Efficacy of Ketotifen Fumarate 0.025% Ophthalmic Solution Compared with Placebo in the Conjunctival Allergen Challenge Model

CLINICAL SCIENCES Efficacy of Ketotifen Fumarate 0.025% Ophthalmic Solution Compared With Placebo in the Conjunctival Allergen Challenge Model

Mark B. Abelson, MD; Matthew J. Chapin, BS; Barry M. Kapik, MS; Naveed B. K. Shams, MD, PhD

Background: Ketotifen fumarate blocks histamine1 (H1) fore allergen challenge. The primary efficacy measure was receptors, stabilizes mast cells, and acts as an eosinophil the subject’s rating of itching at 3, 7, and 10 minutes af- inhibitor (decreases chemotaxis and activation of ter challenge. eosinophils). Results: Of the 89 subjects randomly assigned to masked Objective: To assess the efficacy of ketotifen 0.025% trial medication at visit 3, 72 completed the study. At vis- ophthalmic solution in the prevention of symptoms of its 3, 4, and 5, mean itching scores were significantly bet- allergic conjunctivitis, using the conjunctival allergen chal- ter for ketotifen-treated eyes at all postchallenge time lenge model. points, compared with placebo (PϽ.001). Also at visits 3, 4, and 5, ketotifen was statistically superior to pla- Methods: This was a single-center, double-masked, ran- cebo in reducing ocular hyperemia at all postchallenge domized, placebo-controlled, contralateral-eye compari- time points (PϽ.05). son, allergen challenge trial conducted in the United States. Subjects were randomized to receive ketotifen 0.025% Conclusions: Ketotifen was safe and statistically effec- in one eye and placebo in the other. At visits 1 and 2, tive in reducing ocular itching and hyperemia associ- allergen challenges were performed to determine the al- ated with allergic conjunctivitis. Ketotifen’s rapid onset lergen concentration eliciting a qualifying reaction for each of action (within 15 minutes) and extended duration of subject. At the 3 subsequent visits, subjects received 1 action (at least 8 hours) make it a valuable treatment for drop of ketotifen 0.025% ophthalmic solution in one eye allergic conjunctivitis. and vehicle solution as placebo in the other eye 15 minutes (visit 3), 6 hours (visit 4), and 8 hours (visit 5) be- Arch Ophthalmol. 2003;121:626-630

HE PREVALENCE of ocular al- methamine), antihistamine and mast cell lergic disease, which com- stabilizer combinations (ketotifen fuma- prises several conditions, is rate, azelastine hydrochloride, and olopata- estimated to be 20% and in- dine hydrochloride), corticosteroids (lo- creasing.1 Seasonal aller- teprednol etabonate), and nonsteroidal gic conjunctivitis is the most common type anti-inflammatory drugs (ketorolac T 3 of ocular allergy and may account for up tromethamine). Ketotifen (Zaditen and to 90% of all allergic eye disorders seen by Zaditor, Novartis Ophthalmics, Inc) is one the allergist. Common ocular signs and of the more recently developed agents that symptoms associated with seasonal aller- has multiple pharmacological mecha- gic conjunctivitis are itching, tearing, nisms. It is a benzocycloheptathiophene swelling,2 and conjunctival, episcleral, and derivative that has been developed for the From the Schepens Eye ciliary redness.3 Although vision is not im- treatment of allergic conjunctivitis. Keto- Research Institute and paired by seasonal allergic conjunctivi- tifen is a noncompetitive histamine1 (H1)– Department of Ophthalmology, tis, the symptoms can be uncomfortable receptor antagonist that stabilizes mast Harvard Medical School, and may substantially affect quality of life.4 cells, inhibits platelet-activating factor, and Boston (Dr Abelson), and There are 5 major drug classes used acts as an eosinophil inhibitor (decreases Ophthalmic Research 5 Associates, Inc, North Andover to treat ocular allergies: antihistamines (le- chemotaxis and activation of eosinophils). (Dr Abelson and Mr Chapin), vocabastine hydrochloride and emedas- The aim of this study was to evaluate Mass; and Novartis tine difumarate), mast cell stabilizers (cro- the efficacy of ketotifen 0.025% ophthal- Ophthalmics, Inc, Duluth, Ga molyn sodium, nedocromil sodium, mic solution compared with placebo in the (Mr Kapik and Dr Shams). pemirolast potassium, and lodoxamide tro- prevention of symptoms of allergic con-

(REPRINTED) ARCH OPHTHALMOL / VOL 121, MAY 2003 WWW.ARCHOPHTHALMOL.COM 626

©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 junctivitis, using the conjunctival allergen challenge model.6 At visits 3, 4, and 5, subjects received 1 drop of ketotifen The approval of ketotifen 0.025% by the US Food and Drug 0.025% ophthalmic solution into the conjunctival sac of one Administration was based on 2 allergen challenge stud- eye and placebo as vehicle solution in the other eye 15 min- ies7,8 and 1 large, repeated dose safety study (M.B.A, Steven utes (visit 3), 6 hours (visit 4), and 8 hours (visit 5) before al- Dell, MD, George Lowry, MD, David G. Shulman, MD, and lergen challenge. After visit 2, there was a 14-day recovery pe- riod between subsequent visits. Francis J. Wapner, MD, unpublished data, 1998). Data con- 7 To help maintain masking, the packaging of ketotifen tained in the article come from 1 of the 2 allergen studies and placebo was identical in appearance. All products were conducted for the registration of ketotifen. supplied in 5-mL plastic dropper bottles for ocular administration. METHODS OUTCOME MEASURES SELECTION OF STUDY POPULATION The primary efficacy measure was the subject’s rating of itch- Subjects were aged 18 to 70 years, with a history of allergic hy- ing at 3, 7, and 10 minutes after the allergen challenge. Sec- persensitivity to animal dander, grass, or tree or ragweed pol- ondary efficacy measures were the investigator’s ratings of con- len not currently in season in the site’s geographic area. The junctival, episcleral, and ciliary hyperemia at 7, 10, and 15 principal eligibility criterion for study enrollment was a posi- minutes after the allergen challenge. tive diagnostic test result (skin or radioallergosorbent test) for Ocular itching, hyperemia, and chemosis were measured allergic hypersensitivity or a positive allergen challenge within on a 5-point grading scale from 0 (none) to 4 (severe), and lid 24 months of visit 1. Subjects must also have had a qualifying edema was measured on a 4-point scale from 0 (none) to 3 (ex- allergic reaction, inducing at least 2+ itching and 2+ conjunc- tremely swollen). The primary and secondary efficacy vari- tival redness bilaterally within 10 minutes after challenge at vis- ables were the between-treatment (interocular) differences. For its 1 and 2. Further criteria were best-corrected distance vi- primary and secondary efficacy outcomes, a clinically mean- sual acuity of 20/40 (logMAR 0.3) or better in both eyes on an ingful difference was defined as a mean difference score of at Early Treatment of Diabetic Retinopathy Study chart, intra- least 1.0 U between treatment groups at 2 of the 3 time points. ocular pressure of 21 mm Hg or less in both eyes, and ability Safety was assessed by evaluating changes in visual acu- and willingness to provide written and informed consent. ity (on an Early Treatment of Diabetic Retinopathy Study chart), Women of childbearing potential had to use an adequate form slitlamp biomicroscopy and dilated ophthalmoscopy results, of birth control (for at least 1 month before visit 1) and pro- and tabulating reports of adverse events. duce a negative urine pregnancy test result at visit 1. Exclu- sion criteria included the following: history of any retinal con- STATISTICAL ANALYSIS dition or disease; active bacterial or viral ocular infection; signs and symptoms of allergic conjunctivitis; presence of an inter- For ocular signs and symptoms, it was estimated that a sample acting ocular condition (such as blepharitis, follicular conjunc- size of 80 subjects would provide at least 98% power to detect ␣ tivitis, and open- or narrow-angle glaucoma); or any physical a between-group difference of 0.5, assuming a 2-sided of .05 illness that would make the subject unsuitable. Use of sys- and an SD of 1.07 (paired t test). The estimate of the SD was 8 temic or ocular medication, such as monoamine oxidase in- obtained from a previous study comparing ketotifen with its hibitors, antihistamines, or mast cell stabilizers, or participa- vehicle placebo in an allergen challenge model. tion in an investigational drug or device trial within the previous The primary efficacy analysis was performed on the 30 days before the trial was prohibited. The trial was con- intent-to-treat subjects, defined as those who received drug ducted in accordance with the Declaration of Helsinki and ap- and had at least 1 efficacy assessment. For itching and hyper- proved by the local ethics committee. emia scores, paired t tests on the difference scores between eyes were used to assess differences between treatments at STUDY DESIGN each visit. The percentage of eyes with no itching was compared between treatment groups using the McNemar test for This was a single-center, double-masked, randomized, placebo- matched pairs. All statistical tests were 2-sided, and corre- controlled, contralateral-eye comparison, allergen challenge trial sponding differences were considered statistically significant Ͻ conducted in the United States. Subjects were randomized to at P .05. receive ketotifen 0.025% in one eye and placebo in the other eye at 3 visits. A randomization list was prepared by the spon- RESULTS sor, using computer software (PROC PLAN, SAS version 6.12; SAS Institute Inc, Cary, NC). The study involved 5 visits, with a 2-week screening that Eighty-nine subjects were randomly assigned to masked included ophthalmic examinations at visits 1 (day −21) and 2 trial medication and received 1 or more doses of each (day −14). The screening also included allergen challenges at medication (Figure 1). Seventy-two subjects (81%) com- both visits to determine the allergen type and concentration pleted the study. Of the 17 subjects who did not com- eliciting a qualifying reaction for each subject. Allergen re- plete the study, 8 were lost to follow-up, 3 discontinued sponses were determined by the investigator for each subject voluntarily, 5 were discontinued for protocol viola- at visit 1, starting with the lowest dose and titrating to the high- tions, and 1 left for other reasons. Fifty-four percent (48/ est dose until a qualifying reaction was achieved bilaterally. Al- 89) were male, and 93% (83/89) of the subjects were lergens included ragweed pollen (36 [42%] of 86 subjects), white. The mean age was 38.9 years (range, 19-70 years). meadow fescue pollen (21 [24%] subjects), cat dander (16 subjects), rye pollen (9 [10%] subjects), and tree pollen (7 [8%] Two (2%) subjects had black iris color; 35 (39%), brown; subjects). This study was conducted outside of the pollen sea- 23 (26%), hazel; and 29 (33%), blue. Only 2 (2%) sub- son, and the enrolled subjects were required to have either no jects had a history of ocular surgery. There were no sig- allergy signs and symptoms at the time of testing or had no more nificant differences between the treatment groups at base- than mild redness and itching. line for ocular itching or hyperemia.

(REPRINTED) ARCH OPHTHALMOL / VOL 121, MAY 2003 WWW.ARCHOPHTHALMOL.COM 627

©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Screening: 89 Placebo Ketotifen Fumarate 0.025% Visits 1 and 2 (Days –21 to –14) 3.0 Visit 2 Visit 3 Visit 4 Visit 5 (Baseline) (15 min) (6 h) (8 h)

Received Study Medication: 89 Discontinued Visit 3 Included in ITT Analysis: 89 Protocol Violation: 1 2.5 (Day 0) Included in Safety Analysis: 89 Lost to Follow-up: 4

2.0 Received Study Medication: 83 Discontinued Included in ITT Analysis: 83 Protocol Violation: 4 Visit 4 Included in Safety Analysis: 84 Lost to Follow-up: 4 1.5 (Day 14) Voluntary: 2 Other: 1 1.0 Mean Itching Score Received Study Medication: 73 Discontinued Visit 5 Included in ITT Analysis: 72 Voluntary: 1 (Day 14) 0.5 Included in Safety Analysis: 73

Figure 1. Disposition of subjects. The “Other” subject who discontinued at 0.0 visit 4 did not receive study medication at that visit, but safety assessment 3 710 3 710 3 710 3 710 was performed. The “Voluntary” subject who discontinued at visit 5 received Time After Allergen Challenge, min study medication at that visit but was unable to stay for the 8 hours and subsequently discontinued from the study before allergen challenge; this Figure 2. Mean itching scores for each allergen challenge. subject was included in the intent-to-treat (ITT) analysis.

Table 1. Effect of Ketotifen Fumarate on Ocular Itching in the Allergen Challenge Model*

Ketotifen Score Minus Placebo Score

Assessment Time After Visit 2 Visit 3 Visit 4 Visit 5 Challenge, min (n = 89) (n = 89) (n = 83) (n = 72) 3 0.02 (0.48) −1.41 (1.02) −1.43 (1.10) −1.16 (1.06) 7 0.04 (0.40) −1.80 (1.16) −1.54 (1.01) −1.41 (0.95) 10 0.03 (0.35) −1.39 (1.01) −1.33 (0.97) −1.26 (0.92)

*Data are given as mean (SD) difference between eyes. A negative difference indicates a better outcome for ketotifen-treated eyes.

EFFICACY SAFETY

Ocular Itching There were no statistically significant differences between treatments for prechallenge and postchallenge For visits 3, 4, and 5, mean itching scores after allergen assessments of slitlamp or direct ophthalmoscopy challenge were statistically significantly different findings. between treatment groups, favoring ketotifen-treated One or more adverse events were reported by 13 eyes at all time points after allergen challenge (PϽ.001) (15%) of the 89 subjects, but none were ocular in na- (Table 1 and Figure 2). Mean differences in itching ture. The most frequently occurring adverse events re- scores between ketotifen-treated eyes and eyes that ported by subjects were headache (6 or 7%) and rhinitis received placebo ranged from −1.16 to −1.80 U. The (3 or 3%). The only adverse event considered by the in- percentage of ketotifen-treated eyes with no itching was vestigator to be associated with study treatment was head- also significantly higher than the corresponding per- ache, reported by 4 (5%) of 89 subjects. centage of eyes given placebo at all time points There were no reports of serious or severe adverse (PϽ.001) (Table 2). These differences between groups events, and no individuals discontinued prematurely be- ranged from 52% to 61%. Subgroup analyses revealed cause of adverse events. no significant differences attributable to sex or iris color. COMMENT Hyperemia This clinical study shows that ketotifen 0.025% ophthalmic solution can achieve statistically significant preven- Ketotifen was statistically superior to placebo at every time tion of the development of itching due to allergic con- point in reducing the effect of the allergen challenge on junctivitis, starting within 15 minutes of treatment and ocular hyperemia; ketotifen-treated eyes had signifi- lasting for at least 8 hours. The beneficial effects of keto- cantly lower mean scores compared with eyes given pla- tifen on itching are supported by the results of the mean cebo (PϽ.05) (Table 3). At visit 3 (15-minute chal- itching scores, as well as the proportion of eyes without lenge), mean differences between the treatments ranged any itching. These findings are clinically meaningful, as from −0.52 to −0.76 U. ketotifen provides a rapid onset and long duration of ac-

(REPRINTED) ARCH OPHTHALMOL / VOL 121, MAY 2003 WWW.ARCHOPHTHALMOL.COM 628

©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 tion. Ketotifen was also safe and well tolerated, an impor- ment and placebo, as well as differences in efficacy be- tant finding given that compliance with ophthalmic for- tween active treatments. mulations is enhanced by a favorable tolerability profile.9 Ketotifen modulates early-phase reactions by block- Higher mean scores for conjunctival, ciliary, and epi- ing H1 receptors, stabilizing mast cells, and acting as an eo- scleral hyperemia for all time points at visits 3, 4, and 5 sinophil inhibitor (decreases chemotaxis and activation of were recorded for eyes given placebo. Although the treat- eosinophils).16 Moreover, ketotifen inhibits late-phase re- ment effect of ketotifen on ocular hyperemia was not as actions on a cellular level, such as reducing the effect of marked as for itching, the intensity of hyperemia was sup- platelet-activating factor.17 The multiple mechanisms of ac- pressed enough to achieve statistical significance at all tion of ketotifen would be expected to provide rapid and time points. In allergic conjunctivitis, histamine in- prolonged relief of ocular symptoms in patients with al- duces itching through H1 receptors and hyperemia lergic conjunctivitis. The results from this study provide 10,11 through H1 and H2 receptors. Ketotifen’s smaller treat- support for these effects. In clinical practice, ketotifen’s pro- ment benefit on hyperemia may therefore reflect its rela- longed symptom relief translates into a twice-daily dosing tive selectivity for H1 receptors. regimen, which may result in increased treatment compli- The advantages of using the allergen challenge model ance, thus leading to effective control of ocular symptoms in evaluating the antiallergy effects of pharmacological associated with allergic conjunctivitis. agents have been reviewed previously.6,12 Unlike other In this study, safety and local tolerability of ketoti- models, the allergen challenge model accurately repli- fen 0.025% ophthalmic solution was assessed following cates the signs and symptoms and natural disease pro- the single administration of the drug at visits 3, 4, and 5. cess of seasonal allergic conjunctivitis. In addition, it is No ocular adverse effects were noted. However, the basis safe and reproducible and can be used to accurately de- for safety following repeated dosing of this compound termine the duration of action, on which the dosing fre- comes from a separate clinical trial (M.B.A, Steven Dell, quency can be based. In contrast to environmental stud- MD, George Lowry, MD, David G. Shulman, MD, and ies, a small sample size can be used for allergen challenge Francis J. Wapner, MD, unpublished data, 1998). In the studies, especially in the case of contralateral-eye de- safety study, ketotifen 0.025% ophthalmic solution was signs. The model has been used to evaluate several oph- instilled 4 times daily for 6 weeks in healthy volunteers, thalmic formulations, such as ketorolac,13 levocabastine including children as young as 3 years old, with normal and emedastine,14 and olopatadine.15 Furthermore, it is ocular health. There were 495 subjects randomized into able to detect differential effects between active treat- the trial, with 330 assigned to ketotifen and 165 assigned to placebo (data not presented). Results from this safety study did not identify any issues that would preclude the Table 2. Subjects Reporting No Itching in Each Eye* repeated use of ketotifen 0.025% solution. Taken to- gether, it is concluded that ketotifen 0.025% is safe and Assessment Time After Visit 3 Visit 4 Visit 5 well tolerated. Challenge, min (n = 89) (n = 83) (n = 72) 3 46 (51.7) 44 (53.0) 39 (54.2) 7 54 (60.7) 48 (57.8) 44 (61.1) CONCLUSIONS 10 49 (55.1) 50 (60.2) 44 (61.1) Ketotifen 0.025% ophthalmic solution had a statisti- *Data are given as number (percentage) of ketotifen fumarate–treated cally significant effect in reducing ocular itching and hy- eyes with no itching. peremia related to allergic conjunctivitis. Ketotifen’s rapid

Table 3. Effect of Ketotifen Fumarate on Conjunctival, Ciliary, and Episcleral Hyperemia in the Allergen Challenge Model*

Ketotifen Score Minus Placebo Score Assessment Time After Challenge, min Visit 2 (n = 89) Visit 3 (n = 89) Visit 4 (n = 83) Visit 5 (n = 72) 7 Conjunctival 0.03 (0.38) −0.63 (0.86)† −0.36 (0.71)† −0.36 (0.60)† Ciliary 0.04 (0.43) −0.76 (0.95)† −0.48 (0.66)† −0.36 (0.71)† Episcleral 0.03 (0.40) −0.71 (0.85)† −0.34 (0.66)† −0.34 (0.62)† 10 Conjunctival 0.01 (0.33) −0.53 (0.86)† −0.19 (0.64)‡ −0.20 (0.60)‡ Ciliary −0.01 (0.38) −0.65 (0.98)† −0.29 (0.67)† −0.32 (0.63)† Episcleral 0.01 (0.36) −0.61 (0.91)† −0.23 (0.64)† −0.17 (0.65)§ 15 Conjunctival 0.01 (0.35) −0.54 (0.83)† −0.17 (0.65)§ −0.17 (0.62)§ Ciliary −0.01 (0.37) −0.65 (0.94)† −0.26 (0.65)† −0.21 (0.65)‡ Episcleral 0.01 (0.38) −0.52 (0.86)† −0.14 (0.66)§ −0.22 (0.68)‡

*Data are given as mean (SD) difference between eyes. A negative difference indicates that the mean severity of injection was less in ketotifen-treated eyes compared with placebo-treated eyes. †PϽ.001. ‡PϽ.01. §PϽ.05.

(REPRINTED) ARCH OPHTHALMOL / VOL 121, MAY 2003 WWW.ARCHOPHTHALMOL.COM 629

©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 onset of action (within 15 minutes) and long duration placebo-controlled, efficacy and safety study of ketotifen fumarate 0.025%. of action (at least 8 hours) make it a valuable treatment Paper presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology; April 29-May 4, 2001; Ft Lauderdale, Fla. Abstract 4878- for allergic conjunctivitis. B897. 8. Reaves AT, Abelson MB, Mundorf TK, et al. Two randomized, double-masked, Submitted for publication May 21, 2002; final revision re- placebo-controlled single-dose efficacy and safety studies of ketotifen fumarate ceived December 2, 2002; accepted January 16, 2003. 0.025%. Paper presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology; April 29-May 4, 2001; Ft Lauderdale, Fla. Abstract This study was supported by Novartis Ophthalmics, Inc. 4886-B905. All authors had full access to all the data in the study 9. Hugues FC, Le Jeunne C. Systemic and local tolerability of ophthalmic drug for- and take responsibility for the integrity of the data and the mulations: an update. Drug Saf. 1993;8:365-380. accuracy of the analysis. 10. Abelson MB, Udell IJ. H2-receptors in the human ocular surface. Arch Ophthal- Corresponding author and reprints: Mark B. Abelson, MD, mol. 1981;99:302-304. 11. Abelson MB, Schaefer K. Conjunctivitis of allergic origin: immunologic mecha- Ophthalmic Research Associates, Inc, 863 Turnpike St, North nisms and current approaches to therapy. Surv Ophthalmol. 1993;38(suppl): Andover, MA 01845 (e-mail: [email protected]). 115-132. 12. Abelson MB, Lanier RQ. The added benefit of local Patanol therapy when com- bined with systemic Claritin for the inhibition of ocular itching in the con- REFERENCES junctival antigen challenge model. Acta Ophthalmol Scand Suppl. 1999;228:53- 56. 1. Weeke ER. Epidemiology of hay fever and perennial allergic rhinitis. Monogr Al- 13. Deschenes J, Discepola M, Abelson M. Comparative evaluation of olopatadine lergy. 1987;21:1-20. ophthalmic solution (0.1%) versus ketorolac ophthalmic solution (0.5%) using 2. Allansmith MR, Ross RN. Ocular allergy. Clin Allergy. 1988;18:1-13. the provocative antigen challenge model. Acta Ophthalmol Scand Suppl. 1999; 3. Abelson MB, Chapin MJ. Current and future topical treatments for ocular al- 228:47-52. lergy. Compr Ophthalmol Update. 2000;1:303-320. 14. Netland PA, Leahy C, Krenzer KL. Emedastine ophthalmic solution 0.05% ver- 4. Berdy GJ, Spangler DL, Bensch G, Berdy SS, Brusatti RC. A comparison of the sus levocabastine ophthalmic suspension 0.05% in the treatment of allergic relative efficacy and clinical performance of olopatadine hydrochloride 0.1% conjunctivitis using the conjunctival allergen challenge model. Am J Ophthal- ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution in the mol. 2000;130:717-723. conjunctival antigen challenge model. Clin Ther. 2000;22:826-833. 15. Berdy GJ. Atopic keratoconjunctivitis (AKC). Acta Ophthalmol Scand Suppl. 1999; 5. Grant SM, Goa KL, Fitton A, Sorkin EM. Ketotifen: a review of its pharmacody- 228:7-9. namic and pharmacokinetic properties, and therapeutic use in asthma and al- 16. Nabe M, Miyagawa H, Agrawal DK, Sugiyama H, Townley RG. The effect of ke- lergic disorders. Drugs. 1990;40:412-448. totifen on eosinophils as measured at LTC4 release and by chemotaxis. Allergy 6. Abelson MB, Chambers WA, Smith LM. Conjunctival allergen challenge: a Proc. 1991;12:267-271. clinical approach to studying allergic conjunctivitis. Arch Ophthalmol. 1990;108: 17. Devillier P, Arnoux B, Lalau Keraly C, Landes A, Marsac J, Benveniste J. Inhibi- 84-88. tion of human and rabbit platelet activation by ketotifen. Fundam Clin Pharma- 7. Greiner JV, Abelson MB, DuBiner H, et al. A randomized, double-masked, col. 1990;4:1-9.

CME Announcement

Online CME to Begin in Mid-2003 In mid-2003, online CME will be available for JAMA/ ARCHIVES and will offer many enhancements: • Article-specific questions • Hypertext links from questions to the relevant con- tent • Online CME questionnaire • Printable CME certificates and ability to access total CME credits We apologize for the interruption in CME and hope that you will enjoy the improved online features that will be available in mid-2003.

(REPRINTED) ARCH OPHTHALMOL / VOL 121, MAY 2003 WWW.ARCHOPHTHALMOL.COM 630