CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`215859Orig1s000
`
`CLINICAL PHARMACOLOGY
`REVIEW(S)
`
`

`

`Office of Clinical Pharmacology Review
`
`NDA or BLA Number
`Link to EDR
`Submission Date
`Submission Type
`Brand Name
`Generic Name
`
`Dosage Form and Strength
`
`Route of Administration
`
`Proposed Indication
`
`Applicant
`
`Associated IND & NDA
`
`OCP Review Team
`
`NDA 215859
`\\CDSESUB1\evsprod\NDA215859
`22 Jun 2021
`Priority
`XARELTO®
`Rivaroxaban
`• Granules
` for oral suspension to be mixed with 150
`mL of water to provide 1 mg/mL suspension
`• Film-coated immediate-release tablets: 10, 15 and 20
`mg
`Oral
`• The treatment of venous thromboembolism (VTE) and
`the reduction in risk of recurrent VTE in pediatric
`patients from birth to less than 18 years after at least
`5 days of initial parenteral anticoagulant treatment
`• Thromboprophylaxis in pediatric patients aged 2
`years and older with congenital heart disease (CHD)
`who have undergone the Fontan procedure
`Janssen Pharmaceuticals, Inc.
`IND 064892
`NDA 022406 S-001/S-002/S-003 (VTE/PE)
`NDA 202439 (Atrial Fibrillation)
`Harisudhan Thanukrishnan, PhD; Jihye Ahn, PharmD;
`Manuela Grimstein, PhD; Liang Li, PhD; Xinyuan Zhang,
`PhD; Sudharshan Hariharan, PhD
`
`
`
`
`
`Reference ID: 4903283
`
`1
`
`(b)
`(4)
`
`

`

`Table of Contents
`1. EXECUTIVE SUMMARY .............................................................................................................................. 3
`1.1 Recommendations .............................................................................................................................. 3
`1.2 Post-Marketing Requirements and Commitments ............................................................................. 5
`2. SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT ......................................................................... 5
`2.1 Pharmacology and Clinical Pharmacokinetics ..................................................................................... 5
`2.2 Dosing and Therapeutic Individualization ........................................................................................... 6
`2.2.1 General dosing ............................................................................................................................. 6
`2.2.2 Therapeutic individualization ....................................................................................................... 8
`2.3 Outstanding Issues .............................................................................................................................. 8
`2.4 Summary of Labeling Recommendations ........................................................................................... 8
`3. COMPREHENSIVE CLINICAL PHARMACOLOGY REVIEW ............................................................................ 8
`3.1 Overview of the Product and Regulatory Background ....................................................................... 8
`3.2 General Pharmacology and Pharmacokinetic Characteristics .......................................................... 10
`3.3 Clinical Pharmacology Review Questions ......................................................................................... 11
`3.3.1 To what extent does the available clinical pharmacology information provide pivotal or
`supportive evidence of effectiveness? ............................................................................................... 11
`3.3.2 Is the proposed dosing regimen appropriate for the general patient population for which the
`indication is being sought? ................................................................................................................. 17
`3.3.3 Is an alternative dosing regimen and/or management strategy required for subpopulations
`based on intrinsic factors? .................................................................................................................. 27
`3.3.4 Are there clinically relevant food-drug or drug-drug interactions and what is the appropriate
`management strategy? ....................................................................................................................... 29
`3.3.5 Is the granules for oral suspension formulation bioequivalent to the tablet formulation? ...... 29
`4. APPENDICES ............................................................................................................................................ 30
`4.1 Summary of Bioanalytical Method Validation and Performance ..................................................... 30
`4.2 Clinical PK and/or PD Assessments ................................................................................................... 32
`4.3 Population PK and/or PD Analyses ................................................................................................... 57
`4.3.1 Population PK analysis ............................................................................................................... 57
`4.3.2 Population PK-PD analysis .......................................................................................................... 77
`4.4 Physiologically based Pharmacokinetic Analysis .............................................................................. 87
`
`
`
`
`Reference ID: 4903283
`
`2
`
`

`

`1. EXECUTIVE SUMMARY
`Rivaroxaban is an oral anticoagulant which is approved under NDA 022406 for (A) i. the prophylaxis of
`deep vein thrombosis (DVT) in patients undergoing hip replacement surgery or knee replacement
`surgery; ii. to reduce the risk in the recurrence of DVT and/or pulmonary embolism (PE) in patients at
`risk; iii. for prophylaxis of venous thromboembolism (VTE) in acutely ill patients at a risk for
`thromboembolic complications and not at high risk of bleeding, and for (B) the treatment of DVT and/or
`PE. For the prophylactic indications above, the general approved dosing regimen is 10 mg once daily
`with or without food. For the treatment indication, the general approved dosing regimen is 15 mg twice
`daily with food for the first 21 days followed by 20 mg once daily with food for the remaining treatment.
`Rivaroxaban is also approved under NDA 202439 to reduce the risk of major cardiovascular events in
`patients with coronary artery disease (CAD) and thrombotic vascular events in patients with peripheral
`artery disease (PAD). It is also approved to reduce the risk of stroke and systemic embolism in patients
`with nonvalvular atrial fibrillation (NAF). For the CAD and PAD indications the approved dosing regimen
`is 2.5 mg orally twice daily with or without food in combination with aspirin and for the NAF indication
`the dose is 15 or 20 mg, once daily with food.
`
`To address the Pediatric Research Equity Act requirements and fulfill the FDA’s post-marketing
`requirements, in addition to the approved film coated immediate-release tablets, the Applicant, Janseen
`Pharmaceuticals Inc., developed granules for oral suspension formulation for use in younger pediatric
`patients. Pharmacological response to rivaroxaban was assessed for similarity in PK and coagulation PD
`marker relationships between adults and pediatric patients. A body weight-adjusted dosing was
`established in pediatric patients with an objective to match the exposures achieved in adults based on
`the framework of extrapolation. The Applicant is seeking approval of the following two indications under
`NDA 215859: (1) VTE treatment and reduction of risk of VTE recurrence in pediatric patients from birth
`to <18 years and (2) Thromboprophylaxis in children with congenital heart disease after the Fontan
`procedure aged 2 years and above. Please see ‘General Dosing section 2.2.1’ below for body weight-
`adjusted dosing regimen for the two proposed pediatric indications.
`
`In the current NDA submission for pediatric use, the Applicant submitted study reports for 7 pediatric
`clinical studies including two Phase 1 studies (12892, 17992), two Phase 2 studies (14373, 14374), one
`Phase 1/2 study (17618) and one pivotal Phase 3 study- 14372 (EINSTEIN Jr), totalling to 6 studies in
`pediatric patients with VTE and one pivotal Phase 3 study- CHD3001 (UNIVERSE), in post-Fontan
`pediatric patients. In addition, the submission includes six separate Phase 1 biopharmaceutics studies in
`healthy adults (PH-36262 or 14022, PH-37535 or 16886, PH-38629 or 17769, PH-38690 or 17861, PH-
`40127 or 19365, PH-40136 or 19366).
`
`1.1 Recommendations
`The Office of Clinical Pharmacology (OCP)/ Division of Cardiometabolic and Endocrine Pharmacology and
`Division of Pharmacometrics have reviewed the information contained in NDA 215859. The OCP review
`team recommends approval of NDA 215859, rivaroxaban granules for oral suspension and tablets, for
`use in pediatric patients from birth (at-term) to <18 years of age for the VTE treatment and reduction of
`risk of VTE recurrence and pediatric patients aged 2 years or older after the Fontan procedure for
`
`
`
`Reference ID: 4903283
`
`3
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`

`

`thromboprophylaxis. Key review issues with specific recommendations and comments are summarized
`in the table below:
`
`Review Issue
`Pivotal or supportive evidence of
`effectiveness
`
`General dosing instructions
`
`Dosing in patient subgroups
`(intrinsic and extrinsic factors)
`
`Labeling
`Bridge between the to-be-
`marketed and clinical trial
`formulations
`
`
`Other (specify)
`
`
`
`Reference ID: 4903283
`
`Recommendations and Comments
`Clinical pharmacology information demonstrated similar exposure-
`response relationships for clotting time variables (PT, aPTT and
`anti-factor Xa) between pediatric and adult patients with VTE and
`pediatric patients with CHD after the Fontan procedure. In
`addition, the proposed doses in pediatric patients are expected to
`result in a similar range of steady-state rivaroxaban trough
`concentrations, as observed in adults. Refer to section 3.3.1 for
`details.
`The Applicant proposed body weight-based pediatric dosing
`regimen (See section 2.2.1) based on pediatric clinical experience
`from Studies 14372 (EINSTEIN Jr) and CHD3001 (UNIVERSE) to
`support VTE treatment/recurrent risk reduction and
`thromboprophylaxis after the Fontan procedure indications,
`respectively. The appropriateness of proposed dosing regimen is
`discussed in section 3.3.2. All doses for the VTE indication should
`be administered with feeding or food. The dose for
`thromboprophylaxis indication can be administered with or
`without food. Missed doses can be taken on same day for once or
`twice daily regimens; missed doses should be skipped for the thrice
`daily regimen.
`• Body weight-based starting dosing regimen is required for
`pediatric patients.
`• Doses for pediatric VTE indication to be taken with feeding
`or food.
`• Avoid use of XARELTO® in pediatric patients with eGFR <50
`mL/min/1.73 m2 or in patients younger than 1 year with serum
`creatinine results above 97.5th percentile.
`• Avoid concomitant use with known combined P-gp and strong
`CYP3A inhibitors or combined P-gp and strong CYP3A inducers
`in pediatric patients. Avoid concurrent use of XARELTO® with
`other anticoagulants due to increased bleeding risk unless
`benefit outweighs risk.
`The labeling language by Applicant was generally acceptable.
`The to-be-marketed granules for oral suspension formulation was
`used in clinical trials. The immediate-release (IR) 10, 15 and 20 mg
`tablets that were identical in composition to commercial
`formulation were used in the clinical trials. The granules for oral
`suspension formulation was shown to meet bioequivalence criteria
`for AUC and Cmax in comparison to the commercial IR tablets at the
`10 mg dose in fasted state as well as for the 20 mg dose in fed state
`in healthy adults.
`None
`
`4
`
`

`

`1.2 Post-Marketing Requirements and Commitments
`None
`
`2. SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT
`
`2.1 Pharmacology and Clinical Pharmacokinetics
`Rivaroxaban is a competitive, selective, and direct oral Factor Xa inhibitor. Factor Xa directly converts
`prothrombin to thrombin through the prothrombinase complex, and ultimately, this reaction leads to
`fibrin clot formation and activation of platelets by thrombin. By inhibiting FXa, rivaroxaban decreases
`thrombin generation. Rivaroxaban has no direct effect on platelet aggregation, but indirectly inhibits
`platelet aggregation induced by thrombin. Rivaroxaban produces dose-dependent inhibition of FXa
`activity. Clotting tests, such as prothrombin time (PT), activated partial thromboplastin time (aPTT) and
`HepTest®, are also prolonged dose-dependently.
`
`The clinical PK and PD of rivaroxaban were investigated in adult populations and summarized previously
`under NDAs 022406 and 202439. The clinical pharmacokinetics of rivaroxaban in pediatric studies is
`summarized below:
`
`Absorption:
`PK data following intravenous administration to children are not available, so the absolute bioavailability
`of rivaroxaban in children is unknown. Rivaroxaban is readily absorbed after oral administration as IR
`tablet or granules for oral suspension formulation in children. Following multiple doses of rivaroxaban in
`the EINSTEIN Jr Phase 3 study, median [range] Tmax,ss values were around 2 [1.8-2.6] h in pediatric
`subjects aged 6 to <18 years irrespective of formulation (tablet and granules for oral suspension) and
`around 1.5 [1.3-2.3] h in younger pediatric subjects, all receiving the granules for oral suspension. No
`difference in the absorption rate nor in the extent of absorption between the tablet and granules for
`oral suspension formulation was found, as the two formulations were found to be bioequivalent under
`fed and fasted conditions. In line with data obtained in adults, a decrease in the relative bioavailability
`for increasing doses (in mg/kg) was found, suggesting solubility-limited absorption for higher doses.
`However, similar to the findings with IR tablets, the 20 mg granules for oral suspension when taken with
`food behaved dose-proportionally with regard to rivaroxaban AUC and Cmax compared to 10 mg dose in
`the fasted state.
`
`Distribution:
`In vitro plasma protein binding was evaluated by spiking a nominal concentration of 100 ng/mL
`rivaroxaban in plasma samples collected from children aged <2 years old, 2-6 years old and >6-9 years
`old (N=3 donors per age group). The mean unbound fraction (fu %) in pooled pediatric plasma of
`different age groups: <2 years old, 2-6 years old and >6 years old were 11.1, 11.2 and 9.2%, respectively.
`In comparison, the mean plasma protein binding in adults was approximately 92 to 95%. Although the
`mean protein binding in adults is higher, the range of values observed in adults across different studies
`encompass the values observed in children. It should also be noted that plasma samples were not
`
`
`
`Reference ID: 4903283
`
`5
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`

`

`collected in any of the pediatric trials of rivaroxaban to evaluate protein binding. Based on population
`PK (popPK) model in pediatric patients, apparent volume of distribution (Vss/F) increased with body
`weight in accordance with allometric scaling.
`
`Elimination:
`Rivaroxaban is metabolized via the CYP3A4/5 and CYP2J2 enzymes in adults. Rivaroxaban was not a
`substrate for the fetal isoform of CYP3A7 and the contribution of CYP3A7 to the clearance in pediatric
`population can be excluded. The popPK model in pediatric patients showed that the clearance (CL/F)
`increased with body weight in accordance with allometric scaling. Geometric mean values for
`elimination half-life estimated via popPK modeling decreased with decreasing age and ranged from 4.2 h
`in adolescents to approximately 3 h in children aged 2 to12 years down to 1.9 and 1.6 h in children aged
`0.5-<2 years and less than 6 months, respectively.
`
`2.2 Dosing and Therapeutic Individualization
`
`2.2.1 General dosing
`The applicant has proposed a body weight-based oral dosing for pediatric patients from at-term birth
`(weighing ≥2.6 kg) to <18 years for the treatment or reduction in recurrence of VTE and for
`thromboprophylaxis in patients 2 years or older with congenital heart disease (CHD) after the Fontan
`procedure. The underlying dosing strategies for VTE treatment and CHD thromboprophylaxis were to
`achieve rivaroxaban exposures in children that are similar to that observed in adult DVT patients
`receiving 20 mg rivaroxaban once daily or adults receiving 10 mg rivaroxaban once daily after major
`orthopedic surgery, respectively. As observed in adults, a decrease in relative bioavailability for
`increasing doses (in mg/kg bodyweight) was also found in children, suggesting solubility-limited
`absorption limitations at higher doses. Hence, the pediatric doses for VTE treatment (corresponding to
`adult 20 mg dose), are recommended to be taken with food.
`
`The Applicant proposed pediatric dosing for VTE treatment following initiation of standard anticoagulant
`treatment, is shown in Table 1. All doses for the VTE indication should be taken with feeding or food to
`increase the absorption. Children younger than 6 months should have had oral /(naso)gastric feeding for
`at least 10 days preceding rivaroxaban administration. The proposed dosing regimen for VTE treatment
`was evaluated in EINSTEIN Jr, with the only exception of Japan, where 15 mg once daily was used for
`patients weighing ≥ 50 kg.
`
`
`
`
`
`Reference ID: 4903283
`
`
`
`6
`
`

`

`Table 1. Dosing table for Xarelto in pediatric patients (<18 years) for treatment of Venous
`Thromboembolism (VTE) and reduction in the risk of recurrent VTE
`
`Oral Suspension Only
`
`Dosage Form
`
`Body weight
`
`1 mg XARELTO = 1 mL suspension
`Dosage
`Total daily dose‡
`2 times a day§ 3 times a day§
`Once a day§
`
`0.8 mg
`2.4 mg
`2.6 to <3 kg
`
`
`0.9 mg
`2.7 mg
`3 to <4 kg
`
`
`1.4 mg
`4.2 mg
`4 to <5 kg
`
`
`1.6 mg
`4.8 mg
`5 to <7 kg
`
`
`1.8 mg
`5.4 mg
`7 to <8 kg
`
`
`2.4 mg
`7.2 mg
`8 to <9 kg
`
`
`2.8 mg
`8.4 mg
`9 to <10 kg
`
`
`3.0 mg
`9 mg
`10 to <12 kg
`
`
`5 mg
`10 mg
`12 to <30 kg
`
`
`15 mg
`15 mg
`30 to <50 kg
`
`
`Oral Suspension or
`Tablets
`20 mg
`20 mg
`
`
`≥50 kg
`*
`Initiate XARELTO treatment following at least 5 days of initial parenteral anticoagulation therapy.
`Patients <6 months of age should meet the following criteria: at birth were at least 37 weeks of gestation, have had at least
`†
`10 days of oral feeding, and weigh ≥2.6 kg at the time of dosing
`
`
`All doses should be taken with feeding or with food since exposures match that of 20 mg daily dose in adults.
`‡
`Once a day: approximately 24 hours apart; 2 times a day: approximately 12 hours apart; 3 times a day: approximately 8 hours
`§
`apart
`
`The Applicant proposed dosing for thromboprophylaxis in pediatric patients with CHD 2 years and older
`weighing 7 kilograms or more is shown in Table 2. The dose for thromboprophylaxis after Fontan
`procedure can be taken with or without food. The proposed dosing regimen for thromboprophylaxis in
`patients weighing <30 kg was identical to the regimen evaluated in UNIVERSE (Table 7). However, a
`model-based bridging was used to extrapolate dosing for post-Fontan patients ≥30 kg.
`
`Table 2. Dosing table for Xarelto in pediatric patients (<18 years) for thromboprophylaxis in post-
`Fontan population
`
`Dosage Form
`
`Body weight
`
`
`Oral Suspension Only
`
`7 to <8 kg
`8 to <10 kg
`10 to <12 kg
`12 to <20 kg
`20 to <30 kg
`30 to <50 kg
`≥50 kg
`
` 1 mg XARELTO = 1 mL suspension
`Total daily dose*
`Dosage
`Once a day†
`2 times a day†
`
`
`1.1 mg
`2.2 mg
`
`1.6 mg
`3.2 mg
`
`1.7 mg
`3.4 mg
`
`2.0 mg
`4.0 mg
`
`2.5 mg
`5.0 mg
`7.5 mg
`
`7.5 mg
`10 mg
`
`10 mg
`
`Oral Suspension or
`Tablets
`All doses can be taken with or without food since exposures match that of 10 mg daily dose in adults.
`Once a day: approximately 24 hours apart; 2 times a day: approximately 12 hours apart.
`
`*
`†
`
`
`
`
`
`
`Reference ID: 4903283
`
`
`
`7
`
`(b) (4)
`
`

`

`2.2.2 Therapeutic individualization
`Body weight and Age:
`Due to the expected gain in bodyweight of young children during the course of therapy, dose
`adjustments and/or change in dosing regimen according to the rivaroxaban dosing table for children
`(Table 1) are needed to ensure maintenance of a therapeutic dose.
`
`Renal impairment:
`Patients 1 year of age or older: No dosage adjustment is required with mild renal impairment (eGFR 50
`to ≤80 mL/min/1.73 m2). Avoid the use of rivaroxaban in pediatric patients with moderate or severe
`renal impairment (eGFR <50 mL/min/1.73 m2), as there is limited clinical data in these patients.
`Patients less than 1 year of age: Determine renal function using serum creatinine. Avoid the use of
`rivaroxaban in pediatric patients younger than 1 year with serum creatinine results above
`97.5th percentile, as no clinical data is available.
`
`Hepatic impairment:
`No clinical data are available in pediatric patients with hepatic impairment.
`
`Drug Interactions:
`Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2)
`transporters. Concomitant use with strong inhibitors of both P-gp and CYP3A increase exposure to
`rivaroxaban and may increase the risk of bleeding. Concomitant use with strong inducers of both P-gp
`and CYP3A decrease exposure to rivaroxaban and may increase the risk of thromboembolic events.
`Avoid concomitant use of rivaroxaban with known combined P-gp and strong CYP3A inhibitors or
`combined P-gp and strong CYP3A inducers in pediatric patients.
`
`2.3 Outstanding Issues
`None
`
`2.4 Summary of Labeling Recommendations
`General labeling recommendations were provided to improve the clarity and relevance of updated
`information related to pediatric indications that is conveyed to the healthcare provider. Additional
`recommendation was provided to specify the equations used to estimate renal function in the pediatric
`population that were enrolled into clinical studies.
`
`3. COMPREHENSIVE CLINICAL PHARMACOLOGY REVIEW
`
`3.1 Overview of the Product and Regulatory Background
`Rivaroxaban immediate release tablets (IR) are approved for several adult indications. In the pediatric
`clinical studies, only 10, 15, and 20 mg dose strengths were used and so the 2.5 mg is not supported for
`pediatric use. The granules for oral suspension is a new age-appropriate pediatric formulation and was
`shown to be bioequivalent to the marketed IR formulations.
`
`
`
`Reference ID: 4903283
`
`8
`
`

`

`The Applicant, Janseen Pharmaceuticals Inc., submitted the initial proposed pediatric study request
`(PPSR) for rivaroxaban in Aug/2012. All the clinical pediatric studies in VTE treatment program are a part
`of the Pediatric Research Equity Act (PREA) Post-marketing Requirements under NDA 022406. In
`response to FDA's feedback, a thromboprophylaxis program in pediatric subjects with CHD post-Fontan
`procedure was developed and included in the Written Request (WR) that was issued on 08 June 2017.
`Considering comparable pathophysiology of thromboembolism (TE) between adults and children, FDA
`supported partial extrapolation of safety and efficacy data from adult patients treated with rivaroxaban.
`However, the partial extrapolation was to be supported by an adequate PK and PD bridge to determine
`the appropriate dose, as well as sufficient safety and efficacy data to screen for large discrepancies in
`these endpoints between adults and children that could be caused by differences in underlying
`coagulation system maturity or TE pathophysiology. Since children of all ages, including neonates,
`experience VTE, studies for treatment of pediatric VTE were agreed to be conducted in children from
`birth through late adolescence. The study for prophylaxis after a Fontan procedure was agreed to be
`done in in children 2 years and older, an age group that was considered relevant to that procedure.
`
`Overall, the clinical pharmacology studies were aimed at (a) deriving dosing regimen across pediatric
`patients of all ages that targets similar exposures in adults treated with rivaroxaban, (b) comparing
`correlations for pharmacodynamic coagulation markers like prothrombin time [PT], activated partial
`thromboplastin time [aPTT], anti-factor Xa activity with plasma rivaroxaban concentrations in pediatric
`population versus data in adults and (c) development of an age-appropriate formulation to be used in
`the pediatric clinical studies.
`
`NDA submission overview:
`This NDA submission includes a total of 7 open-label, multicenter PK/PD studies (Table 3) of which 6
`were a part of the WR and/or PMR studies and the Applicant conducted an additional Phase 1 PK/PD
`study (Study 17992) in support of inclusion of the granules for oral suspension formulation into Phase 3
`trials. In addition, the submission includes 6 supporting biopharmaceutic studies in adult healthy
`subjects that characterize the pediatric formulations. The PK/PD studies include establishment of
`pediatric dosing regimen, safety, and efficacy of rivaroxaban in subjects with VTE (across all ages) and
`CHD post-Fontan (2-8 years). The model-based bridging was used to extrapolate dosing for post-Fontan
`patients from 9-18 years of age.
`
`Table 3. Overview of pediatric clinical studies for Rivaroxaban in NDA 215859
`
`Study
`number
`
`Phase Para
`meter
`
`Duration
`
`17992
`
`12892
`
`1
`
`1
`
`PK
`
`Single
`dose
`
`PK/PD Single
`dose
`
`
`
`Reference ID: 4903283
`
`Description
`
`Single-dose PK/PD study
`in subjects with
`previous thrombosis
`Single-dose PK/PD study
`in subjects with
`previous thrombosis
`
`Number
`receiving
`Xarelto
`/placebo
`47
`
`59
`
`Age
`range
`
`2 m to
`<12 y
`
`6 m to
`<18 y
`
`9
`
`

`

`14373
`
`14374
`
`2
`
`2
`
`17618
`
`1/2
`
`14372
`EINSTEIN Jr
`
`3001/18226
`UNIVERSE
`
`3
`
`3
`
`PK/PD 3 months-
`1 year
`
`birth to
`<18 y
`
`PK/PD 1 year
`
`2 y to
`≤8 y
`
`PK/PD 30-days
`repeated
`dose
`
`PK/PD 30-days
`repeated
`dose
`
`PK/PD 7-day
`repeated
`dose
`
`6 y to
`<18 y
`
`6 m to
`<6 y
`
`term
`newborn
`to <6 m
`
`43/20
`
`46
`
`10
`
`
`329/162
`
`76/34
`
`Multiple-dose (30-day)
`safety, efficacy, and
`PK/PD study in subjects
`with VTE
`Multiple-dose (30-day)
`safety, efficacy, and
`PK/PD study in subjects
`with VTE
`Multiple-dose (7-day)
`safety, efficacy, and
`PK/PD study in subjects
`with arterial or venous
`thrombosis
`Efficacy and
`safety in pediatric
`subjects with acute VTE
`Multiple-dose (12
`months) safety, efficacy
`and PK/PD for
`thromboprophylaxis
`post-Fontan procedure
`Source: Table 1 in Summary of Clinical Efficacy; For details on individual studies, refer Section 4.2
`
`3.2 General Pharmacology and Pharmacokinetic Characteristics
`For detailed information and highlights of clinical pharmacology of rivaroxaban, refer to the clinical
`pharmacology review under NDA 022406 on 4/6/2009.
`
`Pharmacology
`Mechanism of Action
`
`General Information
`Bioanalysis
`
`Drug Exposure at Steady
`State Following the
`Therapeutic Dosing
`Regimen
`Dose Proportionality
`
`Pharmacodynamics
`
`
`
`Reference ID: 4903283
`
`Rivaroxaban is a direct FXa inhibitor which competitively inhibits
`human free FXa. Rivaroxaban also inhibits prothrombinase activity.
`This results in downstream inhibition of the FXa mediated conversion
`of prothrombin to thrombin via the prothrombinase complex and
`prevents the fibrin clot formation as well as the activation of platelets
`by thrombin.
`
`Plasma concentrations of rivaroxaban were determined by validated
`HPLC-MS/MS methods. Anti-FXa was determined by colorimetric
`assay. PT and aPTT were determined using commercial coagulation
`analyzer.
`Refer to section 3.3.1 for comparison of exposures in pediatric patients
`to adult patients.
`
`The granules-for-oral-suspension formulation behaved dose
`proportionally for rivaroxaban AUC and Cmax for the 20 mg taken with
`food vs. 10 mg dose in the fasted state.
`Overall, the results of PT, aPTT in pediatric subjects were within the
`adult reference range and as in adults, there is a correlation between
`plasma rivaroxaban concentrations and the degree of its anticoagulant
`
`10
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`

`

`effect in pediatric patients with VTE and CHD post-Fontan for PT. A
`narrower range of aPTT values was observed in CHD post-Fontan
`subjects in UNIVERSE compared to adults. The anti-factor Xa activity
`correlated well with plasma rivaroxaban concentrations in pediatric
`patients.
`
`
`
`3.3 Clinical Pharmacology Review Questions
`
`
`3.3.1 To what extent does the available clinical pharmacology information provide pivotal or
`supportive evidence of effectiveness?
`The clinical pharmacology information provides supportive evidence of effectiveness in the similarity of
`PK-PD relationships and range of steady-state Ctrough values between adult and pediatric patients with
`VTE or pediatric patients with CHD after a Fontan procedure. Doses for the pivotal pediatric trials for
`VTE (Study 14372) and CHD after Fontan (Study CHD3001) were selected with an intent to achieve
`rivaroxaban exposures comparable to that achieved in the adult patients treated for VTE with a dosing
`regimen of 20 and 10 mg once daily, respectively.
`
`Overall, PK and PD data from more than 500 children who received single or multiple doses of
`rivaroxaban were available. Results for PK-PD relationship- and rivaroxaban concentration- comparisons
`between adults and children are described in the following sections.
`
`Similar PK-PD relationships for PT, aPTT and anti-factor Xa between adults and pediatric patients:
`
`The Applicant conducted pooled PK/PD relationship analysis for clotting time variables (aPTT and PT) in
`pediatric VTE patients and compared with the PK/PD relationships observed in adult VTE patients and
`healthy adults (Figure 2). In addition, the pooled PK/PD relationship for anti-factor Xa activity in
`pediatric VTE patients is shown in Figure 1, however because calibration using a different set of
`calibrators and controls were used during assays of pediatric study samples, a direct comparison with
`results from adult studies was not possible.
`
`Comparison between adults and pediatric patients- VTE treatment
`
`The pooled analysis from pediatric studies showed the anti-factor Xa increased linearly with increasing
`rivaroxaban concentration (Figure 1). A close correlation between anti-factor Xa activity assay and PK
`has also been well established in adults. In general, visual inspection did not indicate a relevant
`difference in the correlation between the pediatric data of different age groups or the dosing regimen
`(o.d., b.i.d. and t.i.d.).
`
`
`
`Reference ID: 4903283
`
`11
`
`

`

`Figure 1. Linear regression of anti-factor Xa activity versus plasma concentrationsof pediatric patients
`
`800
`
`700
`
`600
`
`=
`3500
`g
`= 400
`&
`300
`
`200
`
`wy
`IVR
`tn es
`
`Pod
`
`Study 12892
`Study 14372
`Study 14373
`Study 14374
`Study 17618
`Study 17992
`antiXA = 0.655 pg/I + 0.961*CP
`
`treated with rivaroxaban 900
`
`100},
`
`0 Beret
`0
`
`200
`
`400
`
`600
`
`800
`
`rivaroxaban plasma[pg/I]
`
`Anti-factor Xa activity (Rivaroxaban) absolute for children of Studies 12892, 14372, 14373, 14374, 17618 and
`17992 of all age groups, excluding data from three batches of 14372 which were considered outliers due to
`technical problems.
`Source: Module 5.3.3.5 Report PH-40947 (20763), appendix 9
`
`PT and aPTT were determinedasratio to the individual baseline and correlated to plasma
`concentrations. The visual inspection of the pooled data from the pediatric studies (14373, 14374,
`17618, 14372) indicated that the correlations of PT and aPTT (as ratio to baseline) versus plasma
`concentrationsin children across the age groups, were mostly contained within the 99% prediction
`interval of the adult DVT patients who were treated with a 20 mg oncedaily dose of rivaroxaban.
`
`Reference ID: 4903283
`
`12
`
`

`

`
`
`Figure 2. Correlation of PT and aPTT prolongation versus plasma concentrations in pediatric patients
`treated with multiple doses of rivaroxaban by age
`
`
`
`Source: Module 5.3.3.5 Report PH-40947 (20763), Appendix 6, Section 1.1.1.2.3 & Section 1.1.1.4.3
`
`Comparison between adults and pediatric patients- Thromboprophylaxis after Fontan procedure:
`
`The linear model describing the relationship between anti-FXa and the plasma rivaroxaban
`concentrations in UNIVERSE was similar to the pooled analysis from all pediatric studies, as shown in
`Figure 3 . The absolute values of PT and aPTT determined in UNIVERSE were correlated with plasma
`concentrations of rivaroxaban (Figure 4). The PT values were within the range of values that were
`observed in adults (receiving 5 mg twice daily in studies ODIXa-HIP2-10944 and ODIXa-KNEE-10945) and
`was found to correlate with plasma concentrations of rivaroxaban. A narrower range of aPTT values was
`observed in pediatric patients in UNIVERSE compared to adults with a weaker correlation of aPTT with
`plasma rivaroxaban concen