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

`

` E M O R A N D U M
`
` M
`
` DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
` FOOD AND DRUG ADMINISTRATION
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`
`
`
`Date:
`
`From:
`
`
`Subject:
`
`
`
`
`
`
`
`To:
`
`
`June 13, 2011
`
`Kathy M. Robie Suh, M.D., Ph.D.
`Medical Team Leader, Hematology
`Division of Hematology Drug Products (HFD-160)
`
`Medical Team Leader Secondary Clinical Review
`NDA 22-406 resubmission, letter date 1/14/2011; received 1/14/2011
`XARELTOR (rivaroxaban) for prophylaxis of deep vein thrombosis (DVT) and
`pulmonary embolism (PE) in patients undergoing hip or knee replacement surgery
`
`
`
`NDA 22-406
`
`Xarelto (rivaroxaban) Tablets is an orally administered Factor Xa inhibitor being developed for
`several anticoagulation indications. In this NDA application the sponsor is seeking initial
`marketing approval of rivaroxaban for the indication: for the prophylaxis of deep vein
`thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing knee or hip
`replacement surgery. The proposed dose is 10 mg orally once daily with a treatment duration of
`14 days for knee surgery and 35 days for hip surgery.
`
`This is the second review cycle for this drug product. See my Medical Team Leader/CDTL
`review dated 5/27/2009 for background and summary of cycle 1 review findings. Briefly, the
`database consisted of four trials (the RECORD 1, 2, 3, and 4 studies), each comparing
`rivaroxaban to enoxaparin (different regimens) with two studies for knee surgery and two studies
`for hip surgery. All four studies were multinational, randomized (1:1), double-blind, double-
`dummy, parallel groups design. The studies were conducted by Bayer but the right of reference
`for use of the studies was transferred to Johnson & Johnson (J & J) just prior to NDA submission
`and J & J is the sponsor of the NDA.
`
`The first review cycle found convincing statistical evidence for efficacy of rivaroxaban in the
`two proposed clinical settings based on the primary efficacy endpoint total VTE (composite of
`any DVT [venographically determined], non-fatal PE or death) and concluded that, barring gross
`irregularities in conduct of the RECORD studies, rivaroxaban has efficacy as an anticoagulant
`for thromboprophylaxis in the settings of elective hip replacement and knee replacement surgery.
`The predominant effect appeared to be on venographically-detected DVT. The safety data
`suggested that bleeding rates may be somewhat greater with rivaroxaban than with enoxaparin.
`Though the available data did not identify a risk for hepatotoxicity, most of these data were from
`short-term studies and insufficient data were available to rule out a risk for hepatotoxicity with
`
`Reference ID: 2960076
`
`

`

`NDA 22-406
`Page 2 of 8
`longer term use of rivaroxaban. Chronic use is a concern for rivaroxaban, since as an oral agent
`it can be reasonably expected to have some long-term use in practice for treatment of chronic
`indications, such as stroke prevention in patients with atrial fibrillation. A meeting of the
`Cardiovascular and Renal Drugs Advisory Committee on March 19, 2009 voted overwhelmingly
`that a favorable benefit-risk profile had been demonstrated for use of rivaroxaban in the
`prophylaxis of venous thromboembolism (VTE) in patients undergoing hip or knee replacement
`surgery, but voiced some concerns about the strength of the signals for hepatotoxicity and the
`feasibility of long-term studies to further elucidate the hepatotoxicity potential. Subsequent to
`the advisory committee meeting, findings of the Division of Scientific Investigations (DSI)
`inspections of several sites, particularly in RECORD 4, identified deficiencies with regard to
`compliance with study procedures, completeness in reporting of adverse events and other
`irregularities during the conduct of the RECORD studies raising questions about the adequacy of
`study monitoring by Bayer and necessitating further examination of the integrity of the studies
`by DSI.
`
`On May 27, 2010 the Agency issued a Complete Response (CR) letter to Johnson & Johnson
`(Appendix B) citing results from the DSI clinical investigator inspections indicating that some
`sites may be unreliable and results from the sponsor (Bayer) inspection revealing that “the
`sponsor failed to 1)ensure proper monitoring of the study, 2)to ensure that study was conducted
`in accordance with the protocol and/or investigational plan, and 3)to ensure that FDA and all
`investigators were promptly informed of significant new adverse effects or risks.” The sponsor
`was requested to provide a detailed report of their clinical quality assurance (QA) audit plan
`including plan for securing investigator compliance, audit findings, corrective actions including
`termination of investigators, oversight of CROs and Bayer handling of review information
`obtained from the CROs. The sponsor was asked to plan and perform an additional audit and
`provide a full report.
`
`Also, in the CR letter the sponsor was informed that the supplied clinical data were insufficient
`to fully characterize a potential risk for serious liver toxicity. The sponsor was asked to provide
`additional long-term safety data from the studies of rivaroxaban in patients with atrial fibrillation
`(ROCKET studies), post-marketing experience outside the U.S., final reports for other completed
`long-term treatment studies and summary of post-marketing studies initiated outside the U.S.
`
`The CR letter also listed Chemistry, Manufacturing and Controls (CMC) deficiencies that needed
`to be addressed prior to product approval of the application.
`
`In the resubmission the sponsor has provided a full response the CR letter. The submission
`includes:
`• detailed information regarding the auditing and monitoring procedures and results for the
`RECORD studies (including the Bayer QA audit plans, SOPs, audit findings and corrective
`actions, and list of clinical investigators terminated for noncompliance for the RECORD
`studies; information on each CRO hired to monitor the clinical sites for the RECORD
`program, the oversight process for each CRO, and processes to ensure monitoring, as well as
`a list of noncompliant sites reported by the CROs; and the Bayer audits and the independent
`third party
` audits methodology, results and analyses, also including the results of the
`Sponsor’s RECORD 4 study data verification). This information was reviewed by the
`
`Reference ID: 2960076
`
`2
`
`(b) (4)
`
`

`

`NDA 22-406
`Page 3 of 8
`Division of Scientific Investigations (DSI) (See Compliance Review by Susan Thompson,
`M.D., 5/25/2011).
`• Background information on the Hepatic Event Assessment Committee (HEAC) and a
`comprehensive Integrated Summary of Liver Safety
`• Safety findings from post-marketing exposures outside the United States
`• The protocol and safety findings from the observational post marketing study XAMOS
`• The final study report for ATLAS ACS TIMI 46, including electronic datasets
`• Reference to previous submissions indicating and including information about updated Bayer
`and J & J DMFs in support of the application. Information to address the deficiencies in drug
`substance information, drug product specifications, dissolution criteria, stability data and
`description of container and closure system information as requested in the CR letter. (See
`review by Chemistry, Manufacturing and Controls (CMC) (Joyce Z. Crich, Ph.D.,
`6/02/2011).
`• A study synopsis and proposal to conduct a Phase 1 drug interaction study
`(RIVAROXACS1001) in patients with mild or moderate renal impairment concomitantly
`receiving erythromycin, a moderate CYP3A4/moderate P-gp inhibitor to address the Cinical
`Pharmacology recommendation that the sponsor develop a lower strength formulation for use
`in dose modification in certain populations of patients. The sponsor’s arguments and
`information have been reviewed by Clinical Pharmacology (Joseph Grillo, Pharm.D. and
`Nitin Mehrotra, Ph.D., 6/03/2011).
`
`
`Additional information was provided upon Division’s request during the review cycle regarding
`occurrences of events of agranulocytosis, Stevens-Johnson syndrome, and neuraxial hematoma
`within the safety database of rivaroxaban (including all completed and ongoing clinical trials up
`to date and post-marketing experience).
`
`Clinical review of the new data and updated safety information in the resubmission has been
`completed by Min Lu, M.D. (review signed 6/03/2011). Please see Dr. Lu’s review for detailed
`presentation of the new and updated safety data and other information in the application.
`Important in the clinical review of the resubmission were the findings of the DSI review of audit
`and monitoring information for the four RECORD studies. See Dr. Thompson’s Compliance
`Review (signed 5/25/2011) for detailed description and analysis of the audit results. All four
`RECORD studies were conducted by Bayer. Monitoring oversight for RECORD 1, 2 and 3 was
`done by Bayer while RECORD 4 was monitored by
` a contract
`research organization (CRO). After receipt of the CR letter, J & J contracted
`
` for an independent third party audit of the RECORD studies. This audit
`examined 30/617 sites encompassing 945/12729 (7.4%) of enrolled patients across the four
`studies. (For the individual studies percentage of sites examined ranged from 2.0% for
`RECORD 3 to 6.9% for RECORD 4 and percentage of patients from 2.8% for RECORD 3 to
`9.9% for RECORD 4). DSI review of the audit information found deficiencies in all four
`studies. The DSI review comments that the audits of the RECORD 1, 2, and 3 studies found
`deficiencies in drug accountability but did not demonstrate systematic deficiencies in multiple
`aspects of the conduct of the trials that would bring into question data integrity from all study
`sites. However, for RECORD 4 the deficiencies in terms of both extent and scope were more
`pervasive than in the other three studies. Adequacy of monitoring was assessed as ineffective in
`identifying significant violations or in taking actions towards securing compliance. In the
`
`Reference ID: 2960076
`
`3
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 22-406
`Page 4 of 8
`RECORD 4 study 63.1% of audited patients were found to be inadequately monitored as
`compared to 25.5%-40.0% of audited patients in the other three studies. The
`audits
`revealed considerably more unreported adverse events in RECORD 4 (265 events) as compared
`to the other studies (37-110 events) as well as other deficiencies. There were 8 unreported
`serious adverse events noted in the
`audits, all in RECORD 4. Also, post-operative
`randomization (as opposed to protocol-specified pre-operative randomization) occurred in 39.0%
`of audited RECORD 4 patients as compared to 0.4%-0.5% of audited patients in RECORD 1, 2,
`and 3. (See DSI Compliance Review by Susan Thompson, M.D., final signature 5/25/2011, for
`details). Based on the overall findings the DSI review concluded that the data from RECORD 4
`are not considered reliable in support of the indication. For RECORD 1, 2 and 3 studies the data
`were considered reliable for the application, excepting the following sites: Lenart, Porvaneckas,
`and Slappendel in RECORD 1; Corces, Yang Berumen and Ono in RECORD 2; and Brabants in
`RECORD 3. For RECORD 1, RECORD 2, and RECORD 3 the unreliable sites accounted for
`220 (4.8%), 102 (2.3%) and 27 (1.1%) of total enrolled patients, respectively.
`
`Efficacy: Clinical and Statistical review of the four RECORD studies during the first review
`cycle found demonstration of efficacy in each of the four studies. Overall, for the primary
`efficacy endpoint “Total VTE” the event rates (mITT population) for the rivaroxaban and
`enoxaparin groups, respectively were: 1.1% (18/1595) and 3.7% (58/1558) in RECORD 1; 2.0%
`(17/864) and 9.3% (81/869) in RECORD 2; 9.6% (79/824) and 18.9% (166/878) in RECORD 3;
`and 6.9% (67/965) and 10.1% (97/959) in RECORD 4. The efficacy result was driven by
`venographically diagnosed DVT; however, rivaroxaban appeared superior to the comparator arm
`in RECORD 1, 2, and 3 and with a trend favoring rivaroxaban in RECORD 4 for proximal VTE.
`(See Clinical Review by Min Lu, M.D. signed 4/2/2009 and Medical Team Leader Secondary
`Review/CDTL Review by Kathy Robie Suh, signed 5/27/2009 (attached to this review as
`Appendix A)).
`
`Examination of the contribution of the above listed DSI assessed unreliable sites for RECORD 1,
`2 and 3 finds the following contribution of these sites to the primary efficacy evaluation:
`
`
`
`
`RECORD 1:
` Lenart (Hungary)
` Porvaneckas
`(Lithuania)
` Slappendel (The
`Netherlands)
`RECORD 2:
` Corces (USA)
` Yang (China)
` Naraffete (Mexico)
` Ono (Brazil)
`RECORD 3:
` Brabants (Belgium)
`
`
`
`Reference ID: 2960076
`
`Primary Efficacy Endpoint Event (“Total VTE”) in RECORD 1, 2 and 3 Studies DSI Unreliable Sites
`(mITT Population)
`
`Rivaroxaban
`Total patients VTE
`
`
`41
`0
`28
`0
`
`Enoxaparin
`Total patients
`
`40
`30
`
`VTE
`
`1
`0
`
`15
`
`
`9
`12
`8
`10
`
`7
`
`0
`
`
`1
`5
`4
`1
`
`2
`
`13
`
`
`9
`11
`6
`10
`
`11
`
`1
`
`
`0
`0
`0
`0
`
`0
`
`4
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 22-406
`Page 5 of 8
`For RECORD 1 a single VTE event is excluded from each of the treatment arms. For RECORD
`3 two events in the enoxaparin arm are excluded. These exclusions would not appear to have a
`meaningful effect on the overall efficacy result for these two studies. For RECORD 2 a total of
`11 events in the enoxaparin arm and no events in the rivaroxaban arm are excluded. While these
`exclusions may not significantly affect the overall efficacy result for the study, the imbalance in
`the VTE exclusions between the treatment arms narrows the efficacy difference between the two
`arms. In interpreting these numbers it should be borne in mind that only a small fraction of the
`total sites and total patients enrolled were audited; therefore, interpreting the results involves
`some assumptions, such as that the audited sites were reasonably representative of all the sites
`where the studies were conducted with regard to types and extent of deficiencies. For RECORD
`2 the occurrence of the primary efficacy endpoint by geographic area is shown in the table below
`(includes DSI unreliable sites). Though the finding is numerically skewed in the unreliable sites,
`qualitatively it is consistent with the overall RECORD 2 study efficacy results.
`
`
`Incidence of Primary Efficacy Endpoint (“Total VTE”) by Geographic Region (mITT Population)
`
`
`
`
`
`Total
`
`Australia
`Brazil
`Canada
`China
`Colombia
`Denmark
`Estonia
`India
`Indonesia
`Korea (South)
`Latvia
`Lithuania
`Mexico
`New Zealand
`Norway
`Peru
`Portugal
`South Africa
`Sweden
`United Kingdom
`United States
`
`VTE/total patients
`Rivaroxaban
`Enoxaparin
`17/864
`81/869
`
`
`0/7
`0/7
`2/61
`6/55
`0/47
`1/44
`1/121
`16/122
`6/50
`9/56
`0/64
`2/58
`0/24
`1/33
`0/9
`0/10
`¼
`0/4
`0/41
`0/44
`0/15
`0/19
`1/64
`3/60
`0/10
`5/13
`0/3
`0/0
`1/46
`4/42
`3/58
`8/65
`0/4
`0/5
`0/44
`8/43
`0/103
`6/101
`2/64
`9/64
`0/25
`3/24
`
`
`
`With regard to efficacy, overall, the results support that rivaroxaban is effective in reducing VTE
`events in patients undergoing hip or knee surgery. However, considering the shortcoming in the
`monitoring adequacy in the studies, quantitative expression of that effectiveness as compared to
`the enoxaparin comparator in these studies may not be reliable. I would not conclude superiority
`of rivaroxaban over enoxaparin for the indication based on the results of these studies.
`
`
`Reference ID: 2960076
`
`5
`
`

`

`NDA 22-406
`Page 6 of 8
`Safety: With regard to safety, among the audited sites
` in all four RECORD studies
`there were unreported adverse events (AE). The number of these events was greatest for
`RECORD 4 (265 unreported AE in 151 patients). For RECORD 1 there were 113 unreported
`AE in 66 patients; for RECORD 2, there were 131 unreported AE in 69 patients; and for
`RECORD 3 there were 37 unreported AE in 31 patients. For RECORD 4, revisiting of sites by
` for data verification audits of sites that had been audited
` revealed many
`additional unreported AEs, including serious adverse events. The
`audits identified 8
`unreported SAEs, all from RECORD 4; the RECORD 4
` audits revealed an additional 28
`newly reported SAEs in 25 subjects (15 rivaroxaban, 12 enoxaparin, and 1 never randomized).
`The events included 2 newly-reported cases of ALT>3x ULN concurrent with a total bilirubin >2
`x ULN (both in the enoxaparin arm); no new cases of DVT, PE or death were identified. The
`Compliance Review did not indicate any instances where reported adverse events were
`discovered to be attributed to the wrong patient or found not to have occurred.
`
`Results of my examination of the important safety events in the clinical sites in the RECORD
`studies 1, 2, and 3 that were assessed unreliable are summarized in the following table:
`
`
`Occurrence of Serious Adverse Events in RECORD 1, 2 and 3 Studies DSI Unreliable Sites
`(randomized subjects)
`
`
`
`
`
`Rivaroxaban
`Total patients
`SAE
`
`
`44
`2
`36
`4
`
`Deaths
`
`0
`0
`
`Enoxaparin
`Total patients
`SAE
`
`
`44
`3
`36
`1
`
`Deaths
`
`0
`0
`
`31
`
`5
`
`0
`
`30
`
`2
`
`0
`
`RECORD 1:
` Lenart (Hungary)
` Porvaneckas
`(Lithuania)
` Slappendel (The
`Netherlands)
`RECORD 2:
` Corces (USA)
` Yang (China)
` Naraffete (Mexico)
` Ono (Brazil)
`RECORD 3:
` Brabants (Belgium)
`
`
`9
`17
`13
`12
`
`14
`
`
`0
`0
`0
`0
`
`1
`
`
`0
`0
`0
`0
`
`0
`
`
`10
`17
`12
`12
`
`13
`
`
`2
`0
`6
`1
`
`1
`
`
`0
`0
`2
`0
`
`0
`
`
`In RECORD 1, overall the incidence of SAEs was 6.6% (146/2209) in the rivaroxaban arm and
`8.1% (181/2224) in the enoxaparin arm. In RECORD 2, the incidence was 7.3% (90/1228) for
`rivaroxaban and 10.7% (131/1229) for enoxaparin, and in RECORD 3, it was 7.4% (90/1220) for
`rivaroxaban and 8.9% (110/1239) for enoxaparin. Types of SAEs at the unreliable sites were
`similar to those reported overall in the studies. The incidence of major bleedings in RECORD 1
`was 0.27% (6/2209) in the rivaroxaban arm and 0.13% (3/2224) in the enoxaparin arm. In
`RECORD 2, the incidence was 0.8% (1/1228) for rivaroxaban and 0.8% (1/1229) for enoxaparin,
`and in RECORD 3, it was 0.66% (8/1220) for rivaroxaban and 0.65% (8/1239) for enoxaparin.
`No patients at any of the unreliable sites in these studies were reported as having a major
`bleeding event. Though there may be concerns about the quantitative accuracy of the reported
`safety events in for these sites, in general, it appears that the safety findings for these unreliable
`sites were consistent with the overall safety findings for the studies.
`
`
`Reference ID: 2960076
`
`6
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 22-406
`Page 7 of 8
`Statistical Review of the safety evaluation for possible liver toxicity during the first cycle was
`done by Chava Zibman, Ph.D. (2/26/2009). That review was based on aggregate data from the
`four RECORD studies, which all involved treatment with rivaroxaban or enoxaparin for 35 days
`or less. The review commented that, “Because of the structure of the data and issues associated
`with data quality, no formal statistical inference was conducted” in the analysis. Rather, the
`review summarized the liver assessment test results and frequencies of hepatobiliary adverse
`events. The review concluded that based on the data reviewed, “it might be difficult to
`differentiate between Rivaroxaban and Enoxaparin” patients based on signals of liver toxicity in
`the data”. Review and comment on potential for liver toxicity during the first review cycle was
`also provided from the Office of Surveillance and Epidemiology (OSE), Division of
`Epidemiology (DEPI) (Kate Gelperin, M.D., M.P.H., 2/13/2009). Dr. Gelperin’s review
`highlighted previous FDA experience with assessment of severe drug-induced liver injury due to
`ximelagatran, an anticoagulant drug (direct thrombin inhibitor) developed for similar indications,
`where no cases of severe liver injury were found in the short-term (orthopedic) clinical trials;
`however, a strong signal was subsequently identified in long-term (atrial fibrillation) trials and
`also summarized the regulatory history including withdrawals and risk management for drug-
`induced liver injury. For rivaroxaban, the DEPI review concluded that a potential signal for
`severe liver injury associated with rivaroxaban therapy has not been fully characterized by the
`RECORD studies and recommended that full evaluation of safety data from long-term clinical
`trials be done to inform decisions about the balance of therapeutic benefit versus risk with
`rivaroxaban.
`
`During the current review cycle, Statistical Review and Evaluation of potential risk for serious
`liver toxicity was done by John S. Yap, Ph.D. (6/10/2011). The review assessed liver toxicity
`based on the results of five trials of rivaroxaban at dose of 10-30 mg daily for chronic use (>35
`days and up to 4 years) for stroke prevention in patients with atrial fibrillation (ROCKET and J-
`ROCKET studies), and for treatment in patients with deep venous thrombosis (EINSTEIN-DVT
`study or pulmonary embolism (EINSTEIN-PE) and extended DVT/PE treatment (EINSTEIN
`Extension study). The proportions of patients with elevated alanine aminotransferase (ALT) at
`predefined multiples of the upper limit of normal (ULN) were generally balanced between the
`rivaroxaban and warfarin arms in the atrial fibrillation trials and were lower in some cases in the
`rivaroxaban arm as compared to the enoxaparin arm in the VTE studies. Occurrence of “Hy’s
`Law” cases (concurrent values of ALT>3x ULN and total bilirubin >2x ULN) in the atrial
`fibrillation studies was similar in the rivaroxaban (0.45%; 34/7618) and warfarin (0.47%;
`36/7650) arms. In the DVT/PE treatment studies overall Hy’s Law cases were 0.17% (6/3560)
`with rivaroxaban ttreatment and 0.17% (6/3487) with enoxaparin. In the DVT extended
`treatment study there were no Hy’s Law cases. The review concluded that in the controlled
`long-term studies the liver toxicity profile is comparable in the rivaroxaban and control groups.
`
`Rivaroxaban was approved in Canada and European Union for prophylaxis of VTE in patients
`undergoing hip or knee replacement surgery in September 2008 and is approved in some other
`countries as well. Post-marketing safety information and safety information from an
`observational post-marketing safety study were included in the resubmission. The most common
`serious adverse events reported were bleeding events. Other serious adverse events in the reports
`were cerebral hemorrhage (9 cases, 3 deaths), agranulocytosis (3 cases; 1 death), hypersensitivity
`
`Reference ID: 2960076
`
`7
`
`

`

`NDA 22-406
`Page 8 of 8
`reactions (3 cases; no deaths) anaphylactic shock (2 cases; no deaths); anaphylactic reaction (2
`cases; no deaths); Stevens-Johnson syndrome (2 cases; no deaths).
`
`There was no advisory committee meeting for rivaroxaban during this review cycle.
`
`
`Conclusions and Recommendations:
`The resubmission confirms serious monitoring and reporting problems within the RECORD
`studies, particularly for RECORD 4 to the extent that data from RECORD 4 cannot be
`considered reliable. For the remaining RECORD studies, though each had serious problems
`necessitating exclusion of data from one or more audited sites, overall the result for the studies
`appear sufficiently robust to support that rivaroxaban is efficacious for the proposed use. The
`additional safety data from long-term studies do not identify a risk of serious hepatotoxicity as
`compared to the active comparators (enoxaparin and warfarin) with rivaroxaban as used and
`managed in these studies. The major safety risk for rivaroxaban is bleeding. In addition, cases
`of agranulocytosis and Stevens-Johnson syndrome have been reported. The overall safety profile
`of rivaroxaban appears acceptable for approval; however serious events should be clearly
`described in the labeling and be considered for focused post-marketing monitoring.
`
`Overall, the benefit/risk for rivaroxaban appears acceptable for approval for the proposed
`indication. The wording of the indication statement should be the same as for other products
`approved for the indication --- “for the prophylaxis of deep vein thrombosis (DVT) which may
`lead to pulmonary embolism (PE) in patients undergoing hip replacement surgery and in patients
`undergoing knee replacement surgery”. The treatment duration should be 35 days for patients
`undergoing hip replacement surgery and 12 days for patients undergoing knee replacement
`surgery, to reflect actual treatment durations in the studies.
`
`Rivaroxaban does not appear to provide a unique benefit, other than convenience of oral
`administration, over the other products already approved for the proposed indications.
`Qualitatively, the benefits and risks appear similar. Accordingly, the labeling for rivaroxaban
`should be consistent with the labeling for the other products with regard to display of the efficacy
`results and inclusion of relevant warnings for anticoagulation in these patients. Quantitatively,
`because of the issues with the quality of the data collection for the studies, conclusions regarding
`relative efficacy of rivaroxaban and enoxaparin for these uses should not be drawn from the
`studies. Exact wording of labeling will be developed with input and discussion of the entire
`review team.
`
`
`
`Reference ID: 2960076
`
`8
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KATHY M ROBIE SUH
`06/13/2011
`
`Reference ID: 2960076
`
`

`

`Clinical Review
`Min Lu, M.D., M.P.H.
`NDA 22-406/059 Resubmission
`Xarelto (rivaroxaban)
`
`
`CLINICAL REVIEW
`
`Application Type NDA
`Application Number(s) 22-406/059
`Priority or Standard Resubmission
`
`Submit Date(s) 23-Dec-2010
`Received Date(s) 03-Jan-2011
`PDUFA Goal Date
`03-Jul-2011
`Division / Office DHP/OODP
`
`Reviewer Name(s) Min Lu, M.D., M.P.H.
`Review Completion Date 1-June-2011
`
`Established Name Rivaroxaban
`(Proposed) Trade Name XARELTO®
`Therapeutic Class Anticoagulant
`Applicant
`Johnson & Johnson Pharmaceutical
`Research & Development, L.L.C.
`
`Formulation(s) Oral tablet
`Dosing Regimen 10 mg once daily
`Indication(s) Prophylaxis of Deep Vein
`Thrombosis (DVT)
`Intended Population(s) Patients undergoing hip or knee
`replacement surgery
`
`
`Reference ID: 2956161
`
`1
`
`

`

`Clinical Review
`Min Lu, M.D., M.P.H.
`NDA 22-406/059 Resubmission
`Xarelto (rivaroxaban)
`
`
`Table of Contents
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT.............................................. 3
`1.1 Recommendation on Regulatory Action .......................................................................... 3
`1.2 Risk Benefit Assessment .................................................................................................. 3
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies................ 5
`1.4 Recommendations for Postmarket Requirements and Commitments .............................. 5
`INTRODUCTION AND REGULATORY BACKGROUND............................................ 5
`2
`3 ETHICS AND GOOD CLINICAL PRACTICES .............................................................. 6
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES........................................................................................................................ 6
`4.1 Chemistry Manufacturing and Controls ........................................................................... 6
`4.2 Clinical Microbiology....................................................................................................... 6
`4.3 Preclinical Pharmacology/Toxicology ............................................................................. 7
`4.4 Clinical Pharmacology ..................................................................................................... 7
`5 SOURCES OF CLINICAL DATA....................................................................................... 7
`6 REVIEW OF EFFICACY .................................................................................................... 7
`Efficacy Summary ...................................................................................................................... 6
`7 REVIEW OF SAFETY ......................................................................................................... 9
`Safety Summary........................................................................................................................ 10
`7.1 Methods .......................................................................................................................... 16
`7.1.1 Clinical Trials Used to Evaluate Safety .................................................................. 16
`7.1.2 Categorization of Adverse Events........................................................................... 18
`7.1.3
`Pooling of Data Across Studies/Clinical Trials to Estimate and Compare Incidence
`................................................................................................................................. 18
`7.2 Adequacy of Safety Assessments................................................................................... 18
`7.3 Liver Safety Data in Long-term Clinical Studies ........................................................... 19
`7.3.1 ALT Abnormalities ................................................................................................. 17
`7.3.2 ALT >3 x ULN and Total Bilirubin > 2 X ULN..................................................... 25
`7.3.3 Hepatic Disorder Adverse Events ........................................................................... 31
`7.3.4 Causality Assessment.............................................................................................. 38
`7.4
`Ischemic Stroke in Long-term Clinical Studies ............................................................. 52
`8 POSTMARKET EXPERIENCE........................................................................................ 54
`9 APPENDICES...................................................................................................................... 74
`9.1 Literature Review/References ........................................................................................ 74
`9.2 Labeling Recommendations ........................................................................................... 74
`9.3 Advisory Committee Meeting ........................................................................................ 75
`
`Reference ID: 2956161
`
`2
`
`

`

`Clinical Review
`Min Lu, M.D., M.P.H.
`NDA 22-406/059 Resubmission
`Xarelto (rivaroxaban)
`
`
`1 Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`
`From a clinical perspective, rivaroxban is acceptable to be approved for the prophylaxis of deep
`vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients undergoing
`hip or knee replacement surgeries.
`
`1.2 Risk Benefit Assessment
`
`Rivaroxaban has been shown to reduce the rate of total venous thromboembolic events (VTE) in
`patients undergoing hip or knee replacement surgery as compared to the control (enoxaparin or
`enoxaparin followed by placebo). Four randomized controlled trials (RECORD 1-4) were
`conducted to support the currently proposed indication in patients undergoing hip or knee
`replacement surgeries. Rivaroxaban reduced the rate of total venous thromboembolic event
`(VTE) as compared to the control (enoxaparin or enoxaparin followed by placebo) in patients
`undergoing hip surgery (RECORD 1: 1.1% vs. 3.7%, respectively, p<0.001; RECORD 2: 2.0%
`vs. 9.3% [enoxaparin/placebo], respectively; p<0.001) and in patients undergoing knee
`replacement surgery (RECORD 3: 9.6% vs. 18.9%, respectively, p<0.001; RECORD 4: 6.9% vs.
`10.1%, respectively; p<0.05). The rate of total VTE remained statistically significantly lower in
`the rivaroxaban group as compared to the control in patients undergoing hip surgery (RECORD
`1: 1