6044600
`
`
`contraindicated in renal impairment. Ensure normal renal function
`before initiating and at least annually thereafter.
`• Temporarily discontinue JANUMET XR
`in patients undergoing
`
`radiologic studies with intravascular administration of iodinated
`contrast materials or any surgical procedures necessitating
`
`restricted intake of food or fluids. (5.1, 5.3, 5.4, 5.7)
`• There have been postmarketing reports of acute pancreatitis,
`
`including fatal and non-fatal hemorrhagic or necrotizing pancreatitis
`in patients treated with sitagliptin (one of the components of
`JANUMET XR) with or without metformin.
`If pancreatitis
`is
`suspected, promptly discontinue JANUMET XR. (5.2)
`• There have been postmarketing reports of acute renal failure in
`
`patients treated with sitagliptin with or without metformin, sometimes
`requiring dialysis. Before initiating JANUMET XR and at least
`annually thereafter, assess renal function and verify as normal. (4,
`
`5.1, 5.4, 5.10, 6.2)
`• Vitamin B12 deficiency: Metformin may lower Vitamin B12 levels.
`Measure hematologic parameters annually. (5.5, 6.1)
`• 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 minimize the risk of hypoglycemia. (2.1, 5.9)
`• There have been postmarketing reports of serious allergic and
`
`hypersensitivity reactions in patients treated with sitagliptin, such as
`
`anaphylaxis, angioedema, and exfoliative skin conditions including
`Stevens-Johnson syndrome.
`In such cases, promptly stop
`JANUMET XR, 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 XR 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)
`
`
`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, 7.2)
`----------------------- USE IN SPECIFIC POPULATIONS ----------------------­
`
`• Safety and effectiveness of JANUMET XR 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)
`
`
`for PATIENT COUNSELING
`See 17
`
`FDA-approved Medication Guide.
`
`
`INFORMATION and
`
`Revised: 02/2012
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`JANUMET XR safely and effectively. See
`full prescribing
`
`information for JANUMET XR.
`
`
`JANUMET® XR (sitagliptin and metformin HCl extended-release)
`
`tablets
`Initial U.S. Approval: 2012
`
`
`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 XR and
`
`
`hospitalize the patient immediately. (5.1)
`----------------------------INDICATIONS AND USAGE ---------------------------­
`
`JANUMET XR 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 extended-
`release is appropriate. (1, 14)
`
`Important Limitations of Use:
`• Not for the treatment of type 1 diabetes or diabetic ketoacidosis. (1)
`
`• Has not been studied in patients with a history of pancreatitis. (1,
`
`5.2)
`----------------------- DOSAGE AND ADMINISTRATION-----------------------­
`
`• Individualize the starting dose of JANUMET XR 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 extended-release. (2.1)
`• Administer once daily with a meal preferably in the evening.
`
`
`Gradually escalate the dose to reduce the gastrointestinal side
`
`effects due to metformin. (2.1)
`• Maintain the same total daily dose of sitagliptin and metformin when
`
`changing between JANUMET and JANUMET XR, without exceeding
`the maximum recommended daily dose of 2000 mg metformin
`extended-release. (2.1)
`• Swallow whole. Never split, crush or chew. (2.1)
`
`--------------------- DOSAGE FORMS AND STRENGTHS --------------------­
`
`JANUMET XR Tablets: 100 mg sitagliptin/1000 mg metformin HCl
`extended-release, 50 mg sitagliptin/500 mg metformin HCl extended-
`release, and 50 mg sitagliptin/1000 mg metformin HCl extended-
`release. (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)
`• Metabolic acidosis, including diabetic ketoacidosis. (4, 5.1)
`
`• History of a serious hypersensitivity reaction (e.g., anaphylaxis or
`
`angioedema) to JANUMET XR or to one of its components. (5.14,
`6.2)
`------------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`• Lactic acidosis: Warn against excessive alcohol
`intake.
`
`JANUMET XR is not recommended in hepatic impairment and is
`
`Reference ID: 3080889
`
`1
`
`
`

`

`
`
`JANUMET® XR
`
`(sitagliptin and metformin HCl extended-release) 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
` 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
`in Clinical Status of Patients with Previously
` Change
`
`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
`
`6044600
`
`
` Postmarketing Experience
`6.2
`7 DRUG INTERACTIONS
`7.1 Carbonic Anhydrase Inhibitors
`
` Cationic Drugs
`7.2
`7.3 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: 3080889
`
`2
`
`
`

`

`6044600
`
`
`JANUMET® XR
`
`(sitagliptin and metformin HCl extended-release) Tablets
`
`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 impairment, renal impairment, and acute congestive heart failure.
`The onset of lactic acidosis 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 XR (sitagliptin and metformin HCl extended-release) tablets
`
`
`should be discontinued and the patient hospitalized immediately. [See Warnings and Precautions
`
`(5.1).]
`
`1
`
`INDICATIONS AND USAGE
`JANUMET® XR 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 extended-release is
`
`appropriate. [See Clinical Studies (14).]
`Important Limitations of Use
`JANUMET XR should not be used in patients with type 1 diabetes mellitus or for the treatment of
`diabetic ketoacidosis.
`JANUMET XR 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 XR. [See Warnings and Precautions (5.2).]
`
`•
`
`
`DOSAGE AND ADMINISTRATION
`2
`2.1 Recommended Dosing
`The dose of JANUMET XR 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.
`•
`
`In patients not currently treated with metformin, the recommended total daily starting dose of
`JANUMET XR is 100 mg sitagliptin and 1000 mg metformin hydrochloride (HCl) extended-
`
`release. Patients with inadequate glycemic control on this dose of metformin can be titrated
`gradually, to reduce gastrointestinal side effects associated with metformin, up to the
`maximum recommended daily dose.
`In patients already treated with metformin, the recommended total daily starting dose of
`JANUMET XR is 100 mg sitagliptin and the previously prescribed dose of metformin.
`
`• For patients taking metformin immediate-release 850 mg twice daily or 1000 mg twice daily,
`
`the recommended starting dose of JANUMET XR is two 50 mg sitagliptin/1000 mg metformin
`
`hydrochloride extended-release tablets taken together once daily.
`• Maintain the same total daily dose of sitagliptin and metformin when changing between
`
`
`JANUMET (sitagliptin and metformin HCl immediate-release) and JANUMET XR. Patients
`
`
`with inadequate glycemic control on this dose of metformin can be titrated gradually, to reduce
`gastrointestinal side effects associated with metformin, up to the maximum recommended
`
`daily dose.
`JANUMET XR should be administered with food to reduce the gastrointestinal side effects associated
`
`with the metformin component. JANUMET XR should be given once daily with a meal preferably in the
`
`evening. Inform patients that JANUMET XR tablets must not be split, broken, crushed, or chewed before
`swallowing.
`The 100 mg sitagliptin/1000 mg metformin hydrochloride extended-release tablet should be taken as a
`single tablet once daily. Patients using two JANUMET XR tablets (such as two 50 mg sitagliptin/500 mg
`metformin hydrochloride extended-release
`tablets or
`two 50 mg sitagliptin/1000 mg metformin
`hydrochloride extended-release tablets) should take the two tablets together once daily.
`
`Reference ID: 3080889
`
`3
`
`
`

`

`JANUMET® XR
`
`(sitagliptin and metformin HCl extended-release) Tablets
`
`Patients treated with an insulin secretagogue or insulin
`Co-administration of JANUMET XR 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 XR in
`patients previously treated with other oral antihyperglycemic agents and switched to JANUMET XR. Any
`change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as
`changes in glycemic control can occur.
`
`6044600
`
`
`3
`
`4
`
`DOSAGE FORMS AND STRENGTHS
`• 100 mg/1000 mg tablets are blue, bi-convex oval, film-coated tablets with “81” debossed on
`
`
`one side.
`• 50 mg/500 mg tablets are light blue, bi-convex oval, film-coated tablets with “78” debossed on
`
`one side.
`• 50 mg/1000 mg tablets are light green, bi-convex oval, film-coated tablets with “80” debossed
`
`on one side.
`
`CONTRAINDICATIONS
`JANUMET XR is contraindicated in patients with:
`
`• Renal impairment (e.g., serum creatinine levels ≥1.5 mg/dL for men, ≥1.4 mg/dL for women 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)].
`• Hypersensitivity to metformin hydrochloride.
`
`• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should
`
`be treated with insulin.
`• History of a serious hypersensitivity reaction to JANUMET XR or sitagliptin, such as anaphylaxis
`
`
`or angioedema. [See Warnings and Precautions (5.14); Adverse Reactions (6.2).]
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Lactic Acidosis
`Metformin hydrochloride
`Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation
`during treatment with JANUMET XR and 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 concentrations (>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 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 impairment, 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 JANUMET XR. In particular,
`treatment of the elderly should be accompanied by careful monitoring of renal function. JANUMET XR
`treatment should not be initiated in any patient unless measurement of creatinine clearance demonstrates
`
`that renal function is not reduced. In addition, JANUMET XR 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, JANUMET XR should generally be avoided in patients
`
`Reference ID: 3080889
`
`4
`
`
`

`

`6044600
`
`JANUMET® XR
`
`(sitagliptin and metformin HCl extended-release) Tablets
`
`with clinical or laboratory evidence of hepatic impairment. Patients should be cautioned against excessive
`alcohol intake when taking JANUMET XR, because alcohol potentiates the effects of metformin on lactate
`metabolism. In addition, JANUMET XR should be temporarily discontinued prior to any intravascular
`radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids. Use of
`topiramate, a carbonic anhydrase inhibitor, in epilepsy and migraine prophylaxis may frequently cause
`dose-dependent metabolic acidosis (in controlled trials, 32% and 67% for adjunctive treatment in adults
`and pediatric patients, respectively, and 15 to 25% for monotherapy of epilepsy, with decrease in serum
`bicarbonate to less than 20 mEq/L; 3% and 11% for adjunctive treatment in adults and pediatric patients,
`respectively, and 1 to 7% for monotherapy of epilepsy, with decrease in serum bicarbonate to less than
`17 mEq/L) and may exacerbate the risk of metformin-induced lactic acidosis. [See Drug Interactions (7.1);
`Clinical Pharmacology (12).] 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.
`Patients should be educated to promptly report these symptoms to their physician should they occur.
`If present, JANUMET XR should be withdrawn until lactic acidosis is ruled out. Serum electrolytes,
`ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful. Once a
`patient is stabilized on any dose level of JANUMET XR, gastrointestinal symptoms, which are common
`during initiation of therapy, are unlikely to recur. 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 JANUMET XR 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. 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 JANUMET XR, 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).]
`5.2 Pancreatitis
`There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal
`hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin with or without metformin. After
`initiation of JANUMET XR, patients should be observed carefully for signs and symptoms of pancreatitis.
`If pancreatitis
`is suspected, JANUMET XR 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 XR.
`5.3
`Impaired Hepatic Function
`Since impaired hepatic function has been associated with some cases of lactic acidosis,
`JANUMET XR should generally be avoided in patients with clinical or laboratory evidence of hepatic
`disease.
`5.4 Assessment of Renal Function
`Metformin and sitagliptin are substantially excreted by the kidney.
`Metformin hydrochloride
`The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of
`renal function. Therefore, JANUMET XR is contraindicated in patients with renal impairment.
`Before initiation of JANUMET XR and at least annually thereafter, renal function should be assessed
`and verified as normal. In patients in whom development of renal dysfunction is anticipated (e.g., elderly),
`renal function should be assessed more frequently and JANUMET XR discontinued if evidence of renal
`
`impairment is present.
`Sitagliptin
`There have been postmarketing reports of worsening renal function in patients taking sitagliptin with or
`without metformin, including acute renal failure, sometimes requiring dialysis. Before initiation of therapy
`with JANUMET XR 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
`
`Reference ID: 3080889
`
`5
`
`
`

`

`6044600
`
`
`JANUMET® XR
`
`(sitagliptin and metformin HCl extended-release) Tablets
`
`patients, renal function should be assessed more frequently and JANUMET XR 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 XR 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.
`5.6 Alcohol Intake
`Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against
`excessive alcohol intake while receiving JANUMET XR.
`5.7 Surgical Procedures
`Use of JANUMET XR 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 XR 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 XR 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 (7.2)], 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 XR 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
`
`Reference ID: 3080889
`
`6
`
`
`

`

`6044600
`
`JANUMET® XR
`
`(sitagliptin and metformin HCl extended-release) Tablets
`
`acidosis and may also cause prerenal azotemia. When such events occur in patients on JANUMET XR
`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 XR and temporarily administer insulin. JANUMET XR 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 XR. 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 dose. If a hypersensitivity reaction is suspected, discontinue JANUMET XR, assess for other
`potential causes for the event, and institute alternative treatment for diabetes. [See Adverse Reactions
`(6.2).]
`Use caution in a patient with a history of angioedema to another dipeptidyl peptidase-4 (DPP4)
`inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUMET
`XR.
`
`5.15 Macrovascular Outcomes
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction
`with JANUMET XR 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 Immediate-Release 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 immediate-release were co-administered to patients with type 2 diabetes inadequately
`controlled on diet and exercise.
`
`
`Table 1: Sitagliptin and Metformin Immediate-Release 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 Immediate-
`Release 500 mg or
`1000 mg twice daily †
`
`
`
`
`
`
`Placebo
`
`
`Sitagliptin
`100 mg once
`
`daily
`
`Sitagliptin
`50 mg twice daily +
`Metformin Immediate-
`Release 500 mg or 1000
`mg twice daily †
`
`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
`
`Immediate-Release Alone
`In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once daily added to a twice
`daily metformin immediate-release regimen, there were no adverse reactions reported regardless of
`
`Reference ID: 3080889
`
`7
`
`

`

`6044600
`
`
`
`JANUMET® XR
`
`(sitagliptin and metformin HCl extended-release) Tablets
`
`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 immediate-release, 1.9%; placebo and metformin immediate-release,
`2.5%).
`Gastrointestinal Adverse Reactions
`The incidences of pre-selected gastrointestinal adverse experiences in patients treated with sitagliptin
`and metformin immediate-release were similar to those reported for patients treated with metformin
`immediate-release alone. See Table 2.
`
` Table 2: Pre-selected Gastrointestinal Adverse Reactions (Regardless of Investigator Assessment of Causality)
`
`Reported in Patients with Type 2 Diabetes Receiving Sitagliptin and Metformin Immediate-Release
`
`Number of Patients (%)
`
`Study of Sitagliptin and Metformin Immediate-Release in Patients
`Inadequately Controlled on Diet and Exercise
`
`
`
`
`
`Placebo Sitagliptin
`100 mg
`
`once daily
`
`
`Metformin
`Immediate-Release
`500 mg or 1000 mg
`
`twice daily *
`
`Sitagliptin 50 mg bid +
`Metformin Immediate-
`Release 500 mg or
`
`1000 mg twice daily *
`
`Placebo and
`Metformin
`Immediate-
`Release
`≥1500 mg
`
`daily
`
`Study of Sitagliptin Add-on in
`Patients Inadequately Controlled
`on Metformin Immediate-Release
`
`Alone
`Sitagliptin 100 mg
`once daily and
`Metformin
`Immediate-
`Release
`≥1500 mg daily
`
`
`N = 464
`11 (2.4)
`6 (1.3)
`5 (1.1)
`10 (2.2)
`
`N = 237
`6 (2.5)
`2 (0.8)
`2 (0.8)
`9 (3.8)
`
`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 Immediate-Release 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 immediate-release and glimepiride (sitagliptin, N=116;
`placebo, N=113), the adverse reactions reported regardless of investigator assessment of