Reference ID: 5193739
`
`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
`
`----------------------------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
`
`Not recommended in patients with type 1 diabetes mellitus as it would
`not be effective (1)
`Has not been studied in patients with a history of pancreatitis (1)
`
`
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`The recommended dosage of TRADJENTA is 5 mg orally 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,
`5.3)
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`
`Pancreatitis: There have been reports of acute pancreatitis, including
`fatal pancreatitis. If pancreatitis is suspected, promptly discontinue
`TRADJENTA. (5.1)
`Hypoglycemia: Consider lowering the dosage of insulin secretagogue or
`insulin to reduce the risk of hypoglycemia when initiating TRADJENTA
`(5.2)
`_______________________________________________________________________________________________________________________________________
`
`
`
`
`
`
`
`
`
`
`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. (5.3)
`Arthralgia: Severe and disabling arthralgia has been reported in patients
`taking TRADJENTA. Consider as a possible cause for severe joint pain
`and discontinue drug if appropriate. (5.4)
`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. (5.5)
`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. (5.6)
`
`------------------------------ADVERSE REACTIONS-------------------------------
`Most common adverse reaction (incidence 5% and more often than placebo)
`was nasopharyngitis (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Boehringer
`Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257, or FDA at 1-800-
`FDA-1088 or www.fda.gov/medwatch.
`
`------------------------------DRUG INTERACTIONS-------------------------------
`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.
`
`
`
`
`
`
`
`
`
`
`Revised: 6/2023
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage and Administration
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Pancreatitis
`5.2 Hypoglycemia with Concomitant Use with Insulin and Insulin
`Secretagogues
`5.3 Hypersensitivity Reactions
`5.4 Severe and Disabling Arthralgia
`5.5 Bullous Pemphigoid
`5.6 Heart Failure
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`7.1
`Inducers of P-glycoprotein or CYP3A4 Enzymes
`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 in Adults with Type 2 Diabetes Mellitus
`14.2 Cardiovascular Safety Trials in Patients with Type 2 Diabetes
`Mellitus
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`
`
`1
`
`

`

`Reference ID: 5193739
`
`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.
`
`Limitations of Use
`TRADJENTA is not recommended in patients with type 1 diabetes mellitus as it would not be effective.
`
`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 Dosage and Administration
`The recommended dosage of TRADJENTA is 5 mg taken orally once daily, with or without food.
`
` 3
`
`DOSAGE FORMS AND STRENGTHS
`
`Tablets: 5 mg, light red, round, biconvex, bevel-edged, film-coated tablets with “D5” debossed on one side and the Boehringer Ingelheim symbol 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 (5.3) 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 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
`Insulin secretagogues and insulin are known to cause hypoglycemia. The risk of hypoglycemia is increased when TRADJENTA is used in combination with an insulin
`secretagogue (e.g., sulfonylurea) or insulin [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 dosage of the insulin secretagogue or insulin may be
`required to reduce the risk of hypoglycemia when used in combination with TRADJENTA.
`
`5.3 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 mellitus.
`
`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.
`
`5.4 Severe and Disabling Arthralgia
`There have been postmarketing reports of severe and disabling arthralgia in patients taking TRADJENTA [see Adverse Reactions (6)]. The time to onset of symptoms
`following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients
`experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider the drug as a possible cause for severe joint pain and
`discontinue drug if appropriate.
`
`5.5 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
`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.
`
`5.6 Heart Failure
`An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor
`class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.
`
`Consider the risks and benefits of 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.
`
`
`
`
`2
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`

`

`Reference ID: 5193739
`
`ADVERSE REACTIONS
`6
`The following serious adverse reactions are described below or elsewhere in the prescribing information:
`
`Pancreatitis [see Warnings and Precautions (5.1)]
`
`Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.2)]
`
`Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
`
`Severe and Disabling Arthralgia [see Warnings and Precautions (5.4)]
`
`Bullous Pemphigoid [see Warnings and Precautions (5.5)]
`
`Heart Failure [see Warnings and Precautions (5.6)]
`
`
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates
`in the clinical trials of another drug and may not reflect the rates observed in practice.
`
`The safety evaluation of TRADJENTA 5 mg once daily in patients with type 2 diabetes mellitus is based on 14 placebo-controlled trials, 1 active-controlled trial, and
`one trial in patients with severe renal impairment. In the 14 placebo-controlled studies, a total of 3,625 patients were randomized and treated with TRADJENTA 5 mg
`daily and 2,176 with placebo. The mean exposure in patients treated with TRADJENTA across studies was 29.6 weeks. The maximum follow-up was 78 weeks.
`
`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
`studies lasting ≤18 weeks. The use of TRADJENTA in combination with other antihyperglycemic agents was studied in six placebo-controlled trials: two with
`metformin (12 and 24 weeks’ treatment duration); one with a sulfonylurea (18 weeks’ treatment duration); one with metformin and sulfonylurea (24 weeks’ treatment
`duration); one with pioglitazone (24 weeks’ treatment duration); and one with insulin (primary endpoint at 24 weeks).
`
`In a pooled dataset of 14 placebo-controlled clinical trials, adverse reactions that occurred in 2% of patients receiving TRADJENTA (n = 3,625) and more commonly
`than in patients given placebo (n = 2,176), are shown in Table 1.
`
`Table 1 Adverse Reactions Reported in 2% of Patients Treated with TRADJENTA and Greater than Placebo in Placebo-Controlled Clinical Studies of
`
`TRADJENTA Monotherapy or Combination Therapy
`
`
`
`Adverse Reactions
`
`
`Nasopharyngitis
`Diarrhea
`Cough
`
`TRADJENTA 5 mg (%)
`n = 3,625
`7.0
`3.3
`2.1
`
`Placebo (%)
`n = 2,176
`6.1
`3.0
`1.4
`
`
`Rates for other adverse reactions for TRADJENTA 5 mg vs placebo when TRADJENTA was used in combination with specific antidiabetic 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
`insulin therapy. Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema, localized skin
`exfoliation, or bronchial hyperreactivity) and myalgia.
`
`Following 104 weeks’ treatment in a controlled trial comparing TRADJENTA with glimepiride in which all patients were also receiving metformin, adverse reactions
`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
`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
`3.9%).
`
`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
`per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were
`reported following the last administered dose of linagliptin.
`
`Other Adverse Reactions
`Hypoglycemia
`
`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
`
`Placebo (N=84)
`Add-on to Sulfonylurea (18 Weeks)
`1.2
` Hypoglycemia with plasma glucose <54 mg/dL (%)
`0
` Severe* hypoglycemia (%)
`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 trial 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=3,014) and 2.2% in glimepiride group (N=3,000).
`
`
`TRADJENTA (N=161)
`1.9
`0
`TRADJENTA (N=792)
`8.1
`0.6
`TRADJENTA (N=631)
`19.8
`1.7
`
`
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`3
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`

`

`Reference ID: 5193739
`
`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 trial, background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and pioglitazone. For the
`remainder of the trial, dosage 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
`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%)
`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%)
`patients on TRADJENTA and 1 (1.5%) patient on placebo.
`
`Renal function as measured by mean eGFR and creatinine clearance did not change over 52 weeks’ treatment compared to placebo.
`
`Laboratory Test Abnormalities in Clinical Trials
`Changes in laboratory findings were similar in patients treated with TRADJENTA 5 mg compared to patients treated with placebo.
`
`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
`in uric acid (1.3% in the placebo group, 2.7% in the TRADJENTA group).
`
`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
`above 3 times upper limit of normal were seen in 8.2% compared to 1.7% patients in the TRADJENTA and placebo arms, respectively.
`
`Increase in Amylase: In a cardiovascular safety trial comparing TRADJENTA versus glimepiride in patients with type 2 diabetes mellitus, amylase levels above 3 times
`upper limit of normal were seen in 1.0% compared to 0.5% of patients in the TRADJENTA and glimepiride arms, respectively.
`
`The clinical significance of elevations in lipase and amylase with TRADJENTA is unknown in the absence of potential signs and symptoms of pancreatitis [see
`Warnings and Precautions (5.1)].
`
`Vital Signs
`No clinically meaningful changes in vital signs were observed in patients treated with TRADJENTA.
`
`6.2 Postmarketing Experience
`Additional adverse reactions have been identified during postapproval use of TRADJENTA. Because these reactions are reported voluntarily from a population of
`uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
`
`Gastrointestinal Disorders: Acute pancreatitis, including fatal pancreatitis [see Indications and Usage (1)], mouth ulceration, stomatitis
`
`Immune System Disorders: Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions
` Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis, severe and disabling arthralgia
`
`Skin and Subcutaneous Tissue Disorders: Bullous pemphigoid, rash
`
`DRUG INTERACTIONS
`7
`7.1 Inducers of P-glycoprotein or CYP3A4 Enzymes
`Rifampin decreased linagliptin exposure, suggesting that the efficacy of TRADJENTA may be reduced when administered in combination with a strong P-gp or
`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
`Clinical Pharmacology (12.3)].
`
`7.2 Insulin Secretagogues or Insulin
`Insulin and insulin secretagogues are known to cause hypoglycemia. The risk of hypoglycemia is increased when linagliptin is used in combination with an insulin
`secretagogue (e.g., sulfonylurea) or insulin. Coadministration of TRADJENTA with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of
`the insulin secretagogue or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.2)].
`
`USE IN SPECIFIC POPULATIONS
`8
`8.1 Pregnancy
`Risk Summary
`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
`to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].
`
`In animal reproduction studies, no adverse developmental effects were observed when linagliptin was administered to pregnant rats during the period of organogenesis
`at doses similar to the maximum recommended clinical dose, based on exposure [see Data].
`
`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 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
`background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
`
`Clinical Considerations
`Disease-associated maternal and/or embryo/fetal risk
`Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery
`complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
`
`Data
`Animal Data
`No adverse developmental outcome was observed when linagliptin was administered to pregnant Wistar Han rats and Himalayan rabbits during the period of
`organogenesis at doses up to 240 mg/kg/day and 150 mg/kg/day, respectively. These doses represent approximately 943-times (rats) and 1,943-times (rabbits) the 5 mg
`
`4
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`

`Reference ID: 5193739
`
`maximum clinical dose, based on exposure. No adverse functional, behavioral, or reproductive outcome was observed in offspring following administration of
`linagliptin to Wistar Han rats from gestation day 6 to lactation day 21 at a dose 49-times the maximum recommended human dose, based on exposure.
`
`Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits.
`
`8.2 Lactation
`Risk Summary
`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
`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
`any potential adverse effects on the breastfed child from TRADJENTA or from the underlying maternal condition.
`
`8.4 Pediatric Use
`The safety and effectiveness of TRADJENTA have not been established in pediatric patients.
`
`Effectiveness of TRADJENTA was not demonstrated in a 26-week randomized, double-blind, placebo-controlled trial (NCT03429543) in 157 pediatric patients aged
`10 to 17 years with inadequately controlled type 2 diabetes mellitus.
`
`8.5 Geriatric Use
`In linagliptin studies, 1,085 linagliptin-treated patients were 65 years of age and older and 131 patients were 75 years of age and older. In these linagliptin studies, no
`overall differences in safety or effectiveness of linagliptin were observed between geriatric patients and younger adult patients.
`
`8.6 Renal Impairment
`No dosage adjustment is recommended for patients with renal impairment [see Clinical Pharmacology (12.3)].
`
`In the TRADJENTA treatment arm of the CARMELINA trial [see Clinical Studies (14)], 2,200 (63%) patients had renal impairment (eGFR <60 mL/min/1.73 m2).
`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
`mL/min/1.73 m2. The overall incidence of adverse reactions were generally similar between the TRADJENTA and placebo treatment arms.
`
`8.7 Hepatic Impairment
`No dose adjustment is recommended for patients with hepatic impairment [see Clinical Pharmacology (12.3)].
`
`OVERDOSAGE
`10
`In the event of an overdose with TRADJENTA, consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdosage
`management recommendations. Removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely.
`
`DESCRIPTION
`11
`TRADJENTA tablets for oral use contain linagliptin, an inhibitor of the DPP-4 enzyme.
`
`The chemical name of linagliptin is 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-quinazolinyl)methyl]-
`
`The molecular formula is C25H28N8O2 and the molecular weight is 472.54 g/mol. The structural formula is:
`O
`
`N
`
`N N
`
`N
`
`N
`
`N
`
`O
`
`N
`
`NH2
`
`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
`(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).
`
`Each film-coated tablet of TRADJENTA contains 5 mg of linagliptin free base and the following inactive ingredients: copovidone, corn starch, magnesium stearate,
`mannitol, and pregelatinized starch. In addition, the film coating contains the following inactive ingredients: hypromellose, polyethylene glycol, red ferric oxide, talc,
`and titanium dioxide.
`
`CLINICAL PHARMACOLOGY
`12
`12.1 Mechanism of Action
`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
`(GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the
`levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at a
`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
`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 in
`hepatic glucose output.
`
`12.2 Pharmacodynamics
`Linagliptin binds to DPP-4 in a reversible manner and thus increases the concentrations of incretin hormones. Linagliptin glucose-dependently increases insulin
`secretion and lowers glucagon secretion, thus resulting in better regulation of glucose homeostasis. Linagliptin binds selectively to DPP-4 and selectively inhibits DPP-
`4, but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.
`
`
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`Reference ID: 5193739
`
`Cardiac Electrophysiology
`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
`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 dose.
`At the 100 mg dose, peak linagliptin plasma concentrations were approximately 38-fold higher than the peak concentrations following a 5 mg dose.
`
`12.3 Pharmacokinetics
`The pharmacokinetics of linagliptin has been characterized in healthy subjects and patients with type 2 diabetes mellitus. After oral administration of a single 5 mg dose
`to 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 nmol*h/L and maximum concentration (Cmax) was 8.9 nmol/L.
`
`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
`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 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 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 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 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 mellitus.
`
`Absorption
`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.
`TRADJENTA may be administered with or without food.
`
`Distribution
`The mean apparent volume of distribution at steady-state following a single intravenous dose of linagliptin 5 mg to healthy subjects is approximately 1,110 L, indicating
`that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at
`1 nmol/L to 75%-89% at ≥30 nmol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At high concentrations, where DPP-4 is
`fully saturated, 70% to 80% of linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma. Plasma binding is not altered in patients with renal
`or hepatic impairment.
`
`Elimination
`Linagliptin has a terminal half-life of about 200 hours at steady-state, though the accumulation half-life is about 11 hours. Renal clearance at steady-state was
`approximately 70 mL/min.
`
`Metabolism
`Following oral administration, the majority (about 90%) of linagliptin is excreted unchanged, indicating that metabolism represents a minor elimination pathway. A
`small fraction of absorbed linagliptin is metabolized to a pharmacologically inactive metabolite, which shows a steady-state exposure of 13.3% relative to linagliptin.
`
`Excretion
`Following administration of an oral [14C]-linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated via the enterohepatic
`system (80%) or urine (5%) within 4 days of dosing.
`
`Specific Populations
`Patients with Renal Impairment
`An open-label pharmacokinetic study evaluated the pharmacokinetics of linagliptin 5 mg in male and female patients with varying degrees of chronic renal impairment.
`The study included 6 healthy subjects with normal renal function (creatinine clearance [CrCl] ≥80 mL/min), 6 patients with mild renal impairment (CrCl 50 to <80
`mL/min), 6 patients with moderate renal impairment (CrCl 30 to <50 mL/min), 10 patients with type 2 diabetes mellitus and severe renal impairment (CrCl <30
`mL/min), and 11 patients with type 2 diabetes mellitus and normal renal function. Creatinine clearance was measured by 24-hour urinary creatinine clearance
`measurements or estimated from serum creatinine based on the Cockcroft-Gault formula.
`
`Under steady-state conditions, linagliptin exposure in patients with mild renal impairment was comparable to healthy subjects.
`
`In patients with moderate renal impairment under steady-state conditions, mean exposure of linagliptin increased (AUC,ss by 71% and Cmax by 46%) compared with
`healthy subjects. This increase was not associated with a prolonged accumulation half-life, terminal half-life, or an increased accumulation factor. Renal excretion of
`linagliptin was below 5% of the administered dose and was not affected by decreased renal function.
`
`Patients with type 2 diabetes mellitus and severe renal impairment showed steady-stat