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 (1.1)
`
`Important limitations of use:
`Should not be used in patients with type 1 diabetes or for the treatment
`•
`of diabetic ketoacidosis (1.2)
`Has not been studied in patients with a history of pancreatitis (1.2)
`•
`----------------------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------------------------------
`History of hypersensitivity reaction to linagliptin, such as anaphylaxis,
`angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity
`(4)
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`There have been postmarketing reports of acute pancreatitis, including
`•
`fatal pancreatitis. If pancreatitis is suspected, promptly discontinue
`TRADJENTA. (5.1)
`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)
`• When used with an insulin secretagogue (e.g., sulfonylurea) or insulin,
`consider lowering the dose of the insulin secretagogue or insulin to
`reduce the risk of hypoglycemia (5.3)
`There have been postmarketing reports of serious hypersensitivity
`reactions in patients treated with TRADJENTA including anaphylaxis,
`angioedema, and exfoliative skin conditions. In such cases, promptly
`discontinue TRADJENTA, assess for other potential causes, institute
`appropriate monitoring and treatment, and initiate alternative treatment
`for diabetes. (5.4)
`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)
`There have been postmarketing reports of bullous pemphigoid requiring
`hospitalization in patients taking DPP-4 inhibitors. Tell patients to report
`development of blisters or erosions. If bullous pemphigoid is suspected,
`discontinue TRADJENTA. (5.6)
`There have been no clinical studies establishing conclusive evidence of
`macrovascular risk reduction with TRADJENTA (5.7)
`------------------------------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)
`Hypoglycemia was more commonly reported in patients treated with the
`combination of TRADJENTA and sulfonylurea compared with those
`treated with the combination of placebo and sulfonylurea (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.
`
`
`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 Monotherapy
`14.2 Combination Therapy
`14.3 Renal Impairment
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`
`
`Reference ID: 4456135
`
`1
`
`Revised: 7/2019
`
`
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
` 1
`
`
`
` INDICATIONS AND USAGE
`1.1 Monotherapy and Combination Therapy
`Important Limitations of Use
`1.2
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`2.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea)
`or with Insulin
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 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
`5.7 Macrovascular Outcomes
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`Inducers of P-glycoprotein or CYP3A4 Enzymes
`7.1
`
`

`

`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`1.1 Monotherapy and Combination Therapy
`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)].
`
`1.2 Important 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.
`
`2.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
`When TRADJENTA is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be
`required to reduce the risk of hypoglycemia [see Warnings and Precautions (5.2)].
`
`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 a history of a hypersensitivity reaction to linagliptin, such as anaphylaxis, angioedema, exfoliative skin conditions,
`urticaria, or bronchial hyperreactivity [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].
`
`WARNINGS AND PRECAUTIONS
`5
`5.1 Pancreatitis
`There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients taking 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.
`
`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) was
`associated with a higher rate of hypoglycemia compared with placebo in a clinical trial [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 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
`There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug
`therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of
`symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if
`appropriate.
`
`5.6 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.
`
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`Reference ID: 4456135
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`5.7 Macrovascular Outcomes
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA tablets.
`
`ADVERSE REACTIONS
`6
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates
`in the clinical trials of another drug and may not reflect the rates observed in practice.
`
`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
`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
`2176 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 = 3625) and more commonly
`than in patients given placebo (n = 2176), are shown in Table 1. The overall incidence of adverse events with TRADJENTA were similar to placebo.
`
`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
`
`
`
`
`
`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
`insulin therapy.
`
`Following 104 weeks’ treatment in a controlled study 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%).
`
`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. 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.
`
`Hypoglycemia
`In the placebo-controlled studies, 199 (6.6%) of the total 2994 patients treated with TRADJENTA 5 mg reported hypoglycemia compared to 56 patients (3.6%) of 1546
`placebo-treated patients. The incidence of hypoglycemia was similar to placebo when TRADJENTA was administered as monotherapy or in combination with
`metformin, or with pioglitazone. When TRADJENTA was administered in combination with metformin and a sulfonylurea, 181 of 792 (22.9%) patients reported
`hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea. Adverse reactions of hypoglycemia
`were based on all reports of hypoglycemia. A concurrent glucose measurement was not required or was normal in some patients. Therefore, it is not possible to
`conclusively determine that all these reports reflect true hypoglycemia.
`
`In the study of patients receiving TRADJENTA as add-on therapy to a stable dose of insulin for up to 52 weeks (n=1261), no significant difference in the incidence of
`investigator reported hypoglycemia, defined as all symptomatic or asymptomatic episodes with a self-measured blood glucose ≤70 mg/dL, was noted between the
`TRADJENTA- (31.4%) and placebo- (32.9%) treated groups. During the same time period, severe hypoglycemic events, defined as requiring the assistance of another
`person to actively administer carbohydrate, glucagon or other resuscitative actions, were reported in 11 (1.7%) of TRADJENTA treated patients and 7 (1.1%) of
`placebo treated patients. Events that were considered life-threatening or required hospitalization were reported in 3 (0.5%) patients on TRADJENTA and 1 (0.2%) on
`placebo.
`
`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
`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.
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`Renal function as measured by mean eGFR and creatinine clearance did not change over 52 weeks’ treatment compared to placebo.
`
`Laboratory Tests
`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.
`
`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.
`Acute pancreatitis, including fatal pancreatitis [see Indications and Usage (1.2) and Warnings and Precautions (5.1)]
`•
`Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions [see Warnings and Precautions (5.4)]
`•
`Severe and disabling arthralgia [see Warnings and Precautions (5.5)]
`•
`Bullous pemphigoid [see Warnings and Precautions (5.6)]
`•
`Rash
`•
`• Mouth ulceration, stomatitis
`Rhabdomyolysis
`•
`
`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)].
`
`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 6-10% in women with pre-gestational diabetes with a HbA1c>7 and has been reported to be as high as 20-25%
`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, pre-eclampsia, and delivery complications. Poorly controlled diabetes
`increases the fetal risk for major birth defects, still birth, 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 and 150 mg/kg, respectively. These doses represent approximately 943 times (rats) and 1943 times (rabbits) the 5 mg 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 5 mg clinical dose, based on exposure.
`
`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
`Safety and effectiveness of TRADJENTA in pediatric patients under 18 years of age have not been established.
`
`8.5 Geriatric Use
`There were 4040 type 2 diabetes patients treated with linagliptin 5 mg from 15 clinical trials of TRADJENTA; 1085 (27%) were 65 years and over, while 131 (3%)
`were 75 years and over. Of these patients, 2566 were enrolled in 12 double-blind placebo-controlled studies; 591 (23%) were 65 years and over, while 82 (3%) were 75
`years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. Therefore, no dose
`adjustment is recommended in the elderly population. While clinical studies of linagliptin have not identified differences in response between the elderly and younger
`patients, greater sensitivity of some older individuals cannot be ruled out.
`
`8.6 Renal Impairment
`
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`No dose adjustment is recommended for patients with renal impairment [see Clinical Pharmacology (12.3)].
`
`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, contact the Poison Control Center. Employ the usual supportive measures (e.g., remove unabsorbed material from the
`gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status. Removal of linagliptin by hemodialysis
`or peritoneal dialysis is unlikely.
`
`During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of TRADJENTA (equivalent to 120 times the recommended daily dose) there
`were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans.
`
`DESCRIPTION
`11
`TRADJENTA (linagliptin) tablets contain, as the active ingredient, an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.
`
`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-
`quinazolinyl)methyl]-
`
`The empirical formula is C 25H28N8O2 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: mannitol, pregelatinized starch, corn starch,
`copovidone, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: hypromellose, titanium dioxide, talc, polyethylene glycol,
`and red ferric oxide.
`
`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.
`
`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. 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.
`
`Absorption
`The absolute bioavailability of linagliptin is approximately 30%. 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 1110 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
`
`
`5
`
`Reference ID: 4456135
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`

`

`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.
`
`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. Renal clearance at steady state was approximately 70 mL/min.
`
`Specific Populations
`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 τ,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-state exposure approximately 40% higher than that of patients with type 2 diabetes
`mellitus and normal renal function (increase in AUC τ,ss by 42% and Cmax by 35%). For both type 2 diabetes mellitus groups, renal excretion was below 7% of the
`administered dose.
`
`These findings were further supported by the results of population pharmacokinetic analyses.
`
`Hepatic Impairment
`In patients with mild hepatic impairment (Child-Pugh class A), steady-state exposure (AUCτ,ss) of linagliptin was approximately 25% lower