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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 204629/S-018
`NDA 206073/S-019
`NDA 206111/S-018
`NDA 208658/S-006
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`Food and Drug Administration
`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`Boehringer Ingelheim Pharmaceuticals, Inc.
`Attention: Madhuri B. Jerfy, M.S.
`Associate Director, Regulatory Affairs
`900 Ridgebury Road; P.O. Box 368
`Ridgefield, CT 06877
`
`
`Dear Ms. Jerfy:
`
`Please refer to your Supplemental New Drug Applications (sNDAs) dated and received
`September 20, 2018, and your amendments, submitted under section 505(b) of the Federal Food,
`Drug, and Cosmetic Act (FDCA) for Jardiance (empagliflozin) tablets, Glyxambi (empagliflozin
`and linagliptin) tablets, and Synjardy XR (empagliflozin and metformin hydrochloride extended-
`release) tablets, and submitted pursuant to section 505(b)(2) of the FDCA for Synjardy
`(empagliflozin and metformin hydrochloride) tablets.
`
`We also refer to our letter dated August 29, 2018, notifying you, under Section 505(o)(4) of the
`FDCA, of new safety information that we believe should be included in the labeling for the
`sodium-glucose cotransporter-2 (SGLT-2) inhibitors drug class, of which Jardiance, Glyxambi,
`Synjardy, and Synjardy XR are members. This information pertains to the risk of necrotizing
`fasciitis of the perineum (also known as Fournier’s gangrene).
`
`These supplemental new drug applications provide for revisions to the labeling for Jardiance,
`Glyxambi, Synjardy, and Synjardy XR consistent with our August 29, 2018, Safety Labeling
`Change Notification letter, and the comments sent to you in our correspondences dated October
`5, 16, 17, 18, and 19, 2018.
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`APPROVAL & LABELING
`
`We have completed our review of this supplemental application, as amended. It is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text and with the minor editorial revisions listed below.
`
`Reference ID: 4341156
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`

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`NDA 204629/S-018
`NDA 206073/S-019
`NDA 206111/S-018
`NDA 208658/S-006
`Page 2
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`The pagination has been revised so that the Medication Guides’ page numbers begin with
`page number 1.
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`
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`WAIVER OF HIGHLIGHTS SECTION
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`For Jardiance, we are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of
`Highlights of prescribing information. This waiver applies to all future supplements containing
`revised labeling unless we notify you otherwise.
`
`For Glyxambi, Synjardy, and Synjardy XR, please note that we have previously granted a waiver
`of the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of prescribing
`information.
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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
`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 prescribing informations and
`Medication Guides), 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.
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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 changes
`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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`
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`Reference ID: 4341156
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`

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`NDA 204629/S-018
`NDA 206073/S-019
`NDA 206111/S-018
`NDA 208658/S-006
`Page 3
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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 (which includes new salts and new fixed combinations), 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 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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`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 prescribing information to:
`
`
`OPDP Regulatory Project Manager
`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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`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`For more information about submitting promotional materials in eCTD format, see the draft
`Guidance for Industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
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`You must submit final promotional materials and prescribing information, 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/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. 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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`Reference ID: 4341156
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`

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`NDA 204629/S-018
`NDA 206073/S-019
`NDA 206111/S-018
`NDA 208658/S-006
`Page 4
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`All promotional materials that include representations about your drug product must be promptly
`revised to be consistent with the labeling changes approved in this supplement, including any
`new safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials
`should include prominent disclosure of the important new safety information that appears in the
`revised package labeling. Within 7 days of receipt of this letter, submit your statement of intent
`to comply with 21 CFR 314.70(a)(4) to the address above, by fax to 301-847-8444, or
`electronically in eCTD format. For more information about submitting promotional materials in
`eCTD format, see the draft guidance for industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
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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). We also request that you submit all reports (foreign and domestic)
`of Fournier’s gangrene, regardless of labeling status, as 15-day expedited safety reports for a
`period of ten years from the date of this letter.
`
`If you have any questions, call Michael G. White, Ph.D., Regulatory Project Manager, at
`(240) 402-6149.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`William Chong, 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:
`Content of Labeling (Prescribing Information and Medication Guides) for Jardiance,
`Glyxambi, Synjardy, and Synjardy XR
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`
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`Reference ID: 4341156
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`Signature Page 1 of 1
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`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.
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`/s/
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`WILLIAM H CHONG
`10/26/2018
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`Reference ID: 4341156
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`(b
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