CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`022406Orig1s000
`
`
`
`OTHER REVIEW(S)
`
`

`

`
`
`Attachment B: Sample PMR/PMC Development Template
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`PMR/PMC Description: PMR for Rivaroxaban:
`Perform a clinical trial to evaluate the effect of renal impairment (i.e., mild,
`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
`these populations.
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Study/Ttrial Completion:
`Final Report Submission:
`Other:
`
`
`
`
`
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
` Submitted
`02/04/11
` 2/29/2012
` 6/30/2012
` MM/DD/YYYY
`
`
`
`Affects patients with renal impairment (i.e., mild, moderate, severe) plus the concurrent use of P-gp
`and moderate inhibitors of CYP3A4 in combination with renal impairment
`
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is
`a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new
`safety information.”
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 7/1/2011
`
`Page 1 of 4
`
`Reference ID: 2968719
`
`

`

`
`
`The applicant reports that based on its simulations using a population pharmacokinetic
`approach, it anticipates that combined use of a drug that would inhibit non-renal
`clearance by 30% and inhibit active renal clearance by 45% in patients with mild or
`moderate renal impairment may result in an approximate 2 and 2.4 fold increase in
`plasma AUC, respectively, when compared to subjects which is considered significant. Using a
`physiologically based (PBPK) modeling approach FDA reached similar results, but also found that
`this complex DDI may be more pronounced in the elderly.
`
`3. If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
` Accelerated Approval (subpart H/E)
` Animal Efficacy Rule
` Pediatric Research Equity Act
` FDAAA required safety study/clinical trial
`
`
`
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
` Assess a known serious risk related to the use of the drug?
` Assess signals of serious risk related to the use of the drug?
` Identify an unexpected serious risk when available data indicate the potential for a serious
`risk?
`
`
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
` Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to
`assess or identify a serious risk
`
`
`
` Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not sufficient to assess this known serious risk, or has been established but is nevertheless not
`sufficient to assess or identify a serious risk
`
` Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidemiologic studies), animal studies, and laboratory
`experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a
`serious risk
`
`
`
`
`
` Clinical trial: any prospective investigation in which the sponsor or investigator determines
`the method of assigning investigational product or other interventions to one or more human
`subjects?
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the
`study or trial will be performed in a subpopulation, list here.
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 7/1/2011
`
`Page 2 of 4
`
`Reference ID: 2968719
`
`

`

`A multicenter, open-label, sequential design trial in both healthy subjects with normal renal
`function, and otherwise healthy subjects with mild or moderate renal impairment to compare the
`pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban (administered as a
`single 5 mg and 10 mg dose) in subjects with mild or moderate renal impairment receiving multiple
`doses of erythromycin, to the pharmacokinetics and pharmacodynamics of a single 10 mg dose of
`rivaroxaban administered alone in subjects with normal renal function.
`
`The Applicant agreed to conduct this study following a October 14, 2010, with the Agency. A
`protocol synopsis was included in this CR response.
`
`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`Continuation of Question 4
`
`
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`
`
`
`
`
`
`
`
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition,
`different disease severity, or subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify)
`
` Other
`
`
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
` Does the study/clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 7/1/2011
`
`Page 3 of 4
`
`Reference ID: 2968719
`
`

`

`
`
`PMR/PMC Development Coordinator:
` This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine
`the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug
`quality.
`
`
`_______________________________________
`(signature line for BLAs)
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 7/1/2011
`
`Page 4 of 4
`
`Reference ID: 2968719
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TYREE L NEWMAN
`07/01/2011
`
`ROBERT C KANE
`07/01/2011
`
`Reference ID: 2968719
`
`

`

`
`
`PMR/PMC Development Template
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`PMR/PMC Description: PMR for Rivaroxaban:
`A postmarketing pharmacovigilance study of the risk factors, clinical
`management, and outcome of cases of major bleeding in association
`with Xarelto® (rivaroxaban) use.
`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.
`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.
`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 labeling changes) quarterly for three years, then
`annually.
`
` 11/30/2011
` 06/30/2016
` 12/30/2016
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Study/Trial Completion:
`
`Final Report Submission:
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`
`
`PMR/PMC Development Template
`
`Last Updated 7/1/2011
`
`Page 1 of 4
`
`Reference ID: 2968733
`
`

`

`
`
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is
`a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new
`safety information.”
`
`The protocol should include:
`
`
`• Definition of major bleeding (as per your protocol, transfusion of 2 units of blood or loss
`of 2 units is acceptable)
`• Methods to be used for data collection and analysis, including your solicitation of
`reports of bleeding events,
`• Plan for enhanced follow-up with reporters – you will actively query and ascertain key
`facts about the bleeding event, including:
`• Demographics (age, gender, race, location of bleeding)
`• Underlying diagnoses including specific reason for rivaroxaban treatment
`• Other relevant risk factors for bleeding
`• Dose and duration of rivaroxaban therapy
`• Concomitant medications
`• Treatment given for the bleeding (names of products, doses and duration of
`treatment)
`• Any laboratory monitoring tests performed
`• Outcome information on:
`• Bleeding outcome – time to cessation and opinion on the role of therapy given on
`the bleeding cessation
`• Survival / disability / further complications
`
`3. If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
` Accelerated Approval (subpart H/E)
` Animal Efficacy Rule
` Pediatric Research Equity Act
` FDAAA required safety study/clinical trial
`
`
`
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
` Assess a known serious risk related to the use of the drug?
` Assess signals of serious risk related to the use of the drug?
` Identify an unexpected serious risk when available data indicate the potential for a serious
`risk?
`
`
`
`PMR/PMC Development Template
`
`Last Updated 7/1/2011
`
`Page 2 of 4
`
`Reference ID: 2968733
`
`

`

`
`
`
`
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
` Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to
`assess or identify a serious risk
`
` Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not sufficient to assess this known serious risk, or has been established but is nevertheless not
`sufficient to assess or identify a serious risk
`
` Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidemiologic studies), animal studies, and laboratory
`experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a
`serious risk
`
`
`
`
`
` Clinical trial: any prospective investigation in which the sponsor or investigator determines
`the method of assigning investigational product or other interventions to one or more human
`subjects?
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the
`study or trial will be performed in a subpopulation, list here.
`“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 as defined
`in the clinical protocols and current drug labeling.
`
`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`Continuation of Question 4
`
`
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`
`
`
`
`PMR/PMC Development Template
`
`Last Updated 7/1/2011
`
`Page 3 of 4
`
`Reference ID: 2968733
`
`

`

`
`
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition,
`different disease severity, or subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify)
`
` Other
`
`
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
` Does the study/clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`
`
`PMR/PMC Development Coordinator:
` This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine
`the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug
`quality.
`
`
`_______________________________________
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 7/1/2011
`
`Page 4 of 4
`
`Reference ID: 2968733
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TYREE L NEWMAN
`07/01/2011
`
`Reference ID: 2968733
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`Date:
`
`To:
`
`Through:
`
`From:
`
`Subject:
`
`Drug Name:
`
`Application Number:
`
`Applicant:
`
`OSE RCM #:
`
`
`
`
`
`June 14, 2011
`
`Ann Farrell, MD, Director
`Division of Hematology Products
`
`Todd Bridges, RPh, Acting Deputy Director
`Carol Holquist, RPh, Director
`Division of Medication Error Prevention and Analysis (DMEPA)
`
`Denise V. Baugh, PharmD, BCPS, Safety Evaluator
`Division of Medication Error Prevention and Analysis
`
`Label and Labeling Review
`
`Xarelto (Rivaroxaban) Tablets
`10 mg
`
`NDA 22406
`
`Johnson & Johnson Pharmaceutical Research & Development
`
`2011-513
`
`
`
`
`
`
`Reference ID: 2960821
`
`2
`
`

`

` BACKGROUND
`
` 1
`
`1.1
`INTRODUCTION
`This review evaluates the container labels, carton and insert labeling for Xarelto (Rivaroxaban) Tablets
`(NDA 022406). We provide recommendations in Section 4 for improvements to the labels and labeling.
`
`2 METHODS AND MATERIALS
`The Division of Medication Error Prevention and Analysis uses Failure Mode and Effects Analysis
`(FMEA)1, principals of human factors, and lessons learned from post marketing experience in our
`evaluation of labels and labeling of drug products. For this application, we evaluated the following:
`
` – submitted December 23, 2010
`Carton labeling
`Container label (30 count) - submitted December 23, 2010
`Blister label – submitted July 29, 2008 and
`Insert labeling – substantially complete as of June 7, 2011
`
`See Appendix A for the carton labeling, container and blister labels. There is no image for the insert
`labeling.
`
`3 RESULTS
`Our review of the proposed container and blister labels, carton and insert labeling is discussed below.
`
`3.1 LABEL AND LABELING
`In our evaluation of the insert labeling, we recommended: revising the Dosage and Administration
`sections to state that the product should always be taken with food and deletion of error prone
`abbreviations. In our evaluation of the carton labeling, container and blister labels, we made
`recommendations to relocate certain statements and increase the prominence of the established name.
`
`4 CONCLUSIONS AND RECOMMENDATIONS
`Our evaluation of the proposed container and blister labels, carton and insert labeling identified areas of
`improvement to minimize medication errors. Section 4.1, Comments to the Division of Hematology
`Products, contains our recommendation for the proposed insert labeling for Xarelto. We have provided
`our recommendations on the container labels and carton labeling below in Section 4.2, Comments to the
`Applicant. Please forward these recommendations to the Applicant prior to approval.
`Please copy the Division of Medication Error Prevention and Analysis on any communication to the
`Applicant with regard to this review. If you have any further questions or need clarifications on this
`review, please contact Sue Kang, OSE Project Manager, at 301-796-4216.
`
`
`
`
`
`1 Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.
`
`
`
`
`
`Reference ID: 2960821
`
`3
`
`(b) (4)
`
`

`

`
`
`4.1
`
`COMMENTS TO THE DIVISION OF HEMATOLOGY PRODUCTS
`1.
`The Dosage and Administration sections indicate that the 10 mg dose can be taken with or
`without food
`. These instructions are likely to
`lead to confusion and medication errors as administration of a product with or without food
`is typically based upon the active ingredient(s) of the product and not the dose being
`administered. We recommend revision of the labeling to indicate that the proposed product
`should always be taken with food.
`2. We recommend using the terms “greater than” or “less than” instead of the “>” and “<”
`symbols throughout the insert labeling as these symbols have been mistaken as the opposite
`of their intended meaning. FDA launched a campaign on June 14, 2006, warning healthcare
`practitioners and consumers not to use error prone abbreviations, acronyms, dose
`designations, or symbols. As part of the campaign, FDA agreed not to use such error prone
`designations in their approved product labeling.
`3.
`Define the abbreviation “P-gp” the first time it is used in the insert labeling.
`4. We note a typographical error in Section 8.7, Renal Impairment. The words ‘with’ and
`‘and’ (following “n = 8”) should appear in reverse order.
`Add the units of measurement to Creatinine Clearance throughout the labeling and avoid
`using dashes to reflect the range (e.g., revise “CrCL 30 – 50 mL/min” in Section 8.7 to read
`“CrCL 30 mL/min to CrCL 50 mL/min”).
`The last statement in Section 2 Dosage and Administration (in Full Prescribing Information)
`regarding administration of this product via feeding tube appears to contradict the statement
`in Section 12.3 under Clinical Pharmacology. Please clarify the appropriateness of
`administration of this drug product via feeding tube.
`
`5.
`
`6.
`
`2.
`
`4.2
` COMMENTS TO THE APPLICANT
`1.
`Blister Label, Container Label and Carton Labeling
`In accordance with 21 CFR 201.10(g)(2), increase the prominence of the established name to
`be commensurate with the proprietary name taking into account all pertinent factors,
`including typography, layout, contrast, and other printing features.
`Container Label and Carton Labeling
`a. Reduce the size of the graphic which appears to the left of the ‘X’ so that it does not
`distract from the proprietary name.
`b. Relocate the strength, “10 mg” to come after the dosage form so that it reflects the
`traditional sequence of information.
` Carton Labeling (for Hospital Unit Dose Tablets)
`a. Relocate the net quantity to appear in the upper right hand corner of the panels
`
`and away from the statement of strength.
`b. Delete storage statements from principal display panel and top panel to reduce clutter on
`
`the label and decrease redundant statements
`c. Relocate the ‘each tablet contains’ statement from the side panel to the principal display
`
`panel.
`
`3.
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 2960821
`
`4
`
`3 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TODD D BRIDGES on behalf of DENISE V BAUGH
`06/14/2011
`signing for Denise Baugh also.
`
`CAROL A HOLQUIST
`06/15/2011
`
`Reference ID: 2960821
`
`

`

`
`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`NDA REVIEW AND EVALUATION OF CARCINOGENICITY DATA
`
`Application numbers:
`Supporting documents:
`Applicant’s letter dates:
`
`CDER stamp dates:
`
`22406, 202439
`In Electronic Document Room (EDR)
`22406: resubmission on 12/30/2010
`202439: original submission 01/04/11
`22406: resubmission on 01/03/11
`202439: original submission on 01/05/11
`Rivaroxaban (Bay 59-7939)
`Prevention of stroke and systemic embolism in
`patients with non-valvular atrial fibrillation.
`Ortho McNeil Janssen Pharmaceuticals Inc
`[Bayer Schering Pharma AG (Bayer) and
`Johnson & Johnson Pharmaceutical Research
`and Development, L.L.C. (J&JPRD)]
`Division of Cardiovascular and Renal Products
`Review Division:
`Patricia P. Harlow, Ph.D.
`Reviewer:
`Thomas Papoian, Ph.D., D.A.B.T.
`Supervisor/Team Leader:
`Norman Stockbridge, M.D., Ph.D.
`Division Director:
`Alison Blaus
`Project Manager:
`Template Version: September 1, 2010
`Disclaimer
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDAs 22406 and 202439 are owned by Ortho McNeil
`Janssen Pharmaceuticals Inc or are data for which Ortho McNeil Janssen
`Pharmaceuticals Inc has obtained a written right of reference. Any information or data
`necessary for approval of NDAs 22406 and 202439 that Ortho McNeil Janssen
`Pharmaceuticals Inc does not own or have a written right to reference constitutes one of
`the following: (1) published literature, or (2) a prior FDA finding of safety or effectiveness
`for a listed drug, as reflected in the drug’s approved labeling. Any data or information
`described or referenced below from reviews or publicly available summaries of a
`previously approved application is for descriptive purposes only and is not relied upon
`for approval of NDA 22406 and 202439.
`
`Product:
`Indication:
`
`Applicant:
`
`Reference ID: 2959378
`
`1
`
`

`

`NDA 202439
`
`
`
`Patricia Harlow, Ph.D.
`
`5 556 7 7788888 9 9
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY .........................................................................................
`INTRODUCTION....................................................................................................
`1.1
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ......................................................
`1.3 RECOMMENDATIONS............................................................................................
`2 DRUG INFORMATION ............................................................................................
`2.1 DRUG.................................................................................................................
`2.2 RELEVANT INDS, NDAS, BLAS AND DMFS...........................................................
`2.3 DRUG FORMULATION ...........................................................................................
`2.4 COMMENTS ON NOVEL EXCIPIENTS.......................................................................
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN .........................................
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN ......................................
`2.6
`2.7 REGULATORY BACKGROUND ................................................................................
`3 STUDIES SUBMITTED............................................................................................
`
`4 CARCINOGENICITY ...............................................................................................
`
`5
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION ....................................
`
`51
`
`
`6 APPENDIX/ATTACHMENTS.................................................................................
`
`
`53
`
`
`Reference ID: 2959378
`
`2
`
`

`

`NDA 202439
`
`
`
`Patricia Harlow, Ph.D.
`
`Table of Tables
`
`Table 1: Reviewer’s Table Summarizing Mortality in Mice - Document PH-36243........
`Table 2: Reviewer's Summary of Clinical Findings - Document PH-36243 ...................
`Table 3: Reviewer's Summary of Body Weights - Document PH-36243 .......................
`Table 4: Sponsor’s Summaries of Food and Water Intake - Document PH-36243 .......
`Table 5: Reviewer's Summary - Hematology Results - Document PH-36243...............
`Table 6: Reviewer's Summary Thromboplastin Times - Document PH-36243..............
`Table 7: Reviewer's List of Organs Collected - Document PH-36243 ...........................
`Table 8: Reviewer's Summary of Necropsy Findings - Document PH-36243................
`Table 9: Sponsor's Summaries of Organ Weights - Document PH-36243 ....................
`Table 10: Reviewer's Summary of Neoplastic Findings – Document PH-36243 ...........
`Table 11: Reviewer's Summary Non-neoplastic Lesions – Document PH-36243 .........
`Table 12: Reviewer's Summary of Toxicokinetics in Mice - Document PH-36243 ........
`Table 13: Reviewer's Summary of Formulation Analysis - Document PH-36243..........
`Table 14: Reviewer's Summary of Rat Mortality – Document PH-36242 ......................
`Table 15: Reviewer's Summary of Notable Clinical Signs – Document PH-36242........
`Table 16: Reviewer's Summary of Body Weights – Document PH-36242 ....................
`Table 17 : Sponsor's Summaries of Food and Water Intake – Document PH-36242....
`Table 18: Reviewer's Summary of Hematology Parameters – Document PH-36242....
`Table 19: Reviewer's Summary of Thromboplastin Times – Document PH-36242.......
`Table 20: Sponsor's Summary of Clinical Chemistry - A – Document PH-36242..........
`Table 21: Sponsor's Summary of Clinical Chemistry - Part B - Document PH-36242 ...
`Table 22: Reviewer's Summary of Serum Potassium Values - Document PH-36242 ...
`Table 23: Reviewer's Summary of Tissues Collected - Document PH-36242...............
`Table 24: Reviewer's Summary of Gross Pathology - Document PH-36242.................
`Table 25: Sponsor's Summaries of Organ Weights - Document PH-36242 ..................
`Table 26: Reviewer's Summary of Spleen Weights - Document PH-36242 ..................
`Table 27: Reviewer's Summary – Neoplastic Lesions - Document PH-36242 ..............
`Table 28: Reviewer's Summary - Non-neoplastic Lesions - Document PH-36242........
`Table 29: Reviewer's Summary of Toxicokinetic Results – Document PH-36242.........
`Table 30: Reviewer's Summary of Formulation Analyses – Document PH-36242........
`Table 31: Safety Margins for Human Dose of 20 mg Rivaroxaban Daily.......................
`Table 32: Safety Margins for Human Dose of 10 mg Rivaroxaban Daily.......................
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`Reference ID: 2959378
`
`3
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`

`

`NDA 202439
`
`
`
`Patricia Harlow, Ph.D.
`
`Table of Figures
`
` 7
`Figure 1: Structure of Rivaroxaban .................................................................................
`Figure 2: Reviewer's Survival Graphs - Document PH-36243.......................................
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`Figure 3: Sponsor's Body Weight Graphs - Document PH-36243.................................
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`Figure 4: Sponsor's Concentration-Time Profiles in Mice - Document PH-36243 .........
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`Figure 5: Reviewer's Survival Graphs - Document PH-36242.......................................
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`Figure 6: Sponsor's Body Weight Graphs – Document PH-36242................................
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`Figure 7: Sponsor's Plasma Concentration Profiles – Document PH-36242.................
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`Reference ID: 2959378
`
`4
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`

`

`NDA 202439
`
`
`
`Patricia Harlow, Ph.D.
`
`1
`
`Executive Summary
`
`Introduction
`1.1
`Rivaroxaban is a direct factor Xa inhibitor being developed for the prevention and
`treatment of multiple thrombosis-mediated conditions, including short-term prophylaxis
`of deep vein thrombosis in patients undergoing knee or hip replacement surgery under
`NDA 22406 and for the longer-term prevention of stroke and systemic embolism in
`patients with non-valvular atrial fibrillation under NDA 202439.
`According to the ICH Guideline S1A (1996), “Carcinogenicity studies should be
`performed for any pharmaceutical whose expected clinical use is continuous for at least
`6 months. For the longer-term indication under NDA 202439, the study reports of the
`carcinogenicity studies were submitted and reviewed. However, this document was
`written separately from the remainder of the nonclinical review for NDA 202439 to
`support similar incorporation of the carcinogenicity results into the label for the shorter-
`term indication under NDA 22406.
`
`1.2 Brief Discussion of Nonclinical Findings
`Two year carcinogenicity studies were conducted in CD-1 mice and Wistar rats.
`In an adequate 104-week study using 60 CD-1 mice/sex/group, daily doses of 0, 10, 20,
`and 60 mg/kg/day of rivaroxaban in ethanol/solutol HS/tap water (10/40/50% v/v) were
`administered by oral gavage. The systemic exposures (AUCs) of unbound rivaroxaban
`in male and female mice at the highest dose tested (60 mg/kg/day) were 1- and 1.6
`times, respectively, the human exposure of unbound drug at the human dose of 20 mg
`per day, and 3- and 5-times, respectively, the human exposure of unbound drug at the
`human dose of 10 mg daily.
`No significant treatment-related effects were observed in mice on mortality, bodyweight
`gain or food consumption. At study end, slight decreases in hemoglobin concentration
`and hematocrit, slightly prolonged thromboplastin times, and