Clinical Efficacy of Olopatadine Hydrochloride Ophthalmic Solution 0.2% Compared with Placebo in Patients with Allergic Conjunctivitis or Rhinoconjunctivitis: A Randomized, Double-Masked Environmental Study Mark B. Abelson, MD,lB3 Paul J. Gomes, BS,3 Cullen T. Vogelson, PhD,4 Terri A. Pasquine, MS, 4 Robert D. Gross, MD,5 E Dare11 Turner, PhD,4 David T. Wells, RN, BSN,4 Michael VW. Bergamini, PhD,4 and Stella M. Robertson, PhD4 lSchepens Eye Research Institute, Boston, 2Harvard Medical School, Boston, 30phthalmic Research Associates, North Andover, Massachusetts, 4Alcon Research, Ltd., Fort Worth, and 5Department of Ophthalmology, University of Texas Southwestern Medical Centel; Dallas, Texas

ABSTRACT Background: Previous studies have suggested that olopatadine hydrochloride ophthalmic solution 0.2% administered once daily is effective for up to 24 hours after instillation and is well tolerated in adults and children aged 23 years. Objective: The goal of this study was to evaluate the efficacy and safety profile of olopatadine 0.2% compared with placebo in patients with seasonal allergic conjunctivitis or rhinoconjunctivitis. Methods: This was a lo-week, randomized, placebo-controlled, double-masked environmental study conducted during the spring allergy season (April-August) of 2003. Patients assessed their ocular signs and symptoms in terms of frequency (whole-unit scale from 0 to 5) and severity (half-unit scale from 0 to 4), and grass pollen counts were obtained daily for each investigative site. Responder analyses were conducted by pollen level (frequency based) and pollen period (severity based) to evaluate the clinical significance of differences in ocular itching and redness between treatment groups. Results: Two hundred sixty patients (137 females, 123 males) were enrolled in the study, including 28 children aged between 11 and 17 years; the overall population was 74% white, 11% black, 4% Hispanic, and 11% other. The frequency-based responder analyses of ocular itching and redness showed that when grass pollen counts were high (>20 gr/m3 air), a respective 21% and 14% of patients in the olopatadine 0.2% group assessed the frequency of ocular itching and redness as ~2, compared with 47% and 3 1% of patients in the placebo group (P < 0.001 for ocular itching; P < 0.003 for redness). The results of the severity-based responder analyses by peak pollen period were consistent with those of the frequency-based analyses. Compared with placebo, olopatadine 0.2% was associated with significant reductions in calculated mean scores for ocular itching and redness by pollen level and by pollen period. No patient was discontinued from the study because of a treatment-related adverse event, and no patient experienced a treatment-related serious adverse event. Conclusion: In the patients studied, olopatadine 0.2% appeared to be effective and well tolerated when administered once daily for the treatment of the ocular signs and symptoms of allergic conjunctivitis or rhinoconjunctivitis. (Clin Ther: 2004;26:1237-1248) Copyright 0 2004 Excerpta Medica, Inc. Key words: allergic conjunctivitis, ocular allergy, olopatadine, Patanol. Accepted for publication June 16,2004. Printed in the USA. Reproduction in whole

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INTRODUCTION

Allergic conjunctivitis is an allergen-induced inflammatory response that usually affects adults between the ages of 20 and 40 years. 1 Symptoms and signs of allergic conjunctivitis include ocular itching, injection (redness/hyperemia), chemosis, and tearing) The topical ocular antiallergic medication Patanol ® (Alcon Laboratories, Inc., Fort Worth, Texas) contains the active ingredient olopatadine hydrochloride 0.1% and the excipient benzalkonium chloride (BAC). It exerts its antiallergic effects through diverse mechanisms of action. It inhibits the release of preformed and newly synthesized proinflammatory mediators from h u m a n conjunctival mast cells 2-6 and has demonstrated antihistaminic activity both in vitro and in vivo. 2&r-9 It has been shown to inhibit histamine-induced production of proinflammatory cytokines by human conjunctival epithelial cells. ~ Furthermore, it decreases immunologically activated mast cell supernatant-mediated upregulation of intercellular adhesion molecule-1 on human conjunctival epithelial cells. ~° Inhibitory effects on eosinophil influx into the sites of allergic reactions and degranulation of these cells have also been reported.lM3 During pharmacologic evaluation of olopatadine, it was noted that when the drug was administered topically to the eyes of animals, it conferred protection from histamine or allergen (ovalbumin) challenge in sensitized animals for up to 24 hours (data on file, Alcon Laboratories, Inc.). These data, in conjunction with the results of pharmacokinetic and receptorinteraction studies (data on file), suggested the potential for a once-daily formulation of olopatadine. This led to development of a formulation having an olopatadine concentration of 0.2% and the excipients BAC, disodium ethylenediaminetetraacetic acid (EDTA), and povidone (polyvinylpyrrolidone, a solubilizing agent). Previous clinical studies using the conjunctival allergen challenge (CAC) model found olopatadine 0.2% effective in reducing the signs and symptoms of allergic conjunctivitis. ~<~5 The results of these studies, along with those of a 6-week safety trial, ~6 suggest that olopatadine 0.2% administered once daily is effective for up to 24 hours after instillation and is well tolerated in adults and children aged _>3 years. The objective of the present study was to evaluate the efficacy and safety profile of olopatadine 0.2% 1238

once daily compared with placebo in patients with seasonal allergic conjunctivitis or rhinoconjunctivitis. PATIENTS A N D METHODS Inclusion and Exclusion Criteria

The study population included patients aged _>10 years with a history of allergic conjunctivitis or rhinoconjunctivitis, a positive result for grasses on skin-prick testing, and a successful baseline CAC. Patients with only 1 sighted eye or vision that was not correctable to _>0.6 (logMar) in both eyes were excluded. Other reasons for exclusion were any ocular condition, infection, or recent surgical intervention that could affect the study parameters; need for any other topical ocular medication; and a history of moderate to severe allergic asthma in the presence of grass pollen. Contact lens wearers could participate in the study but were asked to remove their lenses during instillation of study medication and to refrain from reinserting them for 10 minutes thereafter. In addition, patients were asked not to wear lenses during study visits. Before participation, all screened and enrolled patients signed an informed consent (assent for minors) form that was approved by the investigational review board ORB). The IRB reviewed the clinical investigatorg brochure and approved the study protocol, patient compensation (a small stipend), and any advertisements or other materials used as screening and/or enrollment aids. This study followed the good clinical practice guidelines and all applicable US Food and Drug Administration regulations. Conjunctival Allergen Challenge

A baseline CAC was performed to confirm individual patients' sensitivity to grass pollen and thereby partially establish eligibility. The CAC involves instillation of a known quantity of allergen solution (in this case, grasses) into the eyes of a sensitized subject. The allergen then binds to the immunoglobulin E receptor on the mast cell, eliciting natural immunologic mast-cell degranulation. This degranulation releases histamine as well as other proinflammatory mediators, inducing effects on end-organ receptors. The CAC model, which has been described by Abelson et al, 17 closely mimics the clinical spectrum of allergic conjunctivitis. This model has been used extensively to assess the efficacy of ophthalmic anti-

M.B.Abelson et al.

allergic drugs, including olopatadine hydrochloride ophthalmic solution, mJ9 The assessment scales used in the CAC have been reported previously2° and were not modified for use in this study. Study Design This double-masked trial was conducted in the United States during the spring allergy season (April-August) of 2003. Patients were block-enrolled at 9 sites in various locations and were randomized to self-administer olopatadine 0.2% or placebo in both eyes once daily. Placebo was the olopatadine 0.2% vehicle, which contained dibasic sodium phosphate, sodium chloride, disodium EDTA, povidone, and BAC. The study involved 11 visits: screening (day 0), 9 weekly interim visits, and the exit visit (week 10). Grass pollen counts for each investigative center were obtained daily. Designated personnel at each study site assigned and distributed the masked medications. A sealed envelope containing the description of the assigned treatment for each patient was provided to each investigator, and the investigator was allowed to open the envelope in the event of a medical emergency. The treatment code, however, was not broken during the course of the study.

EfficacyAnalyses Patients assessed the frequency of ocular itching and redness weekly using a whole-unit scale from 0 = none to 5 = continuously and evaluated the severity of itching and redness in a daily diary using a halfunit scale from 0 = no itching/redness to 4 = severe itching/redness. Between-group differences in response rates were examined in separate analyses of the frequency- and severity-based data for ocular itching and redness in terms of the proportions of patients with scores >0, >1, and >2. Because the scales used to assess frequency and severity were different, "responder" was defined differently for the frequency- and severitybased responder analyses. For frequency, a treatment response was defined as a score between 0 and 2, and for severity, a treatment response was defined as a score between 0 and 1. For the frequency-based variables, separate analyses were conducted for grass pollen levels categorized as low (0-5 gr/m 3 air), medium (5-20 gr/m 3 air), and high (>20 gr/m 3 air). 21

For the severity-based variables, separate analyses were conducted for periods of any 14 days with peak mean pollen counts, 14 consecutive days with peak mean pollen counts, and 2 nonoverlapping 7-day periods with peak mean pollen counts. Mean pollen counts were determined at the investigator (site) level. Safety Analyses Safety parameters included undilated fundus examination, slit-lamp examination, measurements of intraocular pressure and visual acuity, adverse events, changes in concomitant medications, extent of exposure to study drug (obtained from patient selfreports of compliance), and changes in baseline medical conditions. Statistical Analysis Repeat-measures analysis of variance was used to compare between-group differences in mean scores for the frequency of ocular itching and redness at each visit. In addition, a 2-sample t test was used to compare between-group differences in mean scores for the severity of ocular itching and redness on each study day. In the responder analyses, a chi-square test (or the Fisher exact test, if the expected cell frequency was <5) was used to compare response rates for itching and redness between treatment groups. A 2-sample t test was used to compare between-group differences in mean frequency scores for ocular itching and redness by pollen level and pollen period. The intent-to-treat data set was used for all analyses, and P < 0.05 was considered significant. RESULTS Two hundred sixty patients were enrolled at the 9 sites toward the beginning of the expected grass pollen season, as predicted by historical pollen-count data. The peak pollen season lasted roughly 6 weeks (Figure 1). Seven percent of patients reported a history of allergic conjunctivitis, whereas 93% reported a history of allergic rhinoconjunctivitis, and all enrolled patients were sensitive to grass pollen on baseline CAC. Participants ranged in age from 11 to 75 years; 28 were children (age range, 11-17 years). Fifty-three percent were female, and 26% were nonwhite (Table). Sixty-three (24%) patients wore contact lenses.

1239

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respectively. The numbers in the key refer to sites in the following states: 1128 = Kentucky; 1270 = Indiana; 1933 = Kentucky; 1939 = NewYork; 2759 = Massachusetts; 3766 = California; 3803 = Pennsylvania; 3806 = California; 3807 = Missouri.

Figure I. Grass pollen counts, by investigative site and study visit.The labels High, Medium, and Low refer to pollen counts of 0-5, 5-20, and >20 gr/m 3 air,

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M.B.Abelson et al.

Table. Demographic characteristics.

Characteristic

Olopatadine 0.2% (n = 129)

Placebo (n = 13 I)

36,8 (14,8) 11~5

36.0 (13,2) II 72

Age,y Hean (SD) Range Age group, no. (%), y

II 17 i 8 64

15 (12)

13 (10)

i08 (84)

i i4 (87)

6 (5)

4 (3)

Sex, no. (%)* Female Hale

68 (53) 61 (47)

69 (53) 62 (47)

Race, no. (%)* White Black Asian

97 (75) 14 (I I) II (9)

95 (73) 15 (I I) 10 (7)

Hispanic

5 (4)

5 (4)

Other

2 (2)

6 (5)

>65

Iris color, no. (%) Brown Blue Hazel Green

Grey

60 38 22 9 0

(47) (29) (I 7) (7) (0)

62 44 16 8

(47) (34) (I 2) (6)

I (I)

*Percentages may exceed 100 due to rounding.

Overall, mean frequency scores for ocular itching

(Figure 2A) and redness (Figure 2B) by study day were significantly lower in the olopatadine 0.2% group compared with the placebo group at all visits after baseline (P < 0.05). Similarly, the difference in mean severity scores for itching and redness was statistically significant for olopatadine 0.2% compared with placebo on 57 of 70 study days (P < 0.05); olopatadine 0.2% was numerically superior to placebo on 69 days for ocular itching (Figure 3A) and all 70 days for ocular redness (Figure 31}). In the frequency-based responder analysis by pollen level, the response rates for itching (Figure 4A) and redness (Figure 41}) were superior with olopatadine 0.2% compared with placebo when grass pollen counts were low, medium, and high. For example, when grass pollen counts were high (>20 gr/m 3 air), 21% of patients in the olopatadine 0.2% group scored the frequency of ocular itching as >2, compared with 47% of patients in the placebo group

(P < 0.001). At the same pollen level, 14% of patients in the olopatadine 0.2% group scored the frequency of ocular redness as >2, compared with 31% of patients in the placebo group (P < 0.003). In the analysis of frequency-based mean scores by pollen level, the olopatadine 0.2% group had significantly lower mean scores compared with placebo for both itching and redness when grass pollen levels were low (P < 0.005 and P < 0.015, respectively), medium (P < 0.001 and P = 0.002), and high (both, P < 0.001)

(Figure 5). The severity-based responder analysis by pollen period yielded results consistent with those reported for the frequency-based pollen-level analysis. Specifically, for any 14 days with peak mean pollen counts by site, 9% and 7% of patients in the olopatadine 0.2% group scored the severity of ocular itching and redness as >2, compared with 18% and 15% of patients in the placebo group (P < 0.049 and P < 0.048, respectively). For the other pollen periods (14 consecutive days and 2 non1241

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Day Figure 2. Mean (SE) scores for frequency of (A) ocular itching and (B) ocular redness (whole-unit scale from 0 = none to 5 = continuously), by study day. *P < 0.05.

overlapping 7-day periods with peak mean pollen counts), the proportions of patients with scores >0, >1, and >2 for ocular itching (Figure 6A) and redness (Figure 6B) also favored olopatadine 0.2%. In the analysis of severity-based mean scores by pollen period, the olopatadine 0.2% group had significantly lower mean scores compared with placebo for both itching and redness on any 14 days with peak mean pollen counts (P < 0.004 and P < 0.012, respectively), on 14 consecutive days with peak mean pollen counts (P < 0.003 and P < 0.007), and on 2 nonoverlapping 7-day periods with peak mean pollen counts (P < 0.003 and P < 0.013, respectively) (Figure 7).

adverse event. Overall, adverse events (related and not related combined) were reported for 75 (29%) patients, including 41 (32%) of the 129 olopatadine 0.2% recipients and 34 (26%) of the 131 placebo recipients. Only 3 ocular adverse events (ocular discomfort, ocular dryness, and ocular fatigue) were reported in relation to olopatadine 0.2% therapy. Overall, no clinically relevant changes were observed in ocular signs or fundus parameters, and no clinically relevant treatment-related changes were observed in visual acuity or intraocular pressure. Finally, no agerelated effects were noted based on changes from baseline in visual acuity, intraocular pressure, ocular signs, or fundus parameters.

Safety Analyses No patient was discontinued from the study because of a treatment-related adverse event, and no patient experienced a treatment-related serious

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DISCUSSION

Seasonal allergic conjunctivitis differs from many other diseases in that its signs and symptoms are generally

M.B.Abelson et al.

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Day Figure 3. Mean scores for severity of (A) ocular itching and (B) ocular redness (half-unit scale from 0 = no itching/redness to 4 = severe itching/redness), by study day.*P < 0.05.

relatively short lived and depend on environmental conditions, primarily specific pollen levels. The extent to which a patient exhibits an allergic response at any given time is related to his or her immediate pollen exposure. Thus, the overall impact of ocular allergy is a product of the frequency of all signs and symptoms combined and the severity of individual occurrences. It follows that there is a clear difference between observing the magnitude of an ocular sign or symptom at a particular point and determining the frequency of the sign or symptom over a longer period. For example, if a patient experiences ocular itching caused by allergic conjunctivitis, a saline drop will probably reduce the severity of the itching simply by temporarily washing the allergen from the eye; similarly, a placebo is likely to provide some degree of protection by forming a barrier on the ocular surface. However, without the pharmacologic activity necessary to stop a physiologic allergic response, this protection will be short lived; the itching is likely to recur with repeated or prolonged exposure to aller-

gen. The same washing effect may occur with an active drug, but the pharmacologic effect will continue after the immediate benefit of washing dissipates. The active drug will continue to protect the eye with additional exposure to allergen. Thus, ocular antiallergic drugs may be seen as treating allergic conjunctivitis by reducing the overall severity and frequency of signs and symptoms, whereas a placebo merely reduces the immediate severity of the signs and symptoms. Two factors significantly affect the observed responses to allergen in allergic conjunctivitis: individual sensitivities to allergens and the extent to which patients are exposed to specific allergens. Because of the inclusion criteria (history of allergy, positive skintest result, baseline CAC), the patient population in this study was known to be sensitive to grass pollen. Although there is no control over which allergens will be present in a locality during a clinical trial, the 2003 spring pollen season in the United States was particularly favorable, given the levels of pollen observed

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CLINICAL THERAPEUTICS®

A

Medium Pollen Count (5-20 gr/m 3 air)

Low Pollen Count (0-5 gr/m 3 air)

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Figure 4. P r o p o r t i o n s o f patients w i t h specific scores f o r f r e q u e n c y o f (A) o c u l a r itching and (B) o c u l a r redness ( w h o l e unit scale f r o m 0 = n o n e t o 5 = continuously), by grass pollen count. *P < 0.05.

1244

M.B.Abelson et al.

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Redness

2.5-

[] Olopatadine 0.2% • Placebo 2.0-

o 1.5-

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~5 o.s-

0-

I Low

Medium

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I Low

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Pollen Count Figure 5. Mean (SE) scores for the frequency of ocular itching and redness (whole-unit scale from 0 = none to 5 = continuously), by grass pollen count.The labels High, Medium, and Low refer to pollen counts of 0-5, 5-20, and >20 gr/m a air, respectively. *P < 0.05.

across all sites throughout the study period. Thus, the combination of sensitive patients and a favorable pollen season yielded strong measurements of treatment efficacy in terms of both the frequency and severity of ocular itching and redness. The responder analyses evaluated the clinical significance of the between-group differences in ocular itching and redness by pollen level (frequency based) and pollen period (severity based). In these analyses, olopatadine 0.2% reduced the effects of grass pollen on the primary signs and symptoms of allergic conjunctivitis compared with placebo. It should be noted that the scales used in the frequency-based (pollen level) and severity-based (pollen period) responder analyses were different; therefore, "responder" was defined differently for each type of analysis. For the analyses of frequency, in which a treatment response was defined as a score between 0 and 2, the proportion of ocular itching responders significantly favored olopatadine 0.2% at all pollen levels (low, medium,

and high); the percentage of ocular redness responders significantly favored olopatadine 0.2% at the medium and high pollen levels. Similarly, for the analyses of severity, in which a treatment response was defined as a score between 0 and 1, the proportion of ocular itching responders significantly favored olopatadine 0.2% during all pollen periods (any 14 days, 14 consecutive days, and 2 nonoverlapping 7-day periods of peak mean pollen counts); the proportion of ocular redness responders significantly favored olopatadine 0.2% for 2 pollen periods (any 14 days and 14 consecutive days of peak mean pollen counts). Thus, the results of the frequency- and severity-based analyses consistently indicated that olopatadine 0.2% was effective relative to placebo for the treatment of the ocular signs and symptoms of allergic conjunctivitis or rhinoconjunctivitis. The youngest patient enrolled in this trial was aged 11 years. Based on a review of adverse events and measurement of ocular parameters, olopatadine 0.2% 1245

CLINICAL THERAPEUTICS®

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Period 2

Period I

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Period 3

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80 7O 6O o_

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50 4O 3O 2O 10 0 >0

>1

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100 1

001 70

60

a_

50

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*

*

2O

,°°

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Ocular Redness Severity Score Figure 6. Proportions of patients with specific scores for severity of (A) ocular itching and (B) ocular redness (half-unit scale from 0 = no itching/redness to 4 = severe itching/redness), by grass pollen period. Period I indicates any 14 days of peak mean pollen counts; period 2 indicates 14 consecutive days of peak mean pollen counts; and period 3 indicates 2 nonoverlapping 7-day periods of peak mean pollen counts, all by investigative site.*P < 0.05.

~246

M.B.Abelson et al.

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2.0-

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[ ] Olopatadine 0.2% •

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Period 2

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Pollen Period Figure 7. Mean (SE) scores for the severity of ocular itching and redness (half-unit scale from 0 = no itching/redness to 4 = severe itching/redness), by grass pollen period. Period I indicates any 14 days of peak mean pollen counts; period 2 indicates 14 consecutive days of peak mean pollen counts; and period 3 indicates 2 nonoverlapping 7-day periods of peak mean pollen counts, all by investigative site. *P < 0.05.

administered once daily appeared to be well tolerated in patients aged >11 years with a history of seasonal allergic conjunctivitis or rhinoconjunctivitis. CONCLUSION

In the patients enrolled in this trial, olopatadine 0.2% appeared to be effective and well tolerated w h e n administered once daily for the treatment of the ocular signs and symptoms of allergic conjunctivitis or rhinoconjunctivitis. REFERENCES

1. Abelson MB, Smith L, Chapin M. Ocular allergic disease: Mechanisms, disease sub-types, treatment. The Ocular 5urface. 2003;1:127-149. 2. Sharif NA, Xu SX, Miller ST, et al. Characterization of the ocular antiallergic and antihistaminic effects of olopatadine (AL-4943A), a novel drug for treating ocu-

lar allergic diseases. J Pharmacol Exp Ther. 1996;278: 1252-1261. 3. Yanni JM, Stephens DJ, Miller ST, et al. The in vitro and in vivo ocular pharmacology of olopatadine (AL4943A), an effective anti-allergic/antihistaminic agent. J Ocul Pharmacol Ther. 1996;12:389-400. 4. Yanni JM, Weimer LK, Sharif NA, et al. Inhibition of histamine-induced human conjunctival epithelial cell responses by ocular allergy drugs. Arch Ophthalmol. 1999;117:643-647. 5. Yanni JM, Miller ST, Gamache DA, et al. Comparative effects of topical ocular anti-allergy drugs on human conjunctival mast cells. Ann Allergy Asthma Immunol. 1997;79:541-545. 6. Cook EB, Stahl JL, Barney NP, Graziano FM. Olopatadine inhibits TNFalpha release from human conjunctival mast cells. Ann Allergy Asthma Immunol. 2000;84: 504-508.

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7. Sharif NA, Xu SX, Yanni JM. Olopatadine (AL-4943A): Ligand binding and functional studies on a novel, long acting H 1-selective histamine antagonist and anti-allergic agent for use in allergic conjunctivitis. J Octd Pharmacol

Ther. 1996;12:401-407. 8. Ohmori K, Ishii H, Sasaki Y, et al. Effects of KW-4679, a new orally active antiallergic drug, on antigeninduced bronchial hyperresponsiveness, airway inflammation and immediate and late asthmatic responses in guinea pigs. Int Arch Allergy Immunol. 1996;110:64-72. 9. Ohmori K, Hayashi K, Kaise T, et al. Pharmacological, pharmacokinetic and clinical properties of olopatadine hydrochloride, a new antiallergic drug. Jpn J Pharmacol. 2002;88:379-397. 10. Cook EB, Stahl JL, Barney NP, Graziano FM. Olopatadine inhibits anti-immunoglobulin E-stimulated conjunctival mast cell upregulation of ICAM-1 expression on conjunctival epithelial cells. Ann Allergy Asthma Immunol. 2001;87:424-429. 11. Ikemura T, Manabe H, Sasaki Y, et al. KW-4679, an antiallergic drug, inhibits the production of inflammatory lipids in human polymorphonuclear leukocytes and guinea pig eosinophils. Int Arch Allergy Immunol. 1996;110:57-63. 12. Miyake K, Ohmori K, Ishii A, Karasawa A. Inhibitory effect of olopatadine hydrochloride (KW-4679), a novel antiallergic drug, on peptide leukotriene release from human eosinophils. Allergol Int. 2001;50:113-116. 13. Fukuishi N, Matsuhisa M, Shimono T, et al. Inhibitory effect of olopatadine on antigen-induced eosinophil infiltration and the LFA-1 and Mac-1 expression in eosinophils. Jpn J Pharmacol. 2002;88: 463-466.

14. Abelson MB, Gomes PJ, Welch DL, et al. Olopatadine reduces ocular signs and symptoms associated with allergic conjunctivitis 16 hours after instillation. Poster presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology; May 4-8, 2003; Fort Lauderdale, Fla. 15. Greiner JV, Spindel GP, Gomes PJ, et al. Olopatadine is effective for the prevention and treatment of the signs and symptoms of allergic conjunctivitis. Poster presented at: Annual Meeting of the Association for Research m Vision and Ophthalmology; May 4-8, 2003; Fort Lauderdale, Fla. 16. Lichtenstein SJ, Vogelson CT, Wells DT, et al. Olopatadine is safe and well-tolerated in adults and children as young as three-years of age. Presented at: Annual Meeting of the Western Society of Allergy, Asthma, and Immunology; January 18-23, 2003; Maui, Hawaii. 17. Abelson MB, Chambers WA, Smith LM. Conjunctival allergen challenge. A clinical approach to studying allergic conjunctivitis. Arch Ophthalmol. 1990;108:84-88. 18. Spitalny L, Abelson MB. Olopatadine ophthalmic solution decreases itching and redness associated with allergic conjunctivitis. Invest Ophthal Vis 5ci. 1996;37 (Suppl):S593. Abstract. 19. Abelson MB, Spitalny L. Combined analysis of two studies using the conjunctival allergen challenge model to evaluate olopatadine hydrochloride, a new ophthalmic antiallergic agent with dual activity. Am d

Ophthalmol. 1998;125:797-804. 20. Abelson MB. Evaluation of olopatadine, a new ophthalmic antiallergic agent with dual activity, using the conjunctival allergen challenge model. Ann Allergy Asthma Immunol. 1998;81:211-218. 21. Burge HA. Monitoring for airborne allergens. Ann Allergy. 1992;69:9-18.

A d d r e s s c o r r e s p o n d e n c e to: Mark B. Abelson, MD, 863 Turnpike Street, North Andover, MA 01845.

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