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 combination with insulin (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)
`
`
`Hypersensitivity to linagliptin or metformin (4)
`
`
`
`
`
`
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`
`
`Lactic acidosis: Warn against excessive alcohol use. JENTADUETO is
`
`not recommended in hepatic impairment or hypoxic states and is
`
`contraindicated in renal impairment. Ensure normal renal function
`before initiating and at least annually thereafter. (5.1, 5.2, 5.3, 5.6, 5.7)
`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 (5.2)
`Hypoglycemia: When used with a sulfonylurea (SU), a lower dose of
`
`the SU may be required to reduce the risk of hypoglycemia (2.2, 5.4)
`Vitamin B12 deficiency: Metformin may lower vitamin B12 levels.
`Monitor hematologic parameters annually. (5.5)
`
`
`
` Macrovascular outcomes: No conclusive evidence of macrovascular
`
`risk reduction with JENTADUETO or any other antidiabetic drug (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)
`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)
`
`Pancreatitis was reported more often in patients randomized to
`linagliptin (1 per 538 person years versus zero in 433 person years for
`
`comparator) (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)
`
`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: There are no adequate and well-controlled studies in
`
`
`pregnant women. 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)
`
`Pediatric patients: Safety and effectiveness of JENTADUETO in
`patients below the age of 18 have not been established (8.4)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`
`
`
`
`
`
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`
`
`
`
`Revised: 1/2012
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: RISK OF LACTIC ACIDOSIS
`
`
` INDICATIONS AND USAGE
`1
`
`
`Indication
`1.1
`
`Important Limitations of Use
`1.2
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosing
`
`2.2 Concomitant Use With Sulfonylurea
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Lactic Acidosis
`
`5.2 Monitoring of Renal Impairment
`
`5.3
`Impaired Hepatic Function
`
`5.4 Hypoglycemia
`
`5.5 Vitamin B12 Levels
`
`
`5.6 Alcohol Intake
`
`5.7 Hypoxic States
`
`5.8 Macrovascular Outcomes
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`
`Reference ID: 3079250
`
`
`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
`
`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 Metformin
`
`14.2 Add-On Combination Therapy With Metformin
`
`
`1
`
`

`

`
`14.3 Active-Controlled Study vs Glimepiride in Combination with
`Metformin
`
`
`
`14.4 Add-On Combination Therapy with Metformin and a
`Sulfonylurea
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`
`17.1 Instructions
`
`
`
`
`17.2 Laboratory Tests
`
`
`
` *Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`
`
`Reference ID: 3079250
`
`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 combination with insulin.
`
`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 Sulfonylurea
`
`When JENTADUETO is used in combination with an insulin secretagogue (e.g., sulfonylurea), a lower dose of the insulin secretagogue may be required to reduce the
`risk of hypoglycemia [see Warnings and Precautions (5.4)].
`
`
`3
`DOSAGE FORMS AND STRENGTHS
`
`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
`
`
`
`
`
`
`
`4
`CONTRAINDICATIONS
`
`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, 5.2)]
`
`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 urticaria, angioedema, or bronchial hyperreactivity) or metformin [see Adverse Reactions (6.1)]
`
`
`
`
`
`
`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.
`
`
`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
`
`3
`
`Reference ID: 3079250
`
`

`

` 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 patients 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 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.
`
`5.3 Impaired Hepatic Function
`
`
`Because impaired hepatic function has been associated with some cases of lactic acidosis with metformin therapy, JENTADUETO should generally be avoided in
`
`
`patients with clinical or laboratory evidence of hepatic disease [see Warnings and Precautions (5.1)].
`
`5.4 Hypoglycemia
`Linagliptin
`Insulin secretagogues 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)]. Therefore, a lower dose of the insulin secretagogue may be
`
`
`required to reduce the risk of hypoglycemia when used in combination with JENTADUETO [see Dosage and Administration (2.2)].
`
`
`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 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.
`
`
`
`
`4
`
`Reference ID: 3079250
`
`

`

`
`5.6 Alcohol Intake
`
`Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake while receiving
`JENTADUETO [see Warnings and Precautions (5.1)].
`
`
`5.7 Hypoxic States
`Cardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by
`
`
`hypoxemia) have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug
`
`should be promptly discontinued [see Warnings and Precautions (5.1)].
`
`5.8 Macrovascular Outcomes
`
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with linagliptin or metformin or any other antidiabetic drug.
`
`6
`ADVERSE REACTIONS
`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 clinical 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
`
`
`
`Nasopharyngitis
`
`Diarrhea
`
`n (%)
`1 (1.4)
`2 (2.8)
`
`Linagliptin
`Monotherapy
`n=142
`n (%)
`8 (5.6)
`5 (3.5)
`
`Metformin
`Monotherapy
`n=291
`n (%)
`8 (2.7)
`11 (3.8)
`
`Combination of
`
`Linagliptin with Metformin
`n=286
`n (%)
`18 (6.3)
`18 (6.3)
`
`
`
`Other adverse reactions reported in clinical studies with treatment of linagliptin + metformin were hypersensitivity (e.g., urticaria, angioedema, or bronchial
`
`hyperactivity), cough, decreased appetite, nausea, vomiting, pruritus, and pancreatitis.
`
`Linagliptin Monotherapy
`Nasopharyngitis was reported in ≥5% of patients treated with linagliptin and more commonly than in patients treated with placebo (5.8% vs 5.5%). In the clinical trial
`program, pancreatitis was reported in 8 of 4687 patients (4311 patient-years of exposure) while being treated with TRADJENTA compared with 0 of 1183 patients (433
`
`patient-years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.
`
`Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin
`exfoliation, or bronchial hyperactivity) and myalgia.
`
`
`
`Metformin Monotherapy
`
`The most common adverse reactions due to initiation of metformin are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and
`headache.
`
`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
`
`
`deficiency (e.g., megaloblastic anemia) [see Warnings and Precautions (5.4)].
`
`
`Hypoglycemia
`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.
`
`Laboratory Tests
`
`Changes in laboratory findings were similar in patients treated with linagliptin + metformin compared to patients treated with placebo + metformin. Changes in
`
`
`laboratory values that occurred more frequently in the linagliptin + metformin group and 1% more than in the placebo group were not detected.
`
`No clinically meaningful changes in vital signs were observed in patients treated with linagliptin.
`
`
`7
`DRUG INTERACTIONS
`7.1 Drug Interactions with Metformin
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`Cationic Drugs
`Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal
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`tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Although such interactions
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`remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of JENTADUETO and/or the interfering drug is recommended in patients
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`5
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`Reference ID: 3079250
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`who are taking cationic medications that are excreted via the proximal renal tubular secretory system [see Warnings and Precautions (5.2) and Clinical Pharmacology
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`(12.3)].
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`Carbonic Anhydrase Inhibitors
`Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently decrease serum bicarbonate and induce non-anion
`gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with
`JENTADUETO, as the risk of lactic acidosis may increase [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
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`7.2 Drug Interactions With Linagliptin
`Inducers of P-glycoprotein and CYP3A4 Enzymes
`Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-gp inducer or
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`CYP 3A4 inducer. As JENTADUETO is a fixed-dose combination of linagliptin and metformin, use of alternative treatments (not containing linagliptin) is strongly
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`recommended when concomitant treatment with a strong P-gp or CYP 3A4 inducer is necessary [see Clinical Pharmacology (12.3)].
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`7.3 Drugs Affecting Glycemic Control
`Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids,
`phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When
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`such drugs are administered to a patient receiving JENTADUETO, the patient should be closely observed to maintain adequate glycemic control [see Clinical
`Pharmacology (12.3)]. When such drugs are withdrawn from a patient receiving JENTADUETO, the patient should be observed closely for hypoglycemia.
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`USE IN SPECIFIC POPULATIONS
`8
`8.1 Pregnancy
`Pregnancy Category B
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`JENTADUETO
`There are no adequate and well controlled studies in pregnant women with JENTADUETO or its individual components, and some clinical data is available for
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`metformin which indicate that the risk for major malformations was not increased when metformin is taken during the first trimester in pregnancy. In addition,
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`metformin was not associated with increased perinatal complications. Nevertheless, because these clinical data cannot rule out the possibility of harm, JENTADUETO
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`should be used during pregnancy only if clearly needed.
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`JENTADUETO was not teratogenic when administered to Wistar Han rats during the period of organogenesis at doses similar to clinical exposure. At higher maternally
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`toxic doses (9 and 23 times the clinical dose based on exposure), the metformin component of the combination was associated with an increased incidence of fetal rib
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`and scapula malformations.
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`Linagliptin
`Linagliptin was not teratogenic when administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg and
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`150 mg/kg, respectively. These doses represent approximately 943 times the clinical dose in rats and 1943 times the clinical dose in rabbits, based on exposure. No
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`functional, behavioral, or reproductive toxicity was observed in offspring of female Wistar Han rats when administered linagliptin from gestation day 6 to lactation day
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`21 at a dose 49 times the maximum recommended human dose, based on exposure.
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`Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits.
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`Metformin Hydrochloride
`Metformin has been studied for embryofetal effects in 2 rat strains and in rabbits. Metformin was not teratogenic in Sprague Dawley rats up to 600 mg/kg or in Wistar
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`Han rats up to 200 mg/kg (2-3 times the clinical dose based on body surface area or exposure, respectively). At higher maternally toxic doses (9 and 23 times the
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`clinical dose based on exposure), an increased incidence of rib and scapula skeletal malformations was observed in the Wistar Han strain. Metformin was not
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`teratogenic in rabbits at doses up to 140 mg/kg (similar to clinical dose based on body surface area).
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`Metformin administered to female Sprague Dawley rats from gestation day 6 to lactation day 21 up to 600 mg/kg/day (2 times the maximum clinical dose based on
`body surface area) had no effect on prenatal or postnatal development of offspring.
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`Metformin crosses the placenta into the fetus in rats and humans.
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`8.3 Nursing Mothers
`No studies in lactating animals have been conducted with the combined components of JENTADUETO. In studies performed with the individual components, both
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`linagliptin and metformin were secreted in the milk of lactating rats. It is not known whether linagliptin is excreted in human milk. Metformin is excreted in human
`milk in low concentrations. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to
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`discontinue the drug, taking into account the importance of the drug to the mother.
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`8.4 Pediatric Use
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`Safety and effectiveness of JENTADUETO in pediatric patients have not been established.
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`8.5 Geriatric Use
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`Linagliptin is minimally excreted by the kidney; however, metformin is substantially excreted by the kidney. Considering that aging can be associated with reduced
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`renal function, JENTADUETO should be used with caution as age increases [see Warni