A 17 phenyl–substituted prostaglandin analog, 0.0005% latanoprost
decreases intraocular pressure by increasing uveoscleral outflow. Since its
introduction in 1996, several adverse effects have been reported, prominent
among which has been increased pigmentation of the iris and eyelashes. Although
darkening of the periocular skin is listed as an adverse effect in the product
insert, it has never been reported in the literature to our knowledge. We
describe 1 patient who had increased pigmentation of the periocular skin with
the use of latanoprost eye drops and decreased pigmentation within 2 months
of discontinuation of treatment with the eye drops.
A 75-year-old woman with a 2-year history of open-angle glaucoma began
using 0.005% latanoprost eye drops in June 1998. In September 1999 she reported
that the skin around her eyes was much darker than the rest of her face (Figure 1). She stated that this darkening
had occurred gradually during the past year. She was told to discontinue use
of the eye drops in both eyes. When she was seen 1 month later, a discernible
lightening of the periocular skin was noted. Two months after discontinuing
the use of latanoprost eye drops, the periocular skin color was significantly
lighter (Figure 2) and was unchanged
1 year later.
A 75-year-old woman after administering
latanoprost in both eyes for 15 months with darkened skin around both eyes.
The same patient 2 months after
discontinuing latanoprost use in both eyes. The periocular pigmentation is
The first reported and most prominent adverse effect of latanoprost
eye drops is darkening of the irides, with an initial reported incidence of
1% to 8%.1- 3
A more recently reported adverse effect is hyperpigmentation of eyelashes
as well as an increase in length and number.4,5
Both of these adverse effects are related to the melanogenic effect of prostaglandins.
The best-known stimulant of melanogenesis is UV light. How UV light causes
darkening of the skin is still uncertain, but it does cause the epidermal
release of various eicosanoids, including prostaglandins.6
Prostaglandin is one of the most potent stimulants of melanogenesis7 and melanocyte growth.8
Our patient developed hyperpigmentation of both eyelids while using
only latanoprost, and the condition resolved gradually during the 2 months
after discontinuation use of the medication. We have seen 2 other cases of
increased periocular pigmentation, 1 bilateral occurrence after 3 years of
exposure to latanoprost and 1 ipsilateral occurrence after 18 months of exposure
to latanoprost. Unfortunately, photographs to accurately document these cases
for publication were not of good enough quality.
Pharmacia & Upjohn (Peapack, NJ) maintains a worldwide adverse experience
system (WAES), a voluntary self-report database for adverse effects of Pharmacia
& Upjohn products. Through September 1999, there have been fewer than
40 reports of pigmentary changes to the skin in patients using Xalatan (latanoprost)
eye drops (written communication, John W. Granden, Pharmacia & Upjohn,
January 5, 2000). Most have involved darkening of the skin of the eyelids
and periocular region. There were a few reports of hyperpigmentation of the
neck, back, or temporal area of the face. One report of vitiligo and another
of periocular depigmentation in a black woman were received by the WAES. The
reported time of occurrence ranged from 3 weeks to 1 year after initiation
of Xalatan therapy, and the patients involved were mostly women aged 47 to
80 years. Since the end of 1999, there have been 13 reports recorded at the
National Registry of Drug-Induced Ocular Side Effects (NRDIOSE) of periocular
skin color changes purportedly caused by latanoprost (written communication,
Frederick T. Fraunfelder, MD, February 10, 2000). The WAES and NRDIOSE case
reports are unsolicited and nonsubstantiated and may not always represent
valid adverse effects of a medication. Interestingly, a search of various
medical databases from 1964 through January 2000 showed no report of hyperpigmentation
of periocular skin associated with the use of latanoprost eye drops. There
has been only 1 report of hyperpigmentation of periocular skin from a topical
eye drop; this involved a patient using a β-blocker.9
As with the initial report of hyperpigmentation of the eyelashes, we
suspect that increased awareness of periocular skin change as an adverse effect
of latanoprost will reveal a more widespread prevalence than previously suspected.
It should be recognized, however, that the changes in pigment of the iris,
eyelashes, and periocular skin seem to be benign and of little more than cosmetic
consequences. Furthermore, the skin changes seem to be reversible with discontinuing
use of the medication. The transit time from the basal layer to the stratified
corneum is 4 to 5 weeks, and shedding of the cornified layer requires 2 weeks
more. Thus, it takes at least 7 weeks for skin pigmentation to disappear after
discontinuing use of the medication, consistent with one of our patients.
In contrast, iris melanocytes remain stable and changes in iris pigmentation
after latanoprost use persist or regress very slowly. Patients should be warned
that periocular skin color changes could occur but that this adverse effect
is reversible and should not detract from the benefits of this effective medication.
This research was supported in part by the Irene Prime Research Fund
of New York Glaucoma Research Institute, New York, NY (Dr Ritch); by an unrestricted
departmental grant from Research to Prevent Blindness, New York; and by an
unrestricted grant from Pharmacia Corporation, Peapack, NJ.
Dr Zimmerman is the Global Ophthalmic Medical Director at Pharmacia
& Upjohn, Peapack. The other authors have no financial interests in any
products mentioned in this article.
Corresponding author and reprints: Martin Wand, MD, Consulting Ophthalmologists,
PC, 85 Seymour St, #522, Hartford, CT 06106 (e-mail: email@example.com).
Wand M, Ritch R, Isbey EK, Zimmerman TJ. Latanoprost and Periocular Skin Color Changes. Arch Ophthalmol. 2001;119(4):614-615. doi: