FDA Approves Janumet for Type 2 Diabetes, Offering Powerful Glucose Control of a DPP-4 Inhibitor and Metformin in a Single Tablet
JANUMET has been approved, as an adjunct to diet and exercise, to improve blood sugar (glucose) control in adult patients with type 2 diabetes who are not adequately controlled on metformin or sitagliptin alone, or in patients already being treated with the combination of sitagliptin and metformin. JANUMET should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
The FDA approved JANUMET based upon clinical data including sitagliptin plus metformin as separate tablets. A clinical bioequivalence study has demonstrated the equivalence between JANUMET and sitagliptin plus metformin as separate tablets.
"JANUMET is the latest advance in Merck's longstanding commitment to developing effective medicines for type 2 diabetes," said Adam Schechter, president, United States Human Health, Merck & Co., Inc. "With JANUMET and JANUVIA, Merck now has a growing family of products that provides physicians with important treatment options for patients with type 2 diabetes."
JANUMET delivers proven efficacy
A 24-week, randomized, double-blind, placebo-controlled study with 701 patients with mildly to moderately elevated A1C levels (mean baseline 8.0 percent) inadequately controlled on metformin, showed that patients taking JANUMET(2) (n=453) experienced significant additional mean placebo-subtracted reductions in A1C of 0.7 percent beyond that achieved by patients who continued on metformin alone (n=224) (pless than0.001). In the study, more than twice as many patients on JANUMET (213 of 453 patients, or 47 percent) reached the American Diabetes Association's A1C goal of less than7 percent compared with patients on metformin alone (41 of 224 patients, or 18 percent) (pless than0.001).
JANUMET combines two agents with proven ability to deliver significant improvements in glycemic control: metformin, a commonly used effective glucose-lowering agent, and sitagliptin, a DPP-4 inhibitor that provides significant A1C lowering as monotherapy and as add-on therapy to metformin or thiazolidinediones (TZDs) based on clinical trials. JANUMET, like metformin, is dosed twice daily with meals. Consistent with the labeling for metformin alone, the labeling for JANUMET contains a boxed warning for lactic acidosis, a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with JANUMET.
"Physicians use several different medications in combination to address the multiple defects associated with type 2 diabetes, however, less than half of patients achieve and maintain their goal A1C levels," said Nir Barzilai, M.D., professor of Medicine and Molecular Genetics, director of the Institute for Aging Research, Albert Einstein College of Medicine. "JANUMET is an important new treatment option for many patients who need more than one therapy to control their type 2 diabetes because it addresses all three key defects of type 2 diabetes for improved glycemic control."
Patients treated with JANUMET experienced weight loss comparable to metformin alone, with no increased risk of hypoglycemia, edema, or GI disturbances beyond metformin alone
As clinicians select agents to add to the treatment regimens of patients with uncontrolled type 2 diabetes, it is important to consider issues such as weight gain, hypoglycemia, edema, and gastrointestinal disturbances.
In a 24-week study, mean body weight decreased 1.5 lb (n=399) in patients taking JANUMET, similar to patients taking metformin alone (1.3 lb decrease; n=169). There was no increased risk of hypoglycemia in patients treated with JANUMET (1.3 percent vs. metformin alone, 2.1 percent) and no increased risk of edema in patients treated with JANUMET (0.9 percent vs. metformin alone, 1.3 percent). In addition, there was no significant increase in the risk of overall gastrointestinal adverse reactions in patients treated with JANUMET (11.6 percent vs. metformin alone, 9.7 percent). Specific gastrointestinal adverse reactions included diarrhea (JANUMET, 2.4 percent vs. metformin alone, 2.5 percent), abdominal pain (JANUMET, 2.2 percent vs. metformin alone, 3.8 percent), nausea (JANUMET, 1.3 percent vs. metformin alone, 0.8 percent), and vomiting (JANUMET, 1.1 percent vs. metformin alone, 0.8 percent). The most common adverse experience in sitagliptin monotherapy reported regardless of investigator assessment of causality in greater than or equal to 5 percent of patients and more commonly than in patients given placebo was nasopharyngitis.
Clinicians should be mindful that hypoglycemia could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects.
By incorporating the novel mechanism of DPP-4 inhibition, JANUMET uniquely addresses the three key defects of type 2 diabetes
With the two active components, sitagliptin and metformin, JANUMET has a comprehensive mechanism of action that targets all three key defects of type 2 diabetes for improved glycemic control: diminished insulin release, uncontrolled production of glucose, and insulin resistance.
The sitagliptin component in JANUMET address two of the three key defects that cause poor glucose control: diminished insulin release due to beta-cell dysfunction and uncontrolled production of glucose by the liver due to alpha-cell and beta-cell dysfunction. By inhibiting the DPP-4 enzyme, sitagliptin significantly increases the levels of active incretin hormones, increasing the synthesis and release of insulin from the pancreatic beta cells and decreasing the release of glucagon from the pancreatic alpha cells.
JANUMET also contains metformin, which addresses the other key defect: insulin resistance. Metformin improves insulin sensitivity by increasing uptake and utilization of glucose by the muscles and tissues of the body. Metformin also decreases hepatic glucose production in a manner that is complementary to sitagliptin.
JANUMET provides powerful A1C lowering through combined reductions of both post-prandial glucose and fasting plasma glucose
JANUMET has been demonstrated to provide 24-hour glucose response - at mealtimes, between meals and overnight. In a 24-week, placebo-controlled study of patients with inadequate glycemic control on metformin alone, JANUMET significantly reduced post prandial, or post-meal, glucose (PPG) levels beyond metformin alone by a mean of 51 mg/dL in patients with a mean baseline 2-hour PPG of 275 mg/dL (n=387, pless than0.001) and fasting plasma glucose levels (FPG) beyond metformin alone by a mean of 25 mg/dL in patients with a mean baseline FPG of 170 mg/dL (n=454, pless than0.001).
Indications and contraindications for JANUMET
JANUMET is indicated, as an adjunct to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes who are not adequately controlled on metformin or sitagliptin alone or in patients already being treated with the combination of sitagliptin and metformin. Consistent with the labeling for metformin alone, JANUMET is contraindicated in patients with renal disease, renal dysfunction, or abnormal creatinine clearance; and acute or chronic metabolic acidosis, including diabetic ketoacidosis. JANUMET should not be used in patients with type 1 diabetes.
Flexible dosing of JANUMET
JANUMET should be given twice daily with meals, with gradual dose escalation as needed to reduce the gastrointestinal (GI) side effects due to metformin. In this formulation, the dose of sitagliptin remains constant (100 mg daily) and is combined with the two most widely prescribed doses of metformin (1000 mg daily or 2000 mg daily). The recommended starting dose of JANUMET for patients not on prior metformin therapy and for those not adequately controlled on sitagliptin is 50 mg sitagliptin and 500 mg metformin twice-daily with meals. For patients already receiving metformin therapy, the starting dose should be based on the patient's current metformin regimen. The total daily dose should not exceed 100 mg sitagliptin and 2000 mg metformin.
Metformin and sitagliptin are known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive JANUMET. In the elderly, JANUMET should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging can be associated with reduced renal function. Any dose adjustment should be based on a careful assessment of renal function. Before initiation of therapy with JANUMET and at least annually thereafter, renal function should be assessed and verified as normal.
Pricing and availability of JANUMET
The price of twice-daily JANUMET will be $4.86 per day. JANUMET will be broadly available in pharmacies in the near future.
Selected cautionary information for JANUMET
JANUMET should be avoided in patients with evidence of hepatic disease. Before initiation of therapy with JANUMET and at least annually thereafter, renal function should be assessed and verified as normal. Patients should be warned against excessive alcohol intake while receiving JANUMET. Patients may require discontinuation of JANUMET and temporary use of insulin during periods of stress and decreased intake of fluids and food such as may occur with fever, trauma, infection or surgery. Patients previously controlled on JANUMET who develop laboratory abnormalities or clinical illness should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). When lactic acidosis occurs, it is fatal in approximately 50 percent of cases.
About type 2 diabetes
Type 2 diabetes is a condition in which the body has elevated blood sugar or glucose. With type 2 diabetes, the body may not make enough insulin, the insulin that the body produces may not work as well as it should, and/or the liver may release too much glucose.
Nearly 21 million people in the United States (7 percent of the population) have diabetes, with type 2 accounting for 90-95 percent of cases. Approximately half of people diagnosed with type 2 diabetes have not achieved adequate control of their blood sugar levels. Patients with diabetes can develop heart disease, kidney disease, blindness, vascular or neurological problems that can lead to amputation and can suffer increased rates of mortality. JANUMET and JANUVIA are not approved to treat the serious problems that may result from high blood sugar.
It is estimated that one in three Americans born in 2000 will develop diabetes sometime during their lifetime. There are currently more than 230 million people with diabetes worldwide, and if nothing is done to slow the epidemic, the worldwide number may exceed 350 million by 2025. The American Diabetes Association recommends that patients with type 2 diabetes achieve a target A1C level of less than7 percent, while the American Association of Clinical Endocrinologists recommends a target A1C level of less than6.5 percent.
Expanding clinical development program for sitagliptin family
Merck's clinical development program for sitagliptin is robust and continues to expand with 47 studies completed or under way, and nine 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 sitagliptin. Additionally, about 1,900 patients have been treated with sitagliptin 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 currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.
Merck forward-looking statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2006, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.
Prescribing information and patient product information for JANUMET are attached.
(1) A1C is a measure of a person's average blood glucose over a two- to three-month period.
(2) Clinical data referenced in this press release for JANUMET were from studies including sitagliptin plus metformin as separate tablets. A clinical bioequivalence study has demonstrated the equivalence between JANUMET and sitagliptin plus metformin as separate tablets.
JANUMET(TM) and JANUVIA(TM) are trademarks of Merck & Co., Inc. -0-
JANUMET(TM) (sitagliptin/metformin HCl) Tablets 9794100
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
JANUMET safely and effectively. See full prescribing information for
JANUMET.
JANUMET(TM) (sitagliptin/metformin HCl) tablets
Initial U.S. Approval: 2007
WARNING: LACTIC ACIDOSIS
See full prescribing information for complete boxed warning.
-- Lactic acidosis can occur due to metformin accumulation. The
risk increases with conditions such as sepsis, dehydration,
excess alcohol intake, hepatic insufficiency, renal impairment,
and acute congestive heart failure. (5.1)
-- Symptoms include malaise, myalgias, respiratory distress,
increasing somnolence, and nonspecific abdominal distress.
Laboratory abnormalities include low pH, increased anion gap
and elevated blood lactate. (5.1)
-- If acidosis is suspected, discontinue JANUMET and hospitalize
the patient immediately. (5.1)
INDICATIONS AND USAGE
JANUMET is indicated as an adjunct to diet and exercise to improve
glycemic control in adult patients with type 2 diabetes mellitus who
are not adequately controlled on metformin or sitagliptin alone or in
patients already being treated with the combination of sitagliptin and
metformin. (1)
Important Limitation of Use: JANUMET should not be used in
patients with type 1 diabetes or for the treatment of diabetic
ketoacidosis. (1)
DOSAGE AND ADMINISTRATION
-- Individualize the starting dose of JANUMET based on the
patient's current regimen. (2.1)
-- May adjust the dosing based on effectiveness and tolerability
while not exceeding the maximum recommended daily dose of 100
mg sitagliptin and 2000 mg metformin. (2.1)
-- JANUMET should be given twice daily with meals, with gradual
dose escalation, to reduce the gastrointestinal (GI) side
effects due to metformin. (2.1)
DOSAGE FORMS AND STRENGTHS
Tablets: 50 mg sitagliptin/500 mg metformin HCl and 50 mg
sitagliptin/1000 mg metformin HCl (3)
CONTRAINDICATIONS
-- Renal disease or renal dysfunction, e.g., serum creatinine
levels greater than or equal to 1.5 mg/dL (males), greater
than or equal to 1.4 mg/dL (females) or abnormal creatinine
clearance. (4, 5.1, 5.3)
-- Acute or chronic metabolic acidosis, including diabetic
ketoacidosis, with or without coma. (4, 5.1)
-- Temporarily discontinue JANUMET in patients undergoing
radiologic studies involving intravascular administration of
iodinated contrast materials. (4, 5.1, 5.10)
WARNINGS AND PRECAUTIONS
-- Avoid JANUMET use in patients with evidence of hepatic disease.
(5.1, 5.2)
-- Before initiation of therapy with JANUMET and at least annually
thereafter, assess renal function and verify as normal. (4,
5.1, 5.3)
-- Measure hematologic parameters annually. (5.4, 6.1)
-- Warn patients against excessive alcohol intake. (5.1, 5.5)
-- May need to discontinue JANUMET and temporarily use insulin
during periods of stress and decreased intake of fluids and
food as may occur with fever, trauma, infection or surgery.
(5.6, 5.7)
-- Promptly evaluate patients previously controlled on JANUMET who
develop laboratory abnormalities or clinical illness for
evidence of ketoacidosis or lactic acidosis. (5.1, 5.7)
ADVERSE REACTIONS
-- The most common adverse experience in sitagliptin monotherapy
reported regardless of investigator assessment of causality in
greater than or equal to 5% of patients and more commonly than
in patients given placebo was nasopharyngitis. (6.1)
-- The most common (greater than 5%) established adverse reactions
due to initiation of metformin therapy are diarrhea,
nausea/vomiting, flatulence, abdominal discomfort, indigestion,
asthenia, 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.
DRUG INTERACTIONS
-- Cationic drugs eliminated by renal tubular secretion: Use with
caution. (5.9, 7.1)
USE IN SPECIFIC POPULATIONS
-- Safety and effectiveness of JANUMET in children under 18 years
have not been established. (8.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient
labeling.
Revised: Mar 2007
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING - LACTIC ACIDOSIS
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosing
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Lactic Acidosis
5.2 Impaired Hepatic Function
5.3 Assessment of Renal Function
5.4 Vitamin B12 Levels
5.5 Alcohol Intake
5.6 Surgical Procedures
5.7 Change in Clinical Status of Patients with Previously
Controlled Type 2 Diabetes
5.8 Use with Medications Known to Cause Hypoglycemia
5.9 Concomitant Medications Affecting Renal Function or Metformin
Disposition
5.10 Radiologic Studies with Intravascular Iodinated Contrast
Materials
5.11 Hypoxic States
5.12 Loss of Control of Blood Glucose
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
7 DRUG INTERACTIONS
7.1 Cationic Drugs
7.2 Digoxin
7.3 Glyburide
7.4 Furosemide
7.5 Nifedipine
7.6 The Use of Metformin with Other Drugs
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
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
WARNING: LACTIC ACIDOSIS
Lactic acidosis is a rare, but serious complication that can occur
due to metformin accumulation. The risk increases with conditions such
as sepsis, dehydration, excess alcohol intake, hepatic insufficiency,
renal impairment, and acute congestive heart failure.
The onset is often subtle, accompanied only by nonspecific
symptoms such as malaise, myalgias, respiratory distress, increasing
somnolence, and nonspecific abdominal distress.
Laboratory abnormalities include low pH, increased anion gap and
elevated blood lactate.
If acidosis is suspected, JANUMET(1) should be discontinued and
the patient hospitalized immediately. (See Warnings and Precautions
(5.1).)
1 INDICATIONS AND USAGE
JANUMET is indicated as an adjunct to diet and exercise to improve
glycemic control in adult patients with type 2 diabetes mellitus who
are not adequately controlled on metformin or sitagliptin alone or in
patients already being treated with the combination of sitagliptin and
metformin.
Important Limitations of Use
JANUMET should not be used in patients with type 1 diabetes or for
the treatment of diabetic ketoacidosis.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosing
The dosage of antihyperglycemic therapy with JANUMET should be
individualized on the basis of the patient's current regimen,
effectiveness, and tolerability while not exceeding the maximum
recommended daily dose of 100 mg sitagliptin and 2000 mg metformin.
JANUMET should generally be given twice daily with meals, with
gradual dose escalation, to reduce the gastrointestinal (GI) side
effects due to metformin.
The starting dose of JANUMET should be based on the patient's
current regimen. JANUMET should be given twice daily with meals. The
following doses are available:
50 mg sitagliptin/500 mg metformin hydrochloride
50 mg sitagliptin/1000 mg metformin hydrochloride.
Patients inadequately controlled on metformin monotherapy
For patients not adequately controlled on metformin alone, the
usual starting dose of JANUMET should be equal to 100 mg total daily
dose (50 mg twice daily) of sitagliptin plus the dose of metformin
already being taken. For patients taking metformin 850 mg twice daily,
the recommended starting dose of JANUMET is 50 mg sitagliptin/1000 mg
metformin hydrochloride twice daily.
Patients inadequately controlled on sitagliptin monotherapy
For patients not adequately controlled on sitagliptin alone, the
usual starting dose of JANUMET is 50 mg sitagliptin/500 mg metformin
hydrochloride twice daily. Patients may be titrated up to 50 mg
sitagliptin/1000 mg metformin hydrochloride twice daily. Patients
taking sitagliptin monotherapy dose-adjusted for renal insufficiency
should not be switched to JANUMET (see Contraindications (4)).
Patients switching from sitagliptin co-administered with metformin
For patients switching from sitagliptin co-administrated with
metformin, JANUMET may be initiated at the dose of sitagliptin and
metformin already being taken.
No studies have been performed specifically examining the safety
and efficacy of JANUMET in patients previously treated with other oral
antihyperglycemic agents and switched to JANUMET. Any change in
therapy of type 2 diabetes should be undertaken with care and
appropriate monitoring as changes in glycemic control can occur.
3 DOSAGE FORMS AND STRENGTHS
-- 50 mg/500 mg tablets are light pink, capsule-shaped,
film-coated tablets with "575" debossed on one side.
-- 50 mg/1000 mg tablets are red, capsule-shaped, film-coated
tablets with "577" debossed on one side.
4 CONTRAINDICATIONS
JANUMET (sitagliptin/metformin HCl) is contraindicated in patients
with:
-- Renal disease or renal dysfunction, e.g., as suggested by serum
creatinine levels greater than or equal to 1.5 mg/dL (males),
greater than or equal to 1.4 mg/dL (females) or abnormal
creatinine clearance which may also result from conditions such
as cardiovascular collapse (shock), acute myocardial
infarction, and septicemia (see Warnings and Precautions
(5.1)).
-- Acute or chronic metabolic acidosis, including diabetic
ketoacidosis, with or without coma.
JANUMET should be temporarily discontinued in patients undergoing
radiologic studies involving intravascular administration of iodinated
contrast materials, because use of such products may result in acute
alteration of renal function (see Warnings and Precautions (5.10)).
5 WARNINGS AND PRECAUTIONS
5.1 Lactic Acidosis
Metformin hydrochloride
Lactic acidosis is a rare, but serious, metabolic complication
that can occur due to metformin accumulation during treatment with
JANUMET; when it occurs, it is fatal in approximately 50% of cases.
Lactic acidosis may also occur in association with a number of
pathophysiologic conditions, including diabetes mellitus, and whenever
there is significant tissue hypoperfusion and hypoxemia. Lactic
acidosis is characterized by elevated blood lactate levels (greater
than 5 mmol/L), decreased blood pH, electrolyte disturbances with an
increased anion gap, and an increased lactate/pyruvate ratio.
When metformin is implicated as the cause of lactic acidosis,
metformin plasma levels greater than 5 (mu)g/mL are generally found.
The reported incidence of lactic acidosis in patients receiving
metformin hydrochloride is very low (approximately 0.03 cases/1000
patient-years, with approximately 0.015 fatal cases/1000
patient-years). In more than 20,000 patient-years exposure to
metformin in clinical trials, there were no reports of lactic
acidosis. Reported cases have occurred primarily in diabetic patients
with significant renal insufficiency, including both intrinsic renal
disease and renal hypoperfusion, often in the setting of multiple
concomitant medical/surgical problems and multiple concomitant
medications. Patients with congestive heart failure requiring
pharmacologic management, in particular those with unstable or acute
congestive heart failure who are at risk of hypoperfusion and
hypoxemia, are at increased risk of lactic acidosis. The risk of
lactic acidosis increases with the degree of renal dysfunction and the
patient's age. The risk of lactic acidosis may, therefore, be
significantly decreased by regular monitoring of renal function in
patients taking metformin and by use of the minimum effective dose of
metformin. In particular, treatment of the elderly should be
accompanied by careful monitoring of renal function. Metformin
treatment should not be initiated in patients greater than or equal to
80 years of age unless measurement of creatinine clearance
demonstrates that renal function is not reduced, as these patients are
more susceptible to developing lactic acidosis. In addition, metformin
should be promptly withheld in the presence of any condition
associated with hypoxemia, dehydration, or sepsis. Because impaired
hepatic function may significantly limit the ability to clear lactate,
metformin should generally be avoided in patients with clinical or
laboratory evidence of hepatic disease. Patients should be cautioned
against excessive alcohol intake, either acute or chronic, when taking
metformin, since alcohol potentiates the effects of metformin
hydrochloride on lactate metabolism. In addition, metformin should be
temporarily discontinued prior to any intravascular radiocontrast
study and for any surgical procedure (see Warnings and Precautions
(5.3, 5.5, 5.6, 5.10)).
The onset of lactic acidosis often is subtle, and accompanied only
by nonspecific symptoms such as malaise, myalgias, respiratory
distress, increasing somnolence, and nonspecific abdominal distress.
There may be associated hypothermia, hypotension, and resistant
bradyarrhythmias with more marked acidosis. The patient and the
patient's physician must be aware of the possible importance of such
symptoms and the patient should be instructed to notify the physician
immediately if they occur (see Warnings and Precautions (5.11)).
Metformin should be withdrawn until the situation is clarified. Serum
electrolytes, ketones, blood glucose, and if indicated, blood pH,
lactate levels, and even blood metformin levels may be useful. Once a
patient is stabilized on any dose level of metformin, gastrointestinal
symptoms, which are common during initiation of therapy, are unlikely
to be drug related. Later occurrence of gastrointestinal symptoms
could be due to lactic acidosis or other serious disease.
Levels of fasting venous plasma lactate above the upper limit of
normal but less than 5 mmol/L in patients taking metformin do not
necessarily indicate impending lactic acidosis and may be explainable
by other mechanisms, such as poorly controlled diabetes or obesity,
vigorous physical activity, or technical problems in sample handling
(see Warnings and Precautions (5.7, 5.12)).
Lactic acidosis should be suspected in any diabetic patient with
metabolic acidosis lacking evidence of ketoacidosis (ketonuria and
ketonemia).
Lactic acidosis is a medical emergency that must be treated in a
hospital setting. In a patient with lactic acidosis who is taking
metformin, the drug should be discontinued immediately and general
supportive measures promptly instituted. Because metformin
hydrochloride is dialyzable (with a clearance of up to 170 mL/min
under good hemodynamic conditions), prompt hemodialysis is recommended
to correct the acidosis and remove the accumulated metformin. Such
management often results in prompt reversal of symptoms and recovery
(see Contraindications (4); Warnings and Precautions (5.5, 5.6, 5.9,
5.10, 5.11)).
5.2 Impaired Hepatic Function
Since impaired hepatic function has been associated with some
cases of lactic acidosis, JANUMET should generally be avoided in
patients with clinical or laboratory evidence of hepatic disease.
5.3 Assessment of Renal Function
Metformin and sitagliptin are known to be substantially excreted
by the kidney. The risk of metformin accumulation and lactic acidosis
increases with the degree of impairment of renal function. Thus,
patients with serum creatinine levels above the upper limit of normal
for their age should not receive JANUMET. In the elderly, JANUMET
should be carefully titrated to establish the minimum dose for
adequate glycemic effect, because aging can be associated with reduced
renal function. (See Warnings and Precautions (5.1) and Use in
Specific Populations (8.5).)
Before initiation of therapy with JANUMET and at least annually
thereafter, renal function should be assessed and verified as normal.
In patients in whom development of renal dysfunction is anticipated,
particularly in elderly patients, renal function should be assessed
more frequently and JANUMET discontinued if evidence of renal
impairment is present.
5.4 Vitamin B12 Levels
In controlled clinical trials of metformin of 29 weeks duration, a
decrease to subnormal levels of previously normal serum Vitamin B12
levels, without clinical manifestations, was observed in approximately
7% of patients. Such decrease, possibly due to interference with B12
absorption from the B12-intrinsic factor complex, is, however, very
rarely associated with anemia and appears to be rapidly reversible
with discontinuation of metformin or Vitamin B12 supplementation.
Measurement of hematologic parameters on an annual basis is advised in
patients on JANUMET and any apparent abnormalities should be
appropriately investigated and managed. (See Adverse Reactions (6.1).)
Certain individuals (those with inadequate Vitamin B12 or calcium
intake or absorption) appear to be predisposed to developing subnormal
Vitamin B12 levels. In these patients, routine serum Vitamin B12
measurements at two- to three-year intervals may be useful.
5.5 Alcohol Intake
Alcohol is known to potentiate the effect of metformin on lactate
metabolism. Patients, therefore, should be warned against excessive
alcohol intake, acute or chronic, while receiving JANUMET.
5.6 Surgical Procedures
Use of JANUMET should be temporarily suspended for any surgical
procedure (except minor procedures not associated with restricted
intake of food and fluids) and should not be restarted until the
patient's oral intake has resumed and renal function has been
evaluated as normal.
5.7 Change in Clinical Status of Patients with Previously
Controlled Type 2 Diabetes
A patient with type 2 diabetes previously well controlled on
JANUMET who develops laboratory abnormalities or clinical illness
(especially vague and poorly defined illness) should be evaluated
promptly for evidence of ketoacidosis or lactic acidosis. Evaluation
should include serum electrolytes and ketones, blood glucose and, if
indicated, blood pH, lactate, pyruvate, and metformin levels. If
acidosis of either form occurs, JANUMET must be stopped immediately
and other appropriate corrective measures initiated.
5.8 Use with Medications Known to Cause Hypoglycemia
Sitagliptin
In clinical trials of sitagliptin as monotherapy and sitagliptin
as part of combination therapy with metformin or pioglitazone, rates
of hypoglycemia reported with sitagliptin were similar to rates in
patients taking placebo. The use of sitagliptin in combination with
medications known to cause hypoglycemia, such as sulfonylureas or
insulin, has not been adequately studied.
Metformin hydrochloride
Hypoglycemia does not occur in patients receiving metformin alone
under usual circumstances of use, but could occur when caloric intake
is deficient, when strenuous exercise is not compensated by caloric
supplementation, or during concomitant use with other glucose-lowering
agents (such as sulfonylureas and insulin) or ethanol. Elderly,
debilitated, or malnourished patients, and those with adrenal or
pituitary insufficiency or alcohol intoxication are particularly
susceptible to hypoglycemic effects. Hypoglycemia may be difficult to
recognize in the elderly, and in people who are taking
(beta)-adrenergic blocking drugs.
5.9 Concomitant Medications Affecting Renal Function or Metformin
Disposition
Concomitant medication(s) that may affect renal function or result
in significant hemodynamic change or may interfere with the
disposition of metformin, such as cationic drugs that are eliminated
by renal tubular secretion (see Drug Interactions (7.1)), should be
used with caution.
5.10 Radiologic Studies with Intravascular Iodinated Contrast
Materials
Intravascular contrast studies with iodinated materials (for
example, intravenous urogram, intravenous cholangiography,
angiography, and computed tomography (CT) scans with intravascular
contrast materials) can lead to acute alteration of renal function and
have been associated with lactic acidosis in patients receiving
metformin (see Contraindications (4)). Therefore, in patients in whom
any such study is planned, JANUMET should be temporarily discontinued
at the time of or prior to the procedure, and withheld for 48 hours
subsequent to the procedure and reinstituted only after renal function
has been re-evaluated and found to be normal.
5.11 Hypoxic States
Cardiovascular collapse (shock) from whatever cause, acute
congestive heart failure, acute myocardial infarction and other
conditions characterized by hypoxemia have been associated with lactic
acidosis and may also cause prerenal azotemia. When such events occur
in patients on JANUMET therapy, the drug should be promptly
discontinued.
5.12 Loss of Control of Blood Glucose
When a patient stabilized on any diabetic regimen is exposed to
stress such as fever, trauma, infection, or surgery, a temporary loss
of glycemic control may occur. At such times, it may be necessary to
withhold JANUMET and temporarily administer insulin. JANUMET may be
reinstituted after the acute episode is resolved.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
The overall incidence of side effects reported in patients
receiving sitagliptin and metformin was similar to that reported with
patients receiving placebo and metformin.
In a 24-week placebo-controlled trial of sitagliptin 100 mg
administered once daily added to a twice daily metformin regimen,
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. Discontinuation of
therapy due to clinical adverse reactions was similar to the placebo
treatment group (sitagliptin and metformin, 1.9%; placebo and
metformin, 2.5%).
The overall incidence of adverse reactions of hypoglycemia in
patients treated with sitagliptin and metformin was similar to
patients treated with placebo and metformin (100 mg sitagliptin and
metformin, 1.3%; placebo and metformin, 2.1%). 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
sitagliptin and metformin was also similar to placebo and metformin:
nausea (sitagliptin and metformin, 1.3%; placebo and metformin, 0.8%),
vomiting (1.1%, 0.8%), abdominal pain (2.2%, 3.8%), and diarrhea
(2.4%, 2.5%).
No clinically meaningful changes in vital signs or in ECG
(including in QTc interval) were observed with the combination of
sitagliptin and metformin.
The most common adverse experience in sitagliptin monotherapy
reported regardless of investigator assessment of causality in greater
than or equal to 5% of patients and more commonly than in patients
given placebo was nasopharyngitis.
The most common (greater than 5%) established adverse reactions
due to initiation of metformin therapy are diarrhea, nausea/vomiting,
flatulence, abdominal discomfort, indigestion, asthenia, and headache.
Laboratory Tests
Sitagliptin
The incidence of laboratory adverse reactions was similar in
patients treated with sitagliptin and metformin (7.6%) compared to
patients treated with placebo and metformin (8.7%). In most but not
all 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 a
small increase in neutrophils. This change in laboratory parameters is
not considered to be clinically relevant.
Metformin hydrochloride
In controlled clinical trials of metformin of 29 weeks duration, a
decrease to subnormal levels of previously normal serum Vitamin B12
levels, without clinical manifestations, was observed in approximately
7% of patients. Such decrease, possibly due to interference with B12
absorption from the B12-intrinsic factor complex, is, however, very
rarely associated with anemia and appears to be rapidly reversible
with discontinuation of metformin or Vitamin B12 supplementation.
(See Warnings and Precautions (5.4).)
7 DRUG INTERACTIONS
7.1 Cationic Drugs
Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide,
quinidine, quinine, ranitidine, triamterene, trimethoprim, or
vancomycin) that are eliminated by renal tubular secretion
theoretically have the potential for interaction with metformin by
competing for common renal tubular transport systems. Such interaction
between metformin and oral cimetidine has been observed in normal
healthy volunteers in both single- and multiple-dose
metformin-cimetidine drug interaction studies, with a 60% increase in
peak metformin plasma and whole blood concentrations and a 40%
increase in plasma and whole blood metformin AUC. There was no change
in elimination half-life in the single-dose study. Metformin had no
effect on cimetidine pharmacokinetics. Although such interactions
remain theoretical (except for cimetidine), careful patient monitoring
and dose adjustment of JANUMET and/or the interfering drug is
recommended in patients who are taking cationic medications that are
excreted via the proximal renal tubular secretory system.
7.2 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. These
increases are not considered likely to be clinically meaningful.
Digoxin, as a cationic drug, has the potential to compete with
metformin for common renal tubular transport systems, thus affecting
the serum concentrations of either digoxin, metformin or both.
Patients receiving digoxin should be monitored appropriately. No
dosage adjustment of digoxin or JANUMET is recommended.
7.3 Glyburide
In a single-dose interaction study in type 2 diabetes patients,
co-administration of metformin and glyburide did not result in any
changes in either metformin pharmacokinetics or pharmacodynamics.
Decreases in glyburide AUC and Cmax were observed, but were highly
variable. The single-dose nature of this study and the lack of
correlation between glyburide blood levels and pharmacodynamic effects
make the clinical significance of this interaction uncertain.
7.4 Furosemide
A single-dose, metformin-furosemide drug interaction study in
healthy subjects demonstrated that pharmacokinetic parameters of both
compounds were affected by co-administration. Furosemide increased the
metformin plasma and blood Cmax by 22% and blood AUC by 15%, without
any significant change in metformin renal clearance. When administered
with metformin, the Cmax and AUC of furosemide were 31% and 12%
smaller, respectively, than when administered alone, and the terminal
half-life was decreased by 32%, without any significant change in
furosemide renal clearance. No information is available about the
interaction of metformin and furosemide when co-administered
chronically.
7.5 Nifedipine
A single-dose, metformin-nifedipine drug interaction study in
normal healthy volunteers demonstrated that co-administration of
nifedipine increased plasma metformin Cmax and AUC by 20% and 9%,
respectively, and increased the amount excreted in the urine. Tmax and
half-life were unaffected. Nifedipine appears to enhance the
absorption of metformin. Metformin had minimal effects on nifedipine.
7.6 The Use of Metformin with Other Drugs
Certain drugs tend to produce hyperglycemia and may lead to loss
of glycemic control. These drugs include the thiazides and other
diuretics, corticosteroids, phenothiazines, thyroid products,
estrogens, oral contraceptives, phenytoin, nicotinic acid,
sympathomimetics, calcium channel blocking drugs, and isoniazid. When
such drugs are administered to a patient receiving JANUMET the patient
should be closely observed to maintain adequate glycemic control.
In healthy volunteers, the pharmacokinetics of metformin and
propranolol, and metformin and ibuprofen were not affected when
co-administered in single-dose interaction studies.
Metformin is negligibly bound to plasma proteins and is,
therefore, less likely to interact with highly protein-bound drugs
such as salicylates, sulfonamides, chloramphenicol, and probenecid, as
compared to the sulfonylureas, which are extensively bound to serum
proteins.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B:
JANUMET
There are no adequate and well-controlled studies in pregnant
women with JANUMET or its individual components; therefore, the
safety of JANUMET in pregnant women is not known. JANUMET should be
used during pregnancy only if clearly needed.
Merck & Co., Inc. maintains a registry to monitor the pregnancy
outcomes of women exposed to JANUMET while pregnant. Health care
providers are encouraged to report any prenatal exposure to JANUMET by
calling the Pregnancy Registry at (800) 986-8999.
No animal studies have been conducted with the combined products
in JANUMET to evaluate effects on reproduction. The following data are
based on findings in studies performed with sitagliptin or metformin
individually.
Sitagliptin
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 with sitagliptin in pregnant women.
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.
Metformin hydrochloride
Metformin was not teratogenic in rats and rabbits at doses up to
600 mg/kg/day. This represents an exposure of about 2 and 6 times the
maximum recommended human daily dose of 2,000 mg based on body surface
area comparisons for rats and rabbits, respectively. Determination of
fetal concentrations demonstrated a partial placental barrier to
metformin.
8.3 Nursing Mothers
No studies in lactating animals have been conducted with the
combined components of JANUMET. In studies performed with the
individual components, both sitagliptin and metformin are secreted in
the milk of lactating rats. It is not known whether sitagliptin is
excreted in human milk. Because many drugs are excreted in human milk,
caution should be exercised when JANUMET is administered to a nursing
woman.
8.4 Pediatric Use
Safety and effectiveness of JANUMET in pediatric patients under 18
years have not been established.
8.5 Geriatric Use
JANUMET
Because sitagliptin and metformin are substantially excreted by
the kidney, and because aging can be associated with reduced renal
function, JANUMET should be used with caution as age increases. Care
should be taken in dose selection and should be based on careful and
regular monitoring of renal function. (See Warnings and Precautions
(5.1, 5.3); Clinical Pharmacology (12.3).)
Sitagliptin
Of the total number of subjects (N=3884) in Phase II and III
clinical studies of sitagliptin, 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.
Metformin hydrochloride
Controlled clinical studies of metformin did not include
sufficient numbers of elderly patients to determine whether they
respond differently from younger patients, although other reported
clinical experience has not identified differences in responses
between the elderly and young patients. Metformin should only be used
in patients with normal renal function. The initial and maintenance
dosing of metformin should be conservative in patients with advanced
age, due to the potential for decreased renal function in this
population. Any dose adjustment should be based on a careful
assessment of renal function. (See Contraindications (4); Warnings and
Precautions (5.3); and Clinical Pharmacology (12.3).)
10 OVERDOSAGE
Sitagliptin
During controlled clinical trials in healthy subjects, single
doses of up to 800 mg sitagliptin were administered. Maximal mean
increases in QTc of 8.0 msec were observed in one study at a dose of
800 mg sitagliptin, 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
sitagliptin with doses of up to 400 mg per day for periods of 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
indicated 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.
Metformin hydrochloride
Overdose of metformin hydrochloride has occurred, including
ingestion of amounts greater than 50 grams. Hypoglycemia was reported
in approximately 10% of cases, but no causal association with
metformin hydrochloride has been established. Lactic acidosis has been
reported in approximately 32% of metformin overdose cases (see
Warnings and Precautions (5.1)). Metformin is dialyzable with a
clearance of up to 170 mL/min under good hemodynamic conditions.
Therefore, hemodialysis may be useful for removal of accumulated drug
from patients in whom metformin overdosage is suspected.
11 DESCRIPTION
JANUMET (sitagliptin/metformin HCl) tablets contain two oral
antihyperglycemic drugs used in the management of type 2 diabetes:
sitagliptin and metformin hydrochloride.
Sitagliptin is an orally-active inhibitor of the dipeptidyl
peptidase-4 (DPP-4) enzyme. Sitagliptin is present in JANUMET tablets
in the form of sitagliptin phosphate monohydrate. 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 with an empirical formula of C16H15F6N5O-H3PO4-H2O
and a molecular weight of 523.32. The structural formula is:
(OBJECT 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.
Metformin hydrochloride
Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide
hydrochloride) is not chemically or pharmacologically related to any
other classes of oral antihyperglycemic agents. Metformin
hydrochloride is a white to off-white crystalline compound with a
molecular formula of C4H11N5-HCl and a molecular weight of 165.63.
Metformin hydrochloride is freely soluble in water and is practically
insoluble in acetone, ether, and chloroform. The pKa of metformin is
12.4. The pH of a 1% aqueous solution of metformin hydrochloride is
6.68. The structural formula is as shown:
(OBJECT OMITTED)
JANUMET
JANUMET is available for oral administration as tablets containing
64.25 mg sitagliptin phosphate monohydrate and metformin hydrochloride
equivalent to: 50 mg sitagliptin as free base and 500 mg
metformin hydrochloride (JANUMET 50 mg/500 mg) or 1000 mg metformin
hydrochloride (JANUMET 50 mg/1000 mg). Each film-coated tablet of
JANUMET contains the following inactive ingredients: microcrystalline
cellulose, polyvinylpyrrolidone, sodium lauryl sulfate, 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 black iron oxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
JANUMET
JANUMET combines two antihyperglycemic agents with complementary
mechanisms of action to improve glycemic control in patients with type
2 diabetes: sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor,
and metformin hydrochloride, a member of the biguanide class.
Sitagliptin
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 sitagliptin, 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, sitagliptin 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.
Metformin hydrochloride
Metformin is an antihyperglycemic agent which improves glucose
tolerance in patients with type 2 diabetes, lowering both basal and
postprandial plasma glucose. Its pharmacologic mechanisms of action
are different from other classes of oral antihyperglycemic agents.
Metformin decreases hepatic glucose production, decreases intestinal
absorption of glucose, and improves insulin sensitivity by increasing
peripheral glucose uptake and utilization. Unlike sulfonylureas,
metformin does not produce hypoglycemia in either patients with type 2
diabetes or normal subjects (except in special circumstances (see
Warnings and Precautions (5.8))) and does not cause hyperinsulinemia.
With metformin therapy, insulin secretion remains unchanged while
fasting insulin levels and day-long plasma insulin response may
actually decrease.
12.2 Pharmacodynamics
Sitagliptin
General
In patients with type 2 diabetes, administration of sitagliptin
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.
Sitagliptin and Metformin hydrochloride Co-administration
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 what these
findings mean for changes in glycemic control in patients with type 2
diabetes.
In studies with healthy subjects, sitagliptin 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 sitagliptin 100 mg,
sitagliptin 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 at 3 hours postdose
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 sitagliptin 100 mg
(N=81) or sitagliptin 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
JANUMET
The results of a bioequivalence study in healthy subjects
demonstrated that the JANUMET (sitagliptin/metformin HCl) 50 mg/500 mg
and 50 mg/1000 mg combination tablets are bioequivalent to
co-administration of corresponding doses of sitagliptin
(JANUVIA(TM)(2)) and metformin hydrochloride as individual tablets.
Absorption
Sitagliptin
The absolute bioavailability of sitagliptin is approximately 87%.
Co-administration of a high-fat meal with sitagliptin had no effect on
the pharmacokinetics of sitagliptin.
Metformin hydrochloride
The absolute bioavailability of a metformin hydrochloride 500-mg
tablet given under fasting conditions is approximately 50-60%. Studies
using single oral doses of metformin hydrochloride tablets 500 mg to
1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose
proportionality with increasing doses, which is due to decreased
absorption rather than an alteration in elimination. Food decreases
the extent of and slightly delays the absorption of metformin, as
shown by approximately a 40% lower mean peak plasma concentration
(Cmax), a 25% lower area under the plasma concentration versus time
curve (AUC), and a 35-minute prolongation of time to peak plasma
concentration (Tmax) following administration of a single 850-mg
tablet of metformin with food, compared to the same tablet strength
administered fasting. The clinical relevance of these decreases is
unknown.
Distribution
Sitagliptin
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%).
Metformin hydrochloride
The apparent volume of distribution (V/F) of metformin following
single oral doses of metformin hydrochloride tablets 850 mg averaged
654 +/- 358 L. Metformin is negligibly bound to plasma proteins, in
contrast to sulfonylureas, which are more than 90% protein bound.
Metformin partitions into erythrocytes, most likely as a function of
time. At usual clinical doses and dosing schedules of metformin
hydrochloride tablets, steady-state plasma concentrations of metformin
are reached within 24-48 hours and are generally less than 1 mcg/mL.
During controlled clinical trials of metformin, maximum metformin
plasma levels did not exceed 5 mcg/mL, even at maximum doses.
Metabolism
Sitagliptin
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.
Metformin hydrochloride
Intravenous single-dose studies in normal subjects demonstrat
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