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)
`
`•
`
`•
`
`•
`
`•
`
`•
`
`----------------------------INDICATIONS AND USAGE---------------------------
`JENTADUETO is a dipeptidyl peptidase-4 (DPP-4) inhibitor and biguanide
`combination product indicated as an adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus when treatment with
`both linagliptin and metformin is appropriate (1.1)
`
`Important limitations of use:
`Not for treatment of type 1 diabetes or diabetic ketoacidosis (1.2)
`•
`Has not been studied in patients with a history of pancreatitis (1.2)
`•
`----------------------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 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 hydrochloride
`2.5 mg linagliptin/850 mg metformin hydrochloride
`2.5 mg linagliptin/1000 mg metformin hydrochloride (3)
`
`•
`
`-------------------------------CONTRAINDICATIONS------------------------------
`Severe renal impairment (eGFR below 30 mL/min/1.73 m2) (4)
`•
`• Metabolic acidosis, including diabetic ketoacidosis (4)
`History of hypersensitivity reaction to linagliptin, such as anaphylaxis,
`•
`angioedema, exfoliative skin conditions, urticaria, or bronchial
`hyperreactivity (4)
`Hypersensitivity to metformin (4)
`
`•
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`Lactic acidosis: See boxed warning (5.1)
`•
`There have been postmarketing 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)
`There have been postmarketing reports of serious hypersensitivity
`reactions in patients treated with linagliptin (one of the components of
`JENTADUETO) including anaphylaxis, angioedema, and exfoliative
`skin conditions. In such cases, promptly discontinue JENTADUETO,
`assess for other potential causes, institute appropriate monitoring and
`treatment, and initiate alternative treatment for diabetes. (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 postmarketing reports of bullous
`pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors.
`Tell patients to report development of blisters or erosions. If bullous
`pemphigoid is suspected, discontinue JENTADUETO. (5.8)
`• Macrovascular outcomes: No conclusive evidence of macrovascular
`risk reduction with JENTADUETO (5.9)
`------------------------------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)
`Hypoglycemia was more commonly reported in patients treated with the
`combination of JENTADUETO and SU compared with those treated
`with the combination of SU and metformin (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: 7/2019
`
`
`
`Reference ID: 4456135
`
`1
`
`

`

`
`_______________________________________________________________________________________________________________________________________
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: LACTIC ACIDOSIS
` INDICATIONS AND USAGE
`1
`Indication
`1.1
`1.2
`Important Limitations of Use
`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
`5.9 Macrovascular Outcomes
`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
`Insulin Secretagogues and Insulin
`7.3
`7.4 Drugs Affecting Glycemic Control
`
`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 Initial Combination Therapy with Linagliptin and Metformin
`14.2 Initial Combination Therapy with Linagliptin and Metformin vs
`Linagliptin in Treatment-Naïve Patients
`14.3 Add-On Combination Therapy with Metformin
`14.4 Active-Controlled Study vs Glimepiride in Combination with
`Metformin
`14.5 Add-On Combination Therapy with Metformin and a
`Sulfonylurea
`14.6 Add-On Combination Therapy with Insulin
`14.7 Renal Impairment
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`
`
`Reference ID: 4456135
`
`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
`1.1 Indication
`JENTADUETO is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin
`and metformin is appropriate [see Dosage and Administration (2.1) and Clinical Studies (14.1)].
`
`1.2 Important 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 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 hydrochloride twice daily
`•
`In patients already treated with metformin, start with 2.5 mg linagliptin and the current dose of metformin taken at each of the two daily meals (e.g., a patient on
`•
`metformin 1000 mg twice daily would be started on 2.5 mg linagliptin/1000 mg metformin hydrochloride 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 hydrochloride. JENTADUETO tablets are available in the following dosage forms and strengths:
`2.5 mg linagliptin/500 mg metformin hydrochloride 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 hydrochloride 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 hydrochloride 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: 4456135
`
`3
`
`

`

`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. Diabetic ketoacidosis should be treated with insulin [see Warnings and Precautions (5.1)]
`•
`A history of hypersensitivity reaction to linagliptin, such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity [see
`•
`Warnings and Precautions (5.5) and Adverse Reactions (6.1)]
`Hypersensitivity to metformin
`
`•
`
`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
`function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions (7.1)]. 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
`There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients taking 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 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
`
`
`4
`
`Reference ID: 4456135
`
`

`

`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.
`
`5.4 Use with Medications Known to Cause Hypoglycemia
`Linagliptin
`Insulin secretagogues and insulin are known to cause hypoglycemia. The use of linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) was
`associated with a higher rate of hypoglycemia compared with placebo in a clinical trial [see Adverse Reactions (6.1)]. The use of linagliptin in combination with insulin
`in subjects with severe renal impairment was associated with a higher rate of hypoglycemia [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 [see Drug Interactions (7.3)].
`
`Metformin
`Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous
`exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as SUs and insulin) or ethanol. Elderly,
`debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects.
`Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking β-adrenergic blocking drugs.
`
`5.5 Hypersensitivity Reactions
`There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin (one of the components of JENTADUETO). These
`reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred 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 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.
`
`5.6 Vitamin B12 Levels
`In controlled, 29-week clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was
`observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is,
`however, very rarely associated with anemia or neurologic manifestations due to the short duration (<1 year) of the clinical trials. This risk may be more relevant to
`patients receiving long-term treatment with metformin, and adverse hematologic and neurologic reactions have been reported postmarketing. The decrease in vitamin
`B12 levels appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual
`basis is advised in patients on JENTADUETO and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with
`inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin
`B12 measurement at 2- to 3-year intervals may be useful.
`
`5.7 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.
`
`5.8 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.
`
`5.9 Macrovascular Outcomes
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with linagliptin or metformin.
`
`ADVERSE REACTIONS
`6
`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 events 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%).
`
`In a 24-week factorial design study, adverse events 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
`
`Placebo
`n=72
`
`n (%)
`1 (1.4)
`
`Linagliptin
`Monotherapy
`n=142
`n (%)
`8 (5.6)
`
`Metformin
`Monotherapy
`n=291
`n (%)
`8 (2.7)
`
`Combination of
`Linagliptin with Metformin
`n=286
`n (%)
`18 (6.3)
`
`5
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`Nasopharyngitis
`
`
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`Reference ID: 4456135
`
`

`

`Diarrhea
`
`2 (2.8)
`
`5 (3.5)
`
`11 (3.8)
`
`18 (6.3)
`
`
`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 adverse reactions due to initiation of metformin are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, 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. When linagliptin was administered in combination with metformin and a sulfonylurea, 181 (22.9%) of
`792 patients reported hypoglycemia compared with 39 (14.8%) of 263 patients administered placebo in combination with metformin and sulfonylurea. Adverse
`reactions of hypoglycemia were based on all reports of hypoglycemia. A concurrent glucose measurement was not required or was normal in some patients. Therefore,
`it is not possible to conclusively determine that all these reports reflect true hypoglycemia.
`
`Linagliptin
`In the study of patients receiving linagliptin as add-on therapy to a stable dose of insulin for up to 52 weeks (n=1261), no significant difference in the incidence of
`investigator reported hypoglycemia, defined as all symptomatic or asymptomatic episodes with a self-measured blood glucose ≤70 mg/dL, was noted between the
`linagliptin- (31.4%) and placebo- (32.9%) treated groups.
`
`Use in Renal Impairment
`Linagliptin was compared to placebo as add-on to pre-existing antidiabetic therapy over 52 weeks in 133 patients with severe renal impairment (estimated GFR <30
`mL/min). For the initial 12 weeks of the study, background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and pioglitazone. For the
`remainder of the trial, dose adjustments in antidiabetic background therapy were allowed.
`
`In general, the incidence of adverse events including severe hypoglycemia was similar to those reported in other linagliptin trials. The observed incidence of
`hypoglycemia was higher (linagliptin, 63% compared to placebo, 49%) due to an increase in asymptomatic hypoglycemic events especially during the first 12 weeks
`when background glycemic therapies were kept stable. Ten linagliptin-treated pati