HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING CEQUA ophthalmic solution is packaged in sterile, preservative-free, single-use vials. Each vialcontains 0.25 mL fill in 0.9 mL LDPE vial; 10 vials (2 cards of vials) are packaged in apolyfoil aluminum pouch; pouches are packaged in box. The entire contents of each box of60 vials must be dispensed intact.60 Single-Use Vials 0.25 mL each NDC 47335-506-96Storage: Store at 20C to 25C (68F to 77F). Store single-use vials in the original foil pouch.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS . The most common adverse reactions following the use of CEQUA (cyclosporine ophthalmic solution) 0.09% was instillation site pain (22%) and conjunctival hyperemia (6%) (6.1).To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-406-7984 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 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, 769 subjects received at least dose of cyclosporine ophthalmic solution. The majority of the treated subjects were female (83%). The most common adverse reactions reported in greater than 5% of subjects were pain on instillation of drops (22%) and conjunctival hyperemia (6%). Other adverse reactions reported in 1% to 5% of the patients were blepharitis, eye irritation, headache, and urinary tract infection.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis 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 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 55 times higher than the maximum recommended human ophthalmic dose (1.5 mcg/kg/day), normalized to body surface area.MutagenesisIn genetic toxicity tests, 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. Cyclosporine was positive in an in vitro sister chromatid exchange (SCE) assay using human lymphocytes.Impairment of FertilityOral administration of cyclosporine to rats for 12 weeks (male) and weeks (female) prior to mating produced no adverse effects on fertility at doses up to 15 mg/kg/day (1620 times higher than the maximum recommended human ophthalmic dose).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY . 12.1 Mechanism of Action Cyclosporine is calcineurin inhibitor immunosuppressant agent when administered systemically. In patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca, topical administration of cyclosporine is thought to act as partial immunomodulator. The exact mechanism of action is not known.. 12.3 Pharmacokinetics Blood concentrations of cyclosporine after twice daily topical ocular administration of CEQUA into each eye of healthy subjects for up to days, and once on Day 8, were either not detectable or were marginally above the lower limit of assay quantitation of 0.100 ng/mL (range 0.101 to 0.195 ng/mL) for up to hours after single dose, and up to hours after multiple doses.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES Two multicenter, randomized, adequate and well-controlled clinical studies treated 1,048 patients with keratoconjunctivitis sicca (NCT 02254265 and NCT 02688556). In both studies, compared to vehicle at Day 84, there was statistically significant (p<0.01) higher percentage of eyes with increases of >= 10 mm from baseline in Schirmer wetting. This effect was seen in approximately 17% of CEQUA-treated patients versus approximately 9% of vehicle-treated patients.Tear ProductionOTX-101-2014-001OTX-101-2016-001CEQUAN 152VehicleN 152CEQUAN 371VehicleN 373>= 10-mm increase in tear production(% of eyes) at Day 84 16.8%8.6%16.6%9.2%Difference (95% CI)8.2% (1.9%, 14.6%)7.3% (3.3%, 11.3%)p-value versus vehicle <0.01<0.01.

DESCRIPTION SECTION.

11 DESCRIPTION CEQUA (cyclosporine ophthalmic solution) 0.09% contains topical calcineurin inhibitor immunosuppressant. 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 FormulaFormula: C62H111N11O12 Mol. Wt.: 1202.6Cyclosporine is white powder that is insoluble in water. CEQUA is supplied as sterile, clear, colorless ophthalmic solution for topical ophthalmic use. It has an osmolality of 160 to 190 mOsmol/kg and pH of 6.5-7.2. Each mL of CEQUA contains: Active: cyclosporine 0.09%Inactives: Polyoxyl 40 Hydrogenated Castor Oil, Octoxynol-40, polyvinylpyrrolidone, sodium phosphate monobasic dihydrate, sodium phosphate dibasic anhydrous, sodium chloride, water for injection, and sodium hydroxide or hydrochloric acid to adjust pH.. Active: cyclosporine 0.09%. Inactives: Polyoxyl 40 Hydrogenated Castor Oil, Octoxynol-40, polyvinylpyrrolidone, sodium phosphate monobasic dihydrate, sodium phosphate dibasic anhydrous, sodium chloride, water for injection, and sodium hydroxide or hydrochloric acid to adjust pH.. image description.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION Instill one drop of CEQUA twice daily (approximately 12 hours apart) into each eye. CEQUA can be used concomitantly with artificial tears, allowing 15-minute interval between products. Discard the vial immediately after using in both eyes. (2). Instill one drop of CEQUA twice daily (approximately 12 hours apart) into each eye. Discard the vial immediately after using in both eyes (2).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Handling the VialAdvise patients to not allow the tip of the vial to touch the eye or any surface, as this maycontaminate the solution. Advise patients also not to touch the vial tip to their eye to avoid thepotential for injury to the eye [see Warnings and Precautions 5.1 )].Use with Contact LensesCEQUA should not be administered while wearing contact lenses. Patients with decreased tearproduction typically should not wear contact lenses. Advise patients that if contact lenses areworn, they should be removed prior to the administration of the solution. Lenses may bereinserted 15 minutes following administration of CEQUA ophthalmic solution [see Warnings and Precautions (5.2)].AdministrationAdvise patients that the solution from one individual single-use vial is to be used immediatelyafter opening for administration to one or both eyes, and the remaining contents should bediscarded immediately after administration.Rx OnlyManufactured for: Sun Pharma Global FZEBy: Laboratoire UnitherZI de la GuerieF-50211 Coutances CedexFranceCyclosporine (active ingred.) Product of Czech Republic.Product of FranceDistributed by:Sun Pharmaceutical Industries, Inc.Cranbury, NJ 08512Copyright 2021, Sun Pharma Global FZEAll rights reserved03/2021uspi-CEQUA-sol-00003.

LACTATION SECTION.

8.2 Lactation Risk SummaryCyclosporine blood concentrations are low following topical ocular administration of CEQUA [see Clinical Pharmacology 12.3 )]. There is no information regarding the presence of cyclosporine in human milk following topical administration or on the effects of CEQUA on the breastfed infants and milk production. Administration of oral cyclosporine to rats during lactation did not produce adverse effects in offspring at clinically relevant doses [see Pregnancy 8.1 )]. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for CEQUA and any potential adverse effects on the breast-fed child from cyclosporine.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Cyclosporine is calcineurin inhibitor immunosuppressant agent when administered systemically. In patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca, topical administration of cyclosporine is thought to act as partial immunomodulator. The exact mechanism of action is not known.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY . 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis 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 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 55 times higher than the maximum recommended human ophthalmic dose (1.5 mcg/kg/day), normalized to body surface area.MutagenesisIn genetic toxicity tests, 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. Cyclosporine was positive in an in vitro sister chromatid exchange (SCE) assay using human lymphocytes.Impairment of FertilityOral administration of cyclosporine to rats for 12 weeks (male) and weeks (female) prior to mating produced no adverse effects on fertility at doses up to 15 mg/kg/day (1620 times higher than the maximum recommended human ophthalmic dose).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Blood concentrations of cyclosporine after twice daily topical ocular administration of CEQUA into each eye of healthy subjects for up to days, and once on Day 8, were either not detectable or were marginally above the lower limit of assay quantitation of 0.100 ng/mL (range 0.101 to 0.195 ng/mL) for up to hours after single dose, and up to hours after multiple doses.

PREGNANCY SECTION.

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of CEQUA administration in pregnant women to inform drug-associated risk. Oral administration of cyclosporine to pregnant rats or rabbits did not produce teratogenicity at clinically relevant doses [see Data].Data Animal DataOral administration of cyclosporine oral solution (USP) to pregnant rats or rabbits was teratogenic at maternally toxic doses of 30 mg/kg/day in rats and 100 mg/kg/day in rabbits, as indicated by increased pre- and postnatal mortality, reduced fetal weight and skeletal retardations. These doses (normalized to body weight) were approximately 3200 and 21000 times higher than the maximum recommended human ophthalmic dose (MRHOD) of 1.5 mcg/kg/day, respectively. No adverse embryofetal effects were observed in rats or rabbits receiving cyclosporine during organogenesis at oral doses up to 17 mg/kg/day or 30 mg/kg/day, respectively (approximately 1800 and 6400 times higher than the MRHOD, respectively).An oral dose of 45 mg/kg/day cyclosporine (approximately 4800 times higher than MRHOD) administered to rats from Day 15 of pregnancy until Day 21 postpartum produced maternal toxicity and an increase in postnatal mortality in offspring. No adverse effects in dams or offspring were observed at oral doses up to 15 mg/kg/day (approximately 1600 times greater than the MRHOD).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS . 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of CEQUA administration in pregnant women to inform drug-associated risk. Oral administration of cyclosporine to pregnant rats or rabbits did not produce teratogenicity at clinically relevant doses [see Data].Data Animal DataOral administration of cyclosporine oral solution (USP) to pregnant rats or rabbits was teratogenic at maternally toxic doses of 30 mg/kg/day in rats and 100 mg/kg/day in rabbits, as indicated by increased pre- and postnatal mortality, reduced fetal weight and skeletal retardations. These doses (normalized to body weight) were approximately 3200 and 21000 times higher than the maximum recommended human ophthalmic dose (MRHOD) of 1.5 mcg/kg/day, respectively. No adverse embryofetal effects were observed in rats or rabbits receiving cyclosporine during organogenesis at oral doses up to 17 mg/kg/day or 30 mg/kg/day, respectively (approximately 1800 and 6400 times higher than the MRHOD, respectively).An oral dose of 45 mg/kg/day cyclosporine (approximately 4800 times higher than MRHOD) administered to rats from Day 15 of pregnancy until Day 21 postpartum produced maternal toxicity and an increase in postnatal mortality in offspring. No adverse effects in dams or offspring were observed at oral doses up to 15 mg/kg/day (approximately 1600 times greater than the MRHOD).. 8.2 Lactation Risk SummaryCyclosporine blood concentrations are low following topical ocular administration of CEQUA [see Clinical Pharmacology 12.3 )]. There is no information regarding the presence of cyclosporine in human milk following topical administration or on the effects of CEQUA on the breastfed infants and milk production. Administration of oral cyclosporine to rats during lactation did not produce adverse effects in offspring at clinically relevant doses [see Pregnancy 8.1 )]. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for CEQUA and any potential adverse effects on the breast-fed child from cyclosporine.. 8.4 Pediatric Use The safety and efficacy of CEQUA ophthalmic solution have not been established in pediatric patients below the age of 18.. 8.5 Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger adult patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS . To avoid the potential for eye injury and contamination, advise patients not to touch the vial tip to the eye or other surfaces (5.1).. 5.1 Potential for Eye Injury and Contamination To avoid the potential for eye injury and contamination, advise patients not to touch the vial tip to the eye or other surfaces.. 5.2 Use with Contact Lenses CEQUA should not be administered while wearing contact lenses. If contact lenses are worn, they should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following administration of CEQUA ophthalmic solution.