`
`
` 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 highrisk 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)
`
`
`
`
`
`
`
`
` ---------------------------RECENT MAJOR CHANGES --------------------------­
`
`
`
`
`
`
`
`
`
` Indications and Usage
` 12/2020
` Dosage and Administration (2.1)
`
`
`
` 12/2020
`
`
` Contraindications (4)
`
`
`
` 12/2020
`
`
`
`
`
` Warnings and Precautions (5.4,5.6)
`
`
`
` 12/2020
`
`
`
`
` Warnings and Precautions (5.12) Removal
`
`
`
` 12/2020
`
`
`
`
`
`
`
`
`
`
`
`
` ----------------------------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)
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4712165
`
`• 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)
`
`
`
`
`
`
`
`
` ----------------------- 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 or
`
`
`
`
`
` Insulin
`
` 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
`
` lactate
` the effect of metformin on
`
`
`
`
`
`
`
`
`
`
`
` 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: 12/2020
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4712165
`
`
`
` 2
`
`

`

`
`
` 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.
`
`
`
`
`
` 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)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4712165
`
`
`
` 3
`
`

`

`
`
`•
`
`
`
`
`
`
` 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.
`
`
`
`
` 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
` function
` include
` [see Dosage and
`
`
`
`
`
`
`
`
`
`
`
`
` the patient’s renal
` Administration (2.2), Clinical Pharmacology (12.3)]:
`
`
`
`
`
`
`
`
`
` 4
`
`Reference ID: 4712165
`
`

`

`
`
`•
`
`
`• 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.
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`
`
` 5
`
`Reference ID: 4712165
`
`

`

`
`
`
`
`
`
` 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
`
`
` levels was observed in approximately 7% of patients. Such
`
` previously normal serum vitamin B12
`
`
`
`
`
` 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. 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
` topical or systemic
`
`
` recovered with
`In
` reported cases, patients
`
`
`
`
` typically
`inhibitor use.
`
`
` 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
`
`Reference ID: 4712165
`
`

`

`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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)*
`
`
`
`
`
`
`
`
`
`
`
`
` Diarrhea
`
`
` Upper Respiratory
` Tract Infection
`
`
`
`
`
`
` Placebo
`
`
`
`
`
` Sitagliptin
` 100 mg once
`
`
`
` daily
`
`
`
`
`
`
`
`
` Number of Patients (%)
`
`
`
`
`
` Metformin HCl 500 mg/
`
`
`
` Metformin HCl 1000 mg
`
` twice daily†
`
`
`
`
`
` N = 176
`
`
`
`
`
`
`
` N = 179
`
`
`
` N = 364†
`
`
`
`
`
` 7 (4.0)
`
`
`
`
`
` 9 (5.1)
`
`
`
`
`
`
`
` 5 (2.8)
`
`
`
`
`
` 8 (4.5)
`
`
`
` 28 (7.7)
`
`
`
`
`
` 19 (5.2)
`
`
`
`
` 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)
`
`
`
`
`
` 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