NDA 21994/S-012
`Page 10
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`TRAVATAN Z® safely and effectively. See full prescribing information
`for TRAVATAN Z®.
`TRAVATAN Z® (travoprost ophthalmic solution) 0.004%, for topical
`
`ophthalmic use
`Initial U.S. Approval: 2001
`----------------------------INDICATIONS AND USAGE-------------------------­
`
`TRAVATAN Z® is a prostaglandin analog indicated for the reduction of
`elevated intraocular pressure (IOP) in patients with open-angle glaucoma or
`ocular hypertension. (1)
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`One drop in the affected eye(s) once daily in the evening (2)
`---------------------DOSAGE FORMS AND STRENGTHS--------------------­
`Ophthalmic solution containing travoprost 0.04 mg/mL (3)
`-------------------------------CONTRAINDICATIONS----------------------------­
`None (4)
`
`----------------------WARNINGS AND PRECAUTIONS----------------------­
` Pigmentation: 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)
`------------------------------ADVERSE REACTIONS-----------------------------­
`Most common adverse reaction (30% to 50%) is conjunctival hyperemia. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact
`Alcon Laboratories Inc. at 1-800-757-9195 or FDA at 1-800­
`FDA-1088 or www.fda.gov/medwatch.
`-----------------------USE IN SPECIFIC POPULATIONS----------------------­
`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. (8.4)
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`Revised: 9/2017
`
`_______________________________________________________________________________________________________________________________________
`
`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
`5.3
`Intraocular Inflammation
`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 Trials Experience
`6.2
`Postmarketing Experience
`USE IN SPECIFIC POPULATIONS
`
`6
`
`8
`
`Pregnancy
`8.1
`Nursing Mothers
`8.3
`Pediatric Use
`8.4
`Geriatric Use
`8.5
`Hepatic and Renal Impairment
`8.6
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3
`Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`CLINICAL STUDIES
`HOW SUPPLIED/STORAGE AND HANDLING
`PATIENT COUNSELING INFORMATION
`
`11
`12
`
`13
`
`14
`16
`17
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`_______________________________________________________________________________________________________________________________________
`
`Reference ID: 4156862
`
`

`

`NDA 21994/S-012
`Page 11
`
`FULL PRESCRIBING INFORMATION
`
`1
`INDICATIONS AND USAGE
`
`TRAVATAN Z® (travoprost ophthalmic solution) 0.004% is indicated for the reduction of elevated intraocular
`
`pressure in patients with open-angle glaucoma or ocular hypertension.
`
`DOSAGE AND ADMINISTRATION
`2
`The recommended dosage is one drop in the affected eye(s) once daily in the evening. TRAVATAN Z® (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 Z® may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure
`
`(IOP). If more than one topical ophthalmic drug is being used, the drugs should be administered at least 5 minutes
`apart.
`
`DOSAGE FORMS AND STRENGTHS
`3
`Ophthalmic solution containing travoprost 0.04 mg/mL.
`
`CONTRAINDICATIONS
`
`4
`None.
`
`WARNINGS AND PRECAUTIONS
`5
`Pigmentation
`5.1
`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 Z®
`
`(travoprost ophthalmic solution) 0.004% can be continued in patients who develop noticeably increased iris
`pigmentation, these patients should be examined regularly [see Patient Counseling Information (17)].
`5.2
`Eyelash Changes
`TRAVATAN Z® 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 Z® 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
`
`Reference ID: 4156862
`
`

`

`NDA 21994/S-012
`Page 12
`
`solution. TRAVATAN Z® 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 Z® 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)].
`5.7
`Use with Contact Lenses
`Contact lenses should be removed prior to instillation of TRAVATAN Z® and may be reinserted 15 minutes following
`its administration.
`
`ADVERSE REACTIONS
`6
`Clinical Trials Experience
`6.1
`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.
`The most common adverse reaction observed in controlled clinical trials 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 trials included decreased visual acuity, eye
`discomfort, foreign body sensation, pain and pruritus.
`Ocular adverse reactions reported at an incidence of 1% to 4% in clinical trials 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.
`6.2
`Postmarketing Experience
`Additional adverse reactions have been identified during post approval use of TRAVATAN® or TRAVATAN Z® in
`clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency
`cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of
`reporting, possible causal connection to TRAVATAN® or TRAVATAN Z®, or a combination of these factors,
`include: arrhythmia, vomiting, epistaxis, tachycardia, and insomnia.
`In postmarketing use with prostaglandin analogs, periorbital and lid changes including deepening of the eyelid sulcus
`have been observed.
`
`USE IN SPECIFIC POPULATIONS
`8
`Pregnancy
`8.1
`Pregnancy Category C
`Teratogenic effects: Travoprost was teratogenic in rats, at an intravenous 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
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`Reference ID: 4156862
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`

`NDA 21994/S-012
`Page 13
`
`malformations as well as external and visceral malformations, such as fused sternebrae, domed head and
`hydrocephaly. Travoprost was not teratogenic in rats at intravenous 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 intravenous doses greater than 3 mcg/kg/day (75
`times the MRHOD) and in mice at subcutaneous doses greater than 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 Z® (travoprost ophthalmic solution) 0.004%
`administration in pregnant women. Because animal reproductive studies are not always predictive of human response,
`TRAVATAN Z® should be 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 Z® is administered to a nursing woman.
`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
`Travoprost ophthalmic solution 0.004% 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.
`
`DESCRIPTION
`11
`Travoprost is a synthetic prostaglandin F analog. 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 Z® (travoprost ophthalmic solution) 0.004% is supplied as sterile, buffered aqueous solution of
`travoprost with a pH of approximately 5.7 and an osmolality of approximately 290 mOsmol/kg.
`TRAVATAN Z® contains Active: travoprost 0.04 mg/mL; Inactives: polyoxyl 40 hydrogenated castor oil, sofZia®
`
`
`
`Reference ID: 4156862
`
`

`

`NDA 21994/S-012
`Page 14
`
`(boric acid, propylene glycol, sorbitol, zinc chloride), sodium hydroxide and/or hydrochloric acid (to adjust pH) and
`purified water, USP. Preserved in the bottle with an ionic buffered system, sofZia®.
`
`CLINICAL PHARMACOLOGY
`12
`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
`Travoprost is absorbed through the cornea and is hydrolyzed to the active free acid. Data from 4 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.
`
`NONCLINICAL TOXICOLOGY
`13
`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 MRHOD of 0.04 mcg/kg/day on a mcg/kg basis). 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).
`
`CLINICAL STUDIES
`14
`In clinical studies, patients with open-angle glaucoma or ocular hypertension and baseline pressure of 25-27 mmHg
`who were treated with TRAVATAN® (travoprost ophthalmic solution) 0.004% or TRAVATAN Z® (travoprost
`ophthalmic solution) 0.004% dosed once-daily in the evening demonstrated 7-8 mmHg reductions in intraocular
`pressure. In subgroup analyses of these studies, mean IOP reduction in black patients was up to 1.8 mmHg 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.
`
`Reference ID: 4156862
`
`

`

`NDA 21994/S-012
`Page 15
`
`In a multi-center, randomized, controlled trial, patients with mean baseline intraocular pressure of 24-26 mmHg on
`TIMOPTIC* 0.5% twice daily who were treated with TRAVATAN® (travoprost ophthalmic solution) 0.004% dosed
`daily adjunctively to TIMOPTIC* 0.5% twice daily demonstrated 6-7 mmHg reductions in intraocular pressure.
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`TRAVATAN Z® (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 Z® 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.
`2.5 mL fill…………………..NDC 0065-0260-25
`5 mL fill…………………….NDC 0065-0260-05
`Storage: Store at 2°C - 25°C (36°F - 77°F).
`
`PATIENT COUNSELING INFORMATION
`17
`Potential for Pigmentation
`Advise the patient about the potential for increased brown pigmentation of the iris, which may be permanent. Inform
`the patient about the possibility of eyelid skin darkening, which may be reversible after discontinuation of
`TRAVATAN Z® (travoprost ophthalmic solution) 0.004%.
`Potential for Eyelash Changes
`Inform the patient about the possibility of eyelash and vellus hair changes in the treated eye during treatment with
`TRAVATAN Z®. 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.
`Handling the Container
`Instruct the patient 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.
`When to Seek Physician Advice
`Advise the patient 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 Z®.
`Use with Contact Lenses
`Contact lenses should be removed prior to instillation of TRAVATAN Z® and may be reinserted 15 minutes following
`its administration.
`Use with Other Ophthalmic Drugs
`If more than one topical ophthalmic drug is being used, the drugs should be administered at least 5 minutes between
`applications.
`Rx only
`
`*TIMOPTIC is a registered trademark of Merck & Co., Inc.
`
`
`Distributed by:
`
`Alcon Laboratories, Inc.
`
`Fort Worth, Texas 76134
`
`
`Reference ID: 4156862
`
`

`

`NDA 21994/S-012
`
`Page 16
`
`
`Alcon®
`
`a Novartis company
`
`© 2006, 2010, 2011, 2013, 2017 Novartis
`
`
`September 2017
`
`Reference ID: 4156862
`
`
`