`
`
` CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`
`
`
`
` 214120Orig1s000
`
`
`
` PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`

`

`QUALITY ASSESSMENT
`
`
`Recommendation: APPROVAL
`
`NDA214120
`Review #1
`
`Dm g Name/Dosage Fo1m
`Strength
`Route of Administration
`Rx/OTC Dispensed
`Applicant
`
`US agent, if aoolicable
`
`Azacitidine Tablets
`200 mg and 300 mg
`Oral
`Rx
`Celgene Corporation, a wholly owned subsidiaiy of Bristol-
`Myers Squibb
`n/a
`
`SUBMISSION(S)
`REVIEWED
`Original Submission
`Amendment (SD)
`Amendment (SD)
`Amendment (SD)
`Amendment (SD)
`Amendment (SD)
`Amendment (SD)
`Amendment (SD)
`Amendment (SD)
`
`DOCUMENT
`DATE
`03-Mar-2020
`15-May-2020
`21-May-2020
`28-May-2020
`22-Jun-2020
`08-Jul-2020
`06-Jul-2020
`16-Jul-2020
`06-Sept-19
`
`DISCIPLINE(S) AFFECTED
`
`All
`DP
`Process/facilities
`DP, Biophaim, Process/facilities
`DP, Biophan n
`DP
`Process/facilities
`DP
`Process/Facilities
`
`DISCIPLINE
`Dmg Master File/Dmg
`Substance
`Dmg Product
`Process and Facilities
`Microbiolo!lV
`Biopha1maceutics
`Regulato1y Business
`Process Manager
`Application Technical Lead
`Laboratory (OTR)
`
`Quality Review T earn
`PRIMARY REVIEWER
`Kai·ina Zuck
`
`SECONDARY REVIEWER
`Hai·ipada Sai·ker
`
`Nina Ni
`Huiquan Wu
`n/a
`Min Kang
`Rabiya Haider
`
`Anamitro Baneriee
`Bogdan Kurtyka
`n/a
`Om Anand
`n/a
`
`Sherita McLamore
`n/a
`
`n/a
`n/a
`
`OPQ-XOPQ-TEM-0001 v04
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`Page 1of2
`
`Effective Date: 14 Febmaiy 2017
`
`Reference ID 4657513
`
`

`

`QUALITY ASSESSMENT
`
`
`Environmental
`
`Raanan Bloom
`
`n/a
`
`OPQ-XOPQ-TEM-0001v04
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`Page 2 of2
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`Effective Date: 14 Febrnaiy 2017
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`Reference ID 4657513
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`
`

`

`QUALITY ASSESSMENT
`
`
`Quality Review Data Sheet
`
`1. RELATED/SUPPORTING DOCUMENTS
`
`A. DMFs:
`
`DMF# .1 Type
`Cb><4>Type
`III
`
`Holder
`
`IItem Referenced
`
`Status
`CbH4> n/a
`
`Date Review
`Completed Comments
`No Review
`Adequate
`info1mation
`provided in
`theNDA
`Adequate
`info1mation
`provided in
`theNDA
`Adequate
`info1mation
`provided in
`theNDA
`Adequate
`info1mation
`provided in
`theNDA
`Adequate
`info1mation
`provided in
`theNDA
`
`No Review
`
`No Review
`
`No Review
`
`No Review
`
`n/a
`
`n/a
`
`n/a
`
`n/a
`
`Type
`III
`
`Type
`III
`
`Type
`III
`
`Type
`III
`
`Type
`III
`
`Type
`III
`
`Type
`III
`
`Type
`III
`
`n/a
`
`No Review
`
`n/a
`
`No Review
`
`n/a
`
`No Review
`
`n/a
`
`No Review
`
`Adequate
`info1mation
`provided in
`theNDA
`Adequate
`info1mation
`provided in
`theNDA
`Adequate
`info1mation
`provided in
`theNDA
`Adequate
`info1mation
`provided in
`theNDA
`
`B. Other Documents: IND, RLD, or sister applications
`
`OPQ-XOPQ-TEM-0001 v04
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`Page 1of2
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`Effective Date: 14 Febrnruy 2017
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`Reference ID 4657513
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`

`

`QUALITY ASSESSMENT
`
`
`DOCUMENT
`
`IND
`
`APPLICATION NUMBER
`I
`
`(b)(4l
`
`DESCRIPTION
`
`Development of!
`
`(b}(4~
`
`2. CONSULTS
`NIA
`
`OPQ-XOPQ-TEM-0001 v04
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`Page 2 of2
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`Reference ID 465751 3
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`

`
`
`bs;llil#~=*===-~~=-~~~Q_U_AL~I_T_Y_A_s_s_E_ss_ME~N_T~~~----'rgj}@~~
`
`
`Executive Summary
`
`I. Recommendations and Conclusion on Approvability
`
`OPQ recommends APPROVAL ofNDA 214120 for Onureg®(azacitidine) tablets, 200
`mg and 300 mg. As part of this action, OPQ grants a 30-month expiration period for the
`drng product when stored at "20°C to 25°C (68°F to 77°F) excursions permitted between
`15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]." There are no
`outstanding issues and no post-approval quality agreements to be conveyed to the
`applicant.
`
`II.
`
`Summary of Quality Assessments
`
`A. Product Overview
`NDA 214120 was submitted for Onureg®(azacitidine) tablets, 200 and 300 mg in
`accordance with section 505(b)(l ) of the Food, Drng and Cosmetic Act. Onureg®is a
`once daily, orally bioavailable, nucleoside metabolic inhibitor that is indicated as
`
`--~~~~~~~~~~--
`
`(bJ<41 Azacitidine was originally approved under NDA
`50794 in May of2004 for the treatment of myelodysplastic syndrome (MDS).
`Azacitidine received mphan drng designation for the treatment of acute myeloid
`leukemia on 18 June 2008. The proposed product is an oral fo1mulation of the approved
`product. The oral fo1mulation was developed to allow sustained and extended
`administration of azacitidine.
`
`Azacitidine drng substance is a small chiral molecule that is manufactured
`
`(bH4~
`The drng
`(b)(4l immediate-release, film-coated
`product is supplied as a 200 or 300 mg,
`tablets for oral administration. The 200 mg dosage fonn is presented as a pink, oval
`tablet with debossed 200" on one side and "ONU" on the other side. The 300 mg tablet
`is presented as a brown, oval tablet with debossed "300" on one side and "ONU" on the
`other side.
`
`(bH4~ dose for the drng product is 300 mg orally, once daily for the
`The recommended
`first 14 days of each 28-day cycle. The treatment should continue
`(b)C4l
`until unacceptable toxicity
`
`occurs.
`
`Based on the info1mation provided in this application (original submission and in
`responses to info1mation requests), OPQ considers all review issues adequately addressed
`and potential risks to patient safety, product efficacy, and product quality mitigated
`appropriately. Accordingly, OPQ recommends APPROVAL ofNDA 214120 and grants
`
`OPQ-XOPQ-TEM-0001v04
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`Page 1of6
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`Effective Date: 14 Febrnaiy 2017
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`Reference ID 4657513
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`

`
`
`~bs;l====-=-~~~Q_U_AL~I_T_Y_A_s_*lil#~~ s_E_ss_ME~N_T~~~----'rgj}@~~
`
`
`
`
`a shelf life of 30 months for the drng product when stored in HDPE bottles at 20°C to
`25°C (68°F to 77°F). Of note the original application included the drng product packaged
`in both bottles
`(bH41
`
`(b) (4}
`
`Proposed Indication(s) includin~
`Intended Patient Population
`
`(b) (41
`
`Duration of Treatment
`
`Maximum Daily Dose
`
`300 mg
`
`Alternative Methods of
`Administration
`
`None
`
`(b)(4~
`(bJC4~ until unacceptable toxicity.
`
`B. Quality Assessment Overview
`Drug Substance
`Azacitidine drng substance is a white to off-white non-hygroscopic solid that is
`insoluble in acetone and ethanol; spiuingly soluble in water and freely soluble in
`DMSO. Azacitidine is a ring analog of the natmally occmTing pyrimidine nucleoside
`cytidine and differs from cytidine by having a nitrogen atom in the 5 position of the
`heterocyclic ring. Azacitidine exhibits polymo1p hic behavior. Polymo1phic studies
`revealed
`(b) C4l
`
`(b)(4)
`
`(bH4l Azacitidine may be classified as highly soluble and lowly pe1meable;
`however, the Applicant did not submit a request to designate a BCS class and the FDA
`has not designated the BCS class for this product.
`
`The dmg substance will be manufactmed
`(b)(4J
`(bH4l The applicant references NDA 50794 for
`the manufactme and control of the dmg substance. NDA 50794 was approved in May
`of2004 for the treatment of myelodysplastic syndrome (MDS).
`
`The info1mation included in the referenced NDA (NDA 050794) and the info1mation
`submitted in this NDA are adequate to suppoit the approval ofNDA 214120.
`
`OPQ-XOPQ-TEM-0001v04
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`

`
`
`bs;llil#~=*===-~~=-~~~Q_U_AL~I_T_Y_A_s_s_E_ss_ME~N_T~~~----'rgj}@~~
`
`
`Accordingly, NDA 214120 is recommended for approval from a chug substance
`perspective.
`
`Drug Product
`The chug product, Onureg® (oral azacitidine) is a 200 mg and 300 mg,
`(b1<4l
`immediate-release, film-coated tablets for oral administration. The 200 and 300 mg
`tablets are manufactured
`(bH4J The chug product fo1mulation
`includes the active and compendia! excipients that are commonly used in solid oral
`dosage fo1ms (croscaimellose sodium, magnesium steai·ate, mannitol, and silicified
`Inicroc1ystalline cellulose). The tablet coatings contain hypromellose, titanium
`dioxide, lactose monohych·ate, polyethylene glycol/macrogol, and triacetin and either
`iron oxide red (for the 200 mg table) or iron oxide yellow, iron oxide red and black
`iron oxide (the 300 mg tablet). The 200 mg dosage fo1m is presented as a pink, oval
`tablet with debossed 200" on one side and "ONU" on the other side. The 300 mg
`tablet is presented as a brown, oval tablet with debossed "300" on one side and "ONU"
`on the other side. The fo1mulation contains no novel excipients and each of the
`excipients ai·e below the maximum potency as repo1ted in the IIG. Detailed
`descriptions of the quantitative and qualitative chug product fo1mulation ai·e provided
`in the subinission.
`
`The chug product is manufactured
`
`(b) (4j
`
`(b)(4)
`
`(bH4l The applicant demonstrated the suitability of the manufacturing
`process for the chug product at the proposed commercial scale. The description of the
`manufacturing process includes appropriate in-process controls and operating
`parameters and is described in sufficient detail to suppo1t the approval of this NDA.
`
`The chug product specifications include appeai·ance, identification, unifo1mity of
`dosage units, assay, related substances, dissolution, Inicrobial limits
`(b)C4l
`The applicant included a risk assessment for elemental impurities as per ICH Q3D/USP
`<232> and provided justification for the oinission oftests for residual solvents. The
`results of the risk assessment were acceptable and therefore a test for an elemental
`impurity in the chug product release specifications was not proposed and is not
`required. The final chug product specifications ai·e consistent with ICH Q6A and are
`based on batch analyses, manufacturing capability, and stability data. The chug
`product specifications ai·e adequate to establish the chug product identity, potency and
`purity and provide adequate controls to ensure the quality of the chug product through
`the product expi1y. The proposed specification and acceptance criteria for the chug
`product, together with controls for impurities in the chug substance ai·e adequate to
`ensure that the critical quality attributes of this product ai·e well controlled.
`
`In suppo1t of the proposed 30-month expi1y , the applicant included up to 18 months of
`long te1m (25°C/60% RH) and 6 months ofaccelerated (40°C/75% RH) data for four
`commercial scale batches per strength packaged in HDPE bottles
`(bH4l
`
`OPQ-XOPQ-TEM-0001v04
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`Effective Date: 14 Febrnaiy 2017
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`

`
`
`bs;llil#~=*===-~~=-~~~Q_U_AL~I_T_Y_A_s_s_E_ss_ME~N_T~~~----'rgj}@~~
`
`
`CbH4J. Three batches were manufactured
`
`(b) (4j
`Cb) <41 All prima1y
`stability batches were manufactured at the commercial site according to the proposed
`commercial manufacturing process. Stability studies were executed in accordance with
`the ICH IA and QlB; and the available stability data shows consistency over time and
`suppo1ts the proposed expi1y. Therefore, based on the 18 months of stability data
`included in this application for Onureg® (oral azacitidine) tablets, 200 and 300 mg,
`Celgene Co1poration proposed and the FDA accepts the expiration dating period of 30
`months for the dmg product when stored at controlled room temperature 20°C to 25°C
`(68°F to 77°F); excursions pennitted between 15°C to 30°C (59°F to 86°F) and kept in
`the original bottle tightly closed with two lg desiccant canisters. Of note, the applicant
`is not seeking approval
`CbH~l
`
`(b)(4)
`
`Post-Marketing Considerations:
`The applicant plans to subinit
`
`(b)(4~
`(b)(4j
`
`NDA 214120 is recommended for approval from a diug product and diug process
`perspective.
`
`Biopharmaceutics
`The biopha1maceutics review focused on (1) the acceptability of the proposed in vitro
`dissolution method and acceptance criterion for the routine quality control testing of
`the proposed diug product at batch release and on stability and (2) bridging of the
`pivotal clinical and commercial fo1mulations and (3) the acceptability of biowaiver for
`the lower strength, 200 mg.
`
`Dissolution Specification and Method: The dissolution method included a USP
`Apparatus 2 (Baskets) at 75 RPM in 500mLof0.05M Phosphate Buffer at 37°C. The
`proposed dissolution acceptance criterion was Q= ~1% in 15 minutes. The dissolution
`method and acceptance criterion are acceptable as QC method for batch release and
`stability testing of the diug product.
`
`Bridging of the Clinical Formulations: There were 9 different fo1mulation
`investigated during the fo1mulation development. Fo1mulations F8 and intended
`commercialization fo1mulation (ICF) F9 were used in the pivotal clinical trial and
`fo1mulation F9 is the proposed commercial fo1mulation. The F9 and F8 have been
`adequately bridged based on the following: (1) F8 and F9 showed bioequivalence via
`an in vivo BE Study (2) F9 and ICF F9 having minor differences
`CbJ<4J
`and
`(3) F9 and ICF F9 showed siinilar in vitro dissolution profiles. For these reasons the
`registration batches of Azacitidine Tablets fo1mulation ICF F9, 200 mg and 300 mg,
`are deemed adequately bridged with Azacitidine Tablets clinical fo1mulation F8.
`
`OPQ-XOPQ-TEM-0001v04
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`

`

`
`
`bs;llil#~=*===-~~=-~~~Q_U_AL~I_T_Y_A_s_s_E_ss_ME~N_T~~~----'rgj}@~~
`
`
`Biowaiver Request: The Applicant's submitted biowaiver request as per the 21 CFR
`320.22(d)(2) and included the following evidence to suppo11 the approval of the
`proposed 200 mg strength: (1) the 200 mg and 300 mg Azacitidine Tablets are in same
`dosage fo1m but in different strengths, (2) bioavailability of the 300 (3) evidence to
`suppo11 propo11ional similarity of the 200 mg and 300 mg in the active and inactive
`ingredients and (4) a comparison of the in vitro dissolution profiles for the 200 mg and
`300 mg strengths. The Applicant's biowaiver request for the 200 mg is granted.
`
`Based on the info1mation provided (i.e. dissolution profile data for pivotal clinical
`batches and stability data), the proposed dissolution method and acceptance criterion,
`biowaiver request and bridging studies are deemed acceptable. The NDA 214120 is
`recommended for approval from biopha1maceutics perspective.
`
`Facilities
`This application includes 11 sites and all sites were listed as ready for inspection:
`(b) C4J (FEI
`(b) C4J)- Manufacture, analytical testing and
`•
`stability testing of drug substance
`•
`(b)(4J (FEI
`CbH4J) - Manufacture, analytical testing and stability testing
`•
`(b)(4l (FEI
`(b)(4l)- Analytical Testing and Biological Testing
`• ======= - -(b' )C4l (FEI
`(bJC4l)- Biological Testing
`•
`(b)(4l)- Particle Size Testing
`•
`(b)(4l Testing
`(b)(4l)-
`•
`Cb) C4l (FEI
`CbH4J 5)-
`Cb> C4l Testing
`
`•
`======= - -(bJC4l (FEI
`(bJC4l)- Manufacture and testing
`
`•
`(b)(4l (FEI
`(b)(4l)- Microbial Testing
`•
`CbH"J. (FEI ===..(b) C4l)- Packaging and Labeling
`•
`===== -(b' )(4J (FEI
`CbH4J)- Packaging and Labeling
`• Celgene International Sari (FEI 3006323509)- Packaging and Labeling
`
`At the conclusion of the review ofNDA 214120, all facilities listed in were deemed
`acceptable for the responsibility listed in the application. This application is
`recommended for approval from the facilities perspective
`
`Environmental Assessment
`The applicant provided a claim for categorical exclusion and a statement of no
`extraordinaiy circumstances under 21 Code of Federal Regulations (CFR) Sections
`25.31(e) and a statement of no extraordina1y circumstances 21CFR 25.15(d).
`
`The request for categorical exclusion is granted.
`
`C. Special Product Quality Labelin2 Recommendations (NDA only)
`
`n/a
`
`
`D. Final Risk Assessment (see Attachment)
`
`Included at the beginning of the drug product review.
`
`
`OPQ-XOPQ-TEM-0001v04
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`Page 5of6
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`

`

`
`
`~====-=-~~~Q_UAL Y Ass_ssME_~~~----'rgj}@~~
`bs;l*lil#~~ _~I_T____E__~NT
`
`
`
`APPEARS THIS WAY ON ORIGINAL
`
`
`OPQ-XOPQ-TEM-0001v04
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`Page 6of6
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`Effective Date: 14 Febrnaiy 2017
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`Reference ID 4657513
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`

`

`Sherita
`McLamore
`
`Digitally signed by Sherita McLamore
`Date: 8/17/2020 11:12:01AM
`GUID: 503257950000415755492db5bb8b1a5c
`
`Reference ID: 4657513
`
`
`70 Pages have been Withheld in Full as B4 (CCI/TS) immediately following this page
`
`

`

`~ U.S. FOOD & DRUG
`
`-
`
`ADMINISTRATION
`
`CHAPTER IV: LABELING
`
`1.0 PRESCRIBING INFORMATION
`
`Assessment of Product Quality Related Aspects of the Prescribing
`Information:
`
`1.1 HIGHLIGHTS OF PRESCRIBING INFORMATION
`ONUREG~ {azac.itidioe) tablets, for oral ose
`lnltlal U.S. Appro\'al: 2004
`
`- - - -DOSAGE FORJ."1S AND STRENGTHS - - - ­
`Tablets: 200 mg and 300 mg (3).
`
`Information Provided
`in the NOA
`
`Assessor's Comments
`
`Item
`Product Title in Highlights
`Provided and adequate
`Onureq
`Proprietary name
`Provided and adequate
`azacitidine
`Established name(s)
`Provided and adequate
`Route(s) of administration For oral use
`Dosage Forms and Strengths Heading in Highlights
`Tablets: 200 mg and
`Provided and adequate
`Summary of the dosage
`form(s) and strength(s)
`300 mg
`in metric system.
`Assess if the tablet is
`scored. If product meets
`guidelines and criteria for a
`scored tablet, 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 terms include
`pharmacy bulk package
`and imaaina bulk oackaae.
`
`Tablets is not scored
`
`Adequate
`
`NA
`
`NA
`
`1.2 FULL PRESCRIBING INFORMATION
`1.2.1 Section 2 (DOSAGE AND ADMINISTRATION)
`
`OPQ-XOPQ-TEM-0001 v06
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`Reference ID 4657513
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`

`Instruct patients on rhe following:
`
`• Do not split, crush or chew ONUREG tablets.
`
`• Take a dose about the same time each day.
`
`•
`
`•
`
`Ifa dose of ONUREG is missed, or not taken at the usual time, take the dose as soon as
`possible on the same day, and resume the nonnal schedule the following day. Do not take 2
`doses on the same day.
`
`If a dose is vomited, do not take another dose on the same day. Resume the normal schedule
`the following day.
`
`TRADENAME is a hazardous drug. Follow applicable special handling and disposal
`procedures. 1
`
`Item
`
`Information Provided
`in the NOA
`DOSAGE AND ADMINISTRATION section
`Special instructions for
`product preparation (e.g.,
`reconstitution and resulting
`concentration , dilution,
`compatible diluents,
`storage conditions needed
`to maintain the stability of
`the reconstituted or diluted
`product)
`
`See above
`
`Assessor's Comments
`
`Provided and adequate
`
`1.2.2 Section 3 (DOSAGE FORMS AND STRENGTHS)
`
`Tablets:
`
`• 200 mg: pink, oval, film-coated tablet with debossed "200" on one side and "ONU" on the
`other side.
`
`• 300 mg: brown, oval, film-coated tablet with debossed "300" on one side and "ONU" on the
`other side.
`
`OPQ-XOPQ-TEM-0001 v06
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`

`

`Item
`
`See above
`
`Information
`Provided
`in the NOA
`DOSAGE FORMS AND STRENGTHS section
`Available dosage form(s)
`Tablets
`Strength(s) in metric system
`200 mg and 300 mg
`If the active ingredient is a salt,
`NA
`apply the USP Salt Policy per FDA
`Guidance
`A description of the identifying
`characteristics of the dosage
`forms, including shape, color,
`coatina scorina and imorintina
`Assess if the tablet is scored. If
`product meets guidelines and
`criteria for a scored tablet, state
`"functionally scored"
`For injectable drug products for
`parental administration, use
`appropriate labeling term (e.g.,
`single-dose, multiple-dose, single­
`patient-use). Other package type
`terms include pharmacy bulk
`package and imaging bulk
`packaae.
`
`Tablets are not
`scored
`
`NA
`
`Assessor's Comments
`
`Provided and adequate
`Provided and adequate
`NA
`
`Provided and adequate
`
`Adequate
`
`NA
`
`OPQ-XOPQ-TEM-0001 v06
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`Page 3
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`Effective Date: Febrnaiy 1, 2019
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`

`
`
`
`
` 1.2.3 Section 11 (DESCRIPTION)
`
`
`
`
`OPQ-XOPQ-TEM-0001v06
`
`
`
`
`
`Reference ID: 4657513
`
`
`
`
`
`
` Effective Date: February 1, 2019
`
`
`
`
`
` Page 4
`
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`

`

`Item
`
`Information Provided
`in the NOA
`
`Assessor's Comments
`
`See above
`
`DESCRIPTION section
`Proprietary and established See above
`name(s)
`Dosage form (s) and route(s) See above
`of administration
`If the active ingredient is a OS is not a salt
`salt, apply the USP Salt
`Policy and include the
`equivalency statement per
`FDA Guidance.
`List names of all inactive
`ingredients. Use USP/NF
`names. Avoid Brand names.
`For parenteral injectable
`dosage forms, include the
`name and quantities of all
`inactive ingredients. For
`ingredients added to adjust
`the pH or make isotonic,
`include the name and
`statement of effect.
`If alcohol is present, must
`provide the amount of
`alcohol in terms of percent
`volume of absolute alcohol
`Statement of being sterile (if NA
`applicable)
`Pharmacological/
`Therapeutic class
`Chemical name, structural See above
`formula molecular weiqht
`If radioactive, statement of NA
`important nuclear
`characteristics.
`Other important chemical or See above
`physical properties (such as
`pKa or pH)
`
`Provided and adequate
`
`Provided and adequate
`
`Adequate
`
`Provided and adequate
`
`NA
`
`NA
`
`NA
`
`Provided and adequate
`
`Provided and adequate
`
`NA
`
`Provided and adequate
`
`NA
`
`NA
`
`See above
`
`Section 11 (DESCRIPTION) Continued
`
`OPQ-XOPQ-TEM-0001v06
`
`Page 5
`
`Effective Date: February 1, 2019
`
`Reference ID 4657513
`
`

`

`Information Provided
`in the NOA
`
`NA
`
`Assessor's Comments
`NA
`
`NA
`
`NA
`
`Item
`
`For oral prescription drug
`products, include gluten
`statement if applicable
`Remove statements that
`may be misleading or
`promotional (e.g.,
`"synthesized and developed
`by Drug Company X,"
`"structurally unique
`molecular entity"
`
`1.2.4 Section 16 (HOW SUPPLIED/STORAGE AND HANDLING)
`How Supplied
`
`
`TRADENAME tablets are available as:
`
`
`• 200 mg: pink, oval, film-coated tablets with debossed "200" on one side and "ONU" on the
`other side.
`
`• 300 mg: brown, oval, film-coated tablets with debossed "300" on one side and "ONU" on the
`other side.
`
`Table 6 lists the package configurations and strengths.
`
`
`Table 6: ONUREG Package Configurations and NOC Numbers
`
`
`Package Configuration
`
`Tablet Str ength
`
`Bottles of 14 with two desiccant
`cannisters
`
`Bottles of 14 with two desiccant
`cannisters
`
`200mg
`
`300mg
`
`NOC Number
`
`59572-730-14
`
`59572-740-14
`
`Storage
`
`Store bottles at 20°C to 25°C (68°F to 77°F); excursions permitted between l5°C to 30° C (59°F
`to 86°F) [see USP Controlled Room Temperature]. Keep bottle tightly closed. Store and dispense
`in the original bottle (with two desiccant canisters).
`
`Handling and Disposal
`ONUREG is a hazardous drug. Follow applicable special handling and disposal procedures. 1 If
`powder comes in contact with skin, immediately and thoroughly wash with soap and water. If
`powder comes in contact with mucous membranes, immediately flush the area with water.
`
`OPQ-XOPQ-TEM-0001v06
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`Reference ID 4657513
`
`

`

`Assessor's Comments
`
`Provided and adequate
`Provided and adequate
`Provided and adequate
`
`Updated and adequate
`
`Adequate
`
`NA
`
`Item
`
`See above
`
`Information Provided
`in the NOA
`HOW SUPPLIED/STORAGE AND HANDLING section
`Available dosage form (s)
`See above
`StrenQth(s) in metric system See above
`Available units (e.g., bottles See above
`of 100 tablets)
`Identification of dosage
`forms, e.g., shape, color,
`coating, scoring, imprinting,
`NOC number
`-
`--­
`--­
`--­
`--­
`--­
`--­
`--­
`--­
`--­
`--­
`--­
`--­
`--­
`Assess if the tablet is scored. The tablets are not
`If product meets guidelines
`scored
`and criteria for a scored
`tablet, state "functionally
`scored"
`-
`--­
`--­
`--­
`--­
`--­
`--­
`--­
`--­
`--­
`--­
`--­
`--­
`--­
`For injectable drug products NA
`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
`packaQe.
`
`Section 16 (HOW SUPPLIED/STORAGE AND HANDLING) (Continued)
`Information Provided
`in the NOA
`Keep bottle tightly
`closed . Store in the
`original bottle (with two
`desiccant canisters).
`
`Item
`
`Special handling about the
`supplied product (e.g.,
`protect from light,
`refrigerate). lfthere is a
`statement to "Dispense in
`original container," provide
`reason why (e.g. to protect
`from light or moisture, to
`maintain stabilitv, etc.)
`If the product contains a
`desiccant, ensure the size
`and shape differ from the
`dosage form and desiccant
`has a warning such as "Do
`not eat."
`
`Assessor's Comments
`
`Protect the tablets from
`moisture to maintain stability.
`
`See above
`
`"Do not eat" is included in
`both patient counseling
`information and patient
`information sections
`
`OPQ-XOPQ-TEM-0001v06
`
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`
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`
`Reference ID 4657513
`
`

`

`Provided and adequate
`
`NA
`
`(b)(4
`
`Storage conditions. Where See above
`applicable, use USP
`storage range rather than
`storage at a single
`temperature.
`Latex: If product does not NA
`contain latex and
`manufacturing of product
`and container did not
`include use of natural
`rubber latex or synthetic
`derivatives of natural rubber
`latex, state: "Not made with
`natural rubber latex. Avoid
`statements such as "latex­
`free."
`Include information ICbH4~
`(b) (4~
`I
`
`1.2.5 Other Sections of Labeling
`Patient counseling information
`
`Storage Instructions
`CbH4J
`·
`. . 1
`ONUREG . h
`.
`.
`k
`m t e ongma contamer
`Advise at1ents to ee
`Cb)<41advise patients to k...ee_p_t"""h-e -co-n-ta""'i-ne-r-ti'""g"""ht.,.ly closed with
`--------------------------
`both desiccant canisters inside and to not eat the desiccant canisters [see How Supplied/Storage
`and Handling (16.2)}.
`
`1.2.6 Manufacturing Information After Section 17 (for drug products)
`
`OPQ-XOPQ-TEM-0001v06
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`
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`Reference ID 4657513
`
`

`

`Manufactured by:
`
`Celgene Corporation
`A Wholly Owned Subsidiary of Bristol-Myers Squibb
`86 Mon·is A venue
`Surmnit, NJ 0790 l
`
`ONUREG® is a registered trademark of Celgene Corporation.
`
`
`Assessor's Comments
`
`Provided and adequate
`
`I
`
`J
`
`Patent: www.celgene.com/therapies
`
`
`© 2020 Celgene Corporation.
`
`
`All Rights Reserved.
`
`
`ONUPl.001
`
`
`Information Provided
`Item
`in the NOA
`Manufacturing Information After Section 17
`Name and location of
`See above
`business (street address,
`city, state and zip code) of
`the manufacturer, distributor,
`and/or packer
`
`2.0 PATIENT LABELING
`
`
`How should I store ONUREG?
`---------------------------,(bJ<~Y
`
`Keep ONUREG and all medicines out of t he reach of children
`
`OPQ-XOPQ-TEM-0001v06
`
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`
`Effective Date: February 1, 2019
`
`Reference ID 4657513
`
`

`

`W hat are t he ingredients in ONUREG?
`
`Active i ngredient: azacitidine
`
`Inactive ingredient s:
`
`(b)(~Y
`
`Assessment of Product Quality Related Aspects of Patient Labeling (e.g.,
`Medication Guide, Patient Information, Instructions for Use): Adequate
`
`In the Amendment, SND 0022 (21), dated 07/16/2020, the applicant updated all
`ertinent sections of US packaQinQ insert and patient information to remove
`
`(b)(4)
`
`Any deficiencies should be listed at the end in the "ITEMS FOR
`ADDITIONAL ASSESSMENT." None
`
`3.0 CARTON AND CONTAINER LABELING
`
`(b) (4j
`
`OPQ-XOPQ-TEM-0001v06
`
`Page 10
`
`Effective Date: February 1, 2019
`
`Reference ID 4657513
`
`

`

`(b)(41
`
`Information provided in the
`crut on label(s)
`NA
`
`NA
`NA
`NA
`
`NA
`
`NA
`
`NA
`NA
`NA
`NA
`
`3.2 Carton Labeling
`NA
`
`Item
`
`Information provided in the container
`label
`Provided
`
`Provided
`Provided
`Provided
`
`Proprietary name, established
`name (font size and prominence
`(21 CFR 201.10(!£\(2))
`Dosage strength
`Net contents
`" Rx only" displayed prominently
`on the main panel
`NDC number (21 CFR
`207.35(b)(3)(i))
`Lot number and expiration date
`(21 CFR201.17)
`Provided
`Storage conditions
`Bar code (21CFR 201.25)
`Provided
`Name of manufacturer/distributor Provided
`And others, ifspace is available NA
`
`Provided
`
`Provided
`
`Assessment of Carton and Container Labeling: Adequate
`
`(b)c41 The following
`comments have been adequately addressed in the above updated bottle container
`labels. The bottle will not have a carton. It is not required to have a carton for the
`bottle presentation.
`
`• Add "Each table contains 200 mg or 300 mg of azacytidine"
`
`OPQ-XOPQ-TEM-0001v06
`
`Page 11
`
`Effective Date: February 1, 2019
`
`(b) (4J ,
`
`Reference ID 4657513
`
`

`

`• Add "Keep out of reach of children"
`• Add "Do not use if safety seal under cap is broken or missing" for bottle
`configuration only
`
`Any deficiencies should be listed at the end in the "ITEMS FOR ADDITIONAL
`ASSESSMENT." None
`
`ITEMS FOR ADDITIONAL ASSESSMENT
`NA
`
`Overall Assessment and Recommendation:
`Adequate
`
`Primary Labeling Assessor Name and Date: Nina Ni, Ph.D., 0712412020
`
`Secondary Assessor Name and Date: Anamitro Banerjee, Ph.D., 0712412020
`
`OPQ-XOPQ-TEM-0001v06
`
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`
`Effective Date: February 1, 2019
`
`Reference ID 4657513
`
`

`

`Nina
`Ni
`
`Anamitro
`Banerjee
`
`Digitally signed by Nina Ni
`Date: 7/24/2020 11:56:47AM
`GUID: 502d1ab500002afbbe642f8f37136920
`
`Digitally signed by Anamitro Banerjee
`Date: 7/27/2020 04:12:58PM
`GUID: 5075764700003844b7bc89632228509f
`
`Reference ID: 4657513
`
`37 Pages have been Withheld in Full as B4 (CCI/TS) immediately following this page
`
`

`

`QUALITY A QUALITY ASSESSMENT
`
`Chapter VII-Biopharmaceutics
`
`
`NDA/ Type of Submission: NDA 214120-0RIG-1 ; 505(b)(l )
`Applicant Name: Celgene Corporation, New Jersey, US
`Drug Product Name/Strength: ONUREG (Azacitidine) Tablet/ 200 mg and 300 mg
`Route of Administration: Oral
`Applicant Name: Celgene Corporation, New Jersey, US
`Submission Date: 3/3/2020 (Original Submission)
`
`Background: The Applicant submitted this 505(b)(l) NDA seeking approval for ONUREG (Azacitidine)
`Tablets, 200 mg and 300 mg. Azacitidine is a nucleoside metabolic inhibitor indicated
`
`---
`
`CbH4l dose is 300 mg orally, once daily for the first 14 days of each 28-day cycle. This
`Cb>C4l The proposed
`application is primarily suppo1ted by clinical safety and efficacy data obtained from the Pivotal Phase 3 Study
`(CC-486-AML-001).
`
`The proposed two strengths, 200 mg and 300 mg, are compositionally propo1tional with respect to the active and
`inactive ingredients, differing only by the film coatings
`Cb> C4l
`
`(b) (41
`
`Review Summary: This Biophannaceutics Review focuses on evaluation of (1) the in vitro dissolution method
`and acceptance criterion as a quality control (QC) test for the proposed dmg product, Azacitidine Tablets, 200
`mg and 300 mg, (2) the bridging of the fonnulations between one used in the clinical (pivotal) study and the one
`intended for commercial production, and (3) the acceptability ofbiowaiver for the lower strength, 200 mg.
`
`In Vitro Dissolution Method and Acceptance Criterion: ACCEPTABLE
`
`The proposed in vitro dissolution method and dissolution acceptance criterion shown in the table below are
`approved for the Quality Control (QC) testing of Azacitidine Tablets, 200 mg and 300 mg, for batch release
`and stability testing:
`
`Apparatus
`
`Speed
`
`Volume/ Temp
`
`Medium
`
`Acceptance Criterion
`
`USP 2 (Paddle)
`
`75 rpm
`
`500 mL/ 37 °c
`
`0.05M
`Phosphate
`Buffer (pH 6.8)
`
`J~J
`Q= (4)0/o at 15 minutes
`
`Biowaiver Request: ACCEPTABLE
`
`The Applicant's submitted biowaiver request as per the 21 CFR 320.22(d)(2) to suppo1t the approval of the
`proposed 200 mg strength is based on the following: (1) The 200 mg and 300 mg Azacitidine Tablets are in
`same dosage fonn but in different strengths, (2) Bioavailability of the 300 mg has been measmed (Pivotal
`Study: CC-486-AML-002, PK Linearity: AZA-PH-US-2007-CL-005), (3) Evidence to suppo1t propo1tional
`similarity of the 200 mg and 300 mg in the active and inactive ingredients, and (4) The in vitro dissolution
`
`Reference ID 4657513
`
`

`

`QUALITY A QUALITY ASSESSMENT
`
`Chapter VII-Biopharmaceutics
`
`
`profiles of the 200 mg and 300 mg sti·engths are similar. The Applicant's biowaiver request for the lower
`
`sh'ength (200 mg) is granted.
`
`
`Formulation Bridging: ACCEPTABLE
`
`The regish'ation batches, the Intended for Commercialization Fo1mulation (ICF) F9 and the interim
`fonnulation F9 as well as the clinical formulation F8 (used in the Pivotal Study, CC-486-AML-001) have been
`adequately bridged, on the basis of (1) F8 and F9 showing bioequivalence via an in vivo BE Study (CC-486­
`CAGEN-001), (2) F9 and ICF F9 having minor differences
`(bH41
`(b)(4l between the registi·ation batches fonnulation ICF F9 and
`F 9, and (3) F9 and ICF F9 showing similar in viti·o dissolution profiles. Therefore, the registi·ation batches of
`Azacitidine Tablets fonnulation ICF F9, 200 mg and 300 mg, are deemed adequately bridged with Azacitidine
`Tablets clinical fo1mulation F8, (bH41 mg.
`
`--~~~~~~~~~~~~~~~~~-
`
`Overall Recommendation: From the Biophaimaceutics perspective, NDA 214120 for the proposed ONUREG
`(Azacitidine) Tablets, 200 mg and 300 mg, is Adequate and recommended for Approval.
`
`Referen