Side Effects Associated with Prostaglandin Analog Therapy

https://doi.org/10.1016/j.survophthal.2008.08.004Get rights and content

Abstract

Topical prostaglandin analogs, which have become first-line therapy in the medical management of glaucoma, have an excellent safety profile with regard to systemic side effects, but are associated with several ocular side effects. Some of these are common, with no apparent serious consequences other than cosmetic, whereas others are much less common but represent potentially sight-threatening side effects. The former group includes conjunctival hyperemia, elongation and darkening of eyelashes, induced iris darkening, and periocular skin pigmentation. The latter group of side effects, which are relatively rare and lack definitive causal relationship to prostaglandin analog therapy, includes iris cysts, cystoid macular edema, anterior uveitis, and reactivation of herpes simplex keratitis. Most of the literature regarding side effects associated with prostaglandin analogs involves the use of latanoprost, probably because it was the first to be studied. There is no evidence, however, aside from less conjunctival hyperemia with latanoprost, that the commercially available prostaglandin analogs differ significantly with regard to side effects.

Section snippets

Conjunctival Hyperemia

Prostaglandins are a family of autacoids in which some members have powerful effects on the vasculature, including vasoconstriction, vasodilation, or increased vascular permeability. Consequently, the effect on conjuctival vessels was carefully studied during the development of PGAs for topical application as ocular hypotensive agents. In the first study on the human eye, in 1985, Giuffrè found that the tromethamine salt of prostaglandin F (PGF) caused marked conjunctival hyperemia.48 The

Eyelash Changes

Darker and longer eyelashes are interesting and well-documented side effects associated with use of PGAs. The first report of a case with darker eyelashes was in the Scandinavian phase III study where it was observed in one patient.25 However, the prevalence of this side effect was undoubtedly underestimated in the phase III studies. It was a very unexpected effect and the examination protocols were more focused on evaluation of iris color and conjunctival injection than on eyelashes. An early

A Future Role in Hair Disorders?

There have also been some well-documented cases in which topical treatment with latanoprost was associated with growth of eyelashes in patients with alopecia areata.81, 83 This observation led Ross et al to conduct a small, prospective, randomized, and investigator-masked study on 11 patients with alopecia areata involving the eyebrows.99 No increased hair growth could be demonstrated, but as pointed out by the authors, the negative result does not rule out the possibility that different

Induced Iris Darkening

Induced iris darkening is a common side effect of topical PGA treatment18, 21, 139 that is not specific to latanoprost. It seems to be associated with all the prostaglandin antiglaucoma medications based on PGF, although the other PGAs may have iris darkening to a somewhat lesser extent.27, 82, 92, 108 Indeed the darkening is likely to be a class effect. There is evidence that naturally occurring prostaglandins, given topically to monkeys, produce the eye color change.106 This side effect was

Iris Cysts

A rare event, that may or may not have a direct association with PGA therapy, is the development of iris cysts. This association with latanoprost treatment was suggested by Krohn and Hove in a case report70 and was followed by additional reports implicating latanoprost as the possible cause of pigmented epithelial cyst formation.20, 72 In each case, there was decrease in the size of the cyst after stopping latanoprost medication with complete reversal in a matter of months.20, 70, 72

Periocular Skin Pigmentation

Darkening of the skin of the lids or other sites around the eye has been reported as an occasional side effect associated with topical latanoprost therapy,55, 69, 133 as well as the use of other PGAs,23, 35, 40, 43, 62, 133 although a cause-and-effect relationship has been questioned by some104 because the evidence base depends predominantly on case reports. As a result, there is no reliable figure at the present time for the incidence of skin pigmentation in association with PGA therapy. An

Cystoid Macular Edema

Cystoid macular edema (CME) was first recognized by Irvine in 1953 as a vitreal and macular abnormality following intracapsular cataract extraction.60 In 1966, Gass and Norton described the typical petaloid pattern of macular leakage by fluroescein angiography,45 and the condition became known as the Irvine-Gass syndrome. The angiographic findings may be documented without associated visual symptoms (angiographic CME) or less commonly with associated loss of visual acuity (clinical CME).

Anterior Uveitis

Prostaglandins at high levels are well-known mediators of ocular inflammation, inducing breakdown of the blood–aqueous barrier and elevation of the IOP. The development of PGAs as IOP-lowering drugs for treatment in glaucoma not only involved the use of very low concentrations, but of altering compounds to achieve an acceptable side effect profile, while retaining good IOP-lowering efficacy. With regard to latanoprost, as previously noted, this involved a phenyl substitution of PGF

Reactivation of Herpes Simplex Keratitis

In 1999, Wand and associates reported three patients in which herpes simplex keratitis (HSK) developed after initiation of latanoprost therapy.132 Two of these patients had a history of prior HSK, and the third developed HSK within 8 days of starting latanoprost. In one patient, the condition cleared with discontinuation of latanoprost, but recurred when rechallenged with the drug. In another patient with bilateral recurrence, the HSK could not be eradicated with antiviral therapy until the

Conclusion

Ocular side effects with a well–established cause-and-effect relationship to topical PGA therapy include conjunctival hyperemia, eyelash changes, induced iris darkening, and periocular skin pigmentation. Current evidence indicates that these represent only cosmetic concerns, with no serious ocular or systemic consequences. Other potential side effects are significantly less common and lack definitive proof of a causal relationship to PGA therapy, but have more serious sight-threatening

Method of Literature Search

Databases used included Pub Med, Web of Knowledge, International Glaucoma Review, and key review articles. Search words included prostaglandin, latanoprost, conjunctiva, hyperemia, hair growth, eyelash growth, iris pigmentation, cystoid macular edema, uveitis, and herpetic keratitits. Years covered were from 1990 to 2007. Additional sources included the authors’ personal databases. Criteria for inclusion and exclusion of articles were those which pertained to side effects associated with

References (140)

  • M. Centofanti et al.

    Prevention of dermatologic side effects of bimatoprost 0.03% topical therapy

    Am J Ophthalmol

    (2006)
  • C.S. Chen et al.

    Topical prostaglandin F(2alpha) analog induced poliosis

    Am J Ophthalmol

    (2004)
  • K.P. Cracknell et al.

    Latanoprost-induced iris darkening: a morphometric study of human peripheral iridectomies

    Exp Eye Res

    (2003)
  • K.P. Cracknell et al.

    Melanin in the trabecular meshwork is associated with age, POAG but not Latanoprost treatment. A masked morphometric study

    Exp Eye Res

    (2006)
  • K.P.B. Cracknell et al.

    Monte Carlo simulation of latanoprost induced iris darkening

    Comp Meth Prog Biomed

    (2007)
  • N.S. Crossley

    The synthesis and biological activity of potent, selective luteolytic prostaglandins

    Prostaglandins

    (1975)
  • M. Doshi et al.

    Clinical course of bimatoprost-induced periocular skin changes in Caucasians

    Ophthalmology

    (2006)
  • R.D. Fechtner et al.

    Anterior uveitis associated with latanoprost

    Am J Ophthalmol

    (1998)
  • A.J. Flach et al.

    Improvement in visual acuity in chronic aphakic and pseudophakic cystoid macular edema after treatment with topical 0.5% ketorolac tromethamine

    Am J Ophthalmol

    (1991)
  • W. Hanson et al.

    Subcutaneous or topical administration of 16, 16 dimethyl prostaglandin E2 protects from radiation-induced alopecia in mice

    Int J Radiat Oncol Biol Phys

    (1992)
  • L.W. Herndon et al.

    Increased periocular pigmentation with ocular hypotensive lipid use in African Americans

    Am J Ophthalmol

    (2003)
  • D.N. Hu et al.

    McCormick SA: Effect of prostaglandins A(2), E(1), F(2 alpha)and latanoprost on cultured human iridal melanocytes

    Exp Eye Res

    (2000)
  • S.R. Irvine

    A newly defined vitreous syndrome following cataract surgery interpreted according to recent concepts of the structure of the vitreous

    Am J Ophthalmol

    (1953)
  • H.E. Kaufman et al.

    Latanoprost increases the severity and recurrence of herpetic keratitis in the rabbit

    Am J Ophthalmol

    (1999)
  • H.E. Kaufman et al.

    Effects of topical unoprostone and latanoprost on acute and recurrent herpetic keratitis in the rabbit

    Am J Ophthalmol

    (2001)
  • R.H. Keates et al.

    Long-term follow-up of Nd:YAG laser posterior capsulotomy

    J Am Intraocul Implant Soc

    (1984)
  • A.G. Konstas et al.

    Latanoprost 0.005% versus bimatoprost 0.03% in primary open-angle glaucoma patients

    Ophthalmology

    (2005)
  • A.G. Konstas et al.

    Efficacy and safety of latanoprost versus travoprost in exfoliative glaucoma patients

    Ophthalmology

    (2007)
  • M.S. Kook et al.

    Increased eyelid pigmentation associated with use of latanoprost

    Am J Ophthalmol

    (2000)
  • J. Krohn et al.

    Iris cyst associated with topical administration of latanoprost

    Am J Ophthalmol

    (1999)
  • D.M. Kroll et al.

    Reactivation of herpes simplex virus keratitis after initiating bimatoprost treatment for glaucoma

    Am J Ophthalmol

    (2002)
  • N.G. Lindquist et al.

    Increased pigmentation of iridial melanocytes in primates induced by a prostaglandin analogue

    Exp Eye Res

    (1999)
  • N.G. Lindquist et al.

    Age-related melanogenesis in the eye of mice, studied by microautoradiography of 3H-methimazole, a specific marker of melanin synthesis

    Exp Eye Res

    (1998)
  • B.E. McCarey et al.

    Low incidence of iris pigmentation and eyelash changes in 2 randomized clinical trials with unoprostone isopropyl 0.15%

    Ophthalmology

    (2004)
  • S.E. Moroi et al.

    Cystoid macular edema associated with latanoprost therapy in a case series of patients with glaucoma and ocular hypertension

    Ophthalmology

    (1999)
  • P.A. Netland et al.

    Travoprost compared with latanoprost and timolol in patients with open-angle glaucoma or ocular hypertension

    Am J Ophthalmol

    (2001)
  • R.S. Noecker et al.

    A six-month randomized clinical trial comparing the intraocular pressure-lowering efficacy of bimatoprost and latanoprost in patients with ocular hypertension or glaucoma

    Am J Ophthalmol

    (2003)
  • R.K. Parrish et al.

    A comparison of latanoprost, bimatoprost, and travoprost in patients with elevated intraocular pressure: a 12-week, randomized, masked-evaluator multicenter study

    Am J Ophthalmol

    (2003)
  • E.K. Ross et al.

    Lack of efficacy of topical latanoprost in the treatment of eyebrow alopecia areata

    J Am Acad Dermatol

    (2005)
  • J.A. Rowe et al.

    Adverse side effects associated with latanoprost

    Am J Ophthalmol

    (1997)
  • ___

    Incidence of a latanoprost-induced increase in iris pigmentation in Japanese eyes

    Jpn J Ophthalmol

    (2006)
  • Z.A. Abdel-Malek et al.

    In vitro modulation of proliferation and melanization of S91 melanoma cells by prostaglandins

    Cancer Res

    (1987)
  • D.M. Albert et al.

    A study of iridectomy histopathologic features of latanoprost- and non-latanoprost-treated patients

    Arch Ophthalmol

    (2004)
  • D.M. Albert et al.

    Iris melanocyte numbers in Asian, African American, and Caucasian irides

    Trans Am Ophthalmol Soc

    (2003)
  • A. Alm et al.

    McDermott J: A 5-year, multicenter, open-label, safety study of adjunctive latanoprost therapy for glaucoma

    Arch Ophthalmol

    (2004)
  • A. Alm et al.

    PhXA34, a new potent ocular hypotensive drug. A study on dose-response relationship and on aqueous humor dynamics in healthy volunteers

    Arch Ophthalmol

    (1991)
  • M. Astin

    Effects of prostaglandin E2, F2alpha, and latanoprost acid on isolated ocular blood vessels in vitro

    J Ocul Pharmacol Ther

    (1998)
  • M. Astin et al.

    Mediation of prostaglandin f2 alpha-induced ocular surface hyperemia by sensory nerves in rabbits

    Curr Eye Res

    (1997)
  • M. Astin et al.

    Selén G: Role of nitric oxide in PGF2 alpha-induced ocular hyperemia

    Exp Eye Res

    (1994)
  • G. Beam et al.

    Association between ocular herpes simplex virus and topical ocular hypotensive therapy

    J Glaucoma

    (2004)
  • Cited by (0)

    The supplement in which this article is published was funded by Pfizer. The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Dr Grierson holds unrestricted research grants from Pfizer and Alcon.

    View full text