25 (7.8)
Rate (episodes/patient-year)¡ 1.06 0.51
Severe (%)§ 2 (0.6) 1 (0.3)
  Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose
measurement was not required; intent to treat population.
¡ Based on total number of events (i.e., a single patient may have had multiple events).
§ Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss
of consciousness or seizure.
In a 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 was 1.2% in patients treated with JANUVIA 100 mg and 0.9% in patients treated with placebo.

In the study of JANUVIA as add-on combination therapy with metformin and rosiglitazone, the overall incidence of hypoglycemia was 2.2% in patients given add-on JANUVIA and 0.0% in patients given add-on placebo through Week 18. Through Week 54, the overall incidence of hypoglycemia was 3.9% in patients given add-on JANUVIA and 1.0% in patients given add-on placebo.

In the 24-week, placebo-controlled factorial study of initial therapy with JANUVIA in combination with metformin, the incidence of hypoglycemia was 0.6% in patients given placebo, 0.6% in patients given JANUVIA alone, 0.8% in patients given metformin alone, and 1.6% in patients given JANUVIA in combination with metformin.

In the study of JANUVIA as initial therapy with pioglitazone, one patient taking JANUVIA experienced a severe episode of hypoglycemia. There were no severe hypoglycemia episodes reported in other studies except in the study involving co-administration with insulin.

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, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome [see Warnings and Precautions (5.4)]; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis [see Limitations of Use (1.2); Warnings and Precautions (5.1)].

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 pr

Posted: June 2010

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