ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: oPotential for Eye Injury and Contamination [see Warnings and Precautions (5.1)]. oPotential 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 Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 opthalmic 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).. 6.2Post-marketing Experience The following adverse reactions have been identified during post approval use of cyclosporine ophthalmic emulsion. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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 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 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 0.05% cyclosporine ophthalmic emulsion twice daily into each eye of 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. study analyzing sister chromatid exchange (SCE) induction by cyclosporine using human lymphocytes in vitro gave indication of 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 weeks (male) and weeks (female) prior to mating.

CLINICAL PHARMACOLOGY SECTION.

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 partial immunomodulator. The exact mechanism of action is not known.. 12.3 Pharmacokinetics Blood cyclosporine concentrations were measured using 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES Four multicenter, randomized, adequate and well-controlled clinical studies were performed in approximately 1,200 patients with moderate to severe keratoconjunctivitis sicca. Cyclosporine ophthalmic emulsion 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 cyclosporine 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 cyclosporine ophthalmic emulsion.

DESCRIPTION SECTION.

11 DESCRIPTION Cyclosporine ophthalmic emulsion 0.05% contains topical calcineurin inhibitor immunosuppressant with anti-inflammatory effects. Cyclosporines 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:Structural Formula Formula: C62H111N11O12 Mol. Wt.: 1202.6Cyclosporine, USP is white or almost white powder. Cyclosporine ophthalmic emulsion appears as white opaque to slightly translucent homogeneous emulsion. It has an osmolality of 230 to 320 mOsmol/kg and pH of 6.5 to 8.0. Each mL of cyclosporine ophthalmic emulsion contains: Active: cyclosporine USP, 0.05%. Inactives: anhydrous glycerin, carbomer copolymer type A, castor oil, polysorbate 80, water for injection, and sodium hydroxide to adjust pH.. Formula: C62H111N11O12 Mol. Wt.: 1202.6. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION Invert the unit dose vial few times to obtain uniform, white, opaque emulsion before using. Instill one drop of cyclosporine ophthalmic emulsion twice day in each eye approximately 12 hours apart. Cyclosporine ophthalmic emulsion can be used concomitantly with lubricant eye drops, allowing 15-minute interval between products. Discard vial immediately after use.. Instill one drop of cyclosporine ophthalmic emulsion twice day in each eye approximately 12 hours apart. (2).

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING Cyclosporine ophthalmic emulsion, 0.05% is packaged in sterile, preservative-free single-use vials. Each vial contains 0.4 mL fill in 0.5 mL natural colored low density polyethylene vial; five vials are packaged in an aluminum pouch and six pouches are packaged in carton. The entire contents of each carton (30 vials) must be dispensed intact. Cyclosporine ophthalmic emulsion is also provided in 60 count carton that must be dispensed intact.NDC 0378-8760-58carton of 30 vialsNDC 0378-8760-91carton of 60 vialsStore at 20o to 25oC (68o to 77oF). [See USP Controlled Room Temperature.].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Cyclosporine 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.. Cyclosporine ophthalmic emulsion is 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Handling the ContainerAdvise patients to not allow the tip of the vial to touch the eye or any surface, as this may contaminate the emulsion. Advise patients to not touch the vial tip to their eye to avoid the potential for injury to the eye [see Warnings and Precautions (5.1)]Use with Contact Lenses Cyclosporine ophthalmic emulsion 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 cyclosporine ophthalmic emulsion [see Warnings and Precautions (5.2) ].AdministrationAdvise patients that 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.Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Made in U.S.A.JANUARY 2022.

LACTATION SECTION.

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 [see Clinical Pharmacology (12.3)], caution should be exercised when cyclosporine ophthalmic emulsion is administered to nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for cyclosporine ophthalmic emulsion and any potential adverse effects on the breast-fed child from cyclosporine.

NONCLINICAL TOXICOLOGY SECTION.

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 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 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 0.05% cyclosporine ophthalmic emulsion twice daily into each eye of 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. study analyzing sister chromatid exchange (SCE) induction by cyclosporine using human lymphocytes in vitro gave indication of 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 weeks (male) and weeks (female) prior to mating.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 0.05% NDC 0378-8760-58CycloSPORINEOphthalmic Emulsion0.05%FOR USE IN THE EYESSterile, Preservative-FreeRx only 30 Single-Use Vials (0.4 mL Each)Each mL contains:Active: Cyclosporine, USP 0.05%Inactives: anhydrous glycerin, carbomer copolymer typeA, castor oil, polysorbate 80, water for injection, andsodium hydroxide to adjust pH.Usual Dosage: Twice daily approximately 12 hours apart.Invert the vial before using. Use immediately afteropening and then discard. See accompanying prescribinginformation.Keep this and all medication out of the reach ofchildren.Store at 20 to 25C (68 to 77F). [See USP ControlledRoom Temperature.] Store vials in the carton until use.The entire contents of the carton (30 vials) must bedispensed intact.Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Made in U.S.A.. Carton 1.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Blood cyclosporine concentrations were measured using 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.

PREGNANCY SECTION.

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 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).

USE IN SPECIFIC POPULATIONS SECTION.

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 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 [see Clinical Pharmacology (12.3)], caution should be exercised when cyclosporine ophthalmic emulsion is administered to nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for cyclosporine ophthalmic emulsion 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oTo avoid the potential for eye injury and contamination, be careful not to touch the vial tip to your eye or other surfaces. (5.1). oTo avoid the potential for eye injury and contamination, be careful not to touch the vial tip to your eye or other surfaces. (5.1). 5.1Potential for Eye Injury and Contamination Be careful not to touch the vial tip to your eye or other surfaces to avoid potential for eye injury and contamination. 5.2Use with Contact Lenses Cyclosporine ophthalmic emulsion 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 cyclosporine ophthalmic emulsion.