`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`NDA 202343
`
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`
`NDA APPROVAL
`
`
`Merck Sharp & Dohme Corp.
`
`Attention: Richard J. Swanson, Ph.D.
`
`Senior Director, Regulatory Affairs
`
`P.O. Box 1000, UG2C-50
`
`North Wales, PA 19454-1099
`
`
`
`Dear Dr. Swanson:
`
`
`
`Please refer to your New Drug Application (NDA) dated December 6, 2010, received December
`7, 2010, pursuant to section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`JUVISYNC (sitagliptin and simvastatin fixed-dose combination) Tablets, 100 mg/10mg, 100
`mg/20 mg, and 100 mg/40 mg.
`
`We acknowledge receipt of your amendments dated December 16, 2010; and February 16,
`March 25 and 28, April 5, 27 and 28, June 22 (2) and 27, July 13, August 1 and 18, September 2
`(3), 7, 13, 14, 15,20, and 30, and October 5(2), 2011.
`
`We also acknowledge receipt of your letter submitted October 5, 2011 stating that you commit to
`submitting by November 30, 2011, a supplemental NDA to 202,343 to register additional doses
`of JUVISYNC (sitagliptin and simvastatin fixed-dose combination), appropriate for the
`treatment of patients with type 2 diabetes mellitus with moderate renal impairment (50/10, 50/20,
`and 50/40 [mg sitagliptin/mg simvastatin]).
`
`This new drug application provides for the use of JUVISYNC (sitagliptin and simvastatin fixed-
`dose combination) in patients for whom treatment with both sitagliptin and simvastatin is
`appropriate. Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to
`diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Simvastatin
`is an HMG-CoA reductase inhibitor (statin) indicated as an adjunctive therapy to diet to:
`
`
`Reduce the risk of total mortality by reducing CHD deaths and reduce the risk of
`non-fatal myocardial infarction, stroke, and the need for revascularization
`procedures in patients at high risk of coronary events.
`Reduce elevated total-C, LDL-C, Apo B, TG and increase HDL-C in patients with
`primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed
`dyslipidemia.
`Reduce elevated TG in patients with hypertriglyceridemia and reduce TG and
`VLDL-C in patients with primary dysbetalipoproteinemia.
`
`•
`
`•
`
`•
`
`Reference ID: 3025884
`
`

`

`NDA 202343
`Page 2
`
`
`
`•
`
`Reduce total-C and LDL-C in adult patients with homozygous familial
`hypercholesterolemia.
`
`
`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 enclosed agreed-upon labeling text.
`
`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 the enclosed labeling (text for the package insert and text for the
`Medication Guide). 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/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`
`Submit final printed carton and container labels that are identical to the enclosed carton and
`immediate container labels and carton and immediate container labels submitted on September 2
`(carton labeling and 7- and 1000- count container labeling) and 20 (30- and 90-count container
`labeling), 2011, 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 – Human Pharmaceutical Product Applications
`and Related Submissions Using the eCTD Specifications (June 2008).” Alternatively, you may
`submit 12 paper copies, with 6 of the copies individually mounted on heavy-weight paper or
`similar material. For administrative purposes, designate this submission “Final Printed Carton
`and Container Labels for approved NDA 202343.” Approval of this submission by FDA is
`not required before the labeling is used.
`
`Marketing the product with FPL that is not identical to the approved labeling text may render the
`product misbranded and an unapproved new drug.
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`
`We are waiving the pediatric study requirement for this application because this product does not
`represent a meaningful therapeutic benefit over existing therapies for pediatric patients and is
`not likely to be used in a substantial number of pediatric patients.
`
`Reference ID: 3025884
`
`

`

`
`
`NDA 202343
`Page 3
`
`
`
`
` POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
`biological product applications to conduct postmarketing studies and clinical trials for certain
`purposes, if FDA makes certain findings required by the statute.
`
`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient to assess a signal of a serious risk
`of worsening glycemic control associated with the use of simvastatin.
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA will not be sufficient to assess this serious risk.
`
`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to assess a signal of the serious risk described above.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`
`PMR 1826-1 A randomized, double-blind, active-controlled clinical trial to study the
`effect of sitagliptin and simvastatin fixed-dose combination versus sitagliptin on
`glycemic control in type 2 diabetic patients on background metformin therapy.
`
`
`The timetable you submitted on October 5, 2011, states that you will conduct this trial according
`to the following schedule:
`
`
`Final Protocol Submission: by April 2012
`
`Trial Completion:
`by January 2015
`Final Report Submission:
`by July 2015
`
`
`Submit the protocol to your IND 103183, with a cross-reference letter to this NDA. Submit the
`final report to your NDA. Prominently identify the submission with the following wording in
`bold capital letters at the top of the first page of the submission, as appropriate: “Required
`Postmarketing Protocol Under 505(o)”, “Required Postmarketing Final Report Under
`
`505(o)”, “Required Postmarketing Correspondence Under 505(o)”.
`
`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`study or clinical trial required under this section. This section also requires you to periodically
`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
`report annually on the status of any postmarketing commitments or required studies or clinical
`trials.
`
`
`Reference ID: 3025884
`
`

`

`NDA 202343
`Page 4
`
`
`FDA will consider the submission of your annual report under section 506B and 21
`CFR 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section
`505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and 21 CFR
`314.81(b)(2)(vii). We remind you that to comply with 505(o), your annual report must also
`include a report on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Failure to 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 action.
`
`
`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
`to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`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. For instruction on completing the Form FDA 2253, see page 2 of the Form. For more
`
`information about submission of promotional materials to the Division of Drug Marketing,
`Advertising, and Communications (DDMAC), 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).
`
`
`Reference ID: 3025884
`
`

`

`NDA 202343
`Page 5
`
`
`If you have any questions, call Raymond Chiang, Regulatory Project Manager, at (301) 796-
`1940.
`
`
`
`
`
`Sincerely,
`
` {See appended electronic signature page}
`
`Mary H. Parks, M.D.
`
` Director
`Division of Metabolism and Endocrinology
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`
`
`ENCLOSURES:
`Package Insert
`Medication Guide
`Container Label – 100 mg/10mg, 30 tablet bottle (Trade)
`Container Label – 100 mg/10mg, 90 tablet bottle (Trade)
`Container Label – 100 mg/10mg, 1000 tablet bottle (Trade)
`Container Label – 100 mg/20mg, 7 tablet bottle (Sample)
`Container Label – 100 mg/20mg, 30 tablet bottle (Complimentary)
`Container Label – 100 mg/20mg, 30 tablet bottle (Trade)
`Container Label – 100 mg/20mg, 90 tablet bottle (Trade)
`Container Label – 100 mg/20mg, 1000 tablet bottle (Trade)
`Container Label – 100 mg/40mg, 7 tablet bottle (Sample)
`Container Label – 100 mg/40mg, 30 tablet bottle (Complimentary)
`Container Label – 100 mg/40mg, 30 tablet bottle (Trade)
`Container Label – 100 mg/40mg, 90 tablet bottle (Trade)
`Container Label – 100 mg/40mg, 1000 tablet bottle (Trade)
`Carton Label – 100mg/20mg tablets (Physician Sample)
`Carton Label – 100mg/40mg tablets (Physician Sample)
`
`
`
`
`Reference ID: 3025884
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MARY H PARKS
`10/07/2011
`
`Reference ID: 3025884
`
`