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`_________________________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: 06/2013
`
`
`
`
`
`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.
`
`
`
`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)
`
`
`_______________________DOSAGE FORMS AND STRENGTHS_______________________
`Ophthalmic emulsion containing cyclosporine 0.5 mg/mL (3)
`
`_________________________________CONTRAINDICATIONS________________________________
`
`Hypersensitivity (4)
`
`
`
`
`
`
`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
`
`
`
`
`APOTEX 1043, pg. 1
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
` 1
`
`
`INDICATIONS 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.
`
`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).
`
`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.
`
`
`
`APOTEX 1043, pg. 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 injury of the eye
`(from the vial tip touching the eye during administration).
`
`USE IN SPECIFIC POPULATIONS
`
` 8
`
`
`
`
`
`Pregnancy
`
`
`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.
`
` Geriatric Use
`8.5
`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-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
`
`
`APOTEX 1043, pg. 3
`
`
`
`
`
`
`Formula: C62H111N11O12 Mol. Wt.: 1202.6
`
`
`
`CLINICAL PHARMACOLOGY
`
`
`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.
`
`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.
`
`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
`
`NONCLINICAL TOXICOLOGY
`
`
`
`APOTEX 1043, pg. 4
`
`
`
`CLINICAL STUDIES
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`
`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.
`
`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®.
`
`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 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
`
` 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.
`
`PATIENT COUNSELING INFORMATION
`
` ©
`
`
`
` 2014 Allergan, Inc.
`
`APOTEX 1043, pg. 5
`
`
`
`
`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.
`
`
`
`71876US18
`
`
`
`
`
`APOTEX 1043, pg. 6
`
`