contraindicated in renal impairment. Ensure normal renal function
`before initiating and at least annually thereafter. (5.1, 5.3, 5.4, 5.8, 5.9)
`There have been postmarketing reports of acute pancreatitis, including
`fatal pancreatitis. If pancreatitis is suspected, promptly discontinue
`JENTADUETO. (5.2)
`Temporarily discontinue JENTADUETO in patients undergoing
`radiologic studies with intravascular administration of iodinated contrast
`materials or any surgical procedures necessitating restricted intake of
`food and fluids (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 (2.2, 5.5)
`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. (5.6)
`Vitamin B12 deficiency: Metformin may lower vitamin B12 levels.
`Monitor hematologic parameters annually (5.7)
`• Macrovascular outcomes: No conclusive evidence of macrovascular
`risk reduction with JENTADUETO or any other antidiabetic drug (5.10)
`------------------------------ADVERSE REACTIONS------------------------------­
`Adverse reactions reported in ≥5% of patients treated with
`•
`JENTADUETO and more commonly t han 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------------------------------­
`
`
`Cationic drugs eliminated by renal tubular secretion: May reduce
`
`•
`
`
`
`metformin elimination. Use with caution. (7.1)
`
`
`
`Strong P-glycoprotein/CYP3A4 inducer: The efficacy of
`
`
`
`JENTADUETO may be reduced when administered in combination
`
`
`(e.g., rifampin). Use of alternative treatments is strongly recommended.
`
`(7.2)
`---
`--------------------USE IN SPECIFIC POPULATIONS-----------------------­
`
`
`
`
`Pregnancy: JENTADUETO tablets should be used during pregnancy
`
`•
`
`
`
`only if clearly needed. (8.1)
`
`
`
`Nursing mothers: Caution should be exercised when JENTADUETO is
`
`
`
`
`administered to a nursing woman (8.3)
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Revised: 7/2015
`
` 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
`
`
`
`
` Initial U.S. Approval: 2012
`
`
`
`
`
`
`
`
`
`
`WARNING: RISK OF LACTIC ACIDOSIS
`
`See full prescribing information for complete boxed warning.
`
`
`
`Lactic acidosis can occur due to metformin accumulation. The
`
`
`
`•
`risk increases with conditions such as renal impairment, sepsis,
`
`
`
`dehydration, excess alcohol intake, hepatic impairment, and
`
`
`acute congestive heart failure. (5.1)
`
`
`
`Symptoms include malaise, myalgias, respiratory distress,
`
`increasing somnolence, and nonspecific abdominal distress.
`
`
`Laboratory abnormalities include low pH, increased anion gap,
`and elevated blood lactate. (5.1)
`If acidosis is suspected, discontinue JENTADUETO and
`hospitalize the patient immediately (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)
`
`
` Should be given twice daily with meals, with gradual dose escalation to
`
`
` reduce the gastrointestinal side effects due to metformin (2.1)
`
` ---------------------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-----------------------------­
`Renal impairment (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)
`
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: RISK OF LACTIC ACIDOSIS
`
`
`1
`INDICATIONS AND USAGE
`
`
`1.1
`Indication
`
`
`1.2
`Important Limitations of Use
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosing
`
`
`
`
`2.2 Concomitant Use with an Insulin Secretagogue (e.g.,
`
`
`
`Sulfonylurea) or with Insulin
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Lactic Acidosis
`
`
`5.2 Pancreatitis
`
`
`
`
`5.3 Monitoring of Renal Function
`
`
`
`5.4
`Impaired Hepatic Function
`
`
`
`
`
`5.5 Use with Medications Known to Cause Hypoglycemia
`
`
`
`
`Reference ID: 3798274
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`Lactic acidosis: Warn against excessive alcohol use. JENTADUETO is
`
`
`
`•
`not recommended in hepatic impairment or hypoxic states and is
`
`
`
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`
`5.6 Hypersensitivity Reactions
`
`5.7 Vitamin B12 Levels
`
`
`
`5.8 Alcohol Intake
`
`
`5.9 Hypoxic States
`
`
`5.10 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
`
`
`
`7.3 Drugs Affecting Glycemic Control
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`
`
`
` 1
`
`

`

`
` OVERDOSAGE
`
` DESCRIPTION
` CLINICAL PHARMACOLOGY
` 12.1 Mechanism of Action
`
`
` 12.2 Pharmacodynamics
`
`
` 12.3 Pharmacokinetics
`
`
` NONCLINICAL TOXICOLOGY
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
` 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
`
`
`
`
`
`
`
`
`
`10
`
`11
`
`12
`
`
`13
`
`
`14
`
`
`
`
`
`
`
`
` 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
`
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`PATIENT COUNSELING INFORMATION
`
`
`16
`
`17
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`listed.
`
`
`
`
`Reference ID: 3798274
`
`
`
` 2
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`WARNING: RISK OF LACTIC ACIDOSIS
`
`
`Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal
`
`
`
`
`
`
`
`impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure.
`
`
`
`
`
`
`The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and
`
`
`
`
`
`nonspecific abdominal distress.
`
`
`Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.
`
`
`
`
`
`If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`1.1 Indication
`
`
`
`
`
`
`JENTADUETO tablets are 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 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
`
`
`
`
`
`
`
`
`
`
`
`
`
`When JENTADUETO is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may
`
`
`be required to reduce the risk of hypoglycemia [see Warnings and Precautions (5.5)].
`
`
`
`
`
`
`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
`
`
`•
`
`
`•
`
`
`
`CONTRAINDICATIONS
`4
`
`
`
`JENTADUETO is contraindicated in patients with:
`
`
`
`
`
`
`
`
`Renal impairment (e.g., serum creatinine ≥1.5 mg/dL for men, ≥1.4 mg/dL for women, or abnormal creatinine clearance), which may also result from conditions
`
`•
`
`
`
`such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia [see Warnings and Precautions (5.1, 5.3)]
`
`
`
`
`
`
`
`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 (5.6) and Adverse Reactions (6.1)]
`
`Hypersensitivity to metformin
`
`
`•
`
`•
`
`
`•
`
`
`
`WARNINGS AND PRECAUTIONS
`5
`
`
`5.1 Lactic Acidosis
`
`Metformin
`
`
`
`
`
`
`
`
`
`
`
`Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with JENTADUETO and is fatal in approximately
`
`
`
`
`
`50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is
`
`
`
`significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte
`
`
`
`
`
`
`disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels
`
`
`
`of >5 µg/mL are generally found.
`
`
`
`
`Reference ID: 3798274
`
`
`
` 3
`
`

`

`
`
`
`
`
`
`
`
`
` The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years, (with approximately 0.015 fatal cases/1000
`
` patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred
`
`
`
`
`
`
`
` primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple
`
`
`
`
`
`
`
`
`
` concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, particularly
`
`
` when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with
`
`
`
`
`
` the degree of renal impairment and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in
`
`
`
`
`
`
` patients taking metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be
`
`
`
`
` initiated in any patient unless measurement of creatinine clearance demonstrates that renal function is not reduced. In addition, metformin should be promptly withheld
`
`
`
`
`
` in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate,
`
`
`
`
` metformin should be avoided in patients with clinical or laboratory evidence of hepatic impairment. Patients should be cautioned against excessive alcohol intake when
`
`
`
`
`
`
` taking metformin, since alcohol potentiates the effects of metformin on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any
`
`
`
` intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids. Use of topiramate, a carbonic anhydrase inhibitor, in
`
`
`
`
` epilepsy and migraine prophylaxis may cause dose-dependent metabolic acidosis and may exacerbate the risk of metformin-induced lactic acidosis [see Drug
`
`
`
`
`
`
`
` Interactions (7.1) and Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`
`
` The onset of lactic acidosis is often subtle, and accompanied by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and
`
` nonspecific abdominal distress. More severe acidosis may be associated with signs such as hypothermia, hypotension, and resistant bradyarrhythmias. Patients should
`
`
`
`
`
`
`
`
`
` be educated to recognize and promptly report these symptoms. If present, JENTADUETO should be discontinued until lactic acidosis is ruled out. Gastrointestinal
`
`
`
`
`
`
`
`
` symptoms, which are commonly reported during initiation of metformin therapy are less frequently observed in subjects on a chronic, stable, dose of metformin.
`
`
`
`
`
`
`
`
`
`
` Gastrointestinal symptoms in subjects on chronic, stable, dose of metformin could be caused by lactic acidosis or other serious disease.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` To rule out lactic acidosis, serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful. Levels of fasting venous
`
` plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be
`
`
`
`
`
` due to other mechanisms, such as poorly-controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling.
`
`
`
`
`
`
`Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a
`
`
`
`
`medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and
`
`
`
`
`
`
`
`
`supportive measures promptly instituted. Metformin is dialyzable (clearance of up to 170 mL/min under good hemodynamic conditions) and prompt hemodialysis is
`
`
`
`
`
`
`
`
`
`recommended to remove the accumulated metformin and correct the metabolic acidosis. Such management often results in prompt reversal of symptoms and recovery
`
`
`
`
`[see Boxed Warning].
`
`
`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 Monitoring of Renal Function
`
`
`Although linagliptin undergoes minimal renal excretion, metformin is known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic
`
`
`
`
`
`
`
`
`
`
`acidosis increases with the degree of renal impairment. Therefore, JENTADUETO is contraindicated in patients with renal impairment.
`
`
`
`
`
`
`
`
`
`
`Before initiation of therapy with JENTADUETO and at least annually thereafter, renal function should be assessed and verified to be normal. In patients in whom
`
`
`
`
`
`
`
`
`development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and JENTADUETO discontinued if evidence of renal
`
`
`
`
`
`
`
`
`
`impairment is present.
`
`
`
`
`
`Linagliptin may be continued as a single entity tablet at the same total daily dose of 5 mg if JENTADUETO is discontinued due to evidence of renal impairment. No
`
`
`
`
`
`
`
`
`
`
`
`dose adjustment of linagliptin is recommended in patients with renal impairment.
`
`
`
`
`
`
`
`Use of concomitant medications that may affect renal function or metformin disposition:
`
`
`
`
`
`
`
`Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or interfere with the disposition of metformin should be used
`
`
`
`
`with caution [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
`
`
`
`
`
`Radiological studies and surgical procedures:
`
`
`Radiologic studies involving the use of intravascular iodinated contrast materials (e.g., intravenous urogram, intravenous cholangiography, angiography, and computed
`
`
`
`
`
`tomography) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore, in patients in whom
`
`
`
`
`
`any such study is planned, JENTADUETO should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the
`
`
`
`
`
`
`
`
`
`
`procedure and reinstituted only after renal function has been confirmed to be normal.
`
`
`
`
`
`
`
`
`JENTADUETO should be temporarily discontinued for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and
`
`
`
`
`
`
`
`should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal.
`
`
`
`
`
`
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`5.4 Impaired Hepatic Function
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`Because impaired hepatic function has been associated with some cases of lactic acidosis with metformin therapy, JENTADUETO should generally be avoided in
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`patients with clinical or laboratory evidence of hepatic disease [see Warnings and Precautions (5.1)].
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`5.5 Use with Medications Known to Cause Hypoglycemia
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`Linagliptin
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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) was
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`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
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`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
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`secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO [see Dosage and Administration (2.2)].
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`Metformin
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` Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous
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` exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as SUs and insulin) or ethanol. Elderly,
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` debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects.
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` Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking β-adrenergic blocking drugs.
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` 4
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`Reference ID: 3798274
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`

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`5.6 Hypersensitivity Reactions
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`There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin (one of the components of JENTADUETO). These
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`reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with
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`linagliptin, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue JENTADUETO, assess for other potential
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`causes for the event, and institute alternative treatment for diabetes.
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`Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema to another DPP-4
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`inhibitor because it is unknown whether such patients will be predisposed to angioedema with JENTADUETO.
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`5.7 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
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`observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is,
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`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
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`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
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`basis is advised in patients on JENTADUETO and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with
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`inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin
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`B12 measurement at 2- to 3-year intervals may be useful.
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`5.8 Alcohol Intake
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`Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake while receiving
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`JENTADUETO [see Warnings and Precautions (5.1)].
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`5.9 Hypoxic States
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`Cardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by
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`hypoxemia) have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug
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`should be promptly discontinued [see Warnings and Precautions (5.1)].
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`5.10 Macrovascular Outcomes
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`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with linagliptin or metformin or any other antidiabetic drug.
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`ADVERSE REACTIONS
`6
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`6.1 Clinical Trials Experience
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`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates
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`in the clinical trials of another drug and may not reflect the rates observed in practice.
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`Linagliptin/Metformin
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`The safety of concomitantly administered linagliptin (daily dose 5 mg) and metformin (mean daily dose of approximately 1800 mg) has been evaluated in 2816 patients
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`with type 2 diabetes mellitus treated for ≥12 weeks in clinical trials.
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`Three placebo-controlled studies with linagliptin + metformin were conducted: 2 studies were 24 weeks in duration, 1 study was 12 weeks in duration. In the 3
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`placebo-controlled clinical studies, adverse events 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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`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
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`are shown in Table 1.
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`Table 1 Adverse Reactions Reported in ≥5% of Patients Treated with Linagliptin + Metformin and
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`Greater than with Placebo in a 24-week Factorial-Design Study
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` Placebo
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` n=72
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` Nasopharyngitis
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` Diarrhea
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` n (%)
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` 1 (1.4)
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` 2 (2.8)
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` Linagliptin
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` Monotherapy
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` n=142
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` n (%)
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` 8 (5.6)
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` 5 (3.5)
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` Metformin
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` Monotherapy
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` n=291
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` n (%)
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` 8 (2.7)
` 11 (3.8)
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` Combination of
` Linagliptin with Metformin
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` n=286
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` n (%)
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` 18 (6.3)
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` 18 (6.3)
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`Other adverse reactions reported in clinical studies with treatment of linagliptin + metformin were hypersensitivity (e.g., urticaria, angioedema, or bronchial
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`hyperreactivity), cough, decreased appetite, nausea, vomiting, pruritus, and pancreatitis.
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`Linagliptin
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`Adverse reactions reported in ≥2% of patients treated with linagliptin 5 mg and more commonly than in patients treated with placebo included: nasopharyngitis (7.0%
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`vs 6.1%), diarrhea (3.3% vs 3.0%), and cough (2.1% vs 1.4%).
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`Rates for other adverse reactions for linagliptin 5 mg vs placebo when linagliptin was used in combination with specific anti-diabetic agents were: urinary tract
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`infection (3.1% vs 0%) and hypertriglyceridemia (2.4% vs 0%) when linagliptin was used as add-on to sulfonylurea; hyperlipidemia (2.7% vs 0.8%) and weight
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`increased (2.3% vs 0.8%) when linagliptin was used as add-on to pioglitazone; and constipation (2.1% vs 1%) when linagliptin was used as add-on to basal insulin
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`therapy.
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`Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin
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`exfoliation, or bronchial hyperreactivity) and myalgia. In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being
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`treated with linagliptin compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea).
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`Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.
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`Reference ID: 3798274
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` 5
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`

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`Metformin
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`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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`Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarely result in clinically significant vitamin B12
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`deficiency (e.g., megaloblastic anemia) [see Warnings and Precautions (5.5)].
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`Hypoglycemia
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`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
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`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
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`792 patients reported hypoglycemia compared with 39 (14.8%) of 263 patients administered placebo in combination with metformin and sulfonylurea. Adverse
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`reactions of hypoglycemia were based on all reports of hypoglycemia. A concurrent glucose measurement was not required or was normal in some patients. Therefore,
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`it is not possible to conclusively determine that all these reports reflect true hypoglycemia.
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`Linagliptin
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`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
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`investigator reported hypoglycemia, defined as all symptomatic or asymptomatic episodes with a self-measured blood glucose ≤70 mg/dL, was noted between the
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`linagliptin- (31.4%) and placebo- (32.9%) treated groups.
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`Use in Renal Impairment
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`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
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`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
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`remainder of the trial, dose adjustments in antidiabe