Restasis MultiDose

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Potential for Eye Injury and Contamination [ see Warnings and Precautions (5.1) ] The most common adverse reaction following the use of cyclosporine ophthalmic emulsion 0.05% 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. 6.1 Clinical Trials Experience 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 cyclosporine ophthalmic emulsion, 0.05% 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). 6.2 Post-marketing Experience The following adverse reactions have been identified during post approval use of cyclosporine ophthalmic emulsion, 0.05%. 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. 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 bottle tip touching the eye during administration).

4 CONTRAINDICATIONS RESTASIS MULTIDOSE TM is contraindicated in patients with known or suspected hypersensitivity to any of the ingredients in the formulation [ see Adverse Reactions (6.2) ]. Hypersensitivity ( 4 )

11 DESCRIPTION RESTASIS MULTIDOSE TM (cyclosporine ophthalmic emulsion) 0.05% contains a calcineurin inhibitor immunosuppressant with anti-inflammatory effects. Cyclosporine’s chemical name is Cyclo[[( E )-(2 S ,3 R ,4 R )-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 Formula: C 62 H 111 N 11 O 12 Mol. Wt.: 1202.6 Cyclosporine is a fine white powder. RESTASIS MULTIDOSE TM 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 MULTIDOSE TM 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. The following structure formula for RESTASIS MULTIDOSETM is (cyclosporine ophthalmic emulsion) 0.05% contains a calcineurin inhibitor immunosuppressant 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]

2 DOSAGE AND ADMINISTRATION Instill one drop of RESTASIS MULTIDOSE TM ophthalmic emulsion twice a day in each eye approximately 12 hours apart. RESTASIS MULTIDOSE TM can be used concomitantly with lubricant eye drops, allowing a 15-minute interval between products. Prime by squeezing two drops onto a tissue before initial use. ( 2.1 ) Instill one drop of RESTASIS MULTIDOSE TM ophthalmic emulsion twice a day in each eye approximately 12 hours apart. ( 2.2 ) Pull off the clear shipping cover by pulling straight up. Throw the shipping cover away. Do not use RESTASIS MULTIDOSETM if shipping cover or pull tab are damaged or missing. Remove the pull tab on the olive green colored protective cap by pulling the end of the pull tab away from the bottle then winding it counterclockwise. Throw away the pull tab. Remove the olive green colored protective cap by pulling it straight up. Keep the colored protective cap. Prime the bottle for first-time use by squeezing two drops onto a tissue. Do not let the bottle tip touch the tissue. The bottle is now ready for use. After use, recap the bottle with the olive green colored protective cap by pushing it straight down onto the bottle. Turn the bottle upside down a few times before giving your dose to make sure the medicine is mixed well. 2.1 Preparation for First-Time Use Step 1: Pull off the clear shipping cover by pulling straight up. Throw the shipping cover away. Do not use RESTASIS MULTIDOSE TM if shipping cover or pull tab are damaged or missing. Step 2: Remove the pull tab on the olive green colored protective cap by pulling the end of the pull tab away from the bottle then winding it counterclockwise. Throw away the pull tab. Step 3: Remove the olive green colored protective cap by pulling it straight up. Keep the colored protective cap. Step 4: Prime the bottle for first-time use by squeezing two drops onto a tissue. Do not let the bottle tip touch the tissue. Step 5: The bottle is now ready for use. After use, recap the bottle with the olive green colored protective cap by pushing it straight down onto the bottle. 2.2 Preparation for Use Step 6: Turn the bottle upside down a few times before giving your dose to make sure the medicine is mixed well. Step 7: Instill one drop in the affected eye. Replace the olive green colored protective cap.

1 INDICATIONS AND USAGE RESTASIS MULTIDOSE TM 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. RESTASIS MULTIDOSE TM is a calcineurin inhibitor immunosuppressant 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 )

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 Pharmacokinetics 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 cyclosporine ophthalmic emulsion, 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 cyclosporine ophthalmic emulsion, 0.05%.

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 Pharmacokinetics 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 cyclosporine ophthalmic emulsion, 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 cyclosporine ophthalmic emulsion, 0.05%.

20161001

9

3 DOSAGE FORMS AND STRENGTHS Ophthalmic emulsion containing cyclosporine 0.5 mg/mL Cyclosporine ophthalmic emulsion 0.5 mg/mL ( 3 )

Restasis MultiDose cyclosporine CYCLOSPORINE CYCLOSPORINE GLYCERIN CASTOR OIL POLYSORBATE 80 CARBOMER COPOLYMER TYPE A WATER SODIUM HYDROXIDE

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Systemic carcinogenicity studies were conducted 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 recommended human dose of one drop (approximately 28 mcL) of cyclosporine ophthalmic emulsion, 0.05% 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 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.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Systemic carcinogenicity studies were conducted 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 recommended human dose of one drop (approximately 28 mcL) of cyclosporine ophthalmic emulsion, 0.05% 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 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.

NDA050790

Restasis MultiDose

cyclosporine

0023-5301

HUMAN PRESCRIPTION DRUG

OPHTHALMIC

PRINCIPAL DISPLAY PANEL – Restasis Multidose Carton Label Allergan™ NDC 0023-5301-05 Restasis MultiDose ™ (Cyclosporine Ophthalmic Emulsion) 0.05% For Topical Application In the Eye PRIOR TO FIRST USE, PLEASE READ BOTTLE PREPARATION INSTRUCTIONS Sterile, 5.5 mL Preservative-Free Rx Only Allergan™ NDC 0023-5301-05 Restasis MultiDose™ (Cyclosporine Ophthalmic Emulsion) 0.05% For Topical Application In the Eye PRIOR TO FIRST USE, PLEASE READ BOTTLE PREPARATION INSTRUCTIONS Sterile, 5.5 mL Preservative-Free Rx Only

17 PATIENT COUNSELING INFORMATION Handling the Container Advise patients to not allow the tip of the bottle to touch the eye or any surface, as this may contaminate the emulsion. Advise patients to not touch the bottle tip to their eye to avoid the potential for injury to the eye [ see Warnings and Precautions (5.1) ]. Use with Contact Lens es RESTASIS MULTIDOSE™ 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 MULTIDOSE™ ophthalmic emulsion [ see Warnings and Precautions (5.2) ]. Administration Advise patients to read the “Instructions for Use” for detailed first-time use instructions. © 2016 Allergan. All rights reserved. Irvine, CA 92612, U.S.A. All trademarks are the property of their respective owners. Patented: See: www.allergan.com/products/patents Made in Ireland. 72843US12 Allergan Cut here

6.1 Clinical Trials Experience 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 cyclosporine ophthalmic emulsion, 0.05% 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).

8.5 Geriatric Use No overall difference in safety or effectiveness has been observed between elderly and younger patients.

8.4 Pediatric Use Safety and efficacy have not been established in pediatric patients below the age of 16.

8.1 Pregnancy Risk Summary Clinical administration of cyclosporine ophthalmic emulsion 0.05% is not detected systemically following topical ocular administration [see Clinical Pharmacology (12.3) ] , and maternal use is not expected to result in fetal exposure to the drug. Oral administration of cyclosporine to pregnant rats or rabbits did not produce teratogenicity at clinically relevant doses [see Data] . Data Animal Data At maternally toxic doses (30 mg/kg/day in rats and 100 mg/kg/day in rabbits), cyclosporine oral solution (USP) was teratogenic as indicated by increased pre- and postnatal mortality, reduced fetal weight and skeletal retardations. These doses (normalized to body surface area) are 5,000 and 32,000 times greater, respectively, than the daily recommended human dose of one drop (approximately 28 mcL) of cyclosporine ophthalmic emulsion 0.05% 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 during organogenesis at oral doses up to 17 mg/kg/day or 30 mg/kg/day, respectively. These doses in rats and rabbits are approximately 3,000 and 10,000 times greater, respectively, than the daily recommended human dose. An oral dose of 45 mg/kg/day cyclosporine administered to rats from Day 15 of pregnancy until Day 21 postpartum produced maternal toxicity and an increase in postnatal mortality in offspring. This dose is 7,000 times greater than the daily recommended human dose. No adverse effects in dams or offspring were observed at oral doses up to 15 mg/kg/day (2,000 times greater than the daily recommended human dose).

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Clinical administration of cyclosporine ophthalmic emulsion 0.05% is not detected systemically following topical ocular administration [see Clinical Pharmacology (12.3) ] , and maternal use is not expected to result in fetal exposure to the drug. Oral administration of cyclosporine to pregnant rats or rabbits did not produce teratogenicity at clinically relevant doses [see Data] . Data Animal Data At maternally toxic doses (30 mg/kg/day in rats and 100 mg/kg/day in rabbits), cyclosporine oral solution (USP) was teratogenic as indicated by increased pre- and postnatal mortality, reduced fetal weight and skeletal retardations. These doses (normalized to body surface area) are 5,000 and 32,000 times greater, respectively, than the daily recommended human dose of one drop (approximately 28 mcL) of cyclosporine ophthalmic emulsion 0.05% 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 during organogenesis at oral doses up to 17 mg/kg/day or 30 mg/kg/day, respectively. These doses in rats and rabbits are approximately 3,000 and 10,000 times greater, respectively, than the daily recommended human dose. An oral dose of 45 mg/kg/day cyclosporine administered to rats from Day 15 of pregnancy until Day 21 postpartum produced maternal toxicity and an increase in postnatal mortality in offspring. This dose is 7,000 times greater than the daily recommended human dose. No adverse effects in dams or offspring were observed at oral doses up to 15 mg/kg/day (2,000 times greater than the daily recommended human dose). 8.2 Lactation Risk Summary Cyclosporine is known to appear in human milk following systemic administration, but its presence in human milk following topical treatment has not been investigated. Although blood concentrations are undetectable following topical administration of cyclosporine ophthalmic emulsion 0.05% [see Clinical Pharmacology (12.3) ] , caution should be exercised when RESTASIS MULTIDOSE TM is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RESTASIS MULTIDOSE TM and any potential adverse effects on the breast-fed child from cyclosporine. 8.4 Pediatric Use Safety and efficacy 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.

16 HOW SUPPLIED/STORAGE AND HANDLING RESTASIS MULTIDOSE TM ophthalmic emulsion is packaged in a sterile, multi-dose preservative-free bottle. Each bottle consists of a white opaque LDPE bottle, a white opaque polypropylene top with unidirectional valve and air filter, a protective olive green polypropylene cap, and a clear disposable shipping cover over the colored cap. 5.5 mL in 10-mL bottle - NDC 0023-5301-05 Storage: Store at 15-25 °C (59-77 °F).