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-Nmethyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N- methyl-L-valyl] and it has the following structure:

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 1342; purified water and sodium hydroxide to adjust the pH.

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.

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.

RESTASIS® ophthalmic emulsion is packaged in 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 this tray (30 vials) must be dispensed as one unit.

RESTASIS® 30 Vials 0.4 mL each - NDC 0023-9163-30

Storage: Store RESTASIS® ophthalmic emulsion at 15° to 25° C (59°-77° F).

KEEP OUT OF THE REACH OF CHILDREN.

Revised January 2008. Allergan, Inc.Irvine, CA 92612, U.S.A. www.restasis.com. FDA rev date: 10/10/2003

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).

No information provided.

RESTASIS® ophthalmic emulsion has not been studied in patients with a history of herpes keratitis.

General: For ophthalmic use only.

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 (0.001mg/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. 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® ophthalmic emulsion, caution should be exercised when RESTASIS® is administered to a nursing woman.

Pediatric Use:

The safety and efficacy of RESTASIS® ophthalmic emulsion 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.

No information provided.

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.

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, 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.

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® 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®.

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.

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.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

CYCLOSPORINE - OPHTHALMIC

(sye-klo-SPORE-een)

COMMON BRAND NAME(S): Restasis

USES: This medication is used to treat dry eyes due to a certain type of eye condition (keratoconjunctivitis sicca). It works by increasing the amount of tears you make.

HOW TO USE: This medication is applied to the affected eye(s) usually twice a day, about 12 hours apart; or as directed by your doctor.

To apply eye drops, wash your hands first. To avoid contamination, be careful not to touch the tip of the vial or let it touch your eye. Before opening the vial, make sure the eye drops are well mixed by turning the vial upside down several times before use. Open the vial right before you are about to use it. The eye drops should have a milky, white appearance.

Tilt your head back, look upward and pull down the lower eyelid to make a pouch. Place the tip of the vial directly over the eye and apply 1 drop. Look downward and gently close your eye for 1 to 2 minutes. Try not to blink and do not rub the eye.

Discard the remaining contents of the opened vial immediately after use. Do not store the opened vial for later use.

If you wear contact lenses, remove them before using this medication and do not replace them until 15 minutes following use of these eye drops.

If you are also using other drops for dry eyes (e.g., artificial tears), wait 15 minutes between use of the different products.

SIDE EFFECTS: Burning, stinging, redness, pain, or itching of the eye may occur. Blurred vision, feeling as if something is in the eye, or eye discharge may also occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

An allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of an allergic reaction include: rash, severe itching, swelling, dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: an eye infection.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: any allergies.

This drug may cause blurred vision; use caution engaging in activities requiring clear vision such as driving or using machinery.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription products you may use, especially of: other eye drops or ointments.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. This medicine may be harmful if swallowed.

NOTES: Do not share this medication with others.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-77 degrees F (15-25 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.