Drugs Aging DOI 10.1007/s40266-015-0250-4

ADIS DRUG EVALUATION

Brinzolamide/Brimonidine: A Review of Its Use in Patients with Open-Angle Glaucoma or Ocular Hypertension Sarah L. Greig • Emma D. Deeks

Ó Springer International Publishing Switzerland 2015

Abstract Brinzolamide 1 %/brimonidine 0.2 % ophthalmic suspension (SimbrinzaÒ) is a fixed-combination of a carbonic anhydrase inhibitor and an a2-adrenergic receptor agonist that is indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension in both the USA and EU (with the EU indication restricted to patients for whom monotherapy provides insufficient IOP reduction). In phase III randomized trials, both three-times-daily and twicedaily administration of brinzolamide/brimonidine provided significantly greater IOP-lowering efficacy over 3–6 months than either of its individual components alone, and twicedaily brinzolamide/brimonidine was noninferior to concomitant administration of brinzolamide plus brimonidine over 6 months in this regard. Brinzolamide/brimonidine was generally well tolerated, with a tolerability profile that was consistent with its individual components and with no unexpected safety findings. Therefore, brinzolamide/ brimonidine is an effective treatment option for patients with open-angle glaucoma or ocular hypertension, providing a convenient alternative for those patients who require multiple IOP-lowering medications. Brinzolamide/ brimonidine is the first available fixed-combination that does not contain timolol, and maybe particularly suited to patients with comorbidities that restrict treatment with b-adrenergic receptor antagonists. The manuscript was reviewed by: G. Laganovska, Pauls Stradins Clinical University Hospital, Riga Stradins University, Riga, Latvia; C. A. B. Webers, University Eye Clinic Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands. S. L. Greig (&)
E. D. Deeks Springer, Private Bag 65901, Mairangi Bay, 0754 Auckland, New Zealand e-mail: [email protected]

Brinzolamide/Brimonidine in Open-Angle Glaucoma or Ocular Hypertension: A Summary Fixed-combination ophthalmic suspension containing the carbonic anhydrase inhibitor brinzolamide and the a2-adrenergic agonist brimonidine Significantly greater intraocular pressure (IOP)lowering efficacy than monotherapy with either of its individual components Noninferior IOP-lowering efficacy to concomitant administration of brinzolamide plus brimonidine Generally well tolerated, with an adverse event profile that is consistent with its individual components First available fixed-combination glaucoma therapy without the b-adrenergic receptor antagonist timolol

1 Introduction Glaucoma is a leading cause of irreversible blindness worldwide, and describes a group of ocular disorders with multifactorial aetiology that is characterized by elevated intraocular pressure (IOP) and progressive optic neuropathy [1–3]. Glaucoma can be broadly classified into two types based on the gonioscopic anterior chamber angle width: open-angle glaucoma and closed-angle glaucoma [2]. Ocular hypertension is defined as an IOP [21 mmHg with no visual field defect or optic neuropathy [4]. Patients with ocular hypertension have an increased risk of

S. L. Greig, E. D. Deeks

developing open-angle glaucoma [5]. In 2013, the global prevalence of primary open-angle glaucoma in the population aged 40–80 years was estimated at &3 %, with the total number of cases estimated at &44 million [6]. Reduction of elevated IOP is currently the only evidencebased treatment strategy for glaucoma [1]. Topical ocular hypotensive medications reduce the incidence of glaucomatous visual field loss and/or optic nerve deterioration in patients with elevated IOP [5]. The goal of treatment in open-angle glaucoma and ocular hypertension is to maintain the IOP within an individualized target range (typically C25 % lower than pretreatment levels) so that the patient’s condition remains stable or glaucomatous progression is prevented or reduced [7]. IOP-lowering medications include prostaglandin analogues (e.g. latanoprost), b-adrenergic receptor antagonists (e.g. timolol), carbonic anhydrase (CA) inhibitors (CAIs) [e.g. brinzolamide] and a-adrenergic receptor agonists (e.g. brimonidine) [3, 8]. Clinical practice guidelines recommend initiating treatment with one medication [4, 7]; however, in many patients, a single medication does not effectively reduce IOP to within the target range and treatment with at least two medications from different classes is required [8]. Treatment with multiple concomitant IOP-lowering medications has a number of disadvantages, including reduced treatment persistence and adherence, an increased risk of medication washout and increased exposure to preservatives (e.g. benzalkonium chloride) [3, 8]. Decreased adherence to IOP-lowering medications may lower therapeutic efficacy, and has been linked with progressive visual field loss [3]. Several fixed-combinations of IOPlowering medications have been developed in recent years to overcome some of these limitations [3, 8]. Compared with concomitant administration of two separate agents, treatment with such fixed-combinations has been shown to improve persistence and adherence to treatment [9], and may allow for a reduced overall daily exposure to preservatives [8]. However, all of the previously available fixedcombinations contain timolol, which can limit their use in patients with comorbidities that contraindicate b-adrenergic receptor antagonist therapy [10]. Fixed-combination brinzolamide 1 %/brimonidine 0.2 % (SimbrinzaÒ) (hereafter referred to as brinzolamide/ brimonidine) is approved for the reduction of elevated IOP in patients with open-angle glaucoma or ocular hypertension in the USA [11] and EU (where treatment is restricted to patients for whom monotherapy provides insufficient IOP reduction) [12], and is the first fixed-combination ophthalmic suspension glaucoma therapy available without timolol. This article reviews the pharmacological, therapeutic efficacy and tolerability data relevant to the use of brinzolamide/brimonidine in patients with open-angle glaucoma or ocular hypertension.

2 Pharmacodynamic Properties The pharmacodynamic properties of brinzolamide [13–15] and brimonidine [16, 17] have been previously reviewed individually, and are briefly summarized in this section. Both of these agents decrease IOP at least in part through suppression of aqueous humour formation; however, each has a different mechanism of action [11, 12]. 2.1 Brinzolamide Brinzolamide is a highly specific, reversible and noncompetitive inhibitor of CA-II [15]. At least seven different CA isoenzymes have been identified in human tissues, with CA-II being found mainly in erythrocytes, the kidneys, pancreas, eyes, central nervous system (CNS) and the lungs [15]. Of the CA isoenzymes, brinzolamide has the highest affinity and inhibitory potency for CA-II, with a binding affinity constant (Ki) of 0.13 nmol/L and a 50 % maximum inhibitory concentration (IC50) of 3.19 nmol/L [13]. The Ki and IC50 of brinzolamide are, respectively, 246- and 428-fold higher for CA-II than for CA-I [13]. In the eye, CA-II is expressed in the ciliary process, corneal endothelium and pigment epithelium [15]. Inhibition of CA-II in the ciliary epithelium leads to reduction of bicarbonate ion formation and secretion into the posterior chamber, and a subsequent decrease in sodium and fluid transport across the ciliary epithelium. This results in a decrease in aqueous humour production and reduced IOP [15]. Peak ocular hypotensive effects occur 2–3 h after topical brinzolamide administration [11]. In 25 healthy volunteers, treatment with brinzolamide 1 % ophthalmic suspension reduced daytime (8 a.m. to 4 p.m.) and night-time (12 a.m. to 6 a.m.) rates of aqueous humour flow by 19 and 16 %, respectively, and the IOP at 4 p.m. by 10 % compared with placebo (p \ 0.001 for all parameters) [18]. Brinzolamide also enters the blood circulation after topical ocular administration (Sect. 3.1) and binds preferentially to CA-II in erythrocytes, with plasma concentrations of free brinzolamide remaining below quantification [15]. Its primary metabolite, N-desethylbrinzolamide, binds predominantly to CA-I in erythrocytes in the presence of brinzolamide [11]. Human erythrocytes contain &150 lmol/L of CA enzyme, with 20 lmol/L being CA-II and the remainder being CA-I [13]. Therefore, complete saturation of both CA isoenzymes in erythrocytes does not occur, and the concentration of free brinzolamide that reaches the kidneys is insufficient to inhibit CA [15]. Taken together with its low affinity for other CA isoenzymes [13], these properties may explain the low incidence of systemic adverse events after topical brinzolamide administration (Sect. 6) [15].

Brinzolamide/Brimonidine: A Review

2.2 Brimonidine Brimonidine is a highly selective a2-adrenergic receptor agonist that lowers IOP by a dual mechanism of action, involving reduction of aqueous humour production and stimulation of aqueous humour outflow through the uveoscleral pathway [16]. Studies have identified a2-adrenergic receptors in the human iris and ciliary epithelia, as well as in the retina, retinal pigment epithelium, ciliary muscle and choroid [19]. Stimulation of ocular a2-adrenergic receptors leads to inhibition of adenylate cyclase, resulting in suppression of cyclic adenosine monophosphate-dependent aqueous humour formation [19]. Decreases in IOP occur within 1 h of topical brimonidine administration, with the peak effect apparent 2–3 h after instillation and lasting for up to 14 h after dosing [17]. In 21 patients with ocular hypertension, topical twicedaily administration of brimonidine 0.2 % for 1 week resulted in a significant reduction compared with baseline in mean IOP of 4.7 mmHg and aqueous humour flow of 20 %, as well as a significant increase compared with baseline in uveoscleral outflow (p \ 0.05 for all parameters) [20]. A contralateral decrease in aqueous humour flow of 12 % compared with baseline was also observed (p = 0.05) [20]. In another study in ocular hypertensive patients, topical brimonidine 0.2 % twice daily administration resulted in sustained reductions in IOP over 29 days, with a significant (p \ 0.001) reduction in aqueous flow compared with baseline at 3 h after the first administration [21]. At day 29 of treatment, aqueous flow did not differ significantly compared with baseline; however, uveoscleral outflow increased by 60 % compared with baseline (p \ 0.05). Thus, brimonidine appears to cause significant IOP reductions that are maintained by a long-term increase in uveoscleral outflow [21]. Brimonidine enters the systemic circulation after topical administration; however, it undergoes rapid metabolism and excretion (Sect. 3.2), and has not been associated with clinically significant cardiovascular or pulmonary systemic effects [17]. Single-dose topical administration of brimonidine 0.2 % in healthy adults had limited cardiopulmonary effects, including a slight decrease in systolic blood pressure (BP) during exercise recovery and 4 h after administration [22]. In a 1-month dose-response study, patients with ocular hypertension or glaucoma experienced reductions in mean BP from baseline during treatment with brimonidine 0.2 or 0.5 %; however, there were no clinical symptoms and no significant changes in heart rate [23]. In addition to its IOP-lowering effects, preclinical studies suggest that brimonidine has potential neuroprotective properties, with the ability to preserve the integrity of the retinal ganglion cells in the optic nerve; however, the

neuroprotective effects of brimonidine have yet to be demonstrated in clinical trials [24, 25].

3 Pharmacokinetic Properties In healthy volunteers, the steady-state plasma pharmacokinetics of brinzolamide and brimonidine topically administered two or three times daily as the fixedcombination were generally similar to those of the individual agents administered alone [11]. Thus, discussion here focuses on the pharmacokinetic properties of the individual agents. Studies to determine the effects of race, age and renal or hepatic impairment on the pharmacokinetics of brinzolamide/brimonidine have not been conducted [12]. 3.1 Brinzolamide Following topical ocular administration, brinzolamide is absorbed through the cornea, as well as into the systemic circulation [12]. In rabbits, maximum ocular concentrations were found in the anterior tissues, including the cornea, aqueous humour, iris-ciliary body and conjunctiva, with prolonged ocular tissue retention being the result of CA binding [12]. Brinzolamide undergoes extensive systemic distribution into erythrocytes because of its highaffinity for CA-II (Sect. 2.1), and is moderately (&60 %) bound to plasma proteins [11, 12]. The preferential binding of brinzolamide to CA-II in erythrocytes and other tissues results in saturation of the CA-II isoenzyme with repeated administration [13]. Consequently, brinzolamide exhibits nonlinear pharmacokinetics without dose proportionality [13]. Brinzolamide undergoes metabolism via hepatic cytochrome P450 (CYP) isoenzymes, including CYP3A4, CYP2A6, CYP2B6, CYP2C8 and CYP2C9 [12]. Plasma concentrations of brinzolamide and N-desethylbrinzolamide (its primary metabolite) remain below the limit of quantitation because of their preferential distribution to erythrocytes [13]. Brinzolamide is predominantly eliminated as unchanged drug in the urine, with urinary brinzolamide and N-desethylbrinzolamide accounting for &60 and 6 % of an administered dose [12]; lower concentrations of minor metabolites also present in the urine [11]. Brinzolamide has a prolonged elimination half-life (t‘) in whole blood of &111 days [13]. 3.2 Brimonidine Brimonidine is primarily absorbed through the cornea after topical administration [17], and has high affinity for melanin-containing ocular tissues, particularly in the

S. L. Greig, E. D. Deeks

iris-ciliary body [12]. Brimonidine has a linear pharmacokinetic profile at clinically therapeutic dosages, reaching peak plasma concentrations of \1 ng/mL within \1 to 4 h of administration [11, 12]. Brimonidine undergoes extensive systemic metabolism, predominantly by hepatic aldehyde oxidase, with the major metabolites being 2-oxobrimonidine, 3-oxobrimonidine and 2,3-dioxobrimonidine [12]. Oxidative cleavage has also been observed [12]. Excretion of brimonidine is predominantly via the urinary route as metabolites [11, 12]. Following oral administration of radiolabelled brimonidine, &87 % was eliminated within 120 h and 74 % was recovered in the urine [11]. Brimonidine has a systemic t‘ of &2–3 h [11, 12]. 3.3 Special Patient Populations While studies on the effects of renal or hepatic impairment on the pharmacokinetics of brimonidine have not been performed, systemic exposure to brimonidine after topical administration is low, and any changes in plasma exposure are not expected to be clinically relevant [12]. Moreover, although brinzolamide-treated subjects with moderate renal impairment have been found to experience a 1.6- to 2.8-fold increase in systemic exposure to brinzolamide and N-desethylbrinzolamide compared with subjects with normal renal function, the increased steady-state erythrocyte concentrations of these compounds did not cause CA inhibition to levels that are associated with systemic side effects [12]. However, brinzolamide/brimonidine treatment is either contraindicated [12] or not recommended [11] in patients with severe renal impairment (creatinine clearance \30 mL/min). In patients with hepatic impairment, caution is recommended during brinzolamide/brimonidine treatment [11, 12]. The systemic exposure and t‘ of brimonidine in elderly subjects (aged [65 years) are similar to those in young adults [12]; no dosage adjustments are recommended [11, 12].

4 Potential Drug Interactions Specific drug interaction studies with brinzolamide/ brimonidine have not been performed; however, there are a number of potential drug interactions with the individual agents that need to be considered [11, 12]. Acid-base disturbances can occur during treatment with oral CAIs [12]. Brinzolamide is absorbed systemically after topical administration (Sect. 3.1) and the potential for an additive effect with oral CAIs should be considered [11, 12]. Concomitant administration of oral CAIs and brinzolamide/brimonidine is not recommended [11, 12].

CYP3A4 inhibitors, including ketoconazole, itraconazole, clotrimazole, ritonavir and troleandomycin, are expected to inhibit brinzolamide metabolism; the EU labelling information advised caution with concomitant administration of CYP3A4 inhibitors and brinzolamide/ brimonidine [12]. CYP isoenzymes are not inhibited by brinzolamide or N-desethylbrinzolamide at concentrations C100-fold higher than maximum systemic concentrations [12]. Monoamine oxidase inhibitors can potentially interact with the metabolism of brimonidine, which may result in increased systemic adverse effects, such as hypotension [11]. Tricyclic antidepressants can also interfere with the metabolism and uptake of circulating amines, and have been reported to reduce the hypotensive effect of systemic clonidine [11]. However, it is not known whether the concurrent use of tricyclic antidepressants with brinzolamide/ brimonidine will interfere with the IOP-lowering effect of the latter [11]. In the EU, brinzolamide/brimonidine is contraindicated in patients receiving monoamine oxidase inhibitors or antidepressants that affect noradrenergic transmission [12]; the US labelling information recommends exercising caution in patients receiving these agents [11]. Because of the potential for brimonidine to reduce BP following topical administration (Sect. 2.2), caution is advised during concomitant administration of brinzolamide/ brimonidine with antihypertensives and/or cardiac glycosides [11, 12]. The possibility of additive or potentiating effects from CNS depressants (e.g. opioid analgesics, barbiturates, sedatives, anaesthetics and alcohol) should also be considered, and caution is advised during concomitant administration with brinzolamide/brimonidine [11, 12].

5 Therapeutic Efficacy The efficacy of brinzolamide/brimonidine ophthalmic suspension for the reduction of elevated IOP in adult patients (aged C18 years) with open-angle glaucoma or ocular hypertension was established in four large, randomized, double-masked, phase III trials [26–29]. Two were 3-month, identically designed trials with three-times-daily administration conducted in the USA (C-10-033 [26] and C-10-039 [27]; the C-10-039 trial also including a 3-month safety extension [30]), and two were 6-month trials with twice-daily administration conducted in patients from the EU, USA and other countries (C-10-040 [28] and C-10-041 [29]). Patients in all trials had a clinical diagnosis of openangle glaucoma or ocular hypertension in at least one (study) eye, and underwent a washout period where all IOP-lowering medications were stopped for at least 5–28 days depending on the medication [26–29]. Patient

Brinzolamide/Brimonidine: A Review

IOP values were then measured at four (8 a.m., 10 a.m., 3 p.m. and 5 p.m.) [26, 27], three (9 a.m., 11 a.m. and 4 p.m.) [28] or two (9 a.m. and 11 a.m.) [29] timepoints during two eligibility visits. At both visits, a study eye mean IOP of 24–36 mmHg at the first timepoint and 21–36 mmHg at the second timepoint were required [26– 29], as well as an IOP B36 mmHg in both eyes at all timepoints [26, 27] or a mean IOP\36 mmHg in either eye at any timepoint [28]. In the C-10-041 trial, the mean IOP in either eye could not exceed 36 mmHg at any time during the study [29]. In each trial, approximately half of the patients had were aged C65 years, 55–61 % were female, 67–80 % had open-angle glaucoma (including pigment dispersion or pseudoexfoliation [28, 29]) and 20–33 % had ocular hypertension [26–29]. Exclusion criteria were similar across all trials and included a history of intraocular surgery or ocular trauma within the past 6 months, or a history of ocular inflammation, infection or laser surgery within the past 3 months [26–29]. For efficacy analyses, trials used either the intent-to-treat [26–28] or the per-protocol population [29]. 5.1 Three-Times-Daily Administration The C-10-033 and C-10-039 trials compared the IOPlowering efficacy of brinzolamide/brimonidine with that of brinzolamide or brimonidine alone, when administered topically three times daily for 3 months (see Table 1 for details) [26, 27]; the C-10-039 trial also included a 3-month safety extension study [30]. The primary efficacy parameter was the mean IOP at four timepoints (8 a.m., 10 a.m., 3 a.m. and 5 p.m.) at 3 months (Table 1) [26, 27].

Mean IOP values at baseline for each timepoint were similar across all treatment groups, ranging from &27 mmHg at 8 a.m. to &24 mmHg at 5 p.m. across both trials [26, 27]. Three-times-daily brinzolamide/brimonidine was more effective than both brinzolamide and brimonidine alone in lowering mean IOP levels in patients with open-angle glaucoma or ocular hypertension [26, 27]. At 3 months, the least squares (LS) mean IOP of patients receiving brinzolamide/brimonidine was significantly lower than that of either brinzolamide or brimonidine recipients at all four timepoints assessed (Table 1). In the C-10-033 trial, the percentage reduction in IOP from baseline ranged across timepoints from 24.1 to 34.9 % in brinzolamide/brimonidine recipients, 16.9 to 22.6 % in brinzolamide recipients and 14.3 to 25.8 % in brimonidine recipients [26]. In the C-10-039 trial, there was a 3.7–13.4 % higher percentage reduction in IOP from baseline in the brinzolamide/ brimonidine group compared with the monotherapy treatment groups [27]. At 2 and 6 weeks, LS mean IOP values were significantly (p B 0.01) lower in brinzolamide/brimonidine recipients than in either brinzolamide or brimonidine recipients at all four timepoints of each trial [26, 27]. The findings of the C-10-033 and C-10-039 trials are supported by a pooled analysis of the two studies (n = 1,328) [31]. After 3 months of treatment, LS mean IOP values at all timepoints were significantly lower in patients receiving brinzolamide/brimonidine than in patients receiving either brinzolamide or brimonidine (Table 1) [31]. According to the C-10-039 trial extension, the IOPlowering efficacy of fixed-combination brinzolamide/ brimonidine at 6 months was similar to its efficacy at

Table 1 Efficacy of three-times-daily topical fixed-combination of brinzolamide/brimonidine in patients with open-angle glaucoma or ocular hypertension. Results from 3-month, phase III trials and a pooled analysis Study

C-10-033 [26]

C-10-039 [27]

Pooled analysis [31]

Treatment (tid)a

No. of ITT pts

Least squares mean IOP at 3 monthsb (mmHg) 8 a.m.

10 a.m.

3 p.m.

5 p.m.

BRZ/BRM

209

20.5*, 

17.2**, 

18.7**, 

17.0**, 

BRZ

224

21.6

20.4

20.4

20.0

BRM

216

23.3

19.7

21.3

18.8

BRZ/BRM

218

21.1*,  

18.0***,  

19.5**,  

17.2***,  

BRZ

229

22.0

20.8

20.7

20.4

BRM

232

23.2

19.9

21.5

18.9

BRZ/BRM

427

20.8***,  

17.6***,  

19.1***,  

17.1***,  

BRZ

453

21.8

20.6

20.6

20.2

BRM

448

23.2

19.7

21.4

18.8

BRM brimonidine 1 %, BRZ brinzolamide 0.2 %, IOP intraocular pressure, ITT intent-to-treat, pts patients, tid three times daily * p B 0.01, ** p B 0.001, *** p \ 0.0001 vs. BRZ,

 

p B 0.001,

a

Administered in both eyes at 8 a.m., 3 p.m. and 10 p.m

b

Primary efficacy endpoint

  

p \ 0.0001 vs. BRM

S. L. Greig, E. D. Deeks

3 months, with mean IOP values remaining similar at each corresponding timepoint [30]. The percentage reduction in IOP from baseline at 6 months ranged from 20 to 30.7 % for brinzolamide/brimonidine, 16.4 to 22.0 % for brinzolamide and 12.4 to 24.8 % for brimonidine across all four timepoints [30]. 5.2 Twice-Daily Administration Two 6-month trials were designed to compare the IOPlowering effectiveness of twice-daily brinzolamide/ brimonidine with that of either monotherapy with brinzolamide or brimonidine (C-10-040) [28] or concomitant administration of brinzolamide plus brimonidine (C-10-041) [29]. Patients with open-angle glaucoma (including those with pigment dispersion or pseudoexfoliation) or ocular hypertension in at least one eye, and a history of insufficient IOP control on monotherapy or currently receiving multiple IOP-lowering medications were included in both trials (see Table 2 for details) [28, 29]. The primary endpoint for both trials was the LS mean diurnal IOP change from baseline at month 3 (Table 2) [28, 29]. 5.2.1 Compared with Monotherapy Twice-daily brinzolamide/brimonidine was more effective than both brinzolamide and brimonidine alone with regard to lowering IOP in patients with open-angle glaucoma or ocular hypertension in the C-10-040 trial [28]. After 3 months of treatment, there was a significantly greater

reduction in LS mean diurnal IOP from baseline with brinzolamide/brimonidine than with either brinzolamide or brimonidine alone (Table 2), with respective betweengroup differences of -1.4 and -1.5 mmHg (p \ 0.0001 for both treatment groups) [28]. A significantly greater reduction in this parameter was observed in the fixedcombination group than in the monotherapy groups after 2 weeks of therapy and maintained throughout the study (Table 2). At 6 months, brinzolamide/brimonidine recipients had mean percentage reductions in IOP from baseline of 27.7–35.0 % across all three timepoints, compared with reductions of 25.6–27.9 % for brinzolamide and 23.6–30.0 % for brimonidine recipients. At most study visits and timepoints, there were a numerically greater percentage of patients with an IOP \18 mmHg in the brinzolamide/brimonidine group compared with the brinzolamide and brimonidine groups [28]. 5.2.2 Compared with Concomitant Administration The IOP-lowering efficacy of twice-daily fixed-combination brinzolamide/brimonidine was noninferior to that of concomitant therapy with brinzolamide plus brimonidine in patients with open-angle glaucoma or ocular hypertension in the C-10-041 trial [29]. The reduction in LS mean diurnal IOP from baseline at 3 months in patients receiving the fixed-combination was of a similar magnitude to that in patients receiving concomitant therapy, and the predefined noninferiority criteria were met (Table 2). Decreases in LS mean diurnal IOP from baseline of [8 mmHg were

Table 2 Efficacy of twice-daily topical fixed-combination of brinzolamide/brimonidine in patients with open-angle glaucoma or ocular hypertension for whom monotherapy provides insufficient intraocular pressure reduction. Results from 6-month, phase III trials Study

No. of PP pts

BL mean diurnal IOPb (mmHg)

Least squares mean diurnal IOPb change from BL (mmHg) Week 2

Week 6c

Month 3d

Month 6

BRZ/BRM

193

25.9

-7.6*, 

-7.8*, 

-7.9*, 

-7.8*, 

BRZ BRM

191 175

25.9 26.0

-6.1 -6.0

-6.2 -6.2

-6.5 -6.4

-6.7 -6.4

Treatment (bid)a

Compared with monotherapy C-10-040 [12, 28]

Compared with concomitant administration C-10-041 [12, 29]

BRZ/BRM

420

26.4

-8.4

-8.5

-8.5

-8.1

BRZ ? BRM

411

26.5

-8.4

-8.4

-8.3

-8.2

0.0 (-0.4 to 0.3)

-0.1 (-0.4 to 0.2)

-0.1 (-0.5 to 0.2)e

0.1 (-0.3 to 0.4)

Between-group difference (95 % CI)

bid Twice daily, BL baseline, BRM brimonidine 1 %, BRZ brinzolamide 0.2 %, IOP intraocular pressure, PP per-protocol, pts patients * p B 0.0001 vs. BRZ, a

 

p B 0.0001 vs. BRM

Administered in both eyes at 9 a.m. and 9 p.m

b

Average IOP from 9 a.m., 11 a.m. and 4 p.m. [28] or 9 a.m. and 11 a.m. [29] timepoints

c

These data are derived from the EU summary of product characteristics [12]

d

Primary efficacy endpoint Noninferiority of BRZ/BRM vs. BRZ ? BRM was established at month 3, as the upper limit of the 95 % CI for the between-group difference was \1.5 mmHg e

Brinzolamide/Brimonidine: A Review

observed in both treatment groups after 2 weeks of treatment and throughout the duration of the study (Table 2). The noninferiority of brinzolamide/brimonidine was also maintained over 6 months, with the upper limit of the 95 % CI for the between-group difference for each study visit being \1.5 mmHg. The percentage reduction in IOP from baseline was of a similar magnitude in both treatment groups throughout the study, at 9 a.m. ranging from 27.0 to 28.6 % for brinzolamide/brimonidine and 28.2 to 29.1 % for brinzolamide plus brimonidine, and at 11 a.m. ranging from 35.9 to 37.6 % for the fixed-combination and 36.1 to 37.4 % for concomitant therapy. The proportion of patients in either treatment group who achieved an IOP\18 mmHg at 11 a.m. across all study visits was 68.9–71.6 % with brinzolamide/brimonidine versus 65.8–71.6 % with brinzolamide plus brimonidine [29].

6 Tolerability Brinzolamide/brimonidine, administered topically two or three times daily for 3–6 months, was generally well tolerated in patients with open-angle glaucoma or ocular hypertension in all phase III trials discussed in Sect. 5, with an adverse event profile that was consistent with its individual components and similar irrespective of administration frequency [26–31]. In all phase III trials, including the 3-month safety extension of the C-10-039 trial, there were no clinically significant or unexpected treatment-group differences in ocular outcomes or cardiovascular parameters [26–31]. At least one treatment-related adverse event occurred in 24.6 % of brinzolamide/brimonidine recipients, 18.7 % of brinzolamide recipients and 17.4 % of brimonidine recipients in the pooled analysis of the 3-month C-10-033 and C-10-039 trials with three-times-daily administration [31]. The respective incidence rates were 33.0, 18.8 and 24.7 % over 6 months in the C-10-039 extension (also with three-times daily administration) [30], and 28.5, 11.5 and 22.9 % in the 6-month C-10-040 trial with twice-daily administration [28]. Treatment-related adverse events led to study withdrawal in \10 % of brinzolamide/brimonidine, brinzolamide and brimonidine recipients in the pooled analysis (9.9, 2.2 and 7.5 %, respectively) [31] or the C-10-040 trial (9.3, 0.5 and 7.4 %, respectively) [28], and \18 % in the C-10-039 extension (17.2, 2.1 and 14.5 %, respectively) [30]. In the pooled analysis, only one serious adverse event (moderate intensity chest pain) was judged to be treatment-related; this occurred with brinzolamide and resolved after discontinuing treatment [31]. All other serious adverse events were considered to be unrelated to treatment [28, 30, 31], including those in the 3-month extension of the C-10-039 trial (n = 21; seven in

each group) [30] and the C-10-040 trial (n = 10; five with brinzolamide/brimonidine, two with brinzolamide and one with brimonidine) [28]. In the C-10-033 and C-10-039 trials, most of the treatment-related adverse events were ocular-related [26, 27]. In the pooled analysis, the most common treatment-related adverse events with brinzolamide/brimonidine were blurred vision (5.3 vs. 6.5 and 0.2 % with brinzolamide and brimonidine alone), eye irritation (4.1 vs. 1.3 and 2.2 %), dysgeusia (3.9 vs. 8.3 and 0.2 %) and dry mouth (3.0 vs. 0 and 1.3 %) [31]. In the brinzolamide/brimonidine group, ocular hyperaemia and dry eye (i.e. ocular events that may be associated with preservatives) occurred in 2.1 % (vs. 0.7 and 3.3 % with brinzolamide and brimonidine alone) and 1.4 % (vs. 0.9 and 1.5 %) of patients, respectively [31]. Similarly, ocular adverse events accounted for the majority of all treatment-related adverse events in the C-10-040 trial, and included those which are known to be associated with brinzolamide or brimonidine treatment [28]. In this trial, ocular adverse events with the highest incidence with brinzolamide/brimonidine were hyperaemia (5.7 vs. 0.5 and 4.6 % with brinzolamide and brimonidine alone), eye pain (5.7 vs. 1.6 and 0 %), blurred vision (4.7 vs. 0.5 and 1.1 %), conjunctivitis (3.6 vs. 0 and 0.6 %) and eye pruritus (3.6 vs. 1.6 and 2.3 %) [28]. Treatment-related systemic adverse events that occurred with brinzolamide/ brimonidine included dysgeusia (5.7 vs. 2.1 and 1.1 % with brinzolamide and brimonidine alone), dry mouth (3.6 vs. 1.0 and 5.1 %) and somnolence (3.6 vs. 0 and 2.3 %) [28]. The nature of brinzolamide/brimonidine-related adverse events remained generally similar in the C-10-039 trial and its extension; Fig. 1a shows treatment-related adverse events that occurred with C3 % incidence in any treatment group over 6 months in this study [30]. The tolerability profile of the fixed-combination of brinzolamide/brimonidine was generally similar to concomitant treatment with brinzolamide plus brimonidine when administered twice daily in patients with open-angle glaucoma or ocular hypertension over 6 months [29]. In the C-10-041 trial, treatment-emergent adverse events led to discontinuation in 10.6 % of patients receiving brinzolamide/brimonidine and 13.3 % of patients receiving brinzolamide plus brimonidine, with serious treatmentemergent adverse events occurring in 2.4 and 1.8 % of patients; most of the serious adverse events resolved during the study without treatment interruption. There was no evidence to indicate any safety concerns with brinzolamide/brimonidine, with only one serious adverse event (corneal erosion) being considered related to treatment. All other serious adverse events, including one death from a myocardial infarction in the brinzolamide/ brimonidine group, were considered unrelated to treatment [29].

S. L. Greig, E. D. Deeks

systolic and diastolic BP from baseline in brinzolamide/ brimonidine (3.3–4.2 mmHg) and brimonidine (2.9–5.0 mmHg) recipients at 6 months [30]. However, in each of these trials, BP remained relatively stable in individual patients, irrespective of the study medication received [26, 27, 30]. Drug labelling for brinzolamide/brimonidine recommends exercising caution during treatment in patients with severe cardiovascular disease in both the USA [11] and EU [12]; the EU label also advises caution in patients with unstable or uncontrolled cardiovascular disease [12].

a Eye irritation

Eye allergy Conjunctivitis θ Ocular adverse events

Blurred vision

θ

Allergic conjunctivitis

Eye pruritus

7 Dosage and Administration Ocular hyperaemia

Systemic adverse events

Dysgeusia BRZ/BRM (n = 221) BRZ (n = 234) BRM (n = 235)

Dry mouth θ 0

2

4

6

8

10

12

b Hyperaemia Ocular adverse events

Allergic conjunctivitis Blurred vision Dry mouth

Systemic adverse events

Dysgeusia BRZ/BRM (n = 452) BRZ+BRM (n = 436)

Somnolence 0

2

4

6

8

10

12

Incidence (% patients)

Fig. 1 Most common treatment-related adverse events after administration of brinzolamide/brimonidine and its individual components (alone or concomitantly) for 6 months a three-times-daily [30] and b twice-daily [29]. BRM brimonidine 0.2 %, BRZ brinzolamide 1 %, h = zero

At least one treatment-related adverse events occurred in 23.5 % of brinzolamide/brimonidine and 26.8 % of brinzolamide plus brimonidine recipients, with the majority of treatment-related events being ocular in nature and known to be associated with the individual medications. Treatment-related adverse events that occurred with C3 % incidence in any treatment group over 6 months in the C-10-041 trial are shown in Fig. 1b [29]. In the C-10-033 and C-10-039 trials, brinzolamide/ brimonidine and brimonidine recipients experienced a slight decrease in mean systolic and diastolic BP from baseline at 10 a.m. on the 3-month visit [26, 27]. The C-10039 extension also demonstrated small decreases in mean

In the USA [11], the recommended dosage of brinzolamide/brimonidine in patients with open-angle glaucoma or ocular hypertension is one drop in the affected eye(s) three times daily. In the EU [12], the recommended brinzolamide/brimonidine dosage is one drop in the affected eye(s) twice daily in adult patients with open-angle glaucoma or ocular hypertension and insufficient IOP reduction with monotherapy. The EU labelling information states that this dosage should not be exceeded, and that the treatment should be continued with the next scheduled dose when a dose of brinzolamide/brimonidine is missed [12]. Brinzolamide/brimonidine may be used concomitantly with other topical ophthalmic medications to lower IOP; however, the medications must be administered C5 min apart when one or more topical ophthalmic medications are being used [11, 12]. Brinzolamide/brimonidine contains the preservative benzalkonium chloride 0.03 mg/mL, which may be absorbed by soft contact lenses and cause eye irritation. Contact lenses must be removed prior to topical administration of brinzolamide/brimonidine and not reinserted until C15 min after instillation [11, 12]. Local prescribing information should be consulted for detailed information, including contraindications, warnings and precautions, potential drug interactions and administration in special patient populations.

8 Current Status of Brinzolamide/Brimonidine in Open-Angle Glaucoma or Ocular Hypertension Brinzolamide/brimonidine is approved for the reduction of elevated IOP in patients with open-angle glaucoma or ocular hypertension in the USA [11], and in adult patients with open-angle glaucoma or ocular hypertension for whom monotherapy provides insufficient IOP reduction in the EU [12]. In two 3-month phase III clinical trials, brinzolamide/brimonidine administered three times daily was significantly more effective than both brinzolamide and brimonidine monotherapy at lowering IOP levels in

Brinzolamide/Brimonidine: A Review

patients with open-angle glaucoma or ocular hypertension (Sect. 5.1). In 6-month phase III trials, twice-daily brinzolamide/brimonidine was also more effective than monotherapy with either of the individual agents, and had noninferior efficacy to concomitant administration of brinzolamide plus brimonidine (Sect. 5.2). Brinzolamide/brimonidine was generally well tolerated in these clinical trials, with a treatment-related adverse event profile that was consistent with that of its individual components and no unexpected safety findings (Sect. 6). The most common treatment-related adverse events with brinzolamide/brimonidine were ocular in nature, with dysgeusia and dry mouth being the most frequent systemic events. The development of fixed-combinations of IOP-lowering medications has resulted in improved treatment persistence and adherence in patients with open-angle glaucoma or ocular hypertension [9]. Treatment with fixed-combinations rather than multiple concomitant medications also has the potential to reduce the cumulative exposure to preservatives, particularly benzalkonium chloride, which have been associated with ocular symptoms, including hyperaemia, dry eye, stinging or burning and foreign body sensation [3]. Adverse events that may be related to preservatives occurred with a similar frequency with brinzolamide/ brimonidine as compared with brinzolamide or brimonidine monotherapy (Sect. 6). However, data from the C-10-041 trial indicate that the tolerability profile of brinzolamide/ brimonidine over 6 months is generally similar to that of concomitant treatment with brinzolamide plus brimonidine [29]; longer-term robust data would be beneficial. The limitations of these clinical trials included their short durations, which prevented analysis of the long-term efficacy and tolerability of brinzolamide/brimonidine in patients with open-angle glaucoma or ocular hypertension [26, 27, 30]. Moreover, these trials did not compare brinzolamide/brimonidine with other fixed-combination therapies (e.g. dorzolamide/timolol or brimonidine/timolol) or evaluate it as an adjunct to other glaucoma medications from different classes [26, 27]. Further clinical studies to address these issues would be of interest. While all of the currently available fixed-combinations for open-angle glaucoma or ocular hypertension have similar IOP-lowering efficacy, brinzolamide/brimonidine is the only available fixed-combination that does not contain the b-adrenergic receptor antagonist timolol [3]. In a retrospective study of elderly glaucoma patients (median age 80 years), a high percentage of patients with comorbidities (e.g. reactive airways diseases, diabetes and ischaemic heart disease) had been prescribed ocular b-adrenergic receptor antagonists, despite recommendations that these agents should be used with caution in these patients [10]. Ocular b-adrenergic receptor antagonist therapy was

consequently associated with an increased risk of exacerbation of reactive airways disease or hospitalization [10]. Brinzolamide/brimonidine may therefore be a useful option in such patients. In conclusion, fixed-combination brinzolamide/ brimonidine, administered two or three times daily, is an effective treatment option for the reduction of elevated IOP in patients with open-angle glaucoma or ocular hypertension. It provides a convenient alternative for patients who require treatment with multiple IOP-lowering medications and may be particularly suited to patients in whom b-adrenergic receptor antagonists are contraindicated. Data selection sources: Relevant medical literature (including published and unpublished data) on brinzolamide/brimonidine was identified by searching databases including MEDLINE (from 1946) and EMBASE (from 1996) (searches last updated 13 February 2015), bibliographies from published literature, clinical trial registries/databases and websites. Additional information was also requested from the company developing the drug. Search terms: Brimonidine, brinzolamide, Simbrinza, glaucoma, ocular, pressure, hypertension. Study selection: Studies in patients with open-angle glaucoma or ocular hypertension who received brinzolamide/brimonidine. When available, large, well-designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Disclosure The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the authors on the basis of scientific and editorial merit. Sarah Greig and Emma Deeks are salaried employees of Adis/Springer.

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