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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 021995/S-040
`NDA 022044/S-042
`NDA 202270/S-017
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`Food and Drug Administration
`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`Merck Sharp & Dohme Corp.
`Attention: Lou Ann Eader, Ph.D.
`Director, Worldwide Regulatory Affairs
`351 N. Sumneytown Pike, P. O. Box 1000
`UG2CD-48
`North Wales, PA 19454-1099
`
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`Dear Dr. Eader:
`
`Please refer to your supplemental New Drug Application (sNDA) dated and received
`July 31, 2017, and your amendment, submitted under section 505(b) of the Federal Food, Drug,
`and Cosmetic Act (FDCA) for Januvia (sitagliptin) tablets.
`
`We also refer to your sNDAs dated and received August 4, 2017, submitted under section 505(b)
`of the FDCA for Janumet (sitagliptin and metformin) tablets and Janumet XR (sitagliptin and
`metformin extended-release) tablets.
`
`We also refer to our letter dated May 12, 2017, notifying you, under Section 505(o)(4) of the
`FDCA, of new safety information that we believe should be included in the labeling for products
`containing sitagliptin, based on clinical trial data for saxagliptin and alogliptin, two members of
`the class. This information pertains to the risk of heart failure with DPP-4 inhibitor products.
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`These sNDAs provide for revisions to the labeling for Januvia, Janumet, and Janumet XR,
`consistent with our May 12, 2017, letter and the comments sent to you in our August 1, 2017,
`correspondence.
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`APPROVAL & LABELING
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`We have completed our review of these 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 and with the minor editorial revisions listed below and indicated in the
`enclosed labeling.
`
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`• Revision dates updated to reflect the date of approval of these supplements.
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`
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`Reference ID: 4137673
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`

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`NDA 021995/S-040
`NDA 022044/S-042
`NDA 202270/S-017
`Page 2
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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
`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 information,
`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.
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`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 these NDAs, 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 these supplemental applications, 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 these applications, you are exempt from this requirement.
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`Reference ID: 4137673
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`

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`NDA 021995/S-040
`NDA 022044/S-042
`NDA 202270/S-017
`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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`
`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 package insert(s), 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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`All promotional materials that include representations about your drug products must be
`promptly revised to be consistent with the labeling changes approved in these supplements,
`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).
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`Reference ID: 4137673
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`

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`NDA 021995/S-040
`NDA 022044/S-042
`NDA 202270/S-017
`Page 4
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`If you have any questions, call Richard Whitehead, M.S., Regulatory Project Manager, at
`(301) 796-4945.
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`
`Sincerely,
`
`{See appended electronic signature page}
`
`Jennifer Rodriguez Pippins, M.D., M.P.H.
`Deputy Director for Safety
`Division of Metabolism and Endocrinology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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`ENCLOSURES:
`Januvia Content of Labeling
`Janumet Content of Labeling
`Janumet XR Content of Labeling
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`Reference ID: 4137673
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`

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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
`08/10/2017
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`Reference ID: 4137673
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