-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`• When used with an insulin secretagogue (e.g., sulfonylurea), consider
`
`
`lowering the dose of the insulin secretagogue to reduce the risk of
`hypoglycemia (5.1)
`
`There have been no clinical studies establishing conclusive evidence of
`macrovascular risk reduction with TRADJENTA or any other
`
`
`
`
`
`
`Revised: xx/2012
`
`
`antidiabetic drug (5.2)
`_______________________________________________________________________________________________________________________________________
`
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`------------------------------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)
`Pancreatitis was reported more often in patients treated with linagliptin
`(1 per 562 patient years versus zero in 589 patient years for placebo)
`(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------------------------------­
`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)
`
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------­
`
`Pregnancy: There are no adequate and well-controlled studies in
`
`•
`pregnant women. TRADJENTA tablets should be used during
`
`pregnancy only if clearly needed. (8.1)
`
`
`Nursing mothers: Caution should be exercised when TRADJENTA is
`administered to a nursing woman (8.3)
`
`Pediatric patients: Safety and effectiveness of TRADJENTA in patients
`below the age of 18 have not been established (8.4)
`
`Renal or hepatic impairment: No dose adjustment recommended (8.6,
`8.7)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`
`
`
`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
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`17.1 Instructions
`
`
`17.2 Laboratory Tests
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`
` 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
`
`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 combination with insulin (1.2)
`•
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`
`The recommended dose of TRADJENTA is 5 mg once daily.
`
`•
`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 urticaria,
`angioedema, or bronchial hyperreactivity (4)
`
`
`
`
`
`
`
`
`
`
`
`
`
`•
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
`
`
`
` INDICATIONS AND USAGE
`
`
`
`1.1 Monotherapy and Combination Therapy
`
`1.2
`Important Limitations of Use
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosing
`
`
`2.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea)
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Use with Medications Known to Cause Hypoglycemia
`
`
`5.2 Macrovascular Outcomes
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`7 DRUG INTERACTIONS
`
`
`Inducers of P-glycoprotein or CYP3A4 Enzymes
`7.1
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.3 Nursing Mothers
`
`
`8.4 Pediatric Use
`
`
`
`
`
`
`Reference ID: 3133899
`
`1
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
` INDICATIONS AND USAGE
`1
`
`1.1 Monotherapy and Combination Therapy
`TRADJENTA tablets are 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 combination with insulin.
`
`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)
`When TRADJENTA is used in combination with an insulin secretagogue (e.g., sulfonylurea), a lower dose of the insulin secretagogue may be required to reduce the
`risk of hypoglycemia [see Warnings and Precautions (5.1)].
`
`
`3
`DOSAGE FORMS AND STRENGTHS
`
`
`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.
`
`
`4
`CONTRAINDICATIONS
`TRADJENTA is contraindicated in patients with a history of a hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity [see
`
`Adverse Reactions (6.1)].
`
`
`WARNINGS AND PRECAUTIONS
`5
`
`5.1 Use with Medications Known to Cause Hypoglycemia
`
`
`Insulin secretagogues 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)]. Therefore, a lower dose of the insulin secretagogue may be
`
`required to reduce the risk of hypoglycemia when used in combination with TRADJENTA.
`
`5.2 Macrovascular Outcomes
`
`
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA tablets or any other antidiabetic drug.
`
`
`6
`ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates
`in the clinical trials of another drug and may not reflect the rates observed in practice.
`
`
`
`The safety evaluation of linagliptin 5 mg once daily in patient with type 2 diabetes is based on 13 placebo-controlled trials and 1 active-controlled study. In the 13
`
`placebo-controlled studies, a total of 2994 patients were randomized and treated with TRADJENTA 5 mg daily and 1546 with placebo. The mean exposure across
`studies was 21.4 weeks. The maximum follow-up was 78 weeks.
`
`TRADJENTA 5 mg once daily was studied as monotherapy in two placebo-controlled trials of 18 and 24 weeks’ duration. Five placebo-controlled trials investigated
`linagliptin in combination with other oral antihyperglycemic agents: 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); and one with pioglitazone (24 weeks’ treatment duration).
`
`
`In placebo-controlled clinical trials, adverse reactions that occurred in ≥5% of patients receiving TRADJENTA (n = 2994) and more commonly than in patients given
`
`placebo (n = 1546) included nasopharyngitis (5.9% vs 4.8%). Adverse reactions reported in ≥2% of patients treated with TRADJENTA 5 mg daily as monotherapy or
`
`
`in combination with pioglitazone, sulfonylurea, or metformin and at least 2-fold more commonly than in patients treated with placebo are shown in Table 1.
`
`Table 1 Adverse Reactions Reported in ≥2% of Patients Treated with TRADJENTA and at Least 2-Fold Greater than with Placebo in Placebo-Controlled
`Clinical Studies of TRADJENTA Monotherapy or Combination Therapy
`
`
`
`Monotherapy*
`n (%)
`
`TRADJENTA
`
`n = 907
`
`-­
`-­
`
`
`-­
`
`-­
`
`-­
`
`Placebo
`n = 530
`-­
`-­
`-­
`-­
`-­
`
`
`
`
` Nasopharyngitis
`
`Hyperlipidemia
`
`Cough
`Hypertriglyceridemia†
`
`
`Weight increased
`
`SU = sulfonylurea
`
`
`*Pooled data from 8 studies
`
`
`#Pooled data from 3 studies
`†Includes reports of hypertriglyceridemia (n = 2; 1.2%) and blood triglycerides increased (n = 2; 1.2%)
`
`
`
`
`Combination with
`Metformin#
`
`n (%)
`TRADJENTA
`
`n = 876
`
`-­
`-­
`
`
`-­
`
`-­
`
`-­
`
`Placebo
`n = 539
`-­
`-­
`-­
`-­
`
`-­
`
`
`Combination with SU
`n (%)
`
` TRADJENTA
`
`n = 161
`
` 7 (4.3)
`-­
`
`
`-­
`
`4 (2.4)
`
`-­
`
`Placebo
`n = 84
`
` 1 (1.2)
`-­
`
`
`-­
`
`0 (0.0)
`
`-­
`
`
`Combination with
`
`Metformin + SU
`n (%)
`TRADJENTA
`
`n = 791
`
`-­
`-­
`
`
`19 (2.4)
`
`-­
`
`-­
`
`Placebo
`n = 263
`
`-­
`-­
`
`
`3 (1.1)
`
`-­
`
`-­
`
`
`Combination with
`Pioglitazone
`n (%)
` TRADJENTA
`
`n = 259
`
`-­
`7 (2.7)
`
`
`-­
`
`-­
`6 (2.3)
`
`Placebo
`n = 130
`
`--
`1 (0.8)
`
`
`--
`
`-­
`1 (0.8)
`
`2
`
`
`
`
`
`Reference ID: 3133899
`
`

`

`
`Following 52 weeks’ treatment in a controlled study comparing linagliptin with glimepiride in which all patients were also receiving metformin, adverse reactions
`reported in ≥5% patients treated with linagliptin (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were arthralgia (5.7% vs 3.5%),
`
`back pain (6.4% vs 5.2%), and headache (5.7% vs 4.2%).
`
`
`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 8 of 5115 patients (4499 patient years of exposure) while being
`treated with TRADJENTA compared with 0 of 1546 patients (589 patient years of exposure) treated with placebo. 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 linagliptin was administered as monotherapy or in combination with metformin,
`
`or with pioglitazone. When linagliptin 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.
`
`
`Laboratory Tests
`Changes in laboratory findings were similar in patients treated with TRADJENTA 5 mg compared to patients treated with placebo. 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).
`
`
`No clinically meaningful changes in vital signs were observed in patients treated with TRADJENTA.
`
`7
`DRUG INTERACTIONS
`
`
`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 P-gp or CYP3A4 inducer [see Clinical
`
`
`Pharmacology (12.3)].
`
`8
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`Pregnancy Category B
`
`Reproduction studies have been performed in rats and rabbits. There are, however, no adequate and well-controlled studies in pregnant women. Because animal
`
`reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
`
`
`
`Linagliptin administered during the period of organogenesis was not teratogenic at doses up to 30 mg/kg in the rat and 150 mg/kg in the rabbit, or approximately 49 and
`1943 times the clinical dose based on AUC exposure. Doses of linagliptin causing maternal toxicity in the rat and the rabbit also caused developmental delays in
`skeletal ossification and slightly increased embryofetal loss in rat (1000 times the clinical dose) and increased fetal resorptions and visceral and skeletal variations in the
`rabbit (1943 times the clinical dose).
`
`Linagliptin administered to female rats from gestation day 6 to lactation day 21 resulted in decreased body weight and delays in physical and behavioral development in
`
`male and female offspring at maternally toxic doses (exposures >1000 times the clinical dose). No functional, behavioral, or reproductive toxicity was observed in
`
`offspring of rats exposed to 49 times the clinical dose.
`
`
`Linagliptin crossed the placenta into the fetus following oral dosing in pregnant rats and rabbits.
`
`8.3 Nursing Mothers
`Available animal data have shown excretion of linagliptin in milk at a milk-to-plasma ratio of 4:1. It is not known whether this drug is excreted in human milk.
`
`
`Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman.
`
`8.4 Pediatric Use
`Safety and effectiveness of TRADJENTA in pediatric patients 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
`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)].
`
`10
`OVERDOSAGE
`
`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.
`
`
`
`
`Reference ID: 3133899
`
`3
`
`

`

` 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 C25H28N8O2 and the molecular weight is 472.54 g/mol. The structural formula is:
`O
`
`
`
`
`
`N
`
`N
`
`N
`
`O
`
`N
`
`N
`
`N
`
`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.
`
`12
`CLINICAL PHARMACOLOGY
`
`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
`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
`
`
`
`4
`
`Reference ID: 3133899
`
`

`

`
`
` 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 (AUCτ,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 AUCτ,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 and Cmax,ss was
`approximately 36% lower than in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh class B), AUCss of linagliptin was about 14% lower and
`
`
`
`Cmax,ss was approximately 8% lower than in healthy subjects. Patients with severe hepatic impairment (Child-Pugh class C) had comparable exposure of linagliptin in
`
`terms of AUC0-24 and approximately 23% lower Cmax compared with healthy subjects. Reductions in the pharmacokinetic parameters seen in patients with hepatic
`
`
`
`impairment did not result in reductions in DPP-4 inhibition.
`
`Body Mass Index (BMI)/Weight
`
`No dose adjustment is necessary based on BMI/weight. BMI/weight had no clinically meaningful effect on the pharmacokinetics of linagliptin based on a population
`
`
`pharmacokinetic analysis.
`
`Gender
`
`No dose adjustment is necessary based on gender. Gender had no clinically meaningful effect on the pharmacokinetics of linagliptin based on a population
`
`pharmacokinetic analysis.
`
`Geriatric
`
`
`Age did not have a clinically meaningful impact on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis.
`
`
`Pediatric
`
`
`Studies characterizing the pharmacokinetics of linagliptin in pediatric patients have not yet been performed.
`
`
`Race
`
`No dose adjustment is necessary based on race. Race had no clinically meaningful effect on the pharmacokinetics of linagliptin based on available pharmacokinetic
`data, including subjects of White, Hispanic, Black, and Asian racial groups.
`
`
`
`Drug Interactions
`
`In vitro Assessment of Drug Interactions
`
`Linagliptin is a weak to moderate inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes and is not an inducer of CYP isozymes, including
`CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 4A11.
`
`
`
`Linagliptin is a P-glycoprotein (P-gp) substrate, and inhibits P-gp mediated transport of digoxin at high concentrations. Based on these results and in vivo drug
`
`interaction studies, linagliptin is considered unlikely to cause interactions with other P-gp substrates at therapeutic concentrations.
`
`
`In vivo Assessment of Drug Interactions
`
`Inducers of CYP3A4 or P-gp (e.g., rifampin) decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such
`
`drugs, an alternative to linagliptin is strongly recommended. In vivo studies indicated evidence of a low propensity for causing drug interactions with substrates of
`
`CYP3A4, CYP2C9, CYP2C8, P-gp and organic cationic transporter (OCT). No dose adjustment of TRADJENTA is recommended based on results of the described
`
`pharmacokinetic studies.
`
`
`Table 2
`
`
`
`
`Effect of Coadministered Drugs on Systemic Exposure of Linagliptin
`
`
`
`Coadministered Drug
`
`
`
`Dosing of Coadministered Drug*
`
`
`
`
`Dosing of Linagliptin*
`
`
`
`Geometric Mean Ratio
`(ratio with/without coadministered drug)
`
`
`No effect = 1.0
`AUC†
`
` Cmax
`1.03
`1.20
`10 mg QD
`Metformin
`850 mg TID
`
`1.75 mg#
`Glyburide
`1.01
`1.02
`
` 5 mg QD
`1.07
`1.13
`10 mg QD
`Pioglitazone
`45 mg QD
`
`5 mg#
`Ritonavir
`200 mg BID
`2.96
`2.01
`
`
`
`The efficacy of TRADJENTA may be reduced when administered in combination with strong inducers of CYP3A4 or P-gp (e.g., rifampin). Use of
`alternative treatments is strongly recommended [see Drug Interactions (7.1)].
`
`
`Rifampin
`5 mg QD
`600 mg QD
`*Multiple dose (steady state) unless otherwise noted
`#Single dose
`
`
`
`0.60
`
`0.56
`
`5
`
`Reference ID: 3133899
`
`

`

`
`
`
`
`
`
` †AUC = AUC(0 to 24 hours) for single dose treatments and AUC = AUC(TAU) for multiple dose treatments
`
`QD = once daily
`BID = twice daily
`TID = three times daily
`
`
`Table 3
`
`
`
`
`
`Effect of Linagliptin on Systemic Exposure of Coadministered Drugs
`
`
`
`
`Coadministered Drug
`
`
`
`Dosing of Coadministered Drug*
`
`
`
`
`Dosing of Linagliptin*
`
`
`
`Geometric Mean Ratio
`(ratio with/without coadministered drug)
`
`
`No effect = 1.0
`
`Metformin
`
`
`Glyburide
`
`Pioglitazone
`
`
`Digoxin
`
`Simvastatin
`
`850 mg TID
`
`1.75 mg#
`
`45 mg QD
`
`0.25 mg QD
`
`
`40 mg QD
`
`Warfarin
`
`10 mg#
`
`10 mg QD
`
`
`
` 5 mg QD
`
`10 mg QD
`
`5 mg QD
`
`
`10 mg QD
`
`
`
` 5 mg QD
`
`5 mg QD
`
`
`
`
`ethinylestradiol 0.03 mg and
`Ethinylestradiol and
`
`levonorgestrel 0.150 mg QD
`levonorgestrel
`*Multiple dose (steady state) unless otherwise noted
`#Single dose
` †AUC = AUC(INF) for single dose treatments and AUC = AUC(TAU) for multiple dose treatments
`
` **AUC=AUC(0-168) and Cmax=Emax for pharmacodynamic endpoints
`
` INR = International Normalized Ratio
`
` PT = Prothrombin Time
`QD = once daily
`BID = twice daily
`TID = three times daily
`
`
`metformin
`
`
`glyburide
`pioglitazone
`metabolite M-III
`metabolite M-IV
`
`digoxin
`simvastatin
`
`simvastatin acid
`
` R-warfarin
`
` S-warfarin
`
` INR
`
` PT
`ethinylestradiol
`levonorgestrel
`
`AUC†
`1.01
`
`0.86
`0.94
`0.98
`1.04
`1.02
`1.34
`1.33
`0.99
`1.03
`0.93**
`1.03**
`1.01
`1.09
`
` Cmax
`
`0.89
`
`0.86
`0.86
`0.96
`1.05
`0.94
`1.10
`1.21
`1.00
`1.01
`1.04**
`1.15**
`1.08
`1.13
`
`13
`NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Linagliptin did not increase the incidence of tumors in male and female rats in a 2-year study at doses of 6, 18, and 60 mg/kg. The highest dose of 60 mg/kg is
`
`approximately 418 times the clinical dose of 5 mg/day based on AUC exposure. Linagliptin did not increase the incidence of tumors in mice in a 2-year study at doses
`up to 80 mg/kg (males) and 25 mg/kg (females), or approximately 35- and 270-times the clinical dose based on AUC exposure. Higher doses of linagliptin in female
`
`mice (80 mg/kg) increased the incidence of lymphoma at approximately 215-times the clinical dose based on AUC exposure.
`
`
`
`Linagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a chromosomal aberration test in human
`
`lymphocytes, and an in vivo micronucleus assay.
`
`
`In fertility studies in rats, linagliptin had no adverse effects on early embryonic development, mating, fertility, or bearing live young up to the highest dose of 240
`mg/kg (approximately 943-times the clinical dose based on AUC exposure).
`
`
`CLINICAL STUDIES
`14
`
`TRADJENTA has been studied as monotherapy and in combination with metformin, glimepiride, and pioglitazone therapy. TRADJENTA has not been studied in
`
`
`combination with insulin.
`
`
`A total of 3017 patients with type 2 diabetes were randomized and exposed to linagliptin for at least 12 weeks in 9 double-blind, placebo-controlled clinical efficacy
`studies evaluating the effects of linagliptin on glycemic control. The overall ethnic/racial distribution in these studies was 66% White, 33% Asian, and 1% Black, and
`
`included 14% Hispanic/Latino patients. Fifty two percent of patients were male. Patients had an overall mean age of 57 years (range 20 to 80 years). In addition, an
`
`
`active (glimepiride)-controlled study of 52 weeks’ duration was conducted in 1559 patients with type 2 diabetes who had inadequate glycemic control on metformin.
`
`
`
`In patients with type 2 diabetes, treatment with TRADJENTA produced clinically significant improvements in hemoglobin A1c (A1C), fasting plasma glucose (FPG),
`and 2-hour post-prandial glucose (PPG) compared with placebo.
`
`14.1 Monotherapy
`A total of 730 patients with type 2 diabetes participated in 2 double-blind, placebo-controlled studies, one of 18 weeks’ and another of 24 weeks’ duration, to evaluate
`the efficacy and safety of TRADJENTA monotherapy. In both monotherapy studies, patients currently on an antihyperglycemic agent discontinued the agent and
`
`underwent a diet, exercise, and drug washout period of about 6 weeks that included an open-label placebo run-in during the last 2 weeks. Patients with inadequate
`glycemic control (A1C 7% to 10%) after the washout period were randomized; patients not currently on antihyperglycemic agents (off therapy for at least 8 weeks) with
`
`inadequate glycemic control (A1C 7% to 10%) were randomized after completing the 2-week, open-label, placebo run-in period. In the 18-week study, only patients
`ineligible for metformin were recruited. In the 18-week study, 76 patients were randomized to placebo and 151 to linagliptin 5 mg; in the 24-week study, 167 patients
`
`were randomized to placebo and 336 to linagliptin 5 mg. Patients who failed to meet specific glycemic goals during the 1