`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
`
`
`
`
` These highlights do not include all the information needed to use
`
` full prescribing
` JANUMET XR safely and effectively. See
`
`
`
`
` 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)
`
`
`
`
`
`
`
`
`is suspected, discontinue JANUMET XR and
`• If acidosis
`
`
`
`
`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)
`
`--------------------- 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
`
`
`
`
`
`contraindicated in renal impairment. Ensure normal renal function
`
`
`
`
`before initiating and at least annually thereafter. (4, 5.1, 5.3, 5.4,
`
`
`5.6)
`
`in patients undergoing
`• Temporarily discontinue JANUMET XR
`
`
`
`radiologic studies with intravascular administration of iodinated
`contrast materials or any surgical procedures necessitating
`
`
`
`restricted intake of food or fluids. (5.1, 5.4, 5.7, 5.11)
`
`
`• 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.
`is
`If pancreatitis
`
`
`
`
`
`
`
`suspected, promptly discontinue JANUMET XR. (5.2)
`
`
`• There have been postmarketing reports of acute renal failure in
`
`
`
`
`
`treated with sitagliptin with or without metformin,
`patients
`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
`
`In such cases, promptly stop
`Stevens-Johnson syndrome.
`
`for other potential causes,
`JANUMET XR, assess
`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)
`
`
`treated with
`• Adverse reactions reported
`in ≥5% of patients
`
`
`
`
`
`sitagliptin in combination with sulfonylurea and metformin and more
`commonly than in patients treated with placebo in combination with
`
`
`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)
`
`
`
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
`
`
`
`
`Revised: 03/2015
`
`Reference ID: 3740629
`
`
`
`

`

`
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: LACTIC ACIDOSIS
`
`
`INDICATIONS AND USAGE
`1
`
`
`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
`
`
`5.5 Vitamin B12 Levels
`
`
`
`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
`
`
`
`7.1 Carbonic Anhydrase Inhibitors
`
`
`
`
`
`
`7.2 Cationic Drugs
`
`
`7.3 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
`
`
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`
`
`
`
`Reference ID: 3740629
`
`
`
` 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 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 healthcare 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. JANUMET XR should be swallowed whole. The tablets must not be split, crushed, or chewed
`
`
`
`before swallowing. There have been reports of incompletely dissolved JANUMET XR tablets being
`
`
`
`
`
`
`
`eliminated in the feces. It is not known whether this material seen in feces contains active drug. If a patient
`
`
`reports repeatedly seeing tablets in feces, the healthcare provider should assess adequacy of glycemic
`
`
`control [see Patient Counseling Information (17.1)].
`
`
`
`
`
`Reference ID: 3740629
`
`3
`
`
`

`

`
`
`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.
`
`
`
`Patients treated with an insulin secretagogue or insulin
`
`Coadministration 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.
`
`
`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 greater than or equal to 1.5 mg/dL for men,
`
`
`
`
`
`greater than or equal to 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. W hen 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
`
`
`
`
`
`Reference ID: 3740629
`
`4
`
`
`

`

`
`
`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 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
`
`
`lactic acidosis,
`Since
`function has been associated with some cases of
`impaired hepatic
`
`
`
`
`
`
`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
`
`
`
`
`Reference ID: 3740629
`
`5
`
`
`

`

`
`
`
`
`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 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
`
`
`previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately
`7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic
`
`
`factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with
`
`
`
`
`
`
`
`
`
`discontinuation of metformin or Vitamin B12 supplementation. Measurement of hematologic parameters on
`
`
`an annual basis is advised in patients on JANUMET 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
`
`W hen 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.
`
`
`
`
`Reference ID: 3740629
`
`
`6
`
`

`

`
`
`
`
`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. W hen such events occur in patients on JANUMET XR therapy, the
`
`drug should be promptly discontinued.
`
`
`5.13 Loss of Control of Blood Glucose
`
`W hen 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 Coadministration 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 coadministered to patients with type 2 diabetes inadequately
`
`
`controlled on diet and exercise.
`
`
`
`
`
`Reference ID: 3740629
`
`
`7
`
`

`

` Table 1: Sitagliptin and Metformin Immediate-Release Coadministered 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
`
`
`
` Diarrhea
`
`
` Upper Respiratory
`
`
` Tract Infection
`
`5 (2.8)
` 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)
`
`
`2 (1.1)
`
`
` N = 364†
`
`28 (7.7)
`
`19 (5.2)
`
`
`14 (3.8)
`
`
`
`
`
`
`
`
` 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)
`
`
`
`
`
`
`
`
`
`
`
` 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 sitag