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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 206073/S-003
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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, 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 Application (sNDA) dated and received
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`October 22, 2015, and your amendment, submitted under section 505(b) of the Federal Food,
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`Drug, and Cosmetic Act (FDCA) for Glyxambi (empagliflozin and linagliptin) tablets, 10/5 mg
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`and 25/5 mg.
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`We also refer to our letter dated September 25, 2015, notifying you, under Section 505(o)(4) of
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`the FDCA, of new safety information that we believe should be included in the labeling for
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`sodium-glucose cotransporter-2 (SGLT-2) inhibitor products. This information pertains to the
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`risk of ketoacidosis and urosepsis in patients treated with SGLT-2 inhibitors.
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`This “Prior Approval” sNDA provides for revisions to the labeling to address the risks of
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`ketoacidosis and urosepsis, with the use of SGLT-2 inhibitors, consistent with our
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`September 25, 2015, letter. In addition, this supplement provides for the addition of mouth
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`ulcerations and stomatitis to the list of adverse reactions included in Section 6.2, Postmarketing
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`Experience, for consistency with the approved labeling of other linagliptin products.
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`APPROVAL & LABELING
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`We have completed our review of this supplemental application, as amended. It is approved,
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`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
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`text and with the minor editorial revisions listed below and indicated in the enclosed labeling.
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`• Revision date changed to reflect the date of approval of this supplement
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`WAIVER OF HIGHLIGHTS SECTION
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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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`Reference ID: 3856020
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` NDA 206073/S-003
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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 content of
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`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
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`automated drug registration and listing system (eLIST), as described at
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`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 Medication
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`Guide) with the addition of any labeling changes in pending “Changes Being Effected” (CBE)
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`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
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`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf .
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`The SPL will be accessible via publicly available labeling repositories.
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`Also within 14 days, amend all pending supplemental applications for this NDA, including CBE
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`supplements for which FDA has not yet issued an action letter, with the content of labeling
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`[21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the changes approved in this
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`supplemental application, as well as annual reportable changes, and annotate each change. To
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`facilitate review of your submission, provide a highlighted or marked-up copy that shows all
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`changes, as well as a clean Microsoft Word version. The marked-up copy should provide
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`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
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`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
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`administration are required to contain an assessment of the safety and effectiveness of the
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`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
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`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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`POSTMARKETING REQUIREMENT UNDER 505(o)
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`Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
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`biological product applications to conduct postmarketing studies and clinical trials for certain
`purposes, if FDA makes certain findings required by the statute.
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`As previously communicated to you in our letter dated September 25, 2015, we have determined
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`that an analysis of spontaneous postmarketing adverse events reported under subsection
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`505(k)(1) of the FDCA will not be sufficient to assess the known serious risk of ketoacidosis in
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`patients treated with SGLT-2 inhibitors.
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`Reference ID: 3856020
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` NDA 206073/S-003
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` Page 3
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`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
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` 505(k)(3) of the FDCA will not be sufficient to assess this serious risk.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
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`conduct the following:
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`3004-1 An enhanced pharmacovigilance study of ketoacidosis in patients treated with
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`empagliflozin. The study will include reports of ketoacidosis or diabetic
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`ketoacidosis for a period of 5 years, and will include assessment and analysis of
`spontaneous reports of ketoacidosis in patients treated with empagliflozin, with
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`specialized follow-up to collect additional information on these cases.
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`We refer to your submission dated October 22, 2015, which states your intention to conduct one
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`study to address this postmarketing requirement (PMR) for all currently approved products
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`containing empagliflozin. Therefore, this PMR will also apply to Jardiance (empagliflozin)
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`tablets and Synjardy (empagliflozin and metformin hydrochloride) tablets, per our approval
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`letters issued to NDA 204629/S-007 and NDA 206111/S-002, respectively.
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`The timetable you submitted on November 19, 2015, states that you will conduct this study
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`according to the following schedule:
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`Final Protocol Submission: 06/2016
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`Interim Report Submission: 12/2017
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`12/2018
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`12/2019
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`12/2020
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`Study Completion:
`06/2021
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`Final Report Submission:
`12/2021
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`Submit the protocol to your IND 102145, with a cross-reference letter to this NDA. Submit all
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`interim and final reports to your NDA. Prominently identify the submission with the following
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`wording in bold capital letters at the top of the first page of the submission, as appropriate:
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`“Required Postmarketing Protocol Under 505(o)”, “Required Postmarketing Final Report
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`Under 505(o)”, “Required Postmarketing Correspondence Under 505(o)”.
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`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
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`study or clinical trial required under this section. This section also requires you to periodically
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`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
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`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
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`report annually on the status of any postmarketing commitments or required studies or clinical
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`trials.
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`FDA will consider the submission of your annual report under section 506B and 21 CFR
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`314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii)
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`provided that you include the elements listed in 505(o) and 21 CFR 314.81(b)(2)(vii). We
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`remind you that to comply with 505(o), your annual report must also include a report on the
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`Reference ID: 3856020
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` NDA 206073/S-003
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` Page 4
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` status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to
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`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
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`action.
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` PROMOTIONAL MATERIALS
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` You may request advisory comments on proposed introductory advertising and promotional
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` 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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` OPDP Regulatory Project Manager
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` Food and Drug Administration
` Center for Drug Evaluation and Research
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` Office of Prescription Drug Promotion (OPDP)
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` 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.
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`For more information about submitting promotional materials in eCTD format, see the draft
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` 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 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
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`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
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`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
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`more information about submission of promotional materials to the Office of Prescription Drug
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`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
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`All promotional materials that include representations about your drug product must be promptly
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`revised to be consistent with the labeling changes approved in this supplement, including any
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`new safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials
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`should include prominent disclosure of the important new safety information that appears in the
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`revised package labeling. Within 7 days of receipt of this letter, submit your statement of intent
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`to comply with 21 CFR 314.70(a)(4) to the address above, by fax to 301-847-8444, or
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`electronically in eCTD format. For more information about submitting promotional materials in
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`eCTD format, see the draft Guidance for Industry (available at:
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`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
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`CM443702.pdf ).
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`Reference ID: 3856020
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` NDA 206073/S-003
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` Page 5
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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 Michael G. White, Ph.D., Regulatory Project Manager, at
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`(240) 402-6149.
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`Sincerely,
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`{See appended electronic signature page}
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`Jennifer Rodriguez Pippins, M.D., M.P.H.
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`Deputy Director for Safety
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`Division of Metabolism and Endocrinology Products
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`Office of Drug Evaluation II
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`Center for Drug Evaluation and Research
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`ENCLOSURE:
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`Content of Labeling
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`Reference ID: 3856020
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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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`JENNIFER R PIPPINS
`12/04/2015
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`Reference ID: 3856020
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