Included as part of the PRECAUTIONS section.
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 IZBA (travoprost ophthalmic
solution) 0.003% can be continued in patients who develop noticeably increased
iris pigmentation, these patients should be examined regularly. (See PATIENT INFORMATION).
IZBA 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
IZBA should be used with caution in patients with active
intraocular inflammation (e.g., uveitis) because the inflammation may be
Macular edema, including cystoid macular edema, has been
reported during treatment with travoprost ophthalmic solution. IZBA 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
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 INFORMATION).
Use With Contact Lenses
Contact lenses should be removed prior to instillation of
IZBA and may be reinserted 15 minutes following its administration.
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
(for the mouse) and 700 times (for the rat) of the human exposure at the
maximum recommended human ocular dose (MRHOD) of 0.03 mcg/kg, based on
estimated plasma Cmax for active 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 10 mcg/kg/day (40 times the
MRHOD based on estimated plasma Cmax for active free acid). 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 (12 times the
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies of IZBA
(travoprost ophthalmic solution 0.003%) administration in pregnant women.
Malformations were observed in rats at doses that were 1500 times higher the
maximum recommended human ocular dose (MRHOD) based on estimated Cmax values
for the active free acid. Embryo lethality and decreased fetal/neonate
viability were observed in mice at subcutaneous doses 9-fold higher than the
MRHOD based on estimated Cmax for the active free acid. IZBA should be used
during pregnancy only if the potential benefit justifies the potential risk to
Travoprost was teratogenic in rats, at an intravenous
(IV) dose up to 10 mcg/kg/day (1500 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 did not produce malformations in rats at IV doses up to 3 mcg/kg/day
(470 times the MRHOD), or in mice at subcutaneous doses up to 1 mcg/kg/day (9
times the MRHOD). Travoprost produced an increase in post-implantation losses
and a decrease in fetal viability in rats at IV doses of 10 mcg/kg/day (1500
times the MRHOD) and in mice at subcutaneous doses of 1 mcg/kg/day (9 times the
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 (3.2 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.
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 IZBA is
administered to a nursing woman.
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.
No overall clinical differences in safety or
effectiveness have been observed between elderly and other adult patients.