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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 202155
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`Food and Drug Administration
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`Silver Spring MD 20993
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`NDA APPROVAL
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`Bristol-Myers Squibb
`ATTENTION: Linda Gambone, Ph.D.
`Associate Director, Global Regulatory Sciences
`P.O. Box 4000
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`Princeton, NJ 08543-4000
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`Dear Dr. Gambone:
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`Please refer to your New Drug Application (NDA) dated September 28, 2011, received September 28,
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`2011, submitted under section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act for Eliquis
`(apixaban) 2.5 and 5 mg Tablets.
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`We acknowledge receipt of your amendments dated June 27, July 3, 11, 18, and 24, August 14, 22, 30,
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`and 31, September 17, October 10 and 17, November 15 and 29, and December 14, 21, and 28, 2012.
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`The September 17, 2012, submission constituted a complete response to our June 22, 2012, action letter.
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`This new drug application provides for the use of Eliquis (apixaban) tablets for the following indication:
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`ELIQUIS (apixaban) is indicated to reduce the risk of stroke and systemic embolism in patients
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`with nonvalvular atrial fibrillation.
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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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`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 labeling
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`[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).
`Information on submitting SPL files using eLIST may be found in the guidance for industry SPL
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`Standard for Content of Labeling Technical Qs and As, available at
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`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM0723
`92.pdf.
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`The SPL will be accessible via publicly available labeling repositories.
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`Reference ID: 3237516
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` NDA 202155 – Approval Letter
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` Page 2
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`We request that the labeling approved today be available on your website within 10 days of receipt of this
`letter.
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`CARTON AND IMMEDIATE-CONTAINER LABELS
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`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 Providing Regulatory
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`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
`202155.” 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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`MARKET PACKAGE
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`Please submit one market package of the drug product when it is available to the following address:
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`Alison Blaus
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`Food and Drug Administration
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`Center for Drug Evaluation and Research
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`White Oak Building 22, Room: 4158
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`10903 New Hampshire Avenue
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`Silver Spring, Maryland
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`Use zip code 20903 if shipping via United States Postal Service (USPS).
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`Use zip code 20993 if sending via any carrier other than USPS (e.g., UPS, DHL, FedEx).
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`ADVISORY COMMITTEE
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`Your application for ELIQUIS was not referred to an FDA advisory committee because the application
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`did not raise significant safety or efficacy issues that were unexpected for a drug of this class and in the
`intended population.
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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 this application because necessary studies are
`impossible or highly impracticable because the disease is rare in children.
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`Reference ID: 3237516
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` NDA 202155 – Approval Letter
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` Page 3
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` RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
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`Section 505-1 of the FDCA authorizes FDA to require the submission of a risk evaluation and mitigation
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` strategy (REMS), if FDA determines that such a strategy is necessary to ensure that the benefits of the
` drug outweigh the risks [section 505-1(a)]. The details of the REMS requirements were outlined in our
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` REMS notification letter dated February 3, 2012.
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`Your proposed REMS, submitted on December 21 and 28, 2012, and appended to this letter, is approved.
`The REMS consists of a communication plan and a timetable for submission of assessments of the
`REMS.
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`Your REMS must be fully operational before you introduce Eliquis into interstate commerce.
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`The REMS assessment plan should include, but is not limited to, the following:
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`1. A report on the distribution of DHCP letters and Professional Organization Letters
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`2. An evaluation of healthcare providers’ awareness and understanding of the serious risks
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`associated with ELIQUIS (for example, through surveys of healthcare providers).
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`3. With respect to the REMS goals, an assessment of the extent to which the REMS is meeting its
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`goals or whether the goals or other elements should be modified.
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`The requirements for assessments of an approved REMS under section 505-1(g)(3) includes with respect
`to each goal included in the strategy, an assessment of the extent to which the approved strategy,
`including each element of the strategy, is meeting the goal or whether one or more such goals or such
`elements should be modified.
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`We remind you that in addition to the assessments submitted according to the timetable included in the
`approved REMS, you must submit a REMS assessment and may propose a modification to the approved
`REMS when you submit a supplemental application for a new indication for use as described in section
`505-1(g)(2)(A) of the FDCA.
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`If the assessment instruments and methodology for your REMS assessments are not included in the
`REMS supporting document, or if you propose changes to the submitted assessment instruments or
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`methodology, you should update the REMS supporting document to include specific assessment
`instrument and methodology information at least 90 days before the assessments will be conducted.
`Updates to the REMS supporting document may be included in a new document that references previous
`REMS supporting document submission(s) for unchanged portions. Alternatively, updates may be made
`by modifying the complete previous REMS supporting document, with all changes marked and
`highlighted. Prominently identify the submission containing the assessment instruments and
`methodology with the following wording in bold capital letters at the top of the first page of the
`submission:
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`NDA 202155 REMS CORRESPONDENCE
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`(insert concise description of content in bold capital letters, e.g.,
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`UPDATE TO REMS SUPPORTING DOCUMENT - ASSESSMENT METHODOLOGY)
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`An authorized generic drug under this NDA must have an approved REMS prior to marketing. Should
`you decide to market, sell, or distribute an authorized generic drug under this NDA, contact us to discuss
`what will be required in the authorized generic drug REMS submission.
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`Reference ID: 3237516
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` NDA 202155 – Approval Letter
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` Page 4
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`Prominently identify the submission containing the REMS assessments or proposed modifications with
`the following wording in bold capital letters at the top of the first page of the submission:
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`NDA 202155 REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 202155
`PROPOSED REMS MODIFICATION
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`REMS ASSESSMENT
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`FOR NDA 202155
`REMS ASSESSMENT
`PROPOSED REMS MODIFICATION (if included)
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`If you do not submit electronically, please send 5 copies of REMS-related submissions.
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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
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`mock-up form with annotated references, and the package insert to:
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`Food and Drug Administration
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`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`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 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 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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`MEDWATCH-TO-MANUFACTURER PROGRAM
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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
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`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.
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`Reference ID: 3237516
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` NDA 202155 – Approval Letter
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` Page 5
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` POST-ACTION FEEDBACK MEETING
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`New molecular entities and new biologics qualify for a post-action feedback meeting. Such meetings are
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` 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
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` review process and to identify areas that could benefit from improvement. If you would like to have such
`a meeting with us, call the Regulatory Project Manager for this application.
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`If you have any questions, please call:
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`Alison Blaus
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`Regulatory Project Manager
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`(301) 796-1138
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`{See appended electronic signature page}
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`Sincerely,
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`Robert Temple, M.D.
`Deputy Director
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
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`Enclosures:
`Content of Labeling
`Carton and Container Labeling
`REMS
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`Reference ID: 3237516
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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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`ROBERT TEMPLE
`12/28/2012
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`Reference ID: 3237516
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