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`Food and Drug Administration
`Silver Spring MD 20993
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`NDA APPROVAL
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 022406
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`Johnson and Johnson Pharmaceutical Research and Development, LLC
`Attention: Andrea F. Kollath, DVM
`Director, Regulatory Affairs
`920 Route 202, P.O. Box 300
`Raritan, NJ 08869
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`Dear Dr. Kollath:
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`Please refer to your New Drug Application (NDA) dated July 28, 2008, received July 28, 2008,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`Xarelto® (rivaroxaban) 10 mg immediate release Tablets.
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`We acknowledge receipt of your amendments dated January 4, February 2, 18, 25, March 25,
`April 18, 25, 26, 28, May 2, 4, 6, 10, 11, 25 and June 8, 20 and 30, 2011.
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`The December 30, 2010, submission constituted a complete response to our May 27, 2009,
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`action letter.
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`This new drug application provides for the use of Xarelto® (rivaroxaban) 10 mg immediate
`release Tablets, for the prophylaxis of deep vein thrombosis and pulmonary embolism in patients
`undergoing: hip replacement surgery or knee replacement surgery.
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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 [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. Information on
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`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.
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` NDA 22406
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`Page 2
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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 enclosed carton and
`immediate container labels, except with the revisions listed above, 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 22406.” Approval of this submission by FDA is not required before the labeling
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`is used.
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`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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`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 and because there are too few children with disease/condition
`to study.
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`POSTMARKETING REQUIREMENTS UNDER 505(o)
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`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.
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`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 the serious risks of major
`bleeding events and renal impairment.
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`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
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`505(k)(3) of the FDCA will not be sufficient to assess these serious risks.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
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` NDA 22406
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`Page 3
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` PMR 1797-1 A postmarketing pharmacovigilance study of the risk factors, clinical
`management, and outcome of cases of major bleeding in association with
`Xarelto® (rivaroxaban) use.
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`You agree to conduct an “Enhanced Pharmacovigilance Plan” that will consist of the collection,
`analysis, and reporting of events termed “major bleeding,” to consist of active solicitation of the
`events and associated risk factors, subsequent therapy, and outcomes. Major bleeding is defined
`as in the clinical protocols and current drug labeling.
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`You agree to provide reports quarterly for the first three years following drug approval, then
`annually. The final plan will be submitted by October 30, 2011.
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`Submit summary information (total cases and summary of key facts in those cases, with pertinent
`expert analysis of clinically relevant information from the case series and any potential
`regulatory implications such as label changes) quarterly for 3 years, then annually.
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`The timetable you submitted on June 30, 2011 states that you will conduct this study according
`to the following schedule.
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`Final Protocol Submission: November 30, 2011
`Interim report submission: Quarterly thereafter for 3 years, then annually
`Study Completion:
`June 30, 2016
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`Final Report Submission: December 30, 2018
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`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to assess the serious risks of renal impairment.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
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`PMR 1797-2 Perform a clinical trial to evaluate the effect of renal impairment (i.e., mild,
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`moderate, severe) plus the concurrent use of P-gp and moderate inhibitors of
`CYP3A4 on the pharmacokinetics, pharmacodynamics, and safety of rivaroxaban
`in volunteers so that appropriate dosing recommendations can be developed in
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`these populations.
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`The timetable you submitted on June 30, 2011, states that you will conduct this trial according to
`the following schedule:
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`Final Protocol Submission: Submitted February 4, 2011
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`Trial Completion:
`February 29, 2012
`Final Report Submission:
`June 30, 2012
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`Submit protocols to your IND 64892, with a cross-reference letter to this NDA. Submit all final
`reports to your NDA. Prominently identify each submission with the following wording in bold
`capital letters at the top of the first page of the submission, as appropriate: “Required
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` NDA 22406
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`Page 4
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`Postmarketing Protocol Under 505(o)”, “Required Postmarketing Final Report Under
`505(o)”, “Required Postmarketing Correspondence Under 505(o)”.
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`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.
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`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.
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`POSTMARKETING COMMITMENT NOT SUBJECT TO THE REPORTING
`REQUIREMENTS UNDER SECTION 506B
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`We remind you of your postmarketing commitment:
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`PMC 1797-3 Develop and propose a 5 mg strength tablet or scored 10 mg tablet to allow for
`proper dose titration when rivaroxaban needs to be co-administered in patients at
`risk for clinically relevant changes in rivaroxaban exposure. For a scored 10 mg
`tablet, show that half-tablets follow the same dissolution profile and specifications
`(based on percent) as the whole and show that the half-tablets are otherwise
`proportionately equivalent. A 5 mg strength tablet should be sufficiently
`distinguishable from the 10 mg tablet in physical characteristics. If feasible, we
`recommend that you consider a proportional formulation for a 5 mg strength
`tablet. Full chemistry, manufacturing and controls (CMC) information for a 5 mg
`tablet including the batch data and stability data, labels, updated labeling, a
`request for a biowaiver for the lower 5 mg strength based on [proportional]
`formulation and the F2 metric, and an updated environmental assessment section
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`will be submitted in a prior approval supplement.
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`The timetable you submitted on June 30, 2011, states that you will conduct this study according
`to the following schedule:
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`Final CMC Supplement Submission: April 2012
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` NDA 22406
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`Page 5
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`Submit chemistry, manufacturing, and controls protocols and all 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 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, for clinical studies/trials, number of patients entered into each
`study/trial. All submissions, including supplements, relating to these postmarketing
`commitments should be prominently labeled “Postmarketing Commitment Protocol,”
`“Postmarketing Commitment Final Report,” or “Postmarketing Commitment
`Correspondence.”
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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
`2253. For instruction on completing the Form FDA 2253, see page 2 of the Form. For more
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`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.
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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 this product. To participate in the program, please see the enrollment
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`instructions and program description details at
`http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
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` NDA 22406
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`Page 6
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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 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 review process and to identify areas that could benefit from
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`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, call Tyree Newman, Regulatory Project Manager, at (301) 796-3907.
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`ENCLOSURE(S):
`Content of Labeling
`Carton and Container Labeling
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`Sincerely,
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` {See appended electronic signature page}
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`Richard Pazdur, M.D.
`Director
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`Office of Oncology Drug Products
`Center for Drug Evaluation and Research
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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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`RICHARD PAZDUR
`07/01/2011
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`Reference ID: 2968773
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