`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use
` TRADJENTA safely and effectively. See full prescribing information for
`
`
`
` TRADJENTA.
`
` TRADJENTA® (linagliptin tablets), for oral use
`
` Initial U.S. Approval: 2011
`----------------------------RECENT MAJOR CHANGES-------------------------­
`
`
` Warnings and Precautions
`
` 7/2019
`
`
`
` Pancreatitis (5.1)
`
`
`
` 7/2019
`
`
`
`
` Bullous Pemphigoid (5.6)
`
` 7/2019
`
`
`
`
` Macrovascular Outcomes- Removed
`
` --------------------------INDICATIONS AND USAGE--------------------------­
`
` TRADJENTA is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an
` adjunct to diet and exercise to improve glycemic control in adults with type 2
`
`
` diabetes mellitus (1)
`
`
`
` Limitations of Use
`
`
`
`
`
`
`
`Should not be used in patients with type 1 diabetes or for the treatment
`•
`
`
`of diabetic ketoacidosis (1)
`
`
`
`
`Has not been studied in patients with a history of pancreatitis (1)
`•
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`
`
`
`The recommended dose of TRADJENTA is 5 mg once daily (2.1)
`•
`
`
`
`TRADJENTA can be taken with or without food (2.1)
`•
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`Tablets: 5 mg (3)
`-------------------------------CONTRAINDICATIONS-----------------------------­
`
`
`
`
`Hypersensitivity to linagliptin or any of the excipients in TRADJENTA. (4,
`
`5.4)
`
`
`
`
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`
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`
`•
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`•
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`•
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`
`•
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`•
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`
`
`Heart failure: Heart failure has been observed with two other members
`
`
`
`of the DPP-4 inhibitor class. Consider risks and benefits of
`
`
`TRADJENTA in patients who have known risk factors for heart failure.
`
`Monitor for signs and symptoms. (5.2)
`
`
`
`
`Hypoglycemia: When used with an insulin secretagogue (e.g.,
`
`
`
`
`
`sulfonylurea (SU)) or insulin, consider lowering the dose of the insulin
`
`
`
`secretagogue or insulin to reduce the risk of hypoglycemia (5.3)
`
`
`Hypersensitivity reactions: Serious hypersensitivity reactions (e.g.,
`
`
`
`anaphylaxis, angioedema, and exfoliative skin conditions) have occurred
`
`with TRADJENTA. If hypersensitivity reactions occur, discontinue
`
`
`
`
`TRADJENTA, treat promptly, and monitor until signs and symptoms
`
`resolve. (5.4)
`
`
`
`
`
`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. (5.5)
`
`
`Bullous pemphigoid: There have been reports of bullous pemphigoid
`
`
`
`requiring hospitalization. Tell patients to report development of blisters
`
`
`
`
`or erosions. If bullous pemphigoid is suspected, discontinue
`
`
`TRADJENTA. (5.6)
`
`------------------------------ADVERSE REACTIONS------------------------------­
`
`
`
`Adverse reactions reported in ≥5% of patients treated with TRADJENTA and
`
`
`
`
`
`more commonly than in patients treated with placebo included
`
`nasopharyngitis (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------------------------------­
`
`
`
`Strong P-glycoprotein/CYP3A4 inducer: The efficacy of TRADJENTA may
`
`
`be reduced when administered in combination (e.g., with rifampin). Use of
`
`
`alternative treatments is strongly recommended. (7.1)
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`
`Pancreatitis: There have been reports of acute pancreatitis, including
`•
`
`
`
`fatal pancreatitis. If pancreatitis is suspected, promptly discontinue
`
`
`
`
`
`
`Revised: 3/2020
`
`TRADJENTA. (5.1)
`_______________________________________________________________________________________________________________________________________
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1 INDICATIONS AND USAGE
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosing
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Pancreatitis
`
`
`5.2 Heart Failure
`
`
`
`
`5.3 Use with Medications Known to Cause Hypoglycemia
`
`
`5.4 Hypersensitivity Reactions
`
`
`
`5.5 Severe and Disabling Arthralgia
`
`
`5.6 Bullous Pemphigoid
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`6.2 Postmarketing Experience
`
`
`7 DRUG INTERACTIONS
`
`
`Inducers of P-glycoprotein or CYP3A4 Enzymes
`7.1
`
`
`
`7.2
`Insulin Secretagogues or Insulin
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.2 Lactation
`
`
`
`
`
`
`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 Glycemic Control Trials
`
`
`
`
`14.2 Cardiovascular Safety Trials
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`Reference ID: 4583067
`
`
`
` 1
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` INDICATIONS AND USAGE
` 1
`
`
`
`
` TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14.1)].
`
`
`Limitations of Use
`
`
`
`
`
`
`TRADJENTA 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.
`
`
`
`
`
`
`
`
`TRADJENTA 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 TRADJENTA [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`2.1 Recommended Dosing
`
`
`The recommended dose of TRADJENTA is 5 mg once daily.
`
`
`
`TRADJENTA tablets can be taken with or without food.
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`
`
`
`TRADJENTA (linagliptin) 5 mg tablets are light red, round, biconvex, bevel-edged, film-coated tablets with “D5” debossed on one side and the Boehringer Ingelheim
`
`
`logo debossed on the other side.
`
`
`
`CONTRAINDICATIONS
`4
`
`
`
`
`
`
`
`
`
`TRADJENTA is contraindicated in patients with hypersensitivity to linagliptin or any of the excipients in TRADJENTA, reactions such as anaphylaxis, angioedema,
`
`
`
`
`
`
`exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred [see Warnings and Precautions (5.4) and Adverse Reactions (6)].
`
`
`
`
`
`WARNINGS AND PRECAUTIONS
`5
`
`5.1 Pancreatitis
`
`
`
`
`
`
`
`
`Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with TRADJENTA. In the CARMELINA trial [see Clinical Studies (14.2)], acute
`
`
`
`
`
`
`
`
`
`
`pancreatitis was reported in 9 (0.3%) patients treated with TRADJENTA and in 5 (0.1%) patients treated with placebo. Two patients treated with TRADJENTA in the
`CARMELINA trial had acute pancreatitis with a fatal outcome. There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients
`
`
`
`
`
`treated with TRADJENTA.
`
`
`
`
`
`
`
`Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue TRADJENTA 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 TRADJENTA.
`
`
`
`5.2 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.
`
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`
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`Consider the risks and benefits of TRADJENTA prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a
`
`
`
`
`
`
`
`
`history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart
`
`
`
`
`
`failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of
`
`TRADJENTA.
`
`
`
`
`5.3 Use with Medications Known to Cause Hypoglycemia
`
`
`
`
`
`
`
`Insulin secretagogues and insulin are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) or
`
`
`
`
`
`insulin was associated with a higher rate of hypoglycemia compared with placebo in clinical trials [see Adverse Reactions (6.1)]. The use of TRADJENTA 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 TRADJENTA.
`
`
`
`5.4 Hypersensitivity Reactions
`
`
`
`
`
`There have been postmarketing reports of serious hypersensitivity reactions in patients treated with TRADJENTA. These reactions include anaphylaxis, angioedema,
`
`
`
`
`
`and exfoliative skin conditions. Onset of these reactions occurred predominantly within the first 3 months after initiation of treatment with TRADJENTA, with some
`
`
`
`
`
`reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue TRADJENTA, 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 TRADJENTA.
`
`
`
`5.5 Severe and Disabling Arthralgia
`
`
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`
`
`
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`
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`There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug
`
`
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`
`
`
`therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of
`
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`
`
`
`
`
`
`symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if
`
`appropriate.
`
`
`
`5.6 Bullous Pemphigoid
`
`
`
`
`
`
`
`
`
`
`
`Bullous pemphigoid was reported in 7 (0.2%) patients treated with TRADJENTA compared to none in patients treated with placebo in the CARMELINA trial [see
`Clinical Studies (14.2)], and 3 of these patients were hospitalized due to bullous pemphigoid. Postmarketing cases of bullous pemphigoid requiring hospitalization have
`
`
`
`
`
`
`
`been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the
`
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`
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`
`
`
`DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving TRADJENTA. If bullous pemphigoid is suspected, TRADJENTA should be
`
`
`
`
`
`
`
`
`discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
`
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`
`
` 2
`
`Reference ID: 4583067
`
`

`

` ADVERSE REACTIONS
` 6
`
`
` The following serious adverse reactions are described below or elsewhere in the prescribing information:
`
`
`
`
`
` Pancreatitis [see Warnings and Precautions (5.1)]
`•
`
`
` Heart Failure [see Warnings and Precautions (5.2)]
`
`
`•
`
`
` Use with Medications Known to Cause Hypoglycemia [see Warnings and Precautions (5.3)]
`
`
`•
`
` Hypersensitivity Reactions [see Warnings and Precautions (5.4)]
`
`
`
`
`•
`
` Severe and Disabling Arthralgia [see Warnings and Precautions (5.5)]
`
`
`
`•
`
` Bullous Pemphigoid [see Warnings and Precautions (5.6)]
`
`
`
`
`•
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`
`
`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.
`
`
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`The safety evaluation of TRADJENTA 5 mg once daily in patients with type 2 diabetes is based on 14 placebo-controlled trials, 1 active-controlled study, and one study
`
`
`
`
`
`
`
`
`
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`in patients with severe renal impairment. In the 14 placebo-controlled studies, a total of 3625 patients were randomized and treated with TRADJENTA 5 mg daily and
`
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`2176 with placebo. The mean exposure in patients treated with TRADJENTA across studies was 29.6 weeks. The maximum follow-up was 78 weeks.
`
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`TRADJENTA 5 mg once daily was studied as monotherapy in three placebo-controlled trials of 18 and 24 weeks’ duration and in five additional placebo-controlled
`
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`studies lasting ≤18 weeks. The use of TRADJENTA in combination with other antihyperglycemic agents was studied in six placebo-controlled trials: two with
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`metformin (12 and 24 weeks’ treatment duration); one with a sulfonylurea (18 weeks’ treatment duration); one with metformin and sulfonylurea (24 weeks’ treatment
`
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`
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`duration); one with pioglitazone (24 weeks’ treatment duration); and one with insulin (primary endpoint at 24 weeks).
`
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`In a pooled dataset of 14 placebo-controlled clinical trials, adverse reactions that occurred in ≥2% of patients receiving TRADJENTA (n = 3625) and more commonly
`
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`
`
`
`
`than in patients given placebo (n = 2176), are shown in Table 1. The overall incidence of adverse events with TRADJENTA were similar to placebo.
`
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`Table 1 Adverse Reactions Reported in ≥2% of Patients Treated with TRADJENTA and Greater than Placebo in Placebo-Controlled Clinical Studies of
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`TRADJENTA Monotherapy or Combination Therapy
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` Number (%) of Patients
`
`
` Nasopharyngitis
`
` Diarrhea
`
` Cough
`
`
`
`
`
` TRADJENTA 5 mg
`
` n = 3625
`
` 254 (7.0)
`
` 119 (3.3)
`
` 76 (2.1)
`
` Placebo
`
`
` n = 2176
`
` 132 (6.1)
`
` 65 (3.0)
`
` 30 (1.4)
`
`
`
`Rates for other adverse reactions for TRADJENTA 5 mg vs placebo when TRADJENTA was used in combination with specific anti-diabetic agents were: urinary tract
`
`
`
`
`
`
`
`
`
`
`
`
`
`infection (3.1% vs 0%) and hypertriglyceridemia (2.4% vs 0%) when TRADJENTA was used as add-on to sulfonylurea; hyperlipidemia (2.7% vs 0.8%) and weight
`
`
`
`
`
`
`
`
`increased (2.3% vs 0.8%) when TRADJENTA was used as add-on to pioglitazone; and constipation (2.1% vs 1%) when TRADJENTA was used as add-on to basal
`
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`
`
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`insulin therapy. Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema, localized skin
`
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`
`
`
`exfoliation, or bronchial hyperreactivity) and myalgia.
`
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`
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`Following 104 weeks’ treatment in a controlled study comparing TRADJENTA with glimepiride in which all patients were also receiving metformin, adverse reactions
`
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`
`
`
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`reported in ≥5% of patients treated with TRADJENTA (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were back pain (9.1% vs
`
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`8.4%), arthralgia (8.1% vs 6.1%), upper respiratory tract infection (8.0% vs 7.6%), headache (6.4% vs 5.2%), cough (6.1% vs 4.9%), and pain in extremity (5.3% vs
`
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`3.9%).
`
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`In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with TRADJENTA compared with 3.7 cases
`
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`per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were
`
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`reported following the last administered dose of linagliptin.
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`
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`Reference ID: 4583067
`
`
`
` 3
`
`

`

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` Hypoglycemia
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` Table 2 summarizes the incidence of hypoglycemia in placebo-controlled studies of TRADJENTA. The incidence of hypoglycemia increased when TRADJENTA was
` administered with sulfonylurea or insulin.
`
`
`
` Table 2: Incidence (%) of Hypoglycemia in Placebo-Controlled Clinical Studies of TRADJENTA in Patients with Type 2 Diabetes Mellitus
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` TRADJENTA (N=161)
`
` 1.9%
`
` 0%
` TRADJENTA (N=792)
`
` 8.1%
`
` 0.6%
`
` TRADJENTA (N=631)
`
` 19.8%
` 1.7%
`
`
`
` Placebo (N=84)
` Add-on to Sulfonylurea (18 Weeks)
`
`
`
` 1.2%
`
`
` Hypoglycemia with plasma glucose <54 mg/dL
`
`
` Severe* hypoglycemia (%)
`
`
` 0%
`
` Placebo (N=263)
`
` Add-on to Metformin and Sulfonylurea (24 Weeks)
`
` 5.3%
` Hypoglycemia with plasma glucose <54 mg/dL
`
`
`
`
` 0.8%
`
` Severe* hypoglycemia (%)
`
`
`
` Placebo (N=630)
`
` Add-on to Basal Insulin (52 Weeks)
`
`
`
` 21.6%
` Hypoglycemia with plasma glucose <54 mg/dL
`
`
`
` 1.1%
`
` Severe* hypoglycemia (%)
`
`
` *Hypoglycemia requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
`
`
` In an active-controlled (glimepiride) cardiovascular safety study with TRADJENTA (CAROLINA) with median time on treatment of 5.9 years, the incidence of severe
`
`
`
`
`
`
`
` hypoglycemia was 0.3% in the TRADJENTA group (N=3014) and 2.2% in glimepiride group (N=3000).
`
` Use in Renal Impairment
`
`
`
`
`
` TRADJENTA 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 TRADJENTA trials. The observed incidence of
`
`
`
`
`
`hypoglycemia was higher (TRADJENTA, 63% compared to placebo, 49%) due to an increase in asymptomatic hypoglycemic events especially during the first 12
`
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`
`
`
`weeks when background glycemic therapies were kept stable. Ten TRADJENTA-treated patients (15%) and 11 placebo-treated patients (17%) reported at least one
`
`
`
`
`
`episode of confirmed symptomatic hypoglycemia (accompanying finger stick glucose ≤54 mg/dL). During the same time period, severe hypoglycemic events, defined
`
`
`as an event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions, were reported in 3 (4.4%)
`
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`TRADJENTA-treated patients and 3 (4.6%) placebo-treated patients. Events that were considered life-threatening or required hospitalization were reported in 2 (2.9%)
`
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`
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`patients on TRADJENTA and 1 (1.5%) patient on placebo.
`
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`Renal function as measured by mean eGFR and creatinine clearance did not change over 52 weeks’ treatment compared to placebo.
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`Laboratory Tests
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`Changes in laboratory findings were similar in patients treated with TRADJENTA 5 mg compared to patients treated with placebo.
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`Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the TRADJENTA group and ≥1% more than in the placebo group were increases
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`in uric acid (1.3% in the placebo group, 2.7% in the TRADJENTA group).
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`Increase in Lipase: In a placebo-controlled clinical trial with TRADJENTA in type 2 diabetes mellitus patients with micro- or macroalbuminuria, a mean increase of
`30% in lipase concentrations from baseline to 24 weeks was observed in the TRADJENTA arm compared to a mean decrease of 2% in the placebo arm. Lipase levels
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`above 3 times upper limit of normal were seen in 8.2% compared to 1.7% patients in the TRADJENTA and placebo arms, respectively.
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`Increase in Amylase: In a cardiovascular safety study comparing TRADJENTA versus glimepiride in patients with type 2 diabetes mellitus, amylase levels above 3
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`times upper limit of normal were seen in 1.0% compared to 0.5% of patients in the TRADJENTA and glimepiride arms, respectively.
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`The clinical significance of elevations in lipase and amylase with TRADJENTA is unknown in the absence of potential signs and symptoms of pancreatitis [see
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`Warnings and Precautions (5.1)].
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`Vital Signs
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`No clinically meaningful changes in vital signs were observed in patients treated with TRADJENTA.
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`6.2 Postmarketing Experience
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`Additional adverse reactions have been identified during postapproval use of TRADJENTA. Because these reactions are reported voluntarily from a population of
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`uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
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`Acute pancreatitis, including fatal pancreatitis [see Indications and Usage (1)]
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`Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions
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`Severe and disabling arthralgia
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`Bullous pemphigoid
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`Rash
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`• Mouth ulceration, stomatitis
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`Rhabdomyolysis
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`•
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`DRUG INTERACTIONS
`7
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`7.1 Inducers of P-glycoprotein or CYP3A4 Enzymes
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`Rifampin decreased linagliptin exposure, suggesting that the efficacy of TRADJENTA may be reduced when administered in combination with a strong P-gp or
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`CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer [see
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`Clinical Pharmacology (12.3)].
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`7.2 Insulin Secretagogues or Insulin
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`Coadministration of TRADJENTA with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce
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`the risk of hypoglycemia [see Warnings and Precautions (5.3)].
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` 4
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`Reference ID: 4583067
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` USE IN SPECIFIC POPULATIONS
` 8
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` 8.1 Pregnancy
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` Risk Summary
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` The limited data with TRADJENTA use in pregnant women are not sufficient to inform of drug-associated risk for major birth defects and miscarriage. There are risks
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` to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].
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` In animal reproduction studies, no adverse developmental effects were observed when linagliptin was administered to pregnant rats during the period of organogenesis
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` at doses similar to the maximum recommended clinical dose, based on exposure [see Data].
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` The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a HbA1c>7 and has been reported to be as high as 20 to
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` 25% in women with HbA1c>10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated
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` background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
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`Clinical Considerations
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`Disease-associated maternal and/or embryo/fetal risk
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`Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery
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`complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
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`Data
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`Animal Data
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`No adverse developmental outcome was observed when linagliptin was administered to pregnant Wistar Han rats and Himalayan rabbits during the period of
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`organogenesis at doses up to 240 mg/kg and 150 mg/kg, respectively. These doses represent approximately 943 times (rats) and 1943 times (rabbits) the 5 mg clinical
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`dose, based on exposure. No adverse functional, behavioral, or reproductive outcome was observed in offspring following administration of linagliptin to Wistar Han
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`rats from gestation day 6 to lactation day 21 at a dose 49 times the 5 mg clinical dose, based on exposure.
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`8.2 Lactation
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`Risk Summary
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`There is no information regarding the presence of linagliptin in human milk, the effects on the breastfed infant, or the effects on milk production. However, linagliptin is
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`present in rat milk. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TRADJENTA and
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`any potential adverse effects on the breastfed child from TRADJENTA or from the underlying maternal condition.
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`8.4 Pediatric Use
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`Safety and effectiveness of TRADJENTA in pediatric patients under 18 years of age have not been established.
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`8.5 Geriatric Use
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`In the 15 type 2 diabetes studies with linagliptin, 1085 linagliptin-treated patients were 65 years of age and older (including 131 linagliptin-treated patients 75 years of
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`age and older). Of these 15 studies, 12 were double-blind placebo-controlled. In these 12 studies, 591 linagliptin-treated patients were 65 years of age and older
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`(including 82 linagliptin-treated patients 75 years of age and older). In these linagliptin studies, no overall differences in safety or effectiveness of linagliptin were
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`observed between geriatric patients and younger adult patients.
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`8.6 Renal Impairment
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`No dose adjustment is recommended for patients with renal impairment [see Clinical Pharmacology (12.3)].
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`In the TRADJENTA treatment arm of the CARMELINA trial [see Clinical Studies (14.2)], 2200 (63%) patients had renal impairment (eGFR <60 mL/min/1.73 m2).
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`Approximately 20% of the population had eGFR ≥45 to <60 mL/min/1.73 m2, 28% of the population had eGFR ≥30 to <45 mL/min/1.73 m2 and 15% had eGFR <30
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`mL/min/1.73 m2. The overall incidence of adverse reactions were generally similar between the TRADJENTA and placebo treatment arms.
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`8.7 Hepatic Impairment
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`No dose adjustment is recommended for patients with hepatic impairment [see Clinical Pharmacology (12.3)].
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`OVERDOSAGE
`10
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`In the event of an overdose with TRADJENTA, contact the Poison Control Center. Removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely.
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`DESCRIPTION
`11
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`TRADJENTA (linagliptin) tablets contain, as the active ingredient, an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.
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`Linagliptin is described chemically as 1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2­
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`quinazolinyl)methyl]­
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`The empirical formula is C 25H28N8O2 and the molecular weight is 472.54 g/mol. The structural formula is:
`O
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`N
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`N
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`N
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`O
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`N
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`N
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`N
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`N
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`NH2
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`Linagliptin is a white to yellowish, not or only slightly hygroscopic solid substance. It is very slightly soluble in water (0.9 mg/mL). Linagliptin is soluble in methanol
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`(ca. 60 mg/mL), sparingly soluble in ethanol (ca. 10 mg/mL), very slightly soluble in isopropanol (<1 mg/mL), and very slightly soluble in acetone (ca. 1 mg/mL).
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`Reference ID: 4583067
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` 5
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`Each film-coated tablet of TRADJENTA contains 5 mg of linagliptin free base and the following inactive ingredients: mannitol, pregelatinized starch, corn starch,
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`copovidone, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: hypromellose, titanium dioxide, talc, polyethylene glycol,
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`and red ferric oxide.
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`CLINICAL PHARMACOLOGY
`12
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`12.1 Mechanism of Action
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`Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide
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`(GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the
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`levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at a
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`low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells
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`in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha-cells, resulting in a reduction
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`in hepatic glucose output.
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`12.2 Pharmacodynamics
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`Linagliptin binds to DPP-4 in a reversible manner and thus increases the concentrations of incretin hormones. Linagliptin glucose dependently increases insulin
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`secretion and lowers glucagon secretion, thus resulting in better regulation of glucose homeostasis. Linagliptin binds selectively to DPP-4, and selectively inhibits DPP­
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`4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.
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`Cardiac Electrophysiology
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`In a randomized, placebo-controlled, active-comparator, 4-way crossover study, 36 healthy subjects were administered a single oral dose of linagliptin 5 mg, linagliptin
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`100 mg (20 times the recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with either the recommended dose of 5 mg or the 100-mg
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`dose. At the 100-mg dose, peak linagliptin plasma concentrations were approximately 38-fold higher than the peak concentrations following a 5-mg dose.
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`12.3 Pharmacokinetics
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`The pharmacokinetics of linagliptin has been characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a single 5-mg dose to
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`healthy subjects, peak plasma concentrations of linagliptin occurred at approximately 1.5 hours post dose (Tmax); the mean plasma area under the curve (AUC) was 139
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`nmol*h/L and maximum concentration (Cmax ) was 8.9 nmol/L.
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`Plasma concentrations of linagliptin decline in at least a biphasic manner with a long terminal half-life (>100 hours), related to the saturable binding of linagliptin to
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`DPP-4. The prolonged elimination phase does not contribute to the accumulation of the drug. The effective half-life for accumulation of linagliptin, as determined
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`from oral administration of multiple doses of linagliptin 5 mg, is approximately 12 hours. After once-daily dosing, steady-state plasma concentrations of linagliptin 5
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`mg are reached by the third dose, and Cmax and AUC increased by a factor of 1.3 at steady-state compared with the first dose. The intra-subject and inter-subject
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`coefficients of variation for linagliptin AUC were small (12.6% and 28.5%, respectively). Plasma AUC of linagliptin increased in a less than dose-proportional manner
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`in the dose range of 1 to 10 mg. The pharmacokinetics of linagliptin is similar in healthy subjects and in patients with type 2 diabetes.
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`Absorption
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`The absolute bioavailability of linagliptin is approximately 30%. A high-fat meal reduced Cmax by 15% and increased AUC by 4%; this effect is not clinically relevant.
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` TRADJENTA may be administered with or without food.
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` Distribution
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`The mean apparent volume of distribution at steady-state following a single intravenous dose of linagliptin 5 mg to healthy subjects is approximately 1110 L, indicating
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`that linagliptin