NDA 21-994
`Page 3
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`TRAVATAN® Z
`(travoprost ophthalmic solution) 0.004%
`Sterile
`
`DESCRIPTION
`Travoprost is a synthetic prostaglandin F2α 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:
`
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`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 ophthalmic solution is supplied as sterile, buffered aqueous solution of
`travoprost with a pH of approximately 5.7 and an osmolality of approximately 290
`mOsmol/kg. Each mL of TRAVATAN® Z contains: Active: travoprost 0.004%. Inactives:
`polyoxyl 40 hydrogenated castor oil, sofZiaTM (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, sofZiaTM.
`
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`Travoprost free acid is a selective FP prostanoid receptor agonist which is believed to reduce
`intraocular pressure by increasing trabecular meshwork and uveoscleral outflow. The exact
`mechanism of action is unknown at this time.
`
`Pharmacokinetics/Pharmacodynamics
`Absorption:
`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 ± 007 ng/ml (ranged 0.01 to 0.052
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`NDA 21-994
`Page 4
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`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 that there was no significant accumulation.
`
`Metabolism:
`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.
`
`Elimination:
`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.
`
`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) or
`TRAVATAN® Z (travoprost ophthalmic solution)dosed once-daily in the evening demonstrated 7- 8
`mmHg reduction in intraocular pressure. In subgroup analysis of this study, mean IOP reduction in
`black 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 mmHg on TIMOPTIC* 0.5% BID who were treated with travoprost
`0.004% dosed QD adjunctively to TIMOPTIC* 0.5% BID demonstrated 6-7 mmHg
`reductions in intraocular pressure.
`
`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.
`
`INDICATIONS AND USAGE
`TRAVATAN® Z ophthalmic solution is indicated for the reduction of elevated intraocular
`pressure in patients with open-angle glaucoma or ocular hypertension who are intolerant of
`other intraocular pressure lowering medications or insufficiently responsive (failed to achieve
`target IOP determined after multiple measurements over time) to another intraocular pressure
`lowering medication.
`
`CONTRAINDICATIONS
`TRAVATAN® Z is contraindicated in patients with hypersensitivity to travoprost or any
`other ingredients in this product.
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`NDA 21-994
`Page 5
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`WARNINGS
`Prostaglandin analogues, including travoprost ophthalmic solution, 0.004% have been
`reported to cause changes to pigmented tissues. The most frequently reported changes
`have been increased pigmentation of the iris and periorbital tissue (eyelid) and increased
`pigmentation and growth of eyelashes. These changes may be permanent.
`
`Prostaglandin analogues, including travoprost ophthalmic solution, 0.004% may gradually
`change eye color, increasing the amount of brown pigmentation in the iris by increasing the
`number of melanosomes (pigment granules) in melanocytes. The long term effects on the
`melanocytes and the consequences of potential injury to the melanocytes and/or deposition of
`pigment granules to other areas of the eye are currently unknown. The change in iris color
`occurs slowly and may not be noticeable for months to years. Patients should be informed of
`the possibility of iris color change.
`
`Eyelid skin darkening has been reported in association with the use of prostaglandin
`analogues, including travoprost ophthalmic solution, 0.004%.
`
`Prostaglandin analogues, including travoprost ophthalmic solution, 0.004% may gradually
`change eyelashes in the treated eye; these changes include increased length, thickness,
`pigmentation, and/or number of lashes.
`
`Patients who are expected to receive treatment in only one eye should be informed about the
`potential for increased brown pigmentation of the iris, periorbital and/or eyelid tissue, and
`eyelashes in the treated eye and thus heterochromia between the eyes. They should also be
`advised of the potential for a disparity between the eyes in length, thickness, and/or number
`of eyelashes.
`
`PRECAUTIONS
`General
`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 cornea1 disease or a disruption
`of the epithelial surface (see Information for Patients).
`
`Patients may slowly develop increased brown pigmentation of the iris. This change may not
`be noticeable for months to years (see WARNINGS). Iris pigmentation changes may be
`more noticeable in patients with mixed colored irides, i.e., blue-brown, grey-brown, yellow-brown, and
`green-brown; however, it has also been observed in patients with brown eyes.
`The color change is believed to be due to increased melanin content in the stromal
`melanocytes of the iris. The exact mechanism of action is unknown at this time. Typically the
`brown pigmentation around the pupil spreads concentrically towards the periphery in affected
`eyes, but the entire iris or parts of it may become more brownish. Until more information
`about increased brown pigmentation is available, patients should be examined regularly and,
`depending on the situation, treatment may be stopped if increased pigmentation ensues.
`
`TRAVATAN® Z ophthalmic solution should be used with caution in patients with a history
`of intraocular inflammation (iritis/uveitis) and should generally not be used in patients with
`active intraocular inflammation.
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`NDA 21-994
`Page 6
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`Macular edema, including cystoid macular edema, has been reported during treatment with
`prostaglandin F2α analogues. These reports have mainly occurred in aphakic patients,
`pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors
`for macular edema. TRAVATAN® Z should be used with caution in these patients.
`
`TRAVATAN® Z has not been evaluated for the treatment of angle closure, inflammatory or
`neovascular glaucoma.
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`Information for Patients
`Patients should be advised concerning all the information contained in the Warnings and
`Precautions sections. Patients should also be instructed to avoid allowing the tip of the
`dispensing container to contact the eye or surrounding structures because this could cause the
`tip to become contaminated by common bacteria known to cause ocular infections. Serious
`damage to the eye and subsequent loss of vision may result from using contaminated
`solutions.
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`Patients also should be advised that if they develop an intercurrent ocular condition (e.g.,
`trauma, or infection) or have ocular surgery, they should immediately seek their physician’s
`advice concerning the continued use of the multi-dose container.
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`Patients should be advised that if they develop any ocular reactions, particularly conjunctivitis
`and lid reactions, they should immediately seek their physician’s advice.
`
`If more than one topical ophthalmic drug is being used, the drugs should be administered at
`least five (5) minutes apart.
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`Carcinogenesis, Mutagenesis, Impairment of Fertility
`Two-year carcinogenicity studies in mice and rats at subcutaneous doses of 10, 30, or
`100 µg/kg/day did not show any evidence of carcinogenic potential. However, at
`100 µg/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 µg/kg) corresponds to
`exposure levels over 400 times the human exposure at the maximum recommended human
`ocular dose (MRHOD) of 0.04 µg/kg, based on plasma active drug levels.
`
`Travoprost was not mutagenic in the Ames test, mouse micronucleus test and 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 µg/kg/day [250 times the maximum recommended human ocular dose of
`0.04 µg/kg/day on a µg/kg basis (MRHOD)]. At 10 µg/kg/day, the mean number of corpora
`lutea was reduced, and the post-implantation losses were increased. These effects were not
`observed at 3 µg/kg/day (75 times the MRHOD).
`
`Pregnancy: Teratogenic Effects
`Pregnancy Category: C
`Travoprost was teratogenic in rats, at an intravenous (IV) dose up to 10 µg/kg/day (250 times
`the 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.
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`NDA 21-994
`Page 7
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`Travoprost was not teratogenic in rats at IV doses up to 3 µg/kg/day (75 times the MRHOD),
`or in mice at subcutaneous doses up to 1.0 µg/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 µg/kg/day (75 times the MRHOD) and in mice at subcutaneous doses > 0.3
`µg/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 the doses of ≥ 0.12 µg/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 in pregnant women. TRAVATAN® Z
`should be used during pregnancy only if the potential benefit justifies the potential risk to the
`fetus.
`
`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 ophthalmic solution is administered to a nursing woman.
`
`Pediatric Use
`Safety and effectiveness in pediatric patients have not been established.
`
`Geriatric Use
`No overall differences in safety or effectiveness have been observed between elderly and
`other adult patients.
`
`ADVERSE REACTIONS
`The most common adverse event 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 subconjunctival hyperemia.
`
`Ocular adverse events reported at an incidence of 5 to 10 % in these clinical studies included decreased
`visual acuity, eye discomfort, foreign body sensation, pain and pruritis.
`
`Ocular adverse events reported at an incidence of 1 to 4% in clinical studies with TRAVATAN or
`TRAVATAN Z included abnormal vision, blepharitis, blurred vision, cataract, cells, conjunctivitis,
`corneal staining, dry eye, eye disorder, flare, iris discoloration, keratitis, lid margin crusting,
`photophobia, subconjunctival hemorrhage, and tearing.
`
`Nonocular adverse events reported at an incidence of 1 to 5% in these clinical studies were accidental
`injury, 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 infection.
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`NDA 21-994
`Page 8
`
`DOSAGE AND ADMINISTRATION
`The recommended dosage is one drop in the affected eye(s) once-daily in the evening. The
`dosage of TRAVATAN® Z ophthalmic solution should not exceed once-daily since it has
`been shown that more frequent administration of travoprost may decrease the intraocular
`pressure lowering effect.
`
`Reduction of intraocular pressure starts approximately 2 hours after administration of
`travoprost. The maximum effect is observed 12 hours after administration and is maintained
`throughout the day.
`
`TRAVATAN® Z 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.
`
`HOW SUPPLIED
`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 overcap. Tamper evidence is provided with a shrink band around the
`closure and neck area of the package.
`
`2.5 ml fill in 4 mL bottle
`5 mL fill in 7.5 mL bottle
`
`Storage: Store at 2º - 25ºC (36º - 77ºF).
`
`Rx Only
`
`U.S. Patent Nos. 5,889,052 and 6,235,781
`
`NDC 0065-0260-25
`NDC 0065-0260-05
`
` TIMOPTIC is the registered trademark of Merck & Co., Inc.
`
`
`ALCON®
`ALCON LABORATORIES, INC.
`Fort Worth, Texas 76134 USA
`© 2005-2006 Alcon, Inc.
`
` *
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`NDA 21-994
`Page 9
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`Carton Label for 2.5 mL and 5 mL:
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`NDA 21-994
`NDA 21-994
`Page 10
`Page 10
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`
` 4 0 6 1
`"III I II II" II
`Inmrm®
`(lnvuumsluuhlhalmiu
`sululiun)fl.fllll%
`
`
`
`
`Each mL contains:
`
`Active: trayoprest 0.04 mg
`lnactives: polyoxyl 40
`hydrogenated castor oil,
`3%“? (Doric acid, propylene
`glycol, sorhitol, zinc chloride),
`sodium hydroxide andlor
`hydrochloric acid to adjust pH,
`and purified water, USP.
`Preserved in the bottle with an
`ionic buffered system,50feié'_
`
`DROP-TAINER'E' Dispenser
`STORAGE: Store at 2" - 25°C
`
`(36" - 7?°F).
`FOR TOPICAL OPHTHALMIC
`USE ONLY
`USUAL DOSAGE: Instill one
`
`drop in the affected eye(s)
`once daily in the evening.
`US. Patent N05. 5,889,052;
`6,235,781
`© 2006 Alcon, Inc.
`Printed in USA
`
`NDC 0065—0260-05 Rx Only
`
`Tnnvnmr®
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`snlulinnlll.lllll%
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`9001486-0606
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`Alcori
`ALGOII LABORATORIES, Illc.
`Furl worth, TX 76134 [ISA
`www.3lconlabs.com
`
`5 mL
`STERILE
`
`3
`
`00650 26005
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`EXP.:
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`NDA 21-994
`Page 11
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`Carton Label for 2.5 mL Professional Sample:
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`NDA 21-994
`Page 12
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`Container Label for 2.5 mL and 5 mL:
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`Container Label for 2.5 mL Professional Sample:
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