----------------------- WARNINGS AND PRECAUTIONS -----------------------
` Lactic Acidosis: See boxed warning. (5.1)
` Pancreatitis: 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
`patients who have known risk factors for heart failure. Monitor
`patients for signs and symptoms. (5.3)
` Acute Renal Failure: Has been reported postmarketing, 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 and vitamin B12 at 2 to 3
`year intervals and manage any abnormalities. (5.5)
` Hypoglycemia with Concomitant Use with
`Insulin
`Insulin or
`Secretagogues: Increased risk of hypoglycemia when used in
`combination with insulin and/or an insulin secretagogue. A lower dose
`of insulin or insulin secretagogue may be required. (5.6)
` Hypersensitivity Reactions: There have been postmarketing reports
`of serious allergic and hypersensitivity reactions in patients treated
`with sitagliptin such as anaphylaxis, angioedema, and exfoliative skin
`conditions including Stevens-Johnson syndrome. Promptly stop
`JANUMET, assess for other potential causes, institute appropriate
`monitoring and treatment. (5.7)
` 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. (5.8)
` Bullous Pemphigoid: There have been postmarketing reports
`requiring hospitalization in patients taking DPP-4 inhibitors. Tell
`patients to report development of blisters or erosions. If bullous
`pemphigoid is suspected, discontinue JANUMET. (5.9)
`
` ------------------------------ 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)
`
`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)
` 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)
` Alcohol can potentiate the effect of metformin on lactate metabolism.
`Warn patients against excessive alcohol intake. (7)
`
` ----------------------- USE IN SPECIFIC POPULATIONS -----------------------
` Females and Males of Reproductive Potential: Advise
`premenopausal females of the potential for an unintended pregnancy.
`(8.3)
` 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: 06/2022
`
`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
`bradyarrhythmias. Symptoms
`included malaise, myalgias,
`respiratory distress, somnolence, and abdominal pain.
`Laboratory abnormalities included elevated blood lactate 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. (1)
` JANUMET has not been studied in patients with a history of
`pancreatitis. (1, 5.2)
`
` ----------------------- DOSAGE AND ADMINISTRATION -----------------------
` Take JANUMET orally twice daily with meals. (2.1)
`
`Individualize the dosage of JANUMET on the basis of the patient’s
`current regimen, effectiveness, and tolerability. (2.1)
` The maximum recommended daily dose is 100 mg of sitagliptin and
`2000 mg of metformin HCl. (2.1)
` The recommended starting dose in patients not currently treated with
`metformin is 50 mg sitagliptin and 500 mg metformin HCl twice daily,
`with gradual dose escalation
`recommended
`to
`reduce
`gastrointestinal side effects associated with metformin. (2.1)
` 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 HCl 850 mg twice daily, the recommended starting
`dose of JANUMET is 50 mg sitagliptin and 1000 mg metformin HCl
`twice daily. (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.
`o
`JANUMET is not recommended in patients with eGFR between
`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 ---------------------
`JANUMET Tablets:
`
`sitagliptin 50 mg and metformin HCl 500 mg tablets
`
`sitagliptin 50 mg and metformin HCl 1000 mg tablets (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. (5.7, 6.2)
`
`Reference ID: 5001938
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: LACTIC ACIDOSIS
`1
`INDICATIONS AND USAGE
`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
`5.1
`Lactic Acidosis
`5.2 Pancreatitis
`5.3 Heart Failure
`5.4 Acute Renal Failure
`5.5 Vitamin B12 Deficiency
`5.6 Hypoglycemia with Concomitant Use with Insulin or Insulin
`Secretagogues
`5.7 Hypersensitivity Reactions
`5.8 Severe and Disabling Arthralgia
`5.9 Bullous Pemphigoid
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`
`7 DRUG INTERACTIONS
`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: 5001938
`
`

`

`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.
`
`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).]
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosing
` Take JANUMET orally twice daily with meals.
`
`
`Individualize the dosage of JANUMET on the basis of the patient’s current regimen, effectiveness,
`and tolerability.
` The maximum recommended daily dose is 100 mg of sitagliptin and 2000 mg of metformin
`hydrochloride (HCl).
` Do not split or divide JANUMET tablets.
` The recommended starting dose in patients not currently treated with metformin is 50 mg
`sitagliptin and 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 HCl 850 mg twice daily, the recommended starting dose of JANUMET
`is 50 mg sitagliptin and 1000 mg metformin HCl twice daily.
`
`Reference ID: 5001938
`
`

`

`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
`
`DOSAGE FORMS AND STRENGTHS
`
`Tablets:
`
`
`sitagliptin 50 mg and metformin HCl 500 mg tablets are light pink, capsule-shaped, film-coated
`tablets with “575” debossed on one side.
`
`
`
`sitagliptin 50 mg and metformin HCl 1000 mg tablets are red, capsule-shaped, film-coated tablets
`with “577” debossed on one side.
`
`4
`
`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.
` History of a serious hypersensitivity reaction to JANUMET, sitagliptin, or metformin, such as
`anaphylaxis or angioedema. [See Warnings and Precautions (5.7); 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.
`
`
`
`4
`
`Reference ID: 5001938
`
`

`

`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
`
`
`
`5
`
`Reference ID: 5001938
`
`

`

`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.
`
`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 Acute Renal Failure
`
`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. JANUMET is contraindicated in patients with severe
`renal impairment [see Contraindications (4) and Warnings and Precautions (5.1)].
`
`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 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues
`
`JANUMET may increase the risk of hypoglycemia when combined with insulin and/or an insulin
`secretagogue (e.g., sulfonylurea) [see Adverse Reactions (6)]. A lower dose of insulin or insulin
`secretagogue may be required to minimize the risk of hypoglycemia when used in combination with
`JANUMET [see Drug Interactions (7)].
`
`5.7 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.
`
`
`
`6
`
`Reference ID: 5001938
`
`

`

`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.
`
`5.8 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.
`
`5.9 Bullous Pemphigoid
`
`Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-
`4 inhibitor use. In reported cases, patients typically recovered with topical or systemic 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.
`
`6
`
`ADVERSE REACTIONS
`
`The following adverse reactions are also discussed elsewhere in the labeling:
` Lactic Acidosis [see Warnings and Precautions (5.1)]
` Pancreatitis [see Warnings and Precautions (5.2)]
` Heart Failure [see Warnings and Precautions (5.3)]
` Acute Renal Failure [see Warnings and Precautions (5.4)]
` Vitamin B12 Deficiency [see Warnings and Precautions (5.5)]
` Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and
`Precautions (5.6)]
` Hypersensitivity Reactions [see Warnings and Precautions (5.7)]
` Severe and Disabling Arthralgia [see Warnings and Precautions (5.8)]
` Bullous Pemphigoid [see Warnings and Precautions (5.9)]
`
`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.
`
`
`
`7
`
`Reference ID: 5001938
`
`

`

`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)*
`Number of Patients (%)
`
`Metformin HCl 500 mg/
`Metformin HCl 1000 mg
`twice daily†
`
`
`
`
`
`Placebo
`
`
`Sitagliptin
`100 mg once
`daily
`
`
`
`Diarrhea
`
`Upper Respiratory
`Tract Infection
`
`N = 176
`
`N = 179
`
`7 (4.0)
`
`9 (5.1)
`
`5 (2.8)
`
`8 (4.5)
`
`N = 364†
`
`28 (7.7)
`
`19 (5.2)
`
`Headache
`* Intent-to-treat population.
`† Data pooled for the patients given the lower and higher doses of metformin.
`
`5 (2.8)
`
`2 (1.1)
`
`14 (3.8)
`
`Sitagliptin
`50 mg twice daily +
`Metformin HCl 500 mg/
`Metformin HCl 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 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.
`
`Table 2: Pre-selected Gastrointestinal Adverse Reactions (Regardless of Investigator Assessment of
`Causality) Reported in Patients with Type 2 Diabetes Receiving Sitagliptin and Metformin
`Number of Patients (%)
`
`
`Study of Sitagliptin and Metformin in Patients Inadequately Controlled
`on Diet and Exercise
`
`Study of Sitagliptin Add-on in
`Patients Inadequately Controlled
`on Metformin Alone
`
`Placebo
`
`Sitagliptin
`100 mg
`once daily
`
`Diarrhea
`
`Nausea
`Vomiting
`
`N = 176
`
`N = 179
`
`7 (4.0)
`
`2 (1.1)
`1 (0.6)
`
`5 (2.8)
`
`2 (1.1)
`0 (0.0)
`
`Metformin HCl
`500 mg/
`Metformin HCl
`1000 mg
`twice daily*
`
`N = 364
`
`28 (7.7)
`
`20 (5.5)
`2 (0.5)
`
`Sitagliptin 50 mg twice
`daily +
`Metformin HCl 500 mg/
`Metformin HCl 1000 mg
`twice daily*
`
`Placebo and
`Metformin
`HCl
`1500 mg
`daily
`
`Sitagliptin 100 mg
`once daily and
`Metformin HCl
`1500 mg daily
`
`N = 372
`
`28 (7.5)
`
`18 (4.8)
`8 (2.2)
`
`11 (3.0)
`
`N = 237
`
`6 (2.5)
`
`2 (0.8)
`2 (0.8)
`
`9 (3.8)
`
`N = 464
`
`11 (2.4)
`
`6 (1.3)
`5 (1.1)
`
`10 (2.2)
`
`4 (2.3)
`
`6 (3.4)
`
`14 (3.8)
`
`Abdominal
`Pain†
`* Data pooled for the patients given the lower and higher doses of metformin.
`† Abdominal discomfort was included in the analysis of abdominal pain in the study of initial therapy.
`
`Sitagliptin in Combination with Metformin and Glimepiride
`
`In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2
`diabetes inadequately controlled on metformin and glimepiride (sitagliptin, N=116; placebo, N=113), the
`adverse reactions reported regardless of investigator assessment of causality in  5% of patients treated
`with sitagliptin and more commonly than in patients treated with placebo were: hypoglycemia (Table 3) and
`headache (6.9%, 2.7%).
`
`Sitagliptin in Combination with Metformin and Rosiglitazone
`
`In a placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes
`inadequately controlled on metformin and rosiglitazone (sitagliptin, N=181; placebo, N=97), the adverse
`reactions reported regardless of investigator assessment of causality through Week 18 in  5% of patients
`
`
`
`8
`
`Reference ID: 5001938
`
`

`

`treated with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory
`tract infection (sitagliptin, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%). Through Week 54, the
`adverse reactions reported regardless of investigator assessment of causality in  5% of patients treated
`with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory tract
`infection (sitagliptin, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%,
`5.2%), and headache (5.5%, 4.1%).
`
`Sitagliptin in Combination with Metformin and Insulin
`
`In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2
`diabetes inadequately controlled on metformin and insulin (sitagliptin, N=229; placebo, N=233), the only
`adverse reaction reported regardless of investigator assessment of causality in  5% of patients treated with
`sitagliptin and more commonly than in patients treated with placebo was hypoglycemia (Table 3).
`
`Hypoglycemia
`
`In the above studies (N=5), adverse reactions of hypoglycemia were based on all reports of
`symptomatic hypoglycemia; a concurrent glucose measurement was not required although most (77%)
`reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. When the
`combination of sitagliptin and metformin was coadministered with a sulfonylurea or with insulin, the
`percentage of patients reporting at least one adverse reaction of hypoglycemia was higher than that
`observed with placebo and metformin coadministered with a sulfonylurea or with insulin (Table 3).
`
`Table 3: Incidence and Rate of Hypoglycemia* (Regardless of Investigator Assessment of Causality) in
`Placebo-Controlled Clinical Studies of Sitagliptin in Combination with Metformin Coadministered with
`Glimepiride or Insulin
`Sitagliptin 100 mg
`+ Metformin
`+ Glimepiride
`N = 116
`19 (16.4)
`0.82
`0 (0.0)
`
`Placebo
`+ Metformin
`+ Glimepiride
`N = 113
`1 (0.9)
`0.02
`0 (0.0)
`
`Add-On to Glimepiride +
` Metformin (24 weeks)
`
`
`Overall (%)
`Rate (episodes/patient-year)†
`Severe (%)‡
`
`Add-On to Insulin
`+ Metformin (24 weeks)
`
`Placebo
`Sitagliptin 100 mg
`+ Metformin
`+ Metformin
`+ Insulin
`+ Insulin
`N = 233
`N = 229
`
`19 (8.2)
`35 (15.3)
`Overall (%)
`Rate (episodes/patient-year)†
`0.61
`0.98
`Severe (%)‡
`1 (0.4)
`1 (0.4)
`* Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose
`measurement was not required: Intent-to-treat population.
`† Based on total number of events (i.e., a single patient may have had multiple events).
`‡ Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss
`of consciousness or seizure.
`
`The overall incidence of reported adverse reactions of hypoglycemia in patients with type 2 diabetes
`inadequately controlled on diet and exercise was 0.6% in patients given placebo, 0.6% in patients given
`sitagliptin alone, 0.8% in patients given metformin alone, and 1.6% in patients given sitagliptin in
`combination with metformin. In patients with type 2 diabetes inadequately controlled on metformin alone,
`the overall incidence of adverse reactions of hypoglycemia was 1.3% in patients given add-on sitagliptin
`and 2.1% in patients given add-on placebo.
`
`In the study of sitagliptin and add-on combination therapy with metformin a