` NDA 201280/S-018
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` NDA 201281/S-022
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` NDA 206073/S-017
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` NDA 208026/S-008
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` SUPPLEMENT APPROVAL
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` FULFILLMENT OF POSTMARKETING
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` REQUIREMENT
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`Boehringer Ingelheim Pharmaceuticals, Inc.
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`
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`Attention: Joerg Schnitzler, Ph.D. and Madhuri Jerfy, M.S.
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`Senior Associate Director and Associate Director, Regulatory Affairs
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`
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`900 Ridgebury Road, P.O. Box 368
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`Ridgefield, CT 06877
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`Dear Dr. Schnitzler and Ms. Jerfy:
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`Please refer to your supplemental new drug applications (sNDAs) dated and received
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`September 5, 2018, for NDA 201280 and September 12, 2018, for NDA 201281, NDA
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`206073, and NDA 208026, and your amendments, submitted under section 505(b) and
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`pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
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`Tradjenta (linagliptin) tablets, Jentadueto (linagliptin and metformin hydrochloride)
`tablets, Glyxambi (empagliflozin and linagliptin) tablets, and Jentadueto XR (linagliptin
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`and metformin hydrochloride extended-release) tablets.
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`These Prior Approval sNDAs provide for changes to the Prescribing Information and
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`Medication Guides based on results of study 1218.22 entitled, “A Multicenter,
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`International, Randomized, Parallel Group, Double-blind, Placebo-Controlled
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`Cardiovascular Safety and Renal Microvascular Outcome Study with Linagliptin, 5 mg
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`Once Daily in Patients with Type 2 Diabetes Mellitus at High Vascular Risk,”
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`(CARMELINA). The CARMELINA trial was conducted to fulfill PMR 1766-4 for NDA
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`201280.
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`APPROVAL & LABELING
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`We have completed our review of these applications, as amended. They are approved,
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`effective on the date of this letter, for use as recommended in the enclosed agreed-
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`upon labeling.
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`WAIVER OF ½ PAGE LENGTH REQUIREMENT FOR HIGHLIGHTS
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`Please note that we have previously granted a waiver of the requirements of 21 CFR
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`201.57(d)(8) regarding the length of Highlights of Prescribing Information.
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`
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`Reference ID: 4457960
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`

`

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` NDA 201280/S-018
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` NDA 201281/S-022
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` NDA 206073/S-017
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` NDA 208026/S-008
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` Page 2
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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
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`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using
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`the FDA automated drug registration and listing system (eLIST), as described at
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`FDA.gov.1 Content of labeling must be identical to the enclosed labeling (text for the
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`Prescribing Information and Medication Guide), with the addition of any labeling
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`changes in pending “Changes Being Effected” (CBE) supplements, as well as annual
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`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
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`industry SPL Standard for Content of Labeling Technical Qs and As.2
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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 that include labeling
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`changes for this NDA, including CBE supplements for which FDA has not yet issued an
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`action letter, with the content of labeling [21 CFR 314.50(l)(1)(i)] in Microsoft Word
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`format, that includes the changes approved in this supplemental application, as well as
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`annual reportable changes. To facilitate review of your submission(s), provide a
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`highlighted or marked-up copy that shows all changes, as well as a clean Microsoft
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`Word version. The marked-up copy should provide appropriate annotations, including
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`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
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`new active ingredients (which includes new salts and new fixed combinations), new
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`indications, new dosage forms, new dosing regimens, or new routes of administration
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`are required to contain an assessment of the safety and effectiveness of the product for
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`the claimed indication in pediatric patients unless this requirement is waived, deferred,
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`or inapplicable.
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`Because none of these criteria apply to your application, you are exempt from this
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`requirement.
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` 1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
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` 2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
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` Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`
`
`
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`Reference ID: 4457960
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`

`

`
` NDA 201280/S-018
`
` NDA 201281/S-022
`
` NDA 206073/S-017
`
` NDA 208026/S-008
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` Page 3
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`FULFILLMENT OF POSTMARKETING REQUIREMENT
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`The supplemental application for NDA 201280 contained the final report for the
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`following postmarketing requirement listed in the May 2, 2011, approval letter for NDA
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`201280.
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` 1766-4 A randomized, double-blind, placebo-controlled trial evaluating the effect
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` of Tradjenta (linagliptin) tablets on the incidence of major adverse
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` cardiovascular events in patients with type 2 diabetes mellitus.
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`We have reviewed your submission and conclude that the above requirement was
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`fulfilled.
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`We remind you that there is a postmarketing requirement listed in the December 22,
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`2017, postapproval postmarketing requirement letter that is still open for NDA 201280.
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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and
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`promotional labeling. To do so, submit the following, in triplicate, (1) a cover letter
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`requesting advisory comments, (2) the proposed materials in draft or mock-up form with
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`annotated references, and (3) the Prescribing Information to:
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`
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`OPDP Regulatory Project Manager
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`Food and Drug Administration
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`Center for Drug Evaluation and Research
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`Office of Prescription Drug Promotion (OPDP)
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`5901-B Ammendale Road
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`Beltsville, MD 20705-1266
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`
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`Alternatively, you may submit a request for advisory comments electronically in eCTD
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`
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`format. For more information about submitting promotional materials in eCTD format,
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`
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`see the draft guidance for industry Providing Regulatory Submissions in Electronic and
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`Non-Electronic Format-Promotional Labeling and Advertising Materials for Human
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`Prescription Drugs.3
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`
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` 3 When final, this guidance will represent the FDA’s current thinking on this topic. For the most recent
` version of a guidance, check the FDA guidance web page at
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`https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
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`
`U.S. Food and Drug Administration
`
`
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`
`Reference ID: 4457960
`
`

`

`
` NDA 201280/S-018
`
` NDA 201281/S-022
`
` NDA 206073/S-017
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` NDA 208026/S-008
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` Page 4
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`You must submit final promotional materials and Prescribing Information, accompanied
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`by a Form FDA 2253, at the time of initial dissemination or publication
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` [21 CFR 314.81(b)(3)(i)]. Form FDA 2253 is available at FDA.gov.4 Information and
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` Instructions for completing the form can be found at FDA.gov.5 For more information
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`about submission of promotional materials to the Office of Prescription Drug Promotion
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`(OPDP), see FDA.gov.6
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`REPORTING REQUIREMENTS
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` We remind you that you must comply with reporting requirements for an approved NDA
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` (21 CFR 314.80 and 314.81).
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` If you have any questions, call Richard Whitehead, M.S., Regulatory Project Manager,
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` at (301) 796-4945.
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`
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` Sincerely,
`
` {See appended electronic signature page}
`
` Lisa B. Yanoff, M.D.
`
` Director (Acting)
` Division of Metabolism and Endocrinology Products
`
` Office of Drug Evaluation II
` Center for Drug Evaluation and Research
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`
` ENCLOSURES:
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` • Content of Labeling (Prescribing Information and Medication Guides) for
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`
`
`
`
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` Tradjenta, Jentadueto, Glyxambi, and Jentadueto XR
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`4 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
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`5 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
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` 6 http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm
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`
`U.S. Food and Drug Administration
`
`
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`
`Reference ID: 4457960
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`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`LISA B YANOFF
`07/03/2019 03:08:51 PM
`
`Reference ID: 4457960
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`