WARNINGS
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS
Effects On Intraocular Pressure
Bimatoprost ophthalmic solution (UMIGAN®) lowers intraocular pressure (IOP) when instilled directly to the
eye in patients with elevated IOP. In clinical trials, in patients with or without elevated IOP, LATISSE®
lowered IOP, however, the magnitude of the reduction was not cause for clinical concern.
In ocular hypertension studies with LUMIGAN®, it has been shown that exposure of the eye to more than one
dose of bimatoprost daily may decrease the intraocular pressure lowering effect. In patients using LUMIGAN®
or other prostaglandin analogs for the treatment of elevated intraocular pressure, the concomitant use of
LATISSE® may interfere with the desired reduction in IOP. Patients using prostaglandin analogs including
LUMIGAN® for IOP reduction should only use LATISSE® after consulting with their physician and should be
monitored for changes to their intraocular pressure [see PATIENT INFORMATION].
Iris Pigmentation
Increased iris pigmentation has occurred when bimatoprost solution was administered. Patients should be
advised about the potential for increased brown iris pigmentation which is likely to be permanent [see ADVERSE REACTIONS and PATIENT INFORMATION].
The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in
the number of melanocytes. The long term effects of increased pigmentation are not known. Iris color changes
seen with administration of bimatoprost ophthalmic solution 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. Treatment with LATISSE® solution can be continued in patients who develop noticeably
increased iris pigmentation.
Lid Pigmentation
Bimatoprost has been reported to cause pigment changes (darkening) to periorbital pigmented tissues and
eyelashes. The pigmentation is expected to increase as long as bimatoprost is administered, but has been
reported to be reversible upon discontinuation of bimatoprost in most patients [see PATIENT INFORMATION].
Hair Growth Outside The Treatment Area
There is the potential for hair growth to occur in areas where LATISSE® solution comes in repeated contact
with the skin surface. It is important to apply LATISSE® only to the skin of the upper eyelid margin at the base
of the eyelashes using the accompanying sterile applicators, and to carefully blot any excess LATISSE® from
the eyelid margin to avoid it running onto the cheek or other skin areas [see PATIENT INFORMATION].
Intraocular Inflammation
LATISSE® solution should be used with caution in patients with active intraocular inflammation (e.g., uveitis)
because the inflammation may be exacerbated.
Macular Edema
Macular edema, including cystoid macular edema, has been reported during treatment with bimatoprost
ophthalmic solution (UMIGAN®) for elevated IOP. LATISSE® 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.
Contamination Of LATISSE® Or Applicators
The LATISSE® bottle must be kept intact during use. It is important to use LATISSE® solution as instructed,
by placing one drop on the single-use-per-eye applicator. The bottle tip should not be allowed to contact any
other surface since it could become contaminated. The accompanying sterile applicators should only be used on
one eye and then discarded since reuse of applicators increases the potential for contamination and infections.
There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical
ophthalmic products [see PATIENT INFORMATION].
Use With Contact Lenses
LATISSE® contains benzalkonium chloride, which may be absorbed by and cause discoloration of soft contact
lenses. Contact lenses should be removed prior to application of solution and may be reinserted 15 minutes
following its administration [see PATIENT INFORMATION].
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
Nightly Application
Inform patients that LATISSE® (bimatoprost ophthalmic solution) should be applied every night using only the
accompanying sterile applicators. They should start by ensuring their face is clean, all makeup is removed, and
their contact lenses removed (if applicable). Then, carefully place one drop of LATISSE® solution on the
disposable sterile applicator and brush cautiously along the skin of the upper eyelid margin at the base of the
eyelashes. If any LATISSE® solution gets into the eye proper, it will not cause harm. The eye should not be
rinsed.
Additional applications of LATISSE® will not increase the growth of eyelashes.
Inform patients not to apply to the lower eyelash line. Any excess solution outside the upper eyelid margin
should be blotted with a tissue or other absorbent material.
The onset of effect is gradual but is not significant in the majority of patients until 2 months. Counsel patients
that the effect is not permanent and can be expected to gradually return to the original level upon
discontinuation of treatment with LATISSE®.
Handling The Bottle And Applicator
Instruct patients that the LATISSE® bottle must be maintained intact and to avoid allowing the tip of the bottle
or applicator to contact surrounding structures, fingers, or any other unintended surface in order to avoid
contamination of the bottle or applicator by common bacteria known to cause ocular infections. Instruct patients
to only use the applicator supplied with the product once and then discard since reuse could result in using a
contaminated applicator. Serious infections may result from using contaminated solutions or applicators.
Potential For Intraocular Pressure Effects
LATISSE® may lower intraocular pressure although not to a level that will cause clinical harm.
In patients using LUMIGAN® or other prostaglandin analogs for the treatment of elevated intraocular pressure,
the concomitant use of LATISSE® may interfere with the desired reduction in IOP. Patients using prostaglandin
analogs for IOP reduction should only use LATISSE® after consulting with their physician.
Potential For Eyelid Skin Darkening
Inform patients about the possibility of eyelid skin darkening, which may be reversible after discontinuation of
LATISSE®.
Potential For Iris Darkening
Advise patients about the potential for increased brown iris pigmentation which is likely to be permanent.
Increased iris pigmentation has occurred when bimatoprost solution was administered.
Potential For Unexpected Hair Growth Or Eyelash Changes
Inform patients of the possibility of hair growth occurring outside of the target treatment area if LATISSE®
repeatedly touches the same area of skin outside the treatment area. They should also be informed of the
possibility of disparity between eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs,
and/or direction of eyelash growth. Eyelash changes are likely reversible upon discontinuation of treatment.
When To Seek Physician Advice
Advise patients that if they develop a new ocular condition (e.g., trauma or infection), experience a sudden
decrease in visual acuity, 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
LATISSE®. Patients on IOP-lowering medications should not use LATISSE® without prior consultation with
their physician.
Use With Contact Lenses
Advise patients that LATISSE® solution contains benzalkonium chloride, which may be absorbed by and cause
discoloration of soft contact lenses. Contact lenses should be removed prior to application of LATISSE® and
may be reinserted 15 minutes following its administration.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenesis
Bimatoprost was not carcinogenic in either mice or rats when administered by oral gavage for 104 weeks at
doses up to 2 mg/kg/day and 1 mg/kg/day, respectively (192 and 291 times the human systemic exposure
following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally
once daily based on blood AUC levels.
Mutagenesis
Bimatoprost was not mutagenic or clastogenic in the Ames test, in the mouse lymphoma test, or in the in vivo mouse micronucleus tests.
Impairment Of Fertility
Bimatoprost did not impair fertility in male or female rats up to doses of 0.6 mg/kg/day (103 times the human
systemic exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea or
conjunctival sac bilaterally once daily based on blood AUC levels.
Use In Specific Populations
Pregnancy
Risk Summary
There are no adequate and well-controlled studies of LATISSE (bimatoprost ophthalmic solution) 0.03%
administration in pregnant women. There is no increase in the risk of major birth defects or miscarriages based
on bimatoprost postmarketing experience.
In embryofetal development studies, administration of bimatoprost to pregnant mice and rats during
organogenesis, resulted in abortion and early delivery at oral doses at least 33 times (mice) or 94 times (rats) the
human exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea or
conjunctival sac bilaterally once daily, based on the area under the curve (AUC). These adverse effects were not
observed at 2.6 times (mice) and 47 times (rats) the human exposure following topical ophthalmic
administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily, based on AUC.
In pre/postnatal development studies, administration of bimatoprost to pregnant rats from organogenesis to the
end of lactation resulted in reduced gestation length and fetal body weight, and increased fetal and pup mortality
at oral doses at least 41 times the human systemic exposure following topical ophthalmic administration of
bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily, based on AUC. No adverse effects
were observed in rat offspring at exposures estimated at 14 times the human exposure following topical
ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily , based
on AUC.
Because animal reproductive studies are not always predictive of human response LATISSE 0.03% should be
administered during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Data
Animal Data
In an embryofetal development rat study, abortion was observed in pregnant rats administered bimatoprost
orally during organogenesis at 0.6 mg/kg/day (94 times the human systemic exposure following topical
ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily , based
on AUC. The No Observed Adverse Effect Level (NOAEL) for abortion was 0.3 mg/kg/day (estimated at 47
times the human systemic exposure following topical ophthalmic administration of bimatoprost 0.03% to the
cornea or conjunctival sac bilaterally once daily based on AUC). No abnormalities were observed in rat fetuses
at doses up to 0.6 mg/kg/day.
In an embryofetal development mouse study, abortion and early delivery were observed in pregnant mice
administered bimatoprost orally during organogenesis at doses greater than or equal to 0.3 mg/kg/day (33 times
the human systemic exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea
or conjunctival sac bilaterally once daily , based on AUC). The NOAEL for abortion and early delivery was 0.1
mg/kg/day (2.6 times the human systemic exposure following topical ophthalmic administration of bimatoprost
0.03% to the cornea or conjunctival sac bilaterally once daily, based on AUC) . No abnormalities were
observed in mouse fetuses at doses up to 0.6 mg/kg/day (72 times the human systemic exposure following
topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily,
based on AUC).
In a pre/postnatal development study, treatment of pregnant rats with bimatoprost orally from gestation day 7 to
lactation day 20 resulted in reduced gestation length, increased late resorptions, fetal deaths, and postnatal pup
mortality, and reduced pup body weight at doses greater than or equal to 0.3 mg/kg/day. These effects were
observed at exposures at least 41 times the human systemic exposure following topical ophthalmic
administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily, based on AUC).
The NOAEL for postnatal development and mating performance of the offspring was 0.1 mg/kg/day (estimated
at 14 times the human systemic exposure following topical ophthalmic administration of bimatoprost 0.03% to
the cornea or conjunctival sac bilaterally once daily, based on AUC).
Lactation
Risk Summary
It is not known whether topical ocular treatment with LATISSE 0.03% could result in sufficient systemic
absorption to produce detectable quantities in human milk. In animal studies, bimatoprost has been shown to be
present in breast milk of lactating rats at an intravenous dose (i.e., 1 mg/kg) 324 times the recommended human
ophthalmic dose (on a mg/m2 basis), however no animal data is available at clinically relevant doses.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical
need for LATISSE 0.03% and any potential adverse effects on the breastfed child from LATISSE 0.03%.
Pediatric Use
Use of LATISSE® was evaluated in a sixteen week double-masked, randomized, vehicle-controlled study
conducted in pediatric patients who were post-chemotherapy or had alopecia areata, and adolescents who had
hypotrichosis with no associated medical condition. No new safety issues were observed. The results of the
Global Eyelash Assessment are provided in Table 1.
Table 1. Number (%) of subjects with at least a 1-grade increase from baseline at month 4 in Global
Eyelash Assessment
|
Age Range
(years) |
LATISSE® |
Vehicle |
Difference (95% CI) |
Adolescents with hypotrichosis (N=40) |
15 - 17 |
19/26
(73%) |
1/14
(7%) |
66%
(44%, 88%) |
Post Chemotherapy Pediatric Patients (N=16) |
5 - 17 |
11/13
(85%) |
3/3
(100%) |
-15%
(-35%, 4%) |
Alopecia Areata Pediatric Patients (N=15) |
5 - 17 |
4/9
(44%) |
2/6
(33%) |
11%
(-39%, 61%) |
Geriatric Use
No overall clinical differences in safety or effectiveness have been observed between elderly and other adult
patients.