CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-023
`
`CHEMISTRY REVIEW! S!
`
`
`
`

`

`NDA 21-023
`
`Cyclosporine Emulsion 0.05%
`
`4
`
`Division of Anti-inflammatory, Analgesic and Ophthalmic Drugs
`Review of Chemistry, Manufacturing, and Controls
`
`NDA #: 21-023
`
`REVIEW #
`
`4
`
`DATE REVIEWED: 12110/02
`
`SUBMISSION TYPE
`
`DOCUNIENT DATE
`
`CDER DATE
`
`ASSIGNED DATE
`
`Amendment
`
`12/4102
`
`12/5102
`
`12/9/02
`
`NAME & ADDRESS OF APPLICANT:
`
`Allergan Inc.
`2525 Dupont Drive
`P. O. Box 19534
`Irvine, CA 92623
`
`DRUG PRODUCT NAME
`
`Progrietan': RESTASIS
`Established: cyclosporinc
`Code Name/#2 9(1de
`
`ChemeefTherClass: 3p
`
`PHARMACOLOGY CATEGORY:
`DOSAGE FORM: Emulsion
`STRENGTHS: 0.05%
`
`Immunomodulator and anti-inflammatory agent
`
`ROUTE OF ADMINISTRATION: Topical/ocular
`DISPENSED:
`
`X Rx
`
`O'I‘C
`
`PATENT INFORMATION:
`
`US 4,649,047
`US 4,839,342
`US 5,474,979
`
`INDICATION:
`
`T ,
`
` CHEMICAL NAME STRUCTURAL FORMULA MOLECULAR FORMULA AND WEIGHT:
`
`Molecular Formula
`
`C62H1 i 1N1 1012
`
`Molecular Weight
`
`1202.6
`
`Chemical Name & Structure
`
`Cyc10{[(E)-(ZS, 3R, 4R)—3—hydroxy-4-mcthyl—2-(methylamino)—6-octenoy1]—L—2—
`aminobutyiyl-N-melhyglycyl-N-methyl-L-leucyl-L—valyl—N-methyl—L-lcucyLL—alanyl—
`D«alanyl-N-methyl-L-leucyl-N-methyl—L—Ieucyl-N-methyI—L-valyl}
`
`

`

`NDA 2l—023
`
`Cyclosporine Emulsion 0.05%
`
`CH
`
`CHCH
`
`l
`
`all
`
`2
`
`H3C\
`
`N
`
`_
`iCHflZCHLHZ
`
`o
`
`N
`
`/
`
`u c
`1
`
`CH,
`l
`N
`
`0
`
`N
`”
`
`0
`
`CH3
`
`cmcus)2
`N
`
`0
`
`0,20,me
`
`.
`x
`l
`CH,
`
`H3C
`
`HO
`
`N
`
`CH3
`
`0
`
`5
`
`1
`3),
`
`-
`“‘3
`
`H
`N
`
`'CH3
`
`\N/
`
`CH)
`
`CHZCH]
`
`N
`
`0
`r
`i:
`TH
`\n/ Ciilcmt
`0
`Ciircn )
`3 2
`
`USAN Name:
`
`Cyclosporine
`
`Allergen Code Number (AGN#)
`
`AGN l9237l
`Chemical Abstract Number
`
`Other Names
`
`CAS 059865433
`
`Cyclosporine A, cyclosporine, cyclosporin
`
`SUPPORTING DOCUMENTS:
`
`None
`
`REMARKS:
`
`In the chemist‘s review #3, the application was recommended for approval from
`chemistry, manufacture, and control standpoint. However due to clinical deficiencies, the
`NDA was not approved.
`
`In the amendment dated 71’ 12/99, 7/29l99, and Chemist’s review # 2, Allergan agreed to
`monitor impurity
`--a--‘----. , and M m the three validation batches,
`and submitted the results for evaluation, Allergan provides the results of such studies in
`this amendment.
`
`
`
`

`

`
`
`NDA 2| -023
`
`Cyclosporine Emulsion 0.05%
`
`On Dec. 4, 2002, a teleconference was held with Allergan’s representatives discussing
`the impurities acceptance criteria, an agreement was reached to revise the drug product
`specification.
`
`CONCLUSIONS & RECOMMENDATIONS:
`
`The application is recommended for approval. All manufacturing facilities are in (BM?
`compliance (as of 10/24l02) The application may be approved for 24 months anrI -—--
`—-—-
`. expiration dates (when stored at 25° C) for the marketed package and
`”M respectively.
`
`cc:
`
`Orig. NDA 21-023
`HFD-SSO/Division File
`HFD~550/Gorski
`HF-SSO/Chemist/Tso
`HFD-S30/CChen
`
`HFD-SSO/Ng
`HFD-SSO/Boyd
`HF D-SSO/Chambers
`
`HFD—SSO/Mukherjee
`
`
`
`Su C. Tso, PhD.
`Chemist, HFD—550/830
`
`
`
`Linda Ng, PhD.
`Chemistry Team Leader, HFDSSO
`
`

`

`(é
`
`‘ Page(s) Withheld
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Su TSO
`
`12/13/02 01:44:01 PM
`CHEMIST
`
`Linda Ng
`12/13/02 01:55:00 PM
`CHEMIST
`
`See Memo to File by LNg to complement this review
`
`
`
`

`

`NDA 21-023
`
`RESTASIS
`
`cyclosporine Ophthalmic Emulsion, 0.05%
`
`Allergan Inc.
`
`Su C. Tso, Ph. D.
`
`HFD— 550
`
`
`
`

`

`NDA 21-023
`
`Cyclosporine Emulsion 0.05%
`
`The Executive Summary
`
`
`
`
`
`

`

`NDA 2I7023
`
`Cyclosporine Emulsion 0.05%
`
`1. Recommendations
`
`3
`
`A. Recommendation and Conclusion on Approvability
`
`The application is recommended for approval. The apprOval is based on quality,
`safety, and efficacy of the dosage form.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`NIA
`
`II. Summary of Chemistry Assessments
`
`A. Description ofthe Drug Product(s) and Drug Substancetis)
`
`The active drug substance cyclosporine is a white to almost white powder. It is
`
`produced by
`own--
`and is supplied by
`Cyclosporine
`is an approved drug in NBA—50673 and NDA 50—574. This NDA drug product is
`
`an
`emulsion at 0.05% concentration manufactured at Allergan Inc.
`Waco, TX facility. The finished dosage form is packaged in LPDE unit-dose vial
`by ’
`-——-—-—-. technique.
`
`B. Description of How the Drug Product is Intended to be Used
`
`The drug product is indicated for WW
`
`, it is to be used one
`”a.weam..-¢.mmem. W _
`drop twice a day approximately 12 hours apart. The formulation contains no
`preservative in a unit dose vial, therefore the vial should be discarded after use.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`The application is recommended for approval. This recommendation isbased on
`the applicant’s capability of manufacturing, and control of quaiity product (under
`GMP) for human consumption.
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`Su C. Tso, PhD, HFD-550/830, electronically signed in DFS
`
`B. Endorsement Block
`
`Linda Ng, Ph. D., Chemistry Team Leader
`
`
`
`
`
`

`

`Division of Anti-inflammatory, Analgesic and Ophthalmic Drugs
`Review of Chemistry, Manufacturing, and Controls
`
`NDA #: 21-023
`
`REVIEW #
`
`3
`
`DATE REVIEWED: 3/22/00
`
`SUBMISSION TYPE
`
`DOCUMENT DATE
`
`CDER DATE
`
`ASSIGNED DATE
`
`Amendment
`
`9/3I99
`
`9/7/99
`
`9/14/99
`
`NAME 8.: ADDRESS OF APPLICANT:
`
`Allergan Inc.
`2525 Dupont Drive
`P. 0‘ Box 19534
`Irvine. CA 92623
`
`DRUG PRODUCT NAME
`
`Proprietarv: RESTASIS
`Established: cyclosporine
`Code Name/#; 9054):
`
`ChemTer/ThenClass: 3p 1‘
`
`
`
`PHARMACOLOGY CATEGORY:
`DOSAGE FORM: Emulsion
`STRENGTHS: 0.05%
`
`lmmunomodulator and anti-inflammatory agent
`
`ROUTE OF ADMINISTRATION: Topical/ocular
`DISPENSED:
`
`X Rx
`
`OTC
`
`PATENT INFORMATION:
`
`US 4,649,047
`US 4,339,342
`US 5,474,979
`
`INDICATION:
`
`F"
`
`CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA AND WEIGHT:
`
`(1)
`
`Molecular Formula
`
`CsszNnOn
`
`(2)
`
`Molecular Weight
`[202.6
`
`(3)
`
`Chemical Name & Structure
`
`Cyclo{[(E)-(ZS, 3R, 4R}3—hydroxy-4-methyl-2-(melhylamino)«6-octenoyl]-L—2—
`aminobutyryl-N -methyglycyl-Nmethyl-L—leucyl—L—valyi—N-methyl-L~leucyl—L-alanyl-
`D-alanyl-N-methyl-L-leucyl—‘N-methyl—L-leucyl-N-methyi-L~valyl}
`
`
`
`
`
`

`

`
`
`NDA 21-023
`
`Cyclosporine Emulsion 0.05%
`
`2
`
`
`
`113C
`
`HO\\
`
`((113)1CH(ll;
`
`lH
`
`‘0
`
`CIHCH3}1
`_
`
`(CH 31301011
`
`CH 2CH(CH 3):
`
`N_“ CH]
`
`113c\N/i\r/:\1\\/"\TJ\n/ii\/L\N/»1:11J
`
`CHJ
`c112CI-1J LTO
`/”gig)YN\2\N/S/50LCHZCNCM
`
`(In,
`
`CH1
`
`cutcn
`
`3);)
`
`(4)
`
`USAN Name
`
`Cyclosporinc
`
`(5)
`
`Allergan Code Number (AGN#)
`
`AGN 192371
`
`(6)
`
`Chemical Abstract Number
`CAS 059865-13—3
`
`(7')
`
`Other Names
`
`Cyclosporine A, cyclosporine, cyclosporin
`
`SUPPORTING DOCUMENTS:
`
`Chemist Review #1 and # 2
`
`RElVlARKS:
`
`Microbiological deficiencies have been resolved (refer to microbiologist review # 4 dated
`Feb. 2, 2000. The application was recommended for approval from chemistry,
`manufacture, and control standpoint. Method validation package was submitted on
`913/99, but method validation has not been requested due to clinical deficiency.
`
`CONCLUSIONS & RECOMMENDATIONS:
`
`All manufacturing facilities are in GMP compliance (since 3199). The application may be
`approved for ' 6-H and 9"" . expiration dates (when stored at 25° C) for the
`marketed package M respectively.
`
`

`

`NDA 21-023
`
`Cyclosporine Emulsion (105%
`
`3
`
`Orig. NDA 21~023
`I'IFD-SSO/Division File
`HFD—SSO/Gorski
`HF—SSO/Chemistfl‘so
`
`HFD—S30lCChen
`
`HFD-SSO/Ng
`
`HFDASSO/Chambers
`
`HFD-SSO/Boyd
`HFD-ifiO/Mukherjee
`
`(5f
`
`
`
`Su C. T50, PhD.
`Chemist, HFD-SSO/SBO
`
`i
`Lmda Ng, PhD
`_
`Chemistry Team Leader, HFDSSO
`
`
`
`
`
`

`

`Division of Anti—inflammatory, Analgesic and Ophthalmic Drugs
`Review of Chemistry, Manufacturing, and Controls
`
`NDA #: 21-023
`
`REVIEW #1!
`
`2
`
`DATE REVXEWED: 7/28/99
`
`SUBMISSION TYPE
`
`DOCUMENT DATE
`
`CDER DATE
`
`ASSIGNED DATE
`
`Amendment
`Amendment
`
`7/12/99
`7/26/99
`
`7/l3/99
`7/27/99
`
`7/19/99
`7/28/99
`
`NAME & ADDRESS OF APPLICANT:
`
`Allergan Inc.
`2525 Dupont Drive
`Pl 0. Box 19534
`
`Irvine, CA 92623
`
`DRUG PRODUCT NAME
`
`Progrietagg: RESTASIS
`Established: cyclosporinc
`Code Name/#: 9054K
`
`ChemTer/I'herClass: 3p
`
`
`
`l
`
`PHARMACOLOGY CATEGORY:
`DOSAGE FORM: Emulsion
`STRENGTHS: 0.05%
`
`Immunomodulator and anti-inflammatory agent
`
`ROUTE OF ADMINISTRATION: Topical/ocular
`DISPENSED:
`
`X Rx
`
`OTC
`
`PATENT INFORMATION:
`
`US 4,649,047
`US 4,839,342
`US 5,474,979
`
`INDICATION: Wm
`
`CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA AND WEIGHT:
`
`(1)
`
`(2)
`
`(3)
`
`Molecular Formula
`CaszNnOlz
`
`Molecular Weight
`l202.6
`
`Chemical Name & Structure
`Cyclo{[(E)-(ZS, 3R, 4R)-3-hydroxy-4-methyl-2-(methylaminb)-6-octenoyl]-L-2-
`am'mobutyryl-N-memyglycyl-N—methyl-L-Ieucyl—L-valyl—N-methyl—L—Ieucyl-L-alanyl-
`D—alanyl-N-methyl-L-leucyl-N-mefliyl-L-leucyl-N-methyl—L-valyl}
`
`
`
`

`

`
`
`
`
`HC/1N)\N)j/NH\B/Lbj\'/S\A}CHZCH(CH92
`
`CH1
`
`CH CH
`(
`
`3h
`
`(4)
`
`(5)
`
`(6)
`
`(7)
`
`USAN Name
`Cyclosporine
`
`Allergen Code Number (AGN#)
`AGN 192371
`
`Chemical Abstract Number
`CAS 059865-13-3
`
`Other Names
`Cyclosporine A, cyclosporine, cyclosporin
`
`SUPPORTING DOCUMENTS:
`
`FDA phone/fax dated 6/9/99
`FDA fax 7/23/99
`
`REMARKS:
`
`The first CMC reviewed was completed on 5/21/99. The recommendation was
`“approvable” with deficiencies. The applicant was informed of the deficiencies by fax on
`6/9/99. The amendment of 7/12/99 is a response to the deficiencies cited in the fax.
`However, the responses are incomplete and unsatisfactory. A telecom was held with
`Elizabeth Bancroft of Allergan in the presence of Linda Ng, Ph. D. (chemistry team
`leader) on 7/21/99, followed by a fax dated 7/23/99. Amendment dated 7/26/99
`addresses the overall deficiencies. This report summarizes the review of these two
`amendments. Method validation package will be requested.
`
`
`
`NDA 21-023
`
`Cyclosporine Emulsion 0.05%
`
`a]
`
`2
`
`cu]
`
`(CH3)2CHCH2
`
`n,c\
`
`(:iim/lY\1/t\N/,O/,CH3
`
`CHICH3
`
`CH1
`
`(CHJhCHCHz
`
`CHZCH(CH 1)2
`
`N
`
`CH]
`
`cmcnpz
`
`
`
`
`
`
`

`

`
`
`NDA 21-023
`
`Cyclosporine Emulsion 0.05%
`
`CONCLUSIONS & RECOMMENDATIONS:
`
`3
`
`The responses to the deficiencies are satisfactory. Pending a satisfactory micro-review,
`the application is recommended for “approval” from a chemistry, manufacture, and
`control standpoint. All manufacturing facilities are in GMP compliance. The application
`
`may be approved for
`and M expiration dates (when stored at 25° C)
`for the marketed package and
`""
`'
`respectively.
`
`Labeling agreed upon by the applicant should be confirmed later when the final labeling
`is submitted.
`
`cemmr’m‘“ WHWWMWWMM
`The applicant should be reminded of the .
`. "ma—m
`“my.“ Hmm"'—‘HzJ—1XWF.-wr v‘lmmqqie»...
`,
`_
`‘WMM
`,.,
`., m—
`I—"Jm ,
`"H7
`' '“lfmmm-~«~—‘M , “‘
`'
`
`co:
`
`Orig. NDA 21-023
`HFD-SSO/Division File
`HFD-SSO/Gorski
`HF-SSO/Chemist/Tso
`
`HFD-830/CChen
`
`HFD-SSO/Ng
`HFD-SSO/Boyd
`
`HFD—SSO/Chambers ‘
`
`HFD—SSO/Mukheljee
`
`5vii
`
`7 f“
`
`Su C. Tso, PhD.
`Chemist. HFD-S 50/83 0
`
`M
`
`.
`"’
`Linda Ng, PhD.
`Chemistry Team Leader, HFDSSO
`
`
`
`
`
`

`

`i0 - Page(s) Withheld
`
`

`

`
`
`Division of Anti-inflammatory, Analgesic and Ophthalmic Drugs
`Review of Chemistry, Manufacturing, and Controls
`
`NDA #: 21-023
`
`REVIEW #
`
`1
`
`DATE REVIEWED: 5/21/99
`First revision 6/5/99
`
`SUBMISSION TYPE
`
`DOCUMENT DATE
`
`CDER DATE
`
`ASSIGNED DATE
`
`Pre-submission
`Submission
`Amendment
`Amendment
`Amendment
`
`Amendment
`
`12/9/98
`2/24/99
`3/3/99
`3/18/99
`5/5/99
`
`5/10/99 (3)
`
`12/10/98
`2/25/99
`3/5/99
`3/19/99
`5/6/99
`
`5/11/99
`
`12/14/98
`3/2/99
`3/10/99
`3/25/99
`5/ 12/99
`
`5/13/99
`
`NAME 8: ADDRESS OF APPLICANT:
`
`Allergan Inc.
`2525 Dupont Drive
`P. O. Box 19534
`
`ln'ine, CA 92623
`
`DRUG PRODUCT NAME
`
`Progrietarv: RESTASIS
`Established: cyclosporine
`Code Name/#: 9054x
`
`ghemeoefThenclass: 3p
`
`PHARMACOLOGY CATEGORY:
`DOSAGE FORM: Emulsion
`STRENGTHS: 0.05%
`
`lmmunomodulator and anti—inflammatory agent
`
`ROUTE 0F ADMINISTRATION: Topical/ocular
`DISPENSED:
`
`X Rx
`
`OTC
`
`PATENT INFORMATION:
`
`US 4,649,047
`US 4,839,342
`US 5,474,979
`
`INDICATION:
`
`
`
`gHEMICAL NAME STRUCTURAL FORMULA MOLECULAR FORMULA AND WEIGHT:
`
`(1)
`
`(2)
`
`Molecular Formula
`C62HlllNl1012
`
`Molecular Weight
`1202.6
`
`

`

`
`
`NDA 21-023
`
`0.5% cyclosporine Emulsion
`Allergan Inc.
`
`Page 2
`
`(3)
`
`Chemical Name & Structure
`Cyclo{[(E)-(ZS, 3R1 4R)—3-hydroxy—4—m'ethyl-2-(methy1amino)—6-octcncyl]-L-2-aminobutyry1-
`H3
`
`H0
`
`CH
`
`1
`
`CHCH
`3):
`
`2
`
`H3C
`
`\N
`
`CH3
`.1
`
`0
`
`C113
`
`0
`n
`14% CH3
`N/
`I
`l
`012C“)
`
`0
`
`o
`
`N
`I
`CH3
`
`i 1
`
`‘
`1
`1
`1
`1
`
`0
`
`CH(CH])2
`
`(CH3)2CHCH2
`
`I
`CH3
`0
`/NYL\N/fi/
`
`H
`
`H
`N
`
`H3C
`
`CH2C!I(CH 3)2
`0
`N/Y
`
`H
`N
`
`Nfim CH 3
`
`'I
`
`0125111th
`
`-CH CH
`1
`3h
`1
`CHJ
`CH]
`0
`N-methygiycyl—N-methyl-L—leucyl-L—valyl-N-methyl—L-leucyl—L-aianyl-D-alanyl-N-mcthyl-L-
`lcucy!-N—mcLhy1-L-leucyi-N-methyl-L-valyl}
`
`(4)
`
`(5)
`
`(6)
`
`USAN Name
`Cyclosporine
`
`Allergen Code Number (AGN#)
`AGN 19237]
`
`Chemical Abstract Number
`CAS 059865-13-3
`
`(7)
`
`Other Names
`
`Cyclosporine A, ciclosporin, cyclospor'm
`
`SUPPORTING DOCUMENTS:
`
`NDA #5 50—573, NDA # 50-574, IND 32,133, 1ND "'"‘ , &1N[‘ -——*
`
`
`:M nemmomponem
`
`
`
`
`
`
`RELATED DOCUMENTS:
`
`FDA c-mail dated: 12/20/99, 12/22/98, 4/21/99
`FDA phone/fax dated 2/22/99, 4/7/99
`FDA memo dated 3/19/99, 5/3/99, 5/5/99, 5/18/99
`
`

`

`
`
`NDA 21-023
`
`0.5% cyclosporine Emulsion
`Allergan Inc.
`
`Page 3
`
`QONSULTS:
`
`
`validation is consulted to microbiologist for review.
`
`Trade name “RESTASIS” was reviewed and accepted by FDA N&L Committee at the IND
`phase III stage (March 1998). The acceptability of the trade name was continued on 4/21/99 by
`Dan Boring, Ph. D.
`
`BER requested on 3/3/99. Pro-approval inspection for Waco, TX facility was conducted during
`the week of 4/26/99. No FDA form 483 was issued to the firm. Dallas District Office
`recommended “approval”. All other manufacturing facilities are in GMP compliance as of
`4/30/99.
`
`BEMARKS:
`
`The CMC portion of this NDA was submitted as a Pre-submission on 12/9/99. 1n the pre-
`submission, Allergan requests the approval of 0.05% 8 ""‘ cyclosporine emulsion. However in
`the formal submission dated 2/24/99, the sponsorW and requested the
`approval to market the 0.05% strength ,5, Since majority of the data support the application
`are derived from the 0.1% emulsion, therefore this report will include the review and discussion
`of cyclosporine emulsion of’0.1% and 0.05% strength.
`
`
`The chemistry, manufacture,
`._
`Drug substance cyclosporineIS manufactured by
`and control of the drug substance are referenced to NDA ~— 81
`-—-
`These NDAS are
`updated and current (FDA E—mail dated 12/22/99), they are adequate to support the manufacture
`of cyclosporine drug substance.
`
`CMC information of the dosage form is provided in the pre-submission in vol. 1.1 to vol. 1.5.
`Additional CMC information is provided in the submission dated 2/24/99 in vol. 2.2, vol. 2.1 1,
`and vol. 2.12.
`
`CONCLUSIONS & RECOMMENDATIONS:
`
`The application is approvable from a chemistry, manufacture, and control standpoint. All
`manufacturing facilities are in GMP compliance. The application may be approved for -"
`
`—--"'
`and
`expiration dates (when stored at 25° C) for the marketed package and
`'-——_...5
`, respectively. However, the final approval is pending for the satisfactory
`review of :
`
`_
`
`validation by Microbiologist, and
`-—-—"
`-
`0 The responses from the applicant on the following deficiencies:
`
`
`
`

`

`NDA 217023
`
`0.5% cyclosporine Emulsion
`Allergan Inc.
`
`Deficiencies:
`
`Page 4
`
`1. Please modify the drug product specifications as follows:
`
`a.
`
`, in the regulatory
`-“—-"‘"
`..— and'
`Impurities should be controlled
`specifications. The impurities should be subdivided as follows:
`
`Specified impurities:
`o
`Specified & identified for compounds with known structures
`-
`Specified and unidentified for compounds with unknown structures such as m and
`-c’" “‘“
`The retention time for identification purpose can be used.
`
`0 Total for the sum of the specified impurities
`
`Other unspecified or unknown impurities:
`- Other individual unspecified or unknown impurity
`o Other total unspecified or unknown impurities
`
`Total impurities for the sum of all impurities
`
`b. The
`
`--__J
`
`acceptance criteria should be tightened to reflect actual data.
`
`c. A second 1]) test (c.g., HPLC retention time) should be added to the specifications
`
`Impurities testing should be included in the drug substance batches for annual retesting.
`
`The post approval stability protocol should be revised to include impurities testing and a
`stability commitment statement, to be consistent with FDA Stability Guidelines, 1987, p4.
`
`l\J
`
`L.)
`
`
`, should be revised to include testing for the —~—~
`4. The analytical method, HPLC .
`impurity. Supporting validation data for the analytical method should be submitted.
`
`5. The .—-—. method for the "*-
`
`with supporting validation data should be submitted.
`
`6. Labeling:
`
`Packaoe insert:
`
`Under the DESCRIPTION section: vol 2.1 pg. 175
`- The inactive ingredients should be listed in the order of decreasing content
`I The values of osmolality and pH should be the same as thOSe in the regulatory specifications.
`
`
`
`
`
`

`

`NDA 21-023
`
`0.5% cyclosporine Emulsion
`Allergan Inc.
`
`Under the HOW SUPPLIED section:
`
`Page 5
`
`The following package configuration statement should be included:
`
`RESTASIS is packaged in unitldose vials. Each unit—dose contains 0.4 mL fill in a 0.9 mL
`LDPE vial; 32 vials are packaged in a polypropylene tray with
`r______.
`
`For the secondar
`
`acka in
`
`the W llabel:
`
`0 On the PP therrnoformed tray label, a W statement such as “ ~._..—-—.__.,
`M should be added.
`
`7. Please provide microbiological data to support the
`W label.
`
`4——-—-—_-
`
`as stated in the
`
`Orig. NDA 21-023
`I-IFD—SSO/Division File
`HFD-SSO/Chemisth‘so
`
`HFD-830/CChen
`
`HFD—SSO/Ng
`
`HFD-SSO/Boyd
`
`HFD—SSO/Chambers
`
`W
`
`Su C. Tso, PhD.
`Chemist, HFD-SSO
`
`[5{
`
`I-[FD-SSO/Mukherjee
`HFD—SSO/Gorski
`
`Linda Ng, PhD.
`Chemistry Team Leader, HFD-SSO
`
`
`
`
`
`

`

`
`
`l7} ' Page(s) Withheld
`
`

`

`
`
`..
`
`OSAMAY‘1999
`
`FDA CDER EES
`
`Page
`
`I of
`
`2
`
`ESTABLISHIVIENT EVALUATION REQUEST
`SUD/[MARY REPORT
`
`N DA 21023/000
`Application:
`Stamp: 25-FEB-1999 Regulatory Due: 2&AUG-l999
`
`Applicant;
`
`ALLERGAN
`2525 DUPONT DR
`
`IRVINE, CA 926239534
`
`Priority: 3?
`Action Goal:
`
`Brand Name:
`
`Org Code: 550
`District Goal: 26—JUN-1999
`
`RESTASIS(CYCLOSPORINE
`OPHTHALMIC EMULSIO
`
`Established Name:
`Generic Name: CYCLOSPORJNE OPHTHALMIC
`EMULSION 0.05%
`
`Dosage Form:
`Strength:
`
`EML (EMULSION, LOTION)
`0.05%
`
`
`
`FDA ContacLs:
`
`L. GORSKI
`S. TSO
`
`(HFD—SSO)
`(RFD-550)
`
`301-827-2090
`301-827-2539
`
`. Project Manager
`. Review Chemist
`
`L. NG
`(HFD-830)
`391—827-2511
`, Team Leader
`
`fififiméfiion:
`'
`M W
`
`ACCEPTABLE on 30-APR-1999 by M. EGAS (HFD—322) 30 1-594-0095
`
`fl-
`rEstablishrne'rit-z‘ 1643525
`ALLERGAN INC
`8301 MARS DR
`
`WACO, TX 76712
`
`W
`
`DMF NS:
`AADA No:
`
`“—
`
`4":
`
`OAI‘ Status: NONE
`SN!
`Profile:
`Last Milestone: 0C RECOMMENDATION
`Milestone Date
`30-APR-I999
`Decision:
`ACCEPTABLE
`
`Responsibilities: FINISHED DOSAGE
`MANUFACTURER
`
`Reason:
`DISTRICT RECOMMENDATION
`
`
`Establishment: 9610728
`DMF N0:
`ALLERGAN PHARMACEUTICALS IR AADA No:
`CASTLEBAR RD
`
`WESTPORT, COUNTY MAYO, EI
`
`OAI Status: NONE
`Profile: CTL
`Last Milestone: 0c RECOMMENDATION
`Milestone Date
`04-MAR—1999
`Decision:
`ACCEPTABLE
`
`Responsibilities: FINISHED DOSAGE STABILITY
`TESTER
`
`Reason:
`BASED ON PROFILE
`
`
`Establishment: W DMF No:
`AADA NO:
`
`W
`
`0A1 Status: NONE
`Profile: CSN
`Last Milestone: 0C RECOMMENDATION
`
`Responsibilities: DRUG SUBSTANCE
`MANUFACTURER
`
`

`

`05-MAY~E999
`
`FDA CDER EES
`ESTABLISHNIENT EVALUATION REQLIEST
`SUMMARY REPORT
`
`Page
`
`2 of
`-
`
`Milestone Date
`Decision:
`
`lO-MAR-l999
`ACCEPTABLE
`
`Reason:
`
`BASED ON PROFILE
`
`
`
`Establishment:
`
`WM ‘
`9*?“an“; Em
`
`DMF N0:
`
`AADA N0:
`
`OAl Status: NONE
`Profile: CFN
`Last Milestone: 0c RECOMMENDATION
`Milestone Date
`04-MAR-l999
`Decision:
`ACCEPTABLE
`
`Responsibilities: DRUG SUBSTANCE
`MANUFACTURER
`
`Reason:
`BASED ON PROFILE
`
`
`
`
`APPEARS mas WAY
`
`
`
`

`

`ea-I at. an
`
`FDA CDER EES
`
`Page
`
`a of
`
`I‘d
`
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`17..
`
`NDA 210231000
`Application:
`Stamp:
`25-FEB—I999 Regulatory Due: 09—Nov-2002
`
`Applicant:
`
`ALLERGAN
`2525 DUPONT DR
`
`IRVINE, CA 926239534
`
`Priority: 3?
`Action Goal:
`
`Brand Name:
`
`Org Code: 550
`District Goal;
`
`10513134002
`
`RESTASIS(CYCLOSPORINE
`OPHTHALMIC EMULSIO
`
`Established Name:
`Generic Name: CYCLOSPORINE OPHTHALMIC
`EMULSION 0.05%
`
`Dosage Form:
`Strength:
`
`EML (EMULSION, LOTION)
`0_05%
`
`FDA Contacts:
`
`L. GORSKI
`(HFD—SSO)
`301-827—2090
`, Project Manager
`S. TSO
`(HFD-SSO)
`301-827-2539
`, Review Chemist
`, Team Leader
`301-827-2511
`(HFD-830)
`L. NG
`
`Overall Recommendation:
`
`ACCEPTABLE on 24-OCT-2002 bv S. FERGUSON (HFD-324)301—827—0062
`ACCEPTABLE on_30-APH-l999 bv EGASNL
`Establishment: 1643525
`DMF No:
`
`l
`
`,_
`
`ALLERGAN INC
`830] MARS DR
`
`WACO, TX 7(1712
`
`AADA No:
`
`OAI Status: NONE
`SNI
`Profile;
`Last Milestone: 0c RECOMMENDATION
`Milestone Date: 24-OCT-2002
`
`Decision:
`
`
`Reason:
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`Responsibilities: FINISHED DOSAGE
`MANUFACTURER
`
`DMFNO:
`Establishment: 9610728
`ALLERGAN PHARMACEUTICALS IR AADA No:
`
`WESTPORT, COUNTY MAYO, EI
`
`OAI Status: NONE
`Profile: CTL
`Last Milestone: 0C RECOMMENDATION
`Milestone Date: 21-OCT-2002
`
`Decision:
`
`Reason:
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`Responsibilities: FINISHED DOSAGE STABILITY
`TESTER
`
`Establishment: M
`
`DMF No:
`
`M AADA N02
`
`W
`
`Profile: CSN
`
`OAI Status: NONE
`
`

`

`JyuL i-mo.)
`
`FDA CDER BBS
`
`_
`
`Page
`
`2 of
`
`2
`
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Last Milestone: 0c RECOMMENDATION
`Milestone Date: 21—0CT-2002
`Decision:
`ACCEPTABLE
`Reason:
`
`BASED ON PROFILE
`
`Establishment:
`
`w
`
`M
`
`Profile: CFN
`Last Milestone:
`
`Milestone Date:
`Decision:
`
`Reason:
`
`GA] Slams: NONE
`
`0C RECOMMENDATION
`21—0CT-2002
`
`ACCEPTA BLE
`
`BASED ON PROFILE
`
`Responsibilities: DRUG SUBSTANCE
`
`MANUFACTURER
`
`Responsibilities: DRUG SUBSTANCE
`MANUFACTURER
`
`
`
`
`
`

`

`
`
`
`
`Food & Drug Administration
`
`Memorandum
`
`Date:
`
`December 12, 2002
`
`From:
`
`Linda Ng, Ph.D.,
`Chemistry Team Leader, HFD-BSO
`
`Subject:
`
`NDA 21—023, Restasis (cyclosporine ophthalmic emulsion)
`0.05%, Allergan
`
`To:
`
`The File
`
`Via:
`
`Chi wan/Chen, Ph.D.
`Director, HFD—830
`
`HFD—SSO is finalizing the labeling for approval of NDA 21—023.
`Chemistry'
`reviewer,
`Su Tso,
`commented on the labeling in chem
`review #1 dated June 16, 1999.
`This memo serves to complement
`chem review #4, which recommends
`approval
`from a
`chemistry,
`manufacturing and controls perspective.
`
`Here is a summary of revisions recommended for the package insert,
`immediate container label,
`tray and carton labels.
`
`
`
`ubUJN
`
`Package Insert
`Under Description,
`1. Osmolality should have a lower case “0”.
`awn
`. The pH should read “6.5 to 8.0” with removal of
`. The amount as *-~
`should replace “0.05%" for cyclosporine.
`.The inactives list should be in order of glycerin, castor oil,
`polysorbate
`80,
`carbomer
`1342, purified water,
`and
`sodium
`hydroxide to adjust the pH.
`5. Use comma instead of
`wm———
`
`for the listing of inactives.
`
`Under How Supplied,
`1.The type of
`lid should be included and read “..with aluminum
`peelable lid”.
`2. Replace the e»- with “to" for the Fahrenheit range.
`3. Firm should justifv the lower range of 15C for an emulsion and
`the “
`gunn-ufl
`'
`statement. According to the freeze thaw
`data, product quality is maintained.
`
`

`

`
`
`a. The
`
`storage
`
`statement
`
`is
`
`for
`
`15D
`
`to
`
`25°C.
`
`Please
`
`2
`
`prolonged
`that
`substantiate
`detrimental to the emulsion.
`b. Please provide justification for inclusion of the statement
`‘
`*""—-—~
`"
`in the labeling
`” as the latter is
`___4
`4‘ The word “vial” should be replaced by
`the description for
`a
`sealed container as per C—DRR—00907,
`Package Type, CDER Data Standards Manual.
`
`is
`
`not
`
`exposure
`
`at
`
`15°C
`
`Tray Label
`
`WW“%_N”q ,
`m, J,- x_,,
`.,, ”.7 -. n. m. .J. u, ..
`.::«
`, .11!‘.‘\\.‘n“Live!‘RA‘va-fnd'w".‘A_»_{F¢}pn_l_y;l-;;‘¥r¥ ufiivwloffiifi’fij.fiha.‘}‘vt“f-Fflfllfimbs-w‘M—fi ‘
`,
`
`Tray Label and Carton
`
`
`
`“TERM ‘3 as a 5:3:imtwfiewfifii L m a .
`
`.
`
`
`
`For ease of conveying comments to the firm, a comprehensive list
`that
`include other
`CMC comments
`is summarized in the Draft of
`Comments below. The package insert changes are incorporated by the
`Medical Reviewer and thus not
`included.
`
`Other CMC cemments.
`
`l. The
`
`approved expiry for
`
`the product
`
`is
`
`24 months
`
`and the
`
`for
`completion
`of
`a date
`include
`2. Please
`submitted in amendment dated December 4, 2002.
`
`your
`
`commitment
`
`
`
`

`

`_----_--------------------------------------------------------------------------------------------------------------
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
`
`Linda Ng
`12/13/02 12:12:56 PM
`CHEMIST
`
`PM to Convey comments to firm
`
`Chi Wan Chen
`
`12/13/02 12:21:34 PM
`CHEMIST
`
`
`
`
`
`

`

`MEMORANDUM
`
`Department of Health & Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`DATE:
`FROM:
`
`T0:
`
`May 18, 1999
`4g“
`William M. Boyd, MD
`Medical Officer, RFD-550 5mm
`
`1’
`
`Su C. Tso, PhD.
`Linda Ng, PhD.
`Asoke Muhkhetjee, PhD.
`Lori Gorski
`
`THROUGH:
`
`{5?
`Wiley Chambers, MD
`Deputy Division Director, HFD— 550
`
`SUBJECT: W , NDA 21—023 cyclosporine
`ophthalmic emulsion
`
`Impurities control in cyclosporine emulsion
`
`W were found during the stability studies of
`cyclosporine emulsion— one from the WWW
`WW” , and the other from an ‘
`emumMWW
`
`Wg
`
`In protocols 192371 002 and-003, all 877 study subjects regardless of treatment group
`received drops from batches containing M [01' at least 6 months.
`Attached are Tables 9 and 16 from the Medical Officer’ s review that list all serious
`adverse events None of these events was seen as attributable to the m
`
`Non-serious adverse events were most commonly ocular. The most commonly reported
`adverse event, burning, was seen most frequently with the 0.1% cyclosporine
`concentration (21.6%) in protocol-002 and with the 0.05% concentration in protocol-003
`(15.6%).
`
`2) WM oflot#11259
`
`

`

`
`
`Lot #1 1259 was not used in clinical studies.
`
`In a special study conducted on lot #11259 (submitted to NDA 5/ 10/99 BC), quantitation
`of the «A substance indicated that the observed levels of the I---‘ are
`approximately ”if" afler 6 months of study at 25°C/40%RH and 40°Cf20%R1-I.
`The sponsor presupposes the M is a w cased on initial
`chromatographic information.
`
`The sponsor estimates this would amount to an average 0*“ --- _Jdrop. The sponsor also
`finds the Total Daily Dose of the ---- IS less than the 0.1% of the cyclosporine
`TDD and below the Threshold for Identification of Degradation Products as outlined in
`the ICE guideline on Impurities in New Drug Products.
`
`Medical Officer‘s Conclusions:
`
`The concentration of the nun-u found in the lots used in the clinical trials for
`protocols ~002 and ~003 did not appear to cause any minor or significant adverse events
`during a six—month period.
`
`The amount of the
`
`acceptable.
`
`
`
`7
`
`'
`
`that is found in the * W method is
`
`Impurities control in cyclosporine emulsion
`
`The impurities monitored in the stability protocol for NBA 21 023 arem
`.flgmfl-B‘flzWow
`Anal-gar! purchases cyclosponnfl A from Cull-Il-
`According to
`“Hm”;wwwwrmwemm “mew-Winsi... are both process impurities and
`potential degradents.
`
`The sponsor indicates the limit of detection for cyclosporine related impurities is
`and limit quantitation is "'"‘" corresponding to ms» in the 0.05% formulation).
`
`.—
`
`Input is requested on the pharmacological activity and toxicity of these impurities.
`
`_
`W m:-
`WW w: “'5'
`..
`“Rh
`1-.
`
`._.—5~‘~w-Mmaw—=
`
`.
`'” "' “WWW
`.x
`.
`.
`- Wain-«mus
`.
`.
`_
`.
`«Hi-h):'fi'wflv”%§;,h‘\fifiw'émW‘Aumer-tfiwbww
`
`51..
`
`_-___.‘ .-;y~wm
`
`~
`
`was identified as a degradent in the original NDA m-
`_
`_
`W“
`
`for
`
`
`
`

`

`
`
`Medical Officer’s Conclusions:
`
`The W monitoredin the stability study for
`cyclosporine ophthalmic emulsion appear acceptable as w impurities and potential
`degradents. Based on their initially low concentrations and the low concentration of
`cyclosporine in the drug product, these impurities would not be expected to pose a
`toxicity problem and need not be monitored in the stability protocol.
`
`cc
`
`Orig. NDA 21-023
`HFD—SSO/Division File
`
`HFD-SBO/CChen
`
`HFD-SSO/Ng
`HFD-SSO/Boyd
`I-[FD-SSO/Chambers
`HFD-SSO/Tso
`
`1’
`
`"
`
`HFD—SSO/Mukherjee
`HFD—SSO/Gorski
`
`

`

`Table 9 - Protocol-002
`
`Serious Adverse Events Regardless of Causality: Patient Listing
`
`at
`=I.‘_nv_estiigalion"
`
`'
`
`I:
`
`
`41 A
`7 -
`
`
`0.05 A Cyclosparme Treatment Group
`mtesunaifismiaromaon
`
`2366—786
`
`667m
`
`
`
`___—
`
`
`
`2697-412
`
`50 I F I c
`
`2707-513
`
`69 I F I C
`
`
`
`megularuterinemeedmg
`dehydration —
`
`acute CVA, left sided
`
`__—
`
`2709-234
`
`0207-198
`
`52 I F I C
`
`left femoral neck fracture
`
`arypicalchestpain
`0.01 % Cyclesporine Treatment Group
`.77
`86 I F I C
`bronchitis
`
`-]_
`
`.fi-
`
`
`
`
`——-
`2366-387
`malignant tumor. right My
`Mom
`— lymphoma
`MI
`
`
`
`
`
`
`
`___m-
`2706-336
`62 I F I C
`pain in
`and 3 ' digits of feet due to
`._
`3'7
`__—
`__—m-
`2707435
`587M777
`
`
`
`
`
`
`
`_m-
`_-I_
`
`—-_
`
`
`Vehicle Treatment Group
`87mm
`
`severe 3 vessel coronal)! disease
`cardiac arrest
`
`43 I F I C
`61 IF I C
`
`'
`
`_2
`
`366-399
`2430—262
`
`
`
`
`
`
`
`
`
`2697-228
`
`
`
`84/F/C
`
`
`respiratory failure
`
`urosepsis
`stress fracture, sacrum
`
`
`
`93
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`Table 16 - Protocol-003
`
`Serious Adverse Events Regardless of Causality: Patient Listing
`
`
`
`V M _ ., Mm ‘
`.._s
`,.
`._ ..
`
`0.05 % Cyc osponne Trea ment
`roup
`low platelet count
`
`
`
`.
`
`.5
`
`_.
`
`_ s”. 292..» u 51:"
`
`26992294
`
`69 I 9 I c
`
`2696-920
`
`62 we
`
`gssmss
`cirrhosis
`
`sumo-sis
`
`
`
`
`
`
`
`
`
`
`0.1 % Cyclosporine Treatment Group
`
`—__-2-
`———-n-
`2829-222
`~
`92 I FI c
`
`
`
`Vehicle Treatment Group
`——_-E_
`
`
`
`
`
`
`lymphoma—smosbackandlumbosacmm
`
`2299-599
`
`
`24 I F I c _-E-
`-__
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`MEMORANDUM
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`PUBLIC HEALTH SERVICES
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`-
`
`l
`
`DATE:
`
`May 3, 1999
`
`FROM:
`
`TO:
`
`Su C. Tso, Ph.D.
`Chemist, HFD-830/550
`
`M
`
`Wiley Chambers, M D.
`Bill Boyd, MD
`Asoke Mukherjee, PhD
`Lori Gorski
`
`THROUGH:
`
`Linda Ng, PhD
`Chemistry team leader, HFD- 550/830
`
`#5?
`
`SUBJECT:
`
`Impurities control in cyclosporine emulsion, NDA 21—023
`
`’
`
`’
`
`‘
`
`A representative
`Cyclosporine is a cyclic polypeptide manufactured by. W“
`
`as impurities. Allergan
`certificate of analysis shows the presence of
`purchases cyclosporine (also k own as cyclosporine A) from ”mi-u...—
`has many
`NDAS with cyclosporine approved, among them are NDA WM , NDA M NDA
`W ,and NDA am-
`All of these NDAs are approximately 10% cyclosporine
`solutionsin corn oil and castor oil and others excipients. The impurities monitoredin the
`stability protocol are WWW ' with limits of ”- and
`
`““- respectively. According to W . and
`are
`both process impurities and potential degradants. The reported valuesin the stability
`program for NDA W and NDA m are
`‘*"‘
`. at 25 C up to 36 months for .r
`N ,and -wfor."'T'—‘T‘-~
`-
`
`----- .' emulsion while the
`Allergan’s 0.05% cyclosporine emulsion was an
`cyclosporine is WWW”
`In theory the cyclosporine ir W , and the stability of cyclosporine
`should parallel those of the cyclosporine m formulations. Allergan did study the
`stability of cyclosporine with respect to some of the process impurities but did not
`monitored for these """ impurities due to lacking of impurity standards and the low
`concentration of cyclosporine in the finished dosage formulation. Allergan indicated that
`the limit of detection for cyclosporine related impurities is “and limit quantitatién is
`—-—*’, which corresponds to ' («—— in the 0.05% formulation
`
`I need your input on the pharmacological activity and toxicity of these —- impurities to
`determine the need of control these impurities in the stability of the finished dosage form.
`
`

`

`____—7
`
`The structures of WWW
`M are attached for your reference. Your comments and advices are
`appreciated.
`
`CC:
`
`Orig. NDA 21-023
`HFD-SSOfDivision File
`HFD-830/CChen
`HFD—SSO/NG
`
`HFD-SSOIBoyd
`HFD-SSO/Chambcrs
`
`HFD-SSOfMuI-cherjee
`HFDD'550/Gorski
`
`Filed: C:\review]0phthalm\21023impuritiesZ
`
`

`

`J
`
`‘ Page(s) Withheld
`
`
`
`

`

`
`
`MEMORANDUM
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICES
`
`FOOD AND DRUG ADMINISTRATION
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`March 19, 1999
`
`FROM:
`
`TO:
`
`‘6;
`SL1 C. T50, Ph.D.
`Chemist, HFD-830/550 / 1
`
`Wiley Chambers, M D.
`Bill Boyd, MD
`Asoke Mukherjee, PhD
`Lori Gorski
`
`THROUGH:
`
`Linda NG, PhD.
`Chemistry team leader, HFD-550/830
`
`at
`1;
`6"ng
`
`SUBJECT:
`
`'
`
`awwumw ,NDA21—023
`
`M
`
`-m were found during the stability studies of cyclosporin
`emulsion. One from the. “W and the other from the m
`"v-¢.g-—kw-afi mrwr -
`.,._.w.3. .An- mum;.WW
`
`/.
`The M found from the W‘mWWW-“W is identified
`
`
`The max level found at product
`as . W lts level1
`release is ' safe“. and isW when stored at
`
`, and
`25C/40%RH. The applicant claims that this impurity is present in
`at the max level found, it is non toxic Please comment the toxicity of this impurity in
`the drug product. You may refer to the following CMC sections of the NDA (pre-
`submission dated 12/9/98) for your review.
`
`VOLUME