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

`

`PN U.S. FOOD & DRUG
`ADMINISTRATION
`
`RECOMMENDATION
`
`
`
`& Approval
`O Approval with Post-Marketing Commitment
`O Complete Response
`
`NDA 215859
`
`Assessment #01
`
`
`
`[Strength=————Ssd|1.mg/mLrivaroxabanoralsuspension=“$sid
`
`|Rx/OTCDispensed[Rxi“s—“‘“C;é‘“CSOOCOCOCOC*C*C“(‘#$NSCUCS
`
`
`|Applicant====~—_| Janssen Pharmaceuticals Inc.
`
`Original CMC submission
`
`Drug Substance, Drug Product, Micro
`
`Amendment
`
`10/04/2021
`
`Manufacturing
`
`11/04/2021
`
`11/16/2021
`
`Drug Product
`
`Biopharm
`
`QUALITY ASSESSMENT TEAM
`
`|__—Discipline__—i|-PrimaryAssessment|SecondaryAssessment__
`
`
`(OTR
`
`Manufacturing
`
`Nancy Waites, Caryn
`McNab (ORA
`
`Marijke Koppenol-Raab
`
`Daniel Obrzut
`
`Process Manager
`
`Lead
`Laboratory
`
`OPQ-XOPQ-TEM-0001v06
`
`Page 1
`
`Effective Date: February 1, 2019
`
`Reference ID: 4891981
`
`

`

`EXECUTIVE SUMMARY
`
`RECOMMENDATIONS AND CONCLUSION ON APPROVABILITY
`OPQ recommendsapproval of NDA 215859 for marketing of XARELTO
`(rivaroxaban) for oral suspension 1 mg/mL. The applicant provided adequate
`information to ensure theidentity, strength, purity, and quality of the proposed
`
`product. All facilities are in good standing.
`
`
`
`
`
`SUMMARY OF QUALITY ASSESSMENTS
`
`A. Product Overview
`Janssen seeksa priority review of NDA 215859 XARELTO®(rivaroxaban)
`oral suspension under 505(b)(1) to support inclusion of the proposed new
`indications in pediatric patients for the treatment of deep vein thrombosis
`(DVT), pulmonary embolism (PE) and additional cardiovascular disorders.
`This June 22, 2021 submission is a response to a Written Request for
`pediatric studies of rivaroxaban (Xarelto), with a PDUFA goal date of
`December 22, 2021.The proposed maximum doseis 20 mg perday, to be
`taken with food. The Applicant contendsthat the proposed treatment
`provides substantial improvementoveravailable anticoagulant therapies for
`the serious andlife- threatening conditions of venous thromboembolism
`(VTE) and thromboprophylaxis in children with congenital heart disease
`after the Fontan procedure.
`
`XARELTO® (rivaroxaban) granules, @ for oral suspension contains 155 ‘a
`mg of
`) rivaroxaban, suspension excipients
`(0) (4)
`The productis supplied in a 200-mL ambercolored type ©
`glass bottle closed with a white opaque
`(0) (4)
`screw cap. The product is co-packaged with two 5 mLsyringesfororal
`dosing and a press-in bottle adaptor. Prior to use, 150 mL of purified water
`is added to the granules at a pharmacyto provide a 1 mg/mL rivaroxaban
`oral suspension. The current commercial formulation was used throughout
`clinical studies, with smaller quantitiesfilled into the bottles @@ g and®@ g
`versus the current ©g per bottle). The stability data submitted provides
`adequate support for the proposed expiry dating period of 30 monthsat
`25°C, based on extension of shelf-life as per ICH Q1E. The drug product
`suspension can bestored for up to 60 days at room temperature, whichis
`dosed multiple times using the co-packaged oral syringes. Data was
`provided demonstrating adequatestability of the suspensionin the bottle for
`60 days, and compatibility with the co-packaged syringe and nasogastric
`tubes was demonstrated. Key quality issues assessed during the review
`included homogeneity of the suspension, redispersibility, uniformity of
`dosing and microbial content, which were confirmed to be acceptable for
`the drug product. Based on the review of NDA 215859, XARELTO®
`rivaroxaban) oral suspension is determined to be of acceptable quali
`
`Il.
`
`ll.
`
`Reference ID: 4891981
`
`

`

`
`
`with minimal risks to patients identified from a CMC perspective when used
`as directed.
`
`
`
`Proposed
`Indication(s)
`including Intended
`Patient Population
`
`Duration of
`Treatment
`
`Maximum Daily Dose
`Alternative Methods
`of Administration
`
`Treatment of deep vein thrombosis (DVT),
`pulmonary embolism (PE), reducerisk of stroke
`and embolism, and additional cardiovascular
`disorders.
`Oncea dayfor at least 3 monthsin children >2
`years old with thrombosis, up to 12 months when
`clinically necessary. For children <2 yearsold,
`treatment for 1 month, or up to 3 months when
`clinically necessa
`20 mg/da
`Oral tablets.
`
`B. Quality Assessment Overview
`
`Drug Substance: Adequate
`Rivaroxabanis a synthetic small molecule. The drug substanceis the S
`enantiomer. The
`o@ has
`been used throughout the whole development. Particle size distribution
`4) The applicant
`referenced all CMC information on the drug substance to DMF
`The DMF has been reviewed and found adequate to support other
`applications. Recent updates have been reviewed and found adequate to
`support this NDA.
`
`(0) (4).
`
`@ has been addedin addition to the
`A new manufacturing site at
`original manufacturing site registered for the synthesis of Rivaroxaban
`drug substance,
`om The
`(0)(4)
`, quality control procedures and specifications of the active
`substance Rivaroxaban manufacturedin
`4) are the same as
`those already approved. Batch analyses data for the drug substance
`batches manufactured at the new
`@ site is consistent with those
`from current sites.
`
`The specification from the drug product manufactureris consistent with
`the specification from DMF @ and the NDAincludes batch analyses
`data for 3 drug substance batchesusedin the three primary drug product
`stability batches. All 3 drug substance batches meet the specified
`acceptancecriteria, confirming suitability for use in the drug product. An
`updated risk assessment on the elemental impurities showsthat the
`elemental impurity levels are consistently observed below the LOD, and
`the risk from such impurities are low.
`
`
`
`
`
`Reference ID: 4891981
`
`

`

`
`
`The drug substance is packed in
`
`(o) (4)
`. Stability data for drug
`4) show no trend of
`substance batches manufactured at
`om RH
`degradation or increase of impurities through )monthsat
`(0)(4)
`and
`© RH. Stability studies are ongoing for the
`batches, with {months data available at long-term, intermediate and
`accelerated conditions. No changes or degradants have been observed.
`
`
`
`Drug Product: Adequate
`Rivaroxaban granulesfor oral suspension contains 155 {4mg of
`rivaroxabanperbottle, for multiple dosing by an oral syringe. The product
`is diluted with 150 mL of purified water by a pharmacistto a final
`concentration of 1 mg/mL rivaroxaban. All excipients are compendial, not
`of humanor animal origin, and present at acceptable levels for the
`maximum daily dose of 20 mg based on the FDAInactive Ingredients
`database. The drug product specifications are adequate to ensure quality
`and all drug product batches meet specified acceptancecriteria.
`Resuspendability and homogeneity of the diluted mixture was established
`to be acceptable during pharmaceutical developmentstudies, with
`consistent doses dispensed over a 28-day period. Minimal risks were
`identified regarding potential
`© jmpurities, and ICP-MS results
`confirmed that elemental impurities are adequately controlled. The key
`analytical methods are the HPLC method used to assessidentification,
`assay, and related compounds. Primary packaging for the commercial
`product consists of a 200 mL Type @glass bottle with a
`(0)(4)
`co-packaged with two oral dosing syringes, and onepress-in
`bottle adapter (PIBA). The container closure components meet USP
`requirements and 21 CFR compendialcriteria. Syringe device
`components meet the requirements of physicochemical and extractables
`test as per USP aswell as in-vitro biological reactivity tests. The co-
`packaged syringes are washed with water after each dose and discarded
`after a bottle is finished, or within 60 days. Registration drug product
`batches meetall acceptance criteria during long-term and accelerated
`stability studies for 18 months and six months respectively, with no
`significant changesor increases in degradants. Rivaroxaban granulesfor
`oral suspension are not photosensitive and meetpurity specifications
`following exposureto light, heat and high humidity in stress test studies.
`In-use stability was confirmed for a 2-month period, supporting the
`labeling recommendation of 60 days storage after dilution. The overall
`stability data submitted provides adequate support for the proposed expiry
`dating period of 30 months from the date of manufacture at 25°C, based
`on extension of shelf-life as per ICH Q1E. In summary,rivaroxaban
`granules for oral suspension are of acceptable quality, with minimalrisks
`to patients identified when used as directed.
`
`Reference ID: 4891981
`
`
`
`

`

`Labeling: Adequate
`All labeling deficiencies have been addressed. Edits to the carton and
`container labels are addressed by DMEPA,for consistency with the PI.
`The Prescribing Information, Medication Guide and labels comply with all
`
`uirements from a CMC perspective.
`
`Manufacturing: Adequate
`The manufacturing processof the drug product consists of
`This is a new pediatric
`indication for an already approved drug, NDA 22406 (Xarelto
`(Rivaroxaban)tablet, film coated). This NDAis for granules for oral
`suspension. This NDA (NDA 215859) serves as the Sponsor’s response
`to a Written Request for pediatric studies of rivaroxaban (Xarelto) for the
`purpose ofpediatric exclusivity determination, and to fulfill the PREA
`PMRsunder NDA 022406.
`
`granules @ for oral suspension.
`
`In a formulation study, it was determinedthat the particle size distribution
`(PSD)of the drug substance that had been established for the
`Rivaroxaban coated tablets was also appropriate for Rivaroxaban
`
`Reference ID: 4891981
`
`

`

`concurrence. OPMA recommendsapproval.
`
`No PAIs were conducted, all facilities are deemed adequate with ORA
`
`Biopharmaceutics: Adequate
`This submission serves as the Applicant’s response to a Written Request
`for pediatric studies of rivaroxaban (Xarelto) for the purpose of pediatric
`exclusivity determination, andto fulfill the PREA post-marketing
`requirements under NDA 022406 (Rivaroxaban IR Tablets).
`
`The proposed pediatric drug product is formulated as granulesfilled in a
`bottle, that can be administered as a suspension after addition of
`(0) 4)
`water, with a concentration of 1 mg/mL. The formulation offers dose
`flexibility, high convenience, and compliance for patients with dysphagia.
`The recommendeddoseis based on the body weight of the patient andall
`dosesare to be taken with feeding or with food to optimize absorption.
`
`The proposedindications for Rivaroxaban Oral Granulesare: (1)
`treatment of venous thromboembolism (VTE) and the reductionin risk of
`recurrent VTEin pediatric patients from birth to less than 18 years (after
`at least 5 days ofinitial parenteral anticoagulant treatment), and (2)
`thromboprophylaxis in pediatric patients aged 2 years and olderwith
`congenital heart disease (CHD) who have undergone the Fontan
`procedure.
`
`In support of this submission, the Applicant provided efficacy and safety
`data from twopivotal in pediatric patients (EINSTEIN Jr Phase 3, and
`UNIVERSE Phase3) as well as two studies that demonstrated
`bioequivalence between the granules-for-oral-suspension formulation and
`the standard IR Tablet (Study Nos. 19365 and 19366).
`
`This Biopharmaceutics assessmentis focused on the assessment of the
`proposed dissolution method and acceptancecriterion for quality control
`(QC) testing of rivaroxaban granules for oral suspension at release and
`onstability.
`
`The FDA approved quality control dissolution method and acceptance
`criterion (finished drug product batch release andstability testing) are as
`follows:
`
`
`
`Reference ID: 4891981
`
`
`
`

`

`Acceptance
`eae
`Se
`
`(Q) of the labeled
`NLT
`amountof rivaroxaban is
`dissolved in 30 minutes
`
`From the Biopharmaceutics perspective, NDA 215859 for the proposed
`Xarelto® (Rivaroxaban) Granules for Oral Suspension; 1 mg/mL,is
`
`Microbiology: Adequate
`The proposed drug product is a non-sterile granule formulation of
`rivaroxabanintended for oral administration following suspension
`in water. The drug product is manufactured usingPyye
`
`The potential for BCC contamination was demonstrated to be low for the
`solid drug product as well as the the constituted solution. Antimicrobial
`effectiveness testing (AET) per USP<51> was performed on two primary
`stability batchesattheinitial timepoint and after 12 months of storage of
`the granules. Additionally, the Applicant commitedSyye
`
`The tests and acceptance criteria are adequate to assure the
`microbiological quality of the subject drug product.
`
`A post-approval proposal
`
`Adequate and recommended for Approval.
`
`temperature between 20-25°C (with excursion permitted to 15°C to 30°C
`
`Stability studies for the granules are adequate to support the proposed
`shelf life. The reconstituted suspensionis to be stored at room
`
`Reference ID: 4891981
`
`

`

`
`
`and used within 60 days.In-use stability studies performed at the
`beginning of shelf-life and after 12 months of storage confirmedthatall
`samples met the specifications for
`© and microbiological
`Tests. In response to an Information Request, the Applicant agreed to
`revise the pharmacy preparation instructions to use purified water
`for drug product constitution.
`
`
`
`The Applicant has met regulatory expectations with regard to the
`information related to issues of product quality microbiologythatis
`provided in the product labeling.
`
`C. Risk Assessment
`
`
`
`ng:
`Lifecycle
`Attribute)|Factors that|Initial|2:54 mitigation|Final Risk|Considerati
`CQA
`hy a Rawk
`Approach
`Evaluation
`ons/
`©
`anking
`Comments
`
`
`Assay Suspendability|Medium oan Acceptable
`& homogeneity
`of reconstituted
`drug product.
`
`
`
`Physical Insoluble drug|Low Acceptable
`
`
`
`Stability of
`substance,
`diluted
`storage time
`product
`
`Content Suspendability|Medium Acceptable
`
`
`
`Uniformity
`& homogeneity
`of reconstituted
`drug product.
`
`Microbial
`Content
`
`Formulation,
`container
`closure
`
`Low
`
`Acceptable
`
`Dissolution
`
`
`
`Drug
`substance
`solubility,
`polymorphism
`
`Medium
`
`Acceptable
`
`Reference ID: 4891981
`
`

`

`Particle Size|Manufacturing Acceptable
`
`
`process, drug
`substance
`
`solubility
`
`D. List of Deficiencies for Complete Response
`
`1. Overall Quality Deficiencies (Deficiencies that affect multiple sub-
`disciplines
`
`None
`
`2. Drug Substance Deficiencies
`
`None
`
`3. Drug Product Deficiencies
`
`None
`
`
`
`4. Labeling Deficiencies
`None
`
`5. Manufacturing Deficiencies
`None
`
`6. Biopharmaceutics Deficiencies
`None
`
`7. Microbiology Deficiencies
`None
`
`8. Other Deficiencies (Specify
`None
`
`discipline, such as Environmental
`
`|
`
`|
`
`|
`
`Application Technical Lead Name and Date:
`
`Dan Berger
`
`November 18, 2021
`
`Reference ID: 4891981
`
`

`

`QUALITY ASSESSMENT DATA SHEET
`IQA NDA Assessment Guide Reference
`
`1. RELATED/SUPPORTING DOCUMENTS
`
`A. DMFs:
`
`Type
`
`Rsheenced
`
`cardiovascular events.
`
`complet Comments
`‘ActveNA—on
`
`NA|Surncienta N/A inNDA
`feeNA|sumcient
`
`Date
`Assess
`
`ed
`
`Application Number
`
`022406, 202439
`
`Tablets for treatment of
`deep vein thrombosis,
`treatment of pulmonary
`embolism, stroke and
`
`2. CONSULTS
`
`None.
`
`Reference ID: 4891981
`
`

`

`Dan
`Berger
`
`Ee-Sunn
`(Joanne)
`Chia
`
`Digitally signed by Dan Berger
`Date: 11/19/2021 10:01:36AM
`GUID: 56e6e1b5001a2fedae663c62a5ce7513
`
`Digitally signed by Ee-Sunn (Joanne) Chia
`Date: 11/19/2021 02:16:08PM
`GUID: 522a33990002ab8777245f8ac9cb6532
`
`Reference ID: 4891981
`
`47 Pages have been Withheld in Full as b4 (CCI/TS)
`immediately following this page
`
`

`

`PN U.S. FOOD & DRUG
`ADMINISTRATION
`
`CHAPTER IV: LABELING
`
`1.0 PRESCRIBING INFORMATION
`
`Assessment of Product Quality Related Aspects of the Prescribing
`Information:
`
`The prescribing information meetsall regulatory requirements from a CMC
`perspective.
`
`1.1 HIGHLIGHTS OF PRESCRIBING INFORMATION
`Information Provided|4.<essor’s Comments
`in the NDA
`
`ProductTitle in Highlights
`
`Proprietary name
`XARELTO
`Adequate
`Established name(s
`Rivaroxaban
`Adequate
`
`
`Route(s) of administration|Oral=~—~—~—_|Adequate
`
`bulk package.
`
`1 mg/mL (once
`reconstituted)
`
`Adequate
`
`NA
`
`N
`
`A
`
`NA
`
`N
`
`A
`
`Summary of the dosage
`form(s) and strength(s)
`in metric system.
`Assessif the tabletis
`scored. If product meets
`guidelines and criteria for a
`scoredtablet, state
`“functionally scored”
`For injectable drug
`products for parental
`administration, use
`appropriate package type
`term (e.g., single-dose,
`multiple-dose, single-
`patient-use). Other
`package termsinclude
`pharmacy bulk package
`and imaging
`
`1.2 FULL PRESCRIBING INFORMATION
`1.2.1 Section 2 (DOSAGE AND ADMINISTRATION)
`
`OPQ-XOPQ-TEM-0001v06
`
`Page 1
`
`Effective Date: February 1, 2019
`
`Reference ID: 4891981
`
`

`

`Information Provided
`in the NDA
`
`Assessor’s Comments
`
`DOSAGE AND ADMINISTRATION section Special instructions for
`
`Adequate
`Pharmacy: Tap the
`product preparation (e.g.,|bottle until all granules
`reconstitution and resulting|flow freely. Add 150
`concentration, dilution,
`mL of purified water for
`compatible diluents,
`reconstitution. Shake
`storage conditions needed|for 60 seconds. Check
`to maintain the stability of|that all granules are
`the reconstituted or diluted|wetted and the
`product)
`suspension is uniform.
`Push the adaptor
`into bottleneck and
`recap bottle.
`yom
`
`The suspension must
`be used within 60
`days.
`Read instructions For
`Use.
`
`1.2.2 Section 3 (DOSAGE FORMS AND STRENGTHS)
`
`OPQ-XOPQ-TEM-0001v06
`
`Page 2
`
`Effective Date: February 1, 2019
`
`Reference ID: 4891981
`
`

`

`Strength(s) in metric system
`
`Information Provided Assessor’s Comments
`in the NDA
`7 mg/mL
`
`[Adequate
`Adequate
`
`|NA
`
`If the active ingredientis a salt,
`apply the USP Salt Policy per
`FDA Guidance
`A description of the identifying |White to off-white
`characteristics of the dosage
`|granules; once
`forms, including shape, color,
`|reconstituted, provide
`coating, scoring, and imprinting |flavored white to off-
`white opaqueliquid
`|NA
`
`Adequate
`
`Adequate
`
`
`
`Assessif the tablet is scored.
`If product meets guidelines
`and criteria for a scored tablet,
`state “functionally scored”
`For injectable drug products for|NA
`parental administration, use
`appropriate labeling term (e.g.,
`single-dose, multiple-dose,
`single-patient-use). Other
`package type terms include
`pharmacy bulk package and
`bulk package.
`
`OPQ-XOPQ-TEM-0001v06
`
`Page 3
`
`Effective Date: February 1, 2019
`
`Reference ID: 4891981
`
`

`

`DESCRIPTIONsection
`
`name(s
`
`Information Provided
`in the NDA
`
`Assessor’s
`Comments
`Pp
`
`Dosage form(s) and route(s) of||XARELTO granulesfororal
`administration
`suspension
`If the active ingredientis a salt,
`apply the USP Salt Policy and
`include the equivalency
`statement per FDA Guidance.
`List namesofall inactive
`ingredients. Use USP/NF names.
`Avoid Brand names.
`
`Adequate
`
`Anhydrouscitric acid,
`|hypromellose, mannitol,
`microcrystalline cellulose &
`carboxymethylcellulose
`sodium, sodium benzoate,
`sucralose, sweet and creamy
`flavor and xanthan gum.
`|NA
`
`
`
`For parenteral injectable dosage
`forms, include name and
`quantities of all inactive
`
`If alcohol is present, must provide |NA
`the amountof alcohol in terms of
`percent volumeof absolute
`alcohol
`
`applicable
`
`class
`
`NA
`
`NA
`
`formula, molecular weight
`
`CigHisCIN305S, 435.89.
`
`important nuclear characteristics.
`
`Other important chemical or Practically insoluble in water|Adequate
`physical properties (such as pKa
`|and aqueous media.
`or pH
`* 5-Chloro-N-({(5S)-2-0xo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide
`
`Section 11 (DESCRIPTION) Continued
`
`OPQ-XOPQ-TEM-0001v06
`
`Page 4
`
`Effective Date: February 1, 2019
`
`Reference ID: 4891981
`
`

`

`NA
`
`
`Information Provided
`Item
`in the NDA
`Assessor’s Comments
`For oral prescription drug
`NA
`products, include gluten
`statementif applicable
`Removestatements that
`may be misleading or
`promotional(e.g.,
`“synthesized and developed
`by Drug Company xX,”
`“structurally unique
`
`molecular enti
`
`1.2.4 Section 16 (HOW SUPPLIED/STORAGE AND HANDLING
`
`in the NDA
`HOW SUPPLIED/STORAGE AND HANDLING section
`
`Available dosage form(s
`Strength(s) in metric system |1 mg/mL (once
`reconstituted
`
`Adequate
`
`Adequate
`
`package.
`
`of 100 tablets)
`
`Identification of dosage
`White to off-white
`Adequate
`forms, e.g., shape, color,
`granules, NDC 50458-
`coating, scoring, imprinting,
`|575-01
`
`NDC number
`Assessifthe tablet is scored.
`If product meets guidelines
`and criteria for a scored
`tablet, state “functionally
`
`For injectable drug products
`for parental administration,
`use appropriate package
`type term (e.g., single-dose,
`multiple-dose, single-patient-
`use). Other package terms
`include pharmacy bulk
`package and imaging bulk
`
`OPQ-XOPQ-TEM-0001v06
`
`Page 5
`
`Effective Date: February 1, 2019
`
`Reference ID: 4891981
`
`

`

`Section 16 (HOW SUPPLIED/STORAGE AND HANDLING)
`(Continued
`Information Provided
`Assessor’s Comments
`in the NDA
`
`Special handling about the
`supplied product(e.g.,
`protect from light,
`refrigerate). If there is a
`statementto “Dispensein
`original container,” provide
`reason why(e.g. to protect
`from light or moisture, to
`
`If the product contains a
`desiccant, ensure the size
`and shapediffer from the
`dosage form and desiccant
`has a warning such as “Do
`not eat.”
`Storage conditions. Where
`applicable, use USP
`storage rangerather than
`storage at a single
`temperature.
`
`Store at room
`temperature between
`20°C to 25°C (68°F to
`77°F); excursions
`permitted to 15°C to
`30°C (59°F to 86°F
`
`Adequate
`
`If product does not
`Latex:
`contain latex and
`manufacturing of product
`and container did not
`include use of natural
`rubberlatex or synthetic
`derivatives of natural rubber
`latex, state: “Not made with
`natural rubber latex. Avoid
`statements such as “latex-
`free.”
`Include information about
`child-resistant packaging
`
`N
`
`A
`
`1.2.5 Other Sections of Labeling
`No other sections of the labeling contain product quality information.
`
`OPQ-XOPQ-TEM-0001v06
`
`Page 6
`
`Effective Date: February 1, 2019
`
`Reference ID: 4891981
`
`

`

`Manufacturing Information After Section 17 Nameand location of
`
`Manufacturedfor:
`|Janssen
`|Pharmaceuticals, Inc.
`Titusville, NJ 08560
`
`Adequate.
`
`1.2.6 Manufacturing Information After Section 17 (for drug products
`Information Provided
`,
`
`business(street address,
`city, state and zip code) of
`the manufacturer,
`distributor, and/or packer
`
`2.0 PATIENT LABELING
`
`Assessment of Product Quality Related Aspects of Patient Labeling (e.g.,
`Medication Guide, Patient Information, Instructions for Use):
`
`Storage conditions and inactive ingredientlist is provided in the Medication
`Guide. This information complies with all regulatory requirements from a CMC
`perspective.
`
`3.0 CARTON AND CONTAINER LABELING
`
`3.1 Container Label
`
`3.2 Carton Labeling
`
`OPQ-XOPQ-TEM-0001v06
`
`Page 7
`
`Effective Date: February 1, 2019
`
`
`
`Reference ID: 4891981
`
`

`

`Item
`
`Information Provided in| ASS@Ssor’s Comments
`aboutBottle and
`the NDA
`carton Labeling
`Xarelto (rivaroxaban)
`Adequate
`
`Proprietary name, established
`name, and dosage form (font
`size and prominence
`Dosage strength
`oral=~CdAdequate
`Route of administration
`If the active ingredientis a salt,
`NA
`include the equivalency
`statement per FDA Guidance
`
`Aa
`
`155 mg ofrivaroxaban
`Present
`
`Adequate
`
`50458-575-01
`
`Net contents (e.g. tablet count
`“Rx only” displayed on the
`principal displa
`NDC number
`Lot numberand expiration date
`Storage conditions. If applicable,
`include a space onthe carton
`labeling for the userto write the
`new BUD.
`
`
`
`
`
`°F and °C Reversed
`from usual. Adequate
`following requested edits
`sent to DMEPAforthe
`Applicant.
`NA
`
`Store at 68°F to 77°F
`(20°C to 25°C);
`excursions permitted
`between 59°F to 86°F
`15°C to 30°C
`NA
`
`For injectable drug products for
`parental administration, use
`appropriate package type term
`(e.g., single-dose, multiple-dose,
`single-patient-use
`Other package termsinclude
`pharmacy bulk package and
`imaging bulk package which
`require “Not for direct infusion”
`statement.
`If alcohol is present, must
`provide the amountof alcoholin
`terms of percent volume of
`absolute alcohol
`Present Adequate
`Bar code
`
`NA
`
`
`
`OPQ-XOPQ-TEM-0001v06
`
`Page 9
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`Effective Date: February 1, 2019
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`Reference ID: 4891981
`
`

`

`
`
`Item
`
`Information Provided in the
`NDA
`
`Assessor’s
`Comments
`about Bottle
`
`|Finished Product Manufactured|Adequate
`
`Medication Guide (if applicable)
`
`{Storage and active/inactive
`ingredientslisted.
`
`Adequate
`
`
`Labeling Name of manufacturer/distributor
`
`No text on Ferrule and Cap
`overseal
`Whena drug productdiffers from
`the relevant USP standard of
`strength, quality, or purity, as
`determined by the application of
`the tests, procedures, and
`acceptancecriteria set forth in
`the relevant compendium, its
`difference shall be plainly stated
`onits label.
`Andothers, if space is available
`
`NA
`
`NA
`
`Assessmentof Carton and Container Labeling: Adequate
`DMEPAhasagreedto address the required edits to the storage information. With the
`required edits, the labels comply with all regulatory requirements from a CMC
`perspective.
`
`ITEMS FOR ADDITIONAL ASSESSMENT
`
`None
`
`Overall Assessment and Recommendation:
`Edits to the carton and container labels are addressed by DMEPA,for consistency
`with the PI. The Prescribing Information, Medication Guide and labels comply with all
`regulatory requirements from a CMC perspective.
`
`Primary Labeling Assessor Name and Date:
`
`Dan Berger
`
`November8, 2021
`
`Secondary Assessor Name and Date (and Secondary Summary, as needed):
`
`Ee-Sunn Chia
`
`November8, 2021
`
`OPQ-XOPQ-TEM-0001v06
`
`Page 10
`
`Effective Date: February 1, 2019
`
`Reference ID: 4891981
`
`

`

`Dan
`Berger
`
`Ee-Sunn
`(Joanne)
`Chia
`
`Digitally signed by Dan Berger
`Date: 11/08/2021 02:50:53PM
`GUID: 56e6e1b5001a2fedae663c62a5ce7513
`
`Digitally signed by Ee-Sunn (Joanne) Chia
`Date: 11/09/2021 10:28:42AM
`GUID: 522a33990002ab8777245f8ac9cb6532
`
`Reference ID: 4891981
`
`44 Pages have been Withheld in Full as b4 (CCI/TS)
`immediately following this page
`
`

`

`QUALITY ASSESSMENT
`
`CHAPTERVI: BIOPHARMACEUTICS
`
`Product Information
`
`505 (b)(1) Xarelto® (Rivaroxaban) Granules for
`Oral Suspension
`
`NDA Number
`
`215859
`
`Fontan Procedure.
`
`Assessment Cycle Number
`Drug Product Name/ Strength
`
`Route of Administration
`
`OND Division
`
`Proposed Indication
`
`Rivaroxaban granules for oral suspension;
`1 mg/mL
`
`Janssen Research & Development, LLC
`
`NDA022406 and NDA 202439 (Xarelto® IR
`Tablets
`Treatmentof (1) Venous Thromboembolism
`(VTE) and the reductionin the risk of recurrent
`VTE in pediatric patients, and (2)
`thromboprophylaxis in pediatric patients with
`Congenital Heart Disease (CHD) after the
`
`Assessment Recommendation: Adequate
`
`Assessment Summary:
`On 06/22/2021, the Applicant, Janssen Research & Development, LLC!, submitted an
`NDAunder 505(b)(1) seeking marketing approval for Xarelto® (Rivaroxaban) Granules
`for Oral Suspension (1 mg/mL). This submission serves as the Applicant’s response to a
`Written Request for pediatric studies of rivaroxaban (Xarelto) for the purpose of
`pediatric exclusivity determination, andto fulfill the PREA post-marketing requirements
`under NDA 022406 (Rivaroxaban IR Tablets).
`
`The proposedpediatric drug productis formulated as granulesfilled in a bottle, that can
`be administered as a suspensionafter addition of
`4) water, with a concentration of
`1 mg/mL.The formulation offers dose flexibility, high convenience, and compliance for
`patients with dysphagia. The recommended dose is based on the body weight of the
`patient andall doses are to be taken with feeding or with food to optimize absorption.
`
`The proposed indications for Rivaroxaban Oral Granules are: (1) treatment of venous
`thromboembolism (VTE) andthe reduction in risk ofrecurrent VTE in pediatric patients
`from birth to less than 18 years (after at least 5 days of initial parenteral anticoagulant
`
`! Rivaroxaban (JNJ-39039039, BAY 59-7939) was co-developed under a collaboration license agreement between Bayer AG and
`Janssen Pharmaceuticals, Inc. Marketing applications in the US are submitted by Janssen Research & Development, LLC on behalf of
`
`Janssen Pharmaceuticals, Inc. Module 2.5 (Page 9).
`
`OPQ-XOPQ-TEM-0001v07
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`Page 1
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`Effective Date: April 22, 2021
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`Reference ID: 4891981
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`

`

`QUALITY ASSESSMENT
`
`treatment), and (2) thromboprophylaxis in pediatric patients aged 2 years and older with
`congenital heart disease (CHD) who have undergone the Fontan procedure.
`
`In support of this submission, the Applicant provided efficacy and safety data from two
`pivotal in pediatric patients (EINSTEIN Jr Phase 3, and UNIVERSEPhase 3) as well as
`two studies that demonstrated bioequivalence between the granules-for-oral-suspension
`formulation and the standard IR Tablet (Study Nos. 19365 and 19366).
`
`is focused on the assessment of the proposed
`This Biopharmaceutics assessment
`dissolution method and acceptance criterion for quality control (QC) testing of
`rivaroxaban granules for oral suspensionat release and onstability.
`
`The FDA approved quality control dissolution method and acceptancecriterion
`(finished drug productbatch release andstability testing) are as follows:
`
`Medium
`
`Acceptance
`Criterion
`
`NLT “% (Q)ofthe labeled
`:
`:
`amount ofrivaroxaban is
`dissolved in 30 minutes
`
`Comments
`
`Updated Risk
`Rankingafter
`Assessment
`
`Comments
`
`Cycle # APIParticle
`
`Size
`
`As rivaroxaban
`is a low
`
`solubility drug
`substance,
`particle size may
`impact
`dissolution.
`
`,
`.
`Applicant has implemented y
`
`It is noted that the
`dissolution method and
`acceptance criterion can
`discriminate against changes to
`the API particle size.
`
`Overall Recommendation: From the Biopharmaceutics perspective, NDA 215859 for
`the proposed Xarelto® (Rivaroxaban) Granules for Oral Suspension; 1 mg/mL,is
`Adequate and recommended for Approval.
`
`? The APIparticle size specification is the same as thatlisted for the approved Rivaroxaban Tablets (adult
`formulation).
`
`OPQ-XOPQ-TEM-0001v07
`
`Page 2
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`Effective Date: April 22, 2021
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`

`

`QUALITY ASSESSMENT
`
`List Submissions Being Assessed (table):
`
`
`
`Document(s) Assessed
`0001 (1) Original Submission
`0025 (25)
`IR Response
`
`Date Received
`
`October 22, 2021
`
`Highlight Key Issues from Last Cycle and Their Resolution: N/A
`
`Concise Description of Outstanding Issues(list bulletpoints with key information
`and update as needed): N/A
`
`B.1 BCS DESIGNATION
`
`Assessment: No BCS Designation request was made; however, based on the submitted
`data, rrvaroxaban appears to be BCSClassII.
`
`Solubility: According to the Applicant, rivaroxaban is practically insoluble in water and
`aqueous media pH 1-9. Rivaroxaban has a solubility of 5-7 mg/L at 25°C, independent of
`pH.See Table 1 below for solubility at 37°C in various pH media.
`Table 1. Solubility of rivaroxabanin aqueous media ofdifferent pH at 37°C
`Medium
`Solubility
`
`(mg/mL)
`0.0111
`0.0111
`0.0133
`
`0.0100
`
`0.1 MHCI pH 1
`0.01 M HCI pH 2
`Acetate buffer pH 4.5
`Phosphate buffer pH 6.8
`
`Permeability: The Applicant investigated the permeability of rivaroxaban using a
`validated Caco-2 assay and found rivaroxaban to be highly permeable’.
`
`Dissolution: See below.
`
`B.2 DISSOLUTION METHOD AND ACCEPTANCE CRITERION
`Assessment: Adequate
`
`Dissolution Method:
`Seed Rivaroxaban Granules ©@for
`Acceptance
`Criterion
`Oral Suspension
`0.022 M Acetate Buffer pH 4.5
`900 mL; 37°C
`2 (paddle)
`
`NLT ™% (Q)ofthe labeled
`amount of rivaroxaban is
`dissolved in 30 min
`
`Criterion
`
`Volume/Temp
`USP Apparatus
`Rotational Speed
`
`Acceptance
`
`3 NDA 215859 Module 2.5 Clinical Overview(Page 26)
`
`OPQ-XOPQ-TEM-0001v07
`
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`

`

`QUALITY ASSESSMENT
`with different API particle sizes.
`
`e Discriminating ability ofthe dissolution method: The Applicant confirmedthe
`discriminating nature of the selected dissolution method by producing different
`drug productbatches using (1) drug substanceofdifferent particle sizes, (2) a
`change in drug product composition,or (3) different process parameters.
`
`The average dissolution profiles of drug product batches with different particle
`size using the proposed dissolution method are represented in Figure 3 below.
`
`Figure 3. Dissolution profiles of batches manufactured
`
`The dissolution rate of rivaroxaban, as a BCSClass II drug substance,is
`affected by particle size. As the particle size of rivaroxaban increases, the
`dissolution profiles become slower and incomplete. The proposeddissolution
`method was able to distinguish batches with aberrant PSDs. Nevertheless, the
`Applicant implemented
`SOMfito further mitigate risk. It is noted that the PS
`
`OPQ-XOPQ-TEM-0001v07
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`Page 5
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`Effective Date: April 22, 2021
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`Reference ID: 4891981
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`

`

`QUALITY ASSESSMENT
`LD)5.2
`
`specification for the 97 drug substance used for manufacturing Rivaroxaban
`Granules is the same specification listed for the approved Rivaroxaban Tablets.
`
`While the dissolution method was able to discriminate against changesto the
`drug substanceparticle size, it was not sensitiveyyy
`LLL or changes
`in the pH of the suspension after reconstitution. The Applicant showed that
`when the drug product was stressed at 60°C for 2 weeks, similar dissolution
`profiles as compared with the non-stressed sample were observed. Therefore.
`suggesting that the d