HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do nnt include all the infnrmaiinn needed tn use
`RESTASISQ 0.05% safely and effecfively. See full prescribing
`i.nfo1'nIalion for RESTASISQ.
`
`RESTASISE (cydaspaline nphthahnic emulsion) 0.05%
`Initial U.S. Apprnvllz 1983
`
`TINDICAHONS AND USAGE
`RESTASISQ is a tnpiml m indicated to increase tear
`prodlmhmmpahentswhosetearlnudmjlmisprennnedtobesnppressuldue
`to ocular inflammation associated with keratoconjunctivilis since. Increased
`11mtpnxim1iunwasnntseeninpafien13cnnenflylnkin.g1npimlan1i—
`inflamma1n1'y:hI1g5urusingpImclalplug5.(l)
`TDOSAGE AND ADMINISTRATIONT
`InsfiflonedtupofRESTASIS®ophfl1a]micemu]siontwiceadayineache3re
`approximately 12 1101113 apart. (2)
` GE FORMS AND STRENGTHST
`()}l]!fl]fl.|l]].i.(1
`0,5 mg/n1L (3)
`TCONIIIAINDICAIIONST
`'
`(4)
`
`FULL PRESCRIBING INFORIMATION: CONTENTS‘
`
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`3 DOSAGE FORMS AND S'I'RENG'I'H3
`4 CONTRAINDICAIIONS
`5 “FARNINGS AND PRECAUTIONS
`5,1 Pnta1tialforEyeInjm'yand Cnmiaminatitm
`5.2 Use with Cuutact Lenses
`6 ADVERSE REACTIONS
`6.1 Clinical 'Il'ial5 Experience
`6.2 Post—|narkeIing Experience
`8 USE IN SPECIFIC POPULATIONS
`
`WARNINGSANDPRECAUIIONST
`Toavuidflleputezntialfureyeinjuryatul cm1taminal:i.m,beca1'e:li:|lnuI
`tuIn1v:h1iJevialIipI1)yuIn'eyem'ofl1e1'surface5_ (5.1)
` ADVERsE REACTION
`The most commonadverse leaclionfollawing theuse IIERESTASISO was
`ocularhurnjng (11%). (5.1)
`
`Tn 1'epoI't SUSPECTED ADVERSE REACTIONS, Contact Allergan, Inc.
`at 1-800-433-8871 or FDA at 1-800—FDA-1088 (II' WWW_fda.gnv1‘meIlwatnh.
`
`See 17 for PATIENT COUNSELING INFORIMATION.
`
`Revised: 0652013
`
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pb:-.u'macol:ineti.cs
`13 NONCLINICAL TOXICOLOGY
`13,1 Caminogene-iis, Muiagenmis, Impairment ufFerlilj1y
`14 CLINICAL STUDIES
`16 H0“-T SUPPIJEDISTORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMA'I'ION
`17.1 Handling the Conlainer
`17.2 Use Wilh Contact Lenses
`17.3
`
`* Secfiunsnrsdymcfionsmniltedfimnflsefifllpnxcdlinginfininafiunarenut
`listed.
`
`APOTEX 1043, pg. 1
`
`1
`
`ALL 2008
`ARGENTUM PHARMACEUTICALS V. ALLERGAN
`IPR2016-01232
`
`

`

`FULL PRESCRIBING INFORIVIATION
`
`1
`INDICAT'IONS AND USAGE
`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.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`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.
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`Ophthalmic emulsion containing cyclosporine 0.5 mg/mL
`
`4
`CONTRAINDICATIONS
`RESTASIS® is contraindicated in patients with known or suspected hypersensitivity to any of the ingredients in
`the formulation.
`
`5
`
`WARNIINTGS AND PRECAUTIONS
`
`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.
`
`5.2
`Use with Contact Lenses
`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®
`ophthahnic emulsion.
`
`6
`
`ADVERSE REACTIONS
`
`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).
`
`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.
`
`2
`
`APOTEX 1043, pg. 2
`
`2
`
`

`

`Reported reactions have included: hypersensitivity (including eye swelling, urticaria, rare cases of severe
`angioedema, face swelling, tongue swelling, pharyngeal edema, and dyspnea); and superficial injluy of the eye
`(from the vial tip touching the eye during administration).
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`8.1
`
`Pregnancy
`
`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 fi'om 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.
`
`8.4
`Pediatric Use
`The safety and efficacy of RESTASIS® ophthalmic emulsion have not been established in pediatric patients
`below the age of 16.
`
`8.5
`
`Geriatric Use
`
`No overall difference in safety or effectiveness has been observed between elderly and younger patients.
`
`11
`DESCRIPTION
`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-1eucyl-L-valyl-N-methyl-L-leucyb
`L-alanyl-D-alanyl-N-methyl-L—leucyl-N-methyl-L-leucyl-N-methyl-L-valyl] and it has the following structure:
`
`Structural Formula
`
`3
`
`APOTEX 1043, pg. 3
`
`3
`
`

`

`lCH3JgCHGH2
`HscxN
`
`{CH3];CHCH2
`
`0
`
`0
`G
`CH3 0
`H
`
`I
`cH3 0
`N
`
`T
`NW)l\N/CH3
`N
`I
`CH-,‘CH:!KfG
`CH1; 0
`CH|'CH3"
`M CH 0HICHa:
`'
`= 0
`‘I'll
`N ‘CH3
`lil
`
`CH3
`
`0
`
`CH3
`
`0
`CH[C H3]-2
`
`Formula: C62H111N11012
`
`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 mOsmo1/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.
`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1
`
`Mechanism of Action
`
`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.
`
`12.3
`
`Pliarmacokinetics
`
`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, afler 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.
`
`13
`
`NONCLINICAL TOXICOLOGY
`
`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 mutagenicfgenotoxic in the Ames Test, the V79-HGPRT
`Test, the micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese hamster
`
`4
`
`APOTEX 1043, pg. 4
`
`4
`
`

`

`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 ofFertility: 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. 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®.
`
`16
`
`HOW SUPPLIED!STORAGE AND HANDLING
`
`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 or 60 vials are packaged in a polypropylene tray with an aluminum
`peelable lid. The entire contents of each tray (30 vials or 60 vials) must be dispensed intact.
`
`30 Vials 0.4 mL each - NDC 0023-9163-30
`
`60 Vials 0.4 mL each - NDC 0023-9163-60
`
`Storage: Store at 15°-25°C (59°-77°F).
`
`17
`
`PATIENT COUNSELING INFORIVIATION
`
`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. I
`
`17.2
`Use with Contact Lenses
`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.
`
`17.3
`
`Administration
`
`Advise patients that the emulsion from one individual single-use vial is to be used immediately afler opening
`for administration to one or both eyes, and the remaining contents should be discarded immediately afler
`administration.
`
`© 2014 Allergan, Inc.
`
`5
`
`APOTEX 1043, pg. 5
`
`5
`
`

`

`Ixvine, CA 92612, USA.
`® marks owned by Allergan, Inc.
`Patented. See: www.alle1'gaI1.coIIu’p1'oductsfpatent_notices
`Made in the U.S.A.
`
`
`"’ ALLERGAN
`_:'—"®
`
`71876USl8
`
`6
`
`APOTEX 1043, pg. 6
`
`6
`
`