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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 201280/S-003 and S-004
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`Food and Drug Administration
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`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`Boehringer Ingelheim Pharmaceuticals, Inc.
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`Attention: Chung Lee-Sogaard, Ph.D.
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`Associate Director, Drug Regulatory Affairs
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`900 Ridgebury Road, P.O. Box 368
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`Ridgefield, CT 06877
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`Dear Dr. Lee-Sogaard:
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`Please refer to your Supplemental New Drug Applications (sNDA) dated and received on
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`October 14 and 31, 2011, submitted under section 505(b) of the Federal Food, Drug, and
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`Cosmetic Act (FDCA) for Tradjenta (linagliptin) tablets, 5 mg.
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`We acknowledge receipt of your amendments dated November 16 (S-003 and S-004), 2011 and
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`January 10 (S-003), January 31 (S-004), February 24 (S-003), March 5 (S-004), March 30 (S-
`004), May 14 (S-003), May 31 (S-003 and S-004), June 5 (S-003), June 15 (S-003 and S-004),
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`June 21 (S-004), July 6 (S-004), July 13 (S-004), July 16 (S-004), and July 19 (S-004), 2012.
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`We also acknowledge receipt of your email dated August 09, 2012, that includes the agreed-upon
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`labeling.
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`This “Prior Approval” supplemental new drug application provides for modifications to the
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`Patient Package Insert (PPI), changes to the RECENT MAJOR CHANGES, INDICATIONS
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`AND USAGE, and ADVERSE REACTIONS sections of the Highlights of Prescribing
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`Information and changes to the INDICATIONS AND USAGE, DOSAGE AND
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`ADMINISTRATION, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS,
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`AND CLINICAL STUDIES sections of the Full Prescribing Information of the Tradjenta
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`package insert (PI).
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`The changes for S-003 are based on the safety and efficacy results from trial 1218.43, entitled “A
`phase 3, randomised, double-blind, placebo-controlled, parallel group, safety and efficacy study
`of BI 1356 (5 mg), compared to placebo as add on to pre-existing antidiabetic therapy (insulin
`or any combination with insulin; sulphonylurea or glinides as monotherapy; pioglitazone or any
`other antidiabetics, excluding only DPP-4 inhibitors other than BI 1356) over 52 weeks in type
`2 diabetic patients with severe chronic renal impairment.” The changes for S-004 are based on
`the safety and efficacy results from trial 1218.36, entitled “A phase 3, randomized, double-blind,
`placebo-controlled, parallel-group, efficacy and safety study of linagliptin (5 mg), administered
`daily for at least 52 weeks in type 2 diabetic patients in combination with basal insulin therapy.”
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`Reference ID: 3173769
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` NDA 201280/S-003
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` NDA 201280/S-004
`Page 2
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`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.
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`CONTENT OF LABELING
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` As soon as possible, but no later than 14 days from the date of this letter, submit the content of
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`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
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`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.
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`Information on submitting SPL files using eLIST may be found in the guidance for industry
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`titled “SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
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`The SPL will be accessible from publicly available labeling repositories.
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`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).
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`REQUIRED PEDIATRIC ASSESSMENTS
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`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.
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`Because none of these criteria apply to your application, you are exempt from this requirement.
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`Reference ID: 3173769
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` NDA 201280/S-003
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` NDA 201280/S-004
`Page 3
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` PROMOTIONAL MATERIALS
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`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:
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`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
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`You must submit final promotional materials and package insert(s), accompanied by a Form
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`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
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`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.
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
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`We request that for a period of two years, you submit all cases of hypersensitivity reactions
`(including angioedema, anaphylaxis, and Stevens-Johnson Syndrome) reported with Tradjenta
`(linagliptin) as 15-day alert reports, and that you provide detailed analyses of clinical trial and
`post-marketing reports of hypersensitivity reactions (including angioedema, anaphylaxis, and
`Stevens-Johnson Syndrome) as adverse events of special interest in your periodic safety update
`reports (PSURs). These analyses should show cumulative data relative to the date of approval of
`Tradjenta (linagliptin) as well as relative to the prior PSUR. Medical literature reviews for case
`reports/case series of serious hypersensitivity reactions with Tradjenta (linagliptin) should also
`be provided in the PSURs.
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`Reference ID: 3173769
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` NDA 201280/S-003
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` NDA 201280/S-004
`Page 4
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`If you have any questions, call Raymond Chiang, Regulatory Project Manager, at (301) 796-
`1940.
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`Sincerely,
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`{See appended electronic signature page}
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`Mary H. Parks, M.D.
`Director
`Division of Metabolism and Endocrinology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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`ENCLOSURES:
`Package Insert (PI)
`Patient Package Insert (PPI)
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`Reference ID: 3173769
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
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`MARY H PARKS
`08/13/2012
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`Reference ID: 3173769
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