NDA 21-023
`Page 3
`
`RESTASIS
`(cyclosporine ophthalmic emulsion) 0.05%
`Sterile, Preservative-Free
`
`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:
`
`
`H3C
`
`HO
`
`O
`
`O
`
`N C
`
`H3
`
`CH(CH3)2
`
`NC
`
`H3
`
`O
`
`(CH3)2CHCH2
`
`H3C
`
`N
`
`(CH3)2CHCH2
`
`O
`
`N
`
`H3C
`
`O
`
`CH3
`
`O
`
`H
`N
`
`N
`H
`
`CH2CH(CH3)2
`O
`
`N
`
`O
`
`CH3
`
`CH3
`
`CH3
`
`H
`N
`
`O
`
`CH2CH3
`
`H
`N
`
`CH3
`
`O
`
`N
`
`CH3
`
`CH2CH(CH3)2
`
`N
`
`O
`
`CH(CH3)2
`
`
`Mol. Wt.: 1202.6
`
`
`Formula: C62H111N11O12
`
`
`
`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 to 8.0.
`
`Each mL of RESTASIS contains: Active: cyclosporine 0.05%. Inactives: glycerin, castor oil,
`polysorbate 80, carbomer 1342, purified water, and sodium hydroxide to adjust the pH.
`
`CLINICAL PHARMACOLOGY
`
`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.
`
`
`
`Pharmacokinetics:
`
`Blood cyclosporin 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%, BID, in humans for up to 12 months,
`
`1
`
`

`
`NDA 21-023
`Page 4
`
`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.
`
`Clinical Evaluations:
`
`Four multicenter, randomized, adequate and well-controlled clinical studies were performed in
`approximately 1200 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 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.
`
`INDICATIONS AND USAGE
`
`RESTASIS 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.
`
`CONTRAINDICATIONS
`
`RESTASIS is contraindicated in patients with active ocular infections and in patients with known or
`suspected hypersensitivity to any of the ingredients in the formulation.
`
`WARNING
`
`RESTASIS has not been studied in patients with a history of herpes keratitis.
`
`PRECAUTIONS
`
`General: For ophthalmic use only.
`
`Information for Patients:
`
`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.
`
`Do not allow the tip of the vial to touch the eye or any surface, as this may contaminate the emulsion.
`
`
`
`
`2
`
`

`
`NDA 21-023
`Page 5
`
`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.
`
`Carcinogenesis, Mutagenesis, and Impairment of Fertility:
`
`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 1000 and 500 times greater, respectively, than the daily human dose of one drop (28
`µL) of 0.05% RESTASIS BID into each eye of a 60 kg person (0.001 mg/kg/day), assuming that the
`entire dose is absorbed.
`
`Cyclosporine has not been found 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).
`
`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 15,000 times the human daily dose of 0.001
`mg/kg/day) for 9 weeks (male) and 2 weeks (female) prior to mating.
`
`Pregnancy-Teratogenic effects:
`
`Pregnancy category C.
`
`Teratogenic effects: No evidence of teratogenicity was observed in rats or rabbits receiving oral doses
`of cyclosporine up to 300 mg/kg/day during organogenesis. These doses in rats and rabbits are
`approximately 300,000 times greater than the daily human dose of one drop (28 µl) 0.05%
`RESTASIS BID into each eye of a 60 kg person (0.001 mg/kg/day), assuming that the entire dose is
`absorbed.
`
`Non-Teratogenic effects: 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 30,000 and 100,000 times greater, respectively than the daily human dose of one-drop (28 µl) of
`0.05% RESTASIS BID 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.
`
`3
`
`

`
`NDA 21-023
`Page 6
`
`These doses in rats and rabbits are approximately 17,000 and 30,000 times greater, 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 post partum, a maternally toxic level, exhibited an increase in postnatal mortality; this dose is
`45,000 times greater than the daily human topical dose, 0.001 mg/kg/day, assuming that the entire dose
`is absorbed. No adverse events were observed at oral doses up to 15 mg/kg/day (15,000 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:
`
`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, caution should be exercised when
`RESTASIS is administered to a nursing woman.
`
`Pediatric Use:
`
`The safety and efficacy of RESTASIS have not been established in pediatric patients below the age
`of 16.
`
`Geriatric Use:
`
`No overall difference in safety or effectiveness has been observed between elderly and younger
`patients.
`
`ADVERSE REACTIONS
`
`The most common adverse event following the use of RESTASIS was ocular burning (17%).
`
`Other events 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).
`
`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 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.
`
`HOW SUPPLIED
`
`RESTASIS is packaged in single use vials. Each vial contains 0.4 mL fill in a 0.9 mL LDPE vial; 32
`vials are packaged in a polypropylene tray with an aluminum peelable lid.
`
`
`4
`
`

`
`NDA 21-023
`Page 7
`
`RESTASIS 32 Vials 0.4 mL each-NDC 0023-9163-32
`
`Storage: Store RESTASIS at 15° to 25° C (59° to 77° F).
`KEEP OUT OF THE REACH OF CHILDREN.
`Rx Only
`
`
`ALLERGAN
`2002 Allergan, Inc.
`Irvine, CA 92612, U.S.A.
`
`
`
`5