European Journal of Ophthalmology / Vol. 11 / Suppl. 2, 2001 / pp. S72-S77
`
`Brimonidine (Alphagan®): A clinical profile four
`years after launch
`
`R. DAVID
`
`Ophthalmology Clinical Research, Allergan, Irvine, CA - USA
`
`ABSTRACT. The early information on the clinical efficacy, safety, and tolerability of brimoni-
`dine 0.2% were obtained from studies that compared brimonidine monotherapy with timo-
`lol and betaxolol. These studies showed its intra-ocular pressure lowering efficacy to be
`comparable with timolol and superior to betaxolol. The data from the timolol studies showed
`consistent results after four years. These findings have been confirmed by additional stud-
`ies in the clinical setting.
`More recently, several clinical trials have been completed investigating the role of brimonidine
`as adjunctive medication to beta-blockers and as replacement therapy to other intraocular
`pressure lowering compounds. When added to beta-blockers, brimonidine is superior to
`dorzolamide, similar in efficacy but better tolerated than pilocarpine, and more predictable
`than latanoprost.
`Data from replacement studies have indicated that there may be advantages in replacing
`rather than adding medications in the treatment of glaucoma. Eur J Ophthalmol 2001; 11
`(Suppl 2): S72-S77
`
`KEY WORDS. Brimonidine, Clinical trials, Glaucoma
`
`INTRODUCTION
`
`Brimonidine tartrate 0.2% (Alphagan®; Allergan, Inc.)
`is becoming increasingly popular for the initial and
`long-term management of ocular hypertension and glau-
`coma. It has been studied in more than 2000 patients
`in clinical trials and, since its introduction in 1996,
`more than 30 million units have been dispensed. Based
`on this experience, we now have extensive informa-
`tion about this compound.
`In initial clinical studies, brimonidine monotherapy
`was compared with the beta-blockers timolol (1-4) and
`betaxolol (5). This report provides an update on the
`extension of one of the long-term studies that com-
`pared brimonidine with timolol. Results from additional
`clinical trials of various designs are also presented,
`to highlight the use that brimonidine may have in glau-
`coma therapy as monotherapy, adjunctive, or replacement
`medication.
`
`Long-term studies comparing brimonidine and
`beta-blocker monotherapy
`
`A subgroup of patients from 7 sites of one of the
`long-term studies comparing brimonidine 0.2% to tim-
`olol 0.5%, both administered twice daily, continued
`beyond the 1-year protocol (3) through years 3 and 4.
`
`Three-year results
`
`By year 3 brimonidine provided sustained, or even
`improved, intraocular pressure (IOP) reduction at trough,
`compared with timolol 12 hours after instillation (Fig.
`1) (6). This means that with longer-term use, the slight
`advantage reported for timolol over brimonidine at the
`trough IOP measurement (Fig. 1), as reported in the
`1 year studies (1-4), was no longer present. During
`Year 3, brimonidine reduced mean IOP from baseline
`by 5.02 mmHg compared with 5.57 mmHg with tim-
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`26
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`24
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`22
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`20
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`18
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`16
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`14
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`Mean IOP at Trough (mmHg)
`
`David
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`Fig. 1 - Tr ough IOP throughout 36 months
`of follow-up (6).
`
`0
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`6
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`12
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`18
`
`24
`
`30
`
`36
`
`Time (months)
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`Brimonidine 0.2% BID
`Timolol 0.5% BID
`
`olol (p = 0.383). Using 95% confidence intervals with
`equivalence defined as within 2 mmHg, the reduc-
`tions produced by brimonidine were equivalent to those
`produced with timolol after 30 months and 3 years of
`treatment (6).
`Visual field preservation was also compared in the
`1-year clinical trials (4) and in the 3-year study ex-
`tension (6). After year one, 94% of all subjects had
`unchanged or improved visual fields (defined as with-
`in 5 decibels of baseline) after 12 months. At the end
`of year 3, 95% of evaluable patients in the brimoni-
`dine and timolol groups showed no change or improvement
`from baseline. No significant differences were seen
`between treatment groups during years 1 and 3.
`
`Four-year results
`
`Patients from the same seven study sites were re-
`enrolled after completing the 3-year study (month 36),
`and were re-evaluated at months 39, 42, 45, and 48
`(7). During this further extension stage of the study
`comparing brimonidine with timolol, the trough IOP-
`
`lowering effect that was equivalent for both compounds
`by the end of year 3 (6), was sustained throughout
`the fourth year. There were no significant differences
`in IOP-lowering efficacy between groups at trough (p
`≥ 0.231), with an overall mean reduction from base-
`line IOP of 4.9 mmHg with brimonidine (range 4.84 to
`5.96 mmHg) and 6.08 mmHg with timolol (range 5.69
`to 6.44 mmHg). Similarly, throughout year 4, both drug
`regimens continued to significantly lower mean IOP
`at peak (p < 0.001), with an overall mean reduction
`from baseline of 8.14 mmHg in the brimonidine group
`and 6.76 mmHg (p = 0.136) in the timolol group. These
`year-4 results are consistent with the observations
`made during year 3, suggesting that the substantial
`IOP-lowering efficacy of brimonidine, both at peak
`and at trough, is maintained when used continuous-
`ly for the long-term management of ocular hyperten-
`sion and glaucoma.
`At the end of year 4, visual fields were relatively un-
`changed or improved in 93% of patients in the bri-
`monidine group and 91% of the timolol groups (7).
`Because visual field preservation is the ultimate out-
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`Brimonidine: Clinical profile 4 years after launch
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`come measure for therapeutic effectiveness in glau-
`coma, these results demonstrate that brimonidine is
`indeed as effective as timolol for the chronic man-
`agement of glaucoma.
`
`Additional studies comparing brimonidine and be-
`ta-blocker monotherapy
`
`tients on beta-blocker therapy (8).
`The results of these trials in newly diagnosed and
`naïve patients, which equally consider the IOP-low-
`ering efficacy, safety, patient tolerability, and impact
`on patient quality of life, suggested that therapy with
`brimonidine leads to initial clinical success rates com-
`parable with timolol and superior to betaxolol.
`
`Two 4-month multicenter, double-blind trials were
`performed to compare brimonidine 0.2% b.i.d. with
`timolol 0.5% b.i.d. (10) and betaxolol 0.25% suspension
`b.i.d. (11) in patients who were naïve to medical treat-
`ment. In these studies, clinical success was assessed
`by the investigators, using their professional evalua-
`tions of IOP-lowering efficacy, safety, patient tolera-
`bility and impact on patient quality of life.
`In the study comparing brimonidine with timolol, both
`medications provided comparable initial clinical suc-
`cess rates [71% (75/106) with brimonidine vs 70%
`(73/105) with timolol] (10). The overall mean decreases
`in IOP were 6.5 mmHg with brimonidine and 6.2 mmHg
`with timolol. Equal percentages of patients (18%) were
`switched to the other drug regimen at month 1 due
`to either lack of efficacy, adverse events, or other rea-
`sons as determined by the masked-investigator. Fur-
`thermore, similar percentages of patients were con-
`sidered clinically unsuccessful at month 4 due to in-
`adequate IOP-lowering (6.6% with brimonidine vs 9.5%
`with timolol), or adverse events (4.7% with brimoni-
`dine vs 2.8% with timolol).
`In the second study which compared brimonidine
`with betaxolol, clinical success with brimonidine as
`initial therapy was achieved in 74% of glaucoma and
`ocular hypertension patients, which is consistent with
`results obtained in the study comparing brimonidine
`with timolol. This compared favorably with the 57%
`of patients treated with betaxolol (p = 0.027) (11). The
`overall mean IOP decrease from baseline was 5.9 mmHg
`for brimonidine and 3.8 mmHg for betaxolol. Both treat-
`ments were well tolerated.
`In addition, a separate analysis of a subgroup of
`patients from the 1-year comparative study with tim-
`olol focused on patients who were on concomitant
`systemic beta-blocker medication while participating
`in the study. This analysis has shown that while the
`IOP reduction with brimonidine was not influenced by
`the concurrent systemic beta-blocker treatment, the
`IOP lowering achieved with timolol was inferior in pa-
`
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`Long-term safety
`
`Brimonidine and timolol continued to be well tolerat-
`ed through 4 years of treatment, with no significant dif-
`ferences between groups in the incidence of any ad-
`verse event and with few patients discontinuing the study.
`The allergic conjunctivitis associated with pro-
`longed brimonidine treatment was reported to occur
`at an overall rate of 12.7% of patients over 1 year (4).
`In the extension study, the ocular allergy rate with bri-
`monidine therapy was reported to drop to 4.2% dur-
`ing year 3 of continuous use (6). The finding of “oc-
`ular allergy” with brimonidine has raised several ques-
`tions and interpretations: it does not include the typ-
`ical signs and symptoms of a true allergic reaction,
`there is no cross reactivity with apraclonidine and pa-
`tients who were allergic to the latter did not react when
`treated with brimonidine (9). In all cases, the “aller-
`gy” was mild-to-moderate in severity and all symp-
`toms and signs resolved rapidly after discontinuation
`of the drug.
`
`Studies of brimonidine as adjunctive therapy
`
`Recent, postmarketing clinical evaluations have demon-
`strated that brimonidine is efficacious and well tol-
`erated as adjunctive therapy when added to other class-
`es of agents such as beta-blockers.
`In a 3-month study brimonidine 0.2% b.i.d. was com-
`pared with pilocarpine 2% t.i.d., when both medica-
`tions were used adjunctively to a beta-blocker. Bri-
`monidine had a comparable additive ocular hypoten-
`sive efficacy to that of pilocarpine, but with fewer ad-
`verse ocular side effects (12).
`In another study, brimonidine 0.2% b.i.d. was com-
`pared with dorzolamide 2% t.i.d., also as additives
`to timolol 0.5% b.i.d. Brimonidine was significantly
`more efficacious than dorzolamide (p = 0.006) when
`given in combination with beta-blockers (13). In this
`study, significantly more patients reached their IOP
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`reduction goals (≥ 15% reduction from baseline IOP
`on beta-blocker monotherapy) with brimonidine than
`dorzolamide after 1 month (86.3% vs 67.1%; p = 0.005)
`and after 3 months (77.8% vs 44.4%; p = 0.006).
`Other studies compared brimonidine 0.2% b.i.d. with
`latanoprost 0.005% q.d. as adjunctive therapy and
`found that brimonidine was similar in efficacy and prob-
`ably more predictable than latanoprost when used as
`an adjunctive agent (14, 15). In one of these studies
`(15), 85% (17/20) of brimonidine and 65% (13/20) of
`patients treated with latanoprost (p = 0.144) achieved
`their IOP reduction goals (≥ 15% from baseline) after
`1 month while using test medications as adjunctive
`therapy to beta-blockers (15).
`
`Studies of brimonidine as replacement therapy
`
`In the management of glaucoma, when a certain drug
`does not obtain an adequate IOP reduction, the op-
`tion to r eplace rather then add a second medication
`is often adopted. This regimen has the advantage of
`better compliance, less drug-to-drug interaction,
`lower costs and fewer side effects.
`To examine the efficacy and safety of brimonidine
`0.2% b.i.d. as a replacement therapy for patients un-
`controlled on their present mono- or adjunctive ther-
`apy, a post-hoc evaluation of patient records was per-
`formed from a large multicenter study based on clin-
`ical practice (16). In this 2-month, open-label study
`involving 460 patients with open-angle glaucoma or
`ocular hypertension, brimonidine was used as replacement
`therapy and consistently produced additional mean
`IOP reductions from pre-brimonidine treatment base-
`line regardless of the previous monotherapeutic or
`adjunct therapeutic regimen. Overall, brimonidine re-
`placement therapy significantly reduced mean IOP from
`pre-brimonidine treatment baseline by an additional
`2.3 mmHg (9.8%; p = 0.001). While brimonidine ef-
`fectively replaced all medications tested, some re-
`placement regimens showed particularly good responses:
`• When used as replacement for betaxolol monother-
`apy an additional mean IOP reduction of 13.56% (p
`= 0.001) was seen.
`• When replacing latanoprost monotherapy, mean IOP
`was reduced by an additional 12.44% (p = 0.003).
`• When replacing latanoprost in an adjunct regimen,
`mean IOP was reduced by an additional 16.08% (p
`= 0.010).
`
`In addition to showing broadly effective IOP-low-
`ering capability as replacement therapy in this study,
`brimonidine was generally well tolerated, appeared
`safe, and may have had a positive impact on quality
`of life of patients (16). More than 92% of responding
`physicians rated brimonidine replacement therapy as
`excellent or good in comparison to other available
`medications, with none giving it a rating of poor. Few-
`er than 7% of patients reported an adverse event, and
`4 of 5 quality of life survey scores (Glaucoma Dis-
`ability Index Survey) (17) showed significant improvement
`(p < 0.05) from pre-brimonidine treatment baseline
`during this 2-month study.
`In another 2-month study 42 patients with glauco-
`ma or ocular hypertension were examined to evalu-
`ate the IOP-lowering efficacy of brimonidine 0.2% b.i.d.
`(given as replacement for previous two-line therapy)
`(18). Brimonidine produced an equivalent or greater
`IOP-lowering effect than the previous two-line regi-
`men in more than 55% of patients tested. Moreover,
`an equal or additional reduction in mean IOP was seen
`in more than:
`• 50% of patients switched from beta-blocker plus
`latanoprost.
`• 55% of patients switched from beta-blocker plus
`dorzolamide.
`• 80% of patients switched from beta-blocker plus
`pilocarpine.
`The results of this study and those of Lee et al (16)
`suggest that brimonidine is a reliable alternative for
`patients who are unsuccessful on their present one-
`or two-line medication regimen. As mentioned earli-
`er, such substitution may offer cost effectiveness, im-
`proved patient compliance and a reduction in the risk
`of adverse events.
`
`CONCLUSIONS
`
`Brimonidine 0.2% b.i.d., whether given as mono-
`or adjunctive therapy in clinical trials, invariably ap-
`peared safe, even after 4 years of continuous use.
`Furthermore, after four years of clinical experience,
`brimonidine continues to appear well tolerated with-
`out major effects on patients’ quality of life. No clin-
`ically significant effects on heart rate, blood pressure,
`or pulmonary function have been seen with brimoni-
`dine, and there have been no published reports of any
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`Brimonidine: Clinical profile 4 years after launch
`
`serious drug-related adverse events in adults. This
`highly favorable systemic safety profile makes brimonidine
`0.2% b.i.d. an appropriate first-line therapeutic.
`Other than ocular allergy in 4.2% to 12.7% of pa-
`tients (frequency depending on duration of therapy),
`and symptoms of drowsiness and fatigue leading to
`discontinuation in 2.7% of patients over the first year
`of therapy, there appears to be few limiting side ef-
`fects associated with long-term brimonidine therapy.
`All of the known brimonidine-associated side effects
`including ocular allergy and fatigue drowsiness are
`reversible and easily remedied. Moreover, all known
`side effects of brimonidine are generally minor and
`transient, and have little impact on patients’ quality
`of life. However, the use of topical brimonidine should
`be avoided in newborns or young infants in which CNS
`depression has been reported (19, 20). This adverse
`event is most likely a result of differences in drug ca-
`tabolism and
`is due to the
`immaturity of the
`blood–brain barrier (21, 22).
`Clinical studies have shown that brimonidine
`monotherapy is comparable or superior to beta-block-
`ers. Long-term clinical study data show that this pro-
`file is consistent after 4 years. Furthermore, when added
`to beta-blockers as adjunctive therapy, brimonidine
`
`is superior to dorzolamide, similar in efficacy but bet-
`ter tolerated than pilocarpine, and more predictable
`than latanoprost. Data from replacement studies in-
`dicate that brimonidine is a reliable alternative for pa-
`tients who are unsuccessful on their present one- or
`two-line medication regimen.
`The favorable safety and tolerability profile of bri-
`monidine, combined with its good efficacy, makes it
`an agent of choice in treating patients with glauco-
`ma, either as monotherapy, adjunctive therapy, or re-
`placement therapy for patients who do not obtain ad-
`equate IOP reduction, or suffer from side effects, on
`their existing regimens. Switching medication in this
`way may lead to better compliance, less drug-to-drug
`interaction, lower costs, fewer side effects and, most
`importantly, better delivery of care to glaucoma pa-
`tients.
`
`Reprint requests to:
`Robert David, MD
`Senior Medical Director
`Ophthalmology Clinical Research
`Allergan
`2525 Dupont Drive, Irvine, CA 92612, USA
`
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