CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202236Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`
`
`NDA 202-236
`
`Eugenia Nashed, PhD
`Chemist, Division of New Drug Quality Assessment III, Branch VIII
`
`Prasad Peri, PhD
`Branch Chief, Division of New Drug Quality Assessment III, Branch VIII
`
`April 30, 2012
`
`Chemistry, Manufacturing and Controls (CMC) MEMORANDUM
`
`
`Date:
`
`To:
`
`From:
`
`
`
`Through:
`
`
`
`Product:
`
`Dymista (azelastine hydrochloride / fluticasone propionate) Nasal Spray
`(suspension), 137μg/50 μg per spray (0.1%/0.037%)
`
`
`Applicant: Meda Pharmaceuticals
`
`
`Meda Pharmaceuticals submitted a 505(b)(2) new drug application (NDA 202-236) on
`April 1, 2011, for Dymista (azelastine hydrochloride / fluticasone propionate) Nasal
`Spray (suspension), 137μg/50 μg per spray (0.1%/0.037%). It is a fixed combination of
`antihistamine
`(antagonist of H1
`receptor)
`and
`corticosteroid
`(agonist of
`glucocorticosteroid receptor) drug substances for the relief of symptoms of seasonal
`allergic rhinitis in adults and children aged 12 years and older. The drug product is a
`multidose nasal spray suspension contained in an amber glass bottle, fitted with a
`metering
` spray pump from
` Each spray of the
`suspension delivers 137 (cid:541)g of azelastine hydrochloride (equivalent to 125 (cid:541)g of
`azelastine base) and 50 (cid:541)g of fluticasone propionate. Azelastine hydrochloride is
`solubillized in the formulation while the micronized fluticasone propionate occurs as a
`suspension. It will be the first combination nasal spray product on the US market.
`The PDUFA due date for this application is May 1, 2012.
`
`The CMC team recommends APPROVAL action for this NDA based on adequate
`supportive data submitted to this NDA and ACCEPTABLE recommendation for the
`manufacturing and testing sites provided by the Office of Compliance. Refer to EES
`report dated April 30, 2012, reproduced at the end of this document.
`
`24 months drug product expiry period is supported for the trade (120 sprays) and sample
`(28 sprays) presentations of the drug product when stored at 20º-25ºC (68º-77ºF).
`
`Since the last Chemistry review (CMC review dated March 26, 2012), minor changes to
`the drug product specifications and labeling were implemented to reflect the
`recommendations from the review team. All changes are acceptable and copies of the
`final drug product specifications and carton and container are reproduced below.
`
`
`Reference ID: 3124087
`
`(b) (4)
`
`(b) (4)
`
`

`

`Final Drug Product Specifications dated March 27, 2012
`
`DRUG PRODUCT SPECIFICATIONS FOR DYNIISTA'" (AZELASTINE
`HYDROCHLORIDE/FLUTICASONE PROPIONATE) NASAL
`SPRAY, 137 MCGISO MCG (0.1%]0.037%)
`
`Doc-nut No.: SP-Oll—03
`
`Revision Date: 27 Mar 2012
`
`SW:
`
`sp-ou-oz, 23 Mar 2012
`
`Effective Date:
`
`Date
`AW Sim: F. Baez
`Associate Binder, Col-potato My Assurance
`
`AW Sig-am: C. Yam
`Senior Manager, Regulates-y Allin
`
`Date
`
`mmkmwcwmmm
`
`Table 1:
`
`But Mal-Release Specifications
`
`iA
`
`M 001-FGNA012V5
`
`AM OOI-FGNAOIZVS
`
`AM OOI-FGNAOIZVS
`
`USP <79l>
`
`USP ("35>
`
`USP «11>
`
`AM Olo-FGNAOIZVS
`
`AM 01 l-FGNAOI 2V5
`
`AM 001-FGNA012V5
`
`Reference ID: 3124087
`
`

`

`Tablez: WWW
`
`Analytical
`
`AM OOI-FGNAOIZVS
`
`AM MZ-FGNAOI 2V5
`
`AM Ml-FGNAOI 2V5
`
`AM 002-FGNA012V5
`
`USP 491>
`
`AM W-FGNAOIZVS
`
`AM W-FGNAOIZVS
`
`
`
`
`Reference ID: 3124087
`
`

`

`USP <911>
`
`AM 013-
`FSGNAOIZVS
`
`Sunnis:
`
`Not has film 28 allay:
`
`AM 007-FGNA012V5
`
`Tale:
`
`Not his In 120 gay:
`
`AM 004-FGNA01 2V5
`
`AM ODS-PGNAOIZVS
`
`AM 006-FGNA012V5
`
`MelnfiofP-IiduSZJIIm
`
`Maw-1M
`«Manitoba
`
`way-nod
`
`Nnmhu of Spay:
`
`Wall-uncut
`
`Reference ID: 3124087
`
`

`

`‘
`
`‘
`
`MmSSDelivuedDmefiou
`B .
`.
`ofC
`.
`
`AM 006-FGNA012V5
`
`AM 007-FGNA012V5
`
`Spay Com Unifimity
`(Iabd Chin: I37 pym)
`
`(Is/w)
`
`Reference ID: 3124087
`
`

`

`MunKDdivuedDouefium
`
`EndofCont-hu (pg/guy)
`
`.
`
`‘
`
`'
`
`007-FGNA012V5
`
`Spay Content Unifilmily
`
`(led Chin: 137 pygmy)
`
`; 007-FGNA012V5
`
`Reference ID: 3124087
`
`

`

`End of Container (pg/spay)
`
`AM 008-FGNA012V5
`
`—_ mu m...
`Meme Plopionue Spiy
`AM 007-FGNA012V5
`Content Unifonnity
`
`(Libel Claim 50 PS/W)
`
`Mean 96 Delivered Dose fiom
`
`AM 009-FGNA012V5 AM 010-FGNA012V5
`
`Reference ID: 3124087
`
`

`

`AM 01 l-FGNAOIZVS
`
`AM 012-FGNA012V5
`
`AM OOI-FGNAOIZVS
`
`1‘03an
`
`AM OOI-FGNAOIZVS
`
`“MWofUSPQ‘baas l,
`
`AM Oll-FGNA012V5.
`
`Reference ID: 3124087
`
`

`

`
`
`Reference ID: 3124087
`
`

`

`l3
`13
`
`
`
`Product Number; Dosage Form; Ingredient; Strengths
`
`
`
`
`
`DUI: SPFLAY; AZELASTINE HYDROCHLORIDE: 1%
`
`
`
`
`
`Elm; SPRAY: FLLITICASONE PHOPI‘ONATE: 33-65%
`
`
`
`
`
`
`
`
`
`Project Manager
`
`
`Review Chemist
`
`Team Leader
`
`
`[In Bil-A PFi-2012
`
`on U2-MAY—2l11 ‘l
`
`
`on EI2-MAY—2l11 ‘l
`
`
`
`
`
`
`
`
`
`
`
`{HF-U1]
`
`{HFD—BED}
`
`
`3111 T964085
`Bi] 1 T96 TT23
`Bi] 1 T96 TT4S‘
`
`
`
`
`
`
`
`by A. iNYAFiD
`
`
`
`by E ES_F'F{O D
`
`by E ES_PH.O D
`
`
`
`
`
`
`{HFD—323]
`
`
`3EIIT965363
`
`
`
`
`
`Application:
`
`Stamp Date:
`
`
`Regulatory:
`
`
`
`Applicant:
`
`
`
`FDA CDER EES
`
`
`
`ESTABLISHMENT EVALUATION REQUEST
`
`
`DETAIL REPORT
`
`
`Action Goal:
`
`
`District Goal:
`
`
`
`
`
`
`
`
`NDA 21122369’EEJEI
`
`El 1 -AF'Fi—2[]1 1
`
`U‘l-MAY-2612
`
`
`M ED POINTE
`
`265 DAVIDSON AVE STE 300
`
`
`
`
`SOMERSET: NJ BEETS-4121]
`
`
`
`
`
`
`
`DYMISTA
`
`
`Brand Name:
`
`
`Estab. Name:
`
`
`Generic Name:
`
`
`
`
`
`
`
`
`4 S
`
`
`TU
`
`Priority:
`
`Org. Code:
`
`
`
`Application C om ment:
`
`FDA Contacts:
`
`
`
`
`
`3. FATWAFIDHAN
`
`E _ NASH ED
`
`
`A. SCH ROEDEFI
`
`Overall Recommendation:
`
`
`
`
`
`ACCEPTABLE
`PENDING
`PENDING
`
`
`
`
`
`Apri! 30, 2012 2‘. 41 PM
`
`
`
`
`
`FDA. Confidential - internal Distribution OnlyI
`
`
`
`
`
`
`
`
`
`Page 1 or 5
`
`
`
`
`
`Reference ID: 3124087
`Reference ID: 3124087
`
`

`

`14
`
`FDA CDER EES
`ESTABLISHMENT EVALUA110N REQUEST
`DETAIL REPORT
`FE: m1!”
`
`GEN:
`DIPLA LIIITEJ
`USS-141 L150 5103-105 5107-112 “1-”
`VERM. SALDEITE. m. . mm
`
`Am:
`
`W.“2
`
`FINISHED EDSAGE LIBELER
`FINISHED [USAGE MANUFACTURER
`FINISHE mfiE PACKAGER
`
`FINISHED MMGE REflSE TESTER
`FINISHED EDSAGE STABIJTY TESTER
`
`Profile:
`
`THE OUPLA LTD. LOCATED N GOA. MOM l5 RESPGISM FOR MANUFACTURING. PWNG. LABELING. RELEASE
`TESTING OF TrE MUG vacuum. (on tuna-2011 by S. PATWAFIJHAN (PF-D1) 301M)
`AEROSCL mama:mm
`OAIm: NONE
`
`M—. m
`SUBMTOOG
`m-MAV-201 1
`
`OATWARDHAN
`
`SUBMTTEJTU no
`MY~201 1
`AN PROFLE LAST INSPECTED 2008
`
`MP "WM
`
`mm REVIEW
`
`WY-ZIN 1
`
`mWWW 1 NUL-m‘l I
`
`00mm 1 “UL-231 1
`
`ME
`
`PHILP'YE
`
`5W
`
`AOOEPTM
`NSFECTDN
`
`NYARDA
`ACCEPTABLE
`DISTRICTmm"
`
`WILMZZJ‘IPH
`
`WWW-mm”
`
`”2‘5
`
`Reference ID: 3124087
`
`

`

`m coca ass
`
`15
`
`sauna-Hem summon FEOlEST
`05mm. aspon'r
`
`
`
`GUY-N11
`
`"mm
`
`Gav-2011
`
`menu:
`onm
`
`want-022mm
`
`film-“mm
`
`Input;
`
`Reference ID: 3124087
`
`

`

`16
`
`FDA ODER EES
`ESTABLISHDENT EVALUATION REQUEST
`DETAIL REPORT
`
`
`
`“Quart!"
`
`mam-mummy
`
`”4‘5
`
`Reference ID: 3124087
`
`

`

`
`
`17
`17
`
`FDA ICDEFI EEE
`ESTABIJSHMENT EVALUAfl-DN REQUEST
`DETAIL REPORT
`
`
`
`DL‘II'RIST RECEPIII'IENEII'H'DH
`
`mimzm2zmpu
`
`FDA mMfl—Infllfl III-Shim Olly
`
`Pqesnis
`
`
`
`Reference ID: 3124087
`Reference ID: 3124087
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`EUGENIA M NASHED
`04/30/2012
`
`PRASAD PERI
`04/30/2012
`I concur
`
`Reference ID: 3124087
`
`

`

`NDA 202236
`
`DymistaTM (azelastine hydrochloride / fluticasone propionate) Nasal Spray
`(suspension), 137pg/50 pg per spray (0. l%/0.037%)
`
`Summary of the Basis for the Recommended Action
`from Chemistry, Manufacturing, and Controls
`
`Applicant: Meda Pharmaceuticals
`265 Davidson Avenue,
`
`Somerset, NJ 08873-4120
`
`Indication:
`
`For relief of symptoms of seasonal allergic rhinitis in adults and
`adolescents 12 years and older.
`
`om) per spray supplied in an amber glass bottle with
`Presentation: Nasal Spray Suspension,
`(ma) Nasal Spray Pump. Two presentations are proposed for the drug product. the
`commercial product (120 sprays, 23.0 g fill) and a sample product (28 sprays, 6.4 g
`fill). The recommended dose is one spray per nostril twice daily, for a total daily
`dose up to 548 pg of azelastine hydrochloride and 200 pg of fluticasone propionate.
`
`EER Status: Final status is PENDING
`
`Consults:
`
`EA —
`Statistics —
`
`Categorical exclusion provided
`N/A
`
`Methods Validation —
`
`Not recommended
`
`Biopharm—
`Microbiology —
`Phann/toxicology —
`
`N/A
`Acceptable
`Acceptable
`
`Original Submission:
`
`1-April-2001 l
`
`Post—Approval CMC Agreements: None
`
`Background:
`This is the first fixed dose combination for a nasal spray. The drug product was discussed at
`several meetings with the sponsor under IND 77363. This drug product represents a new
`paradigm in allergy treatment. So far no company has sought approval for a Nasal Spray
`combination and the 0ND division anticipates that this approval will lead to several other
`combination products being developed. Note that the applicant also has two single ingredient
`azelastine nasal sprays (NDAs 20114 and NDA 22203) in the market as well.
`
`Drug Substance:
`There are two active pharmaceutical ingredients (APIs) in this drug product: Azelastine
`hydrochloride is manufactured by
`M“) (referenced in DMF mm), and
`fluticasone propionate (referenced in DMF mm) is manufactured by
`mu)
`
`Reference ID: 3112135
`
`

`

`NDA 202236
`
`Summary Basis of Recommended Action – CMC
`
`p. 2
`
` (manufacturer of
` Both DMFs have acceptable review status but
`azelastine) site does not have an acceptable recommendation from CDER’s Office of
`Compliance as yet. Hence the NDA is still recommended for approval pending an acceptable
`OC recommendation
`
`Azelastine hydrochloride (antagonist of H1 receptor) is a white, odorless, crystalline powder
`with a bitter taste. It has a molecular weight of 418.37. It is sparingly soluble in water, methanol,
`and propylene glycol and slightly soluble in ethanol, octanol, and glycerin. It has a melting point
`of 225°C and a pH of 5.2. Its chemical name is (±)-1-(2H)-phthalazinone,4-[(4-chlorophenyl)
`methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-, monohydrochloride. Its molecular formula is
`C22H24ClN3O•HCl with the following chemical structure:
`
`
`Fluticasone propionate (glucocorticosteroid receptor agonist) is a white powder with a melting
`point of 273°C, a molecular weight of 500.6, and the empirical formula is C25H31F3O5S. It is
`practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and
`slightly soluble in methanol and 95% ethanol. Fluticasone propionate is a synthetic
`corticosteroid having the chemical name S-(fluoromethyl)-6(cid:302),9-difluoro-11(cid:533),-17-dihydroxy-16(cid:302)-
`methyl-3-oxoandrosta-1,4-diene-17(cid:533)-carbothioate, 17-propionate, and the following chemical
`structure:
`
`CMC information related to each of the above APIs is supported by the corresponding Drug
`Master File. All Drug Master Files (DMFs) associated with the drug substances were reviewed
`and found acceptable.
`
`Conclusion: The Fluticasone manufacturing site has been found to be acceptable but the Azelastine
`manufacturing site is not yet acceptable from a GMP perspective.
`
`Drug Product:
`The drug product is manufactured by Cipla in Goa, India. The drug product site has an acceptable
`GMP status.
`
`The drug product, Dymista (azelastine hydrochloride/fluticasone propionate) Nasal Spray, is a fixed
`combination of antihistamine (antagonist of H1 receptor) and corticosteroid (agonist of
`glucocorticosteroid receptor) drug substances for the relief of symptoms of seasonal allergic rhinitis
`
`
`Reference ID: 3112135
`
`(b) (4)
`
`(b) (4)
`
`(
`
`
`
`

`

`NDA 202236
`
`Summary Basis of Recommended Action — CMC
`
`p. 3
`
`in adults and children aged 12 years and older. When approved, this will be the first combination
`nasal spray product on the US market. Both APIs are present in several US-approved drug products,
`e.g., Astelin (azelastine hydrochloride) Nasal Spray (NDA 20-114, Meda 1996), and Flonase
`(fluticasone propionate) Nasal Spray (NDA 20—121, GSK 1994).
`
`The drug product is a multidose nasal spray suspension contained in an amber glass bottle, fitted with
`a metering
`mu) spray pump from
`(law) Each spray of the suspension delivers
`137 pg of azelastine hydrochloride (equivalent to 125 pg of azelastine base) and 50 pg of fluticasone
`propionate. Azelastine hydrochloride is solubilized in the formulation While the micronized
`fluticasone propionate occurs as a suspension.
`
`(m4) aqueous formulation of 0. 1% azelastine hydrochloride and
`The drug contains an isotonic.
`suspended 0.037% fluticasone propionate USP with a pH 6.0
`(no) The excipients consist of
`glycerin, microcrystalline cellulose and carboxymethylcellulose sodium
`mu)
`polysorbate 80, edetate disodium (EDTA), benzalkonium chloride (0.1 mg/g); phenylethyl alcohol
`(2.5 mg/g) and purified water. The fill weight of 23 g delivers at a minimum 120 sprays after priming
`(commercial pack), and the fill weight of 6.4 g delivers at a minimum 28 sprays after priming
`(sample pack).
`
`The control strategy used for assuring the drug product quality uses the typical attributes as specified
`in the Nasal Spray Guidance document: they include Description, ID (HPLC and TLC) for
`Azelastine and Fluticasone, pH, Pump Delivery, Net Content, Viscosity, Weight Loss, Number of
`Sprays, Droplet Size Distribution, Spray Pattern, Particle Size Distribution of Fluticasone
`mo,
`Spray Content Uniformity, Azelastine and Fluticasone Impurities, Assay for Benzalkonium Chloride,
`Phenylethyl alcohol, Azelastn'ne, Fluticasone propionate, Microbial limits and Residual Solvents.
`Leachables are indirectly controlled in the container closure extractables.
`
`The submitted stability data support the requested expiry period of 24 months for the currently
`manufactured drug product, when stored at 20—25°C, and when protected from light.
`
`Updated specifications were provided to the application on March 29, 2012 which reflect the
`Agency proposed recommendations.
`
`Conclusion: Drug product is satisfactory.
`
`Overall Conclusion:
`
`From a CMC perspective, the application is recommended for approval, pending
`acceptable recommendation from Office of Compliance with regards to all manufacturing
`and testing facilities.
`
`Prasad Peri, Ph.D.
`
`Branch Chief, Branch VIII
`
`DPA III/ONDQA
`
`2 Pages of Draft Labeling have been WIflIheld in Full as b4 (CCIITS)
`immediately following his page.
`
`Reference ID: 3112135
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`PRASAD PERI
`04/05/2012
`
`Reference ID: 3112135
`
`

`

` NDA 202-236
`
` CHEMISTRY REVIEW #1
`
`NDA 202-236
`
`Dymista (azelastine hydrochloride / fluticasone propionate)
`Nasal Spray (suspension), 137μg/50 μg per spray (0.1%/0.037%)
`
`Meda Pharmaceuticals
`
`Eugenia M. Nashed, Ph.D.
`Office of New Drug Quality Assessment, Division III
`
`Division of Pulmonary, Allergy, and Rheumatology Products
`
`Reference ID: 3107729
`
`
`
`

`

`CHENIISTRY REVIEW #1
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................4
`
`The Executive Summary .........................................................................................9
`
`1. Recommendations ...................................................................................................................... 9
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 9
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments. Agreements, and/or Risk
`Management Steps, if Approvable ................................................................................................... 9
`
`II. Summary of Chemistry Assessments.........................................................................................9
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 9
`
`B. Description of How the Drug Product is Intended to be Used........................................................ 10
`
`C. Basis for Approvability or Not-Approval Recommendation .......................................................... 10
`
`III.
`
`Administrative.................................................................................................................... 13
`
`A. Reviewer’s Signature ...................................................................................................................... 13
`
`B. Endorsement Block......................................................................................................................... 13
`
`C. CC Block ........................................................................................................................................ 13
`
`Chemistry Assessment ........................................................................................... 14
`
`I. Review of Common Technical Document—Quality (Ctd-Q) Module 3.2: Body of Data......... 14
`
`S DRUG SUBSTANCE .................................................................................................................... 14
`
`Drug Substance Specifications (Azelastine hydrochloride) ................................................................. 21
`
`Drug Substance Specifications (Fluticasone propionate) ..................................................................... 25
`
`P DRUG PRODUCT [Dymista (azelastine hydrochloride/fluticasone propionate) Nasal Spray
`Suspension] .................................................................................................................................... 32
`
`Comparison of the Dose Performance for Combination to Monocomparator Drug Products ............. 51
`
`Drug Product Specifications ................................................................................................................. 88
`
`Drug Product Container Closure ........................................................................................................ 111
`
`Drug Product Stability ........................................................................................................................ 126
`
`A APPENDICES ............................................................................................................................ 136
`
`R REGIONAL INFORMATION ................................................................................................... 136
`
`Reference ID: 3107729
`
`Page 2
`
`

`

`CHEMISTRY REVIEW #1
`
`II. Review of Common Technical Document—Quality (Ctd-Q) Module 1 ................................. 137
`
`A. Labeling & Package Insert ........................................................................................................... 137
`
`B. Environmental Assessment or Claim of Categorical Exclusion .................................................. 141
`
`CMC Comments to Agency Letter dated Junee 13, 2011 (74 day letter) ........................................... 142
`
`CMC Comments to Agency Letter dated November 17, 2011 .......................................................... 144
`
`CMC Comments to Agency Letter dated March 16, 2012 ................................................................. 149
`
`Reference ID: 3107729
`
`Page 3
`
`

`

`CHENIISTRY REVIEW #1
`
`Chemistry Review Data Sheet
`
`1. NDA 202-236
`
`2. REVIEW #: 1
`
`3. REVIEW DATE: 26-March-2012
`
`4. REVIEWER: Eugenia M. Nashed, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`None
`
`Document Date
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission; 5 I Reviewed
`
`Document Date
`
`Stamp Date
`
`Assigned Date
`
`Original NDA
`Amendment BZ
`
`01-Apr-20] 1
`
`01-Apr-20] 1
`
`16-May-201 l
`
`29-Apr-20 l l
`
`29-Apr-20 l l
`
`l 6-May-20 1 l
`
`Amendment BL @abel)
`
`l 9-May-20 l l
`
`l 9-May-20 l l
`
`23-May-201 1
`
`Amendment BZ (Resp. 74 day let.)
`
`0 l Jul-20 1 l
`
`0 l Jul-20 1 l
`
`08-Jul-201 l
`
`Amendment BC (Resp. 74 day let.)
`
`0 l-Aug-ZO l l
`
`0 l-Aug-ZO l l
`
`04—Aug-201 l
`
`Amendment BZ (Resp. 74 day let.)
`
`l 6—Sep—201 l
`
`l 7-Sep-201 l
`
`l 8-Sep-20] 1
`
`Amendment BC (Resp. 74 day let.)
`
`23-Sep-201 l
`
`24-Sep-201 l
`
`26-Sep-20] 1
`
`Amendment BZ Olesp. Nov 1R.)
`
`07-Dec-20] l
`
`07-Dec-20] l
`
`09-Dec-20 l l
`
`Amendment BL @abel)
`
`2 7-Feb-20 l 2
`
`2 7-Feb-20 l 2
`
`2 7-Feb-20 l 2
`
`Amendment BC (Resp. March IR)
`
`23-March-20 l 2
`
`26-March-20 l 2
`
`26-March-20 l 2
`
`Amendment BL (PI, Carton, Vial)
`
`23-March-20 l 2
`
`26-March-20 l 2
`
`26-March-20 l 2
`
`Reference ID: 3107729
`
`Page 4
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`

`

` CHENIISTRY REVIEW #1
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name: Meda Pharmaceuticals, Inc.
`
`Address:
`
`265 Davidson Avenue, Suite 300, Somerset, NJ 08873-4120
`
`Representative: Brenda Jadney. Associate Director, Regulatory Affairs
`
`Telephone:
`
`732-564-2362
`
`Fax: 732-564-2443
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: DymistaTM
`b) Non-Proprietary Name (USAN): Azelastine hydrochloride and fluticasone propionate Nasal Spray
`c) Code Name/# (ONDC only):
`(I) Chem. Type/Submission Priority (ONDC only): New combination
`
`0 Chem. Type: 4
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: 505 (b)(2) (new combination)
`
`PHARMACOL- CATEGORY:
`
`Fixed combination of anti-histamine (antagonist of
`H1 receptor) and corticosteroid (agonist of
`glucocorticosteroid receptor) for relief of symptoms
`of seasonal allergic rhinitis in adults and adolescents
`12 years and older.
`
`11. DOSAGE FORM: Nasal Spray Suspension,
`
`0') (4)
`
`12. STRENGTH/POTENCY: Azelastine hydrochloride/fluticasone propionate,
`137 pg /50 pg per spray (0. l%/0.037%).
`
`l3. ROUTE OF ADMINISTRATION: Intranasal,
`One spray per nostril twice a day
`
`14. Rx/OTC DISPENSED:
`
`X Rx
`
`OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKlNG SYSTEM):
`
`Reference ID: 3107729
`
`Page 5
`
`

`

` CHENIISTRY REVIEW #1
`
`SPOTS product — Form Completed
`
`X Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`Azelastine Hydrochloride
`
`\H“
`
`N
`
`o
`
`-CH ~HCI
`3
`
`N
`
`Molecular Formula:
`
`C22H24C1N30 'HCl Molecular Weight: 418.37 g/mol CAS: 80474-14-2
`
`(i)-1 -(2H)-Phthalazinone,4-[(4-chloropheny1)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-,
`monohydrochloride (CAS, USAN)
`
`Fluticasone Propionate
`
`
`
`Molecular Formula:
`
`C25H31F3058
`
`Molecular Weight: 500.6 g/mol CAS: 80474-14-2
`
`S-Fluoromethy] 6a, 9a-difluoro-l lB-hydroxy-l 6a-methyl-3-oxo-l 7a-propionyloxyandrosta-1,4—
`diene-l 7B-carbothioate (USP)
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`Reference ID: 3107729
`
`Page 6
`
`

`

`
`
`A. DMFs:
`
`Edwin Jao
`
`02-Sey2010
`Chang Ho Kim
`
`l2-May-201 l
`
`lAction codes for DMF Table:
`1 — DMF Reviewed.
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type 1 DMF
`3 — Reviewed previously and no revision since last review
`4 — Sufficient information in application
`5 — Authority to reference not granted
`6 — DMF not available
`
`7 — Other (explain under "Comments")
`
`Reference ID: 3107729
`
`Page 7
`
`

`

`CHENIISTRY REVIEW #1
`
`2 Adequate. Inadequate. or N/A (There is enough data in the application. therefore the DMF did
`not need to be reviewed)
`
`B. Other Supporting Documents:
`
`OWNER
`
`ITEM REFERENCED
`
`STATUS
`
`DATE REVIEW
`CONIPLETED
`
`COMLMENTS
`
`Azelastine Nasal Spray
`
`Azelastine Nasal Spray
`
`Pending
`
`Referenced for this NDA.
`
`Azelastine/Fluticasone Combo
`
`Nasal Spray
`
`AstelinNasalspray IMarketed.ReferencedforthisNDA.
`
`Astepro Nasal Spray. 0.1%
`
`Astepro Nasal Spray. 0.15%
`
`Optivar Ophthalmic Solution
`
`Marketed. Referenced for this NDA.
`
`Marketed. Referenced for this NDA.
`
`Marketed. Referenced for this NDA.
`
`C. Related Documents:
`
`APPLICATION
`NUMBER
`
`DESCRIPTION/COMMENT
`
`18. CONSULTS/CMC-RELATED REVIEWS:
`
`CONSULTS
`
`Ent-l
`
`DATE
`FORW’D
`
`May2,2011
`
`STATUS/
`REVIEWER
`E|
`'
`
`s
`
`E
`
`é:
`Sep 23, 2011
`Eif
`
`lllll
`
`Accephblc
`Jan 12, 2012
`Denise Miller
`
`Microbiology
`Illllifill
`ill1
`
`—
`ACfordmgprothmandflmicasoncpnmionate
`mannfinctuling and testing. VAI for azelasline
`hydrochloride (Inspection Jul 2011, with F483). Overall
`recommendation is PENDING.
`Evaluation ofImpurities and Leachables
`
`TheanalyticalmeflmdsarestandardMVrequestisnot
`Jaimedfotdu'sNDA
`
`Categorical Exclusion was requested per 21 CFR
`25.15(a) and 25.31 (b) and it was found acceptable.
`Additional analytical method for B.cepacia was
`requested and added to the uncrobial controls.
`
`Reference ID: 3107729
`
`Page 8
`
`

`

` CHENIISTRY REVIEW #1
`
`The Chemistry Review for NDA 202-236
`
`The Executive Summam
`
`I.
`
`Recommendations
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`The application is recommended for APPROVAL from the CMC perspective, providing
`that an acceptable recommendation will be issued for all manufacturing and testing sites
`from the Office of Compliance.
`
`The Establishment Evaluation Request (EER) for this NDA is pending as of the
`completion date of this review. Acceptable (AC) status is indicated in the EES for Cipla
`establishments in India responsible for the manufacturing and testing of
`M“)
`drug product (Goa). Vollmtary Action
`Indicated (VAI) status is listed in the EES for the azelastine hydrochloride drug substance
`manufacturing site
`M“) The cGMP inspection was completed at
`this establishment in July 2011, with FDA Form 483 issued.
`
`24 months expiry period is supported for the trade (120 sprays) and sample (28 sprays)
`presentations of the drug product when stored at 20°—25°C (68°—77°F).
`
`B.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`
`and/or Risk Management Steps, if Approvable
`
`None.
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`The drug product, Dymista (azelastine hydrochloride/fluticasone propionate) Nasal
`Spray,
`is a fixed combination of anti-inflammatory (antagonist of H1 receptor) and
`corticosteroid (agonist of glucocorticosteroid receptor) drug substances for the relief of
`symptoms of seasonal allergic rhinitis in adults and children aged 12 years and older.
`When approved, this will be the first combination nasal spray product on the US market.
`
`The drug product is a multidose nasal spray suspension contained in an amber glass
`bottle, fitted with a metering
`M“) spray pump
`om)- Each
`spray of the suspension delivers 137 pg of azelastine hydrochloride (equivalent to 125 pg
`of azelastine base) and 50 ug of fluticasone propionate. Azelastine hydrochloride is
`solubillized in the formulation while the micronized fluticasone propionate occurs as a
`suspension. Both APIs are present in several US-approved drug products, e.g., Astelin
`
`Reference ID: 3107729
`
`Page 9
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`

` CHENIISTRY REVIEW #1
`
`(azelastine hydrochloride) Nasal Spray (NDA 20-114, Meda 1996), and Flonase
`(fluticasone propionate) Nasal Spray (NDA 20-121, GSK 1994).
`
`om) aqueous formulation of 0.1% azelastine
`The drug contains an isotonic,
`hydrochloride and suspended 0.037% fluticasone propionate USP with a pH 6.0
`(low
`The
`excipients
`consist
`of
`glycerin, microcrystalline
`cellulose
`and
`carboxymethylcellulose sodium
`ma) polysorbate 80, edetate disodium
`GEDTA), benzalkonium chloride (0.1 mg/g); phenylethyl alcohol (2.5 mg/g) and purified
`water.
`The fill weight of 23 g delivers at a minimum 120 sprays after priming
`(commercial pack), and the fill weight of 6.4 g delivers at a minimum 28 sprays after
`priming (sample pack).
`
`Azelastine hydrochloride is manufactured by
`fluticasone propionate is manufactured by
`manufactured by Cipla in Goa, India.
`
`m4) and
`mm) The drug product is
`
`B. Description of How the Drug Product is Intended to be Used
`
`The drug product, Dymista (azelastine hydrochloride/fluticasone propionate) Nasal Spray
`suspension is indicated for the relief of the symptoms of seasonal allergic rhinitis in
`adults and children aged 12 years and older. The recommended dose is one spray per
`nostril twice daily, for a total daily dose 11p to 548 ug of azelastine hydrochloride and 200
`ug of fluticasone propionate.
`
`The drug product needs to be shaken gently and primed with six sprays before the initial
`use. It should be stored in the upright position with the cap in place at controlled room
`temperature 20° - 25°C (68° - 77°F).
`It should be protected from light. It should not be
`stored in the refrigerator or fieezer.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`This application is recommended for approval from the CMC perspective based on data
`and information submitted in the original NBA and several NDA amendments provided
`in response to Agency information request (IR) letters and teleconferences. The CMC
`approval recommendation is conditional on the acceptable cGMP endorsement from the
`Office of Compliance, which is currently pending.
`
`Upon brief review of the originally submitted data, potential approvability issues were
`identified and forwarded to the Applicant (June 13, 2011, 74-day letter) with 8 CMC
`comments
`concerning comparability of
`the clinical combination products
`and
`monocomponent drug products, and inadequacy of the proposed specifications, analytical
`methods and stability data for the drug product. Partial responses dated Jul 1, Aug 1, Sep
`16, and Sep 23, 2011, were reviewed and IR letter dated Nov 17, 2011, was forwarded to
`the Applicant with 6 CMC cements concerning ruggedness of the container closure,
`controls for the
`mm excipient, inadequate drug product specifications and methods,
`
`Reference ID: 3107729
`
`Page 10
`
`

`

`CHENIISTRY REVIEW #1
`
`and drug product expiry period. The Applicant’s response dated Dec 7, 2011, let to an IR
`letter dated March 19, 2012, with 4 CMC comments addressing the inadequacy of the
`response regarding deficient specifications and methods for drug product, an unjustified
`expiry period and deficient controls for
`M“) excipient. Following our teleconference
`on March 22, 2012, a complete response was submitted by e-mail on March 23, and hard
`copy on March 27, 2012. Additional data concerning the
`(m4)
`content of phenylethyl alcohol and data comparing the dose performance of the drug
`product before and after manufacturing changes, implemented to improve ruggedness of
`the container closure, will be submitted in the first annual report. Final specifications
`with three non—overlapping cut off points for particle size distribution of fluticasone
`propionate in the drug product formulation will be submitted by March 29, 2012, and will
`be addressed in the addendum to this review and in the secondary CMC review. The
`incoming response is not expected to impact the overall approval recommendation for
`this drug product from the CMC perspective.
`
`See below, a summary of the most important CMC issues addressed throughout the
`review of this application.
`
`0 Comparability of the Clinical Combination Products to the Reference
`Monocomponent Drug Products.
`
`The drug product is a fixed combination of two active pharmaceutical ingredients (APl)
`for local delivery to the nose with a metered spray pump. As such, the dose performance
`parameters may have a significant impact on the locally delivered doses, especially since
`one of the APIs (azelastine hydrochloride) is soluble in the drug product formulation
`while the other (fluticasone propionate) is micronized and suspended in the formulation.
`The dose performance comparison data for the combination and monotherapy products
`were not submitted with the original NDA. In response to Agency 1R letters (June 13, and
`Nov 17, 2011)
`the dose performance data comparison charts were submitted in
`amendment dated Sep 23, and Dec 7, 2011, and are evaluated on page 51 of this review.cm
`
`the overall dose performance results are considered to be within the
`acceptable range of variations of NMT
`om)
`The in vitro dose performance
`characteristics of the combination products and monotherapy products used in the pivotal
`clinical trials are considered comparable from the CMC perspective.
`
`0 Product Formulation and Container Closure.
`
`(5)“)
`
`The issue was addressed in Agency IR letters (Nov 17, 2011
`and March 19, 2012) and discussed during teleconference with the Applicant on March
`22, 2012. The Applicant proposed to submit a detailed report with their investigation of
`(mo
`
`Reference ID: 3107729
`
`Page 11
`
`

`

`CHENIISTRY REVIEW #1
`
`(mo in the first annual report. In the interim, the acceptance
`(5m) to reflect the data at 24 months (Expiry). The
`criteria
`mo was discussed with the Microbiology review
`safety
`(m4) levels observed in the product on storage were found acceptable
`team and the
`0M4)
`since adequate, supportive-of-this-level, data for the
`effectiveness were
`submitted OVIicrobiology Review dated Jan 12, 2012).
`
`0 C