Label: CEQUA- cyclosporine solution/ drops

  • NDC Code(s): 47335-506-96, 47335-507-97
  • Packager: Sun Pharmaceutical Industries, Inc.
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: New Drug Application

Drug Label Information

Updated October 30, 2019

If you are a consumer or patient please visit this version.

  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use CEQUA safely and effectively. See full prescribing information for CEQUA.

    CEQUA™ (cyclosporine ophthalmic solution) 0.09%, for topical ophthalmic use
    Initial U.S. Approval: 1983

    INDICATIONS AND USAGE

    CEQUA ophthalmic solution is a calcineurin inhibitor immunosuppressant indicated to increase tear production in patients with keratoconjunctivitis sicca (dry eye) (1).

    DOSAGE AND ADMINISTRATION

    Instill one drop of CEQUA twice daily (approximately 12 hours apart) into each eye. Discard the vial immediately after using in both eyes (2).

    DOSAGE FORMS AND STRENGTHS

    Ophthalmic solution containing cyclosporine 0.9 mg/mL (3).

    CONTRAINDICATIONS

    None (4).

    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).

    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.

    See 17 for PATIENT COUNSELING INFORMATION.

    Revised: 9/2019

  • Table of Contents
  • 1 INDICATIONS AND USAGE

    CEQUA ophthalmic solution is a calcineurin inhibitor immunosuppressant indicated to increase tear production in patients with keratoconjunctivitis sicca (dry eye). (1)

  • 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 a 15-minute interval between products. Discard the vial immediately after using in both eyes. (2)

  • 3 DOSAGE FORMS AND STRENGTHS

    Ophthalmic solution containing cyclosporine 0.9 mg/mL (3)

  • 4 CONTRAINDICATIONS

    None. (4)

  • 5 WARNINGS AND PRECAUTIONS

    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.

  • 6 ADVERSE REACTIONS

    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, 769 subjects received at least 1 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.

  • 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 a drug-associated risk. Oral administration of cyclosporine to pregnant rats or rabbits did not produce teratogenicity at clinically relevant doses [see Data].

    Data

    Animal Data

    Oral 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 Summary

    Cyclosporine 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 mother’s 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.

  • 11 DESCRIPTION

    CEQUA (cyclosporine ophthalmic solution) 0.09% contains a topical calcineurin inhibitor immunosuppressant. 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] and it has the following structure:

    Structural Formula

    Image_1

    Formula: C62H111N11O12 Mol. Wt.: 1202.6

    Cyclosporine is a white powder that is insoluble in water. CEQUA is supplied as a sterile, clear, colorless ophthalmic solution for topical ophthalmic use. It has an osmolality of 160 to 190 mOsmol/kg and a 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.
  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Cyclosporine is a 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 a 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 7 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 2 hours after a single dose, and up to 4 hours after multiple doses.

  • 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 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 55 times higher than the maximum recommended human ophthalmic dose (1.5 mcg/kg/day), normalized to body surface area.

    Mutagenesis

    In 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 Fertility

    Oral administration of cyclosporine to rats for 12 weeks (male) and 2 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

  • 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 a 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 Production

    OTX-101-2014-001

    OTX-101-2016-001

    CEQUA

    N = 152

    Vehicle

    N = 152

    CEQUA

    N = 371

    Vehicle

    N = 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

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    CEQUA ophthalmic solution is packaged in sterile, preservative-free, single-use vials. Each vial

    contains 0.25 mL fill in a 0.9 mL LDPE vial; 10 vials (2 cards of 5 vials) are packaged in a

    polyfoil aluminum pouch; 6 pouches are packaged in a box. The entire contents of each box of

    60 vials must be dispensed intact.

    60 Single-Use Vials 0.25 mL each - NDC 47335-506-96

    Storage: Store at 20°C to 25°C (68°F to 77°F). Store single-use vials in the original foil pouch.

  • 17 PATIENT COUNSELING INFORMATION

    Handling the Vial

    Advise patients to not allow the tip of the vial to touch the eye or any surface, as this may

    contaminate the solution. Advise patients also not to 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

    CEQUA 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 solution. Lenses may be

    reinserted 15 minutes following administration of CEQUA ophthalmic solution [see Warnings

    and Precautions (5.2)].

    Administration

    Advise patients that the solution 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.

    Rx Only

    Manufactured for: Sun Pharma Global FZE

    By: Laboratoire Unither

    ZI de la Guérie

    F-50211 Coutances Cedex

    France

    Product of France

    Distributed by:

    Sun Pharmaceutical Industries, Inc.

    Cranbury, NJ 08512

    Copyright 2019, Sun Pharma Global FZE

    All rights reserved

    09/2019

    uspi-CEQUA-sol-00002

  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL

    NDC 47355-506-96

    For topical use in the eye
    sterile, Preservative-Free

    CequaTM
    (cyclosporine ophthalmic solution) 0.09%

    60 SINGLE-USE VIALS

    6 pouches x 10 single-use vials (0.25 mL each)

    Rx only

    Keep out of reach of children.
    Not child resistant.

    SUN PHARMA

    IMAGE_2
  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL

    NDC 47355-507-97

    For topical use in the eye
    sterile, Preservative-Free

    CequaTM
    (cyclosporine ophthalmic solution) 0.09%

    10 SINGLE-USE SAMPLE VIALS

    1 pouches x 10 single-use vials (0.25 mL each)

    Rx only

    Keep out of reach of children.
    Not child resistant.

    SUN PHARMA

    IMAGE_3
  • INGREDIENTS AND APPEARANCE
    CEQUA 
    cyclosporine solution/ drops
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:47335-506
    Route of AdministrationOPHTHALMIC, TOPICAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    CYCLOSPORINE (UNII: 83HN0GTJ6D) (CYCLOSPORINE - UNII:83HN0GTJ6D) CYCLOSPORINE0.0009 g  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    POLYOXYL 40 HYDROGENATED CASTOR OIL (UNII: 7YC686GQ8F) 0.01 g  in 1 mL
    OCTOXYNOL-40 (UNII: 9T1C662FKS) 0.0005 g  in 1 mL
    SODIUM PHOSPHATE, MONOBASIC, DIHYDRATE (UNII: 5QWK665956) 0.0053 g  in 1 mL
    SODIUM PHOSPHATE, DIBASIC, ANHYDROUS (UNII: 22ADO53M6F) 0.0047 g  in 1 mL
    SODIUM CHLORIDE (UNII: 451W47IQ8X) 0.0005 g  in 1 mL
    POVIDONE K90 (UNII: RDH86HJV5Z) 0.003 g  in 1 mL
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    WATER (UNII: 059QF0KO0R)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:47335-506-966 in 1 BOX08/15/2018
    110 in 1 POUCH
    10.25 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA21091308/15/2018
    CEQUA 
    cyclosporine solution/ drops
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:47335-507
    Route of AdministrationOPHTHALMIC, TOPICAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    CYCLOSPORINE (UNII: 83HN0GTJ6D) (CYCLOSPORINE - UNII:83HN0GTJ6D) CYCLOSPORINE0.0009 mg  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    POLYOXYL 40 HYDROGENATED CASTOR OIL (UNII: 7YC686GQ8F) 0.01 g  in 1 mL
    OCTOXYNOL-40 (UNII: 9T1C662FKS) 0.0005 g  in 1 mL
    SODIUM PHOSPHATE, MONOBASIC, DIHYDRATE (UNII: 5QWK665956) 0.0053 g  in 1 mL
    SODIUM PHOSPHATE, DIBASIC, ANHYDROUS (UNII: 22ADO53M6F) 0.0047 g  in 1 mL
    SODIUM CHLORIDE (UNII: 451W47IQ8X) 0.0005 g  in 1 mL
    POVIDONE K90 (UNII: RDH86HJV5Z) 0.003 g  in 1 mL
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    WATER (UNII: 059QF0KO0R)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:47335-507-971 in 1 BOX08/15/2018
    110 in 1 POUCH
    10.25 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA21091308/15/2018
    Labeler - Sun Pharmaceutical Industries, Inc. (146974886)
    Registrant - Sun Pharmaceutical Industries, Inc. (146974886)
    Establishment
    NameAddressID/FEIBusiness Operations
    Laboratoire Unither574139809MANUFACTURE(47335-506, 47335-507)