`
`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21—023
`
`APPROVED LABELING
`
`

`

`
`
`NDA 21-023
`
`Page 3
`
`RESTASISTM
`
`‘t'l
`
`(cyclosporine ophthalmic emulsion) 0.05%
`Sterile, Preservative-Free
`
`DESCRIPTION
`
`RESTASISTM (cyclosporine ophthalmic emulsion) 0.05% contains a topical immunomodutator with
`anti-inflammatoryr effects. CyclOSporine’s chemical name is Cyclo[[GD-(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:
`
`"I
`pats):
`
`CH (H
`
`“t,
`
`(m )1
`
`-t H- )-rHm
`
`H-L11(CH}I;
`
`Tut")
`
`\J‘N: 0:?ENACHMHCIIJH
`
`CIICH ’-
`:
`’
`
`L‘il!
`
`Formula: C62HH1NHO];
`
`MOLWL112026
`
`Cyclosporinc is a fine white powder. RESTASISTM appears as a white opaque to slightly translucent
`homogeneous emulsion.
`It has an osmolality of 230 to 320 mOsmol/kg and a pH 016.5 to 8.0.
`
`Each mL ofRESTASISTM contains: Active: cyclosporine 0.05%. Inactivcs: 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 OFRESTASISW 0.05%, BID, in humans for up to 12 months,
`
`

`

`NDA 2l-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 RESTASIST“.
`
`Clinical Evaluations:
`
`FOur multicenter, randomized, controlled clinical studies were performed in approximately 1200
`patients with moderate to severe keratoconjunctivitis sicca. RESTASIS demonstrated statistically
`significant increases in Schirrner wetting 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 treated patients. Increased tear production was not seen in patients currently taking topical
`anti—inflarmnatory drugs or using punctal plugs.
`
`No increase in bacterial or fungal ocular infections was reported following administration of
`RESTASIST”.
`
`INDICATIONS AND USAGE
`
`IUESTASIST“l 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
`
`RESTASIST“ 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
`
`RESTASISTM 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.
`
`

`

`NDA 21-023
`
`Page 5
`
`RESTASISTM 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:
`
`In the 78-week
`Systemic carcinogenicity studies were carried out in male and female mice and rats.
`oral (diet) mouse study, at doses of l, 4, and 16 mg/kg/day, evidence ofa 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 ofone drop (28
`(AL) of0.05% RESTASIST“ BID into each eye ofa 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
`rnicronucleus 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 virro gave indication ofa 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 l 5 rng/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 ul) 0.05%
`RESTASISTM BID into each eye of a 60 kg person (0.001 mg/kg/day), assuming that the entire dose is
`abs0rbed.
`
`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- andfetotoxic 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 ul) of
`0.05% RESTASISTM 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.
`
`
`
`

`

` — N
`
`DA 21-023
`
`Page 6
`
`These doses in rats and rabbits are appr0xirnately 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 RESTASISTM in pregnant women. RESTASIST”
`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
`;n human milk after topical treatment has not been investigated. Although blood concentrations are
`
`undetectable after topical administration of RESTASISTM, caution should be exercised when
`
`RESTASISTM is administered to a nursing woman.
`
`Pediatric Use:
`
`The safety and efficacy of RESTASISTM 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 RESTASISTM 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).
`
`I
`
`DOSAGE AND ADMINISTRATION
`
`invert the unit dose vial a few times to obtain a uniform, white, opaque emulsion before using. Instill
`one drop of RESTASISTM twice a day in each eye approximately 12 hours apart. RESTASISW can be
`used concomitantly with artificial tears, allowing a 15 minute interval between products. Discard vial
`immediately after use.
`
`

`

`NDA 21023
`
`Page 7
`
`=Ii ‘15:
`
`HOW SUPPLIED
`
`RESTASISTM is packaged in single use vials. Each vial contains 0.4 mL fill in a 09 mL LDPE via]; 32
`vials are packaged in a polypropylene tray with an aluminum peelable lid.
`RES'l"ASlSTM 32 Vials 0.4 ml. each-NDC 0023316332
`
`Storage: Store RESTASISTM at 15° to 25° C (59° to 77° F).
`KEEP OUT OF THE REACH OF CHILDREN.
`
`Rx Only
`
`E—"ALLERGAN
`
`©2002 Allergan, Inc.
`Irvine. CA 92612. LISA.
`
`
`
`