`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
` These highlights do not include all the information needed to use
`
`
`
`
`
`
`
` full prescribing
` JANUMET XR safely and effectively. See
`
`
`
`
` information for JANUMET XR.
`
`
`
`
`JANUMET® XR (sitagliptin and metformin HCl extended-release)
`
`
`
`tablets
`
`Initial U.S. Approval: 2012
`
`
`
`
`Reference ID: 4043197
`
`
`
`
`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
`
`included malaise,
`resistant bradyarrhythmias. Symptoms
`
`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 XR and
`
`
`
`
`institute general supportive measures in a hospital setting.
`
`Prompt hemodialysis is recommended. (5.1)
`
`
`
`---------------------------RECENT MAJOR CHANGES --------------------------­
`
`
`
`
`Boxed Warning
`01/2017
`
`
`Dosage and Administration (2.1)
`01/2017
`
`
`Dosage and Administration (2.2, 2.3)
`01/2017
`
`
`
`Contraindications (4)
`01/2017
`
`
`Warnings and Precautions
`
`Lactic Acidosis (5.1)
`
`
`
`Impaired Hepatic Function (5.3)
`
`
`
`Assessment of Renal Function (5.3)
`
`
`
`Alcohol Intake (5.6)
`
`
`
`Surgical Procedures (5.7)
`
`
`
`Concomitant Medications Affecting Renal
`
`
`Function or Metformin Disposition (5.10)
`
`
`
`Bullous Pemphigoid (5.10)
`
`
`
`Radiologic Studies with Intravascular Iodinated
`
`Removal 01/2017
`Contrast Materials (5.11)
`
`
`
`
`
`Removal 01/2017
`Hypoxic States (5.12)
`
`
`
`
`
`----------------------------INDICATIONS AND USAGE ---------------------------­
`
`
`
`
`JANUMET XR is a dipeptidyl peptidase-4 (DPP-4) inhibitor and
`
`
`biguanide combination product indicated as an adjunct to diet and
`
`
`
`
`exercise to improve glycemic control in adults with type 2 diabetes
`
`
`
`mellitus when treatment with both sitagliptin and metformin extended-
`
`
`
`release is appropriate. (1, 14)
`
`
`
`
`Important Limitations of Use:
`
`
`• Not for the treatment of type 1 diabetes or diabetic ketoacidosis. (1)
`
`
`
`
`• Has not been studied in patients with a history of pancreatitis. (1,
`
`
`
`
`5.2)
`
`----------------------- DOSAGE AND ADMINISTRATION-----------------------­
`
`
`
`
`• Individualize the starting dose of JANUMET XR based on the
`
`
`
`
`patient’s current regimen. (2.1)
`
`• Adjust the dosing based on effectiveness and tolerability while not
`
`
`
`exceeding the maximum recommended daily dose of 100 mg
`
`
`
`
`sitagliptin and 2000 mg metformin extended-release. (2.1)
`
`
`
`• Administer once daily with a meal preferably in the evening.
`
`
`
`
`
`
`Gradually escalate the dose to reduce the gastrointestinal 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 .
`
`
`
`
`o Discontinue if eGFR later falls below 30 mL/min/1.73 m2 .
`
`
`
`
`
`o Initiation is not recommended in patients with eGFR between 30
`
`
`
`– 45 mL/min/1.73 m2 .
`
`
`
`
`01/2017
`
`Removal 01/2017
`
`
`01/2017
`
`Removal 01/2017
`
`
`Removal 01/2017
`
`
`
`Removal 01/2017
`
`
`01/2017
`
`
`o Assess risk/benefit of continuing if eGFR falls below
`
`
`
`
`
`45 mL/min/1.73 m2 .
`
`
`
`
`o Limit dose of sitagliptin to 50 mg once daily if eGFR falls below
`
`
`
`
`45 mL/min/1.73 m2 .
`
`
`
`• JANUMET XR may need to be discontinued at time of, or prior to,
`
`
`
`
`iodinated contrast imaging procedures. (2.3)
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS --------------------­
`
`
`
`
`
`JANUMET XR Tablets: 100 mg sitagliptin/1000 mg metformin HCl
`
`
`
`
`
`
`extended-release, 50 mg sitagliptin/500 mg metformin HCl extended-
`
`
`release, and 50 mg sitagliptin/1000 mg metformin HCl extended-
`
`
`
`release. (3)
`
`-------------------------------CONTRAINDICATIONS ------------------------------­
`
`
`
`
`• Severe renal impairment: eGFR below 30 mL/min/1.73 m2. (4)
`
`
`
`
`
`
`• Metabolic acidosis, including diabetic ketoacidosis. (4, 5.1)
`
`
`
`
`• History of a serious hypersensitivity reaction (e.g., anaphylaxis or
`
`
`
`angioedema) to JANUMET XR or to one of its components. (5.8,
`
`
`
`
`
`
`
`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
`
`
`
`
`in patients treated with sitagliptin. If pancreatitis is suspected,
`
`
`
`promptly discontinue JANUMET XR. (5.2)
`
`
`• There have been postmarketing reports of acute renal failure in
`
`
`
`
`patients treated with sitagliptin, sometimes requiring dialysis. Before
`
`
`initiating JANUMET XR and at least annually thereafter, assess
`
`
`renal function. (5.3)
`
`• Vitamin B12 deficiency: Metformin may lower Vitamin B12 levels.
`
`
`
`
`
`
`
`
`Measure hematologic parameters annually. (5.4)
`
`
`
`
`• When used with an insulin secretagogue (e.g., sulfonylurea) or with
`
`insulin, a lower dose of the insulin secretagogue or insulin may be
`
`
`required to minimize the risk of hypoglycemia. (5.6)
`
`
`
`• There have been postmarketing reports of serious allergic and
`
`
`
`
`
`hypersensitivity reactions in patients treated with sitagliptin, such as
`
`anaphylaxis, angioedema, and exfoliative skin conditions including
`
`In such cases, promptly stop
`Stevens-Johnson syndrome.
`
`
`for other potential causes,
`JANUMET XR, assess
`institute
`
`appropriate monitoring and
`initiate alternative
`treatment, and
`
`treatment for diabetes. (5.8)
`
`
`
`
`• 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. (5.9)
`
`• 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 XR. (5.10)
`
`
`
`• There have been no clinical studies establishing conclusive
`
`
`
`
`
`
`
`evidence of macrovascular risk reduction with JANUMET XR or any
`
`other anti-diabetic drug. (5.11)
`
`
`
`
`------------------------------ ADVERSE REACTIONS -----------------------------­
`
`
`
`
`
`
`• The most common adverse reactions reported in ≥5% of patients
`
`simultaneously started on sitagliptin and metformin and more
`
`
`commonly than in patients treated with placebo were diarrhea,
`
`
`
`upper respiratory tract infection, and headache. (6.1)
`
`
`
`
`
`treated with
`• Adverse reactions reported
`in ≥5% of patients
`sitagliptin in combination with sulfonylurea and metformin and more
`
`commonly than in patients treated with placebo in combination with
`
`sulfonylurea and metformin were hypoglycemia and headache. (6.1)
`
`
`
`
`
`• Hypoglycemia was the only adverse reaction reported in ≥5% of
`patients treated with sitagliptin in combination with insulin and
`
`metformin and more commonly than in patients treated with
`
`placebo in combination with insulin and metformin. (6.1)
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Merck
`
`
`
`
`
`
`
`
`
`
`Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877­
`
`888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`
`
`-------------------------------DRUG INTERACTIONS ------------------------------­
`
`
`
`
`• 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
`the
`increase
`
`

`

`
`
`
` accumulation of metformin. Consider the benefits and risks of
`
` concomitant use. (7.2)
` the effect of metformin on
` • Alcohol can potentiate
`
`
`lactate
` metabolism. Warn patients against excessive alcohol intake. (7.3)
`
`
`
`
`
` ----------------------- USE IN SPECIFIC POPULATIONS ----------------------­
` • Safety and effectiveness of JANUMET XR in children under 18
`
`
`
`
` years have not been established. (8.4)
`
`
`
`
`
` • There are no adequate and well-controlled studies in pregnant
`
`
`
` women. To report drug exposure during pregnancy call 1-800-986­
` 8999. (8.1)
`
`
`
`
`
` • 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: 01/2017
`
`
`
`
`
`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 Assessment of Renal Function
`
`5.4 Vitamin B12 Levels
`
`
`5.5 Change in Clinical Status of Patients with Previously
`
`
`
`Controlled Type 2 Diabetes
`
`5.6 Use with Medications Known to Cause Hypoglycemia
`
`
`5.7
`Loss of Control of Blood Glucose
`
`
`
`5.8 Hypersensitivity Reactions
`
`
`5.9 Severe and Disabling Arthralgia
`
`
`5.10 Bullous Pemphigoid
`
`
`
`5.11 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
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`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
`
`
`17.1
`Instructions
`
`
`17.2 Laboratory Tests
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`
`
`
`
`
`Reference ID: 4043197
`
`
`
` 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)].
`
`
`
`
`lactic acidosis
`factors
`Risk
`include renal
`impairment,
`for metformin-associated
`
`
`
`
`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)].
`
`
`
`is suspected,
`immediately discontinue
`lactic acidosis
`If metformin-associated
`
`
`
`
`
`
`in a hospital setting. Prompt
`JANUMET XR and
`institute general supportive measures
`
`
`hemodialysis is recommended [see Warnings and Precautions (5.1)].
`
`
`1
`
`
`INDICATIONS AND USAGE
`JANUMET® XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults
`
`
`
`
`
`with type 2 diabetes mellitus when treatment with both sitagliptin and metformin extended-release is
`
`appropriate. [See Clinical Studies (14).]
`
`
`Important Limitations of Use
`
`
`
`
`JANUMET XR should not be used in patients with type 1 diabetes mellitus or for the treatment of
`
`diabetic ketoacidosis.
`
`
`
`JANUMET XR has not been studied in patients with a history of pancreatitis. It is unknown whether
`
`
`
`
`
`
`
`
`
`
`patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using
`
`JANUMET XR. [See Warnings and Precautions (5.2).]
`
`
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`2.1 Recommended Dosing
`The dose of JANUMET XR should be individualized on the basis of the patient’s current regimen,
`
`
`
`effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg
`
`
`
`sitagliptin and 2000 mg metformin. Initial combination therapy or maintenance of combination therapy
`
`
`
`should be individualized and left to the discretion of the healthcare provider.
`
`
`In patients not currently treated with metformin, the recommended total daily starting dose of
`
`
`
`
`
`
`
`
`•
`JANUMET XR is 100 mg sitagliptin and 1000 mg metformin hydrochloride (HCl) extended-
`
`
`
`
`release. Patients with inadequate glycemic control on this dose of metformin can be titrated
`
`gradually, to reduce gastrointestinal side effects associated with metformin, up to the
`
`maximum recommended daily dose.
`
`In patients already treated with metformin, the recommended total daily starting dose of
`
`
`
`JANUMET XR is 100 mg sitagliptin and the previously prescribed dose of metformin.
`
`
`
`
`•
`
`
`
`Reference ID: 4043197
`
`3
`
`
`

`

`
`
`• For patients taking metformin immediate-release 850 mg twice daily or 1000 mg twice daily,
`
`
`
`
`
`
`the recommended starting dose of JANUMET XR is two 50 mg sitagliptin/1000 mg metformin
`
`
`
`
`
`
`hydrochloride extended-release tablets taken together once daily.
`
`• Maintain the same total daily dose of sitagliptin and metformin when changing between
`
`
`
`
`JANUMET (sitagliptin and metformin HCl immediate-release) and JANUMET XR. Patients with
`
`inadequate glycemic control on this dose of metformin can be titrated gradually, to reduce
`
`
`gastrointestinal side effects associated with metformin, up to the maximum recommended
`
`daily dose.
`JANUMET XR should be administered with food to reduce the gastrointestinal side effects associated
`
`
`
`
`with the metformin component. JANUMET XR should be given once daily with a meal preferably in the
`
`
`evening. JANUMET XR should be swallowed whole. The tablets must not be split, crushed, or chewed
`
`
`
`
`before swallowing. There have been reports of incompletely dissolved JANUMET XR tablets being
`
`
`
`
`
`
`
`eliminated in the feces. It is not known whether this material seen in feces contains active drug. If a patient
`
`
`reports repeatedly seeing tablets in feces, the healthcare provider should assess adequacy of glycemic
`
`
`control [see Patient Counseling Information (17.1)].
`
`
`The 100 mg sitagliptin/1000 mg metformin hydrochloride extended-release tablet should be taken as a
`
`
`
`single tablet once daily. Patients using two JANUMET XR tablets (such as two 50 mg sitagliptin/500 mg
`
`
`
`
`
`
`
`
`
`metformin hydrochloride extended-release
`tablets or
`two 50 mg sitagliptin/1000 mg metformin
`
`
`
`
`
`
`hydrochloride extended-release tablets) should take the two tablets together once daily.
`
`
`
`
`No studies have been performed specifically examining the safety and efficacy of JANUMET XR in
`
`
`
`
`
`
`
`
`patients previously treated with other oral antihyperglycemic agents and switched to JANUMET XR. Any
`
`change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as
`
`changes in glycemic control can occur.
`
`
`
`
`2.2 Recommendations for Use in Renal Impairment
`
`
`
`Assess renal function prior to initiation of JANUMET XR and periodically thereafter.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`JANUMET XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below
`30 mL/min/1.73 m2. Discontinue JANUMET XR if the patient’s eGFR later falls below 30 mL/min/1.73 m2
`
`
`
`
`
`
`
`
`
`
`
`
`
` [see Contraindications (4) and Warnings and Precautions (5.1)].
`
`
`
` Initiation of JANUMET XR in patients with an eGFR between 30 and 45 mL/min/1.73 m2 is not
`
`recommended.
`
`In patients taking JANUMET XR whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`risk of continuing therapy and limit dose of the sitagliptin component to 50 mg once daily.
`
`
`
`2.3 Discontinuation for Iodinated Contrast Imaging Procedures
`
`
`
`
`
`Discontinue JANUMET XR 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 XR if renal function is stable [see
`
`Warnings and Precautions (5.1)].
`
`
`
`3
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`
`• 100 mg/1000 mg tablets are blue, bi-convex oval, film-coated tablets with “81” debossed on one
`
`side.
`
`
`
`
`
`
`
`
`
`
`• 50 mg/500 mg tablets are light blue, bi-convex oval, film-coated tablets with “78” debossed on
`
`one side.
`
`
`
`
`• 50 mg/1000 mg tablets are light green, bi-convex oval, film-coated tablets with “80” debossed
`
`on one side.
`
`
`4
`
`
`CONTRAINDICATIONS
`
`JANUMET XR is contraindicated in patients with:
`
`
`
`
`Reference ID: 4043197
`
`
`4
`
`

`

`
`• Severe renal impairment (eGFR below 30 mL/min/1.73 m2) [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`• Hypersensitivity to metformin hydrochloride.
`
`
`
`
`
`
`
`
`
`• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be
`
`treated with insulin.
`
`
`
`
`• History of a serious hypersensitivity reaction to JANUMET XR or sitagliptin, such as anaphylaxis or
`
`
`angioedema. [See Warnings and Precautions (5.8); Adverse Reactions (6.2).]
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Lactic Acidosis
`
`Metformin hydrochloride
`
`
`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 XR. In JANUMET XR-
`
`
`treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is
`
`
`
`recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride 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 XR and report these symptoms to their healthcare provider.
`
`
`
`
`
`
`factors for metformin-associated lactic acidosis,
`For each of the known and possible risk
`
`
`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 XR, obtain an estimated glomerular filtration rate (eGFR).
`JANUMET XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 .
`
`
`
`
`
`
`•
`Discontinue JANUMET XR if the patient’s eGFR later falls below 30 mL/min/1.73 m2 [see
`
`
`
`
`
`
`
`Contraindications (4)].
`
`
`
`
`
`Initiation of JANUMET XR is not recommended in patients with eGFR between 30 and
`45 mL/min/1.73 m2 .
`
`
`
`In patients taking JANUMET XR whose eGFR later falls below 45 mL/min/1.73 m2, assess
`
`
`
`
`
`
`
`
`
`
`the benefit and risk of continuing therapy.
`
`
`
`
`
`
`
`
`
`
`
`• Obtain an eGFR at least annually in all patients taking JANUMET XR. 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 XR with specific drugs may increase the risk of metformin­
`
`
`
`associated lactic acidosis: those that impair renal function, result in significant hemodynamic change,
`
`
`
`Reference ID: 4043197
`
`
`5
`
`

`

`
`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 XR 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 XR if renal function is stable.
`
`
`Surgery and Other Procedures
`
`
`
`
`
`W ithholding of food and fluids during surgical or other procedures may increase the risk for volume
`
`
`
`depletion, hypotension and renal impairment. JANUMET XR 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. W hen such
`
`
`
`events occur, discontinue JANUMET XR.
`
`
`
`Excessive Alcohol Intake
`
`
`
`Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of
`
`metformin-associated lactic acidosis. W arn patients against excessive alcohol intake while receiving
`
`
`JANUMET XR.
`
`
`
`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 XR 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 sitagliptin with or without metformin. After initiation of
`
`
`
`JANUMET XR, patients should be observed carefully for signs and symptoms of pancreatitis. If
`
`
`
`
`pancreatitis is suspected, JANUMET XR should promptly be discontinued and appropriate management
`
`should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the
`
`
`development of pancreatitis while using JANUMET XR.
`
`
`
`5.3 Assessment of Renal Function
`
`Metformin and sitagliptin are substantially excreted by the kidney.
`
`Metformin hydrochloride
`
`
`
`JANUMET XR 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 in patients taking sitagliptin with or
`
`
`
`
`
`
`
`
`without metformin, including acute renal failure, sometimes requiring dialysis. Before initiation of therapy
`
`with JANUMET XR and at least annually thereafter, renal function should be assessed. In patients in
`
`
`
`Reference ID: 4043197
`
`
`6
`
`

`

`
`whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should
`
`
`
`be assessed more frequently and JANUMET XR discontinued if evidence of renal impairment is present.
`
`
` 5.4 Vitamin B12 Levels
` In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of
`
`
`
`
`previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately
`7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic
`
`
`factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with
`
`
`
`
`
`
`
`
`discontinuation of metformin or Vitamin B12 supplementation. Measurement of hematologic parameters on
`
`
`an annual basis is advised in patients on JANUMET XR and any apparent abnormalities should be
`
`appropriately investigated and managed. [See Adverse Reactions (6.1).]
`
`
`Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be
`
`
`predisposed to developing subnormal Vitamin B12 levels. In these patients, routine serum Vitamin B12
`
`
`measurements at two- to three-year intervals may be useful.
`
`
`5.5 Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes
`
`
`A patient with type 2 diabetes previously well controlled on JANUMET XR who develops laboratory
`
`
`abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly
`
`for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones,
`
`
`
`
`
`
`
`
`
`blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form
`
`
`
`
`occurs, JANUMET XR must be stopped immediately and other appropriate corrective measures initiated.
`
`
`5.6 Use with Medications Known to Cause Hypoglycemia
`
`
`Sitagliptin
`
`W hen sitagliptin was used in combination with a sulfonylurea or with insulin, medications known to
`
`cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in
`
`combination with a sulfonylurea or with insulin [see Adverse Reactions (6)]. Therefore, patients also
`
`receiving an insulin secretagogue (e.g., sulfonylurea) or insulin may require a lower dose of the insulin
`secretagogue or insulin to reduce the risk of hypoglycemia [see Drug Interactions (7.4)].
`
`Metformin hydrochloride
`
`Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use,
`
`
`
`
`
`but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric
`
`
`
`
`
`
`
`
`
`
`supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas
`
`
`and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary
`
`
`
`
`
`
`
`insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may
`
`
`
`be difficult to recognize in the elderly, and in people who are taking β-adrenergic blocking drugs.
`
`
`
`5.7 Loss of Control of Blood Glucose
`
`
`W hen a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma,
`
`infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`to withhold JANUMET XR and temporarily administer insulin. JANUMET XR may be reinstituted after the
`
`
`
`
`
`
`
`
`
`acute episode is resolved.
`
`5.8 Hypersensitivity Reactions
`
`
`There have been postmarketing reports of serious hypersensitivity reactions in patients treated with
`sitagliptin, one of the components of JANUMET XR. These reactions include anaphylaxis, angioedema,
`
`
`
`and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred
`
`within the first 3 months after initiation of treatment with sitagliptin, with some reports occurring after the
`
`
`
`
`
`
`
`
`first dose. If a hypersensitivity reaction is suspected, discontinue JANUMET XR, assess for other potential
`
`
`
`
`causes for the event, and institute alternative treatment for diabetes. [See Adverse Reactions (6.2).]
`
`
`Use caution in a patient with a history of angioedema to another dipeptidyl peptidase-4 (DPP4) inhibitor
`
`
`
`because it is unknown whether such patients will be predisposed to angioedema with JANUMET XR.
`
`5.9 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.
`
`
`
`
`
`
`Reference ID: 4043197
`
`
`7
`
`

`

`
`5.10 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 XR. If bullous pemphigoid is suspect