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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 022406/S-024
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`Food and Drug Administration
`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`Janssen Pharmaceuticals, Inc.
`Attention: Huy Truong, MS
`Associate Director, Global Regulatory Affairs
`920 U.S. Highway 202, PO Box 300
`Raritan, NJ 08869-0602
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`Dear Mr. Truong:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated April 28, 2017, received
`April 28, 2017, and your amendments, submitted under section 505(b) of the Federal Food,
`Drug, and Cosmetic Act (FDCA) for XARELTO® (rivaroxaban) tablets, 10 mg, 15 mg, and 20
`mg.
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`We also refer to our approval letter dated October 27, 2017 which contained the following error:
`incorrect signature block.
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`This replacement approval letter incorporates the correction of the error. The effective approval
`date will remain October 27, 2017, the date of the original approval letter.
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`This Prior Approval supplemental new drug application provides for the new dosing regimen of
`10 mg once daily for the reduction in the risk of recurrence of deep vein thrombosis (DVT)
`and/or pulmonary embolism (PE) in patients at continued risk for DVT and/or PE after
`completion of initial treatment lasting at least 6 months.
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`APPROVAL & LABELING
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`We have completed our review of this supplemental 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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`WAIVER OF HIGHLIGHTS SECTION
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`Please note that we have previously granted a waiver of the requirements of 21 CFR
`201.57(d)(8) regarding the length of Highlights of prescribing information.
`
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`Reference ID: 4173711
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`NDA 022406/S-024
`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 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, except with the revisions indicated, the enclosed labeling (text
`for the package insert, 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
`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 via 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 with the revisions
`indicated above 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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`We remind you of the following PREA PMRs listed in the November 2, 2012 supplement
`approval letter as follows:
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`PMR 1966-4 Conduct a single-dose PK/PD and tolerability trial in pediatric patients age birth
`to < 6 months with VTE to determine doses of rivaroxaban (oral suspension) that
`provide similar exposure and/or PD effect to those seen in older pediatric cohorts.
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`Trial Completion:
`Final Report Submission:
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`12/2019
`6/2020
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`Reference ID: 4173711
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`NDA 022406/S-024
`Page 3
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`PMR 1966-5 Conduct a dose-exploration, multicenter clinical trial evaluating the multiple dose
`PK/PD profile and safety of oral rivaroxaban (oral suspension) in pediatric
`patients aged birth to <6 months with VTE.
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`Trial Completion:
`Final Report Submission:
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`12/2019
`12/2020
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`PMR 1966-6 Conduct a randomized, active-controlled, multicenter clinical trial evaluating the
`safety, efficacy and PK/PD (sparse sampling) of at least 3 months of treatment
`with oral rivaroxaban (tablets or oral suspension) in pediatric patients aged birth
`to < 17 years of age who have acute VTE. Patients who require treatment for
`longer than 3 months will be offered continuation of treatment in an open label
`extension of this study with treatment duration of up to 12 months. Patients from
`birth to <6 months of age may be enrolled only after data from a planned interim
`analysis have shown efficacy and safety of rivaroxaban in the older pediatric age
`groups. Age distribution of patients in the study should reflect the occurrence of
`VTE in the pediatric population.
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`Trial Completion:
`Final Report Submission:
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`12/2022
`6/2023
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`The above PMRs are also applicable to Supplement S-024.
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`Submit the protocol(s) to your IND 064892, with a cross-reference letter to this NDA.
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`Reports of these required pediatric postmarketing studies must be submitted as a new drug
`application (NDA) or as a supplement to your approved NDA with the proposed labeling
`changes you believe are warranted based on the data derived from these studies. When
`submitting the reports, please clearly mark your submission "SUBMISSION OF REQUIRED
`PEDIATRIC ASSESSMENTS" in large font, bolded type at the beginning of the cover letter of
`the submission.
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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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`Reference ID: 4173711
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`NDA 022406/S-024
`Page 4
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`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
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`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`For more information about submitting promotional materials in eCTD format, see the draft
`Guidance for Industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
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`You must submit final promotional materials and package insert(s), accompanied by a Form
`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
`FDA 2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. 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, contact Katie Chon, Regulatory Project Manager at
`katie.chon@fda.hhs.gov or (240) 402-6578.
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`Sincerely,
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`{See appended electronic signature page}
`
`Albert Deisseroth, MD, PhD
`Supervisory Associate Division Director
`Division of Hematology Products
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
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`ENCLOSURE:
`Content of Labeling
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`Reference ID: 4173711
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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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`ALBERT B DEISSEROTH
`10/27/2017
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`Reference ID: 4173711
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