 |
|
A 5-Year, Multicenter, Open-Label, Safety Study of Adjunctive Latanoprost Therapy for Glaucoma
Albert Alm, MD;
John Schoenfelder, PhD;
Jacquie McDermott, PhD
Arch Ophthalmol. 2004;122:957-965.
ABSTRACT
| |
Objective To evaluate the 5-year safety and efficacy of adjunctive 0.005% latanoprost once daily.
Methods Patients with primary open-angle or exfoliation glaucoma who completed a 3-year, open-label, uncontrolled, prospective trial could enter a 2-year extension phase. High-resolution color photographs of irides were taken at baseline and at 14 subsequent visits. Photographs were assessed for change in iris pigmentation compared with baseline. Intraocular pressures and adverse events were recorded.
Main Outcome Measure Development and progression of increased iris pigmentation over 5 years.
Results Of the 519 original patients, 380 enrolled in the extension phase with approximately 89% having an eye color known to be susceptible to color change. After 5 years, most patients had no increase in iris pigmentation, but certain colored irides exhibited notably greater susceptibility than others. For those whose irides did change, onset occurred during the first 8 months in 74% and during the first 24 months in 94%. No patient developed an increase in pigmentation after month 36; the rate of progression decreased over time. Adverse event profiles were similar for patients with and without increased pigmentation. The overall mean intraocular pressure reduction from baseline of 25% was sustained with no need for change in intraocular pressure–lowering treatment in 70% of the eyes.
Conclusion Latanoprost therapy is safe and well tolerated for long-term treatment of open-angle glaucoma.
INTRODUCTION
Latanoprost, a prostaglandin F2 analogue, is an effective ocular hypotensive for the treatment of glaucoma and ocular hypertension.1-4 Prostaglandin derivatives lower intraocular pressure (IOP) by increasing the outflow of aqueous humor, mainly uveoscleral outflow.5-6 The mechanism for this action is likely related to increases in the synthesis of matrix metalloproteinases7 and subsequent breakdown of collagen in the extracellular matrix of the ciliary muscle.8-9 Treatment with 0.005% latanoprost given once daily has been shown to be more effective than1-2,4 or as effective as3 the  -adrenergic receptor antagonist 0.5% timolol maleate given twice daily in reducing IOP over a 6-month period. More recently published longer-term trials (up to 3 years) have shown that latanoprost monotherapy provides clinically significant and sustained IOP reduction and is well tolerated both locally and systemically.10-12 Latanoprost also produces an additive IOP-reducing effect when used as adjunctive therapy with -adrenergic antagonists,13-14 adrenergic agonists,15 cholinergic agonists,16 or carbonic anhydrase inhibitors,17 but adjunctive use does not seem to be associated with an increased incidence or severity of adverse events compared with latanoprost monotherapy.
An ocular adverse event reported following short- and long-term latanoprost treatment is increased iris pigmentation, particularly in patients with green/brown, yellow/brown, or blue/gray with brown irides.1-3,10, 18 A similar effect was observed in preclinical trials, where it was shown that ocular application of prostaglandin F2 and prostagladin E2 to primates can lead to iris darkening.19 Increases in iris pigmentation also have been reported following ocular hypotensive therapy with other prostaglandin analogues and seems to be a class-related effect.20-23 There is no evidence suggesting that prostaglandin-induced changes in iridial pigmentation are associated with pathological processes.24
Prostaglandin ocular hypotensive agents have been commercially available for less than a decade and information on their long-term safety is incomplete. In particular, no study has specifically addressed the long-term (>2 year) progression of iris pigmentation. Although latanoprost therapy has been the most widely used of all prostaglandin derivatives, long-term progression had not been evaluated during previous clinical trials because patients were either given the choice or instructed to discontinue latanoprost treatment when increased iris pigmentation was detected.10-12,18
The present study evaluated the safety and efficacy of 0.005% latanoprost administered once daily for 5 years as adjunctive therapy to other IOP-lowering drugs in patients whose IOP was uncontrolled with monotherapy. The study consisted of a 3-year, open-label, uncontrolled, prospective trial with an optional 2-year, open-label extension phase. The primary aim was to examine the incidence and progression of increased iris pigmentation, assessed from iris photographs, in patients who continued in the extension phase. The overall safety of long-term latanoprost adjunctive treatment, particularly in relation to changes in iris pigmentation, was also documented. The secondary objectives were to evaluate the long-term efficacy of latanoprost as an IOP-lowering agent when administered as adjunctive therapy to other ocular hypotensive drugs and to assess whether increased iris pigmentation effects reductions in IOP.
METHODS
STUDY DESIGN
A 3-year, open-label, uncontrolled, prospective trial examined the safety and efficacy of 0.005% latanoprost when administered once daily as adjunctive therapy in patients with primary open-angle glaucoma or exfoliation glaucoma. Patients were enrolled at 27 centers in Sweden, England, the Netherlands, Australia, and Belgium. All patients completing the 3-year study were eligible to be enrolled in an optional 2-year extension phase, except for those enrolled at 2 centers that did not take part in the extension phase. The protocol was approved by the appropriate regulatory authorities and ethics review committee for each study site and was performed in accord with the ethical standards maintained in the 1964 Declaration of Helsinki.
Men or women aged 18 years or older with uncontrolled primary open-angle glaucoma or exfoliation glaucoma were eligible for the initial 3-year study. The condition of eligible patients was judged uncontrolled with monotherapy if the investigator intended to add another IOP-reducing medication. At the time of inclusion, patients were required to be receiving a single IOP-lowering therapy with one of the following medications: -adrenergic antagonist, adrenergic agonist, cholinergic agonist, or carbonic anhydrase inhibitor. Patients receiving dual therapy were eligible after washout of one of the medications. Required washout periods prior to the baseline visit were 3 weeks for -adrenergic antagonists, 2 weeks for adrenergic agonists, and 5 days for cholinergic agonists and carbonic anhydrase inhibitors.
Excluded from the study were patients with pigmentary glaucoma; an advanced glaucomatous condition likely requiring surgery within 3 years; closed or barely open anterior chamber angle or those having a history of acute angle-closure glaucoma; any condition preventing reliable applanation tonometry; any history of treatment with latanoprost; intraocular surgery within 6 months prior to the start of the study; ocular inflammation or infection within the previous 3 months; any abnormal ocular condition or symptom that, in the investigator's judgment, prevented the patient from enrolling in the study; or the inability to adhere to the study plan for visits, examination, or treatment. Female patients of childbearing potential not using adequate contraception, those who were pregnant, and nursing mothers were also ineligible.
The complete 5-year study included 15 scheduled patient visits. During the original 3-year period (visits 1-11), patients were seen at baseline, 1 month, and 4 months, and then at 4-month intervals. The 2-year extension phase comprised visits 12 through 15 at 6-month intervals. At baseline (visit 1), eligible patients gave written informed consent and underwent a screening examination that included the following: a review of ocular and medical history, recording of ongoing concomitant therapy and of ocular medications administered within the preceding 3 months, IOP measurement with a Goldmann applanation tonometer, best-corrected visual acuity, refraction, visual field testing (automated perimetry using program 24-2 on the Humphrey Field analyzer [Carl Zeiss Meditec, Dublin, Calif]; visual fields were evaluated preferably using Statpac 2 [Carl Zeiss Meditec]), gonioscopy, slitlamp examination, ophthalmoscopy, and photography of the optic disc. A series of photographs of the irides (see the "Measuring Iris Pigmentation" subsection below) also were taken at that time.
If a patient met all inclusion and no exclusion criteria at the baseline visit, 0.005% latanoprost was first administered either in the evening of the same day or in the morning of the next day. For the remainder of the study, patients instilled 0.005% latanoprost once daily either in the morning or in the evening, at least 5 minutes prior to administration of other IOP-reducing medication(s). During the study, one or more additional IOP-lowering therapies (-adrenergic antagonists, adrenergic agonists, cholinergic agonists, or carbonic anhydrase inhibitors) could be added or argon laser trabeculoplasty could be performed if IOP was not controlled with the combination of latanoprost and one other medication alone. Other therapies considered necessary for the patient's welfare could be given at the discretion of the investigator. All additional medications and procedures were recorded. Examinations at subsequent visits during the original 3-year period included the previously described ocular measurements with refraction evaluated yearly, visual field testing conducted at 8-month intervals beginning at month 4, and photography of the optic disc at month 36. As the objective of the 2-year extension phase was primarily to investigate long-term changes in iris pigmentation, examinations at visits 12 through 15 were limited to irides photography and IOP measurement.
MEASURING IRIS PIGMENTATION
To document and analyze any change in iris pigmentation, 2 types of color photographs were taken at each visit. "En face" photographs presented an overview of both eyes, including the normal position of the eyelids, and higher-magnification iris photographs of each eye enabled the judgment of tone of sclera and eyelids, as well as the irides. Photographs taken at different exposures and light conditions used the same type of film and aperture/shutter speed according to instructions given to photographers prior to the start of the study. Photographs were scanned into a computerized system (the IRIS system) that permits high-resolution, simultaneous, magnified, side-by-side display for masked assessment. Validation of this system was performed prior to analyses. The intraobserver  was 0.62 (72% agreement) and the interobserver was 0.48 (60% agreement); both parameters met standard acceptance criteria.
A trained reader assessed all high-resolution digital images of the photographs for change in iris pigmentation. The reader was aware that all patients were receiving 0.005% latanoprost therapy. With the exception of the baseline photograph, however, the chronological order of the photographs was masked for the reader. Assessment of change in iris color began with the classification of baseline iris color into 1 of 8 iris color groups: blue/gray, blue/gray with slightly brown (discrete areas of brown pigment), blue/gray with brown, green-brown, yellow-brown, brown (white), brown (black including Native American), and brown (Asian). Baseline iris color was classified by the trained reader who selected from 8 to 10 alternatives; selection was based on the reader's judgment of color not on a standardized scale. For each eye, the reader then compared all postbaseline photographs with the baseline photograph for grade of change in pigmentation (ie, no change or weak, moderate, or marked change). All photographs were ranked by degree of increased iris pigmentation from baseline to detect evidence of subtle progression that might be missed by assignment of grade of change only. Equal ranks were assigned when no difference in iris pigmentation could be seen. In patients for whom no baseline photograph was available, the reader assigned the photograph with the lightest iris color to the position of baseline photograph. The same independent reader reassessed all iris photographs for each analysis.
At the end of the study, all patients were categorized into 1 of 2 groups based on the grading of the iris photographs: those who developed increased iris pigmentation and those who did not develop increased iris pigmentation. Patients with at least 1 grade of weak pigmentation at any time during the study were classified as having developed increased iris pigmentation. Patients in each group then were stratified by baseline iris color. Analyses of progression of increased iris pigmentation from baseline based on grading were limited to those eyes that had data collected during the fifth year of the study and that had been treated from month 1.
Linear regression was used to assess the relationship between the rank given to each photograph and the time from baseline; eyes treated from month 1 that developed increased iris pigmentation were included in these analyses. Because the visit order of the photographs was masked to the reader, except for baseline photographs, the ranking was made independently of the order in which the photographs were taken. If iris pigmentation increased during a specified period, it could be expected that the photographs would be ranked in the correct temporal order, and the regression coefficient would be positive (>0). If no increase occurred, only random effects, such as differences in photographic quality, would determine the ranking. In this case, the regression coefficients would be expected to center on 0.
Interpretation of the iris photograph data can be highly dependent on the photographic quality and the threshold of the reader's assessment of increased iris pigmentation. Therefore, an algorithm was developed to adjust estimates of the proportion of eyes having increased iris pigmentation according to symmetry. Because no eye was expected to show a decrease in iris pigmentation, the proportion of eyes with a regression coefficient less than 0 (suggesting a decrease) would reflect those eyes where only the quality of the photographs suggested a decrease in iris pigmentation. In reality, there had been no change in iris pigmentation in these eyes (ie, these represent false-negative results). By reason of symmetry, the same proportion of false increases could be expected. Therefore, the proportion of eyes with a regression coefficient less than 0 was subtracted from the proportion of eyes with a regression coefficient greater than 0 (indicating increased iris pigmentation), providing an estimate of the proportion of eyes with a true increased iris pigmentation. This estimate was based on eyes treated from month 1 that developed increased iris pigmentation and was referred to as the "symmetry-adjusted estimate."
OTHER SAFETY MEASUREMENTS
Adverse events were recorded at each visit after baseline. An adverse event was defined as any undesirable event or unexpected ocular or nonocular symptom, considered related or unrelated to study medication, that occurred during the 5-year treatment period. Investigators openly questioned patients about adverse events occurring between visits. Objective findings by investigators were considered to be adverse events if they had been absent previously or had increased in severity from a previous visit. Serious adverse events included those that were life-threatening or resulted in death, hospitalization, disability, congenital anomaly, required intervention to prevent permanent damage, or were sight threatening. Study investigators informed the appropriate ethics review committee of any serious adverse event associated with the study medication.
Adverse events were mapped to standardized World Health Organization terms and then tabulated with regard to type, duration, severity, seriousness, action taken, and outcome. Safety evaluations included data from all patients who enrolled in the extension phase and who received at least 1 drop of 0.005% latanoprost between the month 36 and month 60 visits.
EFFICACY MEASUREMENT
At every visit, IOP was measured in both eyes with a calibrated Goldmann applanation tonometer. Where possible, the same examiner performed the IOP readings and the same tonometer was used at each visit for a given patient. If both eyes were designated study eyes, the mean values of the IOP recordings in both eyes were used in the calculations. The change in IOP from baseline to a specific visit was defined as IOP at the specific visit minus IOP at baseline; thus, negative values represent IOP reductions. Intraocular pressure change (mean [SD]) over time was evaluated for all patients who received latanoprost therapy in the extension phase and for whom IOP data were available. Intraocular pressure changes also were summarized separately in patients with and without increased iris pigmentation.
RESULTS
Patient disposition is shown in Figure 1. In brief, 435 (83.8%) of 519 patients completed the original 3-year study, 380 (73.2%) of 519 patients subsequently enrolled in the 2-year extension phase of the study. Of these, 344 (90.5%) of 380 patients completed the extension phase. Reasons for withdrawal were similar for patients in the extension phase and the original 3-year study. Baseline (visit 1) demographic and medical characteristics of the 380 patients enrolling in the extension phase are summarized in Table 1. Characteristics of patients enrolled in the extension phase were similar to those enrolled in the original 3-year study. Ocular abnormalities were noted in many patients at baseline. The most common findings in the 380 patients enrolled in the extension phase were abnormalities of the optic nerve head (70.5% of the patients) and lens abnormalities (42.6% of the patients). Distributions of such baseline abnormalities were similar to those found in the 519 patients enrolled in the original 3-year study.
|
|
|
|
Figure 1. Disposition of patients in the 2-year extension phase.
|
|
|
|
|
|
|
Table 1. Baseline Demographic and Medical Characteristics for Patients Who Enrolled in the 2-Year Extension Phase
|
|
|
IRIS PIGMENTATION
In all, 127 (33.4%) of 380 patients who continued in the extension phase had developed increased iris pigmentation in one or both eyes after 5 years of adjunctive therapy with 0.005% latanoprost. Of the patients who developed increased iris pigmentation, 89% had a baseline eye color known to be susceptible to color change (mixed-color irides containing brown areas; Table 2). In particular, more than three quarters of the patients with either green-brown or yellow-brown eyes were affected. Patients with blue/gray without brown or brown (black or Asian) eyes did not develop increased iris pigmentation; however, these eye color groups contained only a few patients. Patients who developed increased iris pigmentation were demographically similar to the overall patient population.
|
|
|
|
Table 2. Increased Iris Pigmentation by Eye Color at Baseline
|
|
|
At baseline, abnormalities of the optic nerve head and disorders of the iris (eg, status after iridotomy) were slightly, but not significantly, more common in patients who later developed increased iris pigmentation compared with those who did not (74.8% vs 68.4% [P = .195,  2 test] and 19.7% vs 14.6% [P = .208, 2 test], respectively), but retinal damage (eg, degeneration of macula or the posterior pole) was slightly, but not significantly, less common in patients who later developed increased iris pigmentation (15.0% vs 22.5%, respectively; P = .082, 2 test). Overall, 116 (91.3%) of 127 patients with increased iris pigmentation and 236 (93.3%) of 253 patients without increased iris pigmentation were exposed to 0.005% latanoprost therapy for more than 1500 days during the 5-year study. Similar proportions of patients in these 2 groups completed the 2-year extension phase of the study (113/127 [88.9%] and 231/253 [91.3%], respectively). Baseline photographs for either or both eyes were missing for 32 patients; for those eyes, the photograph with the lightest color was used as baseline in the analyses reported here. Additional analyses excluding those patients yielded very similar results.
In the 127 patients who developed increased iris pigmentation, onset occurred during the first 8 months of the 5-year study for 94 (74.0%) of 127 patients, during the first 12 months for 103 (81.1%) of 127 patients, and during the first 24 months for 119 (93.7%) of 127 patients (Figure 2). All patients with increased iris pigmentation developed the condition by month 36.
|
|
|
|
Figure 2. First onset of increased iris pigmentation (patients with increased iris pigmentation, n = 127). The number of patients who had increased iris pigmentation detected at each visit is given above the bar.
|
|
|
Similar results were obtained when onset was analyzed for the 659 individual eyes that were treated since month 1. In all, 215 (37.8%) of 659 patients had increased pigmentation, and 151 (70.2%) of 215 patients affected eyes had onset during the first 8 months of treatment. All but 1 of the affected eyes had onset by month 36. One eye developed increased pigmentation at month 42; this did not represent a new patient with increased pigmentation because the other eye of the patient had developed increased pigmentation at month 32.
The analysis of progression by grade of increased iris pigmentation (no change, weak, moderate, or marked) was based on 179 eyes treated from month 1 and for which data were available during the fifth year after the baseline visit. During the fifth year after the baseline visit, maximal increases in pigmentation were considered marked in 34 (19.0%) of 179 of the affected eyes and moderate in 65 (36.3%) of 179 of the affected eyes. An increase in the incidence of marked increased iris pigmentation was observed each year throughout the 5-year study period, but this incremental yearly increase diminished over time.
The regression analysis of photographic ranking vs chronological order was performed for the 215 eyes treated from month 1 that developed increased iris pigmentation. The 95% confidence intervals for the regression coefficients were greater than 0 for the first, second, and third postbaseline years indicating progression of increased iris pigmentation over time. During the fourth and fifth years, however, 95% confidence intervals for regression coefficients were equally distributed above and below 0, indicating that the rate of progression was not significantly different from 0. Symmetry-adjusted estimates of proportions of eyes with progression of increased iris pigmentation showed a marked reduction in progression over the study period (Table 3).
|
|
|
|
Table 3. Symmetry-Adjusted Estimates of Proportion of Eyes With Progression of Increased Iris Pigmentation According to Time From Baseline*
|
|
|
OTHER ADVERSE EVENTS
Overall, during the 5-year study period, 3150 adverse events were reported for 359 of the 380 patients who enrolled in the 2-year extension phase. During the extension phase, 876 adverse events were reported by 275 of 380 patients. Most adverse events were classified as mild to moderate in intensity. Almost all patients (352 [92.6%] of 380 patients) experienced a vision-related adverse event, the most common of which were visual field defect, eye irritation, cataract, and eye abnormality, with incidences between 30% and 40%. Most ocular adverse events were mild in intensity. The most common systemic adverse events were classified as hypertension, headache, influenzalike symptoms, upper respiratory tract infection, bronchitis, and surgical intervention; proportions of patients reporting these events ranged from 5% to 10%. Most systemic adverse events were mild in intensity. Because patients were receiving dual therapy as a minimum, no attempt was made to assign causality of nonserious adverse events to a particular treatment.
In general, the reporting of ocular adverse events was independent of the presence of increased iris pigmentation. Events reported by more than 10% of the patients in either the increased iris pigmentation or the no increased iris pigmentation groups are summarized in Table 4. During the 60 months of treatment, 653 ocular events were reported in 121 (95.3%) of 127 patients with increased iris pigmentation, while 1070 such events were reported in 231 (91.3%) of 253 patients with no increased iris pigmentation. The incidence of increased iris pigmentation reported as an adverse event was significantly higher in patients whose iris photographs documented such an increase (49.6% vs 6.7%; P<.001, 2 test). (The fact that increased iris pigmentation was reported as an adverse event in fewer than half of the patients with documented increased iris pigmentation reflects that strict criteria were used in assessing iris photographs.) During the entire study, the following adverse events were reported by more than 5% more patients with documented increased iris pigmentation compared with those patients without documented increased iris pigmentation: visual field defect (43.3% vs 37.5%), cataract (37.0% vs 30.8%), eye hyperemia (33.1% vs 26.9%), optic atrophy (22.8% vs 17.4%), and abnormal lacrimation (11.8% vs 5.1%); only the difference in abnormal lacrimation was statistically significant. With the exception of surgical intervention for cataracts, none of these ocular adverse events led to a patient withdrawing from the study. Three patients withdrew owing to surgical intervention for cataracts.
|
|
|
|
Table 4. Ocular Adverse Events Reported by More Than 10% of the Patients in the Increased or No Increased Iris Pigmentation Groups, Months 0 to 60
|
|
|
Hypertrichosis (including lengthening of the eyelashes, darkening of the eyelashes, and the patient's being more aware of their eyelashes) was reported as an ocular adverse event for 54 (14.2%) of 380 patients during the study. There were no severe cases of hypertrichosis and no important difference in the incidence of hypertrichosis was noted between those who did vs those who did not have evidence of increased iris pigmentation based on photographic analyses (15.0% vs 13.8%, respectively; P = .77, 2 test).
During the original 3-year study, and considering all 519 enrolled patients, iritis-anterior uveitis was reported in 5 of 886 latanoprost-treated eyes and in 1 of 146 untreated eyes (Table 5); 1 patient with severe postcataract surgery inflammation was withdrawn from the study. During the 2-year extension phase, iritis-anterior uveitis was reported in 3 of 659 latanoprost-treated eyes and in 1 of 101 untreated eyes.
|
|
|
|
Table 5. Iritis-Anterior Uveitis
|
|
|
Also during the original 3-year study, and considering all 519 enrolled patients, cystoid macular edema was reported in 4 (0.6%) of 886 latanoprost-treated eyes and 1 (0.7%) of 146 untreated eyes (Table 6). One patient with severe cystoid macular edema due to hemispheric retinal vein occlusion was withdrawn from the study. During the 2-year extension phase, no new case of cystoid macular edema was reported.
|
|
|
|
Table 6. Cystoid Macular Edema
|
|
|
Of the 380 patients who enrolled in the extension phase, 140 (36.8%) had a serious adverse event (other than death). Most adverse events were systemic and involved cardiovascular events, malignancies, or skeletal pain and most were classified as such because they required hospitalization for surgical intervention (eg, for cataract extraction and/or trabeculectomy). There was no notable difference in the incidence or profile of serious ocular adverse events between patients who did or did not have increased iris pigmentation (P>.10 for all serious ocular adverse events, Fisher exact test).
One patient died of cardiac arrest after giving informed consent to join the extension phase but before taking any extension phase medication. During the fourth and fifth years of the study, that is, during the extension phase, 10 patients died because of events judged not to be related to the study drug.
A total of 19 patients permanently discontinued treatment with 0.005% latanoprost during the 2-year extension phase because of an adverse event—usually owing to a serious adverse event. Ten patients discontinued participation owing to systemic adverse events and 9 owing to ocular adverse events (trabeculectomy, deep sclerectomy with cataract extraction, iritis, and increased macula lutea degeneration). Proportions of patients discontinuing participation because of an adverse event were similar in those with and without increased iris pigmentation (7.1% vs 5.9%, respectively; P = .66, 2 test).
IOP-LOWERING EFFICACY
Considering all 380 patients who enrolled in the extension phase, mean (SD) IOP levels were reduced from 23.8 (4.4) mm Hg at baseline to 17.8 (3.8) mm Hg after 5 years (Table 7). Mean IOP levels were reduced during the first month of therapy by 6.6 (3.7) mm Hg and remained stable throughout the study (Table 7). The reduction in IOP levels was similar regardless of whether or not iris pigmentation increased.
|
|
|
|
Table 7. Changes in Mean Intraocular Pressure*
|
|
|
Of the 344 patients who completed the entire 5-year study, 224 (65%) of them did not have a change (either surgical or pharmacological) in IOP therapy while they were enrolled in the study. In some patients who received bilateral treatment, treatment needed to be changed in only 1 eye, and 412 (70%) of 590 eyes treated for the entire 5 years did not require a change in IOP therapy.
COMMENT
This study demonstrates that 0.005% latanoprost administered once daily as adjunctive therapy to other ocular hypotensive drugs over a 5-year period is safe and effective in patients with primary open-angle glaucoma or exfoliation glaucoma. Although this was primarily a safety study and latanoprost was used as adjunctive therapy, the mean IOP level was reduced from 23.8 mm Hg at baseline to 17.8 mm Hg at month 1 and that this reduction of greater than 25% was maintained throughout the 5-year study. Almost all ocular and systemic adverse events were mild in intensity. After 5 years, most patients had no increase in iris pigmentation. The well-established adverse effect of latanoprost-induced increased iris pigmentation was observed preponderantly in patients having an eye color known to be susceptible to color change. The incidence, nature, and severity of adverse events were similar for patients assessed as having increased pigmentation and for those who did not. Similarly, reductions in IOP were not associated with changes in pigmentation.
The effect of latanoprost and other prostaglandin derivatives on iris pigmentation has been described previously1-3,10, 12, 18, 20-24 and is confirmed in the present study in that eyes with brown areas on blue/gray, green, or yellow irides are more susceptible to increased iris pigmentation. In addition, changes were infrequently reported in patients with homogeneously blue, gray, green, or brown, or in those with mixed blue/gray irides. Despite these findings, however, the nature of the effects of latanoprost-induced pigmentation on the homogenous brown iris, remains unclear. In a study of 69 Japanese patients with glaucoma, all with brown irides, 27.5% developed increased iris pigmentation after 6 months of latanoprost as monotherapy or adjunctive therapy.25 The present study found increased pigmentation in 1 (14.3%) of 7 white and 0 (0%) of 6 black and Asian patients with brown irides. Interestingly, a 3-year study of latanoprost therapy in patients from Naples, Italy (all brown irides) found no iris pigment changes.11
The current research provides the first available information on the progression of pigment changes during long-term ocular administration of 0.005% latanoprost. Increased iridial pigmentation was observed in 127 (33.4%) of 380 patients after 5 years of adjunctive therapy with latanoprost. The condition developed during the first 12 months in 103 (81%) of 127 affected patients, and all patients with increased iris pigmentation developed it by month 36. In addition, symmetry-adjusted estimates of increased iris pigmentation progression in affected eyes showed a reduction in progression over the study period.
Evidence to date indicates that the effect of latanoprost on iris color is mediated through induction of melanogenesis within iris stromal melanocytes and not cell proliferation.24 Latanoprost increases both melanin content and the activity of tyrosinase, the rate-limiting enzyme in melanin biosynthesis, in cultured uveal melanocytes and melanoma cell lines.26-27 Similarly, iridial melanocytes from latanoprost-treated eyes of cynomolgus monkeys have shown increased amounts of melanin28 and increased transcription of tyrosinase.29 In human iridectomy specimens30-32 and human uveal melanoma lines,27 latanoprost treatment was not associated with cell proliferation, increased mitotic indexes, or morphological changes suggestive of underlying pathology.
Melanin synthesis in response to latanoprost treatment does not appear to have any effects beyond the iris stroma. Ultrastructural analysis has shown that melanocytes do not contain abnormally high numbers of melanin granules after latanoprost treatment.24 Patients observed for 2 years following latanoprost-induced increased pigmentation show no signs of melanin transport outside the iris18 or any indication of melanocyte rupture and scattering in tissue,31 an occurrence that may produce inflammatory pathologic features such as uveitis. No evidence exists to substantiate latanoprost-induced changes in melanin content in the iridial pigment epithelium,18 the source of melanin granules that interfere with trabecular meshwork outflow in pigmentary dispersion syndrome.33 Furthermore, latanoprost does not appear to increase pigmentation in the outflow system.31, 34 When Grierson et al34 studied the outflow system in a posttrabeculectomy specimen from a patient who received latanoprost therapy, no features other than those readily seen in primary open-angle glaucoma were apparent.
In the present study, most adverse events were classified as mild to moderate in intensity, and ocular adverse events generally were not associated with the presence of increased iris pigmentation. Although visual field defects, cataracts, eye hyperemia, optic atrophy, and abnormal lacrimation were reported more frequently in patients with increased iris pigmentation than in patients without increased iris pigmentation, none of these events was considered to be related to pigment induction, and with the exception of surgical intervention for cataracts, none caused a patient to withdraw from the study.
Mild inflammation of the iris or ciliary body (anterior uveitis) was observed in 10 eyes during the 5-year study. This adverse event was as common in eyes not treated with 0.005% latanoprost as in eyes treated with the study medication. Moreover, the late onset of uveitis ( 12 months in 9 of 10 cases) argues against a cause directly related to latanoprost therapy. A history of uveitis and active inflammation or previous ocular surgery have been associated with the development of uveitis in patients receiving latanoprost therapy, but a definitive causal relationship has yet to be demonstrated.35-36
Macular edema, including cystoid macular edema, has been related, albeit rarely, to latanoprost therapy.37-38 Four cases were observed in latanoprost-treated patients during the first 3 years of this study. In the 2 cases viewed as serious, latanoprost therapy was discontinued temporarily in 1 patient, while the other patient withdrew from the study. Both patients enrolled in the study with a history of retinal vein occlusion in at least 1 eye. A study evaluating retinal thickness in the fovea of latanoprost-treated glaucomatous eyes concluded that latanoprost was not a likely cause of retinal disorders in patients with normally functioning blood-ocular barriers.39 In general, individuals at particular risk for developing cystoid macular edema are pseudophakic and aphakic patients with coexisting ocular conditions that may lead to the breakdown of the blood-retinal barrier.37 Such patients may be underrepresented in the enrollment to this study and latanoprost should be used with care in these individuals.
CONCLUSIONS
The results of this open-label, multicenter, multinational, uncontrolled study demonstrate that 0.005% latanoprost administered once daily as adjunctive therapy for up to 5 years is safe and effective in reducing IOP in patients with primary open-angle and exfoliative glaucoma. Treatment with latanoprost was generally well tolerated both locally and systemically. Increased iris pigmentation, detected in one third of the patients during 5 years of treatment with latanoprost, was restricted primarily to patients with nonhomogeneous eye color. All patients who developed increased iris pigmentation did so within 36 months of initiating latanoprost therapy, and the rate of progression of iris pigmentation decreased over time. Finally, the presence of increased iris pigmentation did not affect the efficacy or overall safety of latanoprost therapy.
AUTHOR INFORMATION
Correspondence: Albert Alm, MD, Department of Neuroscience, Ophthalmology, University Hospital, SE 751 85 Uppsala, Sweden (Albert.Alm{at}akademiska.se).
Submitted for publication June 9, 2003; final revision received November 10, 2003; accepted February 12, 2004.
This study was supported by the Pharmacia Corporation. Drs Alm and Schoenfelder had complete access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
We thank Brad Simons, MD, PhD, for clinical support and Charles Hathaway, PhD, and Jane G. Murphy, PhD, for editorial assistance.
From Department of Neuroscience, Ophthalmology, University Hospital, Uppsala, Sweden (Dr Alm); and Pharmacia Ltd, London, England (Drs Schoenfelder and McDermott). The authors have no relevant financial interest in this article.
REFERENCES
1. Alm A, Stjernschantz J, for the Scandinavian Latanoprost Study Group. Effects on intraocular pressure and side effects of 0.005% latanoprost applied once daily, evening or morning: a comparison with timolol. Ophthalmology. 1995;102:1743-1752.
ISI
| PUBMED
2. Camras CB, for the United States Latanoprost Study Group. Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma: a six-month, masked, multicenter trial in the United States. Ophthalmology. 1996;103:138-147.
ISI
| PUBMED
3. Watson P, Stjernschantz J, for the Latanoprost Study Group. A six-month, randomized, double-masked study comparing latanoprost with timolol in open-angle glaucoma and ocular hypertension. Ophthalmology. 1996;103:126-137.
ISI
| PUBMED
4. Mishima HK, Masuda K, Kitazawa Y, Azuma I, Araie M. A comparison of latanoprost and timolol in primary open-angle glaucoma and ocular hypertension: a 12-week study. Arch Ophthalmol. 1996;114:929-932.
FREE FULL TEXT
5. Toris CB, Camras CB, Yablonski ME, Brubaker RF. Effects of exogenous prostaglandins on aqueous humor dynamics and blood-aqueous barrier function. Surv Ophthalmol. 1997;41(suppl 2):S69-S75.
6. Nilsson SF, Samuelsson M, Bill A, Stjernschantz J. Increased uveoscleral outflow as a possible mechanism of ocular hypotension caused by prostaglandin F2-1-isopropylester in the cynomolgus monkey. Exp Eye Res. 1989;48:707-716.
FULL TEXT
|
ISI
| PUBMED
7. Weinreb RN, Lindsey JD. Metalloproteinase gene transcription in human ciliary muscle cells with latanoprost. Invest Ophthalmol Vis Sci. 2002;43:716-722.
FREE FULL TEXT
8. Ocklind A. Effect of latanoprost on the extracellular matrix of the ciliary muscle: a study on cultured cells and tissue sections. Exp Eye Res. 1998;67:179-191.
FULL TEXT
|
ISI
| PUBMED
9. Sagara T, Gaton DD, Lindsey JD, Gabelt B'AT, Kaufman PL, Weinreb RN. Topical prostaglandin F2 treatment reduces collagen types I, III, and IV in the monkey uveoscleral outflow pathway. Arch Ophthalmol. 1999;117:794-801.
FREE FULL TEXT
10. Alm A, Widengård I. Latanoprost: experience of 2-year treatment in Scandinavia. Acta Ophthalmol Scand. 2000;78:71-76.
FULL TEXT
|
ISI
| PUBMED
11. Costagliola C, Del Prete A, Verolino M, et al. Effect of 0.005% latanoprost once daily on intraocular pressure in glaucomatous patients not adequately controlled by -blockers twice daily: a 3-year follow-up: experience and incidence of side effects in a prospective study on 76 patients. Graefes Arch Clin Exp Ophthalmol. 2002;240:379-386.
PUBMED
12. Watson PG, for the Latanoprost Study Group. Latanoprost. Two years' experience of its use in the United Kingdom. Ophthalmology. 1998;105:82-87.
FULL TEXT
|
ISI
| PUBMED
13. Alm A, Widengård I, Kjellgren D, et al. Latanoprost administered once daily caused a maintained reduction of intraocular pressure in glaucoma patients treated concomitantly with timolol. Br J Ophthalmol. 1995;79:12-16.
FREE FULL TEXT
14. Rulo AH, Greve EL, Hoyng PF. Additive effect of latanoprost, a prostaglandin F2 analogue and timolol in patients with elevated intraocular pressure. Br J Ophthalmol. 1994;78:899-902.
FREE FULL TEXT
15. Widengård I, Mäepea O, Alm A. Effects of latanoprost and dipivefrin, alone or combined, on intraocular pressure and on blood-aqueous barrier permeability. Br J Ophthalmol. 1998;82:404-406.
FREE FULL TEXT
16. Friström B, Nilsson SE. Interaction of PhXA41, a new prostaglandin analogue, with pilocarpine: a study on patients with elevated intraocular pressure. Arch Ophthalmol. 1993;111:662-665.
FREE FULL TEXT
17. O'Donoghue EP, for the UK and Ireland Latanoprost Study Group. A comparison of latanoprost and dorzolamide in patients with glaucoma and ocular hypertension: a 3-month, randomised study. Br J Ophthalmol. 2000;84:579-582.
FREE FULL TEXT
18. Wistrand PJ, Stjernschantz J, Olsson K. The incidence and time-course of latanoprost-induced iridial pigmentation as a function of eye color. Surv Ophthalmol. 1997;41(suppl 2):S129-S138.
19. Selen G, Stjernschantz J, Resul B. Prostaglandin-induced iridial pigmentation in primates. Surv Ophthalmol. 1997;41(suppl 2):S125-S128.
20. Fellman RL, Sullivan EK, Ratliff M, et al. Comparison of travoprost 0.0015% and 0.004% with timolol 0.5% in patients with elevated intraocular pressure: a 6-month, masked, multicenter trial. Ophthalmology. 2002;109:998-1008.
FULL TEXT
|
ISI
| PUBMED
21. Netland PA, Landry T, Sullivan EK, et al. Travoprost compared with latanoprost and timolol in patients with open-angle glaucoma or ocular hypertension. Am J Ophthalmol. 2001;132:472-484.
FULL TEXT
|
ISI
| PUBMED
22. Sherwood M, Brandt J, for the Bimatoprost Study Groups 1 and 2. Six-month comparison of bimatoprost once-daily and twice-daily with timolol twice-daily in patients with elevated intraocular pressure. Surv Ophthalmol. 2001;45(suppl 4):S361-S368.
23. Yamamoto T, Kitazawa Y. Iris-color change developed after topical isopropyl unoprostone treatment. J Glaucoma. 1997;6:430-432.
ISI
| PUBMED
24. Grierson I, Cracknell KP, Pfeiffer N. The iris after prostanoid treatment. Curr Opin Ophthalmol. 2001;12:112-118.
FULL TEXT
| PUBMED
25. Chiba T, Kashiwagi K, Kogure S, et al. Iridial pigmentation induced by latanoprost ophthalmic solution in Japanese glaucoma patients. J Glaucoma. 2001;10:406-410.
FULL TEXT
| PUBMED
26. Drago F, Marino A, La Manna C. -Methyl-p-tyrosine inhibits latanoprost-induced melanogenesis in vitro. Exp Eye Res. 1999;68:85-90.
FULL TEXT
|
ISI
| PUBMED
27. Dutkiewicz R, Albert DM, Levin LA. Effects of latanoprost on tyrosinase activity and mitotic index of cultured melanoma lines. Exp Eye Res. 2000;70:563-569.
FULL TEXT
|
ISI
| PUBMED
28. Prota G, Vincensi MR, Napolitano A, Selen G, Stjernschantz J. Latanoprost stimulates eumelanogenesis in iridial melanocytes of cynomolgus monkeys. Pigment Cell Res. 2000;13:147-150.
FULL TEXT
|
ISI
| PUBMED
29. Stjernschantz J, Ocklind A, Wentzel P, Lake S, Hu D-N. Latanoprost-induced increase of tyrosinase transcription in iridial melanocytes. Acta Ophthalmol Scand. 2000;78:618-622.
FULL TEXT
|
ISI
| PUBMED
30. Hu D-N, Stjernschantz J, McCormick SA. Effect of prostaglandins A2, E1, F2 and latanoprost on cultured human iridal melanocytes. Exp Eye Res. 2000;70:113-120.
FULL TEXT
|
ISI
| PUBMED
31. Pfeiffer N, Grierson I, Goldsmith H, Hochgesand D, Winkgen-Böhres A, Appleton P. Histological effects in the iris after 3 months of latanoprost therapy: the Mainz 1 study. Arch Ophthalmol. 2001;119:191-196.
FREE FULL TEXT
32. Tsai JC, Sivak-Callcott JA, Haik BG, Zhang J, McLean IW. Latanoprost-induced iris heterochromia and open-angle glaucoma: a clinicopathologic report. J Glaucoma. 2001;10:411-413.
FULL TEXT
|
ISI
| PUBMED
33. Farrar SM, Shields MB. Current concepts in pigmentary glaucoma. Surv Ophthalmol. 1993;37:233-252.
FULL TEXT
|
ISI
| PUBMED
34. Grierson I, Pfeiffer N, Cracknell KP, Appleton P. Histology and fine structure of the iris and outflow system following latanoprost therapy. Surv Ophthalmol. 2002;47(suppl 1):S176-S184.
35. Smith SL, Pruitt CA, Sine CS, Hudgins AC, Stewart WC. Latanoprost 0.005% and anterior segment uveitis. Acta Ophthalmol Scand. 1999;77:668-672.
FULL TEXT
| PUBMED
36. Fechtner RD, Khouri AS, Zimmerman TJ, et al. Anterior uveitis associated with latanoprost. Am J Ophthalmol. 1998;126:37-41.
FULL TEXT
|
ISI
| PUBMED
37. Gaddie IB, Bennett DW. Cystoid macula edema associated with the use of latanoprost. J Am Optom Assoc. 1998;69:122-128.
PUBMED
38. Warwar RE, Bullock JD, Ballal D. Cystoid macular edema and anterior uveitis associated with latanoprost use: experience and incidence in a retrospective review of 94 patients. Ophthalmology. 1998;105:263-268.
FULL TEXT
|
ISI
| PUBMED
39. Furuichi M, Chiba T, Abe K, et al. Cystoid macular edema associated with topical latanoprost in glaucomatous eyes with a normally functioning blood-ocular barrier. J Glaucoma. 2001;10:233-236.
FULL TEXT
| PUBMED
SECTION EDITOR: ROY BECK, MD, PhD
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati
What's this?
RELATED ARTICLES
Reporting the Results of Randomized Clinical Trials: A Priority of Archives of Ophthalmology
Roy W. Beck
Arch Ophthalmol. 2004;122(7):1038-1039.
EXTRACT
| FULL TEXT
Fish Stories and Clinical Trials
William C. Frayer and William J. Frayer
Arch Ophthalmol. 2004;122(7):1049-1051.
EXTRACT
| FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Heterochromia
Rehman
CMAJ 2008;179:447-448.
ABSTRACT
| FULL TEXT
A Study of Histopathological Features of Latanoprost-Treated Irides With or Without Darkening Compared With Non-Latanoprost-Treated Irides
Albert et al.
Arch Ophthalmol 2008;126:626-631.
ABSTRACT
| FULL TEXT
|
