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NR, Not reported aSignificant differences compared to latanoprost in at least one study.

NR, Not reported aSignificant differences compared to latanoprost in at least one study.

less than 1% of those treated with latanoprost required discontinuation because of these symptoms.

2.5.2 Iris Color Changes. Iris pigment changes are a well-documented side effect of chronic topical PG use in certain patients.28'50 Patients exhibiting darkening of the iris are most commonly those with a concentric brown ring of pigmentation around the pupil and a light gray, green, or blue color of the peripheral iris (figure 2.3).28'50'51 In open-label clinical trials, the overall incidence of increased iris pigmentation detectable by serial photographs over 3 years of treatment with latanoprost was 30%, with higher rates in patients with blue/gray-brown (45%), green-brown (69%), or yellow-brown (70%) eyes than in those with blue/gray (8%) or brown (17%) eyes.28,50 Similarly, in a 5-year, open-label multicenter study, 38% of patients had increases in iris pigmentation with onset occurring within 8 months in 70% of patients who developed darkening.28 While the overall incidence may be up to 30% to 40%, most cases are mild, and only about half the patients with documented changes reported this as a noticeable effect.28,50 Increases in iris pigmentation have also been reported with travoprost,3,49 bimatoprost,4,48 and unoprostone.52 Thus, increased iris pigmentation in patients with hazel or heterochromic irides appears to be a side effect of this entire class of medications.

It is thought that PGs may increase iris pigmentation by substituting for sympathetic innervation to the iris, which is required to maintain the level of pigmentation in iris melanocytes.53 PGs increase the melanin content of melanocytes in the iris, but not the total number of melanocytes.50,54 Specimens of irides from latanoprost-treated eyes with and without hyperpigmentation have revealed no pathologic changes.54-57

There is no evidence that PGs increase intraocular melanin other than in the stro-mal melanocytes in the iris. Changes in pigmentation in the iris pigment epithelium or in the trabecular meshwork have not been observed.50,55,58,59 Therefore, PGs would not be expected to worsen pigmentary dispersion glaucoma or induce uveitis through pigment release.

Camras Colour

Figure 2.3. (A) Eye before treatment. Note the brown ring of pigmentation around the pupil and light pigmentation in the periphery. This baseline iris color is most likely to exhibit darkening during treatment. (B) Same eye following latanoprost treatment. Reprinted with permission from Camras CB, Neely DG, Weiss EL. Latanoprost-induced iris color darkening: a case report with long-term follow-up. J Glaucoma. 2000;9:95-98.

Figure 2.3. (A) Eye before treatment. Note the brown ring of pigmentation around the pupil and light pigmentation in the periphery. This baseline iris color is most likely to exhibit darkening during treatment. (B) Same eye following latanoprost treatment. Reprinted with permission from Camras CB, Neely DG, Weiss EL. Latanoprost-induced iris color darkening: a case report with long-term follow-up. J Glaucoma. 2000;9:95-98.

2.5.3 Eyelash Changes. Topical PG analogs have been reported to increase length, number, thickness, and pigmentation of eyelashes and adjacent hair (figure 2.4) 2,3,44,48,49,60,61 Although phase III clinical trials for latanoprost did not find eyelash changes, one study reported that each of the 43 subjects treated with latanoprost in one eye for 11 to 40 weeks showed hypertrichosis and increased eyelash pigmentation.60 The incidence in a larger scale clinical trial with latanoprost was 14%.28 Eyelash changes have also been documented with travoprost and bi-matoprost both in phase III clinical trials and in subsequent reports.3,44,48,49 Subsequent comparative studies have documented a higher incidence of these changes with bimatoprost and travoprost than with latanoprost.2,3,45,46

2.5.4 Uveitis. There have been anecdotal and retrospective reports of the possible association of PG analogs with anterior uveitis.36,62-65 Earlier reports of anterior uveitis associated with latanoprost use have been summarized by Schumer et al.36 Although these reports have raised the possibility of an association between PG analogs and iritis, no clear causal relationship has been established. Several multicenter, randomized, masked clinical trials have failed to demonstrate a difference in ocular inflammation with PG analogs compared to timolol.3,4,12,21,26,29,30,44,47-49 In a multicenter trial with 198 patients, there were 10 patients in whom a few cells

Figure 2.4. (a) Eyelashes of upper eyelid after latanoprost treatment, and (b) untreated fellow eye of same patient. (c) Lashes of lower eyelid after latanoprost treatment, and (d) untreated fellow eye. Treated lashes are longer, thicker, darker, and more numerous. Reprinted with permission from Johnstone MA, Albert DM. Prostaglandin-induced hair growth. Surv Ophthalmol. 2002;47(suppl 1):S185-S202.

Figure 2.4. (a) Eyelashes of upper eyelid after latanoprost treatment, and (b) untreated fellow eye of same patient. (c) Lashes of lower eyelid after latanoprost treatment, and (d) untreated fellow eye. Treated lashes are longer, thicker, darker, and more numerous. Reprinted with permission from Johnstone MA, Albert DM. Prostaglandin-induced hair growth. Surv Ophthalmol. 2002;47(suppl 1):S185-S202.

were observed in the anterior chamber at least once during 12 months of treatment with latanoprost. Two of the 10 patients also had cells observed at baseline prior to treatment.27 There was no difference between patients treated with latanoprost or timolol in the incidence of aqueous flare or an anterior chamber cellular response during the randomized, masked, 6-month phase of the trial.29'47 Multiple studies using sensitive techniques such as fluorophotometry or laser-flare meters to determine the status of the blood-aqueous barrier or protein concentration in aqueous humor showed no significant effect following PG treatment for as long as 12 months.12,36,66 Comparative studies evaluating the effects of different PG analogs on flare and cellularity have failed to demonstrate a clear difference among them.42,67 Thus, it appears that the risk of developing significant uveitis with PG analogs is low and might be no higher than the risk of uveitis with other topical glaucoma medications such as pilocarpine, dorzolamide, or brimonidine.36 However, one should be aware of the possibility of a uveitic reaction and use caution in treating patients with risk factors for uveitis. PG analogs should be discontinued in patients who develop a significant uveitis when there is no other evident cause.

2.5.5 Cystoid Macular Edema. There have been anecdotal reports of CME associated with PG analog use.36,42,43,68-70 Cases of CME reported with topical latanoprost were compiled and analyzed, and almost all of the reported cases had other known risk factors for CME.36 These risk factors included open posterior capsules, recent intraocular surgery, complicated surgery with vitreous loss, a prior history of CME, concomitant dipivefrin therapy, or recent iritis.36,43 In a review of anecdotal, retrospective reports from which total numbers of eyes treated could be estimated, a total of two cases of CME occurred in at least 894 eyes of patients treated with latanoprost.71 A causal relationship between PG treatment and CME has still not been clearly established. As with uveitis, no controlled clinical studies support the speculation that latanoprost causes CME. There were no cases of CME attributable to PG use in more than 1,000 patients treated in phase III latanoprost clinical trials,30,36 nor were any cases of CME observed in the clinical trials for bimato-

44,48 3,49

prost or travoprost.

Topical PGs do not appear to affect the retinal vasculature. Monkeys treated with high doses of latanoprost and PGF2a analogs showed no evidence of CME or leakage on fluorescein angiography in either phakic or aphakic eyes treated 2 weeks to 6 months.20,72,73 In pseudophakic eyes with elevated IOP, treated with latano-prost twice daily for 4 weeks, there was no angiographic evidence of leakage or changes in the retinal vasculature.73

Other prospective studies have found some evidence for angiographic CME in patients treated with PG analogs. In a prospective study of pseudophakic and aphakic patients, 4 of 16 latanoprost-treated eyes, 1 of 16 bimatoprost-treated eyes, and 1 of 17 travoprost-treated eyes developed angiographic CME.42 Other studies have found an increased incidence of angiographic CME with latanoprost, timolol, and preserved vehicle, but not with preservative-free vehicle.74 They concluded that the benzalkonium chloride preservative was the probable cause of the increased incidence of CME.

Overall, the literature indicates that the risk of developing CME from PG use is low. However, in eyes with risk factors for CME, PGs should be used with caution until controlled trials have further defined the risk of this potential side effect.36,43

2.5.6 Other Local Side Effects. Increased pigmentation of periorbital skin has been associated with topical PG use in some studies.36,48,75 There was a 5% rate of eyelid skin darkening with bimatoprost compared to 0.4% with timolol in the phase III trials.48 A histopathologic study on patients with increased skin pigmentation following bimatoprost use demonstrated that the increased pigmentation was associated with increased melanogenesis but found no evidence of melanocyte proliferation or inflammation.76

Deepening of the lid sulcus has been anecdotally reported in patients being treated with bimatoprost.77 This side effect has not been clearly substantiated.

Rare anecdotal reports have described reactivation of herpes simplex virus ker-atitis or dermatitis in patients treated with topical PG.36 Although a couple of studies in rabbits provided equivocal evidence that latanoprost increased the severity and recurrence rate of herpes simplex keratitis, later studies have refuted this conten-tion.36,78 There is no evidence from any of the numerous controlled clinical trials or from a retrospective, population-based cohort study of claims records that PG analogs increase the risk of herpes simplex virus reactivation.36,79

2.5.7 No Systemic Side Effects. One would not expect significant systemic effects based on the pharmacokinetics of topically applied latanoprost. The biologically active acid of latanoprost that reaches the systemic circulation is metabolized primarily in the liver by fatty acid beta-oxidation and is rapidly eliminated primarily by the kidneys; its half-life is 17 minutes in human plasma. Latanoprost is measurable in human plasma only during the first hour after administration. There have been no systemic side effects attributed to topical PGs in any of the clinical trials. In contrast to timolol, PG analogs have no effect on blood pressure, heart rate, or pulmonary function.29,30,47,80 Topical beta blockers are well known to lower blood pressure, decrease heart rate, and worsen pulmonary function, and to exacerbate depression, cause impotence, and produce other serious side effects in some patients. The apparent lack of systemic side effects might be the most significant advantage that topical PGs have over beta blockers in glaucoma therapy. However, since rare side effects might not be discovered until a drug is in widespread use for many years, the possibility of a systemic side effect in the rare individual exists, especially for the newer PG analogs, as has been anecdotally reported.

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