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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 200678
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`Food and Drug Administration
`Silver Spring MD 20993
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`NDA APPROVAL
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`Bristol-Myers Squibb Company
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`Attention: Pamela J. Smith, M.D.
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`Group Director, Global Regulatory Strategy
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`P.O. Box 4000
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`Princeton, NJ 08543-4000
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`Dear Dr. Smith:
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`Please refer to your New Drug Application (NDA) dated December 29, 2009, received
`December 29, 2009, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic
`Act (FDCA) for Kombiglyze XR (saxagliptin/metformin hydrochloride extended-release)
`tablets, 5 mg saxagliptin/500 mg metformin hydrochloride extended-release, 5 mg
`saxagliptin/1000 mg metformin hydrochloride extended-release, and 2.5 mg saxagliptin/1000 mg
`metformin hydrochloride extended-release.
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`We acknowledge receipt of your amendments dated January 12, February 5, March 10 and 23,
`April 23, 26, 28, and 29, May 25, 27, and 28, June 16, July 20 and 23, August 3 and 13 (2),
`September 1, 21, 22, 24 (2), 28, 29 (2), and 30, October 6, 7, 8, 12, 19, 22, 27, and 28, and
`November 1, 2010.
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`This new drug application provides for the use of Kombiglyze XR (saxagliptin/metformin
`hydrochloride extended-release) tablets as an adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and
`metformin is appropriate.
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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 enclosed agreed-upon labeling text.
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`Sufficient stability data have been submitted to support a 21-month expiration dating period for
`the bottle presentations and a 15-month expiration dating period for the blister presentations.
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`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.
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`Reference ID: 2860621
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` NDA 200678
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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, via the FDA
`automated drug registration and listing system (eLIST), the content of labeling
`[21 CFR 314.50(l)] in structured product labeling (SPL) format, as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm, that is
`identical to the enclosed labeling (text for the package insert and the patient package insert).
`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
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
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`The SPL will be accessible via publicly available labeling repositories.
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`CARTON AND IMMEDIATE CONTAINER LABELS
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`Submit final printed carton and container labels that are identical to the carton and immediate
`container labels submitted on October 22, 2010, 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 200678.”
`Approval of this submission by FDA is not required before the labeling is used.
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`Marketing the product(s) 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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`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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`We are waiving the pediatric study requirement for ages 0 to 9 years (inclusive) because the
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`necessary studies are impossible or highly impracticable (there are too few children in this age range
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`with type 2 diabetes mellitus to study).
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`We are deferring submission of your pediatric study for ages 10 to 16 years for this application
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` because this product is ready for approval for use in adults and the pediatric studies have not
`been completed.
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`Reference ID: 2860621
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` NDA 200678
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` Page 3
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`Your deferred pediatric studies required by section 505B(a) of the Federal Food, Drug, and
`Cosmetic Act are required postmarketing studies. The status of these postmarketing studies must
`be reported annually according to 21 CFR 314.81 and section 505B(a)(3)(B) of the Federal Food,
`Drug, and Cosmetic Act. These required studies are listed below.
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`PMR 1703-1: A clinical pharmacology study in pediatric patients with type 2 diabetes
`comparing the pharmacokinetics of Kombiglyze XR to co-administered saxagliptin and
`metformin immediate-release tablets. As part of this study, you must evaluate whether pediatric
`patients can safely swallow the large Kombiglyze XR tablets.
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`Final Protocol Submission: by October 31, 2011
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`Trial Completion:
`by January 31, 2013
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`Final Report Submission:
`by December 2013
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`PMR 1703-2: A 52-week, randomized, double-blind, placebo-controlled trial to evaluate the
`efficacy and safety of saxagliptin vs. placebo, both as add-on therapy to metformin in pediatric
`patients with inadequate glycemic control on metformin alone. Approximately one-half of the
`patients must be on metformin extended-release therapy at the time of randomization to add-on
`saxagliptin vs. add-on placebo. As part of this study, you must evaluate whether pediatric
`patients can safely swallow the large metformin extended-release tablets.
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`Final Protocol Submission: by June 30, 2011
`Trial Completion:
`by April 30, 2015
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`Final Report Submission:
`by December 31, 2015
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`Submit final study reports to this NDA. For administrative purposes, all submissions related to
`these required pediatric postmarketing studies must be clearly designated “Required Pediatric
`Assessment(s)”.
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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, 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:
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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 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
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`2253. For instruction on completing the Form FDA 2253, see page 2 of the Form. For more
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`Reference ID: 2860621
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`NDA 200678
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`Page 4
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`information about submission of promotional materials to the Division of Drug Marketing,
`Advertising, and Communications (DDMAC), see
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`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
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`LETTERS TO HEALTH CARE PROFESSIONALS
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`If you decide to issue a letter communicating important safety-related information about this
`drug product (i.e., a “Dear Health Care Professional” letter), we request that you submit, at least
`24 hours prior to issuing the letter, an electronic copy of the letter to this NDA to the following
`address:
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`MedWatch Program
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`Office of Special Health Issues
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`Food and Drug Administration
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`10903 New Hampshire Ave
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`Building 32, Mail Stop 5353
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`Silver Spring, MD 20993
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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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`If you have any questions, call Raymond Chiang, Consumer Safety Officer, at (301) 796-1940.
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`Sincerely,
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` {See appended electronic signature page}
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`Mary H. Parks, M.D.
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` Director
`Division of Metabolism and Endocrinology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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`ENCLOSURES:
`Package Insert
`Patient Package Insert
`Container Label – 2.5 mg/1000mg, 6 tablet blister card (sample)
`Container Label – 2.5mg/1000mg, 60 tablet bottle
`Container Label – 2.5 mg/1000mg, 500 tablet bottle
`Container Label – 5mg/500mg, 7 tablet blister card (sample)
`Container Label – 5mg/500mg, 30 tablet bottle
`Container Label – 5 mg/1000mg, 7 tablet blister card (sample)
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`Reference ID: 2860621
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`NDA 200678
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`Page 5
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`Container Label – 5 mg/ 1000mg, 30 tablet bottle
`Container Label – 5mg/1000mg, 90 tablet bottle
`Container Label – 5 mg/1000mg, 500 tablet bottle
`Carton Label - 2.5 mg/1000mg, 6 tablets (sample)
`Carton Label – 5mg/500mg, 7 tablets (sample)
`Carton Label – 5mg/1000mg, 7 tablets (sample)
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`Reference ID: 2860621
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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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`MARY H PARKS
`11/05/2010
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`Reference ID: 2860621
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