FDA Accepts Two Supplemental New Drug Applications to Expand the U.S. Labeling for Januvia
WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Feb 15, 2007 - Merck & Co., Inc. today announced that the U.S. Food and Drug Administration (FDA) has accepted for standard review two supplemental New Drug Applications (sNDAs) for JANUVIA(TM) (sitagliptin), and the Company expects FDA action on both sNDAs by mid-October.One sNDA is filed in support of a proposed new indication for the use of JANUVIA, as an adjunct to diet and exercise, in combination with metformin as initial therapy to improve glycemic control. The other sNDA is filed in support of two proposed new indications for use of JANUVIA, as an adjunct to diet and exercise, as add-on therapy to a sulfonylurea when the single agent alone does not provide adequate glycemic control and as add-on therapy to the combination of a sulfonylurea plus metformin when dual therapy does not provide adequate glycemic control.
JANUVIA is currently indicated for use as monotherapy and as add-on therapy to either of two other types of oral diabetes medications, metformin or thiazolidinediones (TZDs), to improve blood sugar (glucose) control in patients with type 2 diabetes when diet and exercise are not enough. The recommended dose of JANUVIA is 100 mg once daily. JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. In clinical trials, JANUVIA demonstrated an overall incidence of side effects comparable to placebo. The most common side effects 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.
"If these sNDAs are approved, the expanded labeling will include indications for use of JANUVIA as initial therapy with metformin and as add-on to any of the three most commonly prescribed classes of oral antihyperglycemic agents," said John Amatruda, M.D., vice president, clinical research, Merck & Co., Inc. "These data further support the broad utility of JANUVIA as an important treatment option for patients with type 2 diabetes."
Phase III data supporting two sNDAs
The proposed new indication of JANUVIA in combination with metformin as initial therapy is supported by a 24-week, factorial study in 1,091 randomized patients with type 2 diabetes. Results of this study were presented for the first time at the annual meeting of the European Association for the Study of Diabetes in September 2006.
The study showed a significant mean placebo-subtracted reduction in A1C(1) of 2.1 percent from a mean baseline A1C of 8.7 percent (primary analysis of all patients treated, p >0.001) in the patients treated with JANUVIA 50 mg twice daily combined with metformin 1,000 mg twice daily (n=178). In the same study, 66 percent of patients treated with JANUVIA 50 mg twice daily combined with metformin 1,000 mg twice daily achieved goal A1C levels of <7 percent compared to 38 percent of patients treated with metformin 1,000 mg twice daily alone (p <0.01). Even in those patients receiving a lower dose of metformin (JANUVIA 50 mg twice daily and metformin 500 mg twice daily, n=183), significant A1C placebo-subtracted reductions (1.6 percent, p <0.001) and greater goal attainment (43 percent vs. 23 percent with metformin 500 mg twice daily alone, p <0.01) were observed.
In the study, initial therapy of JANUVIA and metformin was generally well tolerated and showed no meaningful differences in tolerability compared to metformin alone. Side effects of JANUVIA 50 mg twice daily and metformin 1,000 mg twice daily compared to metformin 1,000 mg twice daily alone included diarrhea (9 percent vs. 10 percent, respectively), nausea (6 percent vs. 8 percent), abdominal pain/discomfort (3 percent vs. 5 percent) and vomiting (3 percent vs. 1 percent).
The proposed new indications of adding JANUVIA to a sulfonylurea or to a sulfonylurea plus metformin are supported by a 24-week study examining the efficacy and safety of JANUVIA in 441 patients with type 2 diabetes who had inadequate glycemic control on a sulfonylurea alone or a sulfonylurea plus metformin. Results from this Phase III study were submitted to a major medical meeting for presentation later this year.
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 to 50 mL/min). To achieve plasma concentrations of JANUVIA similar to those in patients with normal renal function, lower dosages are recommended in patients with moderate and severe renal insufficiency as well as in ESRD patients requiring hemodialysis. For patients with moderate renal insufficiency (CrCl greater than or equal to 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
JANUVIA should be used during pregnancy only if clearly needed. Caution should be exercised when JANUVIA is administered to a nursing woman. 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. The incidence of selected gastrointestinal adverse reactions in patients treated with JANUVIA was as follows: abdominal pain (JANUVIA, 2.3 percent; placebo, 2.1 percent), nausea (1.4 percent, 0.6 percent) and diarrhea (3.0 percent, 2.3 percent).
Expanding clinical trial program for JANUVIA
Merck's clinical development program for JANUVIA is robust and continues to expand with 43 studies completed or under way, and ten more studies set to begin this year. There are more than 7,600 patients in the Company's clinical studies with about 4,700 of these patients being treated with JANUVIA. Additionally, about 1,100 patients have been treated with JANUVIA for more than a year.
About Merck
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.
Merck forward-looking statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2005, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.
JANUVIA(TM) is a registered trademark for Merck & Co., Inc.
(1) A1C is a measure of a person's average blood glucose over a two- to three-month period.
Prescribing information and patient product information for JANUVIA are attached. -0-
JANUVIA(TM)(sitagliptin phosphate) Tablets 9762700
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
JANUVIA safely and effectively. See full prescribing information for
JANUVIA.
JANUVIA(TM) (sitagliptin phosphate) Tablets
Initial U.S. Approval: 2006
INDICATIONS AND USAGE
JANUVIA is indicated as an adjunct to diet and exercise to improve
glycemic control in patients with type 2 diabetes mellitus (type 2
diabetes). JANUVIA is indicated for:
-- Monotherapy (1.1)
-- Combination therapy with metformin or a peroxisome
proliferator-activated receptor gamma (PPAR-gamma) agonist
(e.g., thiazolidinediones) when the single agent does not
provide adequate glycemic control. (1.2)
Important Limitations of Use: JANUVIA should not be used in
patients with type 1 diabetes mellitus (type 1 diabetes) or for the
treatment of diabetic ketoacidosis. (1.3)
DOSAGE AND ADMINISTRATION
The recommended dose of JANUVIA is 100 mg once daily as
monotherapy or as combination therapy with metformin or a PPAR-gamma
agonist (e.g., thiazolidinediones). (2.1)
JANUVIA can be taken with or without food. (2.1)
Dosage Adjustment in Patients With Moderate, Severe and End Stage
Renal Disease (ESRD) (2.2)
----------------------------------------------------------------------
50 mg once daily 25 mg once daily
----------------------------------------------------------------------
Moderate Severe and ESRD
CrCl greater than or equal to 30 CrCl less than 30 mL/min
to less than 50 mL/min
~Serum Cr levels (mg/dL) ~Serum Cr levels (mg/dL)
Men: greater than 1.7 - Men: greater than 3.0;
less than or equal to 3.0;
Women: greater than 1.5 - Women: greater than 2.5;
less than or equal to 2.5 or on dialysis
----------------------------------------------------------------------
DOSAGE FORMS AND STRENGTHS
Tablets: 100 mg, 50 mg, and 25 mg (3)
CONTRAINDICATIONS
None. (4)
WARNINGS AND PRECAUTIONS
A dosage adjustment is recommended in patients with moderate renal
insufficiency and in patients with severe renal insufficiency or with
ESRD requiring hemodialysis or peritoneal dialysis. Assessment of
renal function is recommended prior to initiation of JANUVIA and
periodically thereafter. Creatinine clearance can be estimated from
serum creatinine using the Cockcroft-Gault formula. (2.2, 5)
ADVERSE REACTIONS
The most common adverse reactions, reported in greater than or
equal to 5% of patients treated with JANUVIA and more commonly than in
patients treated with placebo are: upper respiratory tract infection,
nasopharyngitis, and headache. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Merck & Co., Inc.
at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
Safety and effectiveness of JANUVIA in children under 18 years
have not been established. (8.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient
labeling.
Revised: 10/2006
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Monotherapy
1.2 Combination Therapy
1.3 Important Limitations of Use
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosing
2.2 Patients with Renal Insufficiency
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
7 DRUG INTERACTIONS
7.1 Digoxin
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Monotherapy
14.2 Combination Therapy
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Instructions
17.2 Laboratory Tests
17.3 FDA-Approved Patient Labeling
*Sections or subsections omitted from the full prescribing
information are not listed.
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
1.1 Monotherapy
JANUVIA(1) is indicated as an adjunct to diet and exercise to
improve glycemic control in patients with type 2 diabetes mellitus.
1.2 Combination Therapy
JANUVIA is indicated in patients with type 2 diabetes mellitus to
improve glycemic control in combination with metformin or a PPAR-gamma
agonist (e.g., thiazolidinediones) when the single agent alone, with
diet and exercise, does not provide adequate glycemic control.
1.3 Important Limitations of Use
JANUVIA should not be used in patients with type 1 diabetes or for
the treatment of diabetic ketoacidosis, as it would not be effective
in these settings.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosing
The recommended dose of JANUVIA is 100 mg once daily as
monotherapy or as combination therapy with metformin or a PPAR-gamma
agonist (e.g., thiazolidinediones). JANUVIA can be taken with or
without food.
2.2 Patients with Renal Insufficiency
For patients with mild renal insufficiency (creatinine clearance
(CrCl) greater than or equal to 50 mL/min, approximately corresponding
to serum creatinine levels of less than or equal to 1.7 mg/dL in men
and less than or equal to 1.5 mg/dL in women), no dosage adjustment
for JANUVIA is required.
For patients with moderate renal insufficiency (CrCl greater than
30 to less than 50 mL/min, approximately corresponding to serum
creatinine levels of greater than 1.7 to less than or equal to 3.0
mg/dL in men and greater than 1.5 to less than or equal to 2.5 mg/dL
in women), the dose of JANUVIA is 50 mg once daily.
For patients with severe renal insufficiency (CrCl less than 30
mL/min, approximately corresponding to serum creatinine levels of
greater than 3.0 mg/dL in men and greater than 2.5 mg/dL in women) or
with end-stage renal disease (ESRD) requiring hemodialysis or
peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA
may be administered without regard to the timing of hemodialysis.
Because there is a need for dosage adjustment based upon renal
function, assessment of renal function is recommended prior to
initiation of JANUVIA and periodically thereafter. Creatinine
clearance can be estimated from serum creatinine using the
Cockcroft-Gault formula. (See Clinical Pharmacology (12.3).)
3 DOSAGE FORMS AND STRENGTHS
-- 100 mg tablets are beige, round, film-coated tablets with "277"
on one side.
-- 50 mg tablets are light beige, round, film-coated tablets with
"112" on one side.
-- 25 mg tablets are pink, round, film-coated tablets with "221"
on one side.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
Use in Patients with Renal Insufficiency: A dosage adjustment is
recommended in patients with moderate or severe renal insufficiency
and in patients with ESRD requiring hemodialysis or peritoneal
dialysis. (See Dosage and Administration (2.2); Clinical Pharmacology
(12.3).)
Use with Medications Known to Cause Hypoglycemia: In clinical
trials of JANUVIA as monotherapy and JANUVIA as part of combination
therapy with metformin or pioglitazone, rates of hypoglycemia reported
with JANUVIA were similar to rates in patients taking placebo. The use
of JANUVIA in combination with medications known to cause
hypoglycemia, such as sulfonylureas or insulin, has not been
adequately studied.
6 ADVERSE REACTIONS
Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical trials of
a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in practice.
6.1 Clinical Trials Experience
In controlled clinical studies as both monotherapy and combination
therapy, the overall incidence of adverse reactions with JANUVIA was
similar to that reported with placebo. Discontinuation of therapy due
to clinical adverse reactions was also similar to placebo.
Two placebo-controlled monotherapy studies, one of 18- and one of
24-week duration, included patients treated with JANUVIA 100 mg daily,
JANUVIA 200 mg daily, and placebo. Two 24-week, placebo-controlled
combination studies, one with metformin and one with pioglitazone,
were also conducted. In addition to a stable dose of metformin or
pioglitazone, patients whose diabetes was not adequately controlled
were given either JANUVIA 100 mg daily or placebo. The adverse
reactions, reported regardless of investigator assessment of causality
in greater than or equal to 5% of patients treated with JANUVIA 100 mg
daily as monotherapy or in combination with pioglitazone and more
commonly than in patients treated with placebo, are shown in Table 1.
Table 1
Placebo-Controlled Clinical Studies of JANUVIA Monotherapy or
Combination with Pioglitazone:
Adverse Reactions Reported in Greater than or equal to 5% of
Patients and More Commonly than in Patients Given Placebo, Regardless
of Investigator Assessment of Causality+
----------------------------------------------------------------------
Number of Patients (%)
----------------------------------------------------------------------
Monotherapy JANUVIA, 100 mg Placebo
----------------------------------------------------------------------
N = 443 N = 363
----------------------------------------------------------------------
Nasopharyngitis 23 (5.2) 12 (3.3)
----------------------------------------------------------------------
Combination with Pioglitazone JANUVIA 100 mg + Placebo +
Pioglitazone Pioglitazone
----------------------------------------------------------------------
N = 175 N = 178
----------------------------------------------------------------------
Upper Respiratory Tract Infection 11 (6.3) 6 (3.4)
----------------------------------------------------------------------
Headache 9 (5.1) 7 (3.9)
----------------------------------------------------------------------
+ Intent to treat population
In patients receiving JANUVIA in combination with metformin, there
were no adverse reactions reported regardless of investigator
assessment of causality in greater than or equal to 5% of patients and
more commonly than in patients given placebo.
The overall incidence of hypoglycemia in patients treated with
JANUVIA 100 mg was similar to placebo (1.2% vs 0.9%). The incidence of
selected gastrointestinal adverse reactions in patients treated with
JANUVIA was as follows: abdominal pain (JANUVIA 100 mg, 2.3%; placebo,
2.1%), nausea (1.4%, 0.6%), and diarrhea (3.0%, 2.3%).
No clinically meaningful changes in vital signs or in ECG
(including in QTc interval) were observed in patients treated with
JANUVIA.
Laboratory Tests
The incidence of laboratory adverse reactions in patients treated
with JANUVIA 100 mg was 8.2% compared to 9.8% in patients treated with
placebo. Across clinical studies, a small increase in white blood cell
count (approximately 200 cells/microL difference in WBC vs placebo;
mean baseline WBC approximately 6600 cells/microL) was observed due to
an increase in neutrophils. This observation was seen in most but not
all studies. This change in laboratory parameters is not considered to
be clinically relevant. In a 12-week study of 91 patients with chronic
renal insufficiency, 37 patients with moderate renal insufficiency
were randomized to JANUVIA 50 mg daily, while 14 patients with the
same magnitude of renal impairment were randomized to placebo. Mean
(SE) increases in serum creatinine were observed in patients treated
with JANUVIA (0.12 mg/dL (0.04)) and in patients treated with placebo
(0.07 mg/dL (0.07)). The clinical significance of this added increase
in serum creatinine relative to placebo is not known.
7 DRUG INTERACTIONS
7.1 Digoxin
There was a slight increase in the area under the curve (AUC, 11%)
and mean peak drug concentration (Cmax, 18%) of digoxin with the
co-administration of 100 mg sitagliptin for 10 days. Patients
receiving digoxin should be monitored appropriately. No dosage
adjustment of digoxin or JANUVIA is recommended.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B:
Reproduction studies have been performed in rats and rabbits.
Doses of sitagliptin up to 125 mg/kg (approximately 12 times the human
exposure at the maximum recommended human dose) did not impair
fertility or harm the fetus. There are, however, no adequate and
well-controlled studies in pregnant women. Because animal reproduction
studies are not always predictive of human response, this drug should
be used during pregnancy only if clearly needed. Merck & Co., Inc.
maintains a registry to monitor the pregnancy outcomes of women
exposed to JANUVIA while pregnant. Health care providers are
encouraged to report any prenatal exposure to JANUVIA by calling the
Pregnancy Registry at (800) 986-8999.
Sitagliptin administered to pregnant female rats and rabbits from
gestation day 6 to 20 (organogenesis) was not teratogenic at oral
doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately
30- and 20-times human exposure at the maximum recommended human dose
(MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased
the incidence of rib malformations in offspring at 1000 mg/kg, or
approximately 100 times human exposure at the MRHD.
Sitagliptin administered to female rats from gestation day 6 to
lactation day 21 decreased body weight in male and female offspring at
1000 mg/kg. No functional or behavioral toxicity was observed in
offspring of rats.
Placental transfer of sitagliptin administered to pregnant rats
was approximately 45% at 2 hours and 80% at 24 hours postdose.
Placental transfer of sitagliptin administered to pregnant rabbits was
approximately 66% at 2 hours and 30% at 24 hours.
8.3 Nursing Mothers
Sitagliptin is secreted in the milk of lactating rats at a milk to
plasma ratio of 4:1. It is not known whether sitagliptin is excreted
in human milk. Because many drugs are excreted in human milk, caution
should be exercised when JANUVIA is administered to a nursing woman.
8.4 Pediatric Use
Safety and effectiveness of JANUVIA in pediatric patients have not
been established.
8.5 Geriatric Use
Of the total number of subjects (N=3884) in clinical safety and
efficacy studies of JANUVIA, 725 patients were 65 years and over,
while 61 patients were 75 years and over. No overall differences in
safety or effectiveness were observed between subjects 65 years and
over and younger subjects. While this and other reported clinical
experience have not identified differences in responses between the
elderly and younger patients, greater sensitivity of some older
individuals cannot be ruled out.
This drug is known to be substantially excreted by the kidney.
Because elderly patients are more likely to have decreased renal
function, care should be taken in dose selection in the elderly, and
it may be useful to assess renal function in these patients prior to
initiating dosing and periodically thereafter (see Dosage and
Administration (2.2); Clinical Pharmacology (12.3)).
10 OVERDOSAGE
During controlled clinical trials in healthy subjects, single
doses of up to 800 mg JANUVIA were administered. Maximal mean
increases in QTc of 8.0 msec were observed in one study at a dose of
800 mg JANUVIA, a mean effect that is not considered clinically
important (see Clinical Pharmacology (12.2)). There is no experience
with doses above 800 mg in humans.
In the event of an overdose, it is reasonable to employ the usual
supportive measures, e.g., remove unabsorbed material from the
gastrointestinal tract, employ clinical monitoring (including
obtaining an electrocardiogram), and institute supportive therapy as
dictated by the patient's clinical status.
Sitagliptin is modestly dialyzable. In clinical studies,
approximately 13.5% of the dose was removed over a 3- to 4-hour
hemodialysis session. Prolonged hemodialysis may be considered if
clinically appropriate. It is not known if sitagliptin is dialyzable
by peritoneal dialysis.
11 DESCRIPTION
JANUVIA Tablets contain sitagliptin phosphate, an orally-active
inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.
Sitagliptin phosphate is described chemically as
7-((3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl)-5,6,7,8-
tetrahydro-3- (trifluoromethyl)-1,2,4-triazolo(4,3-a)pyrazine
phosphate (1:1) monohydrate.
The empirical formula is C16H15F6N5O-H3PO4-H2O and the molecular
weight is 523.32. The structural formula is:
(OBJECT OMITTED)
Sitagliptin phosphate is a white to off-white, crystalline,
non-hygroscopic powder. It is soluble in water and N,N-dimethyl
formamide; slightly soluble in methanol; very slightly soluble in
ethanol, acetone, and acetonitrile; and insoluble in isopropanol and
isopropyl acetate.
Each film-coated tablet of JANUVIA contains 32.13, 64.25, or
128.5 mg of sitagliptin phosphate monohydrate, which is equivalent to
25, 50, or 100 mg, respectively, of free base and the following
inactive ingredients: microcrystalline cellulose, anhydrous dibasic
calcium phosphate, croscarmellose sodium, magnesium stearate, and
sodium stearyl fumarate. In addition, the film coating contains the
following inactive ingredients: polyvinyl alcohol, polyethylene
glycol, talc, titanium dioxide, red iron oxide, and yellow iron oxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Sitagliptin is a DPP-4 inhibitor, which is believed to exert its
actions in patients with type 2 diabetes by slowing the inactivation
of incretin hormones. Concentrations of the active intact hormones are
increased by JANUVIA, thereby increasing and prolonging the action of
these hormones. Incretin hormones, including glucagon-like peptide-1
(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are
released by the intestine throughout the day, and levels are increased
in response to a meal. These hormones are rapidly inactivated by the
enzyme, DPP-4. The incretins are part of an endogenous system involved
in the physiologic regulation of glucose homeostasis. When blood
glucose concentrations are normal or elevated, GLP-1 and GIP increase
insulin synthesis and release from pancreatic beta cells by
intracellular signaling pathways involving cyclic AMP. GLP-1 also
lowers glucagon secretion from pancreatic alpha cells, leading to
reduced hepatic glucose production. By increasing and prolonging
active incretin levels, JANUVIA increases insulin release and
decreases glucagon levels in the circulation in a glucose-dependent
manner. Sitagliptin demonstrates selectivity for DPP-4 and does not
inhibit DPP-8 or DPP-9 activity in vitro at concentrations
approximating those from therapeutic doses.
12.2 Pharmacodynamics
General
In patients with type 2 diabetes, administration of JANUVIA led to
inhibition of DPP-4 enzyme activity for a 24-hour period. After an
oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to
3-fold increase in circulating levels of active GLP-1 and GIP,
decreased glucagon concentrations, and increased responsiveness of
insulin release to glucose, resulting in higher C-peptide and insulin
concentrations. The rise in insulin with the decrease in glucagon was
associated with lower fasting glucose concentrations and reduced
glucose excursion following an oral glucose load or a meal.
In studies with healthy subjects, JANUVIA did not lower blood
glucose or cause hypoglycemia.
Cardiac Electrophysiology
In a randomized, placebo-controlled crossover study, 79 healthy
subjects were administered a single oral dose of JANUVIA 100 mg,
JANUVIA 800 mg (8 times the recommended dose), and placebo. At the
recommended dose of 100 mg, there was no effect on the QTc interval
obtained at the peak plasma concentration, or at any other time during
the study. Following the 800 mg dose, the maximum increase in the
placebo-corrected mean change in QTc from baseline was observed at 3
hours postdose and was 8.0 msec. This increase is not considered to be
clinically significant. At the 800 mg dose, peak sitagliptin plasma
concentrations were approximately 11-fold higher than the peak
concentrations following a 100 mg dose.
In patients with type 2 diabetes administered JANUVIA 100 mg
(N=81) or JANUVIA 200 mg (N=63) daily, there were no meaningful
changes in QTc interval based on ECG data obtained at the time of
expected peak plasma concentration.
12.3 Pharmacokinetics
The pharmacokinetics of sitagliptin has been extensively
characterized in healthy subjects and patients with type 2 diabetes.
After oral administration of a 100 mg dose to healthy subjects,
sitagliptin was rapidly absorbed, with peak plasma concentrations
(median Tmax) occurring 1 to 4 hours postdose. Plasma AUC of
sitagliptin increased in a dose-proportional manner. Following a
single oral 100 mg dose to healthy volunteers, mean plasma AUC of
sitagliptin was 8.52 ?M-hr, Cmax was 950 nM, and apparent terminal
half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased
approximately 14% following 100 mg doses at steady-state compared to
the first dose. The intra-subject and inter-subject coefficients of
variation for sitagliptin AUC were small (5.8% and 15.1%). The
pharmacokinetics of sitagliptin was generally similar in healthy
subjects and in patients with type 2 diabetes.
Absorption
The absolute bioavailability of sitagliptin is approximately 87%.
Because coadministration of a high-fat meal with JANUVIA had no effect
on the pharmacokinetics, JANUVIA may be administered with or without
food.
Distribution
The mean volume of distribution at steady state following a single
100 mg intravenous dose of sitagliptin to healthy subjects is
approximately 198 liters. The fraction of sitagliptin reversibly bound
to plasma proteins is low (38%).
Metabolism
Approximately 79% of sitagliptin is excreted unchanged in the
urine with metabolism being a minor pathway of elimination.
Following a (14C)sitagliptin oral dose, approximately 16% of the
radioactivity was excreted as metabolites of sitagliptin. Six
metabolites were detected at trace levels and are not expected to
contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In
vitro studies indicated that the primary enzyme responsible for the
limited metabolism of sitagliptin was CYP3A4, with contribution from
CYP2C8.
Excretion
Following administration of an oral (14C)sitagliptin dose to
healthy subjects, approximately 100% of the administered radioactivity
was eliminated in feces (13%) or urine (87%) within one week of
dosing. The apparent terminal t1/2 following a 100 mg oral dose of
sitagliptin was approximately 12.4 hours and renal clearance was
approximately 350 mL/min.
Elimination of sitagliptin occurs primarily via renal excretion
and involves active tubular secretion. Sitagliptin is a substrate for
human organic anion transporter-3 (hOAT-3), which may be involved in
the renal elimination of sitagliptin. The clinical relevance of hOAT-3
in sitagliptin transport has not been established. Sitagliptin is also
a substrate of p-glycoprotein, which may also be involved in mediating
the renal elimination of sitagliptin. However, cyclosporine, a
p-glycoprotein inhibitor, did not reduce the renal clearance of
sitagliptin.
Special Populations
Renal Insufficiency
A single-dose, open-label study was conducted to evaluate the
pharmacokinetics of JANUVIA (50 mg dose) in patients with varying
degrees of chronic renal insufficiency compared to normal healthy
control subjects. The study included patients with renal insufficiency
classified on the basis of creatinine clearance as mild (50 to less
than 80 mL/min), moderate (30 to less than 50 mL/min), and severe
(less than 30 mL/min), as well as patients with ESRD on hemodialysis.
In addition, the effects of renal insufficiency on sitagliptin
pharmacokinetics in patients with type 2 diabetes and mild or moderate
renal insufficiency were assessed using population pharmacokinetic
analyses. Creatinine clearance was measured by 24-hour urinary
creatinine clearance measurements or estimated from serum creatinine
based on the Cockcroft-Gault formula:
CrCl = (140 - age (years)) x weight (kg) {x 0.85 for female patients}
---------------------------------
(72 x serum creatinine (mg/dL))
Compared to normal healthy control subjects, an approximate 1.1-
to 1.6-fold increase in plasma AUC of sitagliptin was observed in
patients with mild renal insufficiency. Because increases of this
magnitude are not clinically relevant, dosage adjustment in patients
with mild renal insufficiency is not necessary. Plasma AUC levels of
sitagliptin were increased approximately 2-fold and 4-fold in patients
with moderate renal insufficiency and in patients with severe renal
insufficiency, including patients with ESRD on hemodialysis,
respectively. Sitagliptin was modestly removed by hemodialysis (13.5%
over a 3- to 4-hour hemodialysis session starting 4 hours postdose).
To achieve plasma concentrations of sitagliptin similar to those in
patients with normal renal function, lower dosages are recommended in
patients with moderate and severe renal insufficiency, as well as in
ESRD patients requiring hemodialysis. (See Dosage and Administration
(2.2).)
Hepatic Insufficiency
In patients with moderate hepatic insufficiency (Child-Pugh score
7 to 9), mean AUC and Cmax of sitagliptin increased approximately 21%
and 13%, respectively, compared to healthy matched controls following
administration of a single 100 mg dose of JANUVIA. These differences
are not considered to be clinically meaningful. No dosage adjustment
for JANUVIA is necessary for patients with mild or moderate hepatic
insufficiency.
There is no clinical experience in patients with severe hepatic
insufficiency (Child-Pugh score greater than9).
Body Mass Index (BMI)
No dosage adjustment is necessary based on BMI. Body mass index
had no clinically meaningful effect on the pharmacokinetics of
sitagliptin based on a composite analysis of Phase I pharmacokinetic
data and on a population pharmacokinetic analysis of Phase I and Phase
II data.
Gender
No dosage adjustment is necessary based on gender. Gender had no
clinically meaningful effect on the pharmacokinetics of sitagliptin
based on a composite analysis of Phase I pharmacokinetic data and on a
population pharmacokinetic analysis of Phase I and Phase II data.
Geriatric
No dosage adjustment is required based solely on age. When the
effects of age on renal function are taken into account, age alone did
not have a clinically meaningful impact on the pharmacokinetics of
sitagliptin based on a population pharmacokinetic analysis. Elderly
subjects (65 to 80 years) had approximately 19% higher plasma
concentrations of sitagliptin compared to younger subjects.
Pediatric
Studies characterizing the pharmacokinetics of sitagliptin in
pediatric patients have not been performed.
Race
No dosage adjustment is necessary based on race. Race had no
clinically meaningful effect on the pharmacokinetics of sitagliptin
based on a composite analysis of available pharmacokinetic data,
including subjects of white, Hispanic, black, Asian, and other racial
groups.
Drug Interactions
In Vitro Assessment of Drug Interactions
Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9,
2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4. Sitagliptin is
a p-glycoprotein substrate, but does not inhibit p-glycoprotein
mediated transport of digoxin. Based on these results, sitagliptin is
considered unlikely to cause interactions with other drugs that
utilize these pathways.
Sitagliptin is not extensively bound to plasma proteins.
Therefore, the propensity of sitagliptin to be involved in clinically
meaningful drug-drug interactions mediated by plasma protein binding
displacement is very low.
In Vivo Assessment of Drug Interactions
Effects of Sitagliptin on Other Drugs
In clinical studies, as described below, sitagliptin did not
meaningfully alter the pharmacokinetics of metformin, glyburide,
simvastatin, rosiglitazone, warfarin, or oral contraceptives,
providing in vivo evidence of a low propensity for causing drug
interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic
cationic transporter (OCT).
Digoxin: Sitagliptin had a minimal effect on the pharmacokinetics
of digoxin. Following administration of 0.25 mg digoxin concomitantly
with 100 mg of JANUVIA daily for 10 days, the plasma AUC of digoxin
was increased by 11%, and the plasma Cmax by 18%.
Metformin: Co-administration of multiple twice-daily doses of
sitagliptin with metformin, an OCT substrate, did not meaningfully
alter the pharmacokinetics of metformin in patients with type 2
diabetes. Therefore, sitagliptin is not an inhibitor of OCT-mediated
transport.
Sulfonylureas: Single-dose pharmacokinetics of glyburide, a CYP2C9
substrate, was not meaningfully altered in subjects receiving multiple
doses of sitagliptin. Clinically meaningful interactions would not be
expected with other sulfonylureas (e.g., glipizide, tolbutamide, and
glimepiride) which, like glyburide, are primarily eliminated by
CYP2C9. However, the risk of hypoglycemia from the co-administration
of sitagliptin and sulfonylureas is unknown.
Simvastatin: Single-dose pharmacokinetics of simvastatin, a CYP3A4
substrate, was not meaningfully altered in subjects receiving multiple
daily doses of sitagliptin. Therefore, sitagliptin is not an inhibitor
of CYP3A4-mediated metabolism.
Thiazolidinediones: Single-dose pharmacokinetics of rosiglitazone
was not meaningfully altered in subjects receiving multiple daily
doses of sitagliptin, indicating that JANUVIA is not an inhibitor of
CYP2C8-mediated metabolism.
Warfarin: Multiple daily doses of sitagliptin did not meaningfully
alter the pharmacokinetics, as assessed by measurement of S(-) or R(+)
warfarin enantiomers, or pharmacodynamics (as assessed by measurement
of prothrombin INR) of a single dose of warfarin. Because S(-)
warfarin is primarily metabolized by CYP2C9, these data also support
the conclusion that sitagliptin is not a CYP2C9 inhibitor.
Oral Contraceptives: Co-administration with sitagliptin did not
meaningfully alter the steady-state pharmacokinetics of norethindrone
or ethinyl estradiol.
Effects of Other Drugs on Sitagliptin
Clinical data described below suggest that sitagliptin is not
susceptible to clinically meaningful interactions by co-administered
medications:
Metformin: Co-administration of multiple twice-daily doses of
metformin with sitagliptin did not meaningfully alter the
pharmacokinetics of sitagliptin in patients with type 2 diabetes.
Cyclosporine: A study was conducted to assess the effect of
cyclosporine, a potent inhibitor of p-glycoprotein, on the
pharmacokinetics of sitagliptin. Co-administration of a single 100 mg
oral dose of JANUVIA and a single 600 mg oral dose of cyclosporine
increased the AUC and Cmax of sitagliptin by approximately 29% and
68%, respectively. These modest changes in sitagliptin
pharmacokinetics were not considered to be clinically meaningful. The
renal clearance of sitagliptin was also not meaningfully altered.
Therefore, meaningful interactions would not be expected with other
p-glycoprotein inhibitors.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
A two-year carcinogenicity study was conducted in male and female
rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day.
There was an increased incidence of combined liver adenoma/carcinoma
in males and females and of liver carcinoma in females at 500 mg/kg.
This dose results in exposures approximately 60 times the human
exposure at the maximum recommended daily adult human dose (MRHD) of
100 mg/day based on AUC comparisons. Liver tumors were not observed at
150 mg/kg, approximately 20 times the human exposure at the MRHD. A
two-year carcinogenicity study was conducted in male and female mice
given oral doses of sitagliptin of 50, 125, 250, and 500 mg/kg/day.
There was no increase in the incidence of tumors in any organ up to
500 mg/kg, approximately 70 times human exposure at the MRHD.
Sitagliptin was not mutagenic or clastogenic with or without metabolic
activation in the Ames bacterial mutagenicity assay, a Chinese hamster
ovary (CHO) chromosome aberration assay, an in vitro cytogenetics
assay in CHO, an in vitro rat hepatocyte DNA alkaline elution assay,
and an in vivo micronucleus assay.
In rat fertility studies with oral gavage doses of 125, 250, and
1000 mg/kg, males were treated for 4 weeks prior to mating, during
mating, up to scheduled termination (approximately 8 weeks total) and
females were treated 2 weeks prior to mating through gestation day 7.
No adverse effect on fertility was observed at 125 mg/kg
(approximately 12 times human exposure at the MRHD of 100 mg/day based
on AUC comparisons). At higher doses, nondose-related increased
resorptions in females were observed (approximately 25 and 100 times
human exposure at the MRHD based on AUC comparison).
14 CLINICAL STUDIES
There were 2316 patients with type 2 diabetes randomized in four
double-blind, placebo-controlled clinical safety and efficacy studies
conducted to evaluate the effects of sitagliptin on glycemic control.
In these studies, the mean age of patients was 54.8 years, and 62% of
patients were white, 18% were Hispanic, 6% were black, 9% were Asian,
and 4% were of other racial groups.
In patients with type 2 diabetes, treatment with JANUVIA produced
clinically significant improvements in hemoglobin A1C, fasting plasma
glucose (FPG) and 2-hour post-prandial glucose (PPG) compared to
placebo.
14.1 Monotherapy
A total of 1262 patients with type 2 diabetes participated in two
double-blind, placebo-controlled studies, one of 18-week and another
of 24-week duration, to evaluate the efficacy and safety of JANUVIA
monotherapy. In both monotherapy studies, patients currently on an
antihyperglycemic agent discontinued the agent, and underwent a diet,
exercise, and drug wash-out period of about 7 weeks. Patients with
inadequate glycemic control (A1C 7% to 10%) after the wash-out period
were randomized after completing a 2-week single-blind placebo run-in
period; patients not currently on antihyperglycemic agents (off
therapy for at least 8 weeks) with inadequate glycemic control (A1C 7%
to 10%) were randomized after completing the 2-week single-blind
placebo run-in period. In the 18-week study, 521 patients were
randomized to placebo, JANUVIA 100 mg, or JANUVIA 200 mg, and in the
24-week study 741 patients were randomized to placebo, JANUVIA 100 mg,
or JANUVIA 200 mg. Patients who failed to meet specific glycemic goals
during the studies were treated with metformin rescue, added on to
placebo or JANUVIA.
Treatment with JANUVIA at 100 mg daily provided significant
improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table
2). In the 18-week study, 9% of patients receiving JANUVIA 100 mg and
17% who received placebo required rescue therapy. In the 24-week
study, 9% of patients receiving JANUVIA 100 mg and 21% of patients
receiving placebo required rescue therapy. The improvement in A1C was
not affected by gender, age, race, or baseline BMI. As is typical for
trials of agents to treat type 2 diabetes, mean response to JANUVIA in
A1C lowering appears to be related to the degree of A1C elevation at
baseline. Overall, the 200 mg daily dose did not provide greater
glycemic efficacy than the 100 mg daily dose. The effect of JANUVIA on
lipid endpoints was similar to placebo. Body weight did not increase
from baseline with JANUVIA therapy in either study, compared to a
small reduction in patients given placebo.
Table 2
Glycemic Parameters in 18- and 24-Week Placebo-Controlled Studies of
JANUVIA in Patients with Type 2 Diabetes+
----------------------------------------------------------------------
18-Week Study 24-Week Study
----------------- -----------------
JANUVIA Placebo JANUVIA Placebo
100 mg 100 mg
------------------------------------------- -------- -------- --------
A1C (%) N = 193 N = 103 N = 229 N = 244
------------------------------------------- -------- -------- --------
Baseline (mean) 8.0 8.1 8.0 8.0
------------------------------------------- -------- -------- --------
Change from baseline (adjusted
mean++) -0.5 0.1 -0.6 0.2
------------------------------------------- -------- -------- --------
Difference from placebo (adjusted -0.6ss. -0.8ss.
mean++) (95% CI) (-0.8, (-1.0,
-0.4) -0.6)
------------------------------------------- -------- -------- --------
Patients (%) achieving A1C less
than7% 69 (36%) 16 (16%) 93 (41%) 41 (17%)
------------------------------------------- -------- -------- --------
FPG (mg/dL) N = 201 N = 107 N = 234 N = 247
------------------------------------------- -------- -------- --------
Baseline (mean) 180 184 170 176
------------------------------------------- -------- -------- --------
Change from baseline (adjusted
mean++) -13 7 -12 5
------------------------------------------- -------- -------- --------
Difference from placebo (adjusted -20ss. -17ss.
mean++) (95% CI) (-31, (-24,
-9) -10)
------------------------------------------- -------- -------- --------
2-hour PPG (mg/dL) % % N = 201 N = 204
------------------------------------------- -------- -------- --------
Baseline (mean) 257 271
------------------------------------------- -------- -------- --------
Change from baseline (adjusted
mean++) -49 -2
------------------------------------------- -------- -------- --------
Difference from placebo (adjusted -47ss.
mean++) (95% CI) (-59,
-34)
------------------------------------------- -------- -------- --------
+ Intent to Treat Population using last observation on study prior
to metformin rescue therapy.
++ Least squares means adjusted for prior antihyperglycemic
therapy status and baseline value.
ss. pless than0.001 compared to placebo.
% Data not available.
Additional Monotherapy Study
A multinational, randomized, double-blind, placebo-controlled
study was also conducted to assess the safety and tolerability of
JANUVIA in 91 patients with type 2 diabetes and chronic renal
insufficiency (creatinine clearance less than 50 mL/min). Patients
with moderate renal insufficiency received 50 mg daily of JANUVIA and
those with severe renal insufficiency or with ESRD on hemodialysis or
peritoneal dialysis received 25 mg daily. In this study, the safety
and tolerability of JANUVIA were generally similar to placebo. A small
increase in serum creatinine was reported in patients with moderate
renal insufficiency treated with JANUVIA relative to those on placebo.
In addition, the reductions in A1C and FPG with JANUVIA compared to
placebo were generally similar to those observed in other monotherapy
studies. (See Clinical Pharmacology (12.3).)
14.2 Combination Therapy
Combination Therapy with Metformin
A total of 701 patients with type 2 diabetes participated in a
24-week, randomized, double-blind, placebo-controlled study designed
to assess the efficacy of JANUVIA in combination with metformin.
Patients already on metformin (N=431) at a dose of at least 1500 mg
per day were randomized after completing a 2-week single-blind placebo
run-in period. Patients on metformin and another antihyperglycemic
agent (N = 229) and patients not on any antihyperglycemic agents (off
therapy for at least 8 weeks, N = 41) were randomized after a run-in
period of approximately 10 weeks on metformin (at a dose of at least
1500 mg per day) in monotherapy. Patients were randomized to the
addition of either 100 mg of JANUVIA or placebo, administered once
daily. Patients who failed to meet specific glycemic goals during the
studies were treated with pioglitazone rescue.
In combination with metformin, JANUVIA provided significant
improvements in A1C, FPG, and 2-hour PPG compared to placebo with
metformin (Table 3). Rescue glycemic therapy was used in 5% of
patients treated with JANUVIA 100 mg and 14% of patients treated with
placebo. A similar decrease in body weight was observed for both
treatment groups.
Table 3
Glycemic Parameters at Final Visit (24-Week Study)
for JANUVIA in Combination with Metformin+
----------------------------------------------------------------------
JANUVIA Placebo +
100 mg + Metformin
Metformin
----------------------------------------------------------- ---------
A1C (%) N = 453 N = 224
----------------------------------------------------------- ---------
Baseline (mean) 8.0 8.0
----------------------------------------------------------- ---------
Change from baseline (adjusted mean++) -0.7 -0.0
----------------------------------------------------------- ---------
Difference from placebo + metformin (adjusted -0.7ss.
mean++) (95% CI) (-0.8,
-0.5)
----------------------------------------------------------- ---------
Patients (%) achieving A1C less than7% 213 (47%) 41 (18%)
----------------------------------------------------------- ---------
FPG (mg/dL) N = 454 N = 226
----------------------------------------------------------- ---------
Baseline (mean) 170 174
----------------------------------------------------------- ---------
Change from baseline (adjusted mean++) -17 9
----------------------------------------------------------- ---------
Difference from placebo + metformin (adjusted -25ss.
mean++) (95% CI) (-31, -20)
----------------------------------------------------------- ---------
2-hour PPG (mg/dL) N = 387 N = 182
----------------------------------------------------------- ---------
Baseline (mean) 275 272
----------------------------------------------------------- ---------
Change from baseline (adjusted mean++) -62 -11
----------------------------------------------------------- ---------
Difference from placebo + metformin (adjusted -51ss.
mean++) (95% CI) (-61, -41)
----------------------------------------------------------- ---------
+ Intent to Treat Population using last observation on study prior
to pioglitazone rescue therapy.
++ Least squares means adjusted for prior antihyperglycemic
therapy and baseline value.
ss. pless than0.001 compared to placebo + metformin.
Combination Therapy with Pioglitazone
A total of 353 patients with type 2 diabetes participated in a
24-week, randomized, double-blind, placebo-controlled study designed
to assess the efficacy of JANUVIA in combination with pioglitazone.
Patients on any oral antihyperglycemic agent in monotherapy (N=212) or
on a PPAR-gamma agent in combination therapy (N=106) or not on an
antihyperglycemic agent (off therapy for at least 8 weeks, N=34) were
switched to monotherapy with pioglitazone (at a dose of 30-45 mg per
day), and completed a run-in period of approximately 12 weeks in
duration. After the run-in period on pioglitazone monotherapy,
patients were randomized to the addition of either 100 mg of JANUVIA
or placebo, administered once daily. Patients who failed to meet
specific glycemic goals during the studies were treated with metformin
rescue. Glycemic endpoints measured included A1C and fasting glucose.
In combination with pioglitazone, JANUVIA provided significant
improvements in A1C and FPG compared to placebo with pioglitazone
(Table 4). Rescue therapy was used in 7% of patients treated with
JANUVIA 100 mg and 14% of patients treated with placebo. There was no
significant difference between JANUVIA and placebo in body weight
change.
Table 4
Glycemic Parameters at Final Visit (24-Week Study)
for JANUVIA in Combination with Pioglitazone+
----------------------------------------------------------------------
JANUVIA 100 Placebo +
mg + Pioglitazone
Pioglitazone
-------------------------------------------------------- ------------
A1C (%) N = 163 N = 174
-------------------------------------------------------- ------------
Baseline (mean) 8.1 8.0
-------------------------------------------------------- ------------
Change from baseline (adjusted mean++) -0.9 -0.2
-------------------------------------------------------- ------------
Difference from placebo + pioglitazone -0.7ss.
(adjusted mean++) (95% CI) (-0.9, -0.5)
-------------------------------------------------------- ------------
Patients (%) achieving A1C less than7% 74 (45%) 40 (23%)
-------------------------------------------------------- ------------
FPG (mg/dL) N = 163 N = 174
-------------------------------------------------------- ------------
Baseline (mean) 168 166
-------------------------------------------------------- ------------
Change from baseline (adjusted mean++) -17 1
-------------------------------------------------------- ------------
Difference from placebo + pioglitazone -18ss.
(adjusted mean++) (95% CI) (-24, -11)
-------------------------------------------------------- ------------
+ Intent to Treat Population using last observation on study prior
to metformin rescue therapy.
++ Least squares means adjusted for prior antihyperglycemic
therapy status and baseline value.
ss. pless than0.001 compared to placebo + pioglitazone.
16 HOW SUPPLIED/STORAGE AND HANDLING
No. 6737 -- Tablets JANUVIA, 25 mg, are pink, round, film-coated
tablets with "221" on one side. They are supplied as follows:
NDC 0006-0221-31 unit-of-use bottles of 30
NDC 0006-0221-54 unit-of-use bottles of 90
NDC 0006-0221-28 unit dose blister packages of 100.
No. 6738 -- Tablets JANUVIA, 50 mg, are light beige, round,
film-coated tablets with "112" on one side. They are supplied as
follows:
NDC 0006-0112-31 unit-of-use bottles of 30
NDC 0006-0112-54 unit-of-use bottles of 90
NDC 0006-0112-28 unit dose blister packages of 100.
No. 6739 -- Tablets JANUVIA, 100 mg, are beige, round, film-coated
tablets with "277" on one side. They are supplied as follows:
NDC 0006-0277-31 unit-of-use bottles of 30
NDC 0006-0277-54 unit-of-use bottles of 90
NDC 0006-0277-28 unit dose blister packages of 100
NDC 0006-0277-74 bottles of 500
NDC 0006-0277-82 bottles of 1000.
Storage
Store at 20-25(degree)C (68-77(degree)F), excursions permitted to
15-30(degree)C (59-86(degree)F), (see USP Controlled Room
Temperature).
17 PATIENT COUNSELING INFORMATION
(See FDA-Approved Patient Labeling (17.3).)
17.1 Instructions
Patients should be informed of the potential risks and benefits of
JANUVIA and of alternative modes of therapy. Patients should also be
informed about the importance of adherence to dietary instructions,
regular physical activity, periodic blood glucose monitoring and A1C
testing, recognition and management of hypoglycemia and hyperglycemia,
and assessment for diabetes complications. During periods of stress
such as fever, trauma, infection, or surgery, medication requirements
may change and patients should be advised to seek medical advice
promptly.
Physicians should instruct their patients to read the Patient
Package Insert before starting JANUVIA therapy and to reread each time
the prescription is renewed. Patients should be instructed to inform
their doctor or pharmacist if they develop any unusual symptom, or if
any known symptom persists or worsens.
17.2 Laboratory Tests
Patients should be informed that response to all diabetic
therapies should be monitored by periodic measurements of blood
glucose and A1C levels, with a goal of decreasing these levels towards
the normal range. A1C is especially useful for evaluating long-term
glycemic control. Patients should be informed of the potential need to
adjust dose based on changes in renal function tests over time.
Manufactured for:
MERCK & CO., Inc. Whitehouse Station, New Jersey 08889 USA
Manufactured by:
Merck Sharp & Dohme (Italia) S.p.A.
Via Emilia, 21
27100 - Pavia, Italy
Printed in USA
9762700
US Patent No.: 6,699,871
17.3 FDA-Approved Patient Labeling
(1)Trademark of MERCK & CO., Inc., Whitehouse Station, New Jersey
08889 USA
COPYRIGHT (C) 2006 MERCK & CO., Inc.
All rights reserved
-0-
9762700
Patient Information
JANUVIA(TM) (jah-NEW-vee-ah)
(sitagliptin phosphate)
Tablets
Read the Patient Information that comes with JANUVIA(*) before you
start taking it and each time you get a refill. There may be new
information. This leaflet does not take the place of talking with your
doctor about your medical condition or treatment.
What is JANUVIA?
JANUVIA is a prescription medicine used along with diet and
exercise to lower blood sugar in patients with type 2 diabetes
mellitus (type 2 diabetes). JANUVIA may be taken alone or along with
certain other medicines to control blood sugar.
-- JANUVIA lowers blood sugar when blood sugar is high,
especially after a meal. JANUVIA also lowers blood sugar
between meals.
-- JANUVIA helps to improve the levels of insulin produced by
your own body after a meal.
Posted: February 2007
