WARNINGS
TRAVATAN ® Solution has 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.
TRAVATAN® Solution 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 TRAVATAN® Solution. TRAVATAN® Ophthalmic Solution 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 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 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® 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.
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® Ophthalmic Solution should be used with caution in these patients.
TRAVATAN® Solution has not been evaluated for the treatment of angle closure, inflammatory or neovascular glaucoma.
TRAVATAN® Ophthalmic Solution should not be administered while wearing contact lenses.
Patients should be advised that TRAVATAN® Solution contains benzalkonium chloride which may be absorbed 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® Solution.
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.
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.
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.
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 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 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. Travoprost was not teratogenic in rats at IV doses up to 3 µg/kg/day (75 times the MRHOD), and 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® Solution 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® 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.
|
