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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 022406/S-001
`NDA 022406/S-002
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`NDA 022406/S-003
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`Food and Drug Administration
`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`Janssen Research & Development, LLC
`Attention: Huy Q. Truong
`Associate Director, Global Regulatory Affairs
`920 Highway 202, South
`P.O. Box 300
`Raritan, NJ 08869
`
`
`Dear Mr. Truong:
`
`Please refer to your Supplemental New Drug Applications (sNDAs) dated May 1 and 28, 2012,
`received May 2 and 29, 2012, submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act (FDCA) for XARELTO® (rivaroxaban) 15 and 20 mg immediate release tablets.
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`We acknowledge receipt of your amendments dated May 7, 28, July 26, 30, 31,
`August 2, 3, 6, 27, 29, September 4, 27, October 4, 19, 23 and November 2, 2012.
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`These “Prior Approval” supplemental new drug applications provide for the treatment of deep
`vein thrombosis, the treatment of pulmonary embolism, the reduction in risk for deep vein
`thrombosis and the reduction in risk for pulmonary embolism.
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`We have completed our review of these supplemental applications, as amended. They are
`approved, effective on the date of this letter, for use as recommended in the agreed-upon labeling
`text and with the minor editorial revisions listed below.
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`
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`In the highlights section, 2nd bullet: remove the underline for "15 mg orally...21".
`(Treatment of DVT, PE, and Reduction in the Risk of Recurrence of DVT and of PE:
`15 mg orally twice daily with food for the first 21)
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`
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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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`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
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`Reference ID: 3212129
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`

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`
` NDA 22406 S-001, S-002, S-003
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`Page 2
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`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 these
`supplemental applications, 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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`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 May 2, 2012, as soon as they are available, but no more than 30
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`days after they are printed.
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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 deferring submission of your pediatric studies until October 2013, April 2014, July 2015
`and October 2017, respectively, because this product is ready for approval for use in adults and
`the pediatric studies have not been completed.
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`Your deferred pediatric studies required under section 505B(a) of the FDCA 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 FDCA. The required studies are
`listed below.
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`PMR 1966-1 Submit the results of a single-dose pharmacokinetic (PK)/pharmacodynamic (PD)
`and tolerability trial in pediatric patients aged ≥ 6 months to < 17 years with
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`Reference ID: 3212129
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`

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` NDA 22406 S-001, S-002, S-003
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`Page 3
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`venous thromboembolic event(s) (VTE) in appropriate age cohorts to determine
`dosing of rivaroxaban (tablets and oral suspension) that will provide similar
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`exposure and/or PD effect compared to recommended doses in adults. Enroll into
`sequential age cohorts (e.g., beginning with 12 to < 17 years) and use the
`information from the older age cohorts to inform dosing in the younger age
`cohorts.
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`Final Protocol Submission: 6/2013
`Trial Completion:
`12/2014
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`Final Report Submission:
`6/2015
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`Conduct a randomized, dose-exploration, multicenter clinical trial evaluating the
`multiple dose PK/PD profile and safety of oral rivaroxaban (tablets or oral
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`suspension) in pediatric patients aged 6 years to <17 years with VTE. Enroll into
`sequential age cohorts (e.g., beginning with ages 12 to < 17 years) and use the
`information from the older age cohorts to inform dosing in the younger age
`cohorts.
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`Final Protocol Submission: 6/2013
`Trial Completion:
`6/2016
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`Final Report Submission:
`6/2017
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`Conduct a randomized, dose-exploration, multicenter clinical trial evaluating the
`multiple dose PK/PD profile and safety of oral rivaroxaban (tablets or oral
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`suspension) in pediatric patients aged 6 months to < 6 years with VTE.
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`Final Protocol Submission: 12/2016
`Trial Completion:
`12/2019
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`Final Report Submission:
`6/2020
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`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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`PMR 1966-2
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`PMR 1966-3
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`PMR 1966-4
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`Final Protocol Submission: 12/2015
`Trial Completion:
`12/2019
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`Final Report Submission:
`6/2020
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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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`Final Protocol Submission:
`Trial Completion:
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`Final Report Submission:
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`12/2015
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`12/2019
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`12/2020
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`Reference ID: 3212129
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`

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` NDA 22406 S-001, S-002, S-003
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`Page 4
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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
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`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
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`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
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`birth to <6 months of age may be enrolled only after data from a planned interim
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`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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`Final Protocol Submission:
`Trial Completion:
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`Final Report Submission:
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`6/2017
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`12/2022
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`6/2023
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`Submit the protocols 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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`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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`Reference ID: 3212129
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`

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` NDA 22406 S-001, S-002, S-003
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`Page 5
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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 Tyree Newman, Regulatory Project Manager, at (301) 796-3907.
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`Sincerely,
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` {See appended electronic signature page}
`
`Ann T. Farrell, M.D.
`Director
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`Division of Hematology Products
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
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`ENCLOSURE(S):
`Content of Labeling
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`Reference ID: 3212129
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`

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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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`ANN T FARRELL
`11/02/2012
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`Reference ID: 3212129
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`