`
`
` 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 hydrochloride extended-
`
` release) tablets, for oral use
`
`
`
` Initial U.S. Approval: 2012
`
`
`
`
`
`
`
`
`
`
`
`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 XR 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 XR 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:
`
`
`
`• Not for the treatment of type 1 diabetes. (1)
`
`
`
`
`
`
`
`
`
`• Has not been studied in patients with a history of pancreatitis. (1,
`
`
`
`
`
`
`
`
`
`
`
`
`
` 5.2)
`
`• 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:
`
`
`
`• sitagliptin 100 mg and metformin HCl 1000 mg extended-release
`
`
`
`
`
`
`• sitagliptin 50 mg and metformin HCl 500 mg extended-release
`
`
`
`
`
`
`
`• sitagliptin 50 mg and metformin HCl 1000 mg extended-release (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 (e.g., anaphylaxis or
`
`
`
`
`
`
`
`
`
`
` angioedema) to JANUMET XR, sitagliptin, or metformin. (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 in patients treated with sitagliptin. If pancreatitis is
`
`
`
`
`
`
`
` suspected, promptly discontinue JANUMET XR. (5.2)
`
`
`
`
`
`
`• Heart Failure: Has been observed with two other members of the
`
`
`
`
`
`
`
`
`
`
`
`
` DPP-4 inhibitor class. Consider risks and benefits of JANUMET XR
`
`
`
`
`
`
`
`
`
` 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 XR 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 XR, 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 XR. (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.
`
`
`
`
`
`
`
`
`
`
` falls below
`
`
`
`
`
`
`
`
`
` ----------------------- DOSAGE AND ADMINISTRATION ----------------------­
`• Take JANUMET XR orally once daily with a meal. Patients taking
`
`
`
`
`
`
`
`
`
`
`
` two JANUMET XR tablets should take the tablets together. (2.1)
`
`
`
`
`
`
`
`
`• Individualize the dosage of JANUMET XR 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 extended-release. (2.1)
`
`
`
`
`
`• The recommended starting dose in patients not currently treated
`
`
`
`
`
`
`
`
`
`
` with metformin is 100 mg sitagliptin and 1000 mg metformin HCl
`
`
`
`
`
`
`
`
` once daily, with gradual dose escalation recommended to reduce
`
`
`
`
`
`
`
`
` the gastrointestinal effects due to metformin. (2.1)
`
`
`
`
`
`
`
`• The starting dose in patients already treated with metformin should
`
`
`
`
`
`
`
`
`
` provide sitagliptin dosed as 100 mg and the dose of metformin
`
`
`
`
`
`
`
`
`
`
`
`
` already being taken once daily. For patients taking metformin HCl
`
`
`
`
`
`
`
`
` 850 mg twice daily or 1000 mg twice daily, the recommended
`
`
`
`
`
`
`
`
`
`
` starting dose of JANUMET XR is two 50 mg sitagliptin and 1000 mg
`
`
`
`
`
`
`
`
`
`
`
`
` metformin HCl extended-release tablets once daily. (2.1)
`
`
`
`
`
`
`• Maintain the same total daily dose of sitagliptin and metformin when
`
`
`
`
`
`
`
`
`
`
`
` changing between JANUMET and JANUMET XR. (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.
`
`
`
`o Assess
`
`
`
` risk/benefit of continuing
`
` 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.
`
`
`
`
`
`
`
`
` if eGFR
`
`Reference ID: 4712165
`
`
`
`
`
`
`
` Revised: 12/2020
`
`
`
`

`

`
`
`
`
`
` 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
`
`
`
`
` 7 DRUG INTERACTIONS
`
`
`
`
`
`
`
`
`
`
` 8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`Lactation
`
`
` 8.2
`
`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: 4712165
`
`
`
`

`

`
` FULL PRESCRIBING INFORMATION
`
`
`
` WARNING: LACTIC ACIDOSIS
`
` in death,
`
`
`
`
`
`
`
` lactic acidosis have resulted
` Postmarketing cases of metformin-associated
` 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 XR
`
`
` and institute general supportive measures in a hospital setting. Prompt 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.
` Limitations of Use
`
`
`
`
` JANUMET XR should not be used in patients with type 1 diabetes mellitus.
`
`
`
` 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).]
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2
`
`
`
` DOSAGE AND ADMINISTRATION
`
`
`
`
`
`•
`
`
`
`
`
`
`
`
`
`
` 2.1 Recommended Dosing
`
`• Take JANUMET XR orally once daily with a meal. Patients taking two JANUMET XR tablets
`
`
`
`
`
`
`
`
`
` should take the two tablets together once daily.
`
`
`
` Individualize the dosage of JANUMET XR 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) extended-release.
`
`
`
`• The recommended starting dose in patients not currently treated with metformin is 100 mg
`
`
`
`
`
`
`
`
`
`
` sitagliptin and 1000 mg metformin HCl extended-release once 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 100 mg sitagliptin
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` and the previously prescribed dose of metformin.
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`
`• For patients taking metformin HCl immediate-release 850 mg twice daily or 1000 mg twice
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` daily, the recommended starting dose of JANUMET XR is two 50 mg sitagliptin and 1000 mg
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` metformin HCl extended-release tablets taken together once daily.
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`
`• Maintain the same total daily dose of sitagliptin and metformin when changing between
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` JANUMET (sitagliptin and metformin HCl immediate-release) and JANUMET XR.
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`• Do not split, crush or chew JANUMET XR tablets.
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` 3
`
`Reference ID: 4712165
`
`

`

`
`
`•
`
`
`•
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`
` 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)
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` below 30 mL/min/1.73 m2. Discontinue JANUMET XR if the patient’s eGFR later falls below
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` 30 mL/min/1.73 m2 [see Contraindications (4) and Warnings and Precautions (5.1)].
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`
`
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` Initiation of JANUMET XR in patients with an eGFR between 30 and 45 mL/min/1.73 m2 is not
`
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` recommended.
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`
` In patients taking JANUMET XR whose eGFR later falls below 45 mL/min/1.73 m2, assess the
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` benefit risk of continuing therapy and limit dose of the sitagliptin component to 50 mg once
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` daily.
` 2.3 Discontinuation for Iodinated Contrast Imaging Procedures
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` 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,
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` alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re­
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` evaluate eGFR 48 hours after the imaging procedure; restart JANUMET XR if renal function is stable [see
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`
` Warnings and Precautions (5.1)].
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`
` 3
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`
`
` DOSAGE FORMS AND STRENGTHS
`
`
`
`
` Tablets:
`• sitagliptin 100 mg and metformin HCl 1000 mg extended-release tablets are blue, bi-convex
`
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` oval, film-coated tablets with “81” debossed on one side.
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`
`
`• sitagliptin 50 mg and metformin HCl 500 mg extended-release tablets are light blue, bi-convex
`
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` oval, film-coated tablets with “78” debossed on one side.
`
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`
`
`• sitagliptin 50 mg and metformin HCl 1000 mg extended-release tablets are light green, bi­
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` convex oval, film-coated tablets with “80” debossed on one side.
`
`
`
`
` 4
`
`
`
` CONTRAINDICATIONS
`
`
` JANUMET XR is contraindicated in patients with:
`
`• Severe renal impairment (eGFR below 30 mL/min/1.73 m2) [see Warnings and Precautions (5.1)].
`
`
`
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`
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`• Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
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`• History of a serious hypersensitivity reaction to JANUMET XR, sitagliptin, or metformin such as
`
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` anaphylaxis or angioedema. [See Warnings and Precautions (5.7); Adverse Reactions (6.2).]
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`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
`
` 5.1 Lactic Acidosis
`
`
`
`
` There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases.
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` These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise,
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` myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia,
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` hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated
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` lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap
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` acidosis (without evidence of ketonuria or ketonemia), and an increased lactate/pyruvate ratio; metformin
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` plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate
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` blood levels which may increase the risk of lactic acidosis, especially in patients at risk.
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`
` 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-
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`
` treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is
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` recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with a
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` clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in
`
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` reversal of symptoms and recovery.
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` 4
`
`Reference ID: 4712165
`
`

`

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` 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 health care provider.
`
`
`
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`
`
`
` 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
`
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`
`
` below:
`
`
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`
`
` 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
`
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`
` lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted
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` by the kidney. Clinical recommendations based upon the patient’s renal function include [see Dosage and
`
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`
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`
`
`
`
`
` 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
`
`
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`
`
`
`
`
`
`
`
` 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
`
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`
`
`
`
` increased risk for the development of renal impairment (e.g., the elderly), renal function
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`should be assessed more frequently.
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`•
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`•
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` Drug Interactions
`
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` 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,
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`
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`
` interfere with acid-base balance or increase metformin accumulation [see Drug Interactions (7)].
`
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`
` 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,
`
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`
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`
`
`
`
`
` or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and
`
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` 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in
`
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`
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` patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the
`
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`
`
`
`
`
` imaging procedure, and restart JANUMET XR if renal function is stable.
`
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`
`
` 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 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
`
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`
`
`
`
` hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such
`
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`
`
`
`
`
`
` events occur, discontinue JANUMET XR.
`
`
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`
`
` 5
`
`Reference ID: 4712165
`
`

`

`
`
`
` 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 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
`
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`
`
`
`
`
`
`
`
` 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 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.
`
`
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`
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`
`
`
`
` Consider the risks and benefits of JANUMET XR 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
`
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`
`
`
`
` 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 XR.
`
`
`
`
`
` 5.4 Acute Renal Failure
` 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
`
`
`
`
`
`
`
`
`
` 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. JANUMET XR 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 XR and manage any abnormalities [see Adverse Reactions (6.1)].
`
`
`
`
`
` 5.6 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues
`
`
`
`
` JANUMET XR 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 XR [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 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
`
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`
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`
`
`
`
` 6
`
`Reference ID: 4712165
`
`

`

`
`
`
` 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 DPP-4 inhibitor because it is unknown
`
`
`
`
`
` whether such patients will be predisposed to angioedema with JANUMET XR.
`
`
`
` 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.
`
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`
`
`
`
`
`
`
`
`
` 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
`
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`
`
`
`
`
`
`
` erosions while receiving JANUMET XR. If bullous pemphigoid is suspected, JANUMET XR 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 Immediate-Release 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 immediate-release were c