Brimonidine Tartrate
`A One~month Dose Response Study
`
`Robert}. Derick, MD/,2 Alan L. Robin, MD,1,2 T. R. Walters/
`Howard S. Barnebey, MD,4 Neil Choplin, MD,5 Joel Schuman, MD,6
`Elaine P. Kelley, BS/ Kuankuan Chen, MS/ Jack F. Stoecker, BS, MBA7
`
`Background: Brimonidine tartrate is a relatively selective alpha2-agonist that effec(cid:173)
`tively reduces mean intraocular pressure (lOP) and the incidence of lOP spikes after
`laser trabeculoplasty. The authors were interested in evaluating the dose response of
`brimonidine when applied topically for a longer duration in patients with elevated lOPs.
`Methods: The authors conducted a 1-month, multicentered, double-masked, ran(cid:173)
`domized, placebo-controlled, parallel clinical study in 194 patients with ocular hyperten(cid:173)
`sion or glaucoma (mean lOP, 25.6 ::t 3.2 mmHg). The authors administered three concen(cid:173)
`trations of brimonidine (0.08%, 0.2%, and 0.5%) or placebo bilaterally every 12 hours
`for 1 month. The authors evaluated the following parameters: lOP, heart rate, blood
`pressure, visual acuity, pupil size, basal tear secretion as well as patient comfort at
`baseline, day 1, week 1, week 3, and week 4.
`Results: All concentrations of brimonidine significantly reduced lOP, compared to
`baseline and placebo, at all follow-up visits. Maximum mean lOP decreases from baseline
`of 20.8%,27.2%, and 30.1% were observed for the 0.08%,0.20%, and 0.5% treatment
`groups, respectively. On days 1 and 21, the 0.2% and 0.5% treatment groups exhibited
`significantly greater lOP decreases than did the 0.08% group. After the initial steep
`decline in lOP, the effect decreased slightly and stabilized at day 14 at the level that
`was maintained throughout the study. The most frequent side effects reported were
`fatigue and dry mouth. No significant changes in heart rate were reported. Statistically
`significant decreases in mean blood pressure without clinical symptoms were observed
`within the 0.2% and 0.5% treatment groups.
`Conclusion: Brimonidine 0.2% is well tolerated, efficacious, and shows potential
`as an agent in the long-term treatment of elevated lOP.
`Ophthalmology 1997; 104:131-136
`
`Originally received: January 9, 1996.
`Revision accepted: August 5, 1996.
`1 Sinai Hospital, Baltimore. .
`2 Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore.
`3 Austin, Texas.
`4 Seattle, Washington.
`5 The Naval Hospital, San Diego.
`6 New England Eye Center, Boston.
`7 Allergan, Inc, Irvine.
`Dr. Derick is currently affiliated with the William H. Havener Eye
`Center, The Ohio State University, Columbus, Ohio.
`Presented in part at the ARVO Annual Meeting, Sarasota, April 1993.
`Supported in part by a grant from the Zanvyl Krieger Foundation and
`Allergan, Inc.
`Drs. Derick, Walters, Robin, Bamebey, Schuman, and Choplin have no
`
`AlphaTagonists are a relatively new class of glaucoma
`medication derived from clonidine that offer promise for
`the long-term therapy of glaucoma. Apraclonidine, the
`most widely used alphaz-agonist, has been effective in
`lowering the intraocular pressure (lOP) in patients with
`4
`; however, topical allergl- 8 may
`ocular hypertension l
`-
`limit its long-term potential in many eyes. Brimonidine
`
`proprietary interests in Allergan, Inc, or brimonidine. Ms. Kelley and
`Ms. Chen are Allergan employees; Mr. Stoecker is a former Allergan
`employee.
`The opinions expressed in this work are those of the authors, and do
`not reflect those of the Department of the Navy or the Department of
`Defense.
`Reprint requests to Robert J. Derick, MD, 456 W. Tenth Ave, Suite
`5106, Columbus, OH 43210.
`
`131
`
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`
`tartrate (AGN 190342-LF, UK 14,304-18) is a relatively
`selective alphaTagonist that, because of its distinct chemi(cid:173)
`cal structure, may have theoretical advantages over
`apraclonidine. Topically administered brimonidine lowers
`lOP in normotensive and ocular hypertensive monkeys,
`rabbits, and cats over a dose range of 0.001 % to 1.0%.9
`In human subjects, the mechanism has been reported as
`being dual: a decrease in inflow and an increase in uveo(cid:173)
`scleral outflow. 1O Brimonidine is an effective agent in
`reducing elevations in lOP after argon laser trabecu(cid:173)
`loplasty and in patients with elevated IOP. II
`,12
`Brimonidine, like apraclonidine, appears to have mini(cid:173)
`mal effects on heart rate and systemic blood pressure. 13
`Both agents, however, produce similar alphal side effects,
`including dry mouth, fatigue, and conjunctival blanching.
`In this study, we attempted to determine the concentration
`of brimonidine that maximized lOP reduction and mini(cid:173)
`mized side effects.
`
`Methods
`
`This study was a multicentered, double-masked, random(cid:173)
`ized, placebo-controlled, parallel, I-month dose response
`evaluation of brimonidine 0.5%, 0.2%, and 0.08% in pa(cid:173)
`tients with open-angle glaucoma or ocular hypertension.
`We enrolled 194 chronic open-angle glaucoma or ocular
`hypertension patients with the following criteria:
`1. All had untreated lOPs of at least 22 mmHg but
`not more than 35 mmHg in both eyes.
`2. Neither eye could have marked optic nerve damage.
`3. Patients were required to discontinue all topical
`glaucoma medications for up to 30 days before en(cid:173)
`try into the study.
`We did not enroll patients into the study whose lOPs
`were greater than 21 mmHg requiring two or more medi(cid:173)
`cations. The following were not enrolled as patients in
`the study: patients who had glaucoma laser or filtration
`surgery within the past 3 months; women of childbearing
`potential or nursing mothers; patients with contraindica(cid:173)
`tions to alpha-adrenoceptor agonist therapy such as de(cid:173)
`pression, coronary insufficiency, or Raynaud phenome(cid:173)
`non; uncontrolled systemic disease or hypersensitivity to
`the study medication ingredients; patients using systemic
`adrenergic-agonist agents or whose therapy was changed
`during the study to agents that could have a substantial
`effect on lOP; patients with corticosteroid-induced, uvei(cid:173)
`tic, or neovascular glaucoma; and patients with active
`ocular disease, corneal abnormalities, or contact lens(cid:173)
`wearing patients. All institutional review boards approved
`the study, and we gave verbal explanation to all patients,
`and a written informed consent was signed by all study
`participants.
`At the prestudy visit, we obtained a medical and oph(cid:173)
`thalmic history. An initial examination was performed at
`the baseline visit (day 0), which included Snellen visual
`acuity assessment; measurement of pupillary diameter us(cid:173)
`ing a millimeter ruler; slit-lamp evaluation of the anterior
`segment, including subjective determination of conjuncti-
`
`132
`
`val blanching and erythema; ophthalmoscopic examina(cid:173)
`tion of the optic nerve; measurement of basal tear secre(cid:173)
`tion using the Schirmer test; and an automated, static,
`central 24° threshold visual field if one had not been
`performed within the past 3 months. Intraocular pressure,
`resting heart rate, and blood pressure were measured in
`each patient between 7:30 AM and 9:30 AM (early morn(cid:173)
`ing) and 1, 2, 6, and 8 hours later.
`After this baseline examination, we randomized the
`patients in a double-masked fashion into one of four treat(cid:173)
`ment groups: brimonidine 0.5%, 0.2%, 0.08%, or placebo
`(brimonidine vehicle). We instructed patients to instill
`their medications into each eye at 12-hour intervals for a
`duration of 1 month, beginning the evening of the baseline
`examination. The patients did not receive instruction with
`regard to nasolacrimal occlusion. Patients returned 1, 7,
`14,21 , and 28 days later for follow-up examinations. The
`patients were instructed not to use the study medication
`until after the early morning examination.
`Patients returned for follow-up examinations in the
`morning on days 1, 7, 14, and 28 for assessment of the
`following variables: lOP (measured between 7:30 AM and
`9:30 AM) , visual acuity, pupil size, biomicroscopy, heart
`rate, systemic blood pressure, and general and ocular
`comfort. Diurnal lOP measurements (at hours 1,2,6, and
`8) and ophthalmoscopy were performed only on the day
`21 visit after the early morning examination and instilla(cid:173)
`tion of study medication. Efficacy was assessed by evalu(cid:173)
`ating changes from baseline in lOP. Ocular safety was
`assessed by evaluating changes from baseline in visual
`acuity, biomicroscopy, ophthalmoscopy, and Schirmer
`testing. Systemic safety was assessed by evaluating
`changes from baseline in heart rate and blood pressure.
`Patients were questioned about specific ocular and sys(cid:173)
`temic symptoms, including burning and stinging on instil(cid:173)
`lation, blurred vision, dry mouth, and fatigue.
`Numeric values are presented as mean ± standard de(cid:173)
`viation. For lOP, results from both eyes were averaged
`and treated as a unit. Mean changes from baseline were
`analyzed using an analysis of variance with Fisher pro(cid:173)
`tected Least significance procedure for between-group
`comparison and a paired t test for within-group analysis
`of changes from baseline. With respect to diurnal data,
`the diurnal time points of day 0 were used as baseline
`for the corresponding time points of day 2l.
`
`Results
`
`The demographics of the 194 patients enrolled in the
`study are summarized in Table 1. Of the 194 patients
`enrolled in the study, 8 patients were disqualified because
`of improper entry or protocol violations. No significant
`pretreatment differences were noted between treatment
`groups. Mean pretreatment lOPs for the groups ranged
`from 25.3 ± 2.8 mmHg to 25.9 ± 3.4 mmHg. Most
`patients were white. There were slightly more women
`than men.
`All concentrations of brimonidine significantly re(cid:173)
`duced lOP from baseline at all follow-up visits. Maximum
`
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`Derick et al . Brimonidine Tartrate Response Study
`
`Table 1. Demographics
`
`0.08%
`
`0.2%
`
`0.5%
`
`Vehicle
`
`45
`60 ± 12.4
`
`48
`58.9 ± 12.0
`
`48
`59.6 ± 12.9
`
`45
`57.2 ± 1.3.2
`
`28 (62%)
`17 (38%)
`
`36 (80%)
`5 (11%)
`4 (9%)
`
`17 (38%)
`3 (7%)
`24 (53%)
`1 (2%)
`
`25 (52%)
`23 (48%)
`
`38 (79%)
`8 (17%)
`2 (4%)
`
`18 (37%)
`2 (4%)
`25 (52%)
`3 (6%)
`
`21 (44%)
`27 (56%)
`
`40 (83%)
`6 (12%)
`2 (4%)
`
`12 (25%)
`2 (4%)
`27 (56%)
`7 (15%)
`
`18 (40%)
`27 (60%)
`
`31 (69%)
`9 (20%)
`5 (11 %)
`
`8 (18%)
`2 (4%)
`25 (56%)
`10 (22%)
`
`p*
`
`0.534
`
`0.147
`
`0.333
`
`0.956
`
`25.9 ± 3.3
`
`25.7 ± 3.6
`
`25.5 ± 3.4
`
`25.3 ± 2.8
`
`0.656
`
`No. of patients
`Age (yrs)
`Sex
`Female
`Male
`Race
`White
`Black
`Hispanic
`Iris color
`Blue
`Green
`Brown
`Hazel
`Intraocular pressure
`baseline
`
`* Among-group comparisons.
`
`mean lOP decreases from baseline of 16.1 %, 22.4%, and
`30.1 % were observed for the 0.08%, 0.2%, and 0.5%
`treatment groups, respectively (Table 2). On the first day
`of therapy, brimonidine reduced lOP in a dose-related
`fashion. Brimonidine 0.2% and 0.5% decreased mean lOP
`significantly more than did brimonidine 0.08%, and the
`0.5% group exhibited a greater percentage decrease in
`lOP than did the 0.2% group (P < 0.05). On day 14,
`all concentrations of brimonidine had statistically similar
`ocular hypotensive effects. Compared to the day 1 effect,
`there was a significant loss of effect for the 0.5% concen(cid:173)
`tration (P < 0.01) but not for the 0.2% or 0.08% concen(cid:173)
`trations on days 7, 14, 21, and 28.
`Analysis of diurnal lOP data (obtained at baseline and
`day 21) indicated that all treatment groups exhibited a
`significantly greater lOP decrease than did the vehicle
`control placebo group at hours 0, 1, 2, 6, and 8 (Fig 1).
`The 0.2% and 0.5% treatment groups had significantly
`greater decreases than did the 0.08% group during the first
`2 hours. No clinically significant difference was observed
`between the 0.2% and 0.5% treatment groups. At hour 0
`on day 21 (12 hours after the last dose of medication)
`the 0.08%, 0.2%, and 0.5% treatment groups exhibited a
`significantly greater decrease in lOP than did the vehicle
`
`control group (P < 0.001, -3.55 mmHg, -4.68 mmHg,
`and -4.41 mmHg, respectively). In all three treatment
`groups, peak ocular hypotensive efficacy occurred 2 hours
`after instillation. At hour 6, the 0.2% and 0.5% treatment
`groups had greater than 15% reduction in mean lOP. By
`the eighth hour, the percentage decrease had diminished
`to 14.5% and 12.0%, respectively.
`The number of patients with at least a 20% lOP reduction
`is listed in Table 3. Overall, 23 (51 %) of 45 patients in the
`0.08% group, 39 (81%) of 48 patients in the 0.2% group,
`and 40 (83%) of 48 in the 0.5% group showed a reduction
`of 20% or more from baseline at one or more scheduled
`visits over the course of the study. The number of patients
`with a 20% reduction in lOP decreased over the course of
`the month, although this trend was significant only for the
`0.5% concentration. At the final visit (day 28), 7 (16%) of
`45 patients in the 0.08% group, 15 (31 %) of 48 patients in
`the 0.2% group, and 10 (21%) of 48 in the 0.5% group
`showed a 20% lOP reduction from baseline.
`The mean lOP decrease from baseline of 30.1 % and
`22.4% seen at day 1 in the 0.5% and 0.2% brimonidine
`groups, respectively, 12 hours after instillation diminished
`to just over 15% by day 14 in both groups and remained
`at this level for the remainder of the study (Fig 2).
`
`Table 2. Intraocular Pressure Percent Changes from Baseline (Hour 0)
`
`Day of Visit
`
`1
`7
`14
`21
`28
`
`0.08%
`-16.1 ± 11.1
`-16.5 ± 17.1
`-12.1 ± 10.3
`-13.8 ± 9.7
`-13.2 ± 8.9
`
`0.2%
`
`-22.4 ± 14.3
`-18.6 ± 9.9
`-15.8 ± 10.2
`-18.3 ± 9.2
`-15.5 ± 1l.8
`
`0.5%
`-30.1 ± 13.3
`-21.6 ± 11.1
`-15.4 ± 12.0
`-16.9 ± 10.5
`-13.8 ± 11.2
`
`Vehicle
`-4.2 ± 14.4
`-4.3 ± 13.3
`-2.3 ± 10.6
`-6.2 ± 9.0
`-4.6 ± 10.5
`
`p*
`
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`
`* Among-group comparisons.
`
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`Ophthalmology Volume 104, Number 1, January 1997
`
`.- _______ .----e
`
`~.--
`
`27~--------------------------------~
`
`25
`
`.--- ... ---- .... ---
`
`-e__---
`
`o
`
`-5
`
`Q)~
`bJl::t:: -10
`§ S
`..c::s
`U '-' -15
`~~ p., .~
`O~ -20
`-~ ~I=Q
`~ S -25
`::;So
`<I:: -30
`
`-e- vehicle
`_______ 0.08%
`
`-+-0.2%
`
`-A-0.5%
`
`14
`Time (days)
`
`21
`
`28
`
`Figure 2. Mean intraoperative pressure readings before morning instilla(cid:173)
`tion of medication.
`
`(range, -5.7 ± 14.6 mm to 9.1 ± 15.7 mm). At the day
`21 follow-up diurnal examination, a total of 13 patients
`(29%) in the 0.08% treatment group, 20 patients (42%)
`in the 0.2% treatment group, 21 patients (44%) in the
`0.5%, and 12 patients (27%) in the vehicle control group
`experienced decreases in systolic pressure of greater than
`20 mmHg compared to the same time point at baseline.
`No patient experienced symptoms related to these changes
`in blood pressure.
`Mean changes in diurnal diastolic blood pressure
`ranged from -0.9 ± 12.9 mmHg to -4.1 ± 7.2 mmHg
`in the 0.08% treatment group, -0.3 ± 9.2 mmHg to -4.4
`± 9.0 mmHg in the 0.2% treatment group, -2.6 ± 10.2
`mmHg to -7.0 ± 8.3 mmHg in the 0.5% treatment group,
`and -0.3 ± 7.4 mmHg to -2.1 ± 7.7 mmHg in the
`vehicle control group. The mean decrease in diastolic
`blood pressure was significantly greater in the 0.5% treat(cid:173)
`ment group at hour 2 than in the 0.08%, 0.2%, and vehicle
`control groups (P < 0.012; -7.0 ± 8.3 mmHg, -3.7 ±
`8.3, -3.8 ± 7.0, and -1.2 ± 10.0 for 0.5%,0.08%,0.2%,
`and vehicle control groups, respectively).
`Burning and stinging and blurred vision were more
`frequently reported in the 0.5% treatment group than in
`either the 0.2%,0.08%, or vehicle control group. Reports
`of burning or stinging on instillation ranged from 13%
`(0.08% group) to 27% (0.2% group) to 31 % (0.5% group),
`and reports of transient blurred vision ranged from 16%
`(0.08% group) to 15% (0.2% group) to 35% (0.5% group).
`The vehicle control group also had a high reported inci(cid:173)
`dence of burning and stinging (27%) and blurring (18%).
`Symptoms of general discomfort also were reported more
`frequently in the 0.5% treatment group. The most com(cid:173)
`monly reported symptoms included dry mouth (13.3%,
`16.7%, 35.4%) and fatigue-drowsiness (6.7%, 10.4%,
`29.2%) in the 0.08%, 0.2%, and 0.5% groups, respec(cid:173)
`tively.
`
`Discussion
`
`This study shows that brimonidine effectively lowers lOP
`in patients with ocular hypertension in a dose-dependent
`
`- _ vehicle
`_ _ 0.08%
`
`-+-0.2%
`----..-0.5%
`
`~ 23
`
`l 21
`8 19
`
`17
`
`15
`
`o
`
`2
`
`4
`
`6
`
`8
`
`10
`
`0
`
`7
`
`Hour
`Figure 1. Percent reduction in intraocular pressure on day 21 relative to
`vehicle.
`
`Conjunctival blanching appeared to be dose related; it
`was observed bilaterally in eight patients in both the 0.2%
`and 0.5% treatment groups, five patients in the 0.08% group,
`and four in the vehicle control group. Conjunctival erythema
`occurred more commonly with higher concentrations of bri(cid:173)
`monidine than with the lower concentration, occurring in 8
`(17%) of 48 patients in the 0.5% group, 6 (12%) of 48
`patients in the 0.2% group, and only 2 (4%) of 45 patients
`in the 0.08% group. However, we did observe conjunctival
`erythema in 8 (18%) of 45 patients who received only the
`drug vehicle. No clinically significant changes occurred in
`mean pupil size or basal tear secretion.
`The only statistically significant change in mean heart
`rate occurred in treatment groups 0.2% (-4.5 ± 11.3
`beats per minute, P = 0.021) and 0.5%(-3.1 ± 9.3 beats
`per minute, P = 0.035) at hour 6 on day 21. We noted
`statistically significant changes in mean systolic blood
`pressure on day 21; at hour 1 in the 0.08% treatment
`group (-6.0 ± 15.6 mm), hours 1,2,6, and 8 in the 0.2%
`treatment group (range, -5.7 ± 14.3 mm to -7.1 ± 10.2
`mm) and hours 2, 6, and 8 in the 0.5% treatment group
`
`Table 3. Subjects with an lOP Reduction of ~20%
`from Baseline at Each Scheduled Visit:
`Number of Subjects
`
`Visit
`
`0.08%
`
`0.2%
`
`0.5%
`
`Vehicle
`
`No. of patients
`Day 1
`Day 7
`Day 14
`Day 21
`Day 28
`Overall *
`
`45
`12
`15
`8
`10
`7
`23
`
`48
`23
`21
`15
`15
`15
`39
`
`48
`38
`24
`13
`13
`10
`40
`
`45
`5
`5
`2
`2
`5
`11
`
`lOP = intraocular pressure.
`* Number of subjects with an lOP reduction of ;",20% from baseline at
`one or more scheduled visits over the study.
`
`134
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`Derick et al . Brimonidine Tartrate Response Study
`
`fashion. Important features in our study include its double(cid:173)
`masked design and the monitoring of lOP for 12 hours
`after drug instillation. These help control nondrug-related
`variation in the parameters that we observed. By monitoring
`the lOP for several hours during the day at baseline and on
`day 21, we partially controlled for diurnal effects on the
`lOP. A maximum decrease in lOP of 25% attributable to
`brimonidine and relative to vehicle (30% relative to base(cid:173)
`line) is similar to the decrease reported for apraclonidine.14
`The day 1 mean maximal lOP-lowering effect of brimoni(cid:173)
`dine 0.5% was greater than either the 0.2% or 0.08% concen(cid:173)
`tration. After the first day, both the 0.2% and 0.5% concen(cid:173)
`trations had similar efficacy and were more potent than was
`the 0.08% concentration. Apraclonidine has a similar dose
`response with the 0.25% concentration having a greater ef(cid:173)
`fect than the 0.125% concentration and no additional effect
`observed in either the 0.5% or 1.0% concentration.l.l5,16 At 3
`weeks, all three concentrations of brimonidine had a similar
`duration of action of at least 12 hours. However, 8 hours
`after instillation, the lOP percentage decrease had dimin(cid:173)
`ished to 14.5% and 12.0% for the 0.2% and 0.5% groups,
`respectively.
`In separate short-term studies, both brimonidine and
`apraclonidine appear to lose some potency over 1 to 2
`weeks of use. In a I-week dose response study of
`apraclonidine 0.5%, the average lOP reduction decreased
`from 20% to 14% from day 1 to day 8 after initiation of
`therapy. I We observed that brimonidine also has a more
`potent ocular hypotensive effect on day 1, which de(cid:173)
`creases and stabilizes by day 14 to the level maintained
`throughout the 4 weeks. The alphaTreceptor may be most
`sensitive to brimonidine and other adrenergic medications
`acutely, then reach an equilibrium during chronic dosing
`at a slightly higher IOP. 17
`Not only was a dose response relation shown for the
`ocular hypotensive effects ofbrimonidine, but also for the
`effects on systolic blood pressure, conjunctival blanching,
`and ocular and systemic comfort.
`At the day 21 follow-up diurnal examination, more pa(cid:173)
`tients treated with brimonidine 0.5% experienced decreases
`in systolic pressure of greater than 20 mmHg than any of
`the other treatment groups. Clonidine, another relatively se(cid:173)
`lective alphaTagonist, has both ocular and systemic hypoten(cid:173)
`sive action. In one study, clonidine 0.125% to 0.25% was
`as effective as pilocarpine 2% in lowering the lOP; however,
`50% of patients experienced at least a 30 mmHg decrease
`in systolic blood pressure during the I-week trial.18 This
`adverse effect led t6 studies of other compounds that at(cid:173)
`tempted to separate the systemic and ocular effects.
`Apraclonidine is similar to clonidine but has an amide group
`substituted on the para (C-4) position of the benzene ring.
`This chemical change increased the polarity of the com(cid:173)
`pound, decreased its central nervous system absorption, and
`reduced its effects on blood pressure. In several studies of
`both healthy volunteers and patients with elevated lOPs,
`apraclonidine caused minimal effects on mean resting heart
`rate, mean arterial blood pressure, and exercise-induced
`tachycardia. I,15,19 Similarly, brimonidine had little cardiopul(cid:173)
`monary effect in healthy volunteers.13 In a study evaluating
`the efficacy of brimonidine in limiting lOP elevation after
`
`laser trabeculoplasty, brimonidine 0.5% had minimal effects
`on systolic and diastolic blood pressure. II In this I-month
`dose response study, brimonidine did produce, on the day
`21 examinations, statistically significant effects on systemic
`blood pressure, but no adverse clinical effects were seen,
`and the magnitude of blood pressure effects was significantly
`lower than that observed with clonidine. The observed dif(cid:173)
`ferences in the effects on blood pressure between brimoni(cid:173)
`dine and apraclonidine may relate to differences in pharma(cid:173)
`cokinetics. Topical brimonidine may be more similar to
`clonidine than to apraclonidine in this regard. The systemic
`effects of brimonidine need to be evaluated in longer term
`studies, including comparison studies with apraclonidine.
`Conjunctival blanching was observed to occur more
`frequently in both the 0.2% and 0.5% treatment groups
`than in the 0.08% group or the vehicle control group.
`This determination was made subjectively, with bilateral
`use of the medication, and without benefit of reference
`photographs. This effect is not unique to brimonidine,
`however, as conjunctival blanching is also seen com(cid:173)
`monly in patients using apraclonidine?O
`Dry mouth appears to be a frequent symptom experi(cid:173)
`enced by patients using topical alphaTagonists, and this
`effect may be dose related. Dry mouth was reported by
`approximately 13% and 17% of the patients in the 0.08%
`and 0.2% treatment groups, respectively. Approximately
`two-fold (35%) was this incidence of dry mouth reported
`by the 0.5%-treated patients. Dry mouth also was reported
`with studies on apraclonidine. Jampel et all reported that,
`overall, 30% of patients experienced dry mouth or dry
`nose in a I-week study evaluating apraclonidine 0.125%,
`0.25%, and 0.5%.
`The chronic use of apraclonidine appears to be associ(cid:173)
`ated with an allergic type of follicular conjunctivitis simi(cid:173)
`lar to the allergy produced by epinephrine compounds. 5
`With apraclonidine 0.5%, this event is uncommon during
`the first month. The average time of onset was 1,5 months
`during a 3-month evaluation of patients already on maxi(cid:173)
`mum tolerated medical therapy.4 Although the duration
`of this study was not long enough to fully evaluate the
`incidence of topical allergy after brimonidine use, there
`was only one report of redness and swelling that occurred
`(in the 0.08% treatment group) during the 1 month that
`brimonidine was used. Longer term studies may be
`needed to assess the incidence of topical allergy related
`to the use of brimonidine.
`Because there appears to be no evidence to indicate
`that 0.5% is a more potent ocular hypotensive agent than
`is 0.2%, and because there are greater local and systemic
`side effects associated with the 0.5% concentration, bri(cid:173)
`monidine 0.2% appears to be the appropriate concentra(cid:173)
`tion for further long-term studies.
`
`References
`
`1. Jampel RD, Robin AL, Quigley RA, Pollack IP. Apracloni(cid:173)
`dine: a one week dose response study. Arch Ophthalmol
`1988; 106:1069-73.
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`2. Robin AI. Short-term effects of unilateral 1 % apraclonidine
`therapy. Arch Ophthalmol 1988; 106:912-5.
`3. Abrams DA, Robin AL, Crandall AS, et al. A limited com(cid:173)
`parison of apraclonidine's dose response in subjects with
`normal or increased intraocular pressure. Am J Ophthalmol
`1989; 108:230-7.
`4. Robin AL, Ritch R, Shin DH, et al. The short-term effect
`of apraclonidine hydrochloride when added to maximum
`tolerated medical therapy. Am J Ophthalmol 1995; 120:
`423-32.
`5. Wilkerson M, Lewis RA, Shields MB. Follicular conjuncti(cid:173)
`vitis associated with apraclonidine [Letter]. Am J Ophthal(cid:173)
`mol 1991;111:105-6.
`6. Nagasubramanian S, Hitchings RA, DemaillyP, etal. Com(cid:173)
`parison of apraclonidine and timolol in chronic open angle
`glaucoma: a three-month study. Ophthalmology 1993;
`100:1318-23.
`7. Stewart WC, Ritch R, Shin DH, et al. The efficacy of
`apraclonidine as an adjunct to timolol therapy. Arch Oph(cid:173)
`thalmol 1995; 113:287-92.
`8. Robin AL. Questions concerning the role of apraclonidine
`in the management of glaucoma. Arch Ophthalmol 1995;
`113:712-3.
`9. Burke JA, Potter DE. The ocular effects of relatively selec(cid:173)
`tive alphaz-agonist(UK 14,304-18) in cats, rabbits, and
`monkeys. CUff Eye Res 1986;5:665-76.
`10. Toris CB, Carnras CB, Yablonski ME. Effects of brimoni(cid:173)
`dine on aqueous humor dynamics in human eyes. Arch
`Ophthalmol 1995; 113:1514-7.
`11. Barnebey HS, Robin AL, Zimmerman TJ, et al. The effi(cid:173)
`cacy of brimonidine in decreasing elevations in intraocular
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`pressure after laser trabeculoplasty. Ophthalmology 1993;
`100:1083-8.
`12. David R, Spaeth GL, Clevenger CE, et al. Brimonidine in
`the prevention of intraocular pressure elevation following
`argon
`laser
`trabeculoplasty. Arch Ophthalmol 1993;
`111:1387-90.
`13. Norlund JR, Pasquale LR, Robin AL, et al. A comparison
`of the cardiovascular and pulmonary effects of brimonidine
`0.20%, timolol 0.5% and betaxolol suspension 0.25%. Arch
`Ophthalmol1995;113:77-83.
`14. Robin AL, Coleman AL. Apraclonidine hydrochloride: an
`evaluation of plasma concentration, and a comparison of its
`lOP lowering and cardiovascular effects to timolol maleate.
`Trans Am Ophthalmol Soc 1990;88:149-62.
`15. Abrams DA, Robin AL, Pollack IP, et al. The safety and
`efficacy of topical AL02145(p-aminoclonidine HCL) in
`normal volunteers. Arch Ophthalmol 1987; 105:1205-7.
`16. Vocci MJ, Robin AL, Wahl JC, et al. Reformulation and
`drop size of apraclonidine hydrochloride. Am J Ophthalmol
`1992; 113:154-60.
`17. Derick RJ. Adrenergic agonist medications: basic mecha(cid:173)
`nisms. Glaucoma 1995;4(Supp1):SI-S7.
`18. Hodapp E, Kolker AE, Kass MA, et al. The effect of topical
`clonidine on intraocular pressure. Arch Ophthalmol 1981;
`99: 1208-11.
`19. Coleman AL, Robin AL, Pollack IP, et al. Cardiovascular
`and intraocular pressure effects and plasma concentrations
`of apraclonidine hydrochloride. Arch Ophthalmol 1990;
`108:1264-7.
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