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`DEPARTMENT OF HEALTH & HUMAN SERVICES
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`Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
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`NDA 21-995
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`Merck & Co., Inc.
`Attention: Steven A. Aurecchia, M.D.
`Director, Regulatory Affairs
`UG2CD-48
`P.O. Box 1000
`North Wales, PA 19454-1099
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`Dear Dr. Aurecchia:
`
`Please refer to your new drug application (NDA) dated December 16, 2006, received
`December 16, 2006, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic
`Act for Januvia (sitagliptin phosphate) Tablets, 25 mg, 50 mg, and 100 mg.
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`We acknowledge receipt of your submissions dated December 16, 2005, and January 26 and
`30, February 16 and 17, March 1, 3, 13, 22, and 30, April 5 and 25, May 4 and 10, June 13, 21,
`and 23, July 7, 18, and 20, August 2, 14, 15, and 24, September 21, and October 12, 13 and 16
`(2), 2006.
`
`This new drug application provides for the use of Januvia (sitagliptin phosphate) Tablets as an
`adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes
`mellitus as monotherapy and in combination with metformin or a PPARγ agonist (e.g.,
`thiazolidinediones) when diet and exercise plus the single agent do not provide adequate
`glycemic control.
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`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 text.
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`The final printed labeling (FPL) must be identical to the enclosed labeling (text for package
`insert and text for the patient product information submitted on October 16, 2006, immediate
`container and carton labels submitted on December 16, 2005, and sample carton and container
`labels submitted on March 1, 2006.) Marketing the product with FPL that is not identical to the
`approved labeling text may render the product misbranded and an unapproved new drug.
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`Please submit either an electronic version or 20 paper copies of the FPL as soon as it is
`available (no more than 30 days after it is printed). If paper copies are submitted, individually
`mount 15 of the copies on heavy-weight paper or similar material. For administrative purposes,
`designate this submission “FPL for approved NDA 21-995.” Approval of this submission by
`FDA is not required before the labeling is used.
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`

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`NDA 21-995
`Page 2
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`We acknowledge your October 16, 2006, agreement to revise by January 31, 2007, all of the
`labeling pieces to reflect that the dosage amount shown in the labeling refers to the drug base
`rather than the drug salt. At that time, you should again submit either an electronic version or
`20 paper copies of the FPL as soon as it is available (no more than 30 days after it is printed).
`If paper copies are submitted, individually mount 15 of the copies on heavy-weight paper or
`similar material. For administrative purposes, designate this submission “FPL for approved
`NDA 21-995.” Approval of this submission by FDA is not required before the labeling is used.
`Revised content of labeling in SPL format should also be submitted at that time.
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`The agreed-upon dissolution method and acceptance criterion are as follows:
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`Apparatus
`In vitro dissolution medium
`Volume of dissolution medium
`Medium temperature
`Stirring speed
`Acceptance criterion
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`All applications for new active ingredients, new dosage forms, new indications, new routes of
`administration, and new dosing regimens are required to contain an assessment of the safety
`and effectiveness of the product in pediatric patients unless this requirement is waived or
`deferred. We are waiving the pediatric study requirement for ages birth to 10 years, inclusive,
`and deferring pediatric studies for ages 11 to 16 years, inclusive, for this application.
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`Your deferred pediatric study required under section 2 of the Pediatric Research Equity Act
`(PREA) is considered a required postmarketing study commitment. The status of this
`postmarketing study shall be reported annually according to 21 CFR 314.81. This commitment
`is listed below.
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`1. Deferred pediatric study under PREA for the treatment of type 2 diabetes in pediatric
`patients ages 11 to 16, inclusive.
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`--------------
`(b)(4)
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`------- -
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`Protocol Submission:
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`Study Start:
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`Final Report Submission:
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`by March 31, 2008
`by June 30, 2008
`by December 31, 2010
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`For administrative purposes, all submissions related to this pediatric postmarketing study
`commitment should be clearly designated “Required Pediatric Study Commitment”.
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`We remind you of your postmarketing study commitments in your submission dated
`October 16, 2006. These commitments are listed below.
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`NDA 21-995
`Page 3
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`2. Clinical safety and efficacy study of sitagliptin as add-on therapy to insulin.
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`Protocol Submission:
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`Study Start:
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`Final Report Submission:
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`by March 31, 2007
`by June 30, 2007
`by March 31, 2009
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`3. Clinical safety and efficacy study of sitagliptin as add-on therapy to sulfonylureas. (A
`study protocol was previously submitted and the study recently completed.)
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`Final Report Submission:
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`by March 31, 2007
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`Submit clinical protocols to your IND for this product. Submit all study final reports to this
`NDA. In addition, under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii), you should include a
`status summary of each commitment study as well as other postmarketing studies in your
`annual report to this NDA. The status summary should include expected summary completion
`and final report submission dates, any changes in plans since the last annual report, and the
`number of patients entered into each study. All submissions, including supplements, relating to
`these postmarketing study commitments should be prominently labeled “Postmarketing Study
`Commitment Protocol”, “Postmarketing Study Commitment Final Report”, or
`“Postmarketing Study Commitment Correspondence.”
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`In addition, submit three copies of the introductory promotional materials that you propose to
`use for this product. Submit all proposed materials in draft or mock-up form, not final print.
`Send one copy to the Division of Metabolism and Endocrinology Products and two copies of
`both the promotional materials and the package insert directly to:
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`
`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
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`As indicated in our Information Request letter dated September 7, 2006, and teleconference on
`October 13, 2006, your proposed Chemistry, Manufacturing, and Controls (CMC) Regulatory
`Agreement submitted as part of the CMC Pilot Program is under review. Your proposal
`outlines the regulatory mechanisms for managing changes related to process design and control
`spaces post-approval. While a mutually accepted CMC Agreement is not a condition for the
`approval of this application, it will have implications for post-approval changes. Therefore,
`you are reminded that, until the CMC Agreement is approved, the existing regulations and
`guidances should be followed, as appropriate, for the post-approval CMC changes.
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`We have not completed validation of the regulatory methods. However, we expect your
`continued cooperation to resolve any problems that may be identified.
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`NDA 21-995
`Page 4
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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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`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
`www.fda.gov/medwatch/report/mmp.htm.
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`If you have any questions, call Lina AlJuburi, Pharm.D., M.S., Regulatory Project Manager, at
`(301) 796-1168.
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`Sincerely,
`
`{See appended electronic signature page}
`
`Robert J. Meyer, M.D.
`Director
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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`Enclosures: Package Insert, Patient Product Information, Carton Labels, Container Labels,
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`Sample Carton and Container Labels
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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.
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` /s/
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`Robert Meyer
`10/16/2006 07:11:45 PM
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