CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`NDA 201280/S-002
`
`
`TRADJENTA
`
`Trade Name:
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`Linagliptin
`
`Boehringer Ingelheim Pharmaceuticals, Inc.
`
`05/22/2012
`
` 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
`
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`NDA 201280/S-002
`
`CONTENTS
`
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Other Review(s)
`Administrative/Correspondence Document(s)
`
`
`
`X
`
`X
`
`
`
`X
`X
`
`
`X
`X
`
`X
`
`
`X
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 201280/S-002
`NDA 201280/S-002
`
`APPLICA TION NUMBER:
`
`APPROVAL LETTER
`
`APPROVAL LETTER
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`NDA 201280/S-002
`
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`
`SUPPLEMENT APPROVAL
`
`
`Boehringer Ingelheim Pharmaceuticals, Inc.
`Attention: Chung Lee-Sogaard, Ph.D.
`Associate Director, Drug Regulatory Affairs
`900 Ridgebury Road, P.O. Box 368
`Ridgefield, CT 06877
`
`Dear Dr. Lee-Sogaard:
`
`
`Please refer to your Supplemental New Drug Application (sNDA) dated and received on July 22,
`2011, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`Tradjenta (linagliptin) tablets, 5 mg.
`
`We acknowledge receipt of your amendments dated September 21, and 22, and November 16,
`2011, and March 9, and April 19, 2012. We also acknowledge receipt of your email dated May
`21, 2012, that includes the agreed-upon labeling.
`
`This “Prior Approval” supplemental new drug application provides for modifications to the
`Patient Package Insert (PPI), changes to the ADVERSE REACTIONS section of the Highlights
`of Prescribing Information section and changes to the ADVERSE REACTIONS, USE IN
`SPECIFIC POPULATIONS, OVERDOSAGE, CLINICAL PHARMACOLOGY, AND
`CLINICAL STUDIES of the Full Prescribing Information sections of the Tradjenta package
`insert (PI).
`
`These changes are based on the safety and efficacy results from trial 1218.46, entitled “A Phase
`3, randomized, double-blind, placebo-controlled parallel group study to compare the efficacy and
`safety of twice daily administration of the free combination of linagliptin 2.5 mg + metformin
`500 mg or of linagliptin 2.5 mg + metformin 1000 mg, with the individual components of
`metformin (500 mg or 1000 mg, twice daily) and linagliptin (5 mg, once daily) over 24 weeks in
`drug naive or previously treated (4 weeks washout and 2 weeks placebo run-in) type 2 diabetic
`patients with insufficient glycemic control.” The efficacy and safety of trial 1218.46 was fully
`reviewed under the Jentadueto (linagliptin/metformin fixed-dose combination) NDA (201281).
`
`
`
`Reference ID: 3133899
`
`

`

`
`
`
`
` NDA 201280/S-002
`Page 2
`
`
`
`We have completed our review of the supplemental applications, as amended. They are
`approved, effective on the date of this letter, for use as recommended in the enclosed, agreed-
`upon labeling text.
`
` CONTENT OF LABELING
`
` As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert and patient
`
`package insert), with the addition of any labeling changes in pending “Changes Being Effected”
`(CBE) supplements, as well as annual reportable changes not included in the enclosed labeling.
`
`Information on submitting SPL files using eLIST may be found in the guidance for industry
`
`titled “SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible from publicly available labeling repositories.
`
`Also within 14 days, amend all pending supplemental applications for this NDA, including CBE
`supplements for which FDA has not yet issued an action letter, with the content of labeling
`[21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the changes approved in this
`supplemental application, as well as annual reportable changes and annotate each change. To
`facilitate review of your submission, provide a highlighted or marked-up copy that shows all
`changes, as well as a clean Microsoft Word version. The marked-up copy should provide
`appropriate annotations, including supplement number(s) and annual report date(s).
`
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`Because none of these criteria apply to your application, you are exempt from this requirement.
`
`
`
`
`Reference ID: 3133899
`
`

`

`
`
`
`
` NDA 201280/S-002
`Page 3
`
`
` PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the package insert(s) to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`You must submit final promotional materials and package insert(s), accompanied by a Form
`
`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
`
`FDA 2253 is available at http://www.fda.gov/opacom/morechoices/fdaforms/cder.html;
`instructions are provided on page 2 of the form. For more information about submission of
`promotional materials to the Office of Prescription Drug Promotion (OPDP), see
`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`
`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`If you have any questions, call Raymond Chiang, Regulatory Project Manager, at (301) 796-
`1940.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`
`Mary H. Parks, M.D.
`Director
`
`Division of Metabolism and Endocrinology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`
`ENCLOSURES:
`Package Insert (PI)
`Patient Package Insert (PPI)
`
`
`
`
`Reference ID: 3133899
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MARY H PARKS
`05/22/2012
`
`Reference ID: 3133899
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 201280/S-002
`NDA 201280/S-002
`
`APPLICA TION NUMBER:
`
`LABELING
`
`LABELING
`
`
`
`
`
`

`

`-----------------------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).
`
`
`
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`Each film-coated tablet of TRADJENTA contains 5 mg of linagliptin free base and the following inactive ingredients: mannitol, pregelatinized starch, corn starch,
`
`
`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 comp