least annually thereafter, assess renal function and verify as normal.
`
`(4, 5.1, 5.4, 5.10, 6.2)
`• There have been postmarketing reports of acute pancreatitis,
`
`including fatal and non-fatal hemorrhagic or necrotizing pancreatitis.
`If pancreatitis is suspected, promptly discontinue JANUMET. (5.2)
`• Measure hematologic parameters annually. (5.5, 6.1)
`
`• Warn patients against excessive alcohol intake. (5.1, 5.6)
`
`• 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. (5.7, 5.8, 5.12,
`5.13)
`
`• Promptly evaluate patients previously controlled on JANUMET who
`
`develop laboratory abnormalities or clinical illness for evidence of
`ketoacidosis or lactic acidosis. (5.1, 5.8, 5.12, 5.13)
`• When used with an insulin secretagogue (e.g., sulfonylurea) or with
`
`insulin, a lower dose of the insulin secretagogue or insulin may be
`
`required to reduce the risk of hypoglycemia. (2.1, 5.9)
`• There have been postmarketing reports of serious allergic and
`
`hypersensitivity reactions in patients treated with sitagliptin (one of
`the components of JANUMET), such as anaphylaxis, angioedema,
`and exfoliative skin conditions
`including Stevens-Johnson
`syndrome. In such cases, promptly stop JANUMET, assess for other
`
`potential causes, institute appropriate monitoring and treatment, and
`initiate alternative treatment for diabetes. (5.14, 6.2)
`• There have been no clinical studies establishing conclusive
`
`evidence of macrovascular risk reduction with JANUMET or any
`
`other anti-diabetic drug. (5.15)
`------------------------------ ADVERSE REACTIONS------------------------------­
`
`• The most common adverse reactions reported in ≥5% of patients
`
`simultaneously started on sitagliptin and metformin and more
`
`commonly than in patients treated with placebo were diarrhea,
`upper respiratory tract infection, and headache. (6.1)
`• Adverse reactions reported in ≥5% of patients treated with sitagliptin
`
`in combination with sulfonylurea and metformin and more commonly
`
`in combination with
`than
`in patients
`treated with placebo
`sulfonylurea and metformin were hypoglycemia and headache. (6.1)
`• Hypoglycemia was the only adverse reaction reported in ≥5% of
`
`patients treated with sitagliptin in combination with insulin and
`metformin and more commonly than in patients treated with placebo
`in combination with insulin and metformin. (6.1)
`• Nasopharyngitis was the only adverse reaction reported in ≥5% of
`
`patients treated with sitagliptin monotherapy and more commonly
`
`than in patients given placebo. (6.1)
`• The most common (>5%) 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
`
`Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877­
`888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`-------------------------------DRUG INTERACTIONS------------------------------­
`
`• Cationic drugs eliminated by renal tubular secretion: Use with
`
`caution. (5.10, 7.1)
`----------------------- USE IN SPECIFIC POPULATIONS ----------------------­
`
`• Safety and effectiveness of JANUMET in children under 18 years
`
`
`have not been established. (8.4)
`• There are no adequate and well-controlled studies in pregnant
`
`women. To report drug exposure during pregnancy call 1-800-986­
`8999. (8.1)
`
`INFORMATION and
`
`Revised: 04/2012
`
`
`
`for PATIENT COUNSELING
`See 17
`
`FDA-approved Medication Guide.
`
`
`
`
`
`
`
`
`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)
`
`
`
`---------------------------RECENT MAJOR CHANGES --------------------------­
`
`Warnings and Precautions
`
`Hypersensitivity Reactions (5.14)
`03/2012
`----------------------------INDICATIONS AND USAGE ---------------------------­
`
`JANUMET is a dipeptidyl peptidase-4 (DPP-4) inhibitor and biguanide
`
`combination product indicated as an adjunct to diet and exercise to
`improve glycemic control in adults with type 2 diabetes mellitus when
`treatment with both sitagliptin and metformin is appropriate. (1)
`
`Important Limitations of Use:
`• JANUMET should not be used in patients with type 1 diabetes or for
`
`the treatment of diabetic ketoacidosis. (1)
`• JANUMET has not been studied in patients with a history of
`
`
`pancreatitis. (1, 5.2)
`----------------------- 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 dysfunction, e.g., serum creatinine ≥1.5 mg/dL [males],
`
`
`≥1.4 mg/dL [females] or abnormal creatinine clearance. (4, 5.1, 5.4)
`• Acute or chronic metabolic acidosis, including diabetic ketoacidosis,
`
`with or without coma. (4, 5.1)
`• History of a serious hypersensitivity reaction to JANUMET or
`
`sitagliptin (one of
`the components of JANUMET), such as
`anaphylaxis or angioedema. (5.14, 6.2)
`• Temporarily discontinue JANUMET
`in patients undergoing
`
`
`radiologic studies involving intravascular administration of iodinated
`contrast materials. (4, 5.1, 5.11)
`------------------------WARNINGS AND PRECAUTIONS-----------------------­
`• Do not use JANUMET in patients with hepatic disease. (5.1, 5.3)
`
`• There have been postmarketing reports of acute renal failure,
`
`sometimes requiring dialysis. Before initiating JANUMET and at
`
`
`
`Reference ID: 3205083
`
`

`

`
`
`
`
`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
` Pancreatitis
`5.3
`Impaired Hepatic Function
`
`5.4 Assessment of Renal Function
`
` Vitamin B12 Levels
`
`5.5
`5.6 Alcohol Intake
`
`5.7
` Surgical Procedures
`5.8
` Change
`in Clinical Status of Patients with Previously
`
`
`Controlled Type 2 Diabetes
`
`5.9 Use with Medications Known to Cause Hypoglycemia
`
`5.10 Concomitant
` Medications Affecting Renal Function or
`Metformin Disposition
`
`5.11 Radiologic Studies with Intravascular Iodinated Contrast
`
`Materials
`
`5.12 Hypoxic States
`5.13 Loss of Control of Blood Glucose
`
`5.14 Hypersensitivity Reactions
`
`5.15 Macrovascular Outcomes
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`
`6.2
` Postmarketing Experience
`
`7 DRUG INTERACTIONS
`
` Cationic Drugs
`
`7.1
`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
` Pregnancy
`
`8.1
`
` Nursing Mothers
`8.3
`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
`
`
`
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`
`Reference ID: 3205083
`
`2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`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 adults with
`type 2 diabetes mellitus when treatment with both sitagliptin and metformin is appropriate. [See Clinical
`
`Studies (14).]
`Important Limitations of Use
`JANUMET should not be used in patients with type 1 diabetes or for the treatment of diabetic
`ketoacidosis, as it would not be effective in these settings.
`JANUMET has not been studied in patients with a history of pancreatitis. It is unknown whether patients
`
`with a history of pancreatitis are at increased risk for the development of pancreatitis while using JANUMET.
`[See Warnings and Precautions (5.2).]
`
`
`DOSAGE AND ADMINISTRATION
`2
`2.1 Recommended Dosing
`The dosage of 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. Initial combination therapy or maintenance of combination therapy
`should be individualized and left to the discretion of the health care provider.
`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.
`The recommended starting dose in patients not currently treated with metformin is 50 mg
`sitagliptin/500 mg metformin hydrochloride twice daily, with gradual dose escalation recommended to
`
`reduce gastrointestinal side effects associated with metformin.
`The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg
`twice daily (100 mg total daily dose) and 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 treated with an insulin secretagogue or insulin
`Co-administration of JANUMET with an insulin secretagogue (e.g., sulfonylurea) or insulin may
`
`require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia [see
`
`Warnings and Precautions (5.9)].
`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.
`
`Reference ID: 3205083
`
`3
`
`
`

`

`
`3
`
`4
`
`
`
`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.
`
`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.
`
`• History of a serious hypersensitivity reaction to JANUMET or sitagliptin (one of the components
`
`of JANUMET), such as anaphylaxis or angioedema. [See Warnings and Precautions (5.14);
`
`Adverse Reactions (6.2).]
`
`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 (5.11)].
`
`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
`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 (5.4, 5.6, 5.7, 5.11)].
`
`
`Reference ID: 3205083
`
`4
`
`
`

`

`
`
`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 (5.12)]. 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 (5.8, 5.13)].
`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 (5.6, 5.7, 5.10,
`5.11, 5.12)].
`5.2 Pancreatitis
`There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or
`necrotizing pancreatitis, in patients taking JANUMET. After initiation of JANUMET, patients should be observed
`carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, JANUMET should promptly be
`discontinued and appropriate management should be initiated. It is unknown whether patients with a history of
`pancreatitis are at increased risk for the development of pancreatitis while using JANUMET.
`5.3
`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.
`5.4 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); Use in Specific Populations (8.5).]
`There have been postmarketing reports of worsening renal function, including acute renal failure,
`sometimes requiring dialysis. 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.
`5.5 Vitamin B12 Levels
`In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of
`levels, without clinical manifestations, was observed
`in
`previously normal serum Vitamin B12
`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.
`
`Reference ID: 3205083
`
`5
`
`
`

`

`
`5.6 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.
`5.7 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.
`5.8 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.
`5.9 Use with Medications Known to Cause Hypoglycemia
`Sitagliptin
`When sitagliptin was used in combination with a sulfonylurea or with insulin, medications known to
`cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in
`combination with a sulfonylurea or with insulin [see Adverse Reactions (6)]. Therefore, patients also
`receiving an insulin secretagogue (e.g., sulfonylurea) or insulin may require a lower dose of the insulin
`secretagogue or insulin to reduce the risk of hypoglycemia [see Dosage and Administration (2.1)].
`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.
`5.10 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.
`5.11 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.
`5.12 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.
`5.13 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.
`5.14 Hypersensitivity Reactions
`There have been postmarketing reports of serious hypersensitivity reactions in patients treated with
`sitagliptin, one of the components of JANUMET. These reactions include anaphylaxis, angioedema, and
`exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within
`the first 3 months after initiation of treatment with sitagliptin, with some reports occurring after the first
`
`Reference ID: 3205083
`
`6
`
`

`

`
`dose. If a hypersensitivity reaction is suspected, discontinue JANUMET, assess for other potential causes
`for the event, and institute alternative treatment for diabetes. [See Adverse Reactions (6.2).]
`Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution
`in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether
`such patients will be predisposed to angioedema with JANUMET.
`
`5.15 Macrovascular Outcomes
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction
`with JANUMET or any other anti-diabetic drug.
`
`ADVERSE REACTIONS
`6
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed
`in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
`may not reflect the rates observed in practice.
`Sitagliptin and Metformin Co-administration in Patients with Type 2 Diabetes Inadequately Controlled on
`
`Diet and Exercise
`Table 1 summarizes the most common (≥5% of patients) adverse reactions reported (regardless of
`investigator assessment of causality) in a 24-week placebo-controlled factorial study in which sitagliptin
`and metformin were co-administered to patients with type 2 diabetes inadequately controlled on diet and
`exercise.
`
`
`Table 1: Sitagliptin and Metformin Co-administered to Patients with Type 2 Diabetes
`Inadequately Controlled on Diet and Exercise:
`
` Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in ≥5% of
` Patients Receiving Combination Therapy (and Greater than in Patients Receiving Placebo)†
`
`
`Number of Patients (%)
`
`Metformin 500 mg/
`Metformin 1000 mg bid ††
`
`
`
`
`
`
`Placebo
`
`
`Sitagliptin
`100 mg QD
`
`
`
`Sitagliptin
`50 mg bid +
`Metformin 500 mg/
`Metformin 1000 mg bid ††
`
`N = 372††
`
`
` 28 (7.5)
`
`23 (6.2)
`
`
`22 (5.9)
`
`
`Diarrhea
`Upper Respiratory
`
`Tract Infection
`Headache
`† Intent-to-treat population.
`†† Data pooled for the patients given the lower and higher doses of metformin.
`
`N = 176
`
` 7 (4.0)
`
`9 (5.1)
`
`N = 179
`
` 5 (2.8)
`
`8 (4.5)
`
`
`5 (2.8)
`
`
`2 (1.1)
`
`N = 364††
`
`
` 28 (7.7)
`
`19 (5.2)
`
`
`14 (3.8)
`
`
`
`
` Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Alone
`
`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%).
`Gastrointestinal Adverse Reactions
`The incidences of pre-selected gastrointestinal adverse experiences in patients treated with sitagliptin
`and metformin were similar to those reported for patients treated with metformin alone. See Table 2.
`
`
`Reference ID: 3205083
`
`7
`
`
`

`

`
`
`
`
`Sitagliptin 50 mg bid +
`Metformin 500 mg/
`Metformin 1000 mg bid †
`
`
`N = 372
`28 (7.5)
`18 (4.8)
`8 (2.2)
`11 (3.0)
`
`Study of Sitagliptin Add-on in
`Patients Inadequately Controlled
`
`on Metformin Alone
`Placebo and
`Sitagliptin 100 mg
`Metformin
`QD and Metformin
`≥1500 mg
`≥1500 mg daily
`
`
`
`daily
`N = 237
`N = 464
`6 (2.5)
`11 (2.4)
`2 (0.8)
`6 (1.3)
`2 (0.8)
`5 (1.1)
`9 (3.8)
`10 (2.2)
`
`Diarrhea
`Nausea
`Vomiting
`Abdominal
`Pain††
`
`† Data pooled for the patients given the lower and higher doses of metformin.
`†† Abdominal discomfort was included in the analysis of abdominal pain in the study of initial therapy.
`
`Sitagliptin in Combination with Metformin and Glimepiride
`In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2
`
`diabetes inadequately controlled on metformin and glimepiride (sitagliptin, N=116; placebo, N=113), the
`adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients treated
`with sitagliptin and more commonly than in patients treated with placebo were: hypoglycemia (Table 3)
`and headache (6.9%, 2.7%).
`Sitagliptin in Combination with Metformin and Rosiglitazone
`In a placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes
`
`inadequately controlled on metformin and rosiglitazone (sitagliptin, N=181; placebo, N=97), the adverse
`reactions reported regardless of investigator assessment of causality through Week 18 in ≥5% of patients
`treated with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory
`tract infection (sitagliptin, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%). Through Week 54, the
`adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients treated
`with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory tract
`infection (sitagliptin, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%,
`5.2%), and headache (5.5%, 4.1%).
`Sitagliptin in Combination with Metformin and Insulin
`In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2
`
`diabetes inadequately controlled on metformin and insulin (sitagliptin, N=229; placebo, N=233), the only
`adverse reaction reported regardless of investigator assessment of causality in ≥5% of patients treated
`with sitagliptin and more commonly than in patients treated with placebo was hypoglycemia (Table 3).
`Hypoglycemia
`In all (N=5) studies, adverse reactions of hypoglycemia were based on all reports of symptomatic
`hypoglycemia; a concurrent glucose measurement was not required although most (77%) reports of
`hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. When the combination of
`sitagliptin and metformin was co-administered with a sulfonylurea or with insulin, the percentage of
`patients reporting at least one adverse reaction of hypoglycemia was higher than that observed with
`placebo and metformin co-administered with a sulfonylurea or with insulin (Table 3).
`
` Table 2: Pre-selected Gastrointestinal Adverse Reactions (Regar