..-.un..
`
`20_._.<U_n=._.mmU
`
`186
`
`

`
`Original NDA 21_‘023
`Secuon 1
`
`jj
`
`im-—-
`T1-T1T
`I
`
`Allergan Confidential
`Cyclosporine ophthalmic emulsion
`
`. ALLERGAN
`2525 Dupont Drive, P.O. Box 19534, Irvine. Calitomia, USA 92623-9534 Telephone: (714; 246-4500 Wehsita: www.aIIergan.com
`
`1.6
`
`DEBARMENT CERTIFICATION
`
`Under the provisions of Section 306(k) of the Federal Food, Drug and Cosmetic Act,
`
`Allergan, Inc. has made a diligent effort to insure that no individual, corporation,
`
`partnership or association debarred under Section 306(a) or 306(b) of the Act, as
`
`referenced above, has provided any services in connection with this application.
`
` éM&2
`
`Peter Kresel, MS, MBA
`
`Sr. Vice President. Global Regulatory Affairs
`
`Allergan, Inc.
`
`187
`
`

`
`20_.r<O_u=.5.u_m0
`..o.-..
`
`188
`
`

`
`Allergan Confidential
`Cyclosporine ophthalmic emulsion
`
`ALLERCAN
`2525 Dupont Drive, PO. Box 19534, lrvine. California‘ USA 92623-9534 Telephone: !71-‘) 246-4500 Website: www.aIIergan.com
`
`Original ND? 21.02?
`ecuon
`
`j
`———-E
`
`iT
`t-
`
`1.7
`
`FIELD COPY CERTIFICATION
`
`Allergan, Inc. hereby certifies that the Chemistry, Manufacturing and Control section of
`
`this New Drug Application along with a copy of FDA Form 356h and the Summary
`
`section have been submitted to the FDA Dallas District Office as required by 21 CFR
`
`314.50(k)(3). We further certify that the field copy is an identical copy of the sections as
`
`they ppear in the archival and review copy of the application.
`
`Peter Kresel, MS, MBA
`
`Sr. Vice President, Global Regulatory Affairs
`
`Allergan, Inc.
`
`189
`
`

`
`r.r
`
`20_._.<O_u=._.m_m.O
`
`190
`
`

`
`Allcrgan ‘Confidential
`Cyclospormc ophthalmic emulsion
`
`Original NDA 21-023
`Section I
`
`72176
`
`Federal Register/Vol. 63, No. 251 /Thursday, December 31, 1998 /Rules and Regulations
`
`DEPARTMENT or HEALTH AND HUMAN SERVICES
`Public "°8'“' 58"/rcv
`Food and Drug Administration
`CERTIFICATION: FINANCIAL INTERESTS AND
`ARRANGEMENTS OF CLINICAL INVESTIGATORS
`TO BE COMPIJTED BYAPPUCANT
`
`Form Approved: oivle No. xxxx-xxxx
`Expiatlon om: xxrxxlxx
`
`lMth respect to all covered clinical studies (or specific clinical studies listed below (it appropriatell sub—
`mitted In support of this application, I certify to one of the statements below as appropriate. I understand
`that this certification is made in compliance with 21 CFR part 54 end that for the purposes of this
`statement, a clinical investigator includes the spouse and each dependent child of the investigator as
`defined in 21 CFR 54.2(di.
`
`Please mark the applicable chtckbax.
`
`I certify that I have not entered into any financial
`w (1) As the sponsor of the submitted studies,
`arrangement with the listed clinical investigators (enter names of clinical investigators below or
`attach list of names to this forml whereby the value of compensation to the investigator could be
`affected by the outcome of the study as defined In 21 CFR 54.2(el. I also certify that each listed
`clinical investigator required to disclose to the sponsor whether the investigator had a proprietary
`interest in this product or a significant equity in the sponsor as defined in 21 CFR 54.2(bl did not
`disclose any such interests.
`I further certify that no listed investigator was the recipient of
`significant payments of other sorts as defined in 21 CFR 54.2(f).
`List Attached
`
`D (2) As the applicant who is submitting a study or studies sponsored by a firm or party other than the
`applicant,
`I certify that based on information obtained from the sponsor or from participating
`clinical investigators, the listed clinical Investigators (attach list of names to this forml did not
`participate in any financial arrangement with the sponsor of a covered study whereby the value
`of compensation to the investigator for conducting the study could be effected by the outcome
`of the study (as defined in 21 CFR 54.2(ali; had no proprietary interest in this product or
`significant equity interest in the sponsor of the covered study (as defined in 21 CFR 5-‘&.2(b)l: and
`was not the recipient of significant payments of other sorts (as defined in 21 CFR 54.2(fll.
`
`As the applicant who is submitting a study or studies sponsored by a firm or party other than the
`applicant,
`I certify that
`I have acted with due diligence to obtain from the listed clinical
`investigators (attach list of names) or from the sponsor the information required under 54.4 and
`it was not possible to do so. The reason why this information could not be obtained is attached.
`TITLE
`
`NAME
`
`Francis R. Tunney, Jr.
`FIRM /ORGANIZATION
`
`Allergan, Inc.
`
`Acting Chief Financial Officer
`
`-
`~
`-
`-
`Paper-Ivor
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`oolloclion of’ inforrnation is esurreua to rrv-rage I hour per respom.
`including time for reviewing
`irrslmctinns, snrching existing data sources. gathering and rnainnlniru the necessity data. and
`eompletuu an reviewing Ibo oouenron of information. Sad comments regarding rim burden
`utirnncotllyviteraepectefdiiscelleuionofinfotrrationledieuddresslelhengtu:
`
`FORM FDA 3464 noise)
`
`BILLING CODE -IIGD-01~C
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`
`EF
`tnrulbrsladrausussr-ca-Nsbwuzrnliutuu
`
`191
`
`

`
`Allergan Confidential
`Cyclospozine ophthalmic emulsion
`
`Original NDA 21-023
`Section 1
`
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`
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`
`192
`
`

`
`Allcrgan Confidential
`Cyclosporine ophthalmic emulsion
`
`Original NDA 21-O23
`Section 1
`
`
`
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`
`193
`
`

`
`Allergan Confidential
`Cyclosporine ophthalmic emulsion
`
`Original NDA 21-O23
`Section 1
`
`
`
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`
`194
`
`

`
`Allergan Confidential
`Cyclosporine ophthalmic emulsion
`
`Original NDA 21-023
`Section 1
`
`72178
`
`Federal Register/Vol. 63. No. 251 /Thursday. December 31, 1998 / Rules and Regulations
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Hiblic Health Service
`Food and Drug Administration
`DISCLOSURE: FINANCIAL INTERESTS AND
`ARRANGEMENTS OF CLINICAL INVESTIGATORS
`10 BE COMPLETED BYAPPLICANT
`
`Form Approved: OMB No. XXXX-XXXX
`Expgngon 3...; xx/xx/xx
`
`The following information concerning
`
`Marvin Greenberg
`uannyzinaau-v¢a’;aw
`
`, who par-
`
`ticipated as a clinical
`
`investigator in the submitted study
`
`192371-003
`
`Na-my
`
`elliniealndy
`Cyclosporine Ophthalmic emulsion, is submitted in accordance with 21 CFR part
`54. The named individual has participated in financial arrangements or holds financial interests
`that are required to be disclosed as follows:
`
`Please mark the applicable chcckbaxex.
`
`C] any financial arrangement entered into between the sponsor of the covered study and the
`clinical investigator involved in the conduct of the covered study, whereby the value of the
`compensation to the clinical investigator for conducting the study could be influenced by
`the outcome of the study;
`
`any significant payments of other sorts made on or after February 2, 1999 from the spon-
`ear of the covered study such as a grant to fund ongoing research, compensation in the
`form of equipment, retainer for ongoing consultation. or honoraria:
`
`any proprietary interest in the product tested in the covered study held by the clinical
`investigator;
`
`[3 any significant equity interest as defined in 21 CFR 54.2lb), held by the clinical
`gator in the sponsor of the covered study.
`
`investi-
`
`Details of the individual’s disclosable financial arrangements and interests are attached, along
`with a description of steps taken to minimize the potential bias of clinical study results by any
`of the disclosed arrangements or interests.
`NAME
`
`TITLE
`
`Francis K. Tunney, Jr.
`FIRMIORGANIZATION
`
`Acting Chief Financial Officer
`
`Allergan , Inc .
`sncmrr E
`
`on:
`
`a ,3 r
`
`/
`
`Paperwork Reduction Act Statement
`Angengynnyineoridiotersponser.andspersonismtrequiledtorupollllo.:mlla:1iooofin£orrI:Iiounnles:itdisplIyxnounent!yv|li!OMB
`wrlrnlllllnbu. hifliciwmircmmmlwmhodleabnofmmrnfimiudiuudnavungcbhmmpnreqaoue. ixhdintimeforreviewing
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`
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`
`FORM FDA 3455 (10/98)
`
`an-null-an-to-—n|-v-innards mncans
`"
`
`195
`
`

`
`Allergan Confidential
`Cy closporine ophthalmic emulsion
`
`Original ND? 2t1i'02?
`BC on
`
`Financial Disclosure by Clinical Investigators (U.S.)
`
`Financial Disclosure by Clinical Investigators
`
`investigator or Subinvestigalor Name
`(Lzst. rim, Middle mm)
`
`Study Number
`
`On-Illi-II; motiitoring (Only to be done for
`invcstiguarslsubinvutigamn E-om whom
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`
`5-
`
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`
`196
`
`

`
`Allergan Confidential
`Cyclospotine ophthalmic emulsion
`
`Ofiginal NDA 21_‘023
`5600011 1
`
`72178
`
`Federal Register/Vol. 63, No. Z51/Thursday. December 31, 1998 /Rules and Regulations
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Nblic “B-lth SHNWI
`Food and Drug Administration
`DISCLOSURE: FINANCIAL INTERESTS AND
`ARRANGEMENTS OF CLINICAL INVESTIGATORS
`10 IE CDMPLHE BY APPLICANT
`
`Form Applavod: OMB No. )O00(~XXXX
`E:-plnaon om: xxnouxx
`
`The following information concerning
`
`0 - Dara Stevenson
`Nnrfcluimlin-ui'g¢ar
`
`, who par-
`
`ticipated as a clinical
`
`investigator in the submitted study
`
`192371‘002
`
`--var
`
`ea-"am-ox
`Cyclosporine °Phtha1miC emulsion , is submitted in accordance with 21 CFR part
`54. The named individual has participated in financial arrangements or holds financial interests
`that are required to be disclosed as follows:
`
`Plea: mark the applicable checkbaxcs.
`
`D any financial arrangement entered into between the sponsor of the covered study and the
`clinical investigator involved in the conduct of the covered study, whereby the value of the
`compensation to the clinical investigator for conducting the study could be influenced by
`the outcome of the study;
`
`any significant payments of other sorts made on or after February 2, 1999 from the spon-
`sor of the covered study such as a grant to fund ongoing research. compensation in the
`form of equipment. retainer for ongoing consultation, or honoraria;
`
`any proprietary interest in the product tested in the covered study held by the clinical
`investigator;
`
`H any significant equity interest as defined in 21 CFR 54.207), held by the clinical investi-
`gator in the sponsor of the covered study.
`
`Details of the individual’s disclosable financial arrangements and interests are attached, along
`with a description of steps taken to minimize the potential bias of clinical study results by any
`of the disclosed arrangements or interests.
`NAME
`
`TITLE
`
`Francis R. Tunney, Jr.
`FlRM [ORGANIZATION
`
`Allergan, Inc.
`SIGNAT H
`%C_.._- M. 7‘
`
`Acting Chief Financial Officer
`
`I’aperworItRz&txthnActSuIcnent
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`5600 Fisher: Lane, Room l4C—03
`Itockville. MD N837
`
`<-PIaseDONUI’IlEl'UINlIIisI'mII|Inmis|tflr¢s:.
`
`FORM FDA 3455 (10/98)
`
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`5’
`
`197
`
`

`
`.
`Allergan Confidennal
`Cyclosporine ophthalmic emulsion
`
`1NDA21-023
`'
`-
`Ongma
`Sectionl
`
`0 ‘
`
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`

`
`IIr..
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`
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`
`<»<mmmn_z<
`
`199
`
`

`
`Allergan Confidential
`Cyclosporine ophthalmic emulsion
`
`Original NDA 21-023
`St‘-Ctiofl 1
`
`1.9
`
`NOTES TO REVIEWER AND ERRATA
`
`‘C
`
`1.9.1
`
`NOTES TO REVIEWER
`
`Electronic Copy of the NDA
`
`Included with this paper copy of this NDA are 4 CD Rom disks which contain an electronic
`
`copy of the entire NDA. The files on the CDs were created by the CoreDossier® Publishing
`
`System (version 3.1.2), and are in Adobe Portable Document Format (.pdf). The files can be
`
`navigated by use of a large blue circular pointer on the first and last page of each electronic
`
`volume. The files can also be navigated by viewing the volview.pdf or docview.pdf files in
`
`the System Folder located on Disk 1. If more detailed information or instructions are
`
`needed, please contact Allergan at (714) 246-4391.
`
`Color Copies of Photographs
`
`Color copies of photographs within the following studies will be found immediately after the
`
`black and white version of the same page. The duplicate pages with the color photographs
`
`are not paginated.
`
`BIO—98-274
`
`BIO—98-275
`
`Topical ophthalmic evaluation of cyclosporine
`(0.05%,0.2% bid for 12 weeks) in dry eye dogs.
`Allergan, 1998.
`
`Evaluation of topical cyclosporine (0.2% bid for 12
`weeks) in dry eye dogs. Effects on lymphocytic and
`acinar epithelial cell apoptosis are evaluated. Allergan,
`1998
`
`VOL 13 p_ 342
`
`VOL 13 p_ 355
`
`Investigator Summary Report of Conjunctival Biopsy
`
`VOL 85 p_ 029
`
`200
`
`

`
`Allergan Confidential
`Cyclosporine ophthalmic emulsion
`
`1.9.2
`
`ERRATA
`
`Original NDA 21-023
`Section 1
`
`. In some places in the NDA on Index entries, certain tabs and volume cover pages, the clinical
`
`study reports are listed by the following numbers:
`
`192_3_71-O02 or 192131-002 and 192fl 1-003 or 1927_31—O03
`
`A typographical error was made in some locations; the correct project number is 1923]].
`
`Replacement Investigator
`
`During the conduct of clincal study 192371-003, Allergan was informed by Dr. Robert
`
`Laibovitz that he was unable to continue in the study. Allergan informed the Agency at that
`
`time. The study patients were transferred to Dr. Thomas Walters in Austin, Texas.
`
`Dr. Walters’ name and address information was inadvertently omitted from Section 8.2
`
`Investigators, INDs and NDAs, Table 8.2.1 List of Investigators. This information is
`
`included below. However, Dr. Walters’ Curriculum Vitae and Statement of Investigator Form
`
`1572 are included in Section 8.11.3, Clinical Study Report 192371-003, Appendix 14.3,
`
`Principal Investigator Curricula Vitae and Copies of Statement of Investigator Forms 1572.
`
`[vol. 62 p.315]
`
`Table 8.2.1
`
`Investigator List (amendment)
`
`Principal Investigator
`
`Investigator Number
`
`Study Identifier
`
`Thomas R. Walters, M.D.
`
`1634
`
`192371-003
`
`Texan Eye Care
`
`1700 South Mopac
`
`Austin, TX 78746
`
`201
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`

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`Nzo:.omm
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`202
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`

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`Allergan Confidential
`Original NDA 21-O23
`Cyclospoiine ophthalmic emulsion
`Section 2
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`0 Section 2 LABELING .
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`1
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`159
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`2.1 ANNOTATED LABELING .
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`2.2 DRAFT LABELING .
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`1
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`204
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`Original NDA 21-023
`Section 2
`
`Allergan Confidential
`Cyclosporine ophthalmic emulsion
`
`——_‘
`
`.
`
`-E: Allergan, Inc.
`
`RESTASISTM
`
`(cyclosporine ophthalmic emulsion) 0.05%
`
`Sterile, Preservative-Free
`
`DESCRIPTION
`
`RESTASISTM (cyclosporine ophthalmic emulsion) 0.05% is an immunomodulator with anti-
`
`inflammatory effects when used in patients with dry—eye disease. Cyc1osporine’s chemical name
`
`is Cyclo[[(E)—(2S,3R,4R)-3—hydroxy—4—methyl—2—(methylamino)-6-octenoyl]-L-2-aminobutyryl-
`
`N—methylglycyl-N-methyl—L—leucyl-L—valyl—N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-
`
`]eucyl—N—methyl—L—leucyl-N-methyl-L-valyl] and it has the following structure:
`
`Formula: C52H111N11O12
`
`M01. Wt;
`
`Cyclosporine is a fine white powder. RESTASISTM appears as a white opaque to slightly
`
`translucent homogeneous emulsion. It has an Osmolality of 240 to 280 mOsmol/kg and a pH of
`
`7.0-7.8.
`
`Each mL of RESTASISTM contains: Active ingredient: cyclosporine 0.05%. Inactives: carbomer
`
`1342; castor oil; glycerin; polysorbate 80; sodium hydroxide to adjust the pH; and purified
`
`W3t6I'.
`
`205
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`Allergan Confidential
`Cyclosporine ophthalmic emulsion
`
`Original NDA 21-023
`S6Ct10I1 2
`
`CLINICAL PHARMACOLOGY
`
`"O
`
`Mechanism of action:
`
`In dry—eye disease, cyclosporine emulsion acts as a potent, but selective immunomodulator, an
`
`anti-inflammatory agent, and a direct inhibitor of pathological epithelial apoptosis.
`
`Immunomodulation:
`
`Cyclosporine leaves critical functions of host immunity intact (Belin et al, 1990; Kahan, 1994;
`
`Kahan et al, 1983). Only the early stages of T-cell activation (helper T-cells) and not the
`
`lymphocytic effector stages responsible for elimination of intruder cells are suppressed (Borel et
`
`al, 1996; Kahan, 1989).
`
`Topical cyclosporine emulsion achieves its immunomodulatory activity by inhibiting the
`
`activation of NF-KB, a nuclear factor involved in the regulation of immune and pro-
`
`inflammatory cytokine response genes, such as TNF, IL-1, IL-2, and IL-8 (Meyer et al, 1997;
`
`Boss et al, 1998).
`
`Anti-inflammatory:
`
`Helper T cells identified in the tissues of the ocular surface and lacrimal glands play an
`
`important role not only in the immune response, but also in the inflammatory response through
`
`cytokine synthesis. Cyclosporine prevents the synthesis and/or secretion of several pro-
`
`inflammatory cytokines (Schliephake et al, 1997; Mitruka et al, 1998; Svecova et al, 1998; Pette
`
`et al, 1997). It is also known to upregulate secretion of anti-inflammatory cytokines (van der
`
`Pouw Kraan et al, 1996).
`
`Inhibition of pathological apoptosis:
`
`Inflammatory conditions can direct pathological apoptosis of secretory acinar epithelial cells and
`
`facilitate accumulation of lymphocytic infiltrates within the lacrimal glands and conjunctival
`
`epithelium. These events result in loss of normal glandular structure and it’s secretory function.
`
`Cyclosporine has been reported to be a direct inhibitor of pathological apoptosis of acinar
`
`epithelium cells (Scorrano et al, 1997) and has been shown to reverse pathological acinar
`
`apoptosis and lymphocyte proliferation in dry eye dogs (Gao et al, 1998).
`
`206
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`
`Allergan Confidential
`Cyclosporine ophthalmic emulsion
`
`Pharmacokinetics:
`
`Original NDA 21-023
`Section 2
`
`Blood cyclosporin A concentrations were measured using a specific high pressure liquid
`
`chromatography—mass spectrometry assay. Blood concentrations of cyclosporine A, in all the
`
`samples collected, after topical administration of RESTASISTM 0.05%, BID, in humans for up to
`
`12 months, were below the quantitation limit of 0.1 ng/ml. (study reports PK—98—109, PK—98—
`
`112). These levels are more than 6550 times lower than those measured during systemic
`
`cyclosporine treatment for non—life-threatening indications. There was no detectable drug
`
`accumulation in blood during 12 months of treatment with RESTASIS”. As a result of these
`
`findings no renal or hepatic cytotoxicity would be expected to occur following the use of
`
`RESTASISTM.
`
`Maximal concentrations obtained from rabbit and dog studies indicate that the great majority of
`
`drug contained in ocular tissues after ophthalmic administration resides in the outer layers of the
`
`eye, and that little penetrates to the interior (study reports PK—95-010, PK—96-016, PK-96-017,
`
`and PK—98—074). High concentrations and long half—lives in ocular surface tissues suggest that
`
`these tissues act as a reservoir for cyclosporine, sequestering cyclosporine and releasing it slowly
`
`over prolonged periods. Half-lives in conjunctiva, cornea and sclera after multiple ophthalmic
`
`doses to albino rabbits ranged from 32 to 52 hours (study reports PK—95—OlO & PK—98—074).
`
`Half-lives in beagle dogs after multiple ophthalmic doses were also longer than 24 hours (study
`
`reports PK—96—016 & PK—96—017).
`
`Cyclosporine is not metabolized by ocular tissues in albino rabbits.
`
`Clinical Evaluations:
`
`RESTASISTM achieved clinically and statistically significant results versus vehicle for the
`
`individual parameters corneal staining, blurred vision, categorized Schirmer with anesthesia, and
`
`reduction in artificial tear use. Improvement from baseline with RESTASISTM was seen in
`
`virtually all efficacy parameters (study reports 192371-002 & 192371-003). In addition no
`
`bacterial or fungal ocular infections were reported following administration of RESTASIS TM
`
`(study reports 192371-001, 192371-002 & 192371-003).
`
`207
`
`

`
`Allergan Confidential
`Cyclosporine ophthalmic emulsion
`
`Original NDA 21-023
`S6Cti0D 2
`
`.
`
`Results of additional tests performed in the clinical trial following 6 months of treatment
`showed that RESTASISTM reduces the inflammation, immune reactivity underlying KCS and
`improves ocular surface health and tear film in dry—eye patients with and without Sj6gren’s
`
`syndrome (tertiary reports: conjunctival biopsies, 1999; IL-6, 1999; goblet cell density, 1999).
`
`Inflammatory cytokine IL-6 levels in the conjunctival epithelium showed a statistically
`
`significant decrease from baseline (tertiary report IL-6, 1999). Conjunctival biopsies showed:
`
`the immune activation marker HLA-DR decreased 34% compared to a 160% increase with
`
`vehicle, the inflammation marker CD11a decreased 11% compared to a 104% increase with
`
`vehicle, CD3 (total T cells) and CD8 (T suppressor cells) decreased compared to an increase
`
`with vehicle, goblet cell density increased 191% compared to an increase of only 13% with
`
`vehicle (tertiary reports: conjunctival biopsies, 1999; goblet cell density, 1999).
`
`INDICATIONS AND USAGE
`
`RESTASISTM is indicated for the treatment of moderate to severe keratoconjunctivitis sicca; it
`
`restores and maintains normal tear secretion and ocular surface integrity while providing relief
`
`of symptoms associated with dry—eye (NDA Section 8.6).
`
`CONTRAINDICATIONS
`
`RESTASISTM is contraindicated in patients with active, ocular infection and in patients with
`
`previously demonstrated hypersensitivity to any of the ingredients in the formulation.
`
`WARNING
`
`RESTASISTM has not been studied in patients with a history of recurrent herpes keratitis.
`
`PRECAUTIONS
`
`Information for Patients:
`
`To avoid contamination, do not touch the tip of the via] to the eye or any other surface. Use the
`
`contents of the vial within 12 hours after opening and discard. RESTASISTM should not be
`
`administered while wearing contact lenses. Patients should be advised not to discontinue
`
`therapy prematurely. Also refer to attached patient information.
`
`208
`
`

`
`Allergan Confidential
`Cyclosporine ophthalmic emulsion
`
`Original NDA 21-023
`56611011 2
`
`.
`
`Drug Interactions:
`
`There is little information regarding the interaction of ophthalmic drugs co-administered with
`
`topical ophthalmic cyclosporine. Systemic exposure of cyclosporin A from RESTASISTM is
`
`minimal. Therefore, no interaction of topically applied RESTASISTM with systemic drugs is
`
`expected to occur.
`
`Carcinogenesis, Mutagenesis, and Impairment of Fertility:
`
`Systemic carcinogenicity studies were carried out in male and female mice and rats. In the 78-
`
`week oral (diet) mouse study, at doses of 1, 4, and 16 mg/kg/day, evidence of a statistically
`
`significant trend was found for lymphocytic lymphomas in females, and the incidence of
`
`hepatocellular carcinomas in mid-dose males significantly exceeded the control value.
`
`In the 24-month oral (diet) rat study, conducted at 0.5, 2, and 8 mg/kg/day, pancreatic islet cell
`
`adenomas significantly exceeded the control rate in the low dose level. The hepatocellular
`
`carcinomas and pancreatic islet cell adenomas were not dose related (PDR NEORAL®, 1998).
`
`The low doses in mice and rats are approximately 1000 and 500 times greater, respectively, than
`
`the daily human dose of one drop (35 uL) of RESTASISTM BID into each eye (0.001 mg/kg),
`
`assuming that the entire dose is absorbed.
`
`Cyclosporine has not been found mutagenic/genotoxic in the Ames Test, the V79-HGPRT Test,
`
`the micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese
`
`hamster bone—marrow, the mouse dominant lethal assay, and the DNA—repair test in sperm from
`
`treated mice. A recent study analyzing sister chromatid exchange (SCE) induction by
`
`Cyclosporine using human lymphocytes in vitro gave indication of a positive effect (i.e.,
`
`induction of SCE), at high concentrations in this system (PDR NEORALQ, 1998).
`
`No impairment in fertility was demonstrated in studies in male and female rats (PDR
`
`NEORAL®, 1998).
`
`209
`
`

`
`Allergan Confidential
`Cyclosporine ophthalmic emulsion
`
`Pregnancy:
`
`.
`
`Pregnancy Category: B
`
`Original NDA 21-O23
`Section 2
`
`Teratogenic effects: Cyclosporine was found to be non—teratogenic in appropriate test systems.
`
`Rats at up to 17 mg/kg/day and rabbits at up to 30 mg/kg/day, dosed with cyclosporine oral
`
`solution, USP proved to be without any embryolethal or teratogenic effects (Sandoz NDA 50-
`
`573 and 50-574).
`
`These doses in rats and rabbits are approximately 17,000 and 30,000 times greater, respectively,
`
`than the daily human dose of one drop (35 ul) RESTASISTM BID into each eye (0.001 mg/kg),
`
`assuming that the entire dose is absorbed.
`
`Non-Teratogenic effects: Adverse effects were seen in reproduction studies in rats only at dose
`
`levels toxic to dams. At toxic doses (rats at 30 mg/kg/day and rabbits at 100 mg/kg/day),
`
`cyclosporine oral solution, USP, was embryo— and fetotoxic as indicated by increased pre— and
`
`postnatal mortality and reduced fetal weight together with related skeletal retardations (Sandoz
`
`NDA 50-573 and 50-574). These doses are 30,000 times and 100,000 times greater, respectively
`
`than the daily human dose of one-drop (35 ul) of RESTASISTM BID into each eye (0.001
`
`mg/kg), assuming that the entire dose is absorbed.
`
`There are no adequate and well-controlled studies of RESTASISTM in pregnant women.
`
`RESTASISTM should be administered to a pregnant woman only if clearly needed.
`
`Nursing Mothers:
`
`Cyclosporine is known to be excreted in human milk following systemic administration but
`
`excretion in human milk after topical treatment has not been investigated. Although blood
`
`concentrations are undetectable after topical administration of RESTASISTM, caution should be
`
`exercised when RESTASISTM is administered to a nursing woman.
`
`Pediatric Use:
`
`The safety and efficacy of RESTASISTM have not been established in pediatric patients.
`
`210
`
`

`
`Allergan Confidential
`Cyclosporine ophthalmic emulsion
`
`Geriatric Use:
`
`Original NDA 21-023
`3605011 2
`
`.
`
`No overall difference in safety or effectiveness have been observed between elderly and younger
`
`patients.
`
`ADVERSE REACTIONS
`
`The most common adverse event following the use of RESTASISTM was ocular burning (16%).
`
`Other events reported in 1% to 3% of patients (in order of decreasing incidence) included ocular
`
`stinging/irritation, discharge, foreign body sensation, pruritus, conjunctiva] hyperemia,
`
`photophobia, visual disturbance (blurred Vision), headache, eyelid edema, and eye pain (NDA
`
`Section 8.7).
`
`DOSAGE AND ADMINISTRATION
`
`The recommended dosage is one drop of RESTASISTM instilled twice a day in each eye
`
`approximately 12 hours apart. RESTASISTM can be used concomitantly with artificial tears.
`
`Invert the unit dose via] a few times to obtain a uniform, white, opaque emulsion before using.
`
`RESTASISTM was investigated for up to 12 months during clinical trials for moderate to severe
`
`keratoconjunctivitis sicca.
`
`HOW SUPPLIED
`
`RESTASISTM (cyclosporine ophthalmic emulsion) 0.05% is available as a sterile preservative-
`
`free emulsion supplied in vials as follows:
`
`RESTASISTM 32 Vials 0.4 mL each—NDC XXXX—XXXX—XX
`
`Store RESTASISTM at 25° C (77° F); excursions permitted to 15°—30° C (59°—86° F). Do not
`
`freeze.
`
`Rx Only
`
`EALLERCAN
`
`©1999 Allergan, Inc.
`
`Irvine, CA 92612, U.S.A.
`
`211
`
`

`
`Allergan Confidential
`Cyclosporinc ophthalmic emulsion
`
`Original NDA 21-023
`Section 2
`
`.
`
`PATIENT INFORMATION
`Pharmacist: Please cut or tear at dotted line and provide this patient package insert to
`your customer.
`
`RESTASISTM (cyclosporine ophthalmic emulsion) 0.05%
`
`Sterile, Preservative-Free
`
`Please read this leaflet carefully before you start to use your medicine. If you have any
`
`questions, or are not sure about anything, ask your doctor or pharmacist.
`
`Introduction
`
`You are one of millions of people who have a condition called “dry eye.” The medical term for
`
`this is keratoconjunctivitis sicca, or KCS. Your doctor has prescribed RESTASISTM because it
`
`has been proven to be an effective way to treat the combination of uncomfortable symptoms and
`
`underlying inflammation, which characterize dry eye disease.
`
`The following information will answer many of the questions you may have about your
`
`condition or your medicine. It is important that you understand dry eye and the treatment your
`
`doctor has prescribed.
`
`What are tears?
`
`There are two kinds of tears: those produced naturally to lubricate and nourish your eyes, and
`
`those produced in response to irritation or emotions. Both are necessary for your eyes to
`
`function properly.
`
`Natural tears form a film over your eyes to protect them from irritation and keep them
`
`moisturized and lubricated. This tear film also contains nutrients that help keep your eyes
`
`healthy. Blinking helps spread the tear film over the entire surface of your eyes. Insufficient
`
`tear production can lead to redness, pain, and even scanin g of the cornea (the transparent part of
`
`the eye that covers the pupil and iris.)
`
`212
`
`

`
`Allergan Confidential
`Cyclosporine ophthalmic emulsion
`
`What is dry eye?
`
`Original NDA 21-023
`Section 2
`
`.
`
`Dry eye is a reduction in your eyes’ ability to produce sufficient natural tears. It results from a
`
`chronic underlying inflammatory