Clinical experience with brimonidine 0.2% and timolol 0.5% in glaucoma and ocular hypertension

SURVEY OF O P H T H A L M O L O G Y VOLUME 41 • SUPPLEMENT 1 * NOVEMBER 1996

Clinical Experience with Brimonidine 0.2% and Tlmolol 0.5% in Glaucoma and Ocular Hypertension JOEL S. SCHUMAN, MD

New England Eye Center,New Englmut Medical Co#er Hospitals, Tufts University School of Medicine, Boston, Massachusetts, USA Abstract. The ocular hypotensive efficacy and safety of brimonidine tartrate 0.2%, a highly selective alpha2-adrenergic agonist, was compared with that of timolol 0.5%, a nonselective beta-blocker in two multicenter, randomized, double-masked studies. Combined data from a 12-month completed study and 6-month interim data from an ongoing study are reported. Efficacy and safety were evaluated at baseline, weeks 1 and 2, and months 1, 2, 3, 6, 9, and 12. Intraocular pressure (IOP) was measured at peak (2 hours after the morning dose) and trough (12 hours after the evening dose). Patients (n = 926) instilled either brimonidine tartrate 0.2% or timolol maleate 0.5% twice daily. At peak, the mean decreases from baseline IOP ranged from 5.9 _+ 3.2 mm Hg to 7.6 -+ 3.6 mm Hg for brimonidine and 6.0 +- 3.4 mm Hg to 6.6 _+ 3.6 mm Hg for timolol (p < 0.001 within groups compared with baseline). No significant between-group differences were seen at peak except for weeks 1 and 2 and month 3 (p _< 0.04), when brimonidine had lower mean IOR At trough the mean decreases from baseline ranged from 3.7 -- 4.0 mm Hg to 5.0 -+ 3.0 mm Hg for brimonidine and 5.9 - 3.4 to 6.6 _+ 3.0 for timolol. A significant betweengroup difference was seen at trough at all visits (< 0.001), when timolol had a lower mean IOP. Brimonidine and timolol showed sustained efficacy. Both drugs were well-tolerated. The brimonidine group had more ocular allergy, oral dryness and conjunctival follicles. The timolol group had more burning and stinging. In the brimonidine group, 38/513 (7.4%) discontinued treatment due to ocular allergy. The timolol group had significantly lower mean heart rate compared to baseline. The effect on blood pressure was minimal for both drugs. Briinonidine showed efficacy similar to timolol and a relatively low rate of ocular allergy. Brimonidine 0.2% administered twice daily is an effective and safe ocular hypotensive agent that maintains IOP-lowering in chronic use. (Surv Ophthalmol 41 [Suppl 1]: $27-$37, 1996) Key words, alpha2-adrenergic agonist • timolol

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brimonidine

B r i m o n i d i n e tartrate 0.2% ( A L P H A G A NTM, A1lergan, Inc., Irvine, CA, USA) is a p o t e n t a n d highly selective alpha2-adrenergic agonist 3'6 that lowers intraocular pressure (IOP) by decreasing aqueous p r o d u c t i o n and increasing uveoscleral outflow? 4 Alpha2-adrenoreceptor agonists are a class of comp o u n d s known to reduce IOP, but their widespread use has been limited by side effects such as sedation and hypotension (clonidine) 1°and ocular allergy and tachyphylaxis (apraclonidine). 16"2°'23'~5B r i m o n i d i n e differs f r o m these earlier c o m p o u n d s in that it has significantly h i g h e r affinity for the a l p h a 2adrenoceptor.2a'3'13 Brimonidine has been shown to effectively lower I O P in n o r m o t e n s i v e , g l a u c o m a t o u s a n d o c u l a r hypertensive eyes. A d o s e - r a n g i n g study with 168 p a t i e n t s with g l a u c o m a or o c u l a r h y p e r t e n s i o n s h o w e d t h a t b r i m o n i d i n e 0.2% d e c r e a s e d I O P w i t h o u t significant systemic side effects, s A dosi n g - f r e q u e n c y study in 101 patients showed that twice-daily a d m i n i s t r a t i o n o f the d r u g h a d IOP-

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glaucoma

° ocular hypertension

lowering effects similar to that achieved with three times daily administration, and was without significant ocular or systemic side effects. 21,24aAn exerciseinduced tachycardia study with 24 healthy volunteers who received one drop of b r i m o n i d i n e 0.2% before exercise stress testing showed no adverse effects on cardiovascular or p u h n o n a r y parameters, is T h e first reports o f the l o n g - t e r m efficacy a n d safety of the d r u g indicated that brimonidine 0.2% had IOP-lowering c o m p a r a b l e to timolol, no loss o f p o t e n c y over time, a n d an allergy rate m u c h lower than that r e p o r t e d for apraclonidine. 2'° T h e p r e s e n t r e p o r t combines the data f r o m the first, c o m p l e t e d , 1 2 - m o n t h s t u d y ( S t u d y 1) w i t h 6 m o n t h s of interim data from an o n g o i n g long-term study (Study 2).

Materials and Methods STUDY DESIGN Two multi-center, d o u b l e - m a s k e d r a n d o m i z e d , $27

© 1996. Survey of Ophthalmology. (7 Kent Street, Brookline, MA 02146. Tel: 617-566-2138. Fax: 617-566-4019)

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Surv Ophthalmol 41 (Suppl 1) November 1996

parallel-group, active-controlled comparison clinical trials were conducted. Protocols for both studies were similar, allowing for pooled analysis. One study was completed at 12 months (Study 1) and the other (Study 2) is ongoing. Patients instilled either brimonidine 0.2% or timolol maleate 0.5% twice daily for the study duration. Examinations were performed at baseline, weeks 1 and 2, and months 1, 2, 3, 6, 9 and 12. PATIENT SELECTION

Adult patients who had primary open-angle glaucoma or ocular hypertension in both eyes and who were receiving no more than two ocular hypotensive agents were recruited for the studies. The washout period was 4 days for pilocarpine or carbonic anhydrase inhibitors, 2 weeks for topical alpha-adrenergic agonist agents, and 4 weeks for topical beta-adrenergic blocking agents. Patients were required to have post-washout IOP <_23 mm Hg and <35 mm Hg and best-corrected visual acuity of 20/100 or better in each eye. The study was approved by the institutional review board of each participating institution and written informed consent was obtained from each patient. The systemic exclusion criteria included uncontrolled systemic disease, pregnancy, lactation or childbearing potential, contraindications to alphaadrenoceptor agonist or beta-adrenoceptor antagonist therapy, abnormally low or high heart rate or blood pressure for age, known hypersensitivity to any of the ingredients in the study medication or diagnostic agents to be used in the study, alteration of existing chronic therapy that could have a substantial effect on IOP ocular activity of the study drugs, treatment with adrenergic-augmenting psychotropic drugs, and participation in a current or recent (last 30 days) research study. Ophthalmic exclusions were corneal abnormalities, contact lens wear, active ocular disease, dry eye, Sj6gren syndrome, keratitis sicca, required use of other ocular medications, IOP asymmetry of more than 5 mm Hg, extensive visual field loss, laser treatment or ocular surgery within the past 6 months, and optic nerve head cup:disk ratio of <_0.8 in either eye. DRUG ADMINISTRATION

At baseline, the patients were randomly assigned to receive, in a masked fashion, one drop of either brimonidine tartrate 0.2% or timolol 0.5% sterile ophthalmic solution instilled into each eye twice daily at 12-hour intervals. In Study 1, the randomization was 1:1 for brimonidine and timolol. In Study 2, which is ongoing, more patients were enrolled into the brimonidine group and the randomization was 3:2. T h e increased n u m b e r of patients in the brimonidine group allow for additional data to be

collected on brimonidine. EFFICACY AND SAFETY VARIABLES

The primary efficacy variable was intraocular pressure. Cup:disk ratios and visual fields were secondary efficacy variables. IOP was measured at peak (2 hours after the morning instillation) and trough (12 hours after the evening administration). Patients were monitored for adverse events and for other ocular and systemic safety parameters. At each visit, patients were queried specifically as to their ocular comfort (i.e., burning/stinging, blurring, foreign body sensation or photophobia) and general comfort (i.e., headache, dry mouth, fatigue/drowsiness). All adverse events were reported regardless of causality. At each visit, biomicroscopy was performed and abnormalities recorded, visual acuity was measured with a Snellen chart, and pupil size with a pupillometer or millimeter ruler. At baseline and months 6 and 12, an automated perimetry test was used to evaluate visual field, direct or indirect ophthalmoscopy was used to evaluate the fundus and optic nerve head, and the Schirmer tear test was performed to evaluate tear function. Heart rate and blood pressure were measured at each visit with patients in a resting position. Blood samples were obtained at baseline and months 6 and 12 for assessment of hematology parameters and blood chemistry. STATISTICS

The categorical data for demographics was analyzed by the Cochran-Mantel-Haenszel method. 1~ Subject age, IOP, cup:disk ratio, ocular safety variables (pupil size, Schirmer tear test, visual acuity) and systemic safety variables were analyzed using two-way analysis of variance (ANOVA). Mean changes from baseline were calculated using a paired t-test. The null hypothesis, that there was no change from baseline, was tested against the two-sided alternate hypothesis that there was a change. The overall mean change from baseline is calculated for the combined data only (up to six months). Visual fields were analyzed by Chi-square and biomicroscopy, ophthalmoscopy and symptoms of general discomfort and ocular discomfort were analyzed by Chi-square or Fisher's exact test. Statistical significance was set at p < 0.05. Data are reported as the mean plus or minus the standard error (IOP) or plus or minus the standard deviation (safety variables). Results BASELINE DEMOGRAPHICS

The total enrolhnent in Study 1 was 443, with 221 in the brimonidine-treated group and 222 in the

C L I N I C A L E X P E R I E N C E W I T H B R I M O N I D I N E AND T I M O L O L

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TABLE 1 Demographics of Patients Evaluated for Efficacy by Treatment Group. * (Combined 12-month Data from Study 1 and 6-month Data from Study 2) Treatment Group Brimonidine 0.2% Timolol 0.5% Variable (n = 466) (n = 371) Age (No. i SD) 62.9 + 11.2 61.8 ± 10.8 Range (No.) 27.9-86.4 32.8-83.4 Gender Male 222(47.6%) 199(53.6%) Female 244(52.4%) 172(46.4%) Race White 381(81.8%) 300(80.9%) Black 50(10.7%) 36 (9.7%) Hispanic 22 (4.7%) 26 (7.0%) Asian 10 (2.1%) 5 (1.3%) Other t 3 (0.6%) 4 (1.1%) Iris Color Blue 163(35.0%) 128(34.5%) Green 21 (4.5%) 15 (4.0%) Hazel 84(18.0%) 62(16.7%) Brown 195(41.8%) 163(43.9%) Other~ 3 (0.6%) 3 (0.8%) Diagnosis Open-angle glaucoma 272(58.4%) 216(58.2%) Ocular hypertension 180(38.6%) 144(38.8%) Both§ 14 (3.0%) 11 (3.0%) *The demographic characteristics of all 926 patients enrolled were similar to those presented in this efficacy-evaluable subset. 1"Other race: Hawaiian, Arabic, Yemeni, Iraqi, Anglo-Asian ~Other eye color: gray, blue-gray, blue-green and mixed §One eye with open-angle glaucoma and other eye with ocular hypertension.

timolol-treated group. T h e total e n r o l l m e n t in Study 2 was 483, with 292 in the b r i m o n i d i n e - t r e a t e d group a n d 191 in the timolol-treated g r o u p (reflecting an u n e v e n r a n d o m i z a t i o n o f 3:2). Overall, 513 patients p a r t i c i p a t e d in the b r i m o n i d i n e groups a n d 413 in the timolol groups, for a total o f 926 in the two studies. O f these, 837 m e t the protocol criteria for efficacy evaluation, 466 in the b r i m o n i d i n e g r o u p a n d 371 in the timolol group. All 926 participants were included in the analysis o f safety. Table 1 shows the c o m b i n e d d e m o g r a p h i c characteristics o f b o t h c o m p a r i s o n studies. O p e n - a n g l e g l a u c o m a was the m o s t c o m m o n diagnosis, occurr i n g in 58% o f all patients. O c u l a r h y p e r t e n s i o n was s e e n in 39% o f p a t i e n t s , a n d a visual field defect in one eye a n d no field defect in the o t h e r occurred in 3% of patients. T h e m e a n age overall was 62.4 +- 11.0 a n d the m a l e : f e m a l e r a t i o was 50:50. Most p a t i e n t s w e r e white, with d a r k iris c o l o r (hazel or brown). N o significant b e t w e e n g r o u p differences were seen in age, race, sex, iris color or diagnosis. Fifty-three p e r c e n t o f p a t i e n t s in the b r i m o n i dine g r o u p a n d 55% o f those in the timolol g r o u p h a d b e e n t r e a t e d previously with a beta-blocker. INTRAOCULAR PRESSURE In Study 1, which was c o m p l e t e d at 12 m o n t h s

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---o---Timolol 0.5%

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Fig. 1. Effect ofbrimonidine 0.2% and timolol 0.5% at peak (2 hours after the morning instillation of the drug) in two longterm studies. Figure shows combined data from one 12-month completed study (Study 1) and 6 months of an ongoing study (Study 2). Asterisks indicate statistically significantly lower IOP with brimonidine at week 1 (p = 0.011 ), week 2 (p = 0.001), and month 3 (p = 0.043). Lines show mean IOP and vertical bars the standard error of the means.

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a n d f o r w h i c h all 12 m o n t h s results are r e p o r t e d , p e a k I O P was m e a s u r e d at baseline, week 2, a n d m o n t h s 1, 3, 6, a n d 12. T r o u g h I O P was m e a s u r e d at baseline, weeks 1 a n d 2, a n d m o n t h s 1, 2, 3, 6, 9, a n d 12. T h e w e e k 2 p e r i o d a n d t r o u g h d a t a were o b t a i n e d in a subset o f t h e p o p u l a t i o n . I n S t u d y 2, w h i c h is o n g o i n g a n d f o r w h i c h 6 m o n t h s o f i n t e r i m d a t a are p r e s e n t e d , p e a k I O P was m e a s u r e d at b a s e l i n e , w e e k s 1 a n d 2, a n d m o n t h s 1, 3, a n d 6. T r o u g h I O P was m e a s u r e d at baseline, weeks 1 a n d 2, a n d m o n t h s 1, 2, 3, a n d 6. T h e b a s e l i n e ( h o u r 0) I O P in t h e b r i m o n i d i n e g r o u p (n = 221) was 24.9 m m H g a n d in the timolol g r o u p (n = 222) was 24.6 m m H g . T h e b e t w e e n g r o u p differences were n o t statistically significant.

At p e a k (2 h o u r s after t h e m o r n i n g dose), the m e a n d e c r e a s e s f r o m baseline I O P were statistically significant at all follow-up visits in b o t h g r o u p s (Fig. 1). M e a n I O P decreases r a n g e d f r o m 5.9 -+ 3.2 m m H g to 7.6 -+ 3.6 m m H g f o r b r i m o n i d i n e (p < 0.001) a n d 6.0 -+ 3.4 m m H g to 6.6 -+ 3.6 m m H g f o r timolol (p < 0.001). N o significant d i f f e r e n c e was seen b e t w e e n g r o u p s e x c e p t f o r weeks 1 a n d 2 a n d m o n t h 3 (p _< 0.04), w h e n b r i m o n i d i n e - t r e a t e d patients h a d g r e a t e r m e a n decreases t h a n those treated with timolol. M e a n I O P c h a n g e s f r o m baseline at p e a k are shown in Table 2 f o r t h e c o m b i n e d studies, Table 3 for S t u d y 1, a n d Table 4 for S t u d y 2. T h e m o r n i n g t r o u g h ( h o u r 12) b a s e l i n e I O P for b o t h g r o u p s was the same, 25.9 m m H g . M e a n de-

TABLE 2

Timepoint Baseline Week 1 Week 2 Month 1 Month 3 Month 6 Month 12

Intraocular Pressure (lOP) Baseline and Mean Change from Baseline at 2-hour Peak (Combined 12-month Data from Study 1 and 6-month Data from Study 2) Timolol 0.5% Brimonidine 0.2% mm Hg SD Range No. Pts. mm Hg SD Range 15.5 to 34.0 16.0 to 36.0 410 24.64 3.08 24.93 3.22 -19.5 to +2.0 -19.5 to +3.5 233 -6.64 3.60 -7.57 3.58 -17.0 to +3.0 - 18.5 to + i .0 284 -6.09 3.46 -7.14 3.40 -16.0 to +3.0 -18.5 to +7.0 373 -6.31 3.40 -6.64 3.34 -16.0 to +10.5 -21.0 to +3.0 338 -6.29 3.53 -6.83 3.38 -16.0 to +5.5 -17.5 to +6.0 297 -6.05 3.56 -6.30 3.50 -14.0 to +1.5 -13.5 to +0.5 103 --6.01 3.35 -5.92 3.19

No. Pts. 340 164 211 319 309 291 135

p-value 0.267 0.011 0.001 0.262 0.043 0.442 0.843

No. Pts. 173 60 163 158 147 135

p-value 0.701 0.032 0.480 0.013 0.806 0.808

No. Pts. 167 164 151 156 151 144

p-value 0.228 0.004 0.007 0.111 0.335 0.171

TABLE 3

Timepoint Baseline Week 2 Month 1 Month 3 Month 6 Month 12

Intraocular Pressure (lOP) Baseline and Mean Change from Baseline at 2-hour Peak (12-month Data from Study 1) Brimonidine 0.2% Timolol 0.5% mm Hg SD Range No. Pts. mm Hg SD Range 24.75 2.97 16.0 to 34.5 170 24.56 3.04 15.5 to 34.0 --6.83 3.42 -15.5 to +1.0 60 -5.21 3.59 -12.5 to +3.0 -6.40 3.28 -14.5 to +7.0 155 -6.25 3.29 -15.5 to +2.0 -6.97 3.06 -17.0 to +1.0 140 --6.12 3.60 -16.0 to +10.5 -6.12 2.93 -13.5 to +4.0 124 -6.30 3.45 -16.0 to +3.5 -5.92 3.19 -13.5 to 4).5 103 -6.01 3.35 -14.0 to +1.5

Timepoint Baseline Week 1 Week 2 Month 1 Month 3 Month 6

lntraocular Pressure (lOP) Baseline and Mean Change from Baseline at 2-hour Peak (6-month Data from Study 2) Brimonidine 0.2% Timolol 0.5% mm Hg SD Range No. Pts. mm Hg SD Range 25.06 3.38 17.5 to 36.0 240 24.73 3.12 16.5 to 33.5 -7.57 3.58 -19.5 to +3.5 233 -6.64 3.60 -19.5 to +2.0 -7.23 3.40 -18.5 to 0.0 224 -6.45 3.36 -17.0 to +0.5 -6.80 3.38 -18.5 to +1.0 218 -6.37 3.52 -16.0 to +3.0 -6.74 3.60 -21.0 to +3.0 198 -6.47 3.46 -15.5 to +3.0 -6.44 3.86 -17.5 to +6.0 173 -5.80 3.66 -16.0 to +5.5

TABLE 4

CLINICAL EXPERIENCE WITH BRIMONIDINE AND TIMOLOL

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Fig. 2. Effect ofbrimonidine 0.2% and timolol 0.5% at trough (12 hours after the evening instillation of the drug) in two longterm studies. Figure shows combined data from one 12-month completed study (Study 1) and 6 months of an ongoing study (Study 2). Asterisks indicate statistically significantly lower IOP with timolol at all visits (p _< 0.001). Lines show mean IOP and vertical bars the standard error of the means.

c r e a s e s f r o m b a s e l i n e at t r o u g h w e r e statistically sign i f i c a n t i n b o t h t r e a t m e n t g r o u p s a t all f o l l o w u p visits (Fig. 2). M e a n d e c r e a s e s f r o m b a s e l i n e r a n g e d f r o m 3.7 +_ 4.0 m m H g t o 5.0 _+ 3.0 m m H g f o r b r i m o n i d i n e (p < 0.001) a n d 5.9 + 3.4 m m H g to 6.6 _+ 3.0 m m H g for t i m o l o l (p < 0.001). T h e m e a n d e c r e a s e s in I O P w e r e g r e a t e r w i t h t i m o l o l t h a n w i t h brimonidine, but the between-group differences w e r e n o t c l i n i c a l l y s i g n i f i c a n t (-<2 m m H g ) . M e a n I O P c h a n g e s f r o m b a s e l i n e at t r o u g h a r e s h o w n in T a b l e 5 for t h e c o m b i n e d s t u d i e s , T a b l e 6 f o r S t u d y

1, a n d T a b l e 7 for S t u d y 2. B o t h d r u g s s h o w e d a s u s t a i n e d t h e r a p e u t i c effect at b o t h p e a k a n d t r o u g h . N o I O P d r i f t was s e e n o v e r t h e 12 m o n t h s o f S t u d y 1 a n d first 6 m o n t h s o f S t u d y 2, w h i c h is o n g o i n g . SECONDARY EFFICACY VARIABLES M e a n c h a n g e s f r o m b a s e l i n e c u p : d i s k r a t i o values showed no significant differences between the brimonidine and timolol treatment groups over the study periods.

TABLE 5

Timepoint Baseline Week 1 Week 2 Month 1 Month 2 Month 3 Month 6 Month 9 Month 12

Intraocular Pressure (lOP) Baseline and Mean Changefrom Baseline at 12-hour Trough (Combined 12-month Data from Study I and 6-month Data from Study 2) Timolol 0.5% Brimonidine 0.2 o Range mm Hg SD Range No. Pts. mm Hg SD 23.0 to 34.0 25.86 2.80 22.5 to 34.5 460 25.90 2.75 -17.0 to +1.5 -6.45 3.01 -16.5 to +6.0 436 -4.99 2.95 -15.0 to +2.5 -16.0 to +4.0 317 -6.08 3.05 -4.56 2.95 -16.5 to +1.5 -6.37 3.05 -13.5 to +11.0 422 -4.14 3.02 -15.0 to +2.5 -6.63 3.04 -13.5 to +11.5 392 -4.21 3.14 16.0 to +4.0 -6.26 3.19 -13.5 to +5.0 384 -4.22 3.14 -15.0 to +3.5 -6.25 3.17 -12.5 to +7.0 328 -3.83 3.38 -14.0 to +4.0 -6.16 3.10 -12.5 to +6.5 119 -4.20 3.51 16.0 to +6.5 -5.88 3.38 -11.5 to +8.5 106 -3.67 3.98

No. Pts. 368 348 229 350 336 331 321 153 149

p-value 0.895 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

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Timepoint Baseline Week 1 Week 2 Month 1 Month 2 Month 3 Month 6 Month 9 Month 12

TABLE 6 lntraocular Pressure (lOP) Baseline and Mean Change from Baseline at 12-hour Trough (12-month Data from Study 1) Brimonidine 0.2% Timolol 0.5% mm Hg SD Range No. Pts. mm Hg SD Range 25.80 2.31 23.0 to 32.0 186 25.87 2.81 23.0 to 34.0 -5.32 2.90 -16.5 to +6.0 171 ~.47 3.00 -13.5 to +1.5 -4.45 2.82 -10.0 to +2.0 63 -5.81 2.89 -12.0 to +1.5 -4.35 3.27 -13.5 to +11.0 172 ~.57 2.92 -16.5 to +1.0 -4.26 3.25 -11.5 to +11.5 153 ~.84 3.03 15.0 to +2.5 -4.49 3.10 -12.0 to +3.5 154 ~.32 3.40 -16.0 to +4.0 -3.89 3.40 - l l . 0 to +6.0 130 ~.40 3.21 -15.0 to +3.5 -4.20 3.51 -12.5 to +6.5 119 ~.16 3.10 -14.0 to +4.0 -3.67 3.98 -11.5 to +8.5 106 -5.88 3.38 -16.0 to +6.5

No. Pts. 188 174 65 179 171 168 162 153 149

p-value 0.662 <0.001 0.030 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

Timepoint Baseline Week 1 Week 2 Month 1 Month 2 Month 3 Month 6

TABLE 7 Intraocular Pressure (lOP) Baseline and Mean Change from Baseline at 12-hour Trough (6-month Data from Study 2) Brimonidine 0.2% Timolol 0.5% mm Hg SD Range No. Pts. mm Hg SD Range 25.96 3.01 22.5 to 34.5 274 25.85 2.80 23.0 to 34.0 -4.78 2.96 -16.5 to +4.5 265 ~i.44 3.02 -17.0 to +0.5 -4.59 2.98 -16.0 to +4.0 254 ~i.18 3.12 -15.0 to +2.5 -3.98 2.84 -11.5 to +8.0 250 ~.16 3.18 -14.0 to +1.5 -4.18 3.07 -13.5 to +3.0 239 ~i.42 3.04 -14.5 to +2.5 -4.04 3.15 -13.5 to +5.0 230 ~.20 2.97 -14.5 to +2.5 -3.79 3.37 -12.5 to +7.0 198 ~.10 3.12 -15.0 to +2.5

No. Pts. 180 174 164 171 165 163 159

p-value 0.273 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

No change in visual acuity occurred in 488 (95.1%) o f patients in the b r i m o n i d i n e t r e a t m e n t g r o u p a n d 385 (93.2%) o f p a t i e n t s in the timolol t r e a t m e n t g r o u p (p = 0.137). Worsening o f visual acuity o f two lines or m o r e occurred in 24 (4.7%) o f patients in the b r i m o n i d i n e g r o u p a n d 28 (6.8%) o f those in the timolol group. T h e s e findings can be a s s u m e d to be not d r u g - r e l a t e d a n d m a y have b e e n associated with the progression o f cataracts, which can be e x p e c t e d given the d e m o g r a p h i c profile o f this patient population. T h e vast majority (346/369; 93.8%) o f visual fields were u n c h a n g e d or within 5 dB o f baseline in b o t h t r e a t m e n t groups in b o t h studies. Results f r o m the S c h i r m e r tear test showed a clinically significant decrease f r o m baseline in 89 o f 500 patients (17.8%) tested in the b r i m o n i d i n e g r o u p a n d 78 o f 403 patients (19.4%) in the timolol group. A clinically significant decrease was defined as either a baseline < 10 m m a n d follow-up < 5 m m , or a baseline > 10 m m , follow-up < 10 m m a n d a decrease f r o m baseline > 5 m m . T h e b e t w e e n - g r o u p difference was not significant (p = 0.550). Overall, there were negligible m e a n changes f r o m baseline in b o t h t r e a t m e n t groups o f b o t h studies.

ADVERSE EVENTS

T h e overall incidence o f adverse events was similar in b o t h t r e a t m e n t g r o u p s in b o t h studies. N o serious t r e a t m e n t - a s s o c i a t e d a d v e r s e events were r e p o r t e d or observed in any patient. Table 8 shows the side effects in b o t h t r e a t m e n t groups in b o t h studies. U p o n specific inquiry, the m o s t c o m m o n l y r e p o r t e d a d v e r s e events in b o t h groups were dry mouth, ocular h y p e r e m i a , burning/ stinging, headache, a n d foreign b o d y sensation. Dry m o u t h , ocular allergic r e a c t i o n s a n d conjunctival follicles were r e p o r t e d significantly m o r e f r e q u e n t l y in p a t i e n t s r e c e i v i n g b r i m o n i d i n e (p < 0.001), while b u r n i n g / s t i n g i n g was r e p o r t e d m o r e often in timolol-treated patients (p < 0.001). Ocular allergic reactions, which were defined by the investigators as patients w h o h a d an allergic response to the medication, such as allergic conjunctivitis, allergic blepharoconjunctivitis, a n d / o r follicular conjunctivitis, were seen in 49 (9.6%) o f patients treated with b r i m o n i d i n e , a n d caused discontinuation o f the d r u g in 38 (7.4%). N o n e o f the timololtreated patients d e v e l o p e d ocular allergy a n d very few were t e r m i n a t e d f r o m either study for any rea-

CLINICAL EXPERIENCE W I T H B R I M O N I D I N E A N D TIMOLOL

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TABLE 8 Summary of Adverse Events by Treatment Group (Combined 12-month Data from Study 1 and 6-month Data from Study 2) Brimonidine 0.2% Timolol 0.5% (n = 513) (n = 413) Overall Exited Overall Exited No. (%) No. (%) No. (%) No. (%)

Adverse Events* p-value Ocular Allergy1" 49 (9.6) 38 (7.4) 1 (0.2) 1 (0.2) <0.001 Blurred Vision 90 (17.5) 4 (0.8) 83 (20.1) 2 (0.5) 0.322 Burning/Stinging 123 (24.0) 3 (0.6) 168 (40.7) 1 (0.2) <0.001 Corneal Staining/Erosion 41 (8.0) 0 (0.0) 44 (10.7) 0 (0.0) 0.163 Conjunctival follicles 40 (7.8) 0 (0.0) 12 (2.9) 0 (0.0) 0.001 Foreign body sensation 87 (17.0) 1 (0.2) 62 (15.0) 0 (0.0) 0.423 Hyperemia 135 (26.3) 5 (1.0) 95 (23.0) 0 (0.0) 0.246 Pruritus 52 (10.1) 1 (0.2) 36 (8.7) 0 (0.0) 0.464 Systemic Dry mouth 154 (30.0) 7 (1.4) 64 (15.5) 1 (0.2) <0.001 Fatigue/drowsiness 81 (15.8) 13 (2.5) 56 (13.6) 1 (0.2) 0.342 Headache 96 (18.7) 5 (1.0) 78 (18.9) 1 (0.2) 0.947 *Data reflect events with an incidence of _>10% or those with a significant between-group difference. Lens and fundus pathologies were excluded as the incidence was similar in both groups and assumed not to be drug related. ?Allergy = allergic blepharitis, blepharoconjunctivitis or conjunctivitis; ocular allergic reaction; follicular conjunctivitis

son. T h i s m a y b e e x p l a i n e d by t h e selection bias o f the studies. Mydriasis a n d eyelid retraction, c o m m o n l y seen with a p r a c l o n i d i n e , 7 were n o t s e e n in e i t h e r study.

p r e s s u r e or h e a r t rate were n o t e d in any p a t i e n t . Fig. 3 shows h e a r t rates for b o t h d r u g s a n d Fig. 4 shows systolic a n d diastolic b l o o d pressures. Patients receiving timolol e x p e r i e n c e d statistically significant m e a n decreases f r o m b a s e l i n e h e a r t rate at every s c h e d u l e d follow-up visit (-1.8 to - 3 . 0 b e a t s p e r m i n u t e ; p < 0.001). M e a n h e a r t r a t e r e m a i n e d

SYSTEMIC SAFETY N o clinically significant c h a n g e s in systolic b l o o d

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big. 3. Effect ofbrimonidine 0.2% and timolol 0.5% on heart rate in two long-term studies. Figure shows combined data from one 12-month completed study and 6 months of an ongoing study. Asterisks indicate statistically significantly lower heart rate with tirnolol 0.5% (p _< 0.042) at all time points except month 9, which had data from first study only. Lines show mean heart rate and vertical bars the standard deviation.

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relatively u n c h a n g e d in patients receiving brimonidine (-0.1 to - 0 . 5 beats p e r minute; p _> 0.146). Mean decreases were significantly greater (p > 0 . 0 4 2 ) in t h e t i m o l o l g r o u p t h a n in t h e brimonidine group at every follow-up visit except m o n t h 9. Mean changes from baseline in systolic and diastolic blood pressure in b o t h treatment groups in both studies were not clinically significant. T h e effect on systolic blood pressure was limited to a m e a n change ranging from -2.27 to +0.64 m m H g for brimonidine and -1.86 to +0.46 m m H g for timolol. No significant between-group differences were seen at any time point. Mean changes in diastolic blood p r e s s u r e r a n g e d f r o m - 0 . 9 to - 1 . 7 m m H g for b r i m o n i d i n e and -0.2 to -1.3 m m H g for timolol. Brimonidine-treated patients had greater mean decreases in diastolic b l o o d pressure t h a n those treated with timolol at m o n t h s 1 (p = 0.028) and 6 (p = 0.042). In b o t h t r e a t m e n t groups, there were

sporadic incidences o f significant changes in blood pressure. In this study population, these changes had no clinical significance. Although several statistically significant withing r o u p c h a n g e s f r o m b a s e l i n e l a b o r a t o r y values, i n c l u d i n g b l o o d lipid levels, o c c u r r e d with b o t h b r i m o n i d i n e and timolol treatment, these changes r e m a i n e d within n o r m a l r a n g e and were not clinically significant.

Discussion T h e results o f these c o m b i n e d studies show that brimonidine, 0.2%, given twice daily as m o n o t h e r apy in patients with glaucoma or ocular h y p e r t e n sion, has IOP-lowering effects c o m p a r a b l e to timolol a n d n o loss o f efficacy for u p to 1 year. At the 2-hour peak, b r i m o n i d i n e had significantly lower IOP than timolol at weeks 1 and 2 and m o n t h 3. At the 12-hour trough, timolol had _<2 m m H g greater IOP-lowering effect than brimonidine.

CLINICAL EXPERIENCE W I T H B R I M O N I D I N E A N D T I M O L O L

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Effectofbrimonidine 0.2% and timolol 0.5% on diastolicblood pressure in two long-term studies. Asterisks indicate statisticallysignificantlylower diastolicblood pressure with brimonidine at month 1 (p = 0.028) and month 6 (p = 0.042). For diastolic blood pressure the standard deviations ranged from 0.45 to 1.05 mm Hg for the brimonidine group and 0.50 to 0.78 mm Hg for the timolol group. Lines show mean blood pressure and vertical bars the standard deviation.

Fig. 4B.

Brimonidine had minimal effect on cardiovascular parameters and a low rate of ocular allergy. A relatively low incidence of side effects was seen overall in the present study, despite the fact that the protocol called for eliciting many of the side effects commonly associated with alpha 2 agonists or beta-blockers. Ocular allergy, dry m o u t h and conjunctival follicles were seen more frequently with brimonidine, while burning and stinging was reported more frequently with timolol. The timolol group in the present study had low incidences of side effects and a low number of patients who exited the study because of adverse events (Table 8). The study design was biased in favor of beta-blockers because the majority of patients had been exposed to topical beta-blockers just prior to enrollment. This may explain why adverse events typically associated with beta-blocker therapy were not observed in this group. The ocular allergy rate for brimonidine in this study (9.6%) was significantly less than that previously reported for apraclonidine. Apraclonidine 0.5% caused ocular allergy severe enough to require discontinuation of the drug in 15% to 36% of patients in clinical trials? ~ The mean follow-up in one trial was 5.6 months (range 2-15 months). 5 Other

studies, from 8 weeks to 24 months in duration, showed ocular allergy rates ranging from 22% to 30%. 1,16,17,19,22 O c u l a r allergy a s s o c i a t e d with apraclonidine 1% caused discontinuation of the drug in up to 48% of patients, with a mean latency period to onset of allergy of 4.7 months. 4 The IOP-lowering efficacy ofbrimonidine and its lower rate of ocular allergy versus apraclonidine may be due to the difference in chemical structures, brimonidine's selectivity for the alpha 2 over the alpha I receptors and the fact that it is a more stable compound than apraclonidine. Brimonidine has a quinoxaline ring (double ring structure) that is believed to enhance its alpha 2 selectivity?4 Brimonidine is almost 1000-fold selective for the alpha 2 versus the alpha~ receptors, which minimizes alpha~ mediated side effects, including vasoconstriction? In contrast, clonidine and apraclonidine are only 100-fold selective for the alpha s versus the alpha~ receptors? Additionally, brimonidine and clonidine are oxidatively stable, while apraclonidine has an oxidation potential similar to known allergyinducing agents. 15 In the studies presented here, brimonidine had no negative effect on heart rate, a clinically insignificant effect on systemic blood pressure, and caused

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Surv Ophthalmol 41 (Suppl 1) November 1996

n o c h a n g e f r o m n o r m a l b l o o d lipid levels. As an alphaz agonist, it would n o t be e x p e c t e d to cause bronchoconstriction, a n d indeed, does not have an adverse effect on respiratory function. TM T h e clinical safety a n d efficacy profile o f b r i m o n i dine suggests its use as m o n o t h e r a p y , particularly in patients with a relative or absolute contraindication to beta-blockers. Additional studies should be u n d e r t a k e n to explore the potential o f b r i m o n i d i n e as an additive a g e n t in patients for w h o m c o n c o m itant t h e r a p y is a p p r o p r i a t e .

Conclusion B r i m o n i d i n e 0.2% instilled twice-daily effectively lowered elevated I O P in patients with o p e n - a n g l e g l a u c o m a or ocular hypertension. T h e ocular hypotensive efficacy o f b r i m o n i d i n e was c o m p a r a b l e to t h a t o f t i m o l o l . T h e I O P - l o w e r i n g e f f e c t o f b r i m o n i d i n e was sustained for u p to 12 m o n t h s . B r i m o n i d i n e was well tolerated by patients, evoked a low allergic response, a n d h a d a favorable ocular a n d systemic safety profile.

Study Participants and Sites Study 1. Diane Albracht, MD, Castro Valley, California Walter Atlas, MD, Nalle Clinic; Charlotte, North Carolina Howard Barnebey, MD, University of Washington; Seattle, Washington Neil Chopin, MD, US Naval Hospital; San Diego, California E. Randy Craven, MD, Glaucoma Associates; Denver, Colorado Ronald Gross, MD, Baylor College of Medicine; Houston, Texas Stanley Hersh, MD, Waterbury, Connecticut Barry Horwitz, MD, Houston, Texas Robert Jones, MD, Newport Beach, California L. Jay Katz, MD, Wills Eye Hospital; Philadelphia, Pennsylvania Itamar Klemperer, MD, Ben-Gurion University of the Negev; Beer-Sheva, Israel Larry Labarta, MD, Miami Beach, Florida Kathleen Lamping, MD, South Euclid, Ohio Norman Levy, MD PhD, Florida Ophthalmic Institute; Gainesville, Florida Howard E Perell, MD, North Arundal Physicians Center; Glen Burnie, Maryland Michael Rotberg, MD, Charlotte EENT Associates; Charlotte, North Carolina Joel S. Schuman, MD, New England Eye Center; Boston, Massachusetts Les Siegel, MD, Glaucoma Center of Michigan; Southfield, Michigan David Silverstone, MD, New Haven Connecticut Frank Sloan, MD, Myrtle Beach, California Richard Sturm, MD, Lynbrook, New York Stuart Terry, MD, South Texas Cataract and Glaucoma Center; San Antonio, Texas Christopher Tortora, MD, Hawaiian Eye Center; Wahiawa, Hawaii

Jacob Wilensky, MD, University of Illinois at Chicago; Chicago, Illinois Thom Zimmerman, MD, University of Louisville; Louisville, Kentucky

Study 2. Mark B. Abelson, MD, North Andover, Massachusetts A. Gordon Balazi, MD, Montr6al, Quebec, Canada Cecil C. Beehler, MD, Fort Myers, Florida J. Elliott Blaydes, MD, Bluefield, West Virginia Anne M.V. Brooks, MD PhD, East Melbourne, Australia Louis Cantor, MD, Indiana Univ. Med. Ctr., Indianapolis, Indiana David L. Cooke, MD, St. Joseph, Michigan Andrew C.S. Crichton, MD, Calgary, Alberta, Canada Monte Dirks, MD, Fitzsimons Army Med. Ctr., Aurora, Colorado Richard A. Fichman, MD, Manchester, Connecticut Robert J. Foerster, MD, Colorado Springs, Colorado Douglas Gaasterland, MD, Univ. Ophthal Consultants, Washington, DC Ivan Goldberg, MB, Sydney, Australia Benjamin Hasty, MD, Panama City, Florida Oscar Kasner, MD, Montr6al, Quebec, Canada Raymond P. LeBlanc, MD, Nova Scotia Eye Centre, Halifax, Canada Richard A. Lewis, MD, Sacramento, California James McCulley, MD, University of Texas, Dallas, Texas Schlomo Melamed, MD, Chaim Sheba Med. Ctr., Tel-Hashomer, Israel Frederick Mikelberg, MD, Vancouver, Canada John C. Morrison, MD, Oregon Health Sci. Univ., Portland, Oregon Thomas K. Mundorf, MD, Charlotte, North Carolina Paul Murphy, MD, Saskatoon, Saskatchewan, Canada Franklin H. Spirn, MD, Clark, New Jersey Robert Stamper, MD, San Francisco, California Uriel Ticho, MD, Hadassah Univ. Hospital, Jerusalem, Israel David P. Tingey, MD, Ivey Inst. Ophthalmol, London, Ontario, Canada Graham E. Trope, MB PhD, Toronto Hospital-Western Div., Ontario, Canada Thomas R. Walters, MD, Austin, Texas

References 1. Araujo SV, Bond JB, Wilson RP, et al: Long term effect of apraclonidine. BrJ Ophthalmol 79(12):1098-1101, 1995 2. Barnebey H for the Brimonidine Study Group: Long-term efficacy of brimonidine on IOP lowering (abstract). Invest Ophthalmol Vis Sci 37(3 suppl):S1102, 1996 2a.Burke J: Preclinical evaluation of brimonidine. Surv Ophthalmol 41(Suppl 1):$9-S18, 1996 3. Burke J, Manlapaz C, Kharlamb A, et al: Therapeutic use of %-adrenoceptor agonists in glaucoma. In: Lanier S, Limbird L, eds. Alpha2-Adrenergic Receptors: Structure, Function and Therapeutic Implications. Reading, UK: Harwood Academic Publishers, 1996 (in press) 4. Butler P, Mannschreck M, Lin S, et al: Clinical experience with long-term use of 1% apraclonidine. Arch Ophthalmol 113:293-296, 1995 5. Butler PJ, Jones B: Incidence of characteristics of allergic reaction to apraclonidine 0.5%. Invest Ophthalmol Vis Sci 37(3):$201, 1996 6. Cambridge D: UK-14,304, a potent and selective ct-agonist for the characterization of ~x-adrenoceptor subtypes. Eur J Pharmacol 72:413~115, 1981 7. Chacko DM, Camras CB: The potential of%-adrenergic agonists in the medical treatment of glaucoma. Curr Opinion

CLINICAL EXPERIENCE W I T H B R I M O N I D I N E A N D TIMOLOL Ophthalmol 5(II):76--84, 1994 8. Derick RJ, Wahers TR, Robin AL, et al: Brimonidine tartrate: a one month dose response study (abstract). Invest Ophthalmol Vis Sci 34(4 suppl):929, 1993 9. Dirks M for the Brimonidine Study Group: Long-term safety and IOP-lowering efficacy of brimonidine tartrate 0.2% in glaucoma and ocular hypertension (abstract), Invest Ophthalmol Vis Sci 37(3 suppl):S832, 1996 10. Hodapp E, Kolker AE, Kass MA, et al: The effect of topical clonidine on intraocular pressure. Arch Ophthalmol 99: 1208-1211, 1981 11. Landis RJ, Heyman ER, Koch GG: Average partial association in three-way contingency tables: A review and discussion of alternative tests. Int Statistical Review 46:237254, 1978 12. Morrison JC: Side effects of alpha-adrenergic agonists. J Glaucoma 4(suppl 1):$36-$38, 1995 13. Munk SA, Gluchowski C, Dolby L, et al: Analogs of UK 14,304 as %-adrenoceptor agonists. Twist and agent polarity as design elements. Bioorg Med Chem Lett 4(3):459462, 1994 14. Munk SA, Harcourt D, Arasasingham P, et al: Analogs of UK 14,304: structural features responsible for alpha 2 adrenoceptor activity. Bioorg Med CheIn Lett 28;5(15): 1745-50, 1995 15. Munk SA, Wiese A, Thompson CD, et al: Oxidation potential and allergic response of alpha 2 agonists (abstract). Invest Ophthalmol Vis Sci 37(3):$832, 1996 16. Nagasubramanian S, Hitchings RA, Demailly P, et al: Comparison of apraclonidine and timolol in chronic open angle glaucoma. A three-month study. Ophthalmology 100:13181323, 1993 17. Nguyen KD, Shin DH: Prevalence of apraclonidine allergy and its relationship to PROPINE ® allergy (abstract). Invest Ophthalmol Vis Sci 37(3):S1103, 1996 18. Nordlund JR, Pasquale LR, Robin AL, et al: A comparison of the cardiovascular and puhnonary effects of brimonidine 0.2%, timolol 0.5% and betaxolol suspension 0.25%. Arch Ophthalmol 113:77-83, 1995

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19. Pineyro A, Gross RL, Orengo-Nania S: Long term experience with apraclonidine 0.5% (IOPIDINE) in clinical practice (abstract). Invest Ophthalmol Vis Sci 37(3):S 1100, 1996 20. Robin AL: Questions concerning the role of apraclonidine in the m a n a g e m e n t of glaucoma. Arch O p h t h a l m o l 113:712-713, 1995 21. Rosenthal AL, Wahers T, Berg E, et al: A comparison of the safety and efficacy of brimonidine 0.2%, BID versus TID (abstract). Invest O p h t h a l m o l Vis Sci 37(3 suppl):S1102, 1996 22. Sheth BP, Kalenak JW: Frequency of allergy to apraclonidine in a clinical practice (abstract). Invest Ophthalrnol Vis Sci 37(3):S1099, 1996 23. Stewart WE, Ritch R, Shin DH, Lehmann RP, et al: The efficacy of apraclonidine as an adjunct to timolol therapy. Arch Ophthalmol 113:287-292, 1995 24. Toris CB, Gleason ML, Camras CB, et al: Effects ofbrimonidine on aqueous humor dynamics in human eyes. Arch Ophthalmol 113:1514-1517, 1995 24a.Wahers TR: Development and use ofbrimonidine in treating acute and chronic IOP elevations: A review of safety, efficacy, dose response, and dosing studies. Surv Ophthaltool 41(Suppl 1):S19-$26, 1996 25. Wilkerson M, Lewis RA, Shields MG: Follicular conjunctivitis associated with apraclonidine. Am J Ophthalmol 111:105-206, 1991 The author wishes to thank Kuankuan S. Chen, M.S., principal biostatistician, Allergan, Inc., for statistical analyses of the data. Presented in part at the American G l a u c o m a Society, Vancouver, British Columbia, July 30-August 2, 1996 Dr. Schmnan has no proprietary interest in Allergan, Inc., or brimonidine. Reprint address: Joel S. Schuman, MD, New England Eye Center, New England Medical Center Hospitals, Tufts University School of Medicine, 750 Washington Street, Box 450, Boston, MA 02111. Telephone: 617-636-7950; Facsimile: 617636-4866.