• Temporarily discontinue JANUMET
`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, 5.4, 5.7, 5.11)
`
`
`
`• 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)
`
`• There have been postmarketing reports of acute renal failure,
`
`
`sometimes requiring dialysis. Before initiating JANUMET 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 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,
`
`including Stevens-Johnson
`and exfoliative skin conditions
`syndrome. In such cases, promptly stop JANUMET, assess for
`
`institute appropriate monitoring and
`other potential causes,
`
`
`
`treatment, and initiate alternative treatment for diabetes. (5.14, 6.2)
`
`
`
`• Severe and disabling arthralgia has been reported in patients taking
`
`
`
`
`
`DPP-4 inhibitors. Consider as a possible cause for severe joint pain
`
`
`
`
`
`and discontinue drug if appropriate. (5.15)
`
`
`
`• There have been no clinical studies establishing conclusive
`
`evidence of macrovascular risk reduction with JANUMET or any
`
`
`
`
`
`
`other anti-diabetic drug. (5.16)
`
`
`
`------------------------------ 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 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)
`
`
` 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 and 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
`
`08/2015
`Severe and Disabling Arthralgia (5.15)
`
`
`
`
`----------------------------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, 14)
`
`
`
`
`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)
`
`
`• Metabolic acidosis, including diabetic ketoacidosis. (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)
`
`
`
`
`----------------------- WARNINGS AND PRECAUTIONS -----------------------­
`
`
`
`
`• Lactic acidosis: Warn against excessive alcohol intake. JANUMET
`
`
`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)
`
`
`
`
`
`
`
`Reference ID: 3812569
`
`
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`
`
`
`
`Guide.
`
`
`
`
`
`
`Revised: 08/2015
`
`
`
`
`

`

`
`
`
`
` 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 Severe and Disabling Arthralgia
`
`
`
`5.16 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: 3812569
`
`
`
` 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 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 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.
`
`
`
`
`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. JANUMET must not be split or divided before
`
`swallowing.
`
`
`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
`
`
`
`Coadministration 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: 3812569
`
`
`
` 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 and metformin HCl) 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 or sitagliptin (one of the components
`
`
`
`
` of JANUMET), 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 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. 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 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 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
`
`
`
` 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. 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)].
`
`
`
`
`
` 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
`
`
`
`Reference ID: 3812569
`
`
`
` 4
`
`

`

`
`
`
`
`
` 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.
`
`
`Metformin hydrochloride
`
`The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of
`
`
`
`
`
`
`
`
`renal function. Therefore, JANUMET is contraindicated in patients with renal impairment.
`
`
`Before initiation of 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 (e.g., elderly),
`
`
`
`
`
`renal function should be assessed more frequently and JANUMET discontinued if evidence of renal
`
`
`impairment is present.
`
`
`Sitagliptin
`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
`
`
`
`
`
`
`previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately
`7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic
`
`
`factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with
`
`
`
`
`
`
`
`
`discontinuation of metformin or Vitamin B12 supplementation. Measurement of hematologic parameters on
`
`
`an annual basis is advised in patients on JANUMET and any apparent abnormalities should be
`
`
`appropriately investigated and managed. [See Adverse Reactions (6.1).]
`
`
`Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be
`
`
`
`
`predisposed to developing subnormal Vitamin B12 levels. In these patients, routine serum Vitamin B12
`
`
`measurements at two- to three-year intervals may be useful.
`
`
`
`Reference ID: 3812569
`
`
`
` 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
`
`
`
`
`
`
`
` 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 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. W hen 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: 3812569
`
`
`
` 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 Severe and Disabling Arthralgia
`
`
`
`
`There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4
`
`
`
`
`
`inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years.
`
`
`
`
`Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients
`
`
`
`
`experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor.
`
`
`
`Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.
`
`
`5.16 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 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 were coadministered to patients with type 2 diabetes inadequately controlled on diet and
`
`exercise.
`
`
`
`
`
`
`
`
` Table 1: Sitagliptin and Metformin 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)*
`
`
`
`
`
`
`
`
`
` Placebo
`
`
`
`
`
` Sitagliptin
` 100 mg once
`
` daily
`
`
`
`
`
` Number of Patients (%)
`
`
`
` Metformin 500 mg/
` Metformin 1000 mg twice
`
`
` daily†
`
`
` Sitagliptin
`
`
`
`
` 50 mg twice daily +
`
` Metformin 500 mg/
`
`
` Metformin 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 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: 3812569
`
`
`
` 7
`
`

`

`
`
`
`
`
`
`
`
` Table 2: Pre-selected Gastrointestinal Adverse Reactions (Regardless of Investigator Assessment of
`
`
`
` Causality) Reported in Patients with Type 2 Diabetes Receiving Sitagliptin and Metformin
`
`
`
`
`
`
` Study of Sitagliptin Add-on in
`
`
` Patients Inadequately Controlled
`
` on Metformin Alone
`
`
`
` Sitagliptin 100 mg
` Placebo and
`
` once daily and
`
`
` Metformin
` Metformin
`
`≥1500 mg
`
`≥1500 mg daily
`
`
`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 and Glimepiride
` In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with