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

`

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

`

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

`

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

`

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

`

`
`
` NDA 50-790/S-024/S-025
`
`8
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` Cyclosporine is a fine white powder. RESTASIS MULTIDOSETM appears as a white opaque to
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` slightly translucent homogeneous emulsion. It has an osmolality of 230 to 320 mOsmol/kg and a
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` pH of 6.5-8.0. Each mL of RESTASIS MULTIDOSETM ophthalmic emulsion contains: Active:
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`cyclosporine 0.05%. Inactives: glycerin; castor oil; polysorbate 80; carbomer copolymer type A;
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`purified water; and sodium hydroxide to adjust pH.
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`12
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`CLINICAL PHARMACOLOGY
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`12.1
`Mechanism of Action
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`Cyclosporine is an immunosuppressive agent when administered systemically.
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`In patients whose tear production is presumed to be suppressed due to ocular inflammation
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`associated with keratoconjunctivitis sicca, cyclosporine emulsion is thought to act as a partial
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`immunomodulator. The exact mechanism of action is not known.
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`12.3
`Pharmacokinetics
`Blood cyclosporine A concentrations were measured using a specific high pressure liquid
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`chromatography-mass spectrometry assay. Blood concentrations of cyclosporine, in all the
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`samples collected, after topical administration of cyclosporine ophthalmic emulsion, 0.05%,
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`twice daily, in humans for up to 12 months, were below the quantitation limit of 0.1 ng/mL.
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`There was no detectable drug accumulation in blood during 12 months of treatment with
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`cyclosporine ophthalmic emulsion, 0.05%.
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`13
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`NONCLINICAL TOXICOLOGY
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`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
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`Carcinogenesis
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`Systemic carcinogenicity studies were conducted in male and female mice and rats. In the 78­
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`week oral (diet) mouse study, at doses of 1, 4, and 16 mg/kg/day, evidence of a statistically
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`significant trend was found for lymphocytic lymphomas in females, and the incidence of
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`hepatocellular carcinomas in mid-dose males significantly exceeded the control value.
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`In the 24-month oral (diet) rat study, conducted at 0.5, 2, and 8 mg/kg/day, pancreatic islet cell
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`adenomas significantly exceeded the control rate in the low dose level. The hepatocellular
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`carcinomas and pancreatic islet cell adenomas were not dose related. The low doses in mice and
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`rats are approximately 80 times greater (normalized to body surface area) than the daily
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`recommended human dose of one drop (approximately 28 mcL) of cyclosporine ophthalmic
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`emulsion, 0.05% twice daily into each eye of a 60 kg person (0.001 mg/kg/day), assuming that
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`the entire dose is absorbed.
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`Mutagenesis
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`Cyclosporine has not been found to be mutagenic/genotoxic in the Ames Test, the V79-HGPRT
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`Test, the micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in
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`Chinese hamster bone-marrow, the mouse dominant lethal assay, and the DNA-repair test in
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`sperm from treated mice. A study analyzing sister chromatid exchange (SCE) induction by
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`cyclosporine using human lymphocytes in vitro gave indication of a positive effect (i.e.,
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`induction of SCE).
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`Impairment of Fertility
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`Reference ID: 4004790
`
`

`

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

`

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

`

`
`
` NDA 50-790/S-024/S-025
`
`11
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`
`
`
` INSTRUCTIONS FOR USE
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`RESTASIS MULTIDOSETM (Re stay’ sis Mul tee dōs)
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`(cyclosporine ophthalmic emulsion) 0.05%
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`Read this Instructions for Use before you start using RESTASIS MULTIDOSETM and each time you get a
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`refill. There may be new information. This leaflet does not take the place of talking to your healthcare
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`provider about your medical condition or treatment.
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`Important:
` RESTASIS MULTIDOSETM is for use in the eye
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` Wash your hands before using RESTASIS MULTIDOSETM.
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` Do not let the bottle tip touch the eye or any other surfaces to avoid contamination or injury to your
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`eye.
` Use 1 drop of RESTASIS MULTIDOSETM in each eye, 2 times each day, about 12 hours apart.
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`If you wear contact lenses, remove them before using RESTASIS MULTIDOSETM. Wait for at least
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`
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`15 minutes before placing them back in your eyes.
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` RESTASIS MULTIDOSETM can be used with lubricant eye drops, but you should wait at least 15
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`minutes between using each product.
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`Parts of your RESTASIS MULTIDOSETM bottle
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` PREPARING THE BOTTLE FOR FIRST-TIME USE:
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` Step 1: Pull off shipping cover by pulling straight up. Throw
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` the shipping cover away. Do not use RESTASIS
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`MULTIDOSETM if shipping cover or pull tab are damaged or
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`missing.
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`Step 2: Remove the pull tab on the olive green colored
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`protective cap by pulling the end of the pull tab away from the
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`bottle then winding it counterclockwise. Throw away the pull
`tab.
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`Step 3: Remove the olive green colored protective cap by
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`pulling it straight up. Keep the colored protective cap.
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`Step 4: Prime the bottle for first time use by squeezing 2
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`drops onto a tissue. Do not let the bottle tip touch the tissue.
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`Step 5: The bottle is now ready for use. After use, recap the
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`bottle with the olive green colored protective cap by pushing
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`straight down onto the bottle.
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`Reference ID: 4004790
`
`

`

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