`
`
`
` NDA 50-790/S-020
`Page 3
`
` HIGHLIGHTS OF PRESCRIBING
`
`INFORMATION
`
`
`These highlights do not include all the information
`
`needed to use RESTASIS® 0.05% safely and
`
`effectively. See full prescribing information for
`
`RESTASIS®.
`
`
`RESTASIS® (cyclosporine ophthalmic emulsion)
`
`
`0.05%
`
`Initial U.S. Approval: 1983
`
`
`_______________
`INDICATIONS AND USAGE________________
`
`RESTASIS® is a topical immunomodulator 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___________
`
`Instill one drop of RESTASIS® ophthalmic emulsion
`twice a day in each eye approximately 12 hours apart.
`(2)
`
`
`FULL PRESCRIBING INFORMATION:
`CONTENTS*
`
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`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
`
` 8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`
`
`
`
`
`Reference ID: 3223068
`
`________
`DOSAGE FORMS AND STRENGTHS_________
`
`Ophthalmic emulsion containing cyclosporine
`0.5mg/mL (3)
`
`___________________CONTRAINDICATIONS__________________
`
`• Hypersensitivity (4)
`
`
`WARNINGS AND PRECAUTIONS____________
`___________
`
`• To avoid the potential for eye injury and
`
`contamination, be careful not to touch the vial tip to
`
`your eye or other surfaces. (5.1)
`
`
`_________________ADVERSE REACTIONS____________________
`
`The most common adverse reaction following the use of
`RESTASIS® 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
`
`
`Revised: 11/2012
`
`
`
`
`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
`
`17.1 Handling the Container
`17.2 Use with Contact Lenses
`
`17.3 Administration
`
`
`
`
`
`* Sections or subsections omitted from the full
`prescribing information are not listed
`
`
`

`

`
`
` NDA 50-790/S-020
`Page 4
`
`FULL PRESCRIBING INFORMATION
`
`
`INDICATIONS AND USAGE
`1
`RESTASIS® 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.
`
`
`DOSAGE AND ADMINISTRATION
`2
`Invert the unit dose vial a few times to obtain a uniform, white, opaque emulsion before using.
`Instill one drop of RESTASIS® ophthalmic emulsion twice a day in each eye approximately 12
`hours apart. RESTASIS® can be used concomitantly with artificial tears, allowing a 15 minute
`interval between products. Discard vial immediately after use.
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`Ophthalmic emulsion containing cyclosporine 0.5 mg/mL
`
`
`CONTRAINDICATIONS
`4
`RESTASIS® is contraindicated in patients with known or suspected hypersensitivity to any of
`the ingredients in the formulation.
`
`
`
`WARNINGS AND PRECAUTIONS
`5
`Potential for Eye Injury and Contamination
`5.1
`To avoid the potential for eye injury and contamination, be careful not to touch the vial tip to
`your eye or other surfaces.
`
`
`Use with Contact Lenses
`5.2
`RESTASIS® 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 reinserted 15 minutes
`following administration of RESTASIS® ophthalmic emulsion.
`
`
`ADVERSE REACTIONS
`6
` 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 RESTASIS® 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).
`
`
`
`
`Reference ID: 3223068
`
`

`

`
`
` USE IN SPECIFIC POPULATIONS
`Pregnancy
`
` NDA 50-790/S-020
`Page 5
`
`Post-marketing Experience
`6.2
`The following adverse reactions have been identified during post approval use of RESTASIS® .
`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 vial tip touching the eye during administration).
`
`8
`
`8.1
`
`Teratogenic Effects: Pregnancy Category C
`
`Adverse effects were seen in reproduction studies in rats and rabbits 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. These doses are 5,000 and
`32,000 times greater (normalized to body surface area), respectively, than the daily human dose
`of one drop (approximately 28 mcL) of 0.05% RESTASIS® 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 at oral doses up to 17 mg/kg/day
`or 30 mg/kg/day, respectively, during organogenesis. These doses in rats and rabbits are
`approximately 3,000 and 10,000 times greater (normalized to body surface area), respectively,
`than the daily human dose.
`
`Offspring of rats receiving a 45 mg/kg/day oral dose of cyclosporine from Day 15 of pregnancy
`until Day 21 postpartum, a maternally toxic level, exhibited an increase in postnatal mortality;
`this dose is 7,000 times greater than the daily human topical dose (0.001 mg/kg/day) normalized
`to body surface area assuming that the entire dose is absorbed. No adverse events were observed
`at oral doses up to 15 mg/kg/day (2,000 times greater than the daily human dose).
`
`There are no adequate and well-controlled studies of RESTASIS® in pregnant women.
`
`RESTASIS® should be administered to a pregnant woman only if clearly needed.
`
`
`Nursing Mothers
`8.3
`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 RESTASIS® ophthalmic emulsion,
`caution should be exercised when RESTASIS® is administered to a nursing woman.
`
`Pediatric Use
`8.4
`The safety and efficacy of RESTASIS® ophthalmic emulsion have not been established in
`pediatric patients below the age of 16.
`
`8.5
`
`Geriatric Use
`
`
`
`
`Reference ID: 3223068
`
`

`

`
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` NDA 50-790/S-020
`Page 6
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`No overall difference in safety or effectiveness has been observed between elderly and younger
`patients.
`
`
`
`DESCRIPTION
`11
`RESTASIS® (cyclosporine ophthalmic emulsion) 0.05% contains a topical immunomodulator
`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
`
`
` Cyclosporine is a fine white powder. RESTASIS® 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® 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.
`
`
`CLINICAL PHARMACOLOGY
`12
`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 RESTASIS® 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 RESTASIS® ophthalmic emulsion.
`
`
`
`
`Reference ID: 3223068
`
`

`

`
`
` NDA 50-790/S-020
`Page 7
`
`
`NONCLINICAL TOXICOLOGY
`13
` Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1
`Carcinogenesis: 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. The low doses in mice and
`rats are approximately 80 times greater (normalized to body surface area) than the daily human
`dose of one drop (approximately 28 mcL) of 0.05% RESTASIS® 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: 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.
`
`
`
`CLINICAL STUDIES
`14
`Four multicenter, randomized, adequate and well-controlled clinical studies were performed in
`approximately 1,200 patients with moderate to severe keratoconjunctivitis sicca. RESTASIS®
`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 RESTASIS® ophthalmic emulsion-
`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
`RESTASIS® .
`
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`RESTASIS® ophthalmic emulsion is packaged in sterile, preservative-free single-use vials. Each
`vial contains 0.4 mL fill in a 0.9 mL LDPE vial; 30 vials are packaged in a polypropylene tray
`with an aluminum peelable lid. The entire contents of each tray (30 vials) must be dispensed
`intact. RESTASIS® is also provided in a 60 count (2 x 30) package (one month supply) that
`must be dispensed intact.
`
`
`30 Vials 0.4 mL each - NDC 0023-9163-30
`
`
`
`Reference ID: 3223068
`
`

`

` NDA 50-790/S-020
`Page 8
`
`60 (2 x 30) Vials 0.4 mL each - NDC 0023-9163-60
`
`Storage: Store at 15-25°C (59-77°F).
`
`
`PATIENT COUNSELING INFORMATION
`17
`Handling the Container
`17.1
`Advise patients to not allow the tip of the vial to touch the eye or any surface, as this may
`contaminate the emulsion. To avoid the potential for injury to the eye, advise patients to not
`touch the vial tip to their eye [see Warnings and Precautions (5.1)].
`
` Use with Contact Lenses
`17.2
`RESTASIS® 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® ophthalmic emulsion [see
`Warnings and Precautions (5.2)].
`
`Administration
`17.3
`Advise patients that the emulsion from one individual single-use vial is to be used immediately
`
`after opening for administration to one or both eyes, and the remaining contents should be
`
`discarded immediately after administration.
`
`
`© 2012 Allergan, Inc.
`
`Irvine, CA 92612, U.S.A.
`
`
`
`
`
`® marks owned by Allergan, Inc.
`
`Patented. See: www.allergan.com/products/patent_notices
`
`Made in the U.S.A.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`[part number]
`
`
`
`
`
`Reference ID: 3223068
`
`