`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`201280Orig1s000
`
`Tradjenta tablets, 5 mg
`
`Trade Name:
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`linagliptin
`
`Boehringer Ingelheim Pharmaceuticals, Inc.
`
`May 2, 2011
`
` 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:
`
`201280Orig1s000
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`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)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`
`X
`
`X
`X
`X
`X
`X
`X
`
`X
`X
`
`X
`X
`
`X
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`201280Orig1s000
`
`APPROVAL LETTER
`
`
`
`
`

`

`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`NDA 201280
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA APPROVAL
`
`
`
`Boehringer Ingelheim Pharmaceuticals, Inc.
`Attention: Maureen Oakes, Pharm.D.
`Associate Director, Drug Regulatory Affairs
`900 Ridgebury Road, P.O. Box 368
`Ridgefield, CT 06877
`
`
`Dear Dr. Oakes:
`
`Please refer to your New Drug Application (NDA) dated and received July 2, 2010, 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 July 7 and 9, August 2, 3, and 25, September
`2, 23, and 30, October 8 and 28, November 1, 12, and 19, and December 1, 17, and 21, 2010; and
`January 6, 27 (2), 28, and 31, February 4, 7, 11 (2), 14, 16 (2), and 18, March 1 (2), 14, 17, 25,
`and 29, and April 18, 20, and 29, and May 2, 2011.
`
`This new drug application provides for the use of Tradjenta (linagliptin) tablets as an adjunct to
`diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
`
`We have completed our review of this application, as amended. It is 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 the patient
`package insert). 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/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`
`Reference ID: 2940784
`
`

`

`NDA 201280
`Page 2
`
`
`CARTON AND IMMEDIATE-CONTAINER LABELS
`
`Submit final printed carton and container labels that are identical to the enclosed carton and
`immediate-container labels submitted on March 25, 2011, as soon as they are available, but no
`more than 30 days after they are printed. Please submit these labels electronically according to
`the guidance for industry titled Providing Regulatory Submissions in Electronic Format –
`Human Pharmaceutical Product Applications and Related Submissions Using the eCTD
`Specifications. Alternatively, you may submit 12 paper copies, with 6 of the copies individually
`mounted on heavy-weight paper or similar material. For administrative purposes, designate this
`submission “Final Printed Carton and Container Labels for approved NDA 201280.”
`Approval of this submission by FDA is not required before the labeling is used.
`
`Marketing the product with FPL that is not identical to the approved labeling text may render the
`product misbranded and an unapproved new drug.
`
`ADVISORY COMMITTEE
`
`Your application for Tradjenta (linagliptin) tablets was not referred to an FDA advisory
`committee because:
`•
`this drug is not a first-in-class anti-diabetic therapy (two other DPP4-inhibitors are
`currently marketed);
`the indication sought is based on a well-established efficacy endpoint relied upon for
`approval of other drugs across the 11 classes of anti-diabetic therapies;
`• clinical trials assessing efficacy and safety are typical of diabetes programs evaluated by
`FDA for approval of other anti-diabetic therapies; and
`• no unexpected safety concerns were identified in the nonclinical or clinical development
`program.
`
`
`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.
`
`We are waiving the pediatric study requirement for ages 0 to 9 years (inclusive) because the
`necessary studies are impossible or highly impracticable. This is because there are too few
`children in this age range with type 2 diabetes mellitus to study.
`
`We are deferring submission of your pediatric studies for ages 10 to 16 years (inclusive) for this
`application because this product is ready for approval for use in adults and pediatric studies have
`not been completed.
`
`
`•
`
`Reference ID: 2940784
`
`

`

`NDA 201280
`Page 3
`
`
`Your deferred pediatric studies required by section 505B(a) of the FDCA are required
`postmarketing studies. The status of these postmarketing studies must be reported annually
`according to 21 CFR 314.81 and section 505B(a)(3)(B) of the FDCA. These required studies are
`listed below.
`
`PMR 1766-1: A randomized, placebo-controlled, dose-finding study under PREA evaluating at
`least two doses of linagliptin as monotherapy in pediatric patients ages 10 to 16 years (inclusive).
`
`
`Final Protocol Submission: by November 30, 2011
`Trial Completion:
`
`by February 28, 2014
`Final Report Submission:
`by August 31, 2014
`
`
`PMR 1766-2: Deferred randomized and controlled pediatric study under PREA to evaluate
`efficacy, safety, and pharmacokinetics of linagliptin for the treatment of type 2 diabetes mellitus
`in pediatric patients ages 10 to 16 years (inclusive) as monotherapy and when added to
`metformin therapy.
`
`
`Final Protocol Submission: by June 30, 2014
`Trial Completion:
`
`by March 31, 2017
`Final Report Submission:
`by September 30, 2017
`
`
`Submit the protocols to your IND 070963, with a cross-reference letter to this NDA. Submit
`final reports to this NDA. For administrative purposes, all submissions related to this required
`pediatric postmarketing study must be clearly designated “Required Pediatric Assessment(s)”.
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
`biological product applications to conduct postmarketing studies and clinical trials for certain
`purposes, if FDA makes certain findings required by the statute.
`
`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient to assess either a signal of a
`serious risk of cardiovascular events or a serious risk of hypersensitivity reactions associated
`with Tradjenta (linagliptin) tablets treatment.
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA is not yet sufficient to assess these serious risks.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following study:
`
`PMR 1766-3 An epidemiologic study to compare the risk of severe hypersensitivity and severe
`cutaneous reactions in type 2 diabetics exposed to linagliptin to the risk in type 2 diabetics
`exposed to other antidiabetic medications.
`
`
`Reference ID: 2940784
`
`

`

`NDA 201280
`Page 4
`
`
`The timetable you submitted on April 28, 2011, states that you will conduct this study according
`to the following schedule:
`
`
`Final Protocol Submission: by May 30, 2012
`Study Completion:
`
`by November 30, 2018
`Final Report Submission:
`by June 30, 2019
`
`
`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to assess a signal of a serious risk of cardiovascular events with anti-
`diabetic medications, including Tradjenta (linagliptin) tablets, to definitively exclude
`unacceptable cardiovascular toxicity.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`PMR 1766-4 A randomized, double-blind, placebo-controlled trial evaluating the effect of
`Tradjenta (linagliptin) tablets on the incidence of major adverse cardiovascular events in patients
`with type 2 diabetes mellitus.
`
`
`The primary objective of this trial is to establish that the upper bound of the 2-sided 95%
`confidence interval for the estimated risk ratio comparing the incidence of major adverse
`cardiovascular events observed with Tradjenta (linagliptin) tablets to that observed in the
`control group is less than 1.3. Secondary objectives must include an assessment of the
`long-term effects of Tradjenta (linagliptin) tablets on immunological and ,
`hypersensitivity reactions (including serious skin and/or mucosal reactions), neoplasms,
`serious hypoglycemia, pancreatitis, and renal safety. For hypersensitivity reactions,
`especially angioedema, reports should include detailed information on concomitant use of
`an angiotensin-converting enzyme inhibitor or an angiotensin-receptor blocker. For cases
`of pancreatitis, serum amylase and/or lipase concentrations with accompanying normal
`ranges and any imaging reports should be included in the narratives.
`
`
`The timetable you submitted on April 20, 2011, states that you will conduct this trial according
`to the following schedule:
`
`
`Final Protocol Submission: by June 30, 2012
`Trial Completion:
`
`by October 31, 2018
`Final Report Submission:
`by May 31, 2019
`
`
`Submit the protocol to your IND 070963, with a cross-reference letter to this NDA. Submit all
`final reports to your NDA. Prominently identify the submission with the following wording in
`bold capital letters at the top of the first page of the submission, as appropriate: “Required
`Postmarketing Protocol Under 505(o)”, “Required Postmarketing Final Report Under
`505(o)”, “Required Postmarketing Correspondence Under 505(o)”.
`
`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`study or clinical trial required under this section. This section also requires you to periodically
`
`Reference ID: 2940784
`
`

`

`NDA 201280
`Page 5
`
`
`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
`report annually on the status of any postmarketing commitments or required studies or clinical
`trials.
`
`FDA will consider the submission of your annual report under section 506B and 21 CFR
`314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii)
`provided that you include the elements listed in 505(o) and 21 CFR 314.81(b)(2)(vii). We
`remind you that to comply with 505(o), your annual report must also include a report on the
`status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to
`submit an annual report for studies or clinical trials required under 505(o) on the date required
`will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could result in enforcement
`action.
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert
`to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
`2253. For instructions on completing the Form FDA 2253, see page 2 of the Form. For more
`information about submission of promotional materials to the Division of Drug Marketing,
`Advertising, and Communications (DDMAC), 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).
`
`MEDWATCH-TO-MANUFACTURER PROGRAM
`
`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse
`event reports that are received directly by the FDA. New molecular entities and important new
`biologics qualify for inclusion for three years after approval. Your firm is eligible to receive
`copies of reports for this product. To participate in the program, see the enrollment instructions
`
`Reference ID: 2940784
`
`

`

`NDA 201280
`Page 6
`
`
`and program description details at
`http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
`
`POST-ACTION FEEDBACK MEETING
`
`New molecular entities and new biologics qualify for a post-action feedback meeting. Such
`meetings are used to discuss the quality of the application and to evaluate the communication
`process during drug development and marketing application review. The purpose is to learn
`from successful aspects of the review process and to identify areas that could benefit from
`improvement. If you would like to have such a meeting with us, call the Regulatory Project
`Manager for this application.
`
`If you have any questions, call Raymond Chiang, M.S., Regulatory Project Manager, at
`(301) 796-1940.
`
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`Curtis J. Rosebraugh, M.D., M.P.H.
`Director
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`
`Enclosures:
`Package Insert
`Patient Package Insert
` Container Label – 30-tablet bottle
` Container Label – 90-tablet bottle
` Container Label – 1000-tablet bottle
` Container Label – 7-tablet blister card (sample)
` Carton Label – 7 tablet (sample)
`
`Reference ID: 2940784
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CURTIS J ROSEBRAUGH
`05/02/2011
`
`Reference ID: 2940784
`
`(
`
`
`
`