HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
`
` These highlights do not include all the information needed to use
` JENTADUETO XR safely and effectively. See full prescribing
`
`
`
`
` information for JENTADUETO XR.
`
`
`
`
`
`
`JENTADUETO® XR (linagliptin and metformin hydrochloride
`
`
`
`extended-release tablets), for oral use
`
`
`Initial U.S. Approval: 2012
`
`
`
`
`
`x
`
`
`x
`
` WARNING: LACTIC ACIDOSIS
`
`
`
`See full prescribing information for complete boxed warning.
` Postmarketing cases of metformin-associated lactic acidosis
`
`
`
`x
` 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 XR
` and institute general supportive measures in a hospital setting.
`
`
`
`
`Prompt hemodialysis is recommended. (5.1)
`
`
`
`
`
`
`
`
`
`
` ----------------------------RECENT MAJOR CHANGES--------------------------
`
`
` 10/2021
`
`
`
` Indications and Usage, Limitations of Use (1)
`
` Dosage and Administration, Recommended Dosing (2.1)
`
` 10/2021
`
`----------------------------INDICATIONS AND USAGE---------------------------
`
`
`
`
`
` JENTADUETO XR is a combination of 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 (1)
`
`
`
`
`x
`
`Has not been studied in patients with a history of pancreatitis (1)
`
`
`
`
`x
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`
`Individualize the starting dose of JENTADUETO XR based on the
`
`
`
`
`x
`patient's current regimen (2.1)
`
`
`Do not exceed a total daily dose of linagliptin 5 mg and metformin 2000
`
`
`
`
`
`mg (2.1)
`
`Give once daily with a meal (2.1)
`
`
`Swallow whole; do not split, crush, dissolve, or chew (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 XR may need to be discontinued at time of, or prior to,
`
`
`iodinated contrast imaging procedures (2.3)
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`
`Tablets:
`
`
`
`5 mg linagliptin/1000 mg metformin HCl extended-release
`
`
`
`
`
`2.5 mg linagliptin/1000 mg metformin HCl extended-release (3)
`
`
`
`x
`
`
`x
`
`x
`
`x
`
`
`x
`
`-------------------------------CONTRAINDICATIONS------------------------------
`
`Severe renal impairment (eGFR below 30 mL/min/1.73 m2) (4)
`
`
`x
`
`x Metabolic acidosis, including diabetic ketoacidosis (4)
`
`
`
`
`Hypersensitivity to linagliptin, metformin, or any of the excipients in
`
`
`
`x
`JENTADUETO XR (4, 5.4)
`
`
`
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`
`Lactic acidosis: See boxed warning (5.1)
`
`
`
`x
`
`Pancreatitis: There have been reports of acute pancreatitis, including
`
`
`
`
`
`x
`fatal pancreatitis. If pancreatitis is suspected, promptly discontinue
`
`
`
`
`JENTADUETO XR. (5.2)
`
`
`
`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 (5.3)
`
`
`
`
`
`Hypersensitivity reactions: Serious hypersensitivity reactions (e.g.,
`
`
`anaphylaxis, angioedema, and exfoliative skin conditions) have occurred
`
`
`
`with JENTADUETO XR. If hypersensitivity reactions occur discontinue
`
`
`
`
`
`
`
`JENTADUETO XR, treat promptly, and monitor until signs and
`
`
`symptoms resolve. (5.4)
`
`
`
`
`
`
`Vitamin B12 deficiency: Metformin may lower vitamin B12 levels.
`
`
`Monitor hematologic parameters annually. (5.5)
`
`
`
`
`
`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. (5.6)
`
`
`
`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 XR. (5.7)
`
`
`
`Heart failure: Heart failure has been observed with two other members
`
`
`of the DPP-4 inhibitor class. Consider risks and benefits of
`
`
`
`
`
`JENTADUETO XR in patients who have known risk factors for heart
`
`
`
`failure. Monitor for signs and symptoms. (5.8)
`
`------------------------------ADVERSE REACTIONS-------------------------------
`
`
`
`
`
`
`
`
`Adverse reactions reported in t5% of patients treated with linagliptin and
`
`
`
`
`
`
`
`metformin coadministered 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 FDA at 1-800-FDA-
`
`1088 or www.fda.gov/medwatch.
`------------------------------DRUG INTERACTIONS-------------------------------
`
`
`Carbonic anhydrase inhibitors may increase risk of lactic acidosis.
`
`
`
`
`
`x
`Consider more frequent monitoring. (7)
`
`Drugs that reduce metformin clearance (such as ranolazine, vandetanib,
`
`
`
`dolutegravir, and cimetidine) may increase the accumulation of
`
`
`
`
`
`metformin. Consider the benefits and risks of concomitant use. (7)
`
`
`Alcohol can potentiate the effect of metformin on lactate metabolism.
`
`
`
`
`
`Warn patients against excessive alcohol intake. (7)
`
`
`
`
`Strong P-glycoprotein/CYP3A4 inducer: Efficacy may be reduced when
`
`
`
`
`administered in combination (e.g., rifampin). Use of alternative
`
`
`treatments is strongly recommended. (7)
`
`
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`
`
`
`Females and Males of Reproductive Potential: Advise premenopausal
`
`
`
`x
`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)
`
`
`
`
`
`
`
`
`
`
`
`x
`
`
`x
`
`
`x
`
`
`x
`
`
`x
`
`
`x
`
`
`x
`
`
`x
`
`
`x
`
`
`x
`
`x
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`Guide.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Revised:
`10/2021
`
`
`
`
`
`
`
`Reference ID: 4865976
`
`1
`
`

`

`_______________________________________________________________________________________________________________________________________
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: LACTIC ACIDOSIS
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`
`INDICATIONS AND USAGE
`1
`
`8.1 Pregnancy
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`8.2 Lactation
`
`
`2.1 Recommended Dosing
`
`8.3 Females and Males of Reproductive Potential
`
`
`
`
`
`
`2.2 Recommended Dosing in Renal Impairment
`
`8.4 Pediatric Use
`
`
`
`
`
`
`2.3 Discontinuation for Iodinated Contrast Imaging Procedures
`
`8.5 Geriatric Use
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`8.6 Renal Impairment
`
`
`
`
`4 CONTRAINDICATIONS
`
`8.7 Hepatic Impairment
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`10 OVERDOSAGE
`
`
`5.1 Lactic Acidosis
`
`11 DESCRIPTION
`
`
`
`5.2 Pancreatitis
`
`12 CLINICAL PHARMACOLOGY
`
`
`
`
`5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin
`
`12.1 Mechanism of Action
`
`
`Secretagogues
`
`12.2 Pharmacodynamics
`
`
`
`5.4 Hypersensitivity Reactions
`
`12.3 Pharmacokinetics
`
`
`
`
`5.5 Vitamin B12 Deficiency
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`
`
`
`5.6 Severe and Disabling Arthralgia
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`
`
`
`
`5.7 Bullous Pemphigoid
`
`14 CLINICAL STUDIES
`
`
`
`
`5.8 Heart Failure
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
`
`6 ADVERSE REACTIONS
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`
`
`7 DRUG INTERACTIONS
`listed.
`
`
`
`
`
`
`
`Reference ID: 4865976
`
`2
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
` WARNING: LACTIC ACIDOSIS
`
`
`
`
`
`
`
`
`
`
` Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The
`
` onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress,
`
`
`
`
`
`
` somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap
`
`
`
`
`
`
`
`
`
` acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see
`
`
`
`
`
`
`
`
`
`
`
` Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`
`
`
` Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors
`
` such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute
`
`
`
`
`
`
`
`
`
`
`
`
` congestive heart failure), excessive alcohol intake, and hepatic impairment.
`
`
`
`
`
`
`
` Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see
`
`
`
`
`
`
` Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)].
`
`
`
`
` If metformin-associated lactic acidosis is suspected, immediately discontinue JENTADUETO XR and institute general supportive measures in a hospital
`
`
`
`
`
`
`
` setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`
`
`
`
`1
`INDICATIONS AND USAGE
`
`
`
`
`
`
`JENTADUETO XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
`
`
`
`Limitations of Use
`
`
`
`
`
`JENTADUETO XR should not be used in patients with type 1 diabetes.
`
`
`
`
`
`
`
`
`
`
`
`
`JENTADUETO XR 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 XR [see Warnings and Precautions (5.2)].
`
`
`
`
`
`
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosing
`
`
`
`
`
`
`
`
`
`
`The dosage of JENTADUETO XR should be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended total
`
`
`
`
`
`
`
`
`daily dose of linagliptin 5 mg and metformin hydrochloride (HCl) 2000 mg. JENTADUETO XR should be given once daily with a meal.
`
`
`Recommended starting dose:
`
`
`
`
`
`
`
`
`
`
`
`
`In patients currently not treated with metformin, initiate JENTADUETO XR treatment with 5 mg linagliptin/1000 mg metformin HCl extended-release once daily
`x
`
`with a meal.
`
`
`
`
`
`
`
`
`
`In patients already treated with metformin, start JENTADUETO XR with 5 mg of linagliptin total daily dose and a similar total daily dose of metformin HCl once
`
`daily with a meal.
`
`
`
`
`
`
`
`
`
`
`
`In patients already treated with linagliptin and metformin or JENTADUETO, switch to JENTADUETO XR containing 5 mg of linagliptin total daily dose and a
`
`
`
`
`
`
`similar total daily dose of metformin HCl once daily with a meal.
`
`
`x
`
`
`x
`
`
`
`
`
`
`
`
`
`
`JENTADUETO XR should be swallowed whole. The tablets must not be split, crushed, dissolved, or chewed.
`
`
`
`
`
`
`JENTADUETO XR 5 mg linagliptin/1000 mg metformin HCl extended-release tablet should be taken as a single tablet once daily. Patients using 2.5 mg
`
`
`
`
`
`
`
`
`
`linagliptin/1000 mg metformin HCl extended-release tablets should take two tablets together once daily.
`
`
`
`
`2.2 Recommended Dosing in Renal Impairment
`
`
`
`
`
`
`
`Assess renal function prior to initiation of JENTADUETO XR and periodically thereafter.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`JENTADUETO XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2.
`
`
`
`
`
`
`
`
`
`Initiation of JENTADUETO XR in patients with an eGFR between 30-45 mL/min/1.73 m2 is not recommended.
`
`
`
`
`
`
`
`
`In patients taking JENTADUETO XR whose eGFR later falls below 45 mL/min/1.73 m2, assess benefit/risk of continuing therapy.
`
`
`
`
`
`
`
`
`
`
`
`Discontinue JENTADUETO XR 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 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 JENTADUETO XR if renal function is stable [see Warnings and Precautions (5.1)].
`
`
`
`3
`DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
`
`
`JENTADUETO XR tablets are a combination of linagliptin and extended-release metformin HCl available as:
`
`
`
`
`
`
`
`
`
`
`
`5 mg/1000 mg are white, oval-shaped coated tablets with one side printed in black ink with the Boehringer Ingelheim logo and “D5” on the top line and “1000 M”
`x
`
`
`on the bottom line.
`
`
`
`
`
`
`
`
`
`
`
`
`
`2.5 mg/1000 mg are yellow, oval-shaped coated tablets with one side printed in black ink with the Boehringer Ingelheim logo and “D2” on the top line and
`
`
`
`
`“1000 M” on the bottom line.
`
`
`x
`
`
`4
`CONTRAINDICATIONS
`
`
`
`
`JENTADUETO XR is contraindicated in patients with:
`
`
`
`Severe renal impairment (eGFR below 30 mL/min/1.73 m2) [see Warnings and Precautions (5.1)].
`x
`
`
`
`
`Acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.1)].
`
`
`x
`
`
`3
`
`Reference ID: 4865976
`
`

`

`
`x
`
`Hypersensitivity to linagliptin, metformin, or any of the excipients in JENTADUETO XR, reactions such as anaphylaxis, angioedema, exfoliative skin conditions,
`
`
`
`
`
`
`
`
`
`urticaria, or bronchial hyperreactivity have occurred with linagliptin [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].
`
`
`5
`WARNINGS AND PRECAUTIONS
`
`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 XR. In JENTADUETO 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 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 XR 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 XR, obtain an estimated glomerular filtration rate (eGFR).
`•
`
`
`
`
`
`
`
`JENTADUETO XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Contraindications (4)].
`•
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`Initiation of JENTADUETO XR is not recommended in patients with eGFR between 30 – 45 mL/min/1.73 m2.
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`• Obtain an eGFR at least annually in all patients taking JENTADUETO XR. In patients at increased risk for the development of renal impairment (e.g.,
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`the elderly), renal function should be assessed more frequently.
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`In patients taking JENTADUETO XR whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.
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`Drug Interactions: The concomitant use of JENTADUETO XR 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)]. 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 XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30
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`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 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
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`impairment. JENTADUETO XR 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 XR.
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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 XR.
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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 XR 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)], 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
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`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 XR 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 XR.
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`5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
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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
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`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
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`risk of hypoglycemia when used in combination with JENTADUETO XR [see Drug Interactions (7)].
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`Reference ID: 4865976
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`4
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`

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`5.4 Hypersensitivity Reactions
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`There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin. These reactions include anaphylaxis, angioedema, and
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`exfoliative skin conditions. Onset of these reactions occurred predominantly within the first 3 months after initiation of treatment with linagliptin, with some reports
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`occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue JENTADUETO XR, assess for other potential causes for the event, and
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`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 XR.
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`5.5 Vitamin B12 Deficiency
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`In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of
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`metformin-treated patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but
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`appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium
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`intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2 to
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`3 year intervals in patients on JENTADUETO XR and manage any abnormalities [see Adverse Reactions (6.1)].
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`5.6 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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`5.7 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)], 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 XR. If bullous pemphigoid is suspected, JENTADUETO
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`XR should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
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`5.8 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 XR prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure
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`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
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`heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider
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`discontinuation of JENTADUETO XR.
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`6
`ADVERSE REACTIONS
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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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`Use with Medications Known to Cause Hypoglycemia [see Warnings and Precautions (5.3)]
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`x
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`Hypersensitivity Reactions [see Warnings and Precautions (5.4)]
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`x
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`Vitamin B12 Deficiency [see Warnings and Precautions (5.5)]
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`x
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`Severe and Disabling Arthralgia [see Warnings and Precautions (5.6)]
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`x
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`Bullous Pemphigoid [see Warnings and Precautions (5.7)]
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`x
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`Heart Failure [see Warnings and Precautions (5.8)]
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`x
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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 t12 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: 4865976
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`5
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`

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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
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` placebo are shown in Table 1.
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`Table 1 Adverse Reactions Reported in tt5% 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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`Adverse Reactions
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` Placebo (%)
` n=72
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` Nasopharyngitis
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` Diarrhea
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` 1.4
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` 2.8
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`Linagliptin
` Monotherapy (%)
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`n=142
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` 5.6
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` 3.5
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` Metformin
` Monotherapy (%)
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`n=291
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` 2.7
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` 3.8
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` Combination of
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` Linagliptin with Metformin
`(%)
`n=286
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` 6.3
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` 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 antidiabetic agents were: urinary tract infection
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`(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 increased (2.3%
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`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 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 following the last administered dose of linagliptin.
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`Metformin
`The most common adverse reactions due to initiation of metformin are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and
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`headache.
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`In a 24-week clinical trial in which extended-release metformin or placebo was added to g