`
`Trade Name:
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
` 209806Orig1s000
`
` Segluromet tablets, 2.5 mg/500 mg, 2.5 mg/1000 mg,
`7.5 mg/500 mg, and 7.5 mg/1000 mg.
`
`ertugliflozin and metformin hydrochloride
`
`Merck Sharp & Dohme Corp.
`
`December 19, 2017
`
`For the use of Segluromet (ertugliflozin and metformin
`hydrochloride) tablets as an adjunct to diet and exercise
`to improve glycemic control in adults with type 2
`diabetes mellitus who are not adequately controlled on a
`regimen containing ertugliflozin or metformin, or in
`patients who are already treated with both ertugliflozin
`and metformin.
`
`
`
`Generic or Proper
`Name:
`
`Sponsor:
`
`
`Approval Date:
`
`
`Indication:
`
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`209806Orig1s000
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Clinical Review(s)
`Product Quality Review(s)
`Non-Clinical Review(s)
`Statistical Review(s)
`Clinical Microbiology / Virology Review(s)
`Clinical Pharmacology Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`
`X
`
`X
`X
`
`
`X
`X
`X
`X
`
`X
`X
`X
`X
`X
`
`

`

`
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`209806Orig1s000
`
`
`APPROVAL LETTER
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`NDA 209806
`
`Merck Sharp & Dohme Corp.
`Attention: Vivian Fuh, M.D., F.A.C.P.
`Executive Director, Global Regulatory Affairs
`126 E. Lincoln Avenue, P.O. Box 2000
`Mail Drop: RY34-B188
`Rahway, NJ 07065
`
`Dear Dr. Fuh:
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA APPROVAL
`
`Please refer to your New Drug Application (NDA) dated and received December 19, 2017, and
`your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and
`Cosmetic Act (FDCA) for Segluromet (ertugliflozin and metformin hydrochloride) tablets,
`2.5 mg/500 mg, 2.5 mg/1000 mg, 7.5 mg/500 mg, and 7.5 mg/1000 mg.
`
`This new drug application provides for the use of Segluromet (ertugliflozin and metformin
`hydrochloride) tablets as an adjunct to diet and exercise to improve glycemic control in adults
`with type 2 diabetes mellitus who are not adequately controlled on a regimen containing
`ertugliflozin or metformin, or in patients who are already treated with both ertugliflozin and
`metformin.
`
`We have completed our review of this application, as amended. It is approved, effective on the
`date of this letter, for use as recommended in the agreed-upon labeling.
`
`WAIVER OF HIGHLIGHTS SECTION
`
`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.
`
`CONTENT OF LABELING
`
`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, except with the revisions listed, the enclosed labeling
`(text for the prescribing information and Medication Guide). Information on submitting SPL
`files using eLIST may be found in the guidance for industry SPL Standard for Content of
`
`Reference ID: 4197754
`
`

`

`NDA 209806
`Page 2
`
`Labeling Technical Qs and As, available
`at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
`/UCM072392.pdf.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`Submit final printed carton and immediate container labels that are identical to the enclosed
`carton and immediate container labels as soon as they are available, but no more than 30 days
`after they are printed. Please submit these labels electronically according to the guidance for
`industry titled Providing Regulatory Submissions in Electronic Format — Certain Human
`Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications
`(May 2015, Revision 3). For administrative purposes, designate this submission “Final Printed
`Carton and Container Labels for approved NDA 209806.” Approval of this submission by
`FDA is not required before the labeling is used.
`
`ADVISORY COMMITTEE
`
`Your application for Segluromet (ertugliflozin and metformin hydrochloride) was not referred to
`an FDA advisory committee because this drug is not the first in its class.
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`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.
`
`We are waiving the pediatric study requirement for ages 0 through 9 years (inclusive) because
`necessary studies are impossible or highly impracticable. This is because there are too few
`children in this age range with type 2 diabetes mellitus to study.
`
`We are deferring submission of your pediatric study for ages 10 to 17 years (inclusive) for this
`application because this product is ready for approval for use in adults and the pediatric study has
`not been completed.
`
`Your deferred pediatric study required by section 505B(a) of the FDCA is a required
`postmarketing study. The status of this postmarketing study must be reported annually according
`to 21 CFR 314.81 and section 505B(a)(3)(C) of the FDCA. This required study is listed below.
`
`Your requirement under the PREA (PMR 3311-1) as stated in the approval letter for
`NDA 209803 for Steglatro (ertugliflozin) tablets, dated December 19, 2017, also applies to NDA
`209806. Accordingly, your requirement under PREA is as follows:
`
`Reference ID: 4197754
`
`

`

`NDA 209806
`Page 3
`
`3311-1
`
`Conduct a 24-week, randomized, double-blind, placebo-controlled, parallel group
`study of the safety, efficacy, and pharmacokinetics (PK) of ertugliflozin as add-on
`to metformin background therapy for the treatment of type 2 diabetes mellitus in
`pediatric patients ages 10 to 17 years (inclusive), followed by a 30-week double-
`blind, controlled extension. Patients will be randomized to receive one of two
`doses of ertugliflozin or placebo once daily. The ertugliflozin doses will be
`determined using a population PK model derived from the Phase 3 program (in
`adult subjects) for ertugliflozin. As part of the pediatric study, sparse blood
`samples for population PK and exposures-response analysis will be collected. An
`interim analysis of the PK data will be performed during this study to confirm
`acceptable exposure to ertugliflozin with the selected doses.
`
`Final Protocol Submission: October 2018
`Study Completion:
`March 2026
`Final Report Submission:
`September 2026
`
`Submit the protocol to your IND 106447, with a cross-reference letter to NDA 209803 and to
`this NDA.
`
`Reports of this required pediatric postmarketing study must be submitted as a new drug
`application (NDA) or as a supplement to your approved NDA with the proposed labeling
`changes you believe are warranted based on the data derived from these studies. When
`submitting the reports, please clearly mark your submission "SUBMISSION OF REQUIRED
`PEDIATRIC ASSESSMENTS" in large font, bolded type at the beginning of the cover letter of
`the submission.
`
`Please cross-reference this NDA when you submit your final report for PMR 3311-1 to
`NDA 209803.
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert,
`Medication Guide, and patient PI (as applicable) to:
`
`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`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
`
`Reference ID: 4197754
`
`

`

`NDA 209806
`Page 4
`
`at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
`ces/UCM443702.pdf ).
`
`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
`2253. 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.
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`We request that for a period of 5 years from the U.S. approval date, you submit all cases of
`ketoacidosis reported with Segluromet (ertugliflozin and metformin hydrochloride) tablets as
`15-day Alert reports (as described under 21 CFR 314.80(c)(1)), and that you provide detailed
`analyses of events of ketoacidosis reported from clinical study and post-marketing reports in
`your periodic safety report (i.e., the Periodic Adverse Drug Experience Report [PADER]
`required under 21 CFR 314.80(c)(2) or the ICH E2C Periodic Benefit-Risk Evaluation Report
`[PBRER] format). These analyses should show cumulative data relative to the date of approval
`of Segluromet (ertugliflozin and metformin hydrochloride) tablets as well as relative to prior
`periodic safety reports. Medical literature reviews for case reports/case series of ketoacidosis
`reported with Segluromet (ertugliflozin and metformin hydrochloride) tablets should also be
`provided in the periodic safety report.
`
`MEDWATCH-TO-MANUFACTURER PROGRAM
`
`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse
`event reports that are received directly by the FDA. New molecular entities and important new
`biologics qualify for inclusion for three years after approval. Your firm is eligible to receive
`copies of reports for this product. To participate in the program, please see the enrollment
`instructions and program description details
`at http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
`
`POST APPROVAL FEEDBACK MEETING
`
`New molecular entities and new biologics qualify for a post approval feedback meeting. Such
`meetings are used to discuss the quality of the application and to evaluate the communication
`process during drug development and marketing application review. The purpose is to learn
`from successful aspects of the review process and to identify areas that could benefit from
`
`Reference ID: 4197754
`
`

`

`NDA 209806
`Page 5
`
`improvement. If you would like to have such a meeting with us, call the Regulatory Project
`Manager for this application.
`If you have any questions, call Liz Godwin, Regulatory Project Manager, at (240) 402-3438.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Mary T. Thanh Hai, M.D.
`Deputy Director
`Office of Drug Evaluation II
`Office of New Drugs
`Center for Drug Evaluation and Research
`
`Enclosures:
`Content of Labeling
`Carton and Container Labeling
`
`Reference ID: 4197754
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MARY T THANH HAI
`12/19/2017
`
`Reference ID: 4197754
`
`(
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`(
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