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

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`ADDENUM TO April 6, 2009 REVIEW
`
`
`
`
`
`
`NDA: 22-406
`Brand Name
`Generic Name
`Primary Reviewer
`DCP5 Team Leader
`Pharmacometrics Reviewer
`Pharmacometrics Team Leader
`SIMCYP & Drug Metabolism
`OCP Division
`ORM division
`Applicant
`Relevant IND(s)
`Submission Type; Code
`OCP Briefing Date
`Formulation; Strength(s)
`
`Indication
`
`Submission Date(s): 12/30/10
`XARELTO® immediate release tablets
`rivaroxaban
`Joseph A. Grillo, Pharm.D.
`Julie M. Bullock, Pharm.D.
`Nitin Mehrotra, Ph.D.
`Christine Garnett, Pharm.D.
`Ping Zhao, Ph.D.
`5
`OND/OODP/DHP
`Johnson & Johnson Pharmaceutical Research and
`Development, L.L.C (J&J)
`64,892
`Resubmission NME NDA (SDN 70), Priority Review [original
`OCP NME NDA review 4/6/2009]
`None [original submission: March 25, 2009]
`10 mg immediate release tablets
`The prophylaxis of deep vein thrombosis (DVT) and
`pulmonary embolism (PE) in patients undergoing hip
`replacement surgery or knee replacement surgery.
`
`
`
`Table of Contents
`TABLE OF CONTENTS.................................................................................................................. 1
`1 EXECUTIVE SUMMARY ......................................................................................................... 2
`1.1 RECOMMENDATION.............................................................................................................. 3
`1.2 POST MARKETING REQUIREMENTS ...................................................................................... 3
`1.3 POST MARKETING COMMITMENTS........................................................................................ 3
`1.4 COMMENTS TO THE APPLICANT............................................................................................ 3
`1.5 SUMMARY OF IMPORTANT CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS FINDINGS .... 3
`2 QUESTION BASED REVIEW.................................................................................................. 6
`2.1 GENERAL ATTRIBUTES ........................................................................................................ 6
`2.2 GENERAL CLINICAL PHARMACOLOGY .................................................................................. 6
`2.3
`INTRINSIC FACTORS ............................................................................................................ 6
`2.4 EXTRINSIC FACTORS ........................................................................................................... 9
`2.5 GENERAL BIOPHARMACEUTICS.......................................................................................... 14
`2.6 ANALYTICAL SECTION ....................................................................................................... 14
`3 DETAILED LABELING RECOMMENDATIONS ................................................................... 15
`4 APPENDICES ........................................................................................................................ 32
`4.1 PHARMACOMETRIC REVIEW............................................................................................... 32
`4.2 REFERENCED SCIENTIFIC PAPERS ..................................................................................... 46
`
`
`Reference ID: 2955610
`
`1
`
`

`

`
`
`1
`
` Executive Summary
`
`The original NDA application was 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. A clinical pharmacology review dated
`April 6, 2009, found the original application acceptable provided post-marketing related
`issues were addressed. A complete response letter was issued on May 27, 2009, due to
`Clinical and Quality related issues. Although there were no clinical pharmacology related
`deficiencies, the agency did proactively communicate potential a post-marketing related
`issue regarding the need to develop a lower strength tablet for patients with Child Pugh
`class B hepatic impairment without coagulopathy, concurrently taking rivaroxaban with a P-
`gp and strong CYP3A4 inhibitor, and concurrently taking rivaroxaban with a P-gp and mild
`or moderate CYP3A4 inhibitor with mild-moderate renal impairment.
`In its formal response the applicant states that it does not consider using a lower
`rivaroxaban dose for the treatment of Child Pugh class B patients without coagulopathy
`appropriate because its analysis suggests higher baseline prothrombin time (PT) and
`greater sensitivity between rivaroxaban plasma concentrations and PT in this population.
`However, the clinical relevance of the increased baseline PT and higher sensitivity in this
`population is not clear. There was no relationship observed between PT levels and
`proportion of patients with major bleeding in the 11527 and RECORD studies.
`Furthermore, FDA found that using the expected concentrations from a phase 2 study
`(11527), at the proposed clinical dose, the expected difference in PT ratio (PTR) following
`exposure matching in Child Pugh class B patients appears to be within the range seen in
`the combined analysis of the Phase 3 RECORD studies. In addition, both PT and PTR
`were considered to have poor predictive value for bleeding risk in the applicant’s safety
`analysis of the RECORD studies. Therefore, FDA is not persuaded by the applicant’s
`argument against exposure matching in this population.
`In addition, the applicant does not consider using a lower rivaroxaban dose (5 mg QD) for
`patients concurrently receiving Xarelto and a P-gp and strong CYP3A4 inhibitor
`appropriate. This is because applicant’s simulations suggest that steady state, trough
`concentration (Ctrough) are estimated to be approximately 6-times higher in patients taking 5
`mg QD dose with strong CYP3A4 and P-gp inhibitor compared to patients taking 10 mg QD
`alone. The applicant’s simulation analysis was limited by holding the apparent volume of
`distribution (Vd/F) constant in its model and decreasing only apparent clearance (CL/F) to
`drive change in exposure causing prolonged elimination half-life and higher trough levels.
`However, both Vd/F and CL/F were reduced with minimal change in half-life in drug
`interaction studies with these combined inhibitors.
`FDA simulations of this scenario were also conducted using the same method except
`reducing both CL/F and Vd/F to that observed in the applicant’s drug interaction studies.
`The resulting simulations did not support the 6-fold change in steady-state Ctrough
`concentrations following exposure matching. Therefore, FDA is not persuaded by the
`applicant’s argument against exposure matching in this population.
`FDA continues to recommend that the availability of lower dose strengths of rivaroxaban is
`the best option to allow a larger patient population to receive this treatment and this issue
`should still be considered as a post marketing commitment. Until a lower dose formulation
`is developed FDA supports avoidance language in the labeling for these populations.
`
`Reference ID: 2955610
`
` 2
`
`

`

`1.1 Recommendation
`From a clinical pharmacology perspective, this resubmission of the original application is
`ACCEPTABLE provided that the applicant and the Agency come to a mutually satisfactory
`agreement regarding the language in the package insert and the applicant commits to the
`following post marketing commitments addressing clinical pharmacology related safety
`concerns with rivaroxaban treatment.
`
`1.2 Post Marketing Requirements
`None
`
`1.3 Post Marketing Commitments
`
`1.3.1 Develop and propose a 5 mg dosing form (tablet) or scored 10 mg tablet to allow for
`proper dose titration when rivaroxaban needs to be co-administered in patients at risk for
`clinically relevant changes in rivaroxaban exposure. The 5 mg dose form should be
`sufficiently distinguishable from the 10 mg tablet. Full chemistry, manufacturing and
`controls (CMC) information for the 5 mg dosage form including the batch data and
`stability data, labels, updated labeling, and updated environmental assessment section is
`required in a prior approval supplement.
`Protocol submission Date: 45 days from date of action.
`Submission Date: 6 months after FDA agreement to submitted protocol.
`1.3.2 The applicant should 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 following
`the development of the 5 mg tablet formulation.
`Protocol submission Date: We note the applicant has submitted a draft protocol with
`this NDA application and request that it be resubmitted for FDA review under the IND
`within 10 business days of this action.
`Submission Date: 6 months after FDA agreement to submitted protocol.
`
`1.4 Comments to the Applicant
`
`1.4.1 The FDA suggests that the applicant evaluate the effect of a P-gp inhibitor with limited
`CYP3A4 inhibitory activity (e.g., quinidine) on the pharmacokinetics, pharmacodynamics,
`and safety of rivaroxaban in healthy subjects. This study will explore the involvement of
`P-gp in rivaroxaban elimination so that appropriate dosing recommendations can be
`created following the development of the 5 mg tablet formulation.
`
`1.5 Summary of Important Clinical Pharmacology and Biopharmaceutics Findings
`The original NDA application was 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. A clinical pharmacology review dated
`April 6, 2009, found the original application acceptable provided post-marketing related
`issues were addressed. A complete response letter was issued on May 27, 2009, due to
`Clinical and Quality related issues. Although there were no clinical pharmacology related
`deficiencies, the agency did proactively communicate a potential post-marketing related
`issue regarding the need for the development of a lower strength tablet for the following
`patients:
`• Child Pugh class B hepatic impairment without coagulopathy
`
`Reference ID: 2955610
`
` 3
`
`

`

`• Concurrently taking rivaroxaban with a P-gp and strong CYP3A4 inhibitor
`• Concurrently taking rivaroxaban with a P-gp and mild or moderate CYP3A4 inhibitor
`with mild-moderate renal impairment
`This resubmission includes a response to the clinical pharmacology issue regarding the
`need for a lower dose formulation for Xarelto in the above populations. These responses
`were evaluated in this review.
`In its formal response the applicant states that it does not consider using a lower
`rivaroxaban dose for the treatment of Child Pugh class B patients without coagulopathy
`appropriate because its analysis of pharmacodynamic response from the dedicated hepatic
`impairment study suggests greater sensitivity between rivaroxaban plasma concentrations
`and prothrombin time (PT) in this population. Sensitivity was derived from the slope of the
`exposure response plot of PT versus rivaroxaban concentration.
`FDA evaluated the applicant’s proposal and PT analysis and added an analysis of the ratio
`of PT to baseline (PTR) to rivaroxaban concentration to focus on sensitivity rather than
`baseline differences. The baseline PT was greater in Child Pugh class B patients (16.2
`seconds) compared to healthy subjects (13.0 seconds). In addition, relationship between
`PT and major bleeding was explored using the data from the 11527 and RECORD studies.
`The FDA analysis found the following:
`• Using the expected concentrations from a phase 2 study (11527), at the proposed
`clinical dose and assuming exposure matching between Child Pugh class B patients
`and healthy subjects, where the Child Pugh class B patients where given half the dose
`of the healthy subjects, FDA estimated the expected PTR for each group from the
`linear equation describing this relationship. The expected median PTR was ~1.61 in
`the C-P class B patients compared to ~1.34 in the health subjects. This PTR range for
`exposure matched C-P class B patients is within the range reported by the applicant
`for the PTR seen in the combined analysis of the RECORD studies.
`• There was no relationship observed between steady state PT levels and proportion of
`patients with major bleeding in 11527 and RECORD studies.
`• The applicant’s integrated safety summary reports that it found no relationship
`between PT or PTR and relevant bleeding risk.
`Based on this analysis, FDA is not persuaded by the applicant’s argument against
`exposure matching in this population.
`The applicant also states that it does not consider using a lower rivaroxaban dose for
`patients concurrently receiving Xarelto and a P-gp and strong CYP3A4 inhibitor
`appropriate. This is because its simulations suggest that steady state, Ctrough
`concentrations for 5 mg rivaroxaban co-administered with a P-gp and strong CYP3A4
`inhibitor are estimated to be approximately 6-times higher as compared to steady-state
`Ctrough concentrations for 10 mg rivaroxaban administered alone. Simulations were
`performed by the applicant using PK data of patients receiving rivaroxaban 10 mg once
`daily as obtained from the Phase 2 dose ranging study 11527 and inhibiting CL/F by a
`factor of 0.39 (observed in the Phase 1 drug interaction studies with ritonavir and
`ketoconazole) and leaving Vd/F constant.
`The applicant’s decision to decrease CL/F but hold the Vd/F constant in its model results in
`prolonged half-life with clearance driving the change in exposure. This is in contrast to data
`from five drug interaction studies with combined P-gp and CYP3A4 inhibitors of various
`potencies showing both Vd/F and CL/F as prominent factors causing increase in exposures
`such that half-life was minimally changed. FDA repeated the applicant’s simulations using
`the same method except reducing CL/F by a factor of 0.39 and Vd/F by a factor of 0.48 as
`observed in the Phase 1 drug interaction studies with ritonavir and ketoconazole. These
`simulations did not support the significant change in steady-state Ctrough concentrations
`
`Reference ID: 2955610
`
` 4
`
`

`

`following exposure matching that was proposed by the applicant. Based on the simulations,
`the plasma concentration-time profiles were similar for patients taking 5 mg QD with
`concomitant strong CYP3A4 and P-gp inhibitor compared to 10 mg QD alone resulting in
`overlapping steady state Ctrough levels. Furthermore, the half life was increased by 1.25-fold
`which is consistent with the observations of the phase 1 drug interaction studies.
`Based on this analysis and the limitations of the applicant’s approach, FDA is not
`persuaded by the applicant’s argument against exposure matching in this population. The
`applicant also acknowledged the need to better understand the potential complex
`interaction of concurrent rivaroxaban use with a P-gp and mild or moderate CYP3A4
`inhibitor with mild-moderate renal impairment. It also affirmed its plan to conduct a drug
`interaction study in the special population of patients with mild or moderate renal
`impairment concomitantly receiving erythromycin, a combined CYP3A4 (moderate) and P-
`gp inhibitor.
`Therefore, FDA was not persuaded by the applicant’s arguments against exposure
`matching in the Child Pugh class B hepatic impairment without coagulopathy and with
`concurrent rivaroxaban use with a P-gp and strong CYP3A4 inhibitor. FDA agrees with the
`applicants plan to study the potential complex interaction of concurrent rivaroxaban use
`with a P-gp and mild or moderate CYP3A4 inhibitor with mild-moderate renal impairment.
`FDA continues to recommend that the availability of lower dose strengths of rivaroxaban is
`the best option to allow a larger patient population to receive this treatment and this issue
`should still be considered as a post marketing commitment. Until a lower dose formulation
`is developed FDA supports avoidance language in the labeling for these populations.
`
`
`Signatures
`
`______________________________________
`Joseph A. Grillo, Pharm.D
`Clinical Pharmacology Reviewer
`Division of Clinical Pharmacology 5
`
`_____________________________________
`Nitin Mehrotra, Ph.D.
`Reviewer
`Division of Pharmacometrics
`______________________________________
`Nam Atiqur Rahman, Ph.D.
`Division Director
`Division of Clinical Pharmacology 5
`
`
`______________________________________
`Julie M. Bullock, Pharm.D.
`Clinical Pharmacology Team Leader
`Division of Clinical Pharmacology 5
`
`______________________________________
`Christine Garnett, Pharm.D.
`Team Leader
`Division of Pharmacometrics
`
`
`
`Reference ID: 2955610
`
` 5
`
`

`

`2 Question Based Review
`
`2.1 Pertinent Regulatory Background
`
`2.2
`
`The original NDA application was 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. A complete response letter was issued
`on May 27, 2009. For further details on this submission and for review material relevant to
`the labeling, post-marketing comments, and suggestions from the Agency see the clinical
`pharmacology review dated April 6, 2009.
`In the Complete Response letter, the FDA identified concerns over the clinical investigator
`Inspections from the RECORD studies, insufficient clinical data to fully characterize the
`potential risk for serious hepatotoxicity, and the adequacy of the drug substance and
`product information. Although there were no clinical pharmacology related deficiencies, the
`Agency did proactively communicate potential post-marketing related issue regarding the
`need for the development of a lower strength tablet for the following patients:
`• Child Pugh class B hepatic impairment without coagulopathy
`• Concurrently taking rivaroxaban with a P-gp and strong CYP3A4 inhibitor
`• Concurrently taking rivaroxaban with a P-gp and mild or moderate CYP3A4 inhibitor
`with mild-moderate renal impairment
`FDA provided additional clarification regarding this clinical pharmacology related issue in a
`6/9/2009 meeting with the applicant. The applicant also requested a type C meeting with
`FDA, which was held on October 14, 2010, to obtain guidance from the Agency on the
`design of a proposed study to evaluate this complex DDI scenario involving the concurrent
`use of rivaroxaban with a P-gp and mild or moderate CYP3A4 inhibitor in patients with
`mild-moderate renal impairment.
`This resubmission includes a response to the Clinical and Quality related deficiencies as
`well as the clinical pharmacology issue regarding the need for a lower dose formulation for
`Xarelto. Specifically the applicant submitted a response to the need for a lower dose
`formulation in each of the populations listed above with supplemental pop-PK based
`simulation reports and a revised protocol to evaluate the complex DDI scenario.
`
`2.3 General Attributes
`See the 4/6/2009 clinical pharmacology review of the original NDA.
`
`2.4 General Clinical Pharmacology
`See the 4/6/2009 clinical pharmacology review of the original NDA.
`
`2.5
`
`Intrinsic Factors
`
`2.5.1 What intrinsic factors (age, gender, race, weight, height, disease, genetic
`polymorphism, pregnancy, and organ dysfunction) influence exposure (PK
`usually) and/or response, and what is the impact of any differences in exposure on
`efficacy or safety responses?
`See the 4/6/2009 clinical pharmacology review of the original NDA.
`
`2.5.2 Based upon what is known about exposure-response relationships and their
`variability and the groups studied, healthy volunteers vs. patients vs. specific
`populations (examples shown below), what dosage regimen adjustments, if any,
`are recommended for each of these groups? If dosage regimen adjustments are
`
`Reference ID: 2955610
`
` 6
`
`

`

`not based upon exposure-response relationships, describe the alternative basis
`for the recommendation.
`
`2.5.2.1 Elderly
`See the 4/6/2009 clinical pharmacology review of the original NDA.
`
`2.5.2.2 Pediatric patients
`See the 4/6/2009 clinical pharmacology review of the original NDA.
`
`2.5.2.3 Gender
`See the 4/6/2009 clinical pharmacology review of the original NDA.
`
`2.5.2.4 Race
`See the 4/6/2009 clinical pharmacology review of the original NDA.
`
`2.5.2.5 Renal impairment
`See Section 2.6.2.2 and the 4/6/2009 clinical pharmacology review of the original NDA.
`
`2.5.2.6 Hepatic impairment
`In its formal response to the May 27, 2009, CR action included in this submission the
`applicant states that it does not consider exposure matching by using a lower
`rivaroxaban dose for the treatment of Child Pugh (CP) class B patients without
`coagulopathy appropriate. This is because the applicant’s analysis of
`pharmacodynamic response from the dedicated hepatic impairment study (11003)
`reported a steeper PK/PD relationship between rivaroxaban plasma concentrations and
`prothrombin time (PT) in Child Pugh class B patients (i.e., 7.8 seconds/(100 μg/L) for
`Child Pugh class B patients versus 3.1 seconds/(100 μg/L) for healthy subjects with
`normal hepatic function). Sensitivity is derived from the slope of the exposure response
`plot of PT versus rivaroxaban concentration (Table 1).
`Table 1: Descriptive statistics of individual slopes of linear relation
`between PT or PT ratio (PTR) and rivaroxaban concentration
`Prothrombin time (seconds)
`Parameter
`CPB
`
`0.0784
`16.2
`
`0.0048
`1
`
`PT
`
`PTR
`
`Mean Slope
`Mean Intercept
`
`Healthy
`
`0.0308
`13.0
`
`0.0024
`1
`
`CPA
`
`0.0380
`13.3
`
`0.0029
`Mean Slope
`1
`Mean Intercept
`$ raw dataset from the Applicant’s study report 11003
`FDA evaluated the applicant’s proposal and analysis of the data from study 11003. As
`expected, a difference in the baseline PT between Child Pugh class B patients (16.2
`seconds) and healthy subjects (13.0 seconds) is apparent. In order to focus on the
`sensitivity rather than baseline differences, FDA also obtained the slope describing the
`relationship between the ratio of PT to baseline (PTR) and rivaroxaban concentration in
`hepatic impairment and healthy subjects (Table 1) using the applicant’s method of
`analysis. FDA also derived the expected PTR, based on the linear equation from the
`exposure response analysis of study 11003, using exposure data (i.e., Cmax) from the
`
`Reference ID: 2955610
`
` 7
`
`

`

`phase 2b study #11527 where 135 patients received Xarelto dosed at 10 mg daily. The
`results of this analysis are presented in Table 2.
`Table 2: Estimated PTR for hepatic impairment patients and healthy
`subjects using phase 2 Cmax estimates from study 11527# and the
`linear relation between PTR and rivaroxaban concentration from
`study 11003
`Prothrombin time ratio (PTR)
`Concentration
`Parameter
`(μg/L)
`CPA
`CPB
`Healthy
`Study 11527 dosed 10 mg qd (n=135)
`
`
`
`1.28
`1.45
`1.26
`5th Percentile
`125
`1.34
`1.55
`1.31
`25th Percentile
`111
`1.38
`1.61
`1.34
`Median
`154
`1.46
`1.75
`1.41
`75th Percentile
`91.4
`1.58
`1.96
`1.52
`95th Percentile
`196
`#Applicant’s pop-PK report PK000131 for 135 patients receiving a Xarelto dose of 10 mg daily
`Assuming exposure matching between Child Pugh class B patients and healthy
`subjects, where the Child Pugh class B patients where given half the dose of the
`healthy subjects (i.e., 5 mg daily), the expected median PTR (25th , 75th ) would be
`approximately 1.61 (1.55,1.75) in the Child Pugh class B patients compared to
`approximately 1.34 (1.31, 1.41) in the health subjects. This difference is not likely to
`affect bleeding risk since the applicant’s integrated safety summary reports found no
`relationship between PT or PTR and relevant bleeding risk. Plotting the major bleeding
`episodes versus the quartiles for PT from the Phase 2 11527 study and RECORD
`studies did not change this conclusion (Figure 1). Further, the PTR range for exposure
`matched Child Pugh class B patients is within the range reported by the applicant for
`the PTR seen in the RECORD studies (Figure 2) and submitted in support of the
`proposed safety of this drug. Further,
`
`*The vertical black bars represent the mean with 95% confidence interval. Proportion of patients with major bleeding are
`demonstrated as black circles at the median PT of each quartile. The numbers against each quartile are the number of
`patients with major bleeding/total number of patients. The horizontal dashed red line represents the proportion of patients
`with major bleeding in the placebo arm (enoxaparin).
`
`Figure 1: PT-major bleeding relationship for study 11527 (left) and the combined
`analysis of RECORD studies (right).*
`
`
`
`
`
`
`
`Reference ID: 2955610
`
` 8
`
`

`

`N 4496
`
`N 10
`
`N 103
`
`N 4276
`
`2.5
`
`2
`
`1.5
`
`1
`
`0.5
`
`0
`
`PT ratio
`
`All
`
`Major Bleed
`
`Clin Rel Bleed
`
`No Bleed
`
`
`
`#Boxes report median (25th, 75th) and whiskers represent 5th and 95th percentiles for PTR. The red dot
`represents the mean PTR
`$ Day 6 PTR measurements from PH35408 study report table 14.4/5
`
`Figure 2: PTR versus bleeding risk from the combined analysis of data from
`the RECORD studies#,$
`
`Therefore, FDA is not persuaded by the applicant’s argument regarding this issue since
`the expected difference in PT ratio following exposure matching in Child Pugh class B
`patients appears unlikely to increase bleeding risk since the change is within the range
`observed in the phase 3 clinical studies and both PT and PTR are considered to have
`poor predictive value for bleeding risk. FDA still supports the original analysis from the
`4/6/2009 clinical pharmacology review suggesting that the availability of a lower dose
`formulation (e.g., 5 mg tablet) will allow Child Pugh class B patients without
`coagulopathy to receive rivaroxaban (see Figure 5 in Section 4.1). The development of
`a lower dose formulation should still be considered as a post marketing commitment.
`
`2.5.2.7 What pregnancy and lactation use information is there in the application?
`See the 4/6/2009 clinical pharmacology review of the original NDA.
`
`2.6 Extrinsic Factors
`
`2.6.1 What extrinsic factors (drugs, herbal products, diet, smoking, and alcohol use)
`influence dose-exposure and/or -response and what is the impact of any
`differences in exposure on response?
`See the 4/6/2009 clinical pharmacology review of the original NDA.
`
`2.6.2 Drug-drug interactions
`
`2.6.2.1
`
`Is there an in vitro basis to suspect in vivo drug-drug interactions?
`See the 4/6/2009 clinical pharmacology review of the original NDA.
`
`2.6.2.2
`
`Is there a basis to suspect complex drug-drug-disease interactions?
`Yes. The possibility for a significant change in exposure with the use of a combined
`CYP3A4 (weak to moderate) and P-gp/BCRP inhibitor in patients with renal impairment
`that may increase bleeding risk exists based on simulations from both the applicant and
`FDA. The applicant requested a type C meeting with FDA, which was held on October
`14, 2010, to obtain guidance from the Agency on the design of a proposed study to
`evaluate this complex DDI scenario.
`
`Reference ID: 2955610
`
` 9
`
`

`

`In its formal response to the May 27, 2009, CR action included in this submission the
`applicant acknowledged the need to better understand this potential complex
`interaction and affirmed it’s plan to conduct a drug interaction study in the special
`population of patients with mild or moderate renal impairment concomitantly receiving
`erythromycin, a combined CYP3A4 (moderate) and P-gp inhibitor.
`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.
`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 (Table
`3).1
`Table 3: Change in rivaroxaban exposure relative to combined
`CYP3A4/P-gp inhibition and renal impairment
`Scenario
`AUCR of Rivaroxaban
`
`Observed
`
`Reported exposure change
`+Erythromycina
`
`Simulated
`
`Young
`
`Elderly
`
`- Erythromycin
`+ Erythromycin
`
`
`
`50-80
`1.4b
`
`
`15-29
`1.6b
`
`
`severe
`
`2.1
`2.6
`
`1.8 (2.3c)
`2.3 (3.0c)
`
`CLcr (mL/min)
`30-49
`
`1.5b
`1.0
`
`1.3
`Renal Impairment
`
`moderate
`mild
`control
`
`
`
`1.9
`1.6
`1.0
`2.4
`1.9
`1.2
`
`
`
`1.7 (2.2c)
`1.5 (2.0c)
`1.0 (1.3c)
`- Erythromycin
`2.2 (2.9c)
`1.9 (2.5c)
`1.2 (1.6c)
`+ Erythromycin
`a=data from study 11865; b= data from study 11002; c= relative to young control
`The Applicant proposes cautionary wording in the labeling regarding the use of Xarelto
`in this potential complex DDI scenario. FDA disagrees with this proposal since both the
`applicant and FDA simulations suggest the possibility of exposure changes consistent
`with those of other factors resulting in avoidance language due to concern regarding
`bleeding risk. In addition, since 53% of patients participating in the RECORD studies
`were greater than 65 years of age, the FDA simulations suggesting even greater
`exposure changes in the elderly a particular concern for the population that will likely
`use this drug for the proposed indication. Therefore, FDA recommends that the
`concomitant use of Xarelto with a combined weak to moderate inhibitor of CYP3A4 and
`an inhibitor of P-gp and/or BCRP (e.g., verapamil, erythromycin, diltiazem,
`dronedarone quinidine, ranolazine, amiodarone, felodipine, and azithromycin) should
`be avoided in patients with any degree of renal impairment.
`The reviewer agrees with the Applicants plan to study this issue and continues to
`recommend that this issue be a post marketing commitment. Since this NDA
`submission is not the forum for FDA to provide comments on the draft protocol
`submitted by the applicant related to this issue, FDA recommends that the applicant
`resubmit it under the Xarelto IND for review and comment by the Agency.
`
`
`1 P Zhao, L Zhang, JA Grillo, Q Liu, J M Bullock, YJ Moon, et.al. Applications of Physiologically Based Pharmacokinetic
`(PBPK) Modeling and Simulation During Regulatory Review. Clin Pharmacol Ther 2011;89:259-67.
`
`Reference ID: 2955610
`
` 10
`
`

`

`2.6.2.3
`
`Is the drug a substrate of CYP enzymes? Is metabolism influenced by genetics?
`See the 4/6/2009 clinical pharmacology review of the original NDA.
`
`2.6.2.4
`
`Is the drug an inhibitor and/or an inducer of CYP enzymes?
`In its formal response to the May 27, 2009, CR action included in this submission, the
`applicant states that it does not consider the use a lower rivaroxaban dose for patients
`concurrently receiving Xarelto and a P-gp and strong CYP3A4 inhibitor appropriate.
`This is because the applicant’s simulations suggest that steady state, Ctrough
`concentrations for 5 mg rivaroxaban co-administered with a P-gp and strong CYP3A4
`inhibitor are estimated to be approximately 6-times higher compared to steady-state
`Ctrough concentrations for 10 mg rivaroxaban administered alone (Figure 3).. The
`applicant’s simulations were performed using the PK data of patients receiving
`rivaroxaban 10 mg once daily from the Phase 2 dose ranging study 11527 and
`inhibiting clearance (both oxidative metabolism (CYP3A4) and renal secretion (P-gp))
`to the extent observed in the Phase 1 drug interaction studies with ritonavir (11935)
`and ketoconazole (11936).
`
`
`
`
`
`B
`A
`*Inhibition effect was accomplished by reducing clearance by a factor of 0.39 and leaving Vd/F constant.
`# Simulated plasma concentration profile in patients (n=135) taking 10 mg QD without strong CYP3A4 and P-gp inhibitor
`(black) compared to the same patients (n=135) taking 5 mg QD with strong CYP3A4 and P-gp inhibitor (blue). The solid blue
`and black lines represent the mean while the dashed blue and black lines are the 5th and 95th percentiles.
`$ Predicted steady state Cmin levels in patients (n=135) with 5 mg QD dose taking strong inhibitors of both CYP3A4 and P-gp
`(blue) compared to observed steady state trough levels in same patients (n=135) taking 10 mg QD without strong CYP3A4
`and P-gp inhibitor (grey).
`Figure 3: Applicant’s Simulated Steady-State Plasma-Concentration Time Prof