Brimonidine in the treatment of glaucoma and
`ocular hypertension
`
`R E V I E W
`
`Louis B Cantor
`
`Department of Ophthalmology,
`Indiana University, Indianapolis, IN,
`USA
`
`Abstract: Treatment in glaucoma aims to lower intraocular pressure (IOP) to reduce the risk
`of progression and vision loss. The alpha2-adrenergic receptor agonist brimonidine effectively
`lowers IOP and is useful as monotherapy, adjunctive therapy, and replacement therapy in
`open-angle glaucoma and ocular hypertension. A fixed combination of brimonidine and timolol,
`available in some countries, reduces IOP as effectively as concomitant therapy with brimonidine
`and timolol and offers the convenience of 2 drugs in a single eyedrop. Brimonidine is safe
`and well tolerated. Its most common side-effects are conjunctival hyperemia, allergic
`conjunctivitis, and ocular pruritus. The newest formulation of brimonidine, brimonidine-Purite
`0.1%, has a higher pH to improve the ocular bioavailability of brimonidine. This formulation
`contains the lowest effective concentration of brimonidine and is preserved with Purite® to
`enhance ocular tolerability. Brimonidine-Purite 0.1% is as effective in reducing IOP as the
`original brimonidine 0.2% solution preserved with benzalkonium chloride. Recent results
`from preclinical and clinical studies suggest that brimonidine may protect retinal ganglion
`cells and their projections from damage and death independently of its effects on IOP. The
`potential for neuroprotection with brimonidine is an added benefit of its use in glaucoma and
`ocular hypertension.
`Keywords: brimonidine, preservative, glaucoma, intraocular pressure, neuroprotection
`
`Introduction
`Glaucoma is an optic neuropathy characterized by acquired loss of retinal ganglion
`cells (RGCs) and atrophy of the optic nerve leading to vision loss. Elevated intraocular
`pressure (IOP) is a primary risk factor both for the development of glaucoma and for
`progression of optic nerve changes and visual field loss in the disease. Abundant
`evidence indicates that elevated IOP can cause the neuropathology of glaucoma.
`Clinical experience with angle-closure glaucoma and numerous preclinical studies
`in rats and primates have shown that acute and sustained increases in IOP can cause
`optic nerve damage (Morrison 2005; Rasmussen and Kaufman 2005). Primary open-
`angle glaucoma (POAG), the most common type of glaucoma in white populations,
`is characterized by chronically elevated IOP with no known cause for the elevated
`IOP or optic neuropathy. But many individuals with elevated IOP do not show signs
`of glaucomatous optic nerve damage, and conversely, many individuals with IOP
`consistently within the normal range (less than 21 mmHg) have glaucoma (Klein et
`al 1992). These findings suggest that factors beyond IOP have a role in the etiology
`of the disease (Drance 1997).
`
`Correspondence: Louis B Cantor
`Department of Ophthalmology, Indiana
`University School of Medicine,
`Indianapolis, IN 6202, USA
`Tel +1 317 274 8485
`Fax +1 317 278 1007
`Email lcantor@iupui.edu
`
`IOP-lowering treatment
`Regardless of the etiology of the disease, at present, the aim of treatment in glaucoma
`is to reduce IOP. Recent randomized, controlled clinical trials have shown that
`lowering IOP is effective in delaying or preventing the development of glaucoma in
`
`Therapeutics and Clinical Risk Management 2006:2(4) 337–346
`© 2006 Dove Medical Press Limited. All rights reserved
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`Cantor
`
`patients with ocular hypertension (OHT) and in delaying or
`halting the progression of established glaucoma (Heijl et al
`2002; Kass et al 2002). IOP reduction is beneficial in
`reducing the risk of progression of vision loss even when
`IOP is already within the normal range (Collaborative
`Normal-Tension Glaucoma Study Group 1998). Evidence
`suggests that very low IOP provides the best visual outcomes
`for patients (The AGIS Investigators 2000; Lichter et al
`2001). Analysis of data from the Early Manifest Glaucoma
`Trial showed a 10% reduction in the risk of progression
`associated with each 1 mmHg of IOP reduction (Leske et al
`2003).
`IOP-lowering drugs are currently the only medical
`treatment approved for glaucoma management. The classes
`of ocular hypotensive drugs commonly used to reduce IOP
`in glaucoma and OHT include prostaglandin analogues,
`beta-adrenergic receptor antagonists, alpha-adrenergic
`receptor agonists, carbonic anhydrase inhibitors, and
`parasympathomimetics. The once-daily prostaglandin
`analogues (bimatoprost, latanoprost, travoprost) reduce IOP
`most effectively (Hedman and Alm 2000; Netland et al 2001;
`Higginbotham et al 2002) and are often used as initial
`monotherapy. Not all patients can use prostaglandin
`analogues, however. Further, for many patients the IOP
`lowering obtained with monotherapy is inadequate. Even
`patients with OHT or early glaucoma are likely to need more
`than 1 medication to reach sufficiently low pressures. For
`example, in the Ocular Hypertension Treatment Study
`(OHTS) by year 5 almost 40% of patients needed 2 or more
`medications to achieve their target IOP (Kass et al 2002),
`and in the Collaborative Initial Glaucoma Treatment Study
`(CIGTS) after year 2 more than 75% of patients needed 2
`or more medications to reach their target IOP (Lichter et al
`2001).
`Brimonidine, the only selective alpha-adrenergic
`receptor agonist approved for chronic treatment in
`glaucoma, is indicated for reducing IOP in patients with
`open-angle glaucoma or OHT. Brimonidine
`is
`contraindicated in patients receiving monoamine oxidase
`inhibitor therapy, because antidepressants decrease the
`metabolism of circulating monoamines, leading to an
`increase in levels of endogenous monoamines that might
`inhibit the IOP-lowering effect of brimonidine. Brimonidine
`is also contraindicated in patients with hypersensitivity to
`any component of the medication, and it should not be used
`in children under the age of 2 because there have been
`reports of apnea, bradycardia, hypothermia, hypotonia,
`lethargy, and unresponsiveness in infants receiving
`
`brimonidine treatment (Berlin et al 2001; Prok and Hall
`2003).
`
`Pharmacology and mechanism of
`action of brimonidine
`Brimonidine is a selective alpha2-adrenergic receptor
`agonist that shows up to 1780-fold selectivity for alpha2-
`over alpha1-adrenergic receptors (Cantor 2000). After
`topical instillation, brimonidine reduces IOP within 1 hour,
`and the peak effect occurs at 2–3 hours after dosing (Walters
`1996). The trough effect occurs at 10–14 hours after dosing.
`Brimonidine is usually dosed twice daily, and no additional
`IOP lowering is provided at morning trough with tid versus
`bid dosing (Walters 1996). Brimonidine has a dual
`mechanism of IOP lowering: it both reduces aqueous
`humor production and stimulates aqueous humor outflow
`through the uveoscleral pathway (Toris et al 1995). The
`predominant effect of short-term brimonidine treatment
`is inhibition of aqueous production, whereas the
`predominant effect of chronic treatment is stimulation of
`aqueous humor outflow through the uveoscleral pathway
`(Toris et al 1999).
`
`Pharmacokinetics of topical
`brimonidine
`Pharmacokinetic studies in rabbits and monkeys have shown
`that topical brimonidine readily penetrates the eye and
`reaches pharmacologically active concentrations in the
`aqueous humor and ciliary body, the putative sites of its
`IOP-lowering activity (Acheampong et al 1995, 2002). The
`primary absorption route for brimonidine is via the cornea
`(Cantor 2000). Brimonidine that reaches the systemic
`circulation after topical administration in humans is rapidly
`metabolized and has a short plasma half-life of
`approximately 2 hours (Cantor 2000). The rapid metabolism
`and systemic clearance of brimonidine minimizes potential
`systemic effects of the drug, and twice- or thrice-daily dosing
`of brimonidine 0.2% is not associated with clinically
`significant cardiovascular or pulmonary systemic effects in
`adults (Cantor 2000).
`Pharmacologically active concentrations of brimonidine
`are found in vitreous humor samples following topical
`administration of brimonidine 0.2% in rats, rabbits,
`monkeys, and humans (Kent et al 2001; Acheampong et al
`2002). This is important because brimonidine may be present
`at the retina in concentrations sufficient for direct effects
`on RGCs.
`
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`Potential for neuroprotection
`As it has become recognized that glaucoma is a
`multifactorial, progressive neuropathy that often occurs
`independently of elevated IOP, the diagnosis of glaucoma
`has changed from one based on IOP to one based on the
`optic nerve and visual field (Weinreb and Levin 1999). This
`paradigm shift has prompted investigation of a new approach
`to therapy in glaucoma called neuroprotection. The goal of
`neuroprotection is to slow or prevent death of neurons and
`maintain their physiological function (Weinreb and Levin
`1999). One important advantage of a neuroprotective
`strategy is that treatment is possible even when the etiology
`of the disease is unknown or differs among patients (Weinreb
`and Levin 1999). A neuroprotective treatment in glaucoma
`might have no effect on IOP, but it would promote the
`survival of RGCs and their axons (the optic nerve fibers),
`and it could be effective regardless of the specific etiology
`of the disease (Weinreb and Levin 1999).
`Neuroprotection has been investigated as a therapeutic
`approach for neurodegenerative conditions including stroke,
`spinal cord injury, Parkinson’s disease, Huntington’s disease,
`amyotrophic lateral sclerosis, and Alzheimer’s disease. It
`may be difficult to achieve neuroprotection in acute
`conditions such as stroke, because treatment would probably
`have to begin at the time of the insult or soon after to prevent
`irreversible neuronal loss (Osborne et al 2004), but
`neuroprotection may be easier to achieve in chronic diseases
`characterized by progressive cell loss, such as open-angle
`glaucoma.
`Preclinical studies have shown that brimonidine has
`neuroprotective effects in animal models of optic nerve
`injury relevant to glaucoma including partial optic nerve
`crush, chronic ocular hypertension induced by laser cautery
`of episcleral and limbal veins, and retinal ischemia induced
`either by transient elevation of IOP or ligature of ophthalmic
`vessels (Yoles et al 1999; Donello et al 2001; WoldeMussie
`et al 2001; Mayor-Torroglosa et al 2005). Brimonidine was
`shown to promote RGC survival in each of these models,
`and in most studies protection of visual function was also
`demonstrated through measurements of the compound
`action potential or the ERG b-wave. The effects of
`brimonidine are evident after topical administration of a
`0.1% or 0.5% solution of drug (Vidal-Sanz et al 2001) and
`are mediated by activation of alpha2-adrenergic receptors
`(Donello et al 2001). Moreover, the effects appear to be
`independent of IOP lowering, because systemic
`administration of brimonidine, which does not reduce IOP,
`is also neuroprotective (Yoles et al 1999). Recent clinical
`
`Brimonidine therapy in glaucoma and ocular hypertension
`
`studies of brimonidine, discussed later in this review, have
`suggested that topical brimonidine treatment may also
`protect RGCs in human glaucoma.
`
`Brimonidine formulations
`The original brimonidine 0.2% formulation (Alphagan®,
`Allergan, Inc, Irvine, CA, USA) has a pH of 6.4 and is
`preserved with benzalkonium chloride (BAK). BAK is the
`antimicrobial preservative most commonly used in
`ophthalmic solutions, but chronic exposure to solutions
`containing high concentrations of BAK has been associated
`with harmful effects on the corneal surface (Noecker 2001;
`Noecker et al 2004). Moreover, chronic treatment of
`glaucoma and OHT patients with IOP-lowering ophthalmic
`solutions preserved with BAK has been reported to result
`in subclinical inflammation evident by increased expression
`of HLA-DR on conjunctival epithelial cells (Cvenkel and
`Ihan 2002). This is a clinical concern, because chronic
`inflammation and fibrosis can decrease the success rate of
`trabeculectomy surgery (Skuta and Parrish 1987).
`Brimonidine has been reformulated to improve its
`tolerability while maintaining its ocular bioavailability and
`IOP-lowering efficacy. The newer formulations of
`brimonidine are preserved with Purite®, a stabilized
`oxychloro complex and oxidative preservative that is
`converted to natural tear components (sodium and chloride
`ions, oxygen, and water) when exposed to light (Katz 2002).
`Purite is a microbicide and is non-toxic to mammalian cells
`(Grant et al 1996). The first reformulation of brimonidine
`that was introduced contains brimonidine 0.15% in a
`buffered solution of pH 7.2 preserved with Purite 0.005%
`(Alphagan® P 0.15%, Allergan Inc, Irvine, CA, USA).
`Although this formulation has a reduced concentration of
`brimonidine, it was shown in clinical trials to have the same
`IOP-lowering efficacy and better tolerability compared with
`the original brimonidine 0.2% formulation (Katz 2002)
`because the increase in pH provided better bioavailability
`(Dong et al 2004). More recently, a 0.1% formulation of
`brimonidine preserved with Purite at a pH of 7.7 was
`introduced (Alphagan® P 0.1%, Allergan Inc, Irvine, CA,
`USA). As discussed in detail below, the new brimonidine-
`Purite 0.1% formulation also shows efficacy equivalent to
`the original brimonidine 0.2% formulation. Animal studies
`have shown that aqueous humor levels of drug are the same
`with the newer formulations preserved with Purite and the
`old formulation preserved with BAK, despite the lower
`concentration of drug in the bottle, because at higher pH
`more brimonidine is non-ionized, and brimonidine is more
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`

`Cantor
`
`readily absorbed into the eye (Dong 2004; Allergan, data
`on file).
`Clinical efficacy of brimonidine in
`reducing IOP
`In its 1-year pivotal trials for drug approval, twice-daily
`brimonidine 0.2% reduced IOP as well as or better than
`timolol at peak effect (2 hours after dosing) but less
`effectively than timolol at morning trough (Schuman et al
`1997; LeBlanc 1998; Katz 1999). The efficacy of
`brimonidine was sustained over long-term use, and after
`four years of treatment, brimonidine and timolol provided
`comparable IOP lowering at both peak and trough effect
`(David 2001). Brimonidine was well tolerated in the pivotal
`trials. Common side-effects of treatment included oral
`dryness, ocular hyperemia, and ocular allergy. The 1-year
`incidence of treatment-related ocular allergy to brimonidine
`was 11.5% (Katz 1999), but this incidence may have been
`overestimated because of the confusion of dry eye, seasonal
`allergic conjunctivitis, or bacterial conjunctivitis with drug-
`related ocular allergy (Melamed and David 2000).
`Brimonidine has been compared with dorzolamide as
`monotherapy in glaucoma and OHT in 3 separate
`randomized, double-masked studies with a crossover design
`(Stewart et al 2000; Sharpe et al 2004; Whitson et al 2004).
`In each of these studies, brimonidine and dorzolamide
`showed comparable efficacy at trough effect, but at peak
`effect at 2 hours after dosing, brimonidine reduced IOP by
`0.7–1.4 mmHg more than dorzolamide. There was no overall
`difference between drugs in the frequency of side-effects,
`but ocular stinging and burning were more often associated
`with dorzolamide treatment.
`The versatility of brimonidine in reducing IOP was
`demonstrated in a large, open-label study involving 2335
`patients. In this study, brimonidine effectively reduced IOP
`whether used as monotherapy, replacement therapy, or
`adjunctive therapy (Lee et al 2000). As adjunctive therapy,
`brimonidine provided significant mean additional IOP
`lowering when added to other ocular hypotensive
`medications including beta-blockers, carbonic anhydrase
`inhibitors, and the prostaglandin analogue latanoprost (Lee
`and Gornbein 2001). Several randomized controlled clinical
`studies in patients with glaucoma or OHT subsequently
`confirmed that brimonidine provides significant additional
`mean decreases in IOP when added to ongoing beta-blocker
`therapy (Simmons 2001; Simmons and Earl 2002; Sall et al
`2003; Solish et al 2004). Other randomized controlled trials
`showed that brimonidine effectively reduces IOP when used
`
`adjunctively with a prostaglandin analogue (bimatoprost or
`latanoprost) (Netland et al 2003; Zabriskie and Netland
`2003; Konstas et al 2005).
`Brimonidine has been demonstrated to be more effective
`than dorzolamide when used as adjunctive therapy with a
`beta-blocker and at least as effective as dorzolamide when
`used as adjunctive therapy with latanoprost. In 2 randomized
`controlled trials that compared the efficacy and safety of
`brimonidine and dorzolamide as adjunctive therapy with
`beta-blockers, the reduction from baseline IOP (measured
`at peak effect) was significantly greater with adjunctive
`brimonidine than with adjunctive dorzolamide (Simmons
`2001; Carrasco Font et al 2004). Brimonidine-Purite 0.15%
`was compared with dorzolamide as adjunctive therapy with
`latanoprost in a randomized, double-masked, crossover trial
`in 33 glaucoma patients who had uncontrolled IOP after at
`least a 3-week run-in on latanoprost monotherapy (Konstas
`et al 2005). Each study drug was given twice daily as
`adjunctive therapy with latanoprost for 6 weeks, with a 6-
`week washout between treatment periods. The primary
`outcome measure was circadian IOP, measured at 7
`timepoints over 24 hours after 6 weeks of adjunctive therapy.
`The between-group differences in mean IOP reduction from
`baseline were not statistically significant. Of the 31 enrolled
`patients who had data available for analysis, 1 (3.2%) had
`the same circadian IOP (average of all 7 measurements) on
`both drugs, 19 (61.3%) had lower circadian IOP with
`brimonidine-Purite, and 11 (35.5%) had lower circadian IOP
`with dorzolamide, suggesting that brimonidine-Purite 0.15%
`is at least as effective as dorzolamide in providing 24-hour
`IOP control when added to latanoprost.
`
`Clinical comparison of
`brimonidine-Purite 0.1% and
`brimonidine 0.2%
`A prospective, randomized, double-masked, parallel-group
`clinical trial compared brimonidine-Purite 0.1% with
`brimonidine 0.2% for IOP-lowering efficacy and tolerability
`in patients with glaucoma or OHT (Allergan, data on file).
`The study was carried out at 27 centers across the United
`States. Patients with glaucoma or OHT in each eye were
`randomized to treatment with either brimonidine-Purite
`0.1% (n=215) or brimonidine 0.2% (n=218) thrice daily for
`12 months. Follow-up visits were scheduled at weeks 2 and
`6 and months 3, 6, 9, and 12. IOP was measured at 8 AM
`(trough effect, immediately prior to the morning dose), 10
`AM (morning peak effect), and 4 PM (afternoon peak effect,
`
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`2 hours after the afternoon dose) at all follow-up study
`visits except month 9, when it was measured at 8 AM
`and 10 AM only. The primary efficacy measure was mean
`IOP in the intent-to-treat patient population (all
`randomized patients) with last observation carried
`forward for missing values. All patients were treated
`bilaterally, and the average IOP from both eyes was used
`in the analyses.
`Baseline demographic and ophthalmic characteristics of
`patients were similar between the 2 treatment groups. Mean
`IOP at baseline was also comparable between the 2 treatment
`groups at each hour. Throughout follow-up, mean IOP in
`each treatment group ranged from 17 to 22 mmHg and was
`significantly lower than at baseline (p <0.001). The absolute
`values of the limits of the 95% confidence interval (CI) of
`the between-group difference in mean IOP were <1.0 mmHg
`at 12 of 17 timepoints and <1.5 mmHg at all 17 timepoints,
`demonstrating equivalent efficacy of the study formulations
`(Figure 1). Analysis of mean change from baseline IOP also
`showed equivalent efficacy of the study formulations, with
`the absolute values of the limits of the 95% CI of the
`between-group difference <1.0 mmHg at 9 of 17 timepoints
`and consistently <1.5 mmHg. The only significant
`differences in mean IOP reduction between treatment groups
`were at 4 PM at months 3 and 12, when the mean IOP
`reduction was significantly greater with brimonidine-Purite
`0.1% than with brimonidine 0.2% (p ≤0.043). Brimonidine-
`Purite 0.1% provided sustained IOP lowering over 12
`
`Brimonidine therapy in glaucoma and ocular hypertension
`
`months of treatment and was as effective as brimonidine
`0.2% in reducing IOP at all timepoints. Figure 2 shows the
`mean change from baseline IOP with each formulation at
`the 10 AM timepoint of peak effect.
`The percentage of patients with 1 or more treatment-
`related adverse events was lower in the brimonidine-Purite
`0.1% group (41.4%) than in the brimonidine 0.2% group
`(53.2%, p=0.014). The only individual treatment-related
`adverse event with a significant difference in incidence
`between treatment groups was oral dryness, which was less
`frequent in the brimonidine-Purite 0.1% group (1.4% of
`patients) than in the brimonidine 0.2% group (5.5% of
`patients, p=0.019). Biomicroscopic findings of increased
`severity of lid erythema and lid edema were also less
`common in the brimonidine-Purite 0.1% group (p=0.028
`and p=0.006, respectively).
`The rate of discontinuations for adverse events was
`significantly lower in the brimonidine-Purite 0.1% group
`(21.4%) than in the brimonidine 0.2% group (33.5%,
`p=0.005). Only 1 patient in the brimonidine-Purite 0.1%
`group discontinued for a non-ocular, treatment-related
`adverse event (oral dryness). In contrast, patients in the
`brimonidine 0.2% group discontinued for several non-ocular
`treatment-related adverse events including asthenia,
`hypotension, somnolence, depression, and insomnia, as well
`as oral dryness.
`In summary, the results of this trial showed that
`brimonidine-Purite 0.1% is statistically equivalent to
`
`8
`AM
`
`10
`AM
`
`4
`PM
`
`8
`AM
`
`10
`AM
`
`4
`PM
`
`8
`AM
`
`10
`AM
`
`4
`PM
`
`8
`AM
`
`10
`AM
`
`4
`PM
`
`8
`AM
`
`10
`AM
`
`4
`PM
`
`8
`AM
`
`10
`AM
`
`8
`AM
`
`10
`AM
`
`4
`PM
`
`Baseline
`
`Week 2
`
`Week 6
`
`Month 3
`
`Month 6
`
`Month 9
`
`Month 12
`
`1.5
`
`1.0
`
`0.5
`
`0.0
`
`-0.5
`
`-1.0
`
`-1.5
`
`with 95% CI (mm Hg)
`
`(Brimonidine-Purite 0.1% minus Brimonidine 0.2%)
`
`Estimated Difference in Mean IOP
`
`Figure 1 Equivalent IOP-lowering efficacy of brimonidine-Purite 0.1% and brimonidine 0.2%. In a 1-year clinical comparison study of the 2 formulations, the 95% CI
`of the difference in mean IOP between treatment groups (brimonidine-Purite 0.1% minus brimonidine 0.2%) was consistently within the range of –1.5 mmHg to
`1.5 mmHg, demonstrating equivalent efficacy of the study formulations.
`Abbreviations: CI, confidence interval; IOP, intraocular pressure.
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`less drug, and systemic absorption of brimonidine through
`the nasolacrimal pathway is likely to be further reduced with
`the 0.1% formulation. Consistent with this suggestion, in a
`study in rabbits, aqueous humor levels of drug were similar
`after dosing with either the brimonidine-Purite 0.15% or
`0.1% formulation, but plasma levels of brimonidine were
`lower in animals dosed with the brimonidine-Purite 0.1%
`formulation (Allergan, data on file). These results suggest
`the possibility that the new brimonidine-Purite 0.1%
`formulation may have an improved systemic safety profile
`over brimonidine-Purite 0.15%, but clinical comparison
`studies will be needed to confirm this possibility.
`
`Patient acceptance and
`compliance with brimonidine
`treatment
`Brimonidine treatment is usually well received by patients.
`In the phase 3 clinical comparison of brimonidine-Purite
`0.15% and brimonidine 0.2%, most patients (approximately
`80%) considered their eyedrops to be comfortable and were
`satisfied with their treatment (Katz 2002). Patient comfort
`ratings and satisfaction ratings were significantly higher with
`the brimonidine-Purite 0.15% formulation than with
`brimonidine 0.2%.
`It is generally recognized that lack of compliance with
`medical treatment is a significant problem in many diseases,
`and compliance may be particularly poor in slowly
`progressive, largely asymptomatic chronic diseases such as
`glaucoma. Poor compliance can lead to treatment failure,
`yet up to 80% of glaucoma patients may not take their
`medication as prescribed (Olthoff et al 2005). The reasons
`for non-compliance in glaucoma are not completely
`understood, but patients often mention forgetfulness as their
`main reason for not taking their eyedrops (Taylor et al 2002),
`and self-reported difficulty in remembering to take glaucoma
`medications has been significantly associated with patient
`nonadherence to treatment (Sleath et al 2006). Other reasons
`for non-compliance with medical treatment in glaucoma may
`include cost of medications, inconvenience of the dosing
`schedule, inability to instill the eyedrops correctly, and lack
`of understanding of the need for chronic therapy (Winfield
`et al 1990). Side-effects are usually not a significant cause
`of noncompliance (Olthoff et al 2005; Taylor et al 2002).
`Required instillation of drops at 3 or more times during the
`day is strongly associated with reduced compliance (Olthoff
`et al 2005), but this is generally not a concern with
`brimonidine treatment, because brimonidine is usually dosed
`
`Cantor
`
`Month
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`Brimonidine 0.2% (n = 218)
`
`Brimonidine P 0.1% (n = 215)
`
`0
`
`-1
`
`-2
`
`-3
`
`-4
`
`-5
`
`-6
`
`-7
`
`(mm Hg)
`
`Mean Change From Baseline IOP at 10 AM
`
`-8
`Figure 2 Mean change from baseline IOP. Both brimonidine-Purite 0.1% and
`brimonidine 0.2% provided significant IOP reductions that were sustained
`throughout 1 year of therapy. The mean IOP reduction was equivalent with the
`2 formulations throughout follow-up.
`Abbreviations: IOP, intraocular pressure.
`
`brimonidine 0.2% in IOP-lowering efficacy and at least as
`well tolerated in patients with glaucoma and OHT.
`
`Safety and tolerability
`Brimonidine has a favorable safety and tolerability profile.
`Unlike the beta-adrenergic antagonists, there are no
`cardiopulmonary contraindications to its use, and
`brimonidine can be safely and effectively used by patients
`on systemic anti-hypertensive beta-blocker therapy
`(Schuman 2000). In contrast to the prostaglandin analogues,
`brimonidine has not been associated with eyelash growth
`or increased pigmentation of the iris or eyelids. The side-
`effects associated with brimonidine treatment are usually
`ocular and include conjunctival hyperemia, allergic
`conjunctivitis, and ocular pruritus. The most common
`systemic side-effects are oral dryness and fatigue or
`drowsiness.
`The reduced drug concentration in the brimonidine-
`Purite 0.15% formulation compared with brimonidine 0.2%
`led to an improvement in tolerability (Katz 2002). In a
`randomized, double-masked, comparison trial of these
`formulations, glaucoma and OHT patients treated with the
`brimonidine-Purite 0.15% formulation had a 41% lower
`incidence of allergic conjunctivitis (Katz 2002). Oral
`dryness, conjunctival hyperemia, and eye discharge were
`also significantly less common with brimonidine-Purite
`0.15% than with brimonidine 0.2% (Katz 2002).
`The brimonidine–Purite 0.1% formulation also has a
`favorable safety and tolerability profile. Because the active
`drug concentration is 33% less than in the brimonidine-
`Purite 0.15% formulation, the ocular surface is exposed to
`
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`twice daily. There is currently no evidence to suggest that
`compliance with brimonidine treatment is either better or
`worse than treatment compliance with other classes of ocular
`hypotensive medications.
`Clinical trials of neuroprotection
`with brimonidine
`An initial trial evaluating potential neuroprotection by
`brimonidine in patients with acute angle-closure glaucoma
`found no difference between the number of patients who
`progressed during treatment with brimonidine or timolol
`(Aung et al 2004). The study was limited because overall,
`only 59 patients completed the study, and only 11 of these
`patients progressed during the study, but there was a trend
`for the rate of progression to be lower in patients treated
`with brimonidine (Aung et al 2004). A second trial evaluated
`potential neuroprotection by brimonidine in patients with
`non-arteritic anterior ischemic optic neuropathy (NAION)
`(Wilhelm et al 2006). This was a randomized, double-
`masked study that evaluated 29 patients with first eye
`involvement who were treated with brimonidine 0.2% or
`placebo within the first week after loss of visual acuity. After
`3 months of treatment there was a trend for better visual
`field results on all measures in the brimonidine group. The
`study was stopped after an interim analysis, however, when
`the investigators concluded that the number of patients
`needed for statistical significance could not be recruited
`within a practical time frame.
`A randomized, double-masked, pilot study evaluated
`potential neuroprotection by brimonidine in eyes of
`patients undergoing laser treatment for extrafoveal or
`juxtafoveal choroidal neovascularization (CNV) (Ferencz
`et al 2005). Eyes were treated with brimonidine 0.2%
`(study group, 11 eyes) or placebo (control group, 9 eyes)
`twice daily, beginning at 4–48 hours before laser
`treatment and continuing afterwards for 1 month. In each
`treatment group, 2 eyes had recurrence of CNV in the
`subfoveal region and severe visual loss after the
`photocoagulation procedure. For the remaining 16 eyes,
`mean visual acuity at 2 months after laser treatment was
`improved in the brimonidine group but not in the control
`group. The investigators suggested that the improvement
`in visual acuity in brimonidine-treated patients most
`likely resulted from an ability of brimonidine to protect
`RGCs from damage induced by noxious substances
`released from cells destroyed by the laser treatment
`(Ferencz et al 2005).
`
`Brimonidine therapy in glaucoma and ocular hypertension
`
`A recent trial has provided encouraging results
`suggesting neuroprotective effects of brimonidine in
`glaucoma patients (Tsai and Chang 2005). In this
`prospective, randomized, unmasked study, 78 patients with
`newly diagnosed POAG were treated with brimonidine 0.2%
`twice daily or timolol 0.5% ophthalmic gel-forming solution
`once daily in the morning for 12 months. Eligible patients
`were required to have untreated IOP >21 mmHg, a
`glaucomatous appearance of the optic disc, and an abnormal
`visual field on standard automated perimetry. IOP was
`measured at 2-month intervals throughout the study. Retinal
`nerve fiber layer (RNFL) thickness was measured using
`scanning laser polarimetry (GDx) at baseline and at the end
`of the study.
`At baseline, there were no significant between-group
`differences in patient age, sex, visual field mean deviation
`and corrected pattern standard deviation, and IOP. Baseline
`RNFL thickness measurements including the ellipse average,
`superior average, temporal average, inferior average, and
`nasal average were also comparable between treatment
`groups. After 12 months of follow-up, patients in the timolol
`group showed a significant mean decrease in all RNFL
`measurements (p ≤0.044) consistent with glaucomatous
`progression of RGC loss. In contrast, patients in the
`brimonidine group showed no significant changes in any of
`the RNFL thickness measurements (p ≥0.14) and there was
`no evidence for glaucomatous loss of the RNFL. The
`between-group comparison of mean change from baseline
`RNFL thickness showed significantly greater loss of
`temporal average (p=0.005), inferior average (p=0.016), and
`ellipse average (p=0.020) RNFL thickness in the timolol
`group compared with the brimonidine group.
`No significant between-group differences in mean IOP
`were found at baseline or at any follow-up study visit (p
`≥0.038). The mean IOP reduction at the month 12 visit was
`5.6 mmHg in the brimonidine group and 5.3 mmHg in the
`timolol group (p=0.16). Therefore, the differences in RNFL
`loss between the treatment groups are unlikely to be
`explained by better IOP control in the brimonidine group.
`Instead, the findings are likely to be explained by a direct
`neuroprotective effect of brimonidine, which promoted the
`survival of RGCs and their axons, and thereby prevented
`glaucomatous damage to the RNFL. The brimonidine-Purite
`0.15% and 0.1% formulations would be expected to have a
`similar neuroprotective effect, if (as is likely)
`neuroprotection results from brimonidine activity at the
`retina, rather than from systemic effects of the drug.
`
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`Cantor
`
`This latest study provides the strongest published results
`to date suggesting that neuroprotection with brimonidine
`may be a viable strategy for treatment in glaucoma. The use
`of scanning laser polarimetry allowed quantitative
`evaluation of structural changes in the RNFL and
`demonstrated pos