`Page 4
`
`
`HIGHLIGHTS OF PRESCRIBING
`INFORMATION
`These highlights do not include all the information
`needed to use TRAVATAN Z® (travoprost
`
` ophthalmic solution) 0.004% safely and effectively.
`
`
` See full prescribing information for TRAVATAN
`Z® .
`
`TRAVATAN Z® (travoprost ophthalmic solution)
`
`
`0.004%
`
`
`Initial U.S. Approval: 2001
`
`
`
`
`----------INDICATIONS AND USAGE------------
`TRAVATAN Z® is a prostaglandin analog indicated
`
`for the reduction of elevated intraocular pressure 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-----
`
`Solution containing 0.04 mg/mL travoprost
`
`ophthalmic solution. (3)
`
`-----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: 7/2010
`
`
`
`
`
`FULL PRESCRIBING INFORMATION:
`CONTENTS*
`
`
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`
` Pigmentation
`5.1
`5.2
` Eyelash Changes
`
`
`5.3
`Intraocular Inflammation
`
`5.4 Macular Edema
`
`5.5 Angle-closure, Inflammatory, or Neovascular
`
`Glaucoma
` Bacterial Keratitis
`5.6
`
`
`
`
`5.7 Use with Contact Lenses
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Studies Experience
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`
`8.6 Hepatic and Renal Impairment
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`12.3 Pharmacokinetics
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`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
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing
`information are not listed.
`
`
`
`
`
`__________________________________________________________________________________________________
`
`
`
`4
`
`
`
`NDA 21-994/S-001
`Page 5
`
`
`FULL PRESCRIBING INFORMATION
`
`
`INDICATIONS AND USAGE
`1
`
`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. 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 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, 17.1).
`
`
`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 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, 17.3).
`
`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.
`
`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
`
`
`
`5
`
`
`
`
`
`NDA 21-994/S-001
`Page 6
`
`
` 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.
`
`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.
`
`
`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).
`
`
`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 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.
`
`
`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:
`
`
`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
`
`
`
`
`
`
`
`6
`
`
`
`NDA 21-994/S-001
`Page 7
`
`
` 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 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™ (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™.
`
`
`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
`
`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% or TRAVATAN Z®
`(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 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.
`
`
`
`
`
`
`7
`
`
`
`
`
`17.5 Use with 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. 5,889,052 and 6,235,781
`
`* TIMOPTIC is the registered trademark of Merck &
`
`
`Co., Inc.
`
`ALCON®
`
`ALCON LABORATORIES, INC.
`
`
`Fort Worth, Texas 76134 USA
`
`
`
`
`© 2006 Alcon, Inc.
`
`
`
`
`
`
`NDC 0065-0260-25
`NDC 0065-0260-05
`
`NDA 21-994/S-001
`Page 8
`
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
` 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
`
`
`5 mL fill
`
`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 Z®
`
`
`(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 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.
`
`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
`
`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 Z®.
`
`
`
`
`
`
`
`8
`
`