`
` NDA 21-257/S-025
`Page 3
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`
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`Pigmentation of the iris, periorbital tissue (eyelid) and
`
`
`
`eyelashes can occur. Iris pigmentation likely to be
`
`permanent. (5.1)
`
`
`• Eyelash Changes.
`
`
`Gradual change to eyelashes including increased length,
`
`
`thickness and number of lashes. Usually reversible. (5.2)
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`
`TRAVATAN® (travoprost ophthalmic solution) 0.004% safely
`
`
`
` and effectively. See full prescribing information for
`
`TRAVATAN® .
`
`
`
`TRAVATAN® (travoprost ophthalmic solution) 0.004%
`
`
`-------------ADVERSE REACTIONS-----------------
`Initial U.S. Approval: 2001
`
`Most common adverse reaction (30% to 50%) is conjunctival
`
`hyperemia. (6.1)
`----------INDICATIONS AND USAGE-------------
`
`
`TRAVATAN® is a prostaglandin analog indicated for the
`
`reduction of elevated intraocular pressure in patients with open
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact
`angle glaucoma or ocular hypertension. (1)
`
`Alcon Laboratories Inc. at 1-800-757-9195 or FDA at 1-800­
`
`FDA-1088 or www.fda.gov/medwatch.
`-------DOSAGE AND ADMINISTRATION--------
`
`
`One drop in the affected eye(s) once daily in the evening. (2)
`
`
`----------- USE IN SPECIFIC POPULATIONS----------
`
`
`Use in pediatric patients below the age of 16 years is not
`-----DOSAGE FORMS AND STRENGTHS------
`
`recommended because of potential safety concerns related to
`
`Solution containing 0.04 mg/mL travoprost ophthalmic solution.
`
`increased pigmentation following long-term chronic use. (8.4)
`(3)
`
`
`
`See 17 for Patient Counseling Information
`-----WARNINGS AND PRECAUTIONS-------
`Revised: 8/2011
`•
`
`Pigmentation.
`
`_____________________________________________________________________________________________
`
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`
`8.6 Hepatic and Renal Impairment
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`12.3 Pharmacokinetics
`
` NONCLINICAL TOXICOLOGY
`12.1 Mechanism of Action
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17
`PATIENT COUNSELING INFORMATION
`
`
`17.1 Potential for Pigmentation
`
`17.2 Potential for Eyelash Changes
`17.3 Handling the Container
`17.4 When to Seek Physician Advice
`
`17.5 Use with Contact Lenses
`17.6 Use with Other Ophthalmic Drugs
`
`13
`
`
`
`
`
`
`
`
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing
`information are not listed.
`
`
`
`_____________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
` INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Pigmentation
`
`5.2 Eyelash Changes
`Intraocular Inflammation
`5.3
`
`
`5.4 Macular Edema
`
`
`
`5.5 Angle-closure, Inflammatory, or Neovascular
`
`Glaucoma
`
`
`5.6 Bacterial Keratitis
`
`5.7 Use with Contact Lenses
` ADVERSE REACTIONS
`6.1 Clinical Studies Experience
`
`
`
`
`
`6
`
`
`
`8
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`
`8.1
`Pregnancy
`
`8.3 Nursing Mothers
`
`
`
`Reference ID: 3009261
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`Santen/Asahi Glass Exhibit 2040
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
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` NDA 21-257/S-025
`Page 4
`
`FULL PRESCRIBING INFORMATION
`
`
`INDICATIONS AND USAGE
`1
`TRAVATAN® (travoprost ophthalmic solution) 0.004% is indicated for the reduction of
`elevated intraocular pressure in patients with open angle glaucoma or ocular
`hypertension.
`
`
`2 DOSAGE AND ADMINISTRATION
`
`The recommended dosage is one drop in the affected eye(s) once daily in the evening.
`TRAVATAN® (travoprost ophthalmic solution) should not be administered more than
`once daily since it has been shown that more frequent administration of prostaglandin
`analogs may decrease the intraocular pressure lowering effect.
`
`Reduction of the intraocular pressure starts approximately 2 hours after the first
`administration with maximum effect reached after 12 hours.
`
`TRAVATAN® may be used concomitantly with other topical ophthalmic drug products
`to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the
`drugs should be administered at least five (5) minutes apart.
`
`
`3 DOSAGE FORMS AND STRENGTHS
`Ophthalmic solution containing travoprost 0.04 mg/mL.
`
`4 CONTRAINDICATIONS
`None
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Pigmentation
`
`Travoprost ophthalmic solution has been reported to cause changes to pigmented tissues.
`The most frequently reported changes have been increased pigmentation of the iris,
`periorbital tissue (eyelid) and eyelashes. Pigmentation is expected to increase as long as
`travoprost is administered. The pigmentation change is due to increased melanin content
`
`in the melanocytes rather than to an increase in the number of melanocytes. After
`discontinuation of travoprost, pigmentation of the iris is likely to be permanent, while
`
`pigmentation of the periorbital tissue and eyelash changes have been reported to be
`reversible in some patients. Patients who receive treatment should be informed of the
`possibility of increased pigmentation. The long term effects of increased pigmentation are
`not known.
`
`Iris color change may not be noticeable for several months to years. Typically, the brown
`pigmentation around the pupil spreads concentrically towards the periphery of the iris and
`the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the
`
`iris appear to be affected by treatment. While treatment with TRAVATAN® (travoprost
`ophthalmic solution) 0.004% can be continued in patients who develop noticeably
`
`
`
`Reference ID: 3009261
`
`
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` NDA 21-257/S-025
`Page 5
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`increased iris pigmentation, these patients should be examined regularly. (see PATIENT
`COUNSELING INFORMATION, 17.1).
`
`5.2 Eyelash Changes
`
`TRAVATAN® may gradually change eyelashes and vellus hair in the treated eye. These
`changes include increased length, thickness, and number of lashes. Eyelash changes are
`usually reversible upon discontinuation of treatment.
`
`5.3 Intraocular Inflammation
`
`TRAVATAN® should be used with caution in patients with active intraocular
`inflammation (e.g., uveitis) because the inflammation may be exacerbated.
`
`
`5.4 Macular Edema
`
`
`Macular edema, including cystoid macular edema, has been reported during treatment
`with travoprost ophthalmic solution. TRAVATAN® should be used with caution in
`aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in
`patients with known risk factors for macular edema.
`
`5.5 Angle-closure, Inflammatory or Neovascular Glaucoma
`
`TRAVATAN® has not been evaluated for the treatment of angle-closure, inflammatory or
`neovascular glaucoma.
`
`5.6 Bacterial Keratitis
`
`
`There have been reports of bacterial keratitis associated with the use of multiple-dose
`containers of topical ophthalmic products. These containers had been inadvertently
`contaminated by patients who, in most cases, had a concurrent corneal disease or a
`disruption of the ocular epithelial surface (see PATIENT COUNSELING
`
`INFORMATION, 17.3).
`
`5.7 Use with Contact Lenses
`Contact lenses should be removed prior to instillation of TRAVATAN® and may be
`reinserted 15 minutes following its administration.
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Studies Experience
`Because clinical studies are conducted under widely varying conditions, adverse reaction
`rates observed in the clinical studies of a drug cannot be directly compared to rates in the
`clinical studies of another drug and may not reflect the rates observed in practice.
`
`
`The most common adverse reaction observed in controlled clinical studies with
`TRAVATAN® (travoprost ophthalmic solution) 0.004% and TRAVATAN Z®
`(travoprost ophthalmic solution) 0.004% was ocular hyperemia which was reported in 30
`to 50% of patients. Up to 3% of patients discontinued therapy due to conjunctival
`hyperemia. Ocular adverse reactions reported at an incidence of 5 to 10% in these clinical
`studies included decreased visual acuity, eye discomfort, foreign body sensation, pain and
`pruritus.
`
`
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`Reference ID: 3009261
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` NDA 21-257/S-025
`Page 6
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`
`Ocular adverse reactions reported at an incidence of 1 to 4% in clinical studies with
`TRAVATAN® or TRAVATAN Z® included abnormal vision, blepharitis, blurred
`vision, cataract, conjunctivitis, corneal staining, dry eye, iris discoloration, keratitis, lid
`margin crusting, ocular inflammation, photophobia, subconjunctival hemorrhage and
`tearing.
`
`Nonocular adverse reactions reported at an incidence of 1 to 5% in these clinical studies
`were allergy, angina pectoris, anxiety, arthritis, back pain, bradycardia, bronchitis, chest
`pain, cold/flu syndrome, depression, dyspepsia, gastrointestinal disorder, headache,
`hypercholesterolemia, hypertension, hypotension, infection, pain, prostate disorder,
`sinusitis, urinary incontinence and urinary tract infections.
`
`In postmarketing use with prostaglandin analogs, periorbital and lid changes including
`deepening of the eyelid sulcus have been observed.
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`Pregnancy Category C
`Teratogenic effects: Travoprost was teratogenic in rats, at an intravenous (IV) dose up to
`10 mcg/kg/day (250 times the maximal recommended human ocular dose (MRHOD),
`evidenced by an increase in the incidence of skeletal malformations as well as external
`and visceral malformations, such as fused sternebrae, domed head and hydrocephaly.
`Travoprost was not teratogenic in rats at IV doses up to 3 mcg/kg/day (75 times the
`MRHOD), or in mice at subcutaneous doses up to 1 mcg/kg/day (25 times the MRHOD).
`Travoprost produced an increase in post-implantation losses and a decrease in fetal
`viability in rats at IV doses >3 mcg/kg/day (75 times the MRHOD) and in mice at
`subcutaneous doses >0.3 mcg/kg/day (7.5 times the MRHOD).
`
`In the offspring of female rats that received travoprost subcutaneously from Day 7 of
`pregnancy to lactation Day 21 at doses of ≥0.12 mcg/kg/day (3 times the MRHOD), the
`incidence of postnatal mortality was increased, and neonatal body weight gain was
`decreased. Neonatal development was also affected, evidenced by delayed eye opening,
`pinna detachment and preputial separation, and by decreased motor activity.
`
`There are no adequate and well-controlled studies of TRAVATAN® (travoprost
`ophthalmic solution) 0.004% administration in pregnant women. Because animal
`reproductive studies are not always predictive of human response, TRAVATAN® should
`administered during pregnancy only if the potential benefit justifies the potential risk to
`
`the fetus.
`
`8.3 Nursing Mothers
`
`A study in lactating rats demonstrated that radiolabeled travoprost and/or its metabolites
`were excreted in milk. It is not known whether this drug or its metabolites are excreted in
`human milk. Because many drugs are excreted in human milk, caution should be
`exercised when TRAVATAN® is administered to a nursing woman.
`
`
`
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`Reference ID: 3009261
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`Page 7
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` 8.4 Pediatric Use
`
`Use in pediatric patients below the age of 16 years is not recommended because of
`potential safety concerns related to increased pigmentation following long-term chronic
`use.
`
`8.5 Geriatric Use
`
`No overall clinical differences in safety or effectiveness have been observed between
`elderly and other adult patients.
`
`8.6 Hepatic and Renal Impairment
`
`TRAVATAN® has been studied in patients with hepatic impairment and also in patients
`with renal impairment. No clinically relevant changes in hematology, blood chemistry,
`
`or urinalysis laboratory data were observed in these patients.
`
`11 DESCRIPTION
`Travoprost is a synthetic prostaglandin F analogue. Its chemical name is [1R­
`[1α(Z),2β(1E,3R*),3α,5α]]-7-[3,5-Dihydroxy-2-[3-hydroxy-4-[3­
`(trifluoromethyl)phenoxy]-1-butenyl]cyclopentyl]-5-heptenoic acid, 1-methylethylester.
`It has a molecular formula of C26H35F3O6 and a molecular weight of 500.55. The
`chemical structure of travoprost is:
`
`
`
`
`Travoprost is a clear, colorless to slightly yellow oil that is very soluble in acetonitrile,
`
`methanol, octanol, and chloroform. It is practically insoluble in water.
`
`TRAVATAN® (travoprost ophthalmic solution) 0.004% is supplied as sterile, buffered
`aqueous solution of travoprost with a pH of approximately 6.0 and an osmolality of
`
`approximately 290 mOsmol/kg.
`
`TRAVATAN® contains Active: travoprost 0.04 mg/mL; Preservative: benzalkonium
`
`chloride 0.15 mg/mL; Inactives: polyoxyl 40 hydrogenated castor oil, tromethamine,
`boric acid, mannitol, edetate disodium, sodium hydroxide and/or hydrochloric acid (to
`adjust pH) and purified water.
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`Travoprost free acid, a prostaglandin analog is a selective FP prostanoid receptor agonist
`which is believed to reduce intraocular pressure by increasing uveoscleral outflow. The
`exact mechanism of action is unknown at this time.
`
`
`12.3 Pharmacokinetics
`
`
`
`Reference ID: 3009261
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`Travoprost is absorbed through the cornea and is hydrolyzed to the active free acid. Data
`from four multiple dose pharmacokinetic studies (totaling 107 subjects) have shown that
`plasma concentrations of the free acid are below 0.01 ng/ml (the quantitation limit of the
`assay) in two-thirds of the subjects. In those individuals with quantifiable plasma
`
`concentrations (N=38), the mean plasma Cmax was 0.018 ± 0.007 ng/ml (ranged 0.01 to
`
`0.052 ng/mL) and was reached within 30 minutes. From these studies, travoprost is
`estimated to have a plasma half-life of 45 minutes. There was no difference in plasma
`
`
`concentrations between Days 1 and 7, indicating steady-state was reached early and that
`there was no significant accumulation.
`
`Travoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea to its
`biologically active free acid. Systemically, travoprost free acid is metabolized to inactive
`metabolites via beta-oxidation of the α(carboxylic acid) chain to give the 1,2-dinor and
`
`1,2,3,4-tetranor analogs, via oxidation of the 15-hydroxyl moiety, as well as via reduction
`of the 13,14 double bond.
`
`The elimination of travoprost free acid from plasma was rapid and levels were generally
`
`below the limit of quantification within one hour after dosing. The terminal elimination
`half-life of travoprost free acid was estimated from fourteen subjects and ranged from 17
`minutes to 86 minutes with the mean half-life of 45 minutes. Less than 2% of the topical
`ocular dose of travoprost was excreted in the urine within 4 hours as the travoprost free
`acid.
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Two-year carcinogenicity studies in mice and rats at subcutaneous doses of 10, 30, or 100
`mcg/kg/day did not show any evidence of carcinogenic potential. However, at 100
`mcg/kg/day, male rats were only treated for 82 weeks, and the maximum tolerated dose
`(MTD) was not reached in the mouse study. The high dose (100 mcg/kg) corresponds to
`exposure levels over 400 times the human exposure at the maximum recommended
`human ocular dose (MRHOD) of 0.04 mcg/kg, based on plasma active drug levels.
`Travoprost was not mutagenic in the Ames test, mouse micronucleus test or rat
`chromosome aberration assay. A slight increase in the mutant frequency was observed in
`one of two mouse lymphoma assays in the presence of rat S-9 activation enzymes.
`Travoprost did not affect mating or fertility indices in male or female rats at subcutaneous
`doses up to 10 mcg/kg/day [250 times the maximum recommended human ocular dose of
`0.04 mcg/kg/day on a mcg/kg basis (MRHOD)]. At 10 mcg/kg/day, the mean number of
`corpora lutea was reduced, and the post-implantation losses were increased. These effects
`were not observed at 3 mcg/kg/day (75 times the MRHOD).
`
`14 CLINICAL STUDIES
`
`In clinical studies, patients with open-angle glaucoma or ocular hypertension and baseline
`pressure of 25-27 mm Hg who were treated with TRAVATAN® (travoprost ophthalmic
`solution) 0.004% dosed once-daily in the evening demonstrated 7-8 mm Hg reductions in
`intraocular pressure. In subgroup analyses of these studies, mean IOP reduction in black
`
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`Reference ID: 3009261
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`patients was up to 1.8 mm Hg greater than in non-black patients. It is not known at this
`time whether this difference is attributed to race or to heavily pigmented irides.
`
`In a multi-center, randomized, controlled trial, patients with mean baseline intraocular
`pressure of 24-26 mm Hg on TIMOPTIC* 0.5% BID who were treated with
`TRAVATAN® (travoprost ophthalmic solution) 0.004% dosed QD adjunctively to
`TIMOPTIC* 0.5% BID demonstrated 6-7 mm Hg reductions in intraocular pressure.
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`TRAVATAN® (travoprost ophthalmic solution) 0.004% is a sterile, isotonic, buffered,
`preserved, aqueous solution of travoprost (0.04 mg/mL) supplied in Alcon’s oval DROP­
`TAINER® package system.
`
`TRAVATAN® is supplied as a 2.5 mL solution in a 4 mL and a 5 mL solution in a 7.5
`mL natural polypropylene dispenser bottle with a natural polypropylene dropper tip and a
`turquoise polypropylene or high density polyethylene overcap. Tamper evidence is
`provided with a shrink band around the closure and neck area of the package.
`
`NDC 0065-0266-25
`2.5 mL fill
`
`2 units, 2.5 mL fill NDC 0065-0266-17
`5 mL fill
`NDC 0065-0266-34
`
`
`Storage: Store at 2° - 25°C (36° - 77°F).
`
`17 PATIENT COUNSELING INFORMATION
`17.1 Potential for Pigmentation
`
`
`Patients should be advised about the potential for increased brown pigmentation of the
`iris, which may be permanent. Patients should also be informed about the possibility of
`eyelid skin darkening, which may be reversible after discontinuation of TRAVATAN®
`
`(travoprost ophthalmic solution) 0.004%.
`
`17.2 Potential for Eyelash Changes
`
`
`Patients should also be informed of the possibility of eyelash and vellus hair changes in
`the treated eye during treatment with TRAVATAN®. These changes may result in a
`disparity between eyes in length, thickness, pigmentation, number of eyelashes or vellus
`hairs, and/or direction of eyelash growth. Eyelash changes are usually reversible upon
`discontinuation of treatment.
`
`17.3 Handling the Container
`
`
`Patients should be instructed to avoid allowing the tip of the dispensing container to
`contact the eye, surrounding structures, fingers, or any other surface in order to avoid
`contamination of the solution by common bacteria known to cause ocular infections.
`Serious damage to the eye and subsequent loss of vision may result from using
`contaminated solutions.
`
`17.4 When to Seek Physician Advice
`
`
`
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`Reference ID: 3009261
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`Page 10
`
`Patients should also be advised that if they develop an intercurrent ocular condition (e.g.,
`trauma or infection), have ocular surgery, or develop any ocular reactions, particularly
`conjunctivitis and eyelid reactions, they should immediately seek their physician’s advice
`concerning the continued use of TRAVATAN®.
`
`
`17.5 Use with Contact Lenses
`
`
`Patients should be advised that TRAVATAN® contains benzalkonium chloride, which
`may be absorbed by soft contact lenses. Contact lenses should be removed prior to
`instillation of TRAVATAN® and may be reinserted 15 minutes following its
`administration.
`
`17.6 Use with Other Ophthalmic Drugs
`
`
`If more than one topical ophthalmic drug is being used, the drugs should be administered
`at least five (5) minutes between applications.
`
`Rx Only
`
`U.S. Patent Nos. 5,631,287; 5,849,792; 5,889,052; 6,011,062 and 6,235,781
`
`* TIMOPTIC is the registered trademark of Merck & Co., Inc.
`
`ALCON®
`
`ALCON LABORATORIES, INC.
`
`Fort Worth, Texas 76134 USA
`
`© 2006, 2010, 2011 Novartis
`
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`Reference ID: 3009261
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