TRAVATAN
`(travoprost ophthalmic solution) 0.004%
`Sterile
`
`DESCRIPTION
`Travoprost is synthetic prostaglandin F 2< analogue. Its chemical name is isopropyl (Z)-7-[(1R,2R,3R,5)-3,5-dihydroxy-2-R1 E,3-3-hydroxy-4-((ococ-
`trifluoro-m-tolyl)oxy]-1 -butenyUcyclopentyll-5-heptonoate. It has a molecular formula of C26H35F306 and a molecular weight of 500.56. The chemical
`structure of traeoprost is:
`
`C0CH(CH3)2
`
`O_hI’ CIF
`
`3
`
`HO (cid:9)
`
`014
`
`DM-00
`
`Travoprost is a clear, colorless to slightly yellow oil that is very soluble in ace000itrile, methanol, octunol, and chloroform. It is practically insoluble in water.
`TRAVATAN Ophthalmic Solution 0.004% is supplied as sterile, buffered aqueous solution of travaprost with a pH of approximately 6.0 and an asmelality of
`approximately 290 mOsmol/kg.
`Each mL of TRAVATAN 0.004% contains 40 ug traooprost. Beazalkonium chloride 0.015% is added as preservative. Inactive Ingredients ore: palyooyl 40
`hydrogenated castor oil, tromethamine, boric acid, mannitol, edetote disedium, sodium hydroxide and/or hydrochloric acid (to adjust pH( and
`purified water. (cid:9)
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`Traooprost free acid is a selective FP prostanoid receptor agonist which is believed to reduce intraocular pressure by increasing uveoscleral outflow. The
`enact mechanism of action is unknown at this time.
`Pharmacokinetics/Pharmacodynamics
`Absorption: Travaprast is absorbed through the cornea. In humans, peak plasma concentrations of travoprest free acid (25 pg/mL or less) were reached
`within 30 minutes following topical ocular administration and was rapidly eliminated.
`Metabolism: Travoprost an isopropyl ester prodrug, is hydrolyzed by ester0005 in the cornea to its biologically active free acid. Systemically, travoprost free
`acid is metabolized to inactive metabolites via beta-oxidation of the .(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 band.
`Excretion: Elimination of trvvoprost free acid from human plasma is rapid. Plasma levels are below the limit of quantitation (<10 pg/mL) within one hour
`following ocular instillation.
`Clinical Studies
`In clinical studies, patients with open-angle glaucoma or ocular hypertension and baseline pressure of 25 - 27 mmHg who were treated with TRAVATAN
`Ophthalmic Solution 0.004% dosed once-daily in the evening demonstrated 7-6 mmHg reductions in intraocular pressure. In subgroup analyses of these
`studies, mean lOP 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 intraocular pressure of 24 - 26 mmHg on TIMOPTIC 0.5% BID who were treated
`with TRAVATAN 0.004% dosed OD adjunctively to TIMOPTIC 0.5% BID demonstrated 6 - 7 mmHg redactions in intraocular pressure.
`INDICATIONS AND USAGE
`TRAVATAN Ophthalmic Solution is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension
`lop determined after multiple
`who are intolerant of other intraocular pressure lowering medications or insufficiently responsive (failed to achieve target
`measurements over time) to another intraocular pressure lowering medication.
`CONTRAINDICATIONS
`Known hypersensitivity to travoprost, benzalkenium chloride or any other ingredients in this product. TRAVATAN may interfere with the maintenance of
`pregnancy and should not be used by women during pregnancy or by women attempting to become pregnant
`WARNINGS
`TRAVATAN has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation
`of the iris and periorbitat tissue (eyelid) and increased pigmentation and growth of eyelashes. These changes may be permanent.
`TRAVATAN may gradually change eye color, increasing the amount of brown pigmentation in the iris by increasing the number of melanosomes (pigment
`granules) in rnelanocytes. The long term effects on the melunocytes and the consequences of potential injury to the melanocytes and/or deposition of
`pigment granules to ether 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 TRAVATAN.
`TRAVATAN O 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,
`perivrbital and/or eyelid tissue, and eyelashes in the treated eye and thus h000rochromio 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 corneal 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 maybe more noticeable in patients with mined colored irides, i.e., blue-brawn, 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 enact 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 ports 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 should housed with caution in patients with active intraocular inflammation )iritis/ueeitis).
`Macular edema, including cystoid macular edema, has been reported during treatment with prostaglandin F 2 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 should housed with caution in those patients.
`TRAVATAN has not been evaluated for the treatment of angle closure, inflammatory or 005eascular glaucoma.
`TRAVATAN has net been studied in patients with renal or hepatic impairment and should housed with caution in such patients.
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`1’RAVATANn Ophthalmic Solution should not be administered While wearing contact lenses.
`Patients should be advised that TRAVATAN I contains benzalkanium chloride Which maybe adsorbed by contact lenses. Contact lenses should be removed
`prior to the administration of the solution. Lenses may be reinserted 15 minutes following administration of TRAVATAN.
`Since prostaglandins are biologically active and may be absorbed through the skin, women Who are pregnant or attempting to become pregnant should
`exercise appropriate precautions to avoid direct exposure to the contents of the bottle, In case of occidental contact With the contents of the bottle,
`thoroughly cleanse the exposed area With soap and water immediately.
`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 lass of vision may result
`from using contaminated solutions,
`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 consumer.
`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 live (5) minutes apart.
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`Travoprost was out mutagenic in the Ames test, moose 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-S activation enzymes.
`Truaoprest did not affect mating or fertility indices in main or female rats at subcutaneous doses opts 10 hug/kg/day [250 times the maximum recommended
`human ocular dose of 0.04 ’ug/kg/day on a fug/kg basis (MRI-IOD)). At 10 rug/kg/day, the mean number of corpora lutea was reduced, and the post-
`implantation losses were increased. These effects were not observed at 3 fig/kg/day (75 times the MRHOD).
`Pregnancy: Teratogenic Effects
`Pregnancy Category: C
`Travoprost was teratngenic in rats, at an intravenous (l6.) dose opts 10 /ug/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 sternebran, domed head and hydrocephaly. Travoprost was not
`tnratogenic in rats at IV doses up to 3 ’ag/kg/day (75 times the MRHOD(, and in mice at subcutaneous doses up to 1.0 ivg/kg/day (26 times the MRHOD).
`Travoprost produced an increase in post-implantation losses and a decrease in fetal viability in rats at IV doses 3 rug/kg/day (75 times the MRHOD) and in
`mice at subcutaneous doses > 0.3 fIg/kg/day (7.5 times the MRI’IOD).
`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 fIg/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.
`No adequate and well-controlled studies have been performed in pregnant women. TRAVATAN may interfere with the maintenance of pregnancy and should
`not be used by women doting pregnancy or by women attempting to become pregnant.
`Nursing Mothers
`A study in lactating rats demonstrated that radiolabeled travoprost and/or its metabolites were excreted in milk, it is not knows 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.
`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 ocular adverse event observed in controlled clinical studies with TRAVATAN 0.004% was ocular hyperemia which was reported in 35 to
`50% of patients. Approximately 3% of patients discontinued therapy doe to conjunctival hyperemia.
`Ocular adverse events reported at an incidence of 5 to 10% included decreased visual acuity, eye discomfort, foreign body sensation, pain, and pruritus.
`Ocular adverse events reported at an incidence of 1 t 4% included, abnormal vision, blnpharitio, blurred vision, cataract cells, conjunctivitis, dry eye, eye
`disorder, flare, iris discoloration, keratitis, lid margin crusting, photophobia, subconjunctixal hemorrhage, and tearing.
`Nonxcular adverse events reported at a rate of its 5% were accidental injury, angina pectoris, anxiety, arthritis, back pain, bradycardia, bronchitis, chest
`pain, cold syndrome, depression, dyspepsia, gastrointestinal disorder, headache, hypercholesterolemia, hypertension, hypotension, infection, pain, prostate
`disorder, sinusitis, urinary incontinence, and urinary tract infection.
`DOSAGE AND ADMINISTRATION
`The recommended dosage is one drop in the affected eye(s) once-daily in the evening. The dosage of TRAVATAN should not exceed once-daily since it has
`been shown that more frequent administration may decrease the intraocular pressure lowering effect.
`Reduction of intraocular pressure starts approximately 2 hours after administration, and the maximum effect is reached after 12 boors.
`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 foe (5( minutes apart.
`HOW SUPPLIED
`TRAVATANn (travoprost ophthalmic solution( 0,004% is sterile, isotonic, buffered, preserved, aqueous solution of travoprost (0.04 mg/mL( supplied in
`Alcon’s oval DROP-TAINERfi package system inside a sealed foil poach.
`TRAVATAN is supplied as a 2.5 mL solution in 3.5 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.
`NDC 0065-0266-25, 2.5 mL fill
`Storage
`Store between 2 1 - 25(cid:176)C (36 1 - 77 1F(. Discard the container within 6 weeks of removing it from the sealed pouch.
`Rn Only
`U.S. Patent Nos. 5,631,287: 5,849,792; 5,889,052; 6,011,062, and 6,235,781.
`TIMOPTIC is a registered trademark of Merck & Co., Inc.
`
`Aicono
`
`PHARMACEUTICALS
`ALCON LABORATORIES, INC.
`Fort Worth, Texas 76134 USA
`' 2001 Alcoti Laboratories, Inc.
`
`34371 7-0601
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