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--------------------------
`Indications and Usage (1)
`
`
`
` 4/2022
`----------------------------INDICATIONS AND USAGE---------------------------
`JENTADUETO 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)
`
`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)
`
`
`
`
`
`
`
`
`
`-------------------------------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, 5.4)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`-----------------------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)
`Hypoglycemia: Consider lowering the dose of insulin secretagogue or
`insulin to reduce the risk of hypoglycemia when initiating
`JENTADUETO (5.3)
`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. (5.4)
`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)
`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. (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 in patients who have known risk factors for heart
`failure. Monitor for signs and symptoms. (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 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 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
`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: 4/2022
`
`
`
`Reference ID: 4969584
`
`1
`
`

`

`_______________________________________________________________________________________________________________________________________
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: LACTIC ACIDOSIS
`1
`INDICATIONS AND USAGE
`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 Hypoglycemia with Concomitant Use with Insulin and Insulin
`Secretagogues
`5.4 Hypersensitivity Reactions
`5.5 Vitamin B12 Deficiency
`5.6 Severe and Disabling Arthralgia
`5.7 Bullous Pemphigoid
`5.8 Heart Failure
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.3 Females and Males of Reproductive Potential
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`
`
`Reference ID: 4969584
`
`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 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.
`
`Limitations of Use
`JENTADUETO should not be used in patients with type 1 diabetes.
`
`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.
`
`Recommended starting dose:
`
`In patients currently not treated with metformin HCl, initiate treatment with 2.5 mg linagliptin/500 mg metformin HCl twice daily.
`
`In patients already treated with metformin HCl, 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 HCl individual components may be switched to JENTADUETO containing the same doses of each
`component.
`
`
`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 tablets are a combination of linagliptin and metformin HCl available as:
`
`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
`
`
`
`
`
`CONTRAINDICATIONS
`4
`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 (5.4) and Adverse Reactions (6.1)].
`
`
`
`Reference ID: 4969584
`
`2
`
`

`

`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 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
`function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions (7)]. Therefore,
`consider more frequent monitoring of patients.
`
`Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic,
`renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)].
`
`Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function
`and the occurrence of lactic acidosis. Stop 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
`contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart JENTADUETO if renal function is stable.
`
`Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal
`impairment. JENTADUETO should be temporarily discontinued while patients have restricted food and fluid intake.
`
`Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when
`accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia
`have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue JENTADUETO.
`
`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 JENTADUETO.
`
`Hepatic Impairment: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance
`resulting in higher lactate blood levels. Therefore, avoid use of JENTADUETO in patients with clinical or laboratory evidence of hepatic disease.
`
`5.2 Pancreatitis
`Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with linagliptin. In the CARMELINA trial [see Clinical Studies (14)], acute
`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
`treated with linagliptin.
`
`Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue JENTADUETO and initiate appropriate
`management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using JENTADUETO.
`
`5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
`Insulin secretagogues and insulin are known to cause hypoglycemia. The risk of hypoglycemia is increased when JENTADUETO is used in combination with an insulin
`secretagogue (e.g., sulfonylurea) or insulin [see Adverse Reactions (6.1)]. 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.
`
`5.4 Hypersensitivity Reactions
`There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin. These 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
`
`
`
`Reference ID: 4969584
`
`3
`
`

`

`occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue JENTADUETO, assess for other potential causes for the event, and institute
`alternative treatment for diabetes.
`
`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
`inhibitor because it is unknown whether such patients will be predisposed to angioedema with JENTADUETO.
`
`5.5 Vitamin B12 Deficiency
`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
`metformin-treated 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 at 2 to
`3 year intervals in patients on JENTADUETO and manage any abnormalities [see Adverse Reactions (6.1)].
`
`5.6 Severe and Disabling Arthralgia
`There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug
`therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of
`symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if
`appropriate.
`
`5.7 Bullous Pemphigoid
`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
`Studies (14)], and 3 of these patients were hospitalized due to bullous pemphigoid. Postmarketing cases of bullous pemphigoid requiring hospitalization have been
`reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the
`DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving JENTADUETO. If bullous pemphigoid is suspected, JENTADUETO should
`be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
`
`5.8 Heart Failure
`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
`class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.
`
`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
`failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of
`JENTADUETO.
`
`ADVERSE REACTIONS
`6
`The following serious adverse reactions are described below or elsewhere in the prescribing information:
`
`Lactic Acidosis [see Warnings and Precautions (5.1)]
`
`Pancreatitis [see Warnings and Precautions (5.2)]
`
`Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.3)]
`
`Hypersensitivity Reactions [see Warnings and Precautions (5.4)]
`
`Vitamin B12 Deficiency [see Warnings and Precautions (5.5)]
`
`Severe and Disabling Arthralgia [see Warnings and Precautions (5.6)]
`
`Bullous Pemphigoid [see Warnings and Precautions (5.7)]
`Heart Failure [see Warnings and Precautions (5.8)]
`
`
`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.
`
`Linagliptin/Metformin
`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
`with type 2 diabetes mellitus treated for 12 weeks in clinical trials.
`
`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 placebo-
`controlled clinical studies, adverse reactions which occurred in ≥5% of patients receiving linagliptin + metformin (n=875) and were more common than in patients
`given placebo + metformin (n=539) included nasopharyngitis (5.7% vs 4.3%).
`
`
`
`
`Reference ID: 4969584
`
`4
`
`

`

`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.
`
`Table 1 Adverse Reactions Reported in 5% of Patients Treated with Linagliptin + Metformin and
`Greater than with Placebo in a 24-week Factorial-Design Study
`
`
`
`
`Adverse Reactions
`
`
`Placebo (%)
`n=72
`
`Linagliptin
`Monotherapy (%)
`n=142
`
`Metformin
`Monotherapy (%)
`n=291
`
`Combination of
`Linagliptin with Metformin
`(%)
`n=286
`6.3
`6.3
`
`Nasopharyngitis
`Diarrhea
`
`1.4
`2.8
`
`5.6
`3.5
`
`2.7
`3.8
`
`
`Other adverse reactions reported in clinical studies with treatment of linagliptin + metformin were hypersensitivity (e.g., urticaria, angioedema, or bronchial
`hyperreactivity), cough, decreased appetite, nausea, vomiting, pruritus, and pancreatitis.
`
`Linagliptin
`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%
`vs 6.1%), diarrhea (3.3% vs 3.0%), and cough (2.1% vs 1.4%).
`
`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 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 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 therapy.
`
`Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin
`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
`treated with linagliptin compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea).
`Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.
`
`Metformin
`The most common (>5%) established adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort,
`indigestion, asthenia, and headache.
`
`Hypoglycemia
`Linagliptin/Metformin
`In a 24-week factorial design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with
`metformin, and 1 (1.4%) of 72 subjects treated with placebo. The incidence of hypoglycemia with plasma glucose <54 mg/dL was 8.1% in the linagliptin group
`(N=792) compared to 5.3% in the placebo group (N=263) when administered in combination with metformin and sulfonylurea in a 24-week study.
`
`Linagliptin
`The incidence of severe hypoglycemia (requiring assistance) was 1.7% in the linagliptin group (N=631) compared to 1.1% in the placebo group (N=630) when
`administered in combination with basal insulin in a 52-week study.
`
`Laboratory Tests
`Linagliptin
`Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the linagliptin group and ≥1% more than in the placebo group were increases in
`uric acid (1.3% in the placebo group, 2.7% in the linagliptin group).
`
`Increase in Lipase: In a placebo-controlled clinical trial with linagliptin in type 2 diabetes mellitus patients with micro- or macroalbuminuria, a mean increase of 30% in
`lipase concentrations from baseline to 24 weeks was observed in the linagliptin arm compared to a mean decrease of 2% in the placebo arm. Lipase levels above 3 times
`upper limit of normal were seen in 8.2% compared to 1.7% patients in the linagliptin and placebo arms, respectively.
`
`Increase in Amylase: In a cardiovascular safety study comparing linagliptin versus glimepiride in patients with type 2 diabetes mellitus, amylase levels above 3 times
`upper limit of normal were seen in 1.0% compared to 0.5% of patients in the linagliptin and glimepiride arms, respectively.
`
`The clinical significance of elevations in lipase and amylase with linagliptin is unknown in the absence of potential signs and symptoms of pancreatitis [see Warnings
`and Precautions (5.2)].
`
`Metformin
`Decrease in Vitamin B12 : 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 patients.
`
`6.2 Postmarketing Experience
`The following adverse reactions have been identified during postapproval use. Because these reactions are reported voluntarily from a population of uncertain size, it is
`generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
`Linagliptin
`
`Acute pancreatitis, including fatal pancreatitis [see Indications and Usage (1)]
`
`Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions
`
`Severe and disabling arthralgia
`
`Bullous pemphigoid
`
`Rash
` Mouth ulceration, stomatitis
`
`Rhabdomyolysis
`
`
`
`Reference ID: 4969584
`
`5
`
`

`

`Metformin
`
`
`Cholestatic, hepatocellular, and mixed hepatocellular liver injury
`
`DRUG INTERACTIONS
`7
`Table 2 Clinically Relevant Interactions with JENTADUETO
`Carbonic Anhydrase Inhibitors
`Clinical Impact
`
`Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide)
`frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic
`acidosis. Concomitant use of these drugs with JENTADUETO may increase the risk of lactic acidosis.
`Consider more frequent monitoring of these patients.
`Intervention
`Drugs that Reduce Metformin Clearance
`Clinical Impact
`Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal
`elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion
`[MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic
`exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3)].
`Consider the benefits and risks of concomitant use.
`
`Alcohol is known to potentiate the effect of metformin on lactate metabolism.
`Warn patients against excessive alcohol intake while receiving JENTADUETO.
`
`Intervention
`Alcohol
`Clinical Impact
`Intervention
`Insulin or Insulin Secretagogues
`Clinical Impact
`
`The risk of hypoglycemia is increased