`
`
`
`
`XXXXXXX
`
`-------------------------------CONTRAINDICATIONS-------------------------------
`• Renal disease or renal dysfunction, e.g., serum creatinine levels
`≥1.5 mg/dL [males], ≥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)
`in patients undergoing
`• Temporarily discontinue JANUMET
`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 ≥5%
`of patients and more commonly than in patients given placebo was
`nasopharyngitis. (6.1)
`• The most common (>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)
`
`
`for PATIENT COUNSELING
`See 17
`FDA-approved patient labeling.
`
`
`
`
`
`
`
`
`
`INFORMATION and
`
`Revised: Mar 2007
`
`
`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™ (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)
`
`
` •
`
`

`

`JANUMET™
`(sitagliptin/metformin HCl) Tablets
`
`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
`
`XXXXXXX
`
`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, JANUMET1 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.
`
`DOSAGE AND ADMINISTRATION
`2
`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
`
`2
`
`

`

`JANUMET™
`(sitagliptin/metformin HCl) Tablets
`
`XXXXXXX
`
`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 ≥1.5 mg/dL
`[males], ≥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 (>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 >5 µg/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
`
`3
`
`

`

`JANUMET™
`(sitagliptin/metformin HCl) Tablets
`
`XXXXXXX
`
`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 ≥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
`
`4
`
`

`

`JANUMET™
`(sitagliptin/metformin HCl) Tablets
`
`XXXXXXX
`
`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 β-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.
`
`5
`
`

`

`JANUMET™
`(sitagliptin/metformin HCl) Tablets
`
`XXXXXXX
`
`ADVERSE REACTIONS
`6
`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 ≥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 ≥5% of patients and more commonly than in patients given placebo was
`nasopharyngitis.
`The most common (>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).]
`
`DRUG INTERACTIONS
`7
`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
`
`6
`
`

`

`JANUMET™
`(sitagliptin/metformin HCl) Tablets
`
`XXXXXXX
`
`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.
`
`USE IN SPECIFIC POPULATIONS
`8
`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
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`7
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`JANUMET™
`(sitagliptin/metformin HCl) Tablets
`
`XXXXXXX
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`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 r