CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`022406Orig1s000
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`OFFICE DIRECTOR MEMO
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`Office Director Decisional Memo
`NDA 22406ISOOO_ Xarelto (rivaroxaban)
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`1
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`Office Director Decisional Memo
`
`(electronic stamp)
`Richard Pazdur, MD
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`Subject
`Office Director Decisional Memo
`mm
`
`A licant Name
`Date of Submission
`PDUFA Goal Date
`
`Proprietary Name [Established (USAN) Name
`Dosa i e Forms I Stren h
`Proposed lndication(s)
`
`Action/Recommended Action for "ME:
`
`OND Action Packa . e, includin . :
`Division Director
`Medical Officer Review
`
`Oral Tablets/10 mg film-coated
`For the prophylaxis of deep vein thrombosis and pulmonary
`embolism in patients undergoing hip replacement surgery or
`knee relacement su e
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`Statistical Review
`
`Qing Xu, Ph.D.IMark Rothmann, Ph.D.
`
`Pharmacology Toxicology Review Yash Chopra, PhD.IAdebayo Laniyonu, Ph.D. and Patricia Harlow, PhD.I
`Thomas Pa ian, Ph.D.
`
`
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`CMC Review/OBP Review
`
`Microbial” Review
`Clinical Phannacol' . Review
`DDMAC
`
`CDTL Reviews
`OSE/DMEPA
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`OSEIE . idemiol . .
`
`Joyce Crich, Ph.D.lJanice Brown, Ph.D. and Tapash Ghosh, Ph.D.lPatrick
`Marroum, Ph.D.
`
`Susan Thompson, M.D.ITejashari Purohit Sheth, M.D.ILeslie Ball, M.D.
`
`Kate Gel . en'n, M.D.IJohn Senior, M.D.
`
`John Yap, Ph.D.l LaRee Tracy, Ph.D.lAloka Chakravarty, Ph.D.
`Other - statistical safety
`Other— Pediatrics Maternal Health Elizabeth L. Dunnowicz, M.D.lHari C. Sachs, M.D.ILisa Mathis, M.D.
`
`Team
`Other- Pharmacometn'cs
`OND=Office of New Dmgs
`DDMAC=Division of Drug Marketing, Advertising and Communication
`OSE= Office of Surveillance and Epidemiology
`
`Dr. Upasana Bhatnagar, MDl Karen Feibus, M.D.I Lisa Mathis, M.D.
`Nitin Mehrotra, Ph.D.IChristine Gamett, Ph.D.
`
`Reference ID: 296871 3
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`

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`Office Director Decisional Memo
`NDA 22406/S000_ Xarelto (rivaroxaban)
`
`
`Introduction
`1.
`Xarelto is an oral Factor Xa inhibitor initially submitted on July 22, 2008 for the prophylaxis of deep vein
`thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing hip replacement surgery or knee
`replacement surgery. On May 27, 2009, a complete response letter was issued in the first cycle due to the need
`to clarify chemistry, manufacturing and control (CMC) issues; need for additional understanding of potential safety
`issues; and need for additional clarification of data integrity issues. The applicant responded to the complete
`response letter on January 4, 2011.
`
`Xarelto has been approved by the European Medicines Agency since May 6, 2009.
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`2
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`2. Background
`Four drugs are approved in the prevention of venous thromboembolism (VTE) in the setting of hip and/or knee
`replacement surgery. All these drugs are administered parenterally (enoxaparin, fondaparinux, dalteparin and
`unfractionated heparin). Warfarin is the only oral anticoagulant approved for the prophylaxis of venous thrombosis
`and PE in general. However, warfarin is not specifically indicated for the prevention of VTE in the perioperative
`period but is widely used.
`
`Unlike warfarin, rivaroxaban does not require anticoagulation parameter monitoring of the prothrombin time (PT).
`However, rivaroxaban does prolong the partial thromboplastin time (PT) and partial thromboplastin time (PTT).
`
`The original submission had four major trials submitted (RECORD 1, 2, 3, and 4) in support of the application. The
`first-cycle review team determined the trials supported an efficacy determination; however, a number of
`deficiencies were identified in the areas of CMC, clinical safety and data integrity. Therefore, a complete response
`letter was issued.
`
`3. CMC/Device
`The CMC reviewers recommend approval of this NDA and state:
`
`“From a Chemistry, Manufacturing and Controls standpoint, this NDA is recommended for approval a 30 month
`shelf life for the drug product in HDPE bottles and a 18 month shelf life for the drug product in blisters, when
`stored at 20°-25°C (68°F - 77°F) or room temperature; excursions permitted to 15°C - 30°C (59°F - 86°F) [see
`USP Controlled Room Temperature]”.
`
`4. Nonclinical Pharmacology/Toxicology
`The first cycle review did not identify any issues that would preclude approval from a nonclinical standpoint. In the
`2-year carcinogenicity studies in CD-1 Mice and Wistar rats, a slight increase in tumors was noted in the Wistar
`rats study; however, this increase was not statistically significant. The observed increase does not affect the
`approvability of this NDA which is for short-term use.
`
`5. Clinical Pharmacology/Biopharmaceutics
`The recommended dose is 10 mg per day with or without food. Dose modification is suggested if used with a
`strong P-gp and CYP3A4 inducer.
`
`There are no issues which would preclude approval of rivaroxaban based on the clinical pharmacology reviews.
`However, the clinical pharmacology review team is recommending additional post-marketing commitment (PMC)
`and requirements (PMR) to develop a lower dose of rivaroxaban and to evaluate the effect of renal impairment
`with the concurrent use of P-gp and moderate inhibitors of CYP3A4 on the PK, PD and safety of rivaroxaban
`(please refer to the action letter for these PMCs/PMRs).
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`Reference ID: 2968713
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`

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`Office Director Decisional Memo
`NDA 22406/S000_ Xarelto (rivaroxaban)
`
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`6. Clinical Microbiology
`Not applicable
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`3
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`7. Clinical/Statistical-Efficacy
`During the first cycle review, the primary concerns regarding this application were safety (not efficacy) with a
`specific concern that there was insufficient safety information on hepatotoxicity to assess the full-risk benefit
`profile.
`
`From Dr. Lu’s first cycle review, “Four multi-center, randomized controlled trials (RECORD 1-4) were conducted...
`RECORD 1 and 2 studies were conducted in patients undergoing hip replacement surgery (THR) and RECORD 3
`and 4 studies were in patients undergoing knee replacement surgery (TKR).
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`In all 4 RECORD trials, rivaroxaban 10 mg once daily administered orally at least 6 to 8 hours after surgery was
`compared with enoxaparin administered subcutaneously. The enoxaparin dosing regimen was 40mg once daily
`starting 12 hours preoperatively in RECORD 1-3 studies and was 30 mg twice daily starting 12 to 24 hours
`postoperatively in RECORD 4 study. The durations of active treatment for rivaroxaban and enoxaparin were
`similar in the RECORD studies with the exception of RECORD 2, in which treatment duration of Rivaroxaban was
`much longer than enoxaparin control (rivaroxaban 35 days versus enoxaparin 13 days). The dose regimen of
`enoxaparin (40 mg once daily) control in RECORD 3 study is not a recommended dose regimen of enoxaparin for
`the prophylaxis of DVT in patients undergoing TKR in the United States.
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`Altogether a total of 12,729 patients (6356 in the rivaroxaban group and 6373 in the enoxaparin group were
`randomized in 4 RECORD studies and 8,512 (67%) (4248 in the rivaroxaban group and 4264 in the enoxaparin
`group) were included in the Modified Intent to Treat (MITT) population for the primary efficacy analysis. About 30-
`39% of randomized patients in RECORD studies were excluded from MITT population mainly due to no adequate
`assessment of DVT.
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`The primary efficacy endpoint was a composite endpoint of total VTE consisting of any DVT (proximal and/or
`distal), non-fatal PE, or death from all causes at the end of treatment in all 4 RECORD studies.
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`The statistical analyses supporting approval from the statistical team’s review are in the table below.
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`Table 1. Summary of Primary Efficacy Endpoint Analysis Results (Total VTE)
`Absolute Risk Reduction
`Study
`Rivaroxaban % (n/N) Enoxaparin % (n/N)
`RECORD 1
`1.1% (18/1595)
`3.7% (58/1558)
`2.6%
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`7.3%
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`9.3%
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`3.2%
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`p-value
`p<0.0001
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`p<0.0001
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`p<0.0001
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`p=0.012
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`RECORD 2
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`2.0% (17/864)
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`9.3% (81/869)
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`RECORD 3
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`9.6% (79/824)
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`18.9% (166/878)
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`RECORD 4
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`6.9% (67/965)
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`10.1% (97/959)
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`The Division of Scientific Investigations (DSI) identified some problematic sites and investigators during inspection
`and assessment. Thus, the statistical review team also performed sensitivity analyses excluding the known
`unreliable sites. The statistical review team reanalyzed the data removing these sites where there were drug
`accountability and other issues. For each RECORD trial, the sensitivity analysis using the modified ITT population
`demonstrates a statistically significant difference in favor of rivaroxaban for the primary endpoint. The results are
`provided in table 2 below.
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`Reference ID: 2968713
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`RECORD 2
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`2.1% (17/828)
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`8.4% (70/830)
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`RECORD 3
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`9.7% (79/813)
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`18.8% (164/871)
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`RECORD 4
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`7.1% (53/742)
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`10.8% (79/731)
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`Office Director Decisional Memo
`NDA 22406/S000_ Xarelto (rivaroxaban)
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`Table 2. Summary of Primary Efficacy Endpoint Analysis Results (Total VTE) Excluding Unreliable Sites
`Study
`Rivaroxaban % (n/N) Enoxaparin % (n/N)
`Absolute Risk Reduction
`p-value
`RECORD 1
`1.1% (17/1513)
`3.9% (57/1473)
`2.8%
`p<0.0001
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`p<0.0001
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`p<0.0001
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`p=0.0174
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`4
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`6.3%
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`9.1%
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`3.7%
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`Removing the problematic investigators/sites suggested that the results are still supportive of efficacy claims.
`However, the Agency has additional concerns regarding the study conduct and data collected in RECORD 4 which
`are discussed later.
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`8. Safety
`During the first review cycle, the review team identified areas for rigorous safety review: bleeding events,
`cardiovascular events, hepatotoxicity, and renal toxicity.
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`Bleeding Events:
`Review of the bleeding events revealed an increase in major bleeding events for the rivaroxaban treated patients;
`however, the difference was not statistically significant.
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`Cardiovascular Events:
`No statistically significant differences were noted between treatment groups during treatment. However, a slightly
`higher incidence of ischemic stroke was noted after subjects stopped rivaroxaban treatment. The significance of
`this increase is unclear.
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`Hepatotoxicity:
`The greatest concern during the first cycle review was for hepatotoxicity. The review team requested additional
`long term follow-up data from the ROCKET studies where rivaroxaban was used for stroke prophylaxis in patients
`with atrial fibrillation. The longer term data did not reveal a significantly different liver toxicity profile compared with
`warfarin and enoxaparin.
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`Renal toxicity:
`There were slightly higher incidences of creatinine and urea elevations in the rivaroxaban-treated subjects
`compared with the active control subjects.
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`In the second cycle, Dr. Lu concluded:
`
`“The other adverse events reported more frequently with rivaroxaban as compared to the control were pruritus,
`wound healing complications, pain in extremity, increased muscle tone and cramping, wound secreation, blister,
`syncope, and dysuria in clinical trials. Other significant adverse events reported associated with rivaroxaban
`treatment in post-marketing spontaneous reports were cerebral hemorrhage, epidural hematoma, hypersensitivity
`reactions including anaphylactic shock, agranulocytosis, and Steven-Johnson syndrome”.
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`There is a lack of knowledge about a method to reverse anticoagulation (including excessive anticoagulation). The
`division will request from the sponsor a method to amass cases of major bleeding seen post-approval, collect
`information on rivaroxaban dosing, outcome of major bleeding, and any treatment for the major bleeding.
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`Reference ID: 2968713
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`

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`Office Director Decisional Memo
`NDA 22406/S000_ Xarelto (rivaroxaban)
`
`I concur with the conclusions of the clinical and statistical review teams.
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`5
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`9. Advisory Committee Meeting
`This product was discussed at a Cardiovascular and Renal Advisory Committee meeting on March 19, 2009. The
`Committee voted 15 (yes) to 2 (no) that the available clinical data demonstrate a favorable risk-benefit profile.
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`10. Pediatrics
`The applicant requested a full waiver and the pediatric review committee concurred.
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`11. Other Relevant Regulatory Issues
`Maternal Health was consulted and provided labeling recommendations which were incorporated into labeling.
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`OSE was consulted including DMEPA who provided labeling input.
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`Division of Scientific Investigation (DSI)
`In the May 2009 Complete Response letter, DSI identified items from their initial investigation and inspections that
`were reviewed in this second-cycle review. Based on the applicant’s responses, DSI believes that the data from
`RECORD trials 1, 2, and 3 are reliable but the data from RECORD 4 are not reliable. The data integrity concerns
`for RECORD 4 involve the following areas:
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`1. Post-operative Randomization: DSI inspection discovered that some patients in the RECORD trials were post-
`operatively randomized to a particular treatment group. Based on the inspection, the percentage of patients was
`less than 1% for the RECORD trials 1, 2, and 3. However, for RECORD 4 this percentage was approximately
`39%. Despite the high percentage of post-operative randomization, post-operative randomization is unlikely to
`have introduced any bias in favor of rivaroxaban over enoxaparin for efficacy or safety.
`
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`2. Unreported Adverse Events: All four RECORD trials had unreported adverse events. The trial with the highest
`number of unreported adverse events was RECORD 4. In the
` audit, RECORD 4 trial had 265 unreported
`adverse events. In the
`audit, RECORD 4 trial had 504 unreported adverse events. The applicant
`analyzed the safety data including and excluding RECORD 4 data and the percentages for each adverse
`event/reaction did not change significantly.
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`3. Drug Accountability Issues: Drug accountability issues were identified in 27-33% of the audited sites. These
`issues were observed for all RECORD trials.
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`4. Inadequate Monitoring: DSI inspection of Bayer did uncover problems with the monitoring of the 4 RECORD
`trials. An inspection of Johnson & Johnson did not uncover similar problems.
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`Conclusion
`While DSI had some concerns regarding each of the RECORD trials, the RECORD 4 trial had significantly more
`numerous and severe study conduct, oversight and data collection issues. Given the totality of concerns with
`RECORD 4, Dr. Farrell concluded that the RECORD 4 information appears unreliable and cannot be used for an
`approval decision.
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`In summary, RECORD 1 and 2 trials provide the support for the use of rivaroxaban in patients undergoing hip
`replacement surgery. The RECORD 3 trial which demonstrated the rivaroxaban’s efficacy for prevention of VTE in
`patients undergoing knee replacement surgery is heavily supported by the RECORD 1 and 2 trials and to an
`uncertain extent by the RECORD 4 trial.
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`
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`Reference ID: 2968713
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`(b) (4)
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`(b) (4)
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`

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`Office Director Decisional Memo
`NDA 22406/S000_ Xarelto (rivaroxaban)
`
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`12. Labeling
`The labeling was reviewed by all disciplines and consultant staff.
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`6
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`13. Decision/Action/Risk Benefit Assessment
`Recommended regulatory action: Approval.
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`Risk Benefit Assessment:
`The risk benefit assessment suggests that oral rivaroxaban is effective for the prophylaxis of venous
`thrombembolic events in patients undergoing elective hip or knee replacement surgery. The most common side
`effects include post-operative bleeding.
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`Recommendation for Postmarketing Risk Management Activities:
`Routine postmarketing surveillance except for enhanced pharmacovigilance for major bleeding events.
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`Recommendation for other Postmarketing Study Requirements (PMR)/Commitments (PMC):
`Please refer to the action letter.
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`Reference ID: 2968713
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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/
`----------------------------------------------------
`
`TAMY E KIM
`07/01/2011
`
`RICHARD PAZDUR
`07/01/2011
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`Reference ID: 2968713
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`