`
`Trade Name:
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
`50790Orig1s25
`
`
` RESTASIS MULTIDOSE
`
`cyclosporine
`
`Allergan Inc.
`
`October 27, 2016
`
`RESTASIS MULTIDOSE is a calcineurin inhibitor
`immunosuppressant indicated to increase tear production
`in patients whose tear production is presumed to be
`suppressed due to ocular inflammation associated with
`keratoconjunctivitis sicca.
`
`
`
`Generic or Proper
`Name:
`
`Sponsor:
`
`
`Approval Date:
`
`
`Indication:
`
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`50790Orig1s25
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology / Virology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`X
`X
`
`
`
`
`
`X
`
`
`X
`
`
`
`X
`
`X
`X
`
`

`

`
`
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`50790Orig1s25
`
`
`APPROVAL LETTER
`
`

`

`O
`
`i _/CDEPARTMENTOFHEALTHANDHUMANSERVICES
`
`NDA 50790/S-024
`
`NDA 50790/S-025
`
`Allergan, Inc.
`Attention: Linda McCauley, PhD
`Manager, Global Regulatory Affairs
`2525 Dupont Drive
`PO Box 19534
`
`Irvine, CA 92623-9534
`
`Dear Dr. McCauley:
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`SUPPLENIENT APPROVAL
`
`Please refer to your Supplemental New Drug Applications (sNDA) dated November 3, 2015, received
`November 3, 2015, and your amendments, submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act (FDCA) for RESTASIS MULTIDOSETM (cyclosporine ophthalmic emulsion) 0.05%.
`
`
`Supplement 024 proposes adding a Multi—Dose
`Container Closure System.
`
`Supplement 025 proposes adding labeling for the Multi-Dose
`Container Closure
`System. It also provides for conversion of Section 8 to Pregnancy and Lactation Labeling (PLLR) format and
`proposes changes to Section 13.
`
`APPROVAL & LABELING
`
`We have completed our review of these two supplemental applications, as amended. They are both approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling text.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of labeling
`[21 CFR 3 1450(1)] in structured product labeling (SPL) format using the FDA automated drug registration and
`listing system (eLIST), as described at
`hflpJ/wwwfda.gov/ForIndustiy/DataStandards/StmcturedProductLabelingzdefaulthtm. Content of labeling
`must be identical to the enclosed labeling (text for the package insert) with the addition of any labeling changes
`in pending “Changes Being Effected” (CBE) supplements, as well as annual reportable changes not included in
`the enclosed labeling.
`
`Information on submitting SPL files using eList may be found in the guidance for industry titled “SPL Standard
`for Content of Labeling Technical Qs and As at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM072392.pdf
`
`Reference ID: 4004790
`
`

`

`NDA 50-790/S-024/S-025
`
`2
`
`The SPL will be accessible from publicly available labeling repositories.
`
`Also within 14 days, amend all pending supplemental applications that include labeling changes for this NDA,
`including CBE supplements for which FDA has not yet issued an action letter, with the content of labeling
`[21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the changes approved in this supplemental
`application, as well as annual reportable changes and annotate each change. To facilitate review of your
`submission, provide a highlighted or marked-up copy that shows all changes, as well as a clean Microsoft Word
`version. The marked-up copy should provide appropriate annotations, including supplement number(s) and
`annual report date(s).
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR 314.80 and
`314.81).
`
`If you have any questions, call Jacquelyn Smith, MA, Senior Regulatory Project Manager, at (301) 796-1600.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Wiley A. Chambers, MD
`Deputy Director
`Division of Transplant and Ophthalmology Products
`Office of Antimicrobial Products
`Center for Drug Evaluation and Research
`
`ENCLOSURE(S):
`Content of Labeling
`Carton and Container Labeling
`
`Reference ID: 4004790
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`50790Orig1s25
`
`OTHER ACTION LETTERS
`
`
`
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`NDA 50790/S-025
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`COMPLETE RESPONSE
`
`Allergan, Inc.
`Attention: Kathrin Schalper, PhD, RAC, PMP
`Senior Manager, Global Regulatory Affairs
`2525 Dupont Drive
`Irvine, CA 92612
`
`Dear Dr. Schalper:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated November 3, 2015,
`received November 3, 2015, submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act (FDCA) for RESTASIS® (cyclosporine ophthalmic emulsion) 0.05%.
`
`This supplemental new drug application proposes to add labeling for a Multi-Dose
` Container Closure System. It also provides for conversion of Section 8 to
`Pregnancy and Lactation Labeling (PLLR) format and proposes changes to Section 13. We have
`completed the review of your package insert, as amended, and have determined that we cannot
`approve your labeling in its present form. We are providing our proposed revisions in the
`attached labeling.
`
`Specifically, we have removed all references to the Multi-Dose
`Container Closure System because this system is unapproved.
`
`
`
`Section 8 USE IN SPECIFIC POPULATIONS and Section 13 NONCLINICAL TOXICOLOGY
`have been revised as indicated in the attached labeling.
`
`Editorial revisions have also been made in Section 2 DOSAGE AND ADMINSTRATION and
`Section 6 ADVERSE REACTIONS.
`
`PRESCRIBING INFORMATION
`
`Your proposed prescribing information (PI) must conform to the content and format regulations
`found at 21 CFR 201.56(a) and (d) and 201.57. As you develop your proposed PI, we encourage
`you to review the labeling review resources on the PLR Requirements for Prescribing
`Information and Pregnancy and Lactation Labeling Final Rule websites, which include:
`
`• The Final Rule (Physician Labeling Rule) on the content and format of the PI for human
`drug and biological products
`
`Reference ID: 3923331
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 50790/S-025
`Page 2
`
`• The Final Rule (Pregnancy and Lactation Labeling Rule) on the content and format of
`information in the PI on pregnancy, lactation, and females and males of reproductive
`potential
`• Regulations and related guidance documents
`• A sample tool illustrating the format for Highlights and Contents, and
`• The Selected Requirements for Prescribing Information (SRPI) − a checklist of important
`format items from labeling regulations and guidances.
`• FDA’s established pharmacologic class (EPC) text phrases for inclusion in the Highlights
`Indications and Usage heading.
`
`Submit draft labeling that addresses our proposed revisions in the attached labeling.
`
`Prior to resubmitting the labeling, use the SRPI checklist to correct any formatting errors to
`ensure conformance with the format items in regulations and guidances. In addition, submit
`updated content of labeling [21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL) format
`as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.
`
`To facilitate review of your submission, provide a highlighted or marked-up copy that shows all
`changes, as well as a clean Word version. The marked-up copy should include annotations that
`support any proposed changes.
`
`OTHER
`
`Within one year after the date of this letter, you are required to resubmit or take other actions
`available under 21 CFR 314.110. If you do not take one of these actions, we may consider your
`lack of response a request to withdraw the application under 21 CFR 314.65. You may also
`request an extension of time in which to resubmit the application. A resubmission must fully
`address all the deficiencies listed. A partial response to this letter will not be processed as a
`resubmission and will not start a new review cycle.
`
`You may request a meeting or teleconference with us to discuss what steps you need to take
`before the application may be approved. If you wish to have such a meeting, submit your
`meeting request as described in the FDA Guidance for Industry, “Formal Meetings Between
`FDA and Sponsors or Applicants,” May 2009 at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM153222.pdf.
`
`Reference ID: 3923331
`
`6 Page(s) of Draft Labeling has been Withheld in Full as b4 (CCI/
`TS) immediately following this page
`
`

`

`NDA 50790/S-025
`Page 3
`
`If you have any questions, call Jacquelyn Smith, MA, Senior Regulatory Project Manager, at
`(301) 796-1600.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Wiley A. Chambers, MD
`Deputy Director
`Division of Transplant and Ophthalmology Products
`Office of Antimicrobial Products
`Center for Drug Evaluation and Research
`
`ENCLOSURE(S):
`Labeling
`
`Reference ID: 3923331
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`WILEY A CHAMBERS
`05/02/2016
`
`Reference ID: 3923331
`
`

`

`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`50790Orig1s25
`
`
`LABELING
`
`

`

`NDA 50-790/S-024/S-025
`
`3
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`RESTASIS MULTIDOSETM safely and effectively. See full prescribing
`information for RESTASIS MULTIDOSETM.
`
`RESTASIS MULTIDOSETM (cyclosporine ophthalmic emulsion) 0.05%
`For topical ophthalmic use
`Initial U.S. Approval: 1983
`
`____________________________INDICATIONS AND USAGE_______________________________
`RESTASIS MULTIDOSETM is a calcineurin inhibitor immunosuppressant
`indicated to increase tear production in patients whose tear production is
`presumed to be suppressed due to ocular inflammation associated with
`keratoconjunctivitis sicca. Increased tear production was not seen in patients
`currently taking topical anti-inflammatory drugs or using punctal plugs. (1)
`
`________________________DOSAGE AND ADMINISTRATION_________________________
`Prime by squeezing two drops onto a tissue before initial use. (2.1)
`•
`Instill one drop of RESTASIS MULTIDOSETM ophthalmic emulsion
`•
`twice a day in each eye approximately 12 hours apart. (2.2)
`
`_______________________DOSAGE FORMS AND STRENGTHS_______________________
`Cyclosporine ophthalmic emulsion 0.5 mg/mL (3)
`
`_________________________________CONTRAINDICATIONS________________________________
`Hypersensitivity (4)
`•
`
`_________________________WARNINGS AND PRECAUTIONS__________________________
`To avoid the potential for eye injury and contamination, be careful not to
`•
`touch the bottle tip to your eye or other surfaces. (5.1)
`
`______________________________ADVERSE REACTIONS___________________________________
`The most common adverse reaction following the use of cyclosporine
`ophthalmic emulsion 0.05% was ocular burning (17%). (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Allergan, Inc.
`at 1-800-433-8871 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`Revised: 10/2016
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Preparation for First-Time Use
`2.2 Preparation for Use
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Potential for Eye Injury and Contamination
`5.2 Use with Contact Lenses
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Post-marketing Experience
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.4 Pediatric Use
`8.5 Geriatric Use
`
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`* Sections or subsections omitted from the full prescribing information
`are not listed.
`
`Reference ID: 4004790
`
`

`

`NDA 50-790/S-024/S-025
`
`FULL PRESCRIBING INFORMATION
`
`4
`
`INDICATIONS AND USAGE
`1
`RESTASIS MULTIDOSETM ophthalmic emulsion is indicated to increase tear production in
`patients whose tear production is presumed to be suppressed due to ocular inflammation
`associated with keratoconjunctivitis sicca. Increased tear production was not seen in patients
`currently taking topical anti-inflammatory drugs or using punctal plugs.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`Instill one drop of RESTASIS MULTIDOSETM ophthalmic emulsion twice a day in each eye
`approximately 12 hours apart. RESTASIS MULTIDOSETM can be used concomitantly with
`lubricant eye drops, allowing a 15-minute interval between products.
`
`2.1
`
`Preparation for First-Time Use
`
`Step 1: Pull off the clear shipping cover by pulling straight up. Throw the shipping cover away.
`
`Do not use RESTASIS MULTIDOSETM if shipping cover or pull tab are damaged or missing.
`
`Step 2: Remove the pull tab on the olive green colored protective cap by pulling the end of the
`pull tab away from the bottle then winding it counterclockwise. Throw away the pull tab.
`
`Step 3: Remove the olive green colored protective cap by pulling it straight up. Keep the colored
`protective cap.
`
`Reference ID: 4004790
`
`

`

`NDA 50-790/S-024/S-025
`
`5
`
`Step 4: Prime the bottle for first-time use by squeezing two drops onto a tissue. Do not let the
`bottle tip touch the tissue.
`
`Step 5: The bottle is now ready for use. After use, recap the bottle with the olive green colored
`protective cap by pushing it straight down onto the bottle.
`
`2.2
`
`Preparation for Use
`
`Step 6: Turn the bottle upside down a few times before giving your dose to make sure the
`medicine is mixed well.
`
`Step 7: Instill one drop in the affected eye. Replace the olive green colored protective cap.
`
`DOSAGE FORMS AND STRENGTHS
`3
`Ophthalmic emulsion containing cyclosporine 0.5 mg/mL
`
`CONTRAINDICATIONS
`4
`RESTASIS MULTIDOSETM is contraindicated in patients with known or suspected
`hypersensitivity to any of the ingredients in the formulation [see Adverse Reactions (6.2)].
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`Potential for Eye Injury and Contamination
`5.1
`Be careful not to touch the bottle tip to your eye or other surfaces to avoid potential for eye
`injury and contamination.
`
`Uses with Contact Lenses
`5.2
`RESTASIS MULTIDOSETM should not be administered while wearing contact lenses. Patients
`with decreased tear production typically should not wear contact lenses. If contact lenses are
`worn, they should be removed prior to the administration of the emulsion. Lenses may be
`
`Reference ID: 4004790
`
`

`

`NDA 50-790/S-024/S-025
`
`6
`
`reinserted 15 minutes following administration of RESTASIS MULTIDOSETM ophthalmic
`emulsion.
`
`6
`
`ADVERSE REACTIONS
`
`The following serious adverse reactions are described elsewhere in the labeling:
`• Potential for Eye Injury and Contamination [see Warnings and Precautions (5.1)]
`
`Clinical Trials Experience
`6.1
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
`of another drug and may not reflect the rates observed in practice.
`
`In clinical trials, the most common adverse reaction following the use of cyclosporine
`ophthalmic emulsion, 0.05% was ocular burning (17%).
`
`Other reactions reported in 1% to 5% of patients included conjunctival hyperemia, discharge,
`epiphora, eye pain, foreign body sensation, pruritus, stinging, and visual disturbance (most often
`blurring).
`
`Post-marketing Experience
`6.2
`The following adverse reactions have been identified during post approval use of cyclosporine
`ophthalmic emulsion, 0.05%. Because these reactions are reported voluntarily from a population
`of uncertain size, it is not always possible to reliably estimate their frequency or establish a
`causal relationship to drug exposure.
`
`Reported reactions have included: hypersensitivity (including eye swelling, urticaria, rare cases
`of severe angioedema, face swelling, tongue swelling, pharyngeal edema, and dyspnea); and
`superficial injury of the eye (from the bottle tip touching the eye during administration).
`
`8
`
`8.1
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`
`Risk Summary
`Clinical administration of cyclosporine ophthalmic emulsion 0.05% is not detected systemically
`following topical ocular administration [see Clinical Pharmacology (12.3)], and maternal use is
`not expected to result in fetal exposure to the drug. Oral administration of cyclosporine to
`pregnant rats or rabbits did not produce teratogenicity at clinically relevant doses [see Data].
`
`Data
`Animal Data
`At maternally toxic doses (30 mg/kg/day in rats and 100 mg/kg/day in rabbits), cyclosporine oral
`solution (USP) was teratogenic as indicated by increased pre- and postnatal mortality, reduced
`fetal weight and skeletal retardations. These doses (normalized to body surface area) are 5,000
`and 32,000 times greater, respectively, than the daily recommended human dose of one drop
`(approximately 28 mcL) of cyclosporine ophthalmic emulsion 0.05% twice daily into each eye
`of a 60 kg person (0.001 mg/kg/day), assuming that the entire dose is absorbed. No evidence of
`embryofetal toxicity was observed in rats or rabbits receiving cyclosporine during organogenesis
`
`Reference ID: 4004790
`
`

`

`NDA 50-790/S-024/S-025
`
`7
`
`at oral doses up to 17 mg/kg/day or 30 mg/kg/day, respectively. These doses in rats and rabbits
`are approximately 3,000 and 10,000 times greater, respectively, than the daily recommended
`human dose.
`
`An oral dose of 45 mg/kg/day cyclosporine administered to rats from Day 15 of pregnancy until
`Day 21 postpartum produced maternal toxicity and an increase in postnatal mortality in
`offspring. This dose is 7,000 times greater than the daily recommended human dose. No adverse
`effects in dams or offspring were observed at oral doses up to 15 mg/kg/day (2,000 times greater
`than the daily recommended human dose).
`
`8.2
`
`Lactation
`
`Risk Summary
`Cyclosporine is known to appear in human milk following systemic administration, but its
`presence in human milk following topical treatment has not been investigated. Although blood
`concentrations are undetectable following topical administration of cyclosporine ophthalmic
`emulsion 0.05% [see Clinical Pharmacology (12.3)], caution should be exercised when
`RESTASIS MULTIDOSETM is administered to a nursing woman. The developmental and health
`benefits of breastfeeding should be considered along with the mother’s clinical need for
`RESTASIS MULTIDOSETM and any potential adverse effects on the breast-fed child from
`cyclosporine.
`
`Pediatric Use
`8.4
`Safety and efficacy have not been established in pediatric patients below the age of 16.
`
`Geriatric Use
`8.5
`No overall difference in safety or effectiveness has been observed between elderly and younger
`patients.
`
`11 DESCRIPTION
`RESTASIS MULTIDOSETM (cyclosporine ophthalmic emulsion) 0.05% contains a calcineurin
`inhibitor immunosuppressant with anti-inflammatory effects. Cyclosporine’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-
`leucyl-N-methyl-L-leucyl-N-methyl-L-valyl] and it has the following structure:
`
`Structural Formula
`
`Formula: C62H111N11O12 Mol. Wt.: 1202.6
`
`Reference ID: 4004790
`
`

`

`NDA 50-790/S-024/S-025
`
`8
`
`Cyclosporine is a fine white powder. RESTASIS MULTIDOSETM appears as a white opaque to
`slightly translucent homogeneous emulsion. It has an osmolality of 230 to 320 mOsmol/kg and a
`pH of 6.5-8.0. Each mL of RESTASIS MULTIDOSETM ophthalmic emulsion contains: Active:
`cyclosporine 0.05%. Inactives: glycerin; castor oil; polysorbate 80; carbomer copolymer type A;
`purified water; and sodium hydroxide to adjust pH.
`
`12
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action
`12.1
`Cyclosporine is an immunosuppressive agent when administered systemically.
`
`In patients whose tear production is presumed to be suppressed due to ocular inflammation
`associated with keratoconjunctivitis sicca, cyclosporine emulsion is thought to act as a partial
`immunomodulator. The exact mechanism of action is not known.
`
`Pharmacokinetics
`12.3
`Blood cyclosporine A concentrations were measured using a specific high pressure liquid
`chromatography-mass spectrometry assay. Blood concentrations of cyclosporine, in all the
`samples collected, after topical administration of cyclosporine ophthalmic emulsion, 0.05%,
`twice daily, in humans for up to 12 months, were below the quantitation limit of 0.1 ng/mL.
`There was no detectable drug accumulation in blood during 12 months of treatment with
`cyclosporine ophthalmic emulsion, 0.05%.
`
`13
`
`NONCLINICAL TOXICOLOGY
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1
`Carcinogenesis
`Systemic carcinogenicity studies were conducted 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. The low doses in mice and
`rats are approximately 80 times greater (normalized to body surface area) than the daily
`recommended human dose of one drop (approximately 28 mcL) of cyclosporine ophthalmic
`emulsion, 0.05% twice daily into each eye of a 60 kg person (0.001 mg/kg/day), assuming that
`the entire dose is absorbed.
`
`Mutagenesis
`Cyclosporine has not been found to be 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 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).
`
`Impairment of Fertility
`
`Reference ID: 4004790
`
`

`

`NDA 50-790/S-024/S-025
`
`9
`
`No impairment in fertility was demonstrated in studies in male and female rats receiving oral
`doses of cyclosporine up to 15 mg/kg/day (approximately 2,000 times the human daily dose of
`0.001 mg/kg/day normalized to body surface area) for 9 weeks (male) and 2 weeks (female) prior
`to mating.
`
`14
`
`CLINICAL STUDIES
`
`Four multicenter, randomized, adequate and well-controlled clinical studies were performed in
`approximately 1,200 patients with moderate to severe keratoconjunctivitis sicca. Cyclosporine
`ophthalmic emulsion, 0.05% demonstrated statistically significant increases in Schirmer wetting
`of 10 mm versus vehicle at six months in patients whose tear production was presumed to be
`suppressed due to ocular inflammation. This effect was seen in approximately 15% of
`cyclosporine ophthalmic emulsion, 0.05%-treated patients versus approximately 5% of vehicle-
`treated patients. Increased tear production was not seen in patients currently taking topical anti-
`inflammatory drugs or using punctal plugs.
`
`No increase in bacterial or fungal ocular infections was reported following administration of
`cyclosporine ophthalmic emulsion, 0.05%.
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`RESTASIS MULTIDOSETM ophthalmic emulsion is packaged in a sterile, multi-dose
`preservative-free bottle. Each bottle consists of a white opaque LDPE bottle, a white opaque
`polypropylene top with unidirectional valve and air filter, a protective olive green polypropylene
`cap, and a clear disposable shipping cover over the colored cap.
`
`5.5 mL in 10-mL bottle - NDC 0023-9163-05
`
`Storage: Store at 15-25 °C (59-77 °F).
`
`PATIENT COUNSELING INFORMATION
`17
`Handling the Container
`Advise patients to not allow the tip of the bottle to touch the eye or any surface, as this may
`contaminate the emulsion. Advise patients to not touch the bottle tip to their eye to avoid the
`potential for injury to the eye [see Warnings and Precautions (5.1)].
`
`Use with Contact Lenses
`RESTASIS MULTIDOSETM should not be administered while wearing contact lenses. Patients
`with decreased tear production typically should not wear contact lenses. Advise patients that if
`contact lenses are worn, they should be removed prior to the administration of the emulsion.
`Lenses may be reinserted 15 minutes following administration of RESTASIS MULTIDOSETM
`ophthalmic emulsion [see Warnings and Precautions (5.2)].
`
`Administration
`Advise patients to read the “Instructions for Use” for detailed first-time use instructions.
`
`© 2016 Allergan. All rights reserved.
`Irvine, CA 92612, U.S.A.
`All trademarks are the property of their respective owners.
`Patented: See: www.allergan.com/products/patents
`
`Reference ID: 4004790
`
`

`

`NDA 50-790/S-024/S-025
`
`Made in Ireland.
`
`10
`
`Reference ID: 4004790
`
`

`

`NDA 50-790/S-024/S-025
`
`11
`
`INSTRUCTIONS FOR USE
`
`RESTASIS MULTIDOSET" (Re stay’ sis Mul tee dos)
`(cyclosporine ophthalmic emulsion) 0.05%
`
`Read this Instructions for Use before you start using RESTASIS MULTIDOSET" and each time you get a
`refill. There may be new information. This leaflet does not take the place of talking to your healthcare
`provider about your medical condition or treatment.
`
`Important:
`
`- RESTASIS MULTIDOSE“I is for use in the eye
`Wash your hands before using RESTASIS MULTIDOSE‘".
`Do not let the bottle tip touch the eye or any other surfaces to avoid contamination or injury to your
`eye.
`
`. Use 1 drop of RESTASIS MULTIDOSET"I in each eye, 2 times each day, about 12 hours apart.
`0
`If you wear contact lenses, remove them before using RESTASIS MULTIDOSET". Wait for at least
`15 minutes before placing them back in your eyes.
`0 RESTASIS MULTIDOSE“I can be used with lubricant eye drops, but you should wait at least 15
`minutes between using each product.
`
`
`Parts of your RESTASIS MULTIDOSEm bottle
`Shlmng amr
`Cohen 9101th up
`Punish Bane no
`
`03);? it )1
`
`PREPARING THE BOTTLE FOR FIRST-TIME USE:
`
`Step 1: Pull off shipping cover by pulling straight up. Throw
`
`the shipping cover away. Do not use RESTASIS
`MULTIDOSET" if shipping cover or pull tab are damaged or
`missing.
`
`Step 2: Remove the pull tab on the olive green colored
`protective cap by pulling the end of the pull tab away from the
`
`bottle then winding it counterclockwise. Throw away the pull
`tab.
`
`Step 3: Remove the olive green colored protective cap by
`pulling it straight up. Keep the colored protective cap.
`
`straight down onto the bottle.
`
`Step 4: Prime the bottle for first time use by squeezing 2
`drops onto a tissue. Do not let the bottle tip touch the tissue.
`
`Step 5: The bottle is now ready for use. After use, recap the
`bottle with the olive green colored protective cap by pushing
`
`Reference ID: 4004790
`
`

`

`NDA 50-790/S-024/S-025
`
`12
`
`GIVING YOUR DOSE:
`
`Step 6: Turn the bottle upside down a few times before giving
`your dose to make sure the medicine is mixed well.
`
`Step 7: Instill one drop in the affected eye. Replace the olive
`green colored protective cap.
`
`How do I store RESTASIS MULTIDOSETM?
`
`•
`
`Store RESTASIS MULTIDOSETM between 15-25 °C (59-77 °F).
`
`Keep RESTASIS MULTIDOSETM and all medicines out of the reach of children.
`
`This Instructions for Use has been approved by the Food and Drug Administration.
`
`© 2016 Allergan. All rights reserved. Irvine, CA 92612, U.S.A.
`All trademarks are the property of their respective owners.Patented: See: www allergan com/products/patents Made in Ireland.
`
`Approved: 10/2016
`
`Reference ID: 4004790
`
`

`

`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`50790Orig1s25
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`

`

`Medical Officer’s Review of NDA 50-790
`Prior Approval Supplements
`
`Submission Date:
`September 7, 2016
`Receipt Date:
`September 7, 2016
`Submission Date: October 27, 2016
`Receipt Date:
`October 27, 2016
`Review Date:
`October 27, 2016
`
`Allergan, Inc.
`2525 Dupont Drive
`Irvine, CA 92612
`
`Linda McCauley, Ph.D
`Manager, Global Regulatory Affairs
`714-246-6217
`
`RESTASIS (cyclosporine ophthalmic emulsion) 0.05%
`
`calcineurin inhibitor immunosuppressant
`
`NDA 50-790/S-024/S-025
`SDN-1036
`
`SDN-1062
`
`Applicant:
`
`Applicant’s
`Representative:
`
`Drug:
`
`Pharmacologic
`Category:
`
`Submitted:
`
`Reference is made to the CMC Prior Approval Supplement (PAS) submitted for NDA 50-790 /
`S-024 on November 3, 2015. The CMC Supplement provided for a new multi-dose, preservative free
`presentation of RESTASIS and included labeling specific to the new container closure system. Additional
`reference is made to the Acknowledgement — Prior Approval Supplement from the Agency dated 29
`February 2016 notifying Allergan that the above referenced supplement was split into a CMC S-024 and a
`Labeling S-025 for administrative reasons. Allergan received Complete Response letters for both
`Supplements.
`
`Reference is also made to the June 27, 2016, Resubmission of Prior approval CMC Supplement for the new
`multi-dose, preservative-free presentation of RESTASIS which addresses all of the CMC and Labeling
`deficiencies in the Complete Response Letter from CMC dated March 2, 2016, and the Complete Response
`Letter for Labeling dated May 2, 2016.
`
`Reference is also made to the teleconference on August 31, 2016, at which the Division expressed concerns
`about RESTASIS®
`, the proprietary name under review at the time, and proposed RESTASIS
`MultiDose. The applicant has now submitted an Amendment to the Prior Approval CMC Supplement with
`revised labeling reflecting the new proposed proprietary name, RESTASIS MultiDoseTM.
`
`Chemistry Manufacturing Review #2 of S-024 (dated 10/14/16)
`
`See CMC review #1 in DARRTS dated 2/29/16 for additional background. All the CMC aspects of this
`supplemental application (S-024) were found acceptable in review #1. However, the microbiology review
`raised deficiencies that needed to be resolved prior to approval of this supplement. A Complete Response
`Letter (CR) dated March 2, 2016, containing all the microbiology deficiencies was sent to the applicant.
`
`Reference ID: 4005132
`
`(b) (4)
`
`

`

`NDA 50-790/S-024/S-025
`
`2
`
`The applicant responded to all the deficiencies in the submission dated June 27, 2016. Review of these
`responses by the Agency, generated a second Information Request (IR), which was sent to the applicant on
`September 2, 2016. The applicant responded to this IR in the submission dated September 14, 2016.
`
`Review of all the responses to the microbiology deficiencies was conducted by Dr. Yarery Smith from the
`microbiology review team. Dr. Smith found all the responses acceptable on October 11, 2016.
`
`All CMC outstanding issues in this supplement have been satisfactorily resolved. From the point of view of
`CMC, this supplement is recommended for approval.
`
`Product Quality Microbiology Review #2 of S-024 (dated 10/11/16)
`
`See Product Quality Microbiology review #1 in Panorama dated 2/25/16 for additional background. The
`supplement (S-024) is now recommended for approval on the basis of sterility assurance.
`
`The outstanding microbiological issues related to this supplemental application and noted in the Complete
`Response Letter (CR) dated March 2, 2016, have been adequately addressed.
`
`Division of Medication Error Prevention and Analysis (DMEPA) Review of S-025
`
`DMEPA completed a review of the submitted labeling on 10/24