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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 200678/S-003
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`NDA 200678/S-004
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`Food and Drug Administration
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`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`Bristol-Myers Squibb Company
`Attention: Pamela J. Smith, M.D.
`Group Director, GRS
`P.O. Box 4000
`Princeton, NJ 08543-4000
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`Dear Dr. Smith:
`
`Please refer to your Supplemental New Drug Applications (sNDA) dated and received on May
`18, 2011, 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/500
`mg, 5 mg/1000 mg, and 2.5 mg/1000 mg.
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`We acknowledge receipt of your amendments dated September 14 (2) (S-003), October 14 (S-
`003 and S-004), December 16 (S-003 and S-004), 2011 and January 31 (S-003 and S-004), 2012.
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`We also acknowledge receipt of your email dated March 1, 2012, that includes the agreed-upon
`labeling.
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`The “Prior Approval” supplemental new drug applications provide for modifications to the
`Medication Guide, changes to the RECENT MAJOR CHANGES, INDICATIONS AND
`USAGE, WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS sections of the
`Highlights of Prescribing Information section, and changes to the INDICATIONS AND
`USAGE, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS,
`ADVERSE REACTIONS, CLINICAL PHARMACOLOGY AND CLINICAL STUDIES
`sections of the Full Prescribing Information section of the Kombiglyze XR package insert.
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`These changes are based on the safety and efficacy results from study CV181057, entitled “A
`multicenter, randomized, double-blind, phase 3 trial to evaluate the efficacy and safety of
`saxagliptin added to insulin monotherapy or to insulin in combination with metformin in subjects
`with type 2 diabetes who have inadequate glycemic control on insulin alone or on insulin in
`combination with metformin” (S-003), study CV181067, entitled “The effect of saxagliptin on
`the pharmacokinetics of the active moiety of a combined oral contraceptive containing ethinyl
`estradiol and norgestimate in healthy female subjects” (S-004), and study CV181054, entitled “A
`52 week, randomized, double-blind, active-comparator controlled, phase 3b study to evaluate the
`efficacy and safety of saxagliptin in combination with metformin compared with an sulfonylurea
`(SU) in combination with metformin in adults with type 2 diabetes who have inadequate
`glycemic control on metformin therapy alone” (S-004). All three studies included in these
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`Reference ID: 3097788
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` NDA 200678/S-003
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` NDA 200678/S-004
`Page 2
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`submissions have been previously reviewed under the saxagliptin NDA and are already labeled
`for saxagliptin.
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`We have completed our review of the 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.
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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
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`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 Medication
`Guide), 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
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`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 for this NDA, 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 this
`supplemental application, 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 your application, you are exempt from this requirement.
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`Reference ID: 3097788
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` NDA 200678/S-003
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` NDA 200678/S-004
`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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`Food and Drug Administration
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`Center for Drug Evaluation and Research
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`Office of Prescription Drug Promotion (OPDP)
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`5901-B Ammendale Road
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`Beltsville, MD 20705-1266
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`You must submit final promotional materials and package insert(s), accompanied by a Form
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`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
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`FDA 2253 is available at http://www.fda.gov/opacom/morechoices/fdaforms/cder.html;
`instructions are provided on page 2 of the form. 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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`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, Regulatory Project Manager, 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.
`Director
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`Division of Metabolism and Endocrinology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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`ENCLOSURES:
`Package Insert
`Medication Guide
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`Reference ID: 3097788
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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
`03/07/2012
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`Reference ID: 3097788
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