`
`-------------------------------CONTRAINDICATIONS-----------------------------
`Severe renal impairment (eGFR below 30 mL/min/1.73 m2) (4)
`
`
`
`
`•
`• Metabolic acidosis, including diabetic ketoacidosis (4)
`
`
`
`Hypersensitivity to linagliptin, metformin, or any of the excipients in
`
`
`
`
`•
`JENTADUETO (4, 5.5)
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` These highlights do not include all the information needed to use
` JENTADUETO safely and effectively. See full prescribing information
`
`
`
` for JENTADUETO.
`
`
`
`
` JENTADUETO® (linagliptin and metformin hydrochloride 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 high risk groups are provided in the Full
`
`
`
` Prescribing Information. (5.1)
`
`
`
` If lactic acidosis is suspected, discontinue JENTADUETO and
`
`
` institute general supportive measures in a hospital setting.
`
`
`
` Prompt hemodialysis is recommended. (5.1)
`
`
`
`
`•
`
`
`•
`
`----------------------------RECENT MAJOR CHANGES-------------------------
`
`Warnings and Precautions
`
`
`
`Pancreatitis (5.2)
`7/2019
`
`
`Bullous Pemphigoid (5.8)
`7/2019
`
`
`Macrovascular Outcomes – Removed
`7/2019
`
`
`
`
`
`----------------------------INDICATIONS AND USAGE--------------------------
`
`JENTADUETO contains linagliptin, 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 treatment of type 1 diabetes or diabetic ketoacidosis (1)
`
`
`
`
`
`
`•
`Has not been studied in patients with a history of pancreatitis (1)
`
`
`
`
`•
`----------------------DOSAGE AND ADMINISTRATION----------------------
`Individualize the starting dose of JENTADUETO based on the patient's
`
`
`
`
`•
`current regimen (2.1)
`
`The maximum recommended dose is 2.5 mg linagliptin/1000 mg
`
`
`metformin HCl twice daily (2.1)
`
`
`
`
`Give twice daily with meals, with gradual dose escalation to reduce the
`
`
`
`gastrointestinal effects due to metformin (2.1)
`
`Prior to initiation, assess renal function with estimated glomerular
`
`
`filtration rate (eGFR) (2.2)
`
`o Do not use in patients with eGFR below 30 mL/min/1.73 m2
`
`
`
`
`
`
`o Initiation is not recommended in patients with eGFR between
`
`30 - 45 mL/min/1.73 m2
`
`o Assess risk/benefit of continuing if eGFR falls below
`
`
`
`
`45 mL/min/1.73 m2
`
`
`
`
`
`o Discontinue if eGFR falls below 30 mL/min/1.73 m2
`
`
`
`JENTADUETO may need to be discontinued at time of, or prior to,
`
`
`
`iodinated contrast imaging procedures (2.3)
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------
`
`Tablets:
`
`
`
`2.5 mg linagliptin/500 mg metformin HCl
`
`
`2.5 mg linagliptin/850 mg metformin HCl
`
`
`
`2.5 mg linagliptin/1000 mg metformin HCl (3)
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------
`Lactic acidosis: See boxed warning (5.1)
`
`
`
`
`•
`Pancreatitis: There have been reports of acute pancreatitis, including
`
`
`•
`fatal pancreatitis. If pancreatitis is suspected, promptly discontinue
`
`
`
`JENTADUETO. (5.2)
`
`Heart failure: Heart failure has been observed with two other members
`
`
`
`
`of the DPP-4 inhibitor class. Consider risks and benefits of
`
`
`
`
`JENTADUETO in patients who have known risk factors for heart
`
`
`
`failure. Monitor for signs and symptoms. (5.3)
`
`
`
`
`Hypoglycemia: When used with an insulin secretagogue (e.g.,
`
`
`
`
`sulfonylurea (SU)) or insulin, consider lowering the dose of the insulin
`
`
`
`
`secretagogue or insulin to reduce the risk of hypoglycemia (5.4)
`
`
`
`Hypersensitivity reactions: Serious hypersensitivity reactions (e.g.,
`
`
`
`
`anaphylaxis, angioedema, and exfoliative skin conditions) have occurred
`
`
`with JENTADUETO. If hypersensitivity reactions occur discontinue
`
`
`
`JENTADUETO, treat promptly, and monitor until signs and symptoms
`
`
`
`
`resolve. (5.5)
`
`Vitamin B12 deficiency: Metformin may lower vitamin B12 levels.
`
`
`
`
`Monitor hematologic parameters annually. (5.6)
`
`
`
`Arthralgia: 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. (5.7)
`
`
`
`Bullous pemphigoid: There have been reports of bullous pemphigoid
`
`
`
`requiring hospitalization. Tell patients to report development of blisters
`
`
`or erosions. If bullous pemphigoid is suspected, discontinue
`
`
`
`
`JENTADUETO. (5.8)
`
`------------------------------ADVERSE REACTIONS------------------------------
`Adverse reactions reported in ≥5% of patients treated with JENTADUETO
`
`
`
`
`and more commonly than in patients treated with placebo are nasopharyngitis
`
`
`
`
`and diarrhea (6.1)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Boehringer
`
`Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or 1-800-459-9906
`
`
`TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`
`------------------------------DRUG INTERACTIONS------------------------------
`
`
`Carbonic anhydrase inhibitors may increase risk of lactic acidosis.
`•
`
`
`Consider more frequent monitoring. (7.1)
`
`Drugs that reduce metformin clearance (such as ranolazine, vandetanib,
`
`
`dolutegravir, and cimetidine) may increase the accumulation of
`
`
`
`
`
`
`metformin. Consider the benefits and risks of concomitant use. (7.1)
`
`
`Alcohol can potentiate the effect of metformin on lactate metabolism.
`
`
`
`Warn patients against excessive alcohol intake. (7.1)
`
`
`
`Strong P-glycoprotein/CYP3A4 inducer: Efficacy may be reduced when
`
`
`
`administered in combination (e.g., rifampin). Use of alternative
`
`
`treatments is strongly recommended. (7.2)
`-----------------------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: 3/2020
`
`
`
`Reference ID: 4583067
`
`
`
` 1
`
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`
`
`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
`
`
`14.1 Glycemic Control Trials
`
`
`
`14.2 Linagliptin Cardiovascular Safety Trials
`
`
`
`
`
`
`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 Recommended Dosing in Renal Impairment
`
`
`
`
`
`2.3 Discontinuation for Iodinated Contrast Imaging Procedures
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Lactic Acidosis
`
`
`
`5.2 Pancreatitis
`
`
`
`5.3 Heart Failure
`
`
`
`5.4 Use with Medications Known to Cause Hypoglycemia
`
`
`
`
`5.5 Hypersensitivity Reactions
`
`
`
`5.6 Vitamin B12 Levels
`
`
`
`
`5.7 Severe and Disabling Arthralgia
`
`
`
`
`5.8 Bullous Pemphigoid
`
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Drug Interactions with Metformin
`
`
`
`
`7.2 Drug Interactions with Linagliptin
`
`
`
`
`7.3
`Insulin Secretagogues or Insulin
`
`
`
`
`
`7.4 Drugs Affecting Glycemic Control
`
`
`
`
`
`
`
`
`Reference ID: 4583067
`
`
`
` 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 (7.1), and Use in Specific Populations (8.6, 8.7)].
`
`
`
`
`
`
`
`If metformin-associated lactic acidosis is suspected, immediately discontinue JENTADUETO and institute general supportive measures in a hospital
`
`
`
`setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].
`
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`JENTADUETO is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Dosage and Administration (2.1)
`
`
`
`
`
`
`
`
`
`
`
`and Clinical Studies (14.1)].
`
`
`
`
`
`Limitations of Use
`
`JENTADUETO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.
`
`
`
`
`
`
`
`
`
`
`JENTADUETO has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for
`
`
`
`
`
`
`
`
`
`the development of pancreatitis while using JENTADUETO [see Warnings and Precautions (5.2)].
`
`
`
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`2.1 Recommended Dosing
`
`
`The dosage of JENTADUETO should be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended dose of 2.5
`
`
`
`
`
`
`
`
`
`mg linagliptin/1000 mg metformin hydrochloride (HCl) twice daily. JENTADUETO should be given twice daily with meals. Dose escalation should be gradual to
`
`
`
`
`
`
`
`
`
`
`
`
`reduce the gastrointestinal (GI) side effects associated with metformin use. For available dosage forms and strengths [see Dosage Forms and Strengths (3)].
`
`
`
`
`
`
`
`
`
`
`Recommended starting dose:
`
`
`In patients currently not treated with metformin, initiate treatment with 2.5 mg linagliptin/500 mg metformin HCl twice daily.
`
`
`
`
`
`
`
`
`
`
`
`
`
`•
`In patients already treated with metformin, start with 2.5 mg linagliptin and the current dose of metformin HCl taken at each of the two daily meals (e.g., a patient
`
`
`
`
`
`
`
`
`
`
`
`
`•
`on metformin HCl 1000 mg twice daily would be started on 2.5 mg linagliptin/1000 mg metformin HCl twice daily with meals).
`
`
`
`
`
`
`
`
`
`Patients already treated with linagliptin and metformin individual components may be switched to JENTADUETO containing the same doses of each component.
`
`
`
`
`
`
`
`
`
`
`
`
`
`•
`
`No studies have been performed specifically examining the safety and efficacy of JENTADUETO in patients previously treated with other oral antihyperglycemic
`
`
`
`
`
`
`agents and switched to JENTADUETO. Any change in therapy of type 2 diabetes mellitus should be undertaken with care and appropriate monitoring as changes in
`
`
`
`
`
`
`
`
`glycemic control can occur.
`
`
`2.2 Recommended Dosing in Renal Impairment
`
`
`
`Assess renal function prior to initiation of JENTADUETO and periodically thereafter.
`
`
`
`
`JENTADUETO is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2.
`
`
`
`
`
`
`
`
`
`
`
`Initiation of JENTADUETO in patients with an eGFR between 30-45 mL/min/1.73 m2 is not recommended.
`
`
`
`
`In patients taking JENTADUETO whose eGFR later falls below 45 mL/min/1.73 m2, assess benefit risk of continuing therapy.
`
`
`
`
`
`Discontinue JENTADUETO if the patient’s eGFR later falls below 30 mL/min/1.73 m2 [see Contraindications (4) and Warnings and Precautions (5.1)].
`
`
`
`
`
`
`2.3 Discontinuation for Iodinated Contrast Imaging Procedures
`
`
`
`
`Discontinue JENTADUETO 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 JENTADUETO if renal function is stable [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`JENTADUETO is a combination of linagliptin and metformin HCl. JENTADUETO tablets are available in the following dosage forms and strengths:
`
`
`
`
`
`
`
`
`
`2.5 mg linagliptin/500 mg metformin HCl tablets are light yellow, oval, biconvex tablets debossed with “D2/500” on one side and the Boehringer Ingelheim logo
`
`
`
`
`
`
`
`•
`on the other side
`
`2.5 mg linagliptin/850 mg metformin HCl tablets are light orange, oval, biconvex tablets debossed with “D2/850” on one side and the Boehringer Ingelheim logo
`
`
`
`
`
`
`on the other side
`
`2.5 mg linagliptin/1000 mg metformin HCl tablets are light pink, oval, biconvex tablets debossed with “D2/1000” on one side and the Boehringer Ingelheim logo
`
`
`
`
`
`
`
`
`
`on the other side
`
`
`
`•
`
`
`•
`
`
`
`Reference ID: 4583067
`
`
`
` 3
`
`
`
` 4
` CONTRAINDICATIONS
`
`
`
`
`
` JENTADUETO 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. [see Warnings and Precautions (5.1)]
`
`•
`
`
`
`
`
`
`
`Hypersensitivity to linagliptin, metformin, or any of the excipients in JENTADUETO, reactions such as anaphylaxis, angioedema, exfoliative skin conditions,
`•
`
`
`
`
`
`urticaria, or bronchial hyperreactivity have occurred with linagliptin [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)]
`
`
`
`
`
`
`
`WARNINGS AND PRECAUTIONS
`5
`
`
`5.1 Lactic Acidosis
`
`Metformin
`
`
`
`
`
`
`
`
`
`
`
`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 generally >5 mcg/mL. Metformin
`
`
`
`
`
`
`decreases liver uptake of lactate increasing lactate blood levels which may increase 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 JENTADUETO. In JENTADUETO-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 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 JENTADUETO and report these
`
`symptoms to their healthcare 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 the patient’s renal function include [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]:
`
`
`
`
`
`
`
`
`• Before initiating JENTADUETO, obtain an estimated glomerular filtration rate (eGFR).
`
`
`
`•
`JENTADUETO is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Contraindications (4)].
`
`
`
`•
`Initiation of JENTADUETO is not recommended in patients with eGFR between 30 – 45 mL/min/1.73 m2.
`
`
`
`
`
`
`
`
`
`
`
`• Obtain an eGFR at least annually in all patients taking JENTADUETO. In patients at increased risk for the development of renal impairment (e.g., the
`
`
`
`elderly), renal function should be assessed more frequently.
`
`
`•
`In patients taking JENTADUETO whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Drug Interactions: The concomitant use of JENTADUETO with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal
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`function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions (7.1)]. Therefore,
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`consider more frequent monitoring of patients.
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`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,
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`renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)].
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`Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function
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`and the occurrence of lactic acidosis. Stop JENTADUETO 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
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`contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart JENTADUETO 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
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`impairment. JENTADUETO should be temporarily discontinued while patients have restricted food and fluid intake.
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`Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when
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`accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia
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`have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue JENTADUETO.
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`Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis.
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`Warn patients against excessive alcohol intake while receiving JENTADUETO.
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`Hepatic Impairment: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance
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`resulting in higher lactate blood levels. Therefore, avoid use of JENTADUETO in patients with clinical or laboratory evidence of hepatic disease.
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`5.2 Pancreatitis
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`Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with linagliptin. In the CARMELINA trial [see Clinical Studies (14.2)], acute
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`pancreatitis was reported in 9 (0.3%) patients treated with linagliptin and in 5 (0.1%) patients treated with placebo. Two patients treated with linagliptin in the
`CARMELINA trial had acute pancreatitis with a fatal outcome. There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients
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`treated with linagliptin.
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`Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue JENTADUETO and initiate appropriate
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`management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using JENTADUETO.
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`Reference ID: 4583067
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` 4
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` 5.3 Heart Failure
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` An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor
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` class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.
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` Consider the risks and benefits of JENTADUETO 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
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` failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of
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` JENTADUETO.
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` 5.4 Use with Medications Known to Cause Hypoglycemia
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` Insulin secretagogues and insulin are known to cause hypoglycemia. The use of linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin
` was associated with a higher rate of hypoglycemia compared with placebo in clinical trials [see Adverse Reactions (6.1)]. Metformin may increase the risk of
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` hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the
` risk of hypoglycemia when used in combination with JENTADUETO [see Drug Interactions (7.3)].
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` 5.5 Hypersensitivity Reactions
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` There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin (one of the components of JENTADUETO). These
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` reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred predominantly within the first 3 months after initiation of
` treatment with linagliptin, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue JENTADUETO, assess for
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` other potential causes for the event, and institute alternative treatment for diabetes.
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` Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema to another DPP-4
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` inhibitor because it is unknown whether such patients will be predisposed to angioedema with JENTADUETO.
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` 5.6 Vitamin B12 Levels
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`In controlled, 29-week clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was
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`observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex,
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`may be associated with anemia or neurologic manifestations. This risk may be more relevant to patients receiving long-term treatment with metformin, and adverse
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`hematologic and neurologic reactions have been reported postmarketing. The decrease in vitamin B12 levels appears to be rapidly reversible with discontinuation of
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`metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis and routine serum vitamin B12 measurement at 2- to 3-year
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`intervals is advised in patients on JENTADUETO and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with
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`inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels.
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`5.7 Severe and Disabling Arthralgia
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`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
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`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
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`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
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`appropriate.
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`5.8 Bullous Pemphigoid
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`Bullous pemphigoid was reported in 7 (0.2%) patients treated with linagliptin compared to none in patients treated with placebo in the CARMELINA trial [see Clinical
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`Studies (14.2)], and 3 of these patients were hospitalized due to bullous pemphigoid. Postmarketing cases of bullous pemphigoid requiring hospitalization have been
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`reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the
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`DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving JENTADUETO. If bullous pemphigoid is suspected, JENTADUETO should
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`be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
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`ADVERSE REACTIONS
`6
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`The following serious adverse reactions are described below or elsewhere in the prescribing information:
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`Lactic Acidosis [see Warnings and Precautions (5.1)]
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`Pancreatitis [see Warnings and Precautions (5.2)]
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`Heart Failure [see Warnings and Precautions (5.3)]
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`Use with Medications Known to Cause Hypoglycemia [see Warnings and Precautions (5.4)]
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`Hypersensitivity Reactions [see Warnings and Precautions (5.5)]
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`Vitamin B12 Levels [see Warnings and Precautions (5.6)]
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`Severe and Disabling Arthralgia [see Warnings and Precautions (5.7)]
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`Bullous Pemphigoid [see Warnings and Precautions (5.8)]
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`•
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`6.1 Clinical Trials Experience
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`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
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`in the clinical trials of another drug and may not reflect the rates observed in practice.
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`Linagliptin/Metformin
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`The safety of concomitantly administered linagliptin (daily dose 5 mg) and metformin (mean daily dose of approximately 1800 mg) has been evaluated in 2816 patients
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`with type 2 diabetes mellitus treated for ≥12 weeks in clinical trials.
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`Three placebo-controlled studies with linagliptin + metformin were conducted: 2 studies were 24 weeks in duration, 1 study was 12 weeks in duration. In the 3
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`placebo-controlled clinical studies, adverse reactions which occurred in ≥5% of patients receiving linagliptin + metformin (n=875) and were more common than in
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`patients given placebo + metformin (n=539) included nasopharyngitis (5.7% vs 4.3%).
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`Reference ID: 4583067
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` 5
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` In a 24-week factorial design study, adverse reactions reported in ≥5% of patients receiving linagliptin + metformin and were more common than in patients given
` placebo are shown in Table 1.
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`Table 1 Adverse Reactions Reported in ≥5% of Patients Treated with Linagliptin + Metformin and
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`Greater than with Placebo in a 24-week Factorial-Design Study
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` Placebo
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` n=72
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`Nasopharyngitis
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`Diarrhea
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` n (%)
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` 1 (1.4)
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` 2 (2.8)
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` Linagliptin
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` Monotherapy
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` n=142
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` n (%)
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` 8 (5.6)
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` 5 (3.5)
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` Metformin
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` Monotherapy
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` n=291
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` n (%)
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` 8 (2.7)
` 11 (3.8)
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` Combination of
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` Linagliptin with Metformin
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` n=286
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` n (%)
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` 18 (6.3)
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` 18 (6.3)
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`Other adverse reactions reported in clinical studies with treatment of linagliptin + metformin were hypersensitivity (e.g., urticaria, angioedema, or bronchial
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`hyperreactivity), cough, decreased appetite, nausea, vomiting, pruritus, and pancreatitis.
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`Linagliptin
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`Adverse reactions reported in ≥2% of patients treated with linagliptin 5 mg and more commonly than in patients treated with placebo included: nasopharyngitis (7.0%
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`vs 6.1%), diarrhea (3.3% vs 3.0%), and cough (2.1% vs 1.4%).
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`Rates for other adverse reactions for linagliptin 5 mg vs placebo when linagliptin was used in combination with specific anti-diabetic agents were: urinary tract
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`infection (3.1% vs 0%) and hypertriglyceridemia (2.4% vs 0%) when linagliptin was used as add-on to sulfonylurea; hyperlipidemia (2.7% vs 0.8%) and weight
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`increased (2.3% vs 0.8%) when linagliptin was used as add-on to pioglitazone; and constipation (2.1% vs 1%) when linagliptin was used as add-on to basal insulin
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`therapy.
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`Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin
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`exfoliation, or bronchial hyperreactivity) and myalgia. In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being
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`treated with linagliptin compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea).
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`Three additional cases of pancreatitis were reported foll