1.
`
`Introduction
`
`2. Mechanism of action
`
`3.
`
`4.
`
`5.
`
`6.
`
`Clinical applications
`
`Safety evaluation
`
`Conclusion
`
`Expert opinion
`
`Drug Safety Evaluation
`
`Brimonidine for glaucoma
`
`†
`, Kanna Ramaesh & Donald MI Montgomery
`Mamun Q Rahman
`†
`Gartnavel General Hospital, Tennent Institute of Ophthalmology, Glasgow, UK
`
`Importance of the field: Brimonidine is a drug used in the management of
`glaucoma throughout the world and is the most modern a2-adrenoceptor ago-
`nist available. This review comprehensively discusses the use of brimonidine
`for glaucoma.
`Areas covered in this review: A historical insight into the development of
`selective adrenergic glaucoma drugs is given, followed by a description of
`the mechanisms of action and a discussion of the main clinical trials investigat-
`ing clinical applications. The safety of brimonidine is evaluated, and our
`expert opinion is provided on how brimonidine is used in our clinical practice.
`The most relevant literature on the role of brimonidine in glaucoma
`is discussed.
`What the reader will gain: A clear understanding of the role of brimonidine
`for glaucoma treatment, with an explanation of its efficacy, limitations and
`use in clinical practice.
`Take home message: Brimonidine is an effective drug for lowering intraocular
`pressure. It has potentially serious systemic effects in children, in whom it
`is contraindicated. Its use in adults is limited by its ocular side effects such
`as allergy. Brimonidine is, however, an important part of the range of
`intraocular pressure lowering drugs available to prescribers.
`
`Keywords: a
`
`2-adrenoceptor agonist, brimonidine, combigan, glaucoma, neuroprotection
`
`Expert Opin. Drug Saf. (2010) 9(3):483-491
`
`1. Introduction
`
`Glaucoma is a group of slowly progressive diseases affecting the optic nerve. Many
`patients are unaware that they have the condition until irreversible damage to the
`optic nerve has occurred [1]. Untreated, progressive visual field loss can occur, and
`glaucoma is the second leading cause of blindness worldwide [2]. Glaucoma is con-
`sidered to be a multifactorial disease and intraocular pressure (IOP) is a significant
`risk factor associated with the development of optic nerve neuropathy [3,4].
`High IOP may be controlled both medically and surgically. Surgical treatments
`for glaucoma are only used when medical or laser treatments have failed to reach
`a satisfactory IOP. An in-depth discussion of the surgical treatments of glaucoma
`is beyond the scope of this review, but the current ‘gold standard’ surgical treatment
`is trabeculectomy. Surgical treatments are continually evolving with recent develop-
`ments such as the use of expanded polytetrafluoroethylene implants [5] and
`OlogenÔ implants [6]. There are also some reports that some novel devices such
`as the Trabectome (Neomedix, Inc., USA), iStent (Glaukos, USA) and Solx shunt
`(Solx, USA) (suprachoroidal shunt) may control IOP satisfactorily and without
`the need for antifibrotic agents or external filtering bleb formation [7].
`Medical therapy has been used to lower IOP for many years, and the earliest glau-
`coma therapies were drugs that stimulated either the parasympathetic or the sympa-
`thetic system. The oldest recorded glaucoma medications were topical cholinergic
`agents, with pilocarpine and physostigmine being used in the late 19th century [8,9]
`and ecothiopate iodide in the 1950s [10]. Epinephrine (adrenaline) as a repeated sub-
`conjunctival injection, or as a topical drop, has been used to treat glaucoma from
`the 1920s, but variable IOP lowering results and adverse side effects such as cardiac
`
`10.1517/14740331003709736 © 2010 Informa UK Ltd ISSN 1474-0338
`All rights reserved: reproduction in whole or in part not permitted
`
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`Brimonidine
`
`Box 1. Drug summary.
`
`Drug name
`Phase
`Indication
`Pharmacology
`description/mechanism
`of action
`Route of administration
`Chemical structure
`
`Brimonidine
`Post marketing
`Raised intraocular pressure
`a2-Adrenoceptor agonist
`
`Topical to eyes
`
`HN
`
`HN
`
`N
`
`Br
`
`N
`
`Pivotal trial
`
`N
`
`Brimonidine study group
`trials [41-45,59,60]
`
`arrhythmias caused the avoidance of its use [11,12]. Renewed
`interest in sympatheticomimetic agents eventually led to the
`development of dipivalyl epinephrine (dipivefrine, DPE), a
`prodrug of epinephrine that penetrates the eye about 17 times
`better than its parent compound [13]. Due to its superior top-
`ical penetration, a concentration of 0.1% DPE was found to
`be as effective as 1 -- 2% epinephrine hydrochloride [14,15],
`but DPE’s systemic and topical side effects also caused it to
`fall out of use.
`The search continued to develop a drug that would have
`the ability to lower IOP, whilst minimizing systemic sympa-
`theticomimetic side effects. This led to the development of
`selective adrenergic agents. The first agent of this emerging
`class of drugs was clonidine (Figure 1A), an a
`2-adrenoceptor
`agonist [16]. Although the topical form lowered IOP, it also
`significantly lowered blood pressure, and it has only been
`approved for glaucoma treatment in Europe and not in
`the US. In the 1980s, a second generation a
`2-adrenoceptor
`agonist, apraclonidine, was produced (Figure 1B). It contains
`a para-amino group that makes it more hydrophilic, limiting
`its transport through the BBB, and thereby limiting CNS-
`mediated systemic adrenergic affects. However, apraclonidine
`was found to have a high rate of tachyphylaxis and topical side
`effects such as conjunctivitis [17], and it is now only used
`to control short-term IOP spikes such as following yttrium
`aluminium garnet laser iridotomies.
`third generation a
`2-adrenoceptor
`Brimonidine
`is
`a
`agonist introduced in 1996 (Box 1). Its chemical nomencla-
`ture is 5-bromo-6-(2-imidazolidinylideneamino) quinoxaline
`L-tartrate, and it was formerly known as UK-14304-18 and
`AGN 190342-LF (Figure 1C). It differs from clonidine
`and apraclonidine by containing a quinoxaline ring system
`and bromine as a side group, instead of chlorine. It has been
`
`found to have a significantly higher a
`2-adrenoceptor affinity,
`in the order of 23- to 32-fold [18]. The purpose of this paper is
`to review the use of brimonidine as a modern drug for the
`treatment of glaucoma.
`
`2. Mechanism of action
`Brimonidine exerts its effects in the eye due to its high a
`2-
`adrenoceptor affinity, for which it is considered a standard
`In radioligand binding assays
`reference compound [19].
`using human colonic cell lines (a
`2-adrenoceptors) and human
`(a
`1-adrenoceptors),
`the ratio of
`cerebral cortex neurons
`2:a1-adrenoceptor
`a
`selectivity was 974 for brimonidine,
`
`151 for clonidine and 30 for aparaclonidine, thus, indica-
`ting that brimonidine was 6 -- 32 times more selective for
`a
`2-adrenoceptors than clonidine and apraclonidine, respec-
`tively [18]. Studies using in vitro ligand binding and auto-
`radiography have demonstrated a large number of specific
`brimonidine binding sites on human iris and ciliary epithelium,
`with a smaller number of binding sites on human ciliary
`muscle [20].
`IOP by both reducing aqueous
`Brimonidine lowers
`humor production and increasing aqueous outflow via the
`uveoscleral pathway [21]. Both of these mechanisms are medi-
`ated by stimulation of ocular a
`2-adrenoceptors. Topical
`application of brimonidine reduced aqueous production in
`monkeys [22] and increased uveoscleral outflow in rabbits [23].
`In humans, aqueous production (measured by fluoropho-
`tometry) was reduced by 20% in the treated eyes and by
`12% in the contralateral untreated eyes of patients with ocu-
`lar hypertension receiving brimonidine 0.2% twice daily for
`1 week [21]. Furthermore, a fivefold increase in uveoscleral
`outflow was evident in treated eyes only. In this study,
`brimonidine did not appear to affect the episcleral venous
`pressure, fluorophotometric outflow facility or tonographic
`outflow facility [21].
`Brimonidine may also have a neuroprotective effect inde-
`pendent of its ability to lower IOP. The mechanisms under-
`lying this are not
`fully understood but may include an
`upregulation of basic fibroblast growth factor [24], causing a
`cell hyperpolarization and a reduction in the release of gluta-
`mate from neurons [25], or an upregulation of antiapoptotic
`genes [26]. Previous studies in human tissue have identified a
`number of brimonidine binding sites in the retina, retinal
`pigment epithelium and choroid [20], and a
`2-adrenoceptors
`have also been identified in the retina and retinal pigment
`epithelium [27]. Moreover, one study has demonstrated that
`vitreous samples from patients taking brimonidine contained
`mean concentrations of the drug of 185 nM [28], and this
`is in excess of the 2 nM level previously determined to activate
`a
`2-adrenoceptors [18]. It has been found that intraperitoneal
`injections of brimonidine produced a dose-dependent reduc-
`tion in the secondary degeneration of retinal ganglion cells in
`an acute optic nerve crush model [29]. Similarly, a previous
`study using a model of chronic ocular hypertension in rats in
`
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`A.
`
`Cl
`
`HN
`
`HN
`
`N
`
`Cl
`
`B.
`
`Cl
`
`HN
`
`HN
`
`N
`
`Cl
`
`Rahman, Ramaesh & Montgomery
`
`HN
`
`HN
`
`N
`
`C.
`
`Br
`
`N
`
`NH2
`
`N
`
`Figure 1. The a-adrenoceptor agonists. A. Clonidine, the first a-adrenoceptor agonist used in glaucoma. B. Apraclonidine, a
`second generation a-adrenoceptor agonist. Note the para-amino group that differentiates it from clonidine. C. Brimonidine,
`the latest third generation a-adrenoceptor agonist which differs from apraclonidine by containing a quinoxaline ring system
`and bromine as a side group, instead of chlorine.
`
`which the episcleral and limbal veins were photocoagulated to
`increase IOP revealed that systemic application of brimonidine
`was associated with a statistically significant reduction in the
`loss of retinal ganglion cells [30]. However, there is no definitive
`evidence in the current literature that brimonidine has a neuro-
`protective effect in humans; studies to investigate this are
`currently ongoing [31,32].
`The topical application of brimonidine results in IOP
`reduction within 1 h. The peak effect is achieved within 2 --
`3 h and the trough drug effect occurs 10 -- 14 h after installa-
`tion [33]. Animal studies, and a few studies involving human
`subjects, have suggested that mainly the cornea, and to a lesser
`extent the sclera and conjunctiva, are the major pathways for
`intraocular absorption of brimonidine [34]. The retention
`and absorption of brimonidine may be increased by drug
`binding to ocular melanin [35]. Brimonidine has been demon-
`strated to have marked affinity for melanin containing ocular
`tissues in vivo with peak concentrations of the drug in the iris-
`ciliary body, being fourfold higher in pigmented than in
`albino rabbits [36]. Brimonidine undergoes extensive hepatic
`metabolism. Oxidation of the drug by liver aldehyde oxidase
`has been implicated as the major metabolic pathway in
`humans resulting in the formation of 2-oxobrimonidine,
`3-oxobrimonidine and 2,3-dioxobrimonidine [37]. The elimi-
`nation half-life in human plasma after a single topical dose has
`been found to be about 2 h [38].
`
`3. Clinical applications
`
`Initial clinical studies of brimonidine investigated its role
`in the prevention of laser trabeculoplasty pressure spikes,
`and these showed that
`the efficacy of brimonidine in
`0.5 and 0.2% concentrations was similar to that of apraclo-
`nidine [39]. An early study found that brimonidine in
`concentrations of 0.08, 0.2 and 0.5% with twice daily
`dosing lowered IOP by 20 -- 30% in glaucoma and ocular
`hypertension patients [40]. The study was, however, limited
`in its scope as it was nonrandomized, and only 1 month in
`
`duration. The 0.2% concentration had the least ocular
`and systemic side effects and was at
`the peak of
`the
`dose--response curve.
`This report was followed by more robust studies. Two
`large, 1 year, randomized, double-masked, multi-center clini-
`cal trials comparing brimonidine tartrate 0.2% with timolol
`maleate 0.5% reported that IOP was significantly lower at
`peak (2 h after instillation) in the brimonidine group, but
`that the ocular hypotensive effect was not as great as timolol
`at trough (12 h after instillation) [41]. Overall, brimonidine
`showed sustained IOP lowering efficacy comparable with
`timolol, but with significantly fewer negative chronotropic
`effects on the heart. Data from trials after 3 or 4 years of con-
`tinuous use demonstrated that brimonidine maintained
`an IOP lowering efficacy comparable with timolol, and assess-
`ment of long-term visual field preservation was similar with
`both drugs [42,43].
`A further 3 month, multi-centered, randomized, double-
`blind, parallel group study compared brimonidine with betax-
`olol 0.25% and reported that brimonidine had significantly
`higher decreases in IOP at both peak and trough with greater
`tolerability [44]. A later study also judged that brimonidine
`had a higher clinical success rate than betaxolol when compar-
`ing factors such as IOP reduction, adverse effects and quality
`of life effects [45]. It must, however, be noted that this study
`had a relatively small sample size and was carried out over a
`short period of time; adverse effects and allergic reactions
`might not have had time to manifest fully.
`A large meta-analysis of 15 publications on 14 trials com-
`paring latanoprost 0.005% to brimonidine 0.2% found that
`once daily dosage of latanoprost lowered IOP more effectively
`than brimonidine used twice daily up to 1 year after initial
`treatment for normal tension glaucoma, ocular hypertension
`and open angle glaucoma [46]. Moreover, this meta-analysis
`found that brimonidine had a higher association with
`fatigue than latanoprost.
`Three separate studies have evaluated the efficacy and safety
`of brimonidine compared with dorzolamide when used as
`
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`Brimonidine
`
`monotherapy, and whilst there was no overall difference
`in IOP lowering efficacy, ocular burning and stinging were
`more common with dorzolamide [47-49]. These studies are,
`however, limited by their low patient numbers and relatively
`short periods of follow-up.
`A direct ranking of the efficacy of IOP reduction by glau-
`coma drugs is difficult as not all studies compare all drugs
`directly, but a recent study using network meta-analysis of
`28 randomized control trials of eight different glaucoma drugs
`(brimonidine, bimatoprost, travoprost, latanoptost, timolol,
`dorzolamide, betaxolol and brinzolamide) found that brimo-
`nidine had the fourth highest drop in IOP at peak, but had
`the lowest IOP reduction of the eight drugs investigated at
`trough [50].
`The efficacy and safety of brimonidine as an adjunctive
`therapy has also been investigated in several randomized
`controlled studies. The addition of brimonidine to ongoing
`b-blocker therapy [51,52] and to latanoprost [52,53] both result
`in significant further IOP reduction. Brimonidine 0.15%
`has also been found to give the most reduction in IOP when
`used as adjunctive therapy with a prostaglandin analogue
`than either brinzolamide or dorzolamide [54]. Similarly, the
`addition of brimonidine 0.2% to maximum tolerated medical
`therapy in patients with several different types of glaucoma
`resulted in a decrease in IOP from 16 to 32% [55].
`In 2007, a novel fixed combination of timolol 0.5% and
`brimonidine 0.2% (Combigan, Allergan, Irvine, CA, USA)
`was introduced. Two 12 month, randomized, double masked
`multi-center clinical trials investigated the efficacy of Combi-
`gan in comparison with either of the component drugs sepa-
`rately, and it was found that Combigan had a superior IOP
`lowering effect than monotherapy. Adverse effects were found
`to be lower with Combigan than with brimonidine, but higher
`than with timolol [56]. A recent 3 month randomized control
`trial comparing Combigan with 2% dorzolamide--0.5% timo-
`lol (Cosopt, Merck, Whitehouse Station, NJ, USA) fixed
`combination therapy found that Combigan had both greater
`efficacy in lowering IOP and was better tolerated with fewer
`patients complaining of ocular burning, stinging or unusual
`taste than with dorzolamide--timolol [57]. However, no signif-
`icant difference in either efficacy or tolerability was found
`between Combigan and 2% dorzolamide--0.5% timolol in
`an earlier study [58]. The reason for this discrepancy is not
`entirely clear but the earlier study had a more robust method-
`ology and included the effect of diurnal variation on IOP; this
`was not done in the later study.
`These clinical studies show that brimonidine is an effective
`ocular hypotensive agent as a monotherapy, an adjunctive
`agent and a combination therapy and that the effect is
`sustained over time.
`
`4. Safety evaluation
`
`Several studies have reported the overall safety and efficacy of
`brimonidine 0.2% after 1, 3 and 4 years. Brimonidine is not
`
`known to be associated with clinically significant effects on
`mean heart rate, lung function or blood pressure [42,59,60]
`and is not contraindicated in patients with cardiopulmonary
`disease. The most common systemic side effects include
`fatigue or drowsiness, dry mouth and headache [42,59,60].
`There is laboratory evidence that a
`2-adrenoceptor agonists
`may potentiate smooth muscle vasoconstriction in arteries [61],
`and brimonidine is, therefore, contraindicated in cerebral or
`coronary insufficiency, postural hypotension and Raynaud’s
`disease. Post-mortem studies in the brains of depressed suicide
`victims have found an increase in the density and affinity of
`a
`2-adrenoceptors [62,63], and brimonidine is, therefore, con-
`traindicated in depression. Due to its extensive hepatic metab-
`olism, brimonidine use is also contraindicated in patients with
`hepatic insufficiency.
`Long-term administration of brimonidine is limited by its
`propensity to cause ocular allergic reactions. The incidence
`of blepharitis and belpharoconjunctivitis has been reported
`as 9 -- 12.7% [41,59,64], follicular conjunctivitis has been found
`in 7.8 -- 12.7% of patients [41,59] and conjunctival hyperemia
`has an incidence of 26.3 -- 30.3% [65,66]. However, allergic
`reactions may take several years to manifest, and there is evi-
`dence from a recent 26 year surveillance of glaucoma medical
`therapy that these 1 year studies may have significantly under-
`estimated the
`true
`incidence of ocular
`allergy with
`brimonidine, which may be as high as 32.3% [65].
`Brimonidine may also increase the likelihood of allergy to
`subsequently used preparations. It has been reported that in
`patients allergic to both brimonidine and another drug, the
`mean time interval between the first and second drug allergies
`was shorter when brimonidine was used initially and allergy to
`it occurred first [66]. This is of clinical significance, as this sug-
`gests that an allergy to brimonidine may jeopardize the future
`medical management of patients with glaucoma, resulting in
`the need for surgery.
`Such ocular allergic reactions may be due to a class effect as
`similar problems are seen with other a-adrenoceptor agonists
`such as apraclonidine [17]. The reasons for this are unclear, but
`it has been hypothesized that adrenergic agents may reduce
`the volume of conjunctival cells, thus, producing a widening
`of intercellular spaces through which potential allergens may
`reach the subepithelial tissues causing allergy [67]. It may,
`therefore, be advisable to avoid adrenergic agents such as bri-
`monidine in patients with a known history of other ocular
`surface allergies such as atopy and hay fever.
`In an attempt to reduce ocular surface allergy, Allergan,
`Inc. have also released a reformulated solution of brimonidine
`with chlorine dioxide as a preservative (PuriteÔ), in place of
`benzalkonium chloride (BAK), and reduced the concentration
`of brimonidine to 0.15%. Whilst this appears to have similar
`efficacy in reducing IOP as brimonidine 0.2% preserved
`with BAK, one early study demonstrated a reduction in
`adverse effects [68], but another has shown no difference [69].
`Moreover, a recent meta-analysis of two Phase III studies
`showed that
`although reducing
`the
`concentration of
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`episodes being reported with other sympatheticomimetic
`drugs is not enough to establish absolute causality [75], the
`potential occurrence of this sight threatening problem is
`worth noting.
`Importantly, brimonidine is absolutely contraindicated in
`children. It has been linked with side effects associated
`with CNS depression in neonates and infants, with several
`infants requiring hospitalization after its use [76,77]. In one
`series, two young children (aged <4 years) were unarousable
`after its administration, and five other children experienced
`extreme fatigue [78]. These effects may occur because children
`have a less mature BBB to stop brimonidine and prevent CNS
`effects. Moreover, CNS depression mimicking opioid toxicity
`with apnea and bradycardia has been reported in a young
`child after accidental ingestion [79], and similarly, sedation,
`cardiorespiratory depression and hyperglycemia have been
`reported within minutes of an accidental
`ingestion of a
`single drop of brimonidine in a neonate [80].
`
`5. Conclusion
`Brimonidine is a third generation a
`2-adrenoceptor agonist
`whose efficacy in IOP reduction has been confirmed in several
`studies. It is available both as a monotherapy and as a fixed
`combination therapy with timolol, in the form of Combigan.
`In adults, its use is limited by its high incidence of ocular side
`effects, such as allergy. Its serious systemic side effects in
`young patients mean that it is absolutely contraindicated in
`children. Although it
`is now rarely used as a first-line
`glaucoma drug, brimonidine remains an important part of
`the range of IOP reducing drugs available to physicians as
`an adjunctive agent or in patients in whom other classes of
`drugs may not be suitable.
`
`6. Expert opinion
`
`Our evidence based practice is largely governed by results
`from a large and unique computerized database that has
`been established at a single consultant’s (D Montgomery)
`glaucoma clinic at Glasgow Royal Infirmary, with the main
`aim of investigating the tolerability of glaucoma medications
`in patients with primary open angle glaucoma, ocular hyper-
`tension and normal tension glaucoma [65]. This contains com-
`plete treatment histories of >950 patients, with data collected
`from 1981 to the present day, representing >7000 patient
`treatment years. This has shown that
`there has been a
`decline in the use of brimonidine over the past decade.
`With the introduction of novel drugs such as brimonidine
`in the mid-1990s, our clinic adopted the treatment protocol
`shown in Figure 2A. This attempted to arrange the newer
`agents in a hierarchy, with brimonidine selected as the favored
`second-line agent following b-blockers. Initial audit using the
`database, however, quickly revealed an unacceptable increase
`in the discontinuation rate due to adverse effects in the years
`that followed. It was clear that brimonidine was particularly
`
`A. Treatment protocol in1997
`
`B. Treatment protocol in 2000
`
`Timolol age < 65
`
`Betaxolol age > 65
`
`Brimonidine
`
`Latanoprost
`
`Timolol
`
`(xalacom)
`
`Brinzolamide
`
`Latanoprost or dorzolamide
`
`Brimonidine
`
`Allergy
`Other adverse effects
`
`0.20
`
`0.15
`
`0.10
`
`0.05
`
`0.00
`
`2001-2003
`1993-1996
`1997-2000
`
`2004
`
`2005
`
`2006
`
`2007
`
`Year
`
`Frequency/100 treated patients
`
`C.
`
`Figure 2. Drug treatment protocols and the number of
`discontinuations per treatment year. A. The initial treat-
`ment protocol in 1997 with brimonide as favored second-
`line agent. B. The modified treatment protocol in 2000 after
`our initial audit of adverse effects. C. The number of drug
`discontinuations per year. Note the dramatic decline
`following the change of protocol in 2001 -- 2003.
`
`brimonidine purite to 0.1% reduced the systemic side effects,
`no difference was made to the ocular surface side effects [70].
`The fixed combination of timolol 0.5% and brimonidine
`0.2% (Combigan) dosed twice daily has, however, shown
`lower rates of allergy compared with brimonidine alone, but
`higher than with timolol [56,71]. This may be because timolol’s
`b-blocker effects may cause vasoconstriction and reduced
`conjunctival hyperemia. It may also be attributable to the
`lower concentration of BAK present in Combigan than in
`brimonidine alone [56].
`There are also several case reports linking brimonidine
`to granulomatous uveitis [72-74]. These episodes occurred
`10 -- 15 months after topical administration, and all resolved
`following cessation of administration. In several cases, rechal-
`lenging the patient with brimonidine caused a recurrence
`[72,73]. Although these cases are sporadic and the lack of similar
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`Brimonidine
`
`implicated, and we found that brimonidine had both the
`highest number of patient discontinuations due to all adverse
`effects (46.9%) and the highest number of patient discontin-
`uations specifically due to allergy (32.3%) [65]. Moreover, fur-
`ther information from our database revealed that brimonidine
`appeared to increase the propensity of allergy to subsequently
`used topical IOP lowering drugs such as dorzolamide or
`latanoprost [66].
`These findings informed the introduction of a new proto-
`col in 2000 (Figure 2B). The effect of this change can be
`seen in Figure 2C. From 1997 to 2000, there was a twofold
`increase in the number of discontinuations per treatment
`year, but in the 4 year period following the introduction of
`the treatment protocol, the rate of discontinuations fell to
`almost a third of the level previously seen. Therefore, whilst
`the IOP lowering ability of brimonidine is not in doubt, the
`adverse effects it causes limit its use in our practice.
`We now routinely use brimonidine as a fourth-line adjunc-
`tive agent; only after a prostaglandin analogue, timolol or a
`topical carbonic anhydrase inhibitor has failed to control
`IOP. Prostaglandin analogues are our favored first-line agents.
`These are contraindicated in patients with active uveitis, fol-
`lowing surgery, a history of herpes simplex keratitis and in
`patients with lightly pigmented irides who may be worried
`about a potential change in iris color. In these circumstances,
`our next drug choice would be timolol. This is contraindi-
`cated in patients with significant cardiopulmonary diseases,
`and our next choice would then be a topical carbonic anhy-
`drase inhibitor. These are contraindicated in patients with
`renal and hepatic diseases and in patients in the first trimester
`
`of pregnancy. Only if these three classes of drugs were contra-
`indicated would we then consider using brimonidine as a
`first-line agent in the routine management of a new patient
`with glaucoma, and this situation is very rare.
`Rationalizing a treatment regime to use the minimum
`number of medications greatly aids compliance and effective-
`ness of medical therapy. The use of fixed combination timolol
`0.5%/brimonidine 0.2% (Combigan) can play a role in
`patients who are already on brimonidine and require further
`IOP reduction, especially as the literature suggests that there
`is an increase in tolerability than with timolol alone. How-
`ever, to date, we have only a very small number of patients
`using Combigan, and we cannot draw any firm conclusions
`on its use. We also do not have any patients on the brimoni-
`dine preparation with purite and, therefore, cannot comment
`on its tolerability.
`Research is ongoing into the potential neuroprotective
`effect that brimonidine might have. At the moment, there is
`no clear evidence of its neuroprotective effect in humans,
`but were this to be proven this might change the prescribing
`practice of physicians; brimonidine might then be prescribed
`more often in particular groups of patients who have demon-
`strated progressive field loss, for example. We, therefore, await
`the validation of brimonidine’s potential neuroprotective
`effect in human clinical trials.
`
`Declaration of interest
`
`The authors state no conflict of interest and have received no
`payment in preparation of this manuscript.
`
`488
`
`Expert Opin. Drug Saf. (2010) 9(3)
`
`Page 6 of 9
`
`SLAYBACK EXHIBIT 1032
`
`

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