NDA 21994/S-013
`Page 4
`FULL PRESCRIBING INFORMATION
`
`1
`INDICATIONS AND USAGE
`
`TRAVATAN Z® (travoprost ophthalmic solution) 0.004% is indicated for the reduction of elevated intraocular
`
`pressure (IOP) 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) 0.004% should not be administered more than once daily since it has been shown that more
`frequent administration of prostaglandin analogs may decrease the IOP lowering effect.
`Reduction of the IOP starts approximately 2 hours after the first administration with maximum effect reached after 12
`hours.
`TRAVATAN Z (travoprost ophthalmic solution) 0.004% may be used concomitantly with other topical ophthalmic
`drug products to lower 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 (travoprost ophthalmic solution) 0.004% 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 [see Patient Counseling Information (17)].
`5.3
`Intraocular Inflammation
`TRAVATAN Z (travoprost ophthalmic solution) 0.004% 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 Z (travoprost ophthalmic solution) 0.004% should be used with caution in aphakic patients, in
`
`Reference ID: 4580586
`
`

`

`NDA 21994/S-013
`Page 5
`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 (travoprost ophthalmic solution) 0.004% 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 (travoprost ophthalmic solution) 0.004% 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 (travoprost
`
`ophthalmic solution) 0.004% or TRAVATAN Z (travoprost ophthalmic solution) 0.004% 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.
`Non-ocular 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 (travoprost ophthalmic
`solution) 0.004% or TRAVATAN Z (travoprost ophthalmic solution) 0.004% 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
`Risk Summary
`There are no adequate and well-controlled studies in pregnant women to inform a drug-associated risk.
`In animal reproduction studies, subcutaneous (SC) administration of travoprost to pregnant mice and rats throughout
`
`Reference ID: 4580586
`
`

`

`NDA 21994/S-013
`Page 6
`the period of organogenesis produced embryo-fetal lethality, spontaneous abortion, and premature delivery at
`potentially clinically relevant doses.
`Advise pregnant women of a potential risk to a fetus. 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.
` The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the
`
`U.S. general population, the estimated background risk of major birth defects is 2%-4% and of miscarriage is 15%­
`20% of clinically recognized pregnancies.
`Data
`Animal Data
`An embryo-fetal study was conducted in pregnant rats administered travoprost once daily by SC injection from
`gestation day (GD) 6 to 18, to target the period of organogenesis. At 10 mcg/kg (60 times the maximum
`recommended human ocular dose [MRHOD], based on estimated plasma Cmax), travoprost was teratogenic in rats,
`evidenced by an increase in the incidence of skeletal malformations as well as external and visceral malformations,
`including fused sternebrae, domed head and hydrocephaly. Travoprost caused post-implantation loss at 10 mcg/kg.
`The no observed adverse effect level (NOAEL) for post-implantation loss was 3 mcg/kg (18 times the MRHOD,
`based on estimated plasma Cmax). The maternal NOAEL was 10 mcg/kg.
`An embryo-fetal study was conducted in pregnant mice administered travoprost once daily by SC injection from GD 6
`to 11, to target the period of organogenesis. At 1 mcg/kg (6 times the MRHOD, based on estimated plasma Cmax),
`travoprost caused postimplantation loss and decreased fetal weight. The no observed adverse effect level (NOAEL)
`for malformations was 0.3 mcg/kg (2 times the MRHOD, based on estimated plasma Cmax). The maternal NOAEL
`was 1 mcg/kg.
`Pre/postnatal studies were conducted in rats administered travoprost once daily by subcutaneous injection from GD 7
`(early embryonic period) to postnatal Day 21 (end of lactation period). At doses of greater than or equal to 0.12
`mcg/kg/day (0.7 times the MRHOD, based on estimated plasma Cmax), adverse pregnancy outcomes (embryo-fetal
`lethality, abortion, and early delivery), low-birth weight and developmental delays were observed. The NOAEL for
`adverse pregnancy outcomes, low-birth weight and developmental delay was 0.1 mcg/kg (0.6 times the MHROD,
`based on estimated plasma Cmax). The NOAEL for maternal toxicity was 0.72 mcg/kg (4 times the MHROD, based on
`estimated plasma Cmax).
`8.2
`Lactation
`Risk Summary
`There are no data on the effects of travoprost on the breastfed child or milk production. It is not known if travoprost is
`present in human milk following ophthalmic administration. A study in lactating rats demonstrated that radio-labeled
`travoprost and/or its metabolites were excreted in milk following subcutaneous administration.
`The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for
`TRAVATAN Z (travoprost ophthalmic solution) 0.004% and any potential adverse effects on the breast-fed child
`from TRAVATAN Z (travoprost ophthalmic solution) 0.004%.
`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
`
`Reference ID: 4580586
`
`

`

`NDA 21994/S-013
`Page 7
`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 g/mol. 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 (travoprost ophthalmic solution) 0.004% contains Active: travoprost 0.04 mg/mL; Inactives: polyoxyl
`40 hydrogenated castor oil, sofZia® (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
`IOP 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
`
`Reference ID: 4580586
`
`

`

`NDA 21994/S-013
`Page 8
`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 326 times (mouse) and 547 times (rat) the human exposure at the MRHOD of 0.04 mcg/kg, based on
`estimated plasma Cmax for active travoprost free acid.
`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 3 mcg/kg/day
`(18 times the MRHOD based on estimated plasma Cmax). At 10 mcg/kg/day (60 times the MRHOD, based on
`estimated plasma Cmax), the mean number of corpora lutea was reduced, and the post-implantation losses were
`increased.
`
`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 IOP. In sub­
`group 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.
`In a multi-center, randomized, controlled trial, patients with mean baseline IOP 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 IOP.
`
`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 (travoprost ophthalmic solution) 0.004% 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 to 25°C (36°F-77°F).
`After opening, TRAVATAN Z can be used until the expiration date on the bottle.
`
`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% [see Warnings and Precautions (5.1)].
`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 (travoprost ophthalmic solution) 0.004%. 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 [see Warnings and Precautions (5.2)].
`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
`
`Reference ID: 4580586
`
`

`

`NDA 21994/S-013
`Page 9
`solutions [see Warnings and Precautions (5.6)].
`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® (travoprost ophthalmic solution) 0.004% [see
`Warnings and Precautions (5.3, 5.4, 5.5)].
`Use with Contact Lenses
`Contact lenses should be removed prior to instillation of TRAVATAN Z (travoprost ophthalmic solution) 0.004% and
`may be reinserted 15 minutes following its administration [see Warnings and Precautions (5.7)].
`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.
`
`TIMOPTIC** is a registered trademark of Merck & Co., Inc.
`
`DROP-TAINER is a trademark of Alcon
`
`Distributed by:
`
`Novartis Pharmaceuticals Corporation
`East Hanover, New Jersey 07936
`
`© Novartis
`
`Reference ID: 4580586
`
`