patients who have known risk factors for heart failure. Monitor
`
`
`
`
`
`patients for signs and symptoms. (5.3)
`
`• There have been postmarketing reports of acute renal failure,
`
`
`sometimes requiring dialysis. Before initiating JANUMET and at
`least annually thereafter, assess renal function. (5.4)
`
`
`• Vitamin B12 deficiency: Metformin may lower vitamin B12 levels.
`
`
`
`
`
`Measure hematologic parameters annually. (5.5)
`
`• 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. (5.7)
`
`• There have been postmarketing reports of serious allergic and
`
`hypersensitivity reactions in patients treated with sitagliptin (one of
`
`
`
`the components of JANUMET), such as anaphylaxis, angioedema,
`
`and exfoliative skin conditions
`including Stevens-Johnson
`syndrome. In such cases, promptly stop JANUMET, assess for other
`
`potential causes, institute appropriate monitoring and treatment, and
`initiate alternative treatment for diabetes. (5.9)
`
`• 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. (5.10)
`
`
`
`• There have been postmarketing reports of bullous pemphigoid
`
`
`
`requiring hospitalization in patients taking DPP-4 inhibitors. Tell
`
`patients to report development of blisters or erosions. If bullous
`
`pemphigoid is suspected, discontinue JANUMET. (5.11)
`
`• There have been no clinical studies establishing conclusive
`
`evidence of macrovascular risk reduction with JANUMET. (5.12)
`
`
`------------------------------ 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)
`
`
` 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 hydrochloride) tablets, for
`
`
`
`
`oral use
`
`Initial U.S. Approval: 2007
`
`
`
`
`WARNING: LACTIC ACIDOSIS
`
`See full prescribing information for complete boxed warning.
`
`
`
`
`• Postmarketing cases of metformin-associated lactic acidosis
`
`
`have resulted in death, hypothermia, hypotension, and resistant
`
`
`included malaise, myalgias,
`bradyarrhythmias. Symptoms
`
`
`respiratory distress, somnolence, and abdominal pain.
`
`lactate
`Laboratory abnormalities
`included elevated blood
`
`
`
`
`levels, anion gap acidosis, increased lactate/pyruvate ratio, and
`
`
`metformin plasma levels generally >5 mcg/mL. (5.1)
`
`
`• Risk factors include renal impairment, concomitant use of
`
`
`certain drugs, age ≥65 years old, radiological studies with
`
`
`
`contrast, surgery and other procedures, hypoxic states,
`excessive alcohol intake, and hepatic impairment. Steps to
`
`reduce the risk of and manage metformin-associated lactic
`acidosis in these high risk groups are provided in the Full
`
`
`
`
`Prescribing Information. (5.1)
`
`
`• If lactic acidosis is suspected, discontinue JANUMET and
`
`
`
`institute general supportive measures in a hospital setting.
`Prompt hemodialysis is recommended. (5.1)
`
`----------------------------INDICATIONS AND USAGE ---------------------------­
`
`
`
`
`JANUMET is a combination of sitagliptin, a dipeptidyl peptidase-4
`
`
`
`(DPP-4) inhibitor, and metformin hydrochloride (HCl), a biguanide,
`
`
`indicated as an adjunct to diet and exercise to improve glycemic
`
`
`control in adults with type 2 diabetes mellitus. (1)
`
`
`
`
`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)
`
`• 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)
`
`
`• Give twice daily with meals, with gradual dose escalation, to reduce
`
`
`
`
`the gastrointestinal effects due to metformin. (2.1)
`
`• Prior to initiation, assess renal function with estimated glomerular
`
`
`filtration rate (eGFR) (2.2)
`
`o Do not use in patients with eGFR below 30 mL/min/1.73 m2.
`
`
`
`
`
`
`
`JANUMET is not recommended in patients with eGFR between
`o
`
`
`30 and less than 45 mL/min/1.73 m2.
`
`• JANUMET may need to be discontinued at time of, or prior to,
`
`
`
`iodinated contrast imaging procedures. (2.3)
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS --------------------­
`
`
`
`
`Tablets: 50 mg sitagliptin/500 mg metformin HCl and 50 mg
`
`
`
`
`
`sitagliptin/1000 mg metformin HCl (3)
`
`
`-------------------------------CONTRAINDICATIONS ------------------------------­
`
`
`
`• Severe renal impairment: (eGFR below 30 mL/min/1.73 m2) (4)
`
`
`
`
`
`
`• Metabolic acidosis, including diabetic ketoacidosis. (4)
`
`
`• History of a serious hypersensitivity reaction
`to JANUMET,
`
`
`sitagliptin, or metformin, such as anaphylaxis or angioedema. (5.9,
`
`
`
`
`
`6.2)
`
`------------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`
`
`• Lactic acidosis: See boxed warning. (5.1)
`
`
`
`• 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)
`
`• Heart failure has been observed with two other members of the
`
`
`
`DPP-4 inhibitor class. Consider risks and benefits of JANUMET in
`
`
`
`
`
`Reference ID: 4475738
`
`
`
`
`
`
`
`
`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 ------------------------------­
`
`
`
`
`• Carbonic anhydrase inhibitors may increase risk of lactic acidosis.
`
`Consider more frequent monitoring. (7.1)
`
`• Drugs that reduce metformin clearance (such as ranolazine,
`
`
`vandetanib, dolutegravir, and cimetidine) may
`increase
`the
`
`
`accumulation of metformin. Consider the benefits and risks of
`
`concomitant use. (7.2)
`
`the effect of metformin on
`lactate
`• Alcohol can potentiate
`
`
`metabolism. Warn patients against excessive alcohol intake. (7.3)
`
`----------------------- USE IN SPECIFIC POPULATIONS ----------------------­
`
`
`
`
`• There are no adequate and well-controlled studies in pregnant
`
`women. To report drug exposure during pregnancy call 1-800-986­
`
`
`8999. (8.1)
`
`• Geriatric Use: Assess renal function more frequently. (8.5)
`
`
`
`• Hepatic Impairment: Avoid use in patients with hepatic impairment.
`
`
`
`
`(8.7)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
`
`
`
`
`
`
`Revised: 8/2019
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`WARNING: LACTIC ACIDOSIS
`
`
`INDICATIONS AND USAGE
`1
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`
`2.1 Recommended Dosing
`
`
`
`2.2 Recommendations for Use in Renal Impairment
`
`
`
`2.3 Discontinuation for Iodinated Contrast Imaging Procedures
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`Lactic Acidosis
`
`5.1
`
`
`5.2 Pancreatitis
`
`
`
`5.3 Heart Failure
`
`
`
`5.4 Assessment of Renal Function
`
`
`5.5 Vitamin B12 Deficiency
`
`
`
`
`
`5.6 Change
`in Clinical Status of Patients with Previously
`
`
`Controlled Type 2 Diabetes
`
`
`
`
`5.7 Use with Medications Known to Cause Hypoglycemia
`
`
`
`5.8
`Loss of Control of Blood Glucose
`
`
`
`5.9 Hypersensitivity Reactions
`
`
`
`5.10 Severe and Disabling Arthralgia
`
`
`
`5.11 Bullous Pemphigoid
`
`
`
`5.12 Macrovascular Outcomes
`
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`
`
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Carbonic Anhydrase Inhibitors
`
`
`
`7.2 Drugs that Reduce Metformin Clearance
`
`
`
`7.3 Alcohol
`
`
`
`7.4
`Insulin Secretagogues or Insulin
`
`
`
`7.5 Use of Metformin with Other Drugs
`
`
`
`7.6 Digoxin
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`8.2
`Lactation
`
`
`
`8.3 Females and Males of Reproductive Potential
`
`
`
`8.4 Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`8.6 Renal Impairment
`
`
`
`8.7 Hepatic Impairment
`
`
`
`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
`
`
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`Reference ID: 4475738
`
`

`

`
`
`
`
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`WARNING: LACTIC ACIDOSIS
`
`
`
`
`Postmarketing cases of metformin-associated lactic acidosis have resulted in death,
`
`
`hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated
`
`
`
`
`
`
`
`
`lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise,
`myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic
`
`
`acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis
`
`
`
`(without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin
`
`
`
`
`plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`
`Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant
`
`
`
`
`
`
`
`
`
`
`
`
`use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or
`
`greater, having a radiological study with contrast, surgery and other procedures, hypoxic states
`
`
`
`
`
`
`
`(e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
`
`
`
`Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high
`
`
`
`
`
`risk groups are provided in the full prescribing information [see Dosage and Administration (2.2),
`
`
`
`
`
`Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific
`
`Populations (8.6, 8.7)].
`
`
`
`
`
`If metformin-associated lactic acidosis is suspected, immediately discontinue JANUMET
`
`
`
`
`
`
`
`
`
`
`and institute general supportive measures in a hospital setting. Prompt hemodialysis is
`
`recommended [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.
`
`
`Limitations of Use
`
`
`
`
`JANUMET should not be used in patients with type 1 diabetes mellitus 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 hydrochloride (HCl). 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 HCl
`
`
`
`
`
`50 mg sitagliptin/1000 mg metformin HCl.
`
`
`
`
`The recommended starting dose in patients not currently treated with metformin is 50 mg
`
`
`
`
`
`
`sitagliptin/500 mg metformin HCl 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 HCl twice daily.
`
`
`3
`
`Reference ID: 4475738
`
`

`

`
`
`
` 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.
` 2.2 Recommendations for Use in Renal Impairment
`
`
`
`
`
`
`
`
`
` Assess renal function prior to initiation of JANUMET and periodically thereafter.
`
`
`
`
`
`
`
`
`
` JANUMET is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below
`
`
` 30 mL/min/1.73 m2 [see Contraindications (4) and Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`JANUMET is not recommended in patients with an eGFR between 30 and less than
`
`
`
`
`
`
`
`45 mL/min/1.73 m2 because these patients require a lower dosage of sitagliptin than what is available in
`
`
`
`
`
`
`
`
`
`the fixed combination JANUMET product.
`
`
`2.3 Discontinuation for Iodinated Contrast Imaging Procedures
`
`
`
`Discontinue JANUMET at the time of, or prior to, an iodinated contrast imaging procedure in
`
`patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease,
`
`
`
`
`alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re­
`
`evaluate eGFR 48 hours after the imaging procedure; restart JANUMET if renal function is stable [see
`
`
`
`
`
`
`Warnings and Precautions (5.1)].
`
`
`
`3
`
`
`4
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`
`
`Tablets:
`
`• 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 is contraindicated in patients with:
`
`
`
`
`
`• Severe renal impairment (eGFR below 30 mL/min/1.73 m2) [see Warnings and Precautions
`
`
`
`
`
`
`
`(5.1)].
`
`• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis
`
`
`
`
`
`should be treated with insulin.
`
`• History of a serious hypersensitivity reaction to JANUMET, sitagliptin, or metformin, such as
`
`
`
`
`
`
`anaphylaxis or angioedema. [See Warnings and Precautions (5.9); Adverse Reactions (6.2).]
`
`
`
`
`
`
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`
`5.1 Lactic Acidosis
`
`
`There have been postmarketing cases of metformin-associated lactic acidosis, including fatal
`
`cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as
`
`
`malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia,
`
`
`
`
`
`
`
`
`
`
`hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated
`
`
`lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap
`
`
`acidosis (without evidence of ketonuria or ketonemia), and an increased lactate/pyruvate ratio; metformin
`
`
`
`
`
`
`plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate
`
`
`
`
`
`
`
`
`blood levels which may increase the risk of lactic acidosis, especially in patients at risk.
`
`
`
`
`
`
`
`
`
`
`If metformin-associated lactic acidosis is suspected, general supportive measures should be
`instituted promptly in a hospital setting, along with immediate discontinuation of JANUMET. In JANUMET-
`
`
`
`
`
`treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is
`
`
`recommended to correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable,
`
`
`with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often
`
`resulted in reversal of symptoms and recovery.
`
`
`
`
`Educate patients and their families about the symptoms of lactic acidosis and if these symptoms
`
`
`
`occur instruct them to discontinue JANUMET and report these symptoms to their health care provider.
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4475738
`
`
`
` 4
`
`
`

`

`
`
` For each of the known and possible risk factors for metformin-associated lactic acidosis,
`
`
`
`
` recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided
` below:
`
`
`
`
` Renal Impairment
` The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with
`
`
`
`
`
`
`
`
`
` significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis
`
` increases with the severity of renal impairment because metformin is substantially excreted by the kidney.
`
`
`
`
`
`
`
`
`Clinical recommendations based upon
`the patient’s renal
`function
` include
`
`[see Dosage and
`
`
`
` Administration (2.2), Clinical Pharmacology (12.3)]:
`
`
`
`
`• Before initiating JANUMET, obtain an estimated glomerular filtration rate (eGFR).
`
`
`
`
`
`JANUMET is contraindicated in patients with an eGFR below 30 mL/min/1.73 m2 [see
`
`
`
`
`
`•
`
`Contraindications (4)].
`
`
`
`
`
`JANUMET is not recommended in patients with an eGFR between 30 and less than
`
`
`
`
`
`45 mL/min/1.73 m2 because these patients require a lower dosage of sitagliptin than what
`
`
`
`
`
`is available in the fixed combination JANUMET product.
`
`
`
`
`
`
`
`
`
`
`• Obtain an eGFR at least annually in all patients taking JANUMET. In patients at increased
`
`
`
`risk for the development of renal impairment (e.g., the elderly), renal function should be
`
`assessed more frequently.
`
`
`•
`
`
`
`Drug Interactions
`
`
`The concomitant use of JANUMET with specific drugs may increase the risk of metformin­
`
`
`
`
`
`associated lactic acidosis: those that impair renal function, result in significant hemodynamic change,
`
`interfere with acid-base balance or increase metformin accumulation [see Drug Interactions (7)].
`
`
`
`
`
`Therefore, consider more frequent monitoring of patients.
`
`
`
`Age 65 or Greater
`
`
`
`The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly
`
`
`
`
`
`
`
`
`
`
`patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients.
`
`
`
`
`
`Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)].
`
`
`
`
`
`
`
`Radiological Studies with Contrast
`
`
`
`
`
`
`
`
`Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an
`
`
`
`
`
`
`
`
`acute decrease in renal function and the occurrence of lactic acidosis. Stop JANUMET at the time of, or
`
`
`
`
`prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and
`60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in
`
`
`
`
`
`
`
`
`patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the
`
`
`
`imaging procedure, and restart JANUMET if renal function is stable.
`
`
`
`
`
`
`
`Surgery and Other Procedures
`
`
`
`Withholding of food and fluids during surgical or other procedures may increase the risk for volume
`
`
`
`
`
`
`
`
`
`depletion, hypotension and renal impairment. JANUMET should be temporarily discontinued while
`
`
`patients have restricted food and fluid intake.
`
`
`
`Hypoxic States
`
`
`Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting
`
`
`
`
`
`
`of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia).
`
`
`Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated
`
`
`
`with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When
`
`
`
`
`
`
`such events occur, discontinue JANUMET.
`
`
`
`
`Excessive Alcohol Intake
`
`
`Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of
`
`
`
`
`
`
`
`
`
`
`metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving
`
`
`
`JANUMET.
`
`
`
`
`Reference ID: 4475738
`
`
`
` 5
`
`
`

`

`
`
`
`
`
`Hepatic Impairment
`
`
`Patients with hepatic impairment have developed with cases of metformin-associated lactic
`
`acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels.
`
`
`
`
`
`
`
`
`
`
`Therefore, avoid use of JANUMET in patients with clinical or laboratory evidence of hepatic disease.
`
`
`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 Heart Failure
`
`An association between dipeptidyl peptidase-4 (DPP-4) inhibitor treatment and heart failure has
`
`
`
`
`been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class.
`
`
`
`
`
`
`
`These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Consider the risks and benefits of JANUMET prior to initiating treatment in patients at risk for heart
`
`
`
`
`
`
`
`
`
`
`
`failure, such as those with a prior history of heart failure and a history of renal impairment, and observe
`
`
`
`
`
`
`
`
`
`
`these patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic
`
`
`symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate
`
`
`
`
`
`
`and manage according to current standards of care and consider discontinuation of JANUMET.
`
`
`
`
`
`5.4 Assessment of Renal Function
`
`
`
`
`Metformin and sitagliptin are known to be substantially excreted by the kidney.
`
`Metformin HCl
`
`JANUMET is contraindicated in patients with severe renal impairment [see Contraindications (4)
`
`and Warnings and Precautions (5.1)].
`
`
`
`
`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. 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 Deficiency
`
`
`
`
`
`In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of
`
`previously normal serum vitamin B12 levels was observed in approximately 7% of patients. Such
`
`
`
`
`
`decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be
`
`
`
`
`
`
`associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin
`
`
`B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or
`
`
`
`
`
`
`
`
`absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic
`parameters on an annual basis and vitamin B12 measurements at 2- to 3-year intervals in patients on
`
`
`
`
`
`JANUMET and manage any abnormalities [see Adverse Reactions (6.1)].
`
`
`
`
`
`5.6 Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes
`
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`
`
`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
`
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`
`
`for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones,
`
`
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`
`
`
`
`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.
`
`5.7 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 Drug Interactions (7.4)].
`
`
`
`
`
`
`
`
`
`Reference ID: 4475738
`
`
`
` 6
`
`
`

`

`
`
` Metformin HCl
`
`
`
`
`
` 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.
`
` 5.8 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
`
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`
` to withhold JANUMET and temporarily administer insulin. JANUMET may be reinstituted after the acute
`
`
`
`
`
` episode is resolved.
` 5.9 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
`
`
` 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 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.
`
`
`
` 5.10 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.
`
`
`
`
`
`
`
`
` 5.11 Bullous Pemphigoid
`
`
`
`
`
` Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP­
`
`4
`
`reported cases, patients
`
`
`
` topical or systemic
`inhibitor use.
`In
` typically
`recovered with
`
` immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report
`
` development of blisters or erosions while receiving JANUMET. If bullous pemphigoid is suspected,
`
` JANUMET should be discontinued and referral to a dermatologist should be considered for diagnosis and
`
`
`
`
`
`
` appropriate treatment.
`
`
`
` 5.12 Macrovascular Outcomes
`
` There have been no clinical studies establishing conclusive evidence of macrovascular risk
`
`reduction with JANUMET.
`
`
`
`
`
`
`
` 6
`
`
`
` ADVERSE REACTIONS
`
`
` 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.
`
`
`
`
`
`Reference ID: 4475738
`
`
`
` 7
`
`
`

`

`
`
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`
`
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`
`
`
`
` 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†
`
`
`
` 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)
`
`
`5 (2.8)
`
`
` 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 500 mg/
`
`
` Metformin 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 Alone
`
`
`
`
`
`
`
`
`
` In a 24-week placebo-controlled trial of sitaglipti