Cyclosporine

1 INDICATIONS AND USAGE Cyclosporine ophthalmic emulsion, 0.05% 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. Cyclosporine ophthalmic emulsion, 0.05% 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 )

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 cyclosporine ophthalmic emulsion, 0.05% twice a day in each eye approximately 12 hours apart. Cyclosporine ophthalmic emulsion, 0.05% can be used concomitantly with lubricant eye drops, allowing a 15-minute interval between products. Discard vial immediately after use. Instill one drop of cyclosporine ophthalmic emulsion, 0.05% twice a day in each eye approximately 12 hours apart. ( 2 )

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

4 CONTRAINDICATIONS Cyclosporine ophthalmic emulsion, 0.05% is contraindicated in patients with known or suspected hypersensitivity to any of the ingredients in the formulation. Hypersensitivity ( 4 )

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 was ocular burning (17%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Devatis, Inc. at 1-833-534-4406 or druginfo@devatis.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch or www.devatis.com. 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 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. 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 vial tip touching the eye during administration).

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 cyclosporine ophthalmic emulsion, 0.05% is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for cyclosporine ophthalmic emulsion, 0.05% 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.

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.

11 DESCRIPTION Cyclosporine ophthalmic emulsion, 0.05% contains a topical 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. Cyclosporine ophthalmic emulsion, 0.05% 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 cyclosporine 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 for Cyclosporine ophthalmic emulsion, 0.05% contains a topical 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]

16 HOW SUPPLIED/STORAGE AND HANDLING Cyclosporine ophthalmic emulsion, 0.05% is packaged in sterile, preservative-free, single-dose vials. Each vial contains 0.4 mL fill in a 0.9 mL LDPE vial; 5 vials are packed in one foil wrap. Cyclosporine Ophthalmic Emulsion, 30 vials, 0.4 mL each - NDC 0480-4076-30 There are 6 foil wraps per carton with a leaflet. The entire contents of this carton (30 vials) must be dispensed as one unit. Cyclosporine Ophthalmic Emulsion, 60 vials, 0.4 mL each - NDC 0480-4076-60 There are 12 foil wraps per carton with a leaflet. The entire contents of this carton (60 vials) must be dispensed as one unit. Storage Store at 15° to 25°C (59° to 77°F).