New Data Released at Major Diabetes Meeting on Initial Combination Therapy with Januvia (sitagliptin), Merck's Diabetes Medicine, and Metformin through Two Years of Treatment
JANUVIA is indicated, as an adjunct to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes. JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. JANUVIA has not been studied in combination with insulin. JANUVIA is contraindicated for patients with history of a serious hypersensitivity reaction to sitagliptin, including anaphylaxis and angioedema.
JANUVIA is a selective, once-daily dipeptidyl peptidase-4 (DPP-4) inhibitor that enhances a natural body system, called the incretin system, to help regulate blood sugar. JANUVIA and metformin act in different ways to increase blood levels of active GLP-1 (glucagon-like peptide-1), a hormone that, when blood sugar is higher than normal, enhances the production and secretion of insulin from beta cells in the pancreas. Insulin lowers blood sugar.
"We wanted to evaluate the combined and complementary effects of JANUVIA and metformin on the critical role of beta cell function in type 2 diabetes as well as to assess efficacy out two years," said John Amatruda, M.D., senior vice president, clinical research, Diabetes & Obesity, Merck & Co., Inc. "The improvements in markers of beta cell function we saw in this study may contribute to the significant lowering of blood sugar levels that was observed during two years of therapy with the initial combination of JANUVIA and metformin."
"These two-year data on initial therapy with sitagliptin and metformin are interesting, particularly to the many physicians who over time need to treat their patients with combination therapy to help achieve and maintain glycemic control," said Priscilla Hollander, M.D., Ph.D., director, Ruth Collins Diabetes Center, Baylor University Medical Center, Dallas.
The U.S. Food and Drug Administration approved JANUVIA in October 2006. JANUVIA is the first and only DPP-4 inhibitor available in the United States.
In controlled clinical studies for JANUVIA as both monotherapy and combination therapy with metformin or pioglitazone, the overall incidence of adverse reactions, hypoglycemia, and discontinuation of therapy due to clinical adverse reactions with JANUVIA were similar to placebo. In these clinical studies, the most common adverse reactions reported with JANUVIA (greater than or equal to 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.
Significant impact of co-administration of JANUVIA and metformin on markers of beta cell function and A1C levels out to two years
Initial combination therapy with JANUVIA and metformin significantly improved markers of beta cell function and significantly improved blood sugar levels compared with either metformin or JANUVIA alone at both one year and after two years of treatment. The study began with a 24-week, placebo-controlled phase (n=1,091), followed by a 30-week, double-blind, active-controlled period (n=762). The mean baseline A1C of the two populations was 8.8 and 8.7 percent, respectively. Five-hundred-eighty-seven patients entered into a study extension out to two years (including those who had initiated glycemic rescue therapy) and 402 of those patients (mean baseline A1C of 8.6 percent) were included in the all-patients-treated analysis of efficacy at two years.
To assess beta cell function, a self-selected subset of patients underwent a frequently-sampled meal tolerance test at baseline and at week 54 (n=203) and/or week 104 (n=125). Patients ingested a standard meal (one nutrition bar and one nutrition drink within 15 minutes), followed by blood collection at different time points relative to the start of meal. At both one year and two years, there were substantial improvements on two well known endpoints to assess beta cell function for patients on the combination of JANUVIA and metformin: HOMA-(beta) and pro-insulin-to-insulin ratio.
To assess glucose-lowering, the change from baseline A1C levels were measured at one year and two years. The mean A1C reductions from baseline in this study were 1.8 percent (at one year, n=153) and 1.7 percent (at two years, n=105) in patients treated with JANUVIA 50 mg/metformin 1000 mg twice daily. Additionally, mean A1C reductions from baseline were 1.4 percent (at one year, n=147; at two years, n=96) in patients treated with JANUVIA 50 mg/metformin 500 mg twice daily, 1.3 percent (at one year, n=134; at two years, n=87) in patients treated with metformin 1000 mg twice daily, 1.0 percent (at one year, n=117) and 1.1 percent (at two years, n=64) in patients treated with metformin 500 mg twice daily. For patients treated with JANUVIA 100 mg once daily, there was a 0.8 percent reduction in A1C levels from baseline at one year (n=106) and a 1.2 percent reduction from baseline at two years (n=50).
Initial combination therapy or maintenance of combination therapy should be individualized and are left to the discretion of the health care provider.
Safety of JANUVIA and metformin in combination evaluated in a pooled analysis of studies up to two years duration
The longer-term safety and tolerability of combining JANUVIA and metformin were evaluated by pooling data from five completed, Phase III studies that evaluated sitaglipin as add-on therapy to metformin or as initial co-administration therapy with metformin for durations of 30 weeks up to two years. For clinical adverse experiences (AEs), there were no notable differences in the overall incidence of AEs (73 percent vs. 73 percent), serious AEs (8.5 percent vs. 8.0 percent) and discontinuation due to AEs (3.4 percent vs. 4.0 percent) between the JANUVIA/metformin and comparator groups, respectively. The incidence of drug-related AEs was lower with sitagliptin/metformin compared with the comparator group (15.5 percent vs. 23.1 percent). This difference was mainly due to the increased incidence of hypoglycemia in patients treated with a sulfonylurea in the comparator group.
Of the approximately 1,000 specific clinical AEs reported in this analysis, a total of 16 specific clinical AEs occurred more frequently in one or the other group, with six AEs occurring more frequently in the sitagliptin/metformin group and 10 AEs in the comparator group.
This pooled safety analysis included 3,028 patients of which 1,636 were in the JANUVIA/metformin group and 1,392 in the placebo/active comparator group which included those treated with placebo plus metformin with or without a sulfonylurea.
Dosing of JANUVIA
The recommended dose of JANUVIA is 100 mg once daily, with or without food, for all approved indications. No dosage adjustment is needed for patients with mild to moderate hepatic insufficiency or in patients with mild renal insufficiency (CrCl greater than or equal to50 mL/min). To achieve plasma concentrations of JANUVIA similar to those in patients with normal renal function, lower dosages are recommended in patients with moderate and severe renal insufficiency as well as in end-stage renal disease (ESRD) patients requiring hemodialysis. For patients with moderate renal insufficiency (CrCl greater than or equal to30 to less than50 mL/min), the dose of JANUVIA is 50 mg once daily. For those with severe renal insufficiency (CrCl less than30 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.
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. Approximately 12,000 patients have participated in the Company's clinical studies of sitagliptin, with about 7,400 of these patients being treated with sitagliptin. Additionally, about 2,300 patients have been treated with sitagliptin for more than a year and, of these, approximately 500 patients have been treated for at least two years.
Merck's commitment to patient education
Journey for Control(TM) is Merck's comprehensive educational program designed to enlighten and empower patients by giving them the information and tools they need to make the lifestyle changes that lead to improved self-management. The Merck Journey for Control Program is proud to sponsor the U.S. Diabetes Conversation Map(R) Program, which was developed by Healthy Interactions in collaboration with the American Diabetes Association. The U.S. Diabetes Conversation Map Program is an innovative teaching method which provides participants with a process by which they can plan changes in their decision making and behaviors. For more information, visit www.JourneyforControl.com.
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.
(1) A1C is a measure of a person's average blood glucose over a two-month to three-month period.
Prescribing information and patient product information for JANUVIA is attached.
JANUVIA(TM)
(sitagliptin) Tablets 9762704
9762704
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use JANUVIA safely and effectively. See full prescribing information for JANUVIA.
JANUVIA(TM) (sitagliptin) Tablets
Initial U.S. Approval: 2006
RECENT MAJOR CHANGES
Indications and Usage
Monotherapy and Combination Therapy (1.1) 10/2007
Important Limitations of Use (1.2) 10/2007
Dosage and Administration
Recommended Dosing (2.1) 10/2007
Concomitant Use with a Sulfonylurea (2.3) 10/2007
Contraindications (4) 10/2007
Warnings and Precautions
Use with Medications Known to Cause Hypoglycemia (5.2) 10/2007
Hypersensitivity Reactions (5.3) 10/2007
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) -0-
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 (5.3, 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)
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: 10/2007
JANUVIA(TM) 9726700
(sitagliptin phosphate) Tablets
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
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
JANUVIA(1) 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).)
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. -0-
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 + Placebo +
Pioglitazone 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 JANUVIA 100 mg Placebo
(+/- Metformin) + Glimepiride + Glimepiride
(+/- Metformin) (+/- 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. -0-
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 Metformin Sitagliptin
(JANUVIA) 500 or 1000 50 mg bid +
100 mg QD mg bid( ++) Metformin
500 or 1000 mg
bid( ++)
----------------------------------------------------------------------
N = 176 N = 179 N = 364(++) N = 372(++)
----------------------------------------------------------------------
Upper Respiratory
Infection 9 (5.1) 8 (4.5) 19 (5.2) 23 (6.2)
----------------------------------------------------------------------
Headache 5 (2.8) 2 (1.1) 14 (3.8) 22 (5.9)
----------------------------------------------------------------------
(+) Intent-to-treat population.
(++ )Data pooled for the patients given the lower and higher doses of metformin.
No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed in patients treated with JANUVIA.
Laboratory Tests
Across clinical studies, the incidence of laboratory adverse reactions was similar in patients treated with JANUVIA 100 mg compared to patients treated with placebo. A small increase in white blood cell count (WBC) was observed due to an increase in neutrophils. This increase in WBC (of approximately 200 cells/microL vs placebo, in four pooled placebo-controlled clinical studies, with a mean baseline WBC count of approximately 6600 cells/microL) is not considered to be clinically relevant. In a 12-week study of 91 patients with chronic renal insufficiency, 37 patients with moderate renal insufficiency were randomized to JANUVIA 50 mg daily, while 14 patients with the same magnitude of renal impairment were randomized to placebo. Mean (SE) increases in serum creatinine were observed in patients treated with JANUVIA (0.12 mg/dL (0.04)) and in patients treated with placebo (0.07 mg/dL (0.07)). The clinical significance of this added increase in serum creatinine relative to placebo is not known.
6.2 Postmarketing Experience
The following additional adverse reactions have been identified during postapproval use of JANUVIA. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity reactions include anaphylaxis, angioedema, rash, urticaria, and exfoliative skin conditions including Stevens-Johnson syndrome. (See Warnings and Precautions (5.3).)
7 DRUG INTERACTIONS
7.1 Digoxin
There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 18%) of digoxin with the co-administration of 100 mg sitagliptin for 10 days. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or JANUVIA is recommended.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B:
Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Merck & Co., Inc. maintains a registry to monitor the pregnancy outcomes of women exposed to JANUVIA while pregnant. Health care providers are encouraged to report any prenatal exposure to JANUVIA by calling the Pregnancy Registry at (800) 986-8999.
Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately 30- and 20-times human exposure at the maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100 times human exposure at the MRHD.
Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1000 mg/kg. No functional or behavioral toxicity was observed in offspring of rats.
Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours postdose. Placental transfer of sitagliptin administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.
8.3 Nursing Mothers
Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when JANUVIA is administered to a nursing woman.
8.4 Pediatric Use
Safety and effectiveness of JANUVIA in pediatric patients under 18 years of age have not been established.
8.5 Geriatric Use
Of the total number of subjects (N=3884) in pre-approval clinical safety and efficacy studies of JANUVIA, 725 patients were 65 years and over, while 61 patients were 75 years and over. No overall differences in safety or effectiveness were observed between subjects 65 years and over and younger subjects. While this and other reported clinical experience have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.
This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly, and it may be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter (see Dosage and Administration (2.2); Clinical Pharmacology (12.3)).
10 OVERDOSAGE
During controlled clinical trials in healthy subjects, single doses of up to 800 mg JANUVIA were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg JANUVIA, a mean effect that is not considered clinically important (see Clinical Pharmacology (12.2)). There is no experience with doses above 800 mg in humans. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with JANUVIA with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for up to 28 days.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as dictated by the patient's clinical status.
Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.
11 DESCRIPTION
JANUVIA Tablets contain sitagliptin phosphate, an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.
Sitagliptin phosphate monohydrate is described chemically as 7-((3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl )-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo(4,3-a)pyrazine phosphate (1:1) monohydrate.
The empirical formula is C16H15F6N5O--H3PO4--H2O and the molecular weight is 523.32. The structural formula is:
(Graphic Omitted)
Sitagliptin phosphate monohydrate is a white to off-white, crystalline, non-hygroscopic powder. It is soluble in water and N,N-dimethyl formamide; slightly soluble in methanol; very slightly soluble in ethanol, acetone, and acetonitrile; and insoluble in isopropanol and isopropyl acetate.
Each film-coated tablet of JANUVIA contains 32.13, 64.25, or 128.5 mg of sitagliptin phosphate monohydrate, which is equivalent to 25, 50, or 100 mg, respectively, of free base and the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide, and yellow iron oxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by JANUVIA, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
12.2 Pharmacodynamics
General
In patients with type 2 diabetes, administration of JANUVIA led to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.
In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, whereas metformin alone increased active and total GLP-1 concentrations to similar extents. Co-administration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations. It is unclear how these findings relate to changes in glycemic control in patients with type 2 diabetes.
In studies with healthy subjects, JANUVIA did not lower blood glucose or cause hypoglycemia.
Cardiac Electrophysiology
In a randomized, placebo-controlled crossover study, 79 healthy subjects were administered a single oral dose of JANUVIA 100 mg, JANUVIA 800 mg (8 times the recommended dose), and placebo. At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800 mg dose, the maximum increase in the placebo-corrected mean change in QTc from baseline was observed at 3 hours postdose and was 8.0 msec. This increase is not considered to be clinically significant. At the 800 mg dose, peak sitagliptin plasma concentrations were approximately 11 times higher than the peak concentrations following a 100 mg dose.
In patients with type 2 diabetes administered JANUVIA 100 mg (N=81) or JANUVIA 200 mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.
12.3 Pharmacokinetics
The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose. Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 (mu)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 <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: -0-
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 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
JANUVIA has been studied as monotherapy and in combination with metformin, pioglitazone, glimepiride, and glimepiride+metformin.
There were approximately 3800 patients with type 2 diabetes randomized in six double-blind, placebo-controlled clinical safety and efficacy studies conducted to evaluate the effects of sitagliptin on glycemic control. The ethnic/racial distribution in these studies was approximately 60% white, 20% Hispanic, 8% Asian, 6% black, and 6% other groups. Patients had an overall mean age of approximately 55 years (range 18 to 87 years). In addition, an active (glipizide)-controlled study of 52-weeks duration was conducted in 1172 patients with type 2 diabetes who had inadequate glycemic control on metformin.
In patients with type 2 diabetes, treatment with JANUVIA produced clinically significant improvements in hemoglobin A1C, fasting plasma glucose (FPG) and 2-hour post-prandial glucose (PPG) compared to placebo.
14.1 Monotherapy
A total of 1262 patients with type 2 diabetes participated in two double-blind, placebo-controlled studies, one of 18-week and another of 24-week duration, to evaluate the efficacy and safety of JANUVIA monotherapy. In both monotherapy studies, patients currently on an antihyperglycemic agent discontinued the agent, and underwent a diet, exercise, and drug washout period of about 7 weeks. Patients with inadequate glycemic control (A1C 7% to 10%) after the washout period were randomized after completing a 2-week single-blind placebo run-in period; patients not currently on antihyperglycemic agents (off therapy for at least 8 weeks) with inadequate glycemic control (A1C 7% to 10%) were randomized after completing the 2-week single-blind placebo run-in period. In the 18-week study, 521 patients were randomized to placebo, JANUVIA 100 mg, or JANUVIA 200 mg, and in the 24-week study 741 patients were randomized to placebo, JANUVIA 100 mg, or JANUVIA 200 mg. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue, added on to placebo or JANUVIA.
Treatment with JANUVIA at 100 mg daily provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table 3). 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 compared to placebo was not affected by gender, age, race, prior antihyperglycemic therapy, or baseline BMI. As is typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with JANUVIA appears to be related to the degree of A1C elevation at baseline. In these 18- and 24-week studies, among patients who were not on an antihyperglycemic agent at study entry, the reductions from baseline in A1C were -0.7% and -0.8%, respectively, for those given JANUVIA, and -0.1% and -0.2%, respectively, for those given placebo. 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. -0-
Table 3
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 <7% 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. p<0.001 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 <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
Add-on 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 with inadequate glycemic control (A1C 7% to 10%) 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 4). 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. -0-
Table 4
Glycemic Parameters at Final Visit (24-Week Study)
for JANUVIA in Add-on Combination Therapy with Metformin+
----------------------------------------------------------------------
JANUVIA 100 Placebo +
mg + Metformin
Metformin
----------------------------------------------------------------------
A1C (%) N = 453 N = 224
----------------------------------------------------------------------
Baseline (mean)
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