Combination of brinzolamide and brimonidine for glaucoma and ocular hypertension: critical appraisal and patient focus

Figures & data

Table 1 Treatment adherence rates among patients with glaucoma

Study	Patient population	Study setting	Study design	N	Assessment technique	Study dates	Duration	Rate (%)
Loon et al^Citation32	Adult patients with chronic glaucoma who were receiving topical glaucoma therapy for >3 months	National university hospital in Singapore	Prospective, cross-sectional	314	RAM adherence questionnaire	NR	NR	19.7a
Rees et al^Citation33	Adult patients with glaucoma or ocular hypertension who had received ≥1 topical medication for ≥6 months	Tertiary referral ophthalmology hospitals in the US, Australia, and Singapore	Cross-sectional	475	Modified RAM adherence questionnaire	NR	NR	47.5–65.4b
Ung et al^Citation28	Adult patients with primary open-angle glaucoma, primary angle-closure glaucoma, exfoliative glaucoma, low-tension glaucoma, or who were suspected as having glaucoma >1 year who had filled a prescription for topical ocular hypertension medications	San Francisco General Hospital glaucoma clinic in the US	Retrospective, cross-sectional	126	Patient questionnaire	2011	1 year	50c
Vandenbroeck et al^Citation29	Adult patients with glaucoma or ocular hypertension who were receiving topical glaucoma medication	Hospital and private practice ophthalmology centers in Belgium	Multicenter, cross-sectional	663	Self-report questionnaire	NR	2 weeks	58.5d
Hong et al^Citation30	Adult patients with glaucoma	Medical university clinic in South Korea	Cross-sectional	125	Patient questionnaire	NR	NR	46.15–70.59e
Rees et al^Citation26	Adult patients with glaucoma or ocular hypertension who had received ≥1 topical medication for ≥6 months	Public tertiary ophthalmic hospital	Cross-sectional	131	Modified RAM adherence questionnaire	NR	2 months	55a
Djafari et al^Citation23	Adult patients with primary open-angle glaucoma, ocular hypertension, or who were suspected as having glaucoma for ≥2 years and were covered by the Régie d’Assurance Maladie du Québec pharmaceutical insurance program	Medicare database in Quebec, Canada	Descriptive database	181	Pharmaceutical claims database search	2004	1 year	71.8f
Olthoff et al^Citation31	Adult patients who were receiving treatment for primary open-angle glaucoma	the Netherlands	Cross-sectional	166	Patient questionnaire	NR	4 weeks	73.5d
Nordstrom et al^Citation18	Adult patients with confirmed or suspected open-angle glaucoma who received ≥1 topical ocular hypotensive medication and were continuously enrolled in the United Healthcare database for ≥365 days	Ingenix Research Database in the US	Retrospective cohort	5,300	Prescriptionrefill	1995–2001	36 months	15–58g
Sleath et al^Citation27	Adult patients with glaucoma who were receiving ≥2 IOP-lowering medications	Private ophthalmology clinics in the US	Cross-sectional survey	324	Patient questionnaire	2004	1 week	86h

Notes:

a Patients who reported a full adherence score on the RAM questionnaire

b patients who disagreed or strongly disagreed in response to the questions “I sometimes forget to take my eye drops” and “I sometimes alter the dose or miss a dose of my eye drops to suit my own needs”, and who reported “never” in answer to the questions “Some people I have talked to say that they miss out on a dose of their eye drops or adjust the doses to suit their own needs. How often do you do that?” and “Sometimes people forget to take their eye drops. How often does this happen to you?”

c patients who reported >80% adherence in response to the question “We understand that many individuals who have been prescribed glaucoma medication find it very difficult to take them regularly and often miss doses. On a scale from 0 to 100, with 0% being you never take your medications to 100% being you always take your medications and never miss a dose, how often did you take your medications?”

d patients who reported no missed doses

e patients who reported missing fewer than 1–2 doses per month

f patients who received ≥75% of their medication doses based on comparison of the number of days the patient had pharmaceutical coverage for medication versus the number of days the patient’s medical chart indicated medication was to be taken

g patients who had a current refill of their initially prescribed medication

h patients who reported taking 100% of their medication.

Abbreviations: IOP, intraocular pressure; NR, not reported; RAM, reported adherence to medication.

Figure 1 Kaplan–Meier analysis of treatment persistence among fixed and unfixed glaucoma medications.

Notes: Treatment persistence was evaluated from a medication database as medication possession ratio during a 1-year period after the index prescription date. Reproduced from Schwartz GF, Burk C, Bennett T, Patel VD. Adherence and persistence with glaucoma therapy: brimonidine/timolol versus dorzolamide/timolol and various two-bottle combinations. J Clin Exp Ophthalmol. 2012;3(8):1–6.²¹ Copyright © 2012 Schwartz GF, et al.
Abbreviations: CAI, carbonic anhydrase inhibitor; PGA, prostaglandin analog.

Figure 2 LS mean IOP during a 3-month clinical trial with a 3-month safety extension.

Notes: Error bars represent SEs; *BBFC versus brinzolamide or brimonidine, P<0.001. Adapted from Nguyen QH, McMenemy MG, Realini T, Whitson JT, Goode SM. Phase 3 randomized 3-month trial with an ongoing 3-month safety extension of fixed-combination brinzolamide 1%/brimonidine 0.2%. J Ocul Pharmacol Ther. 2013;29(3):290–297.⁵⁴ The publisher for this copyrighted material is Mary Ann Liebert, Inc., publishers. Copyright © 2013.
Abbreviations: BBFC, brinzolamide 1%/brimonidine 0.2% fixed combination; IOP, intraocular pressure; LS, least squares; SE, standard error.

Table 2 Intraocular pressure across visits and time pointsa

Drug	Baseline				Week 2
	8 am	10 am	3 pm	5 pm	8 am	10 am	3 pm	5 pm
BBFC
Number	209	209	209	209	209	205	205	204
Mean (SD), mmHg	26.9 (2.6)	25.3 (2.8)	23.7 (3.0)	23.2 (3.1)	19.7 (3.4)	16.4 (3.0)	17.8 (3.0)	15.9 (2.9)
LS, mean (SE), mmHg	NA	NA	NA	NA	20.4 (0.3)	17.1 (0.3)	18.4 (0.3)	16.6 (0.3)
Brinzolamide
Number	224	224	224	224	223	221	220	220
Mean (SD), mmHg	27.1 (2.6)	25.4 (2.7)	23.8 (3.2)	23.6 (3.4)	21.3 (3.7)	19.9 (3.4)	19.7 (3.6)	19.1 (3.3)
LS, mean (SE), mmHg	NA	NA	NA	NA	22.0 (0.3)	20.5 (0.3)	20.4 (0.3)	19.7 (0.3)
Brimonidine
Number	216	216	216	216	216	212	212	212
Mean (SD), mmHg	27.0 (2.6)	25.4 (2.8)	24.0 (3.3)	23.7 (3.3)	21.6 (4.1)	18.6 (3.6)	19.8 (3.9)	17.6 (3.2)
LS, mean (SE), mmHg	NA	NA	NA	NA	22.4 (0.3)	19.4 (0.3)	20.6 (0.3)	18.4 (0.3)
P-valueb
BBFC vs brinzolamide	NA	NA	NA	NA	<0.001	<0.001	<0.001	<0.001
BBFC vs brimonidine	NA	NA	NA	NA	<0.001	<0.001	<0.001	<0.001
	6 wk				3 mo
	8 am	10 am	3 pm	5 pm	8 am	10 am	3 pm	5 pm
BBFC
Number	198	197	196	196	189	189	189	189
Mean (SD), mmHg	19.7 (3.9)	16.8 (3.4)	18.3 (3.6)	16.4 (3.4)	19.8 (4.2)	16.5 (3.6)	18.0 (3.7)	16.3 (3.7)
LS, mean (SE), mmHg	20.4 (0.3)	17.5 (0.3)	18.9 (0.3)	17.0 (0.3)	20.5 (0.3)	17.2 (0.3)	18.7 (0.3)	17.0 (0.3)
Brinzolamide
Number	215	214	214	214	213	213	212	212
Mean (SD), mmHg	21.2 (4.3)	19.5 (3.7)	19.5 (3.3)	19.0 (3.5)	20.9 (4.2)	19.7 (4.0)	19.7 (3.7)	19.3 (3.7)
LS, mean (SE), mmHg	21.9 (0.3)	20.2 (0.3)	20.2 (0.3)	19.7 (0.3)	21.6 (0.3)	20.4 (0.3)	20.4 (0.3)	20.0 (0.3)
Brimonidine
Number	203	201	200	199	192	192	192	190
Mean (SD), mmHg	21.8 (4.3)	18.6 (3.4)	20.2 (3.9)	17.7 (3.2)	22.5 (4.4)	18.9 (3.7)	20.5 (3.8)	17.9 (3.3)
LS, mean (SE), mmHg	22.6 (0.3)	19.5 (0.3)	21.1 (0.3)	18.6 (0.3)	23.3 (0.3)	19.7 (0.3)	21.3 (0.3)	18.8 (0.3)
P-valueb
BBFC vs brinzolamide	<0.001	<0.001	<0.001	<0.001	0.002	<0.001	<0.001	<0.001
BBFC vs brimonidine	<0.001	<0.001	<0.001	<0.001	<0.001	<0.001	<0.001	<0.001

Notes:

a Intraocular pressure was analyzed using the intent-to-treat population.

b Pairwise t-test on LS means. Reprinted with permission from Katz G, Dubiner H, Samples J, Vold S, Sall K. Three-month randomized trial of fixed-combination brinzolamide, 1%, and brimonidine, 0.2%. JAMA Ophthalmol. 2013;131(6):724–730.⁵³ Copyright © 2013 American Medical Association. All rights reserved.

Abbreviations: BBFC, brinzolamide 1%/brimonidine 0.2% fixed combination.

Table 3 Mean 3-month IOP reductions with currently available fixed-combination glaucoma medications

Fixed combination	N	Hours after dosing	Mean ± SD absolute IOP change from baselinea (mmHg)	Mean ± SD IOP change from baselinea (%)
Dorzolamide/timolol^Citation64	114	0	−7.7±4.2	−27.4±13.1
	112	2	−9.0±4.3	−32.7±12.9
Dorzolamide/timolol^Citation70	151	0	−4.2±3.3	−16.3±12.5
	151	2	−5.4±3.1	−21.6±12.3
Dorzolamide/timolol^Citation74	120	0	−3.6±3.0	−13.8±11.1
	119	2	−5.0±3.5	−19.7±12.9
	116	8	−3.7±3.4	−14.9±13.2
Brinzolamide/timolol^Citation75	171	0	−8.3±3.8	30.6c
	171	2	−8.7±3.9	33.7c
Brimonidine/timolol^Citation66	385	0	−7.0b	NA
	385	2	−7.5b	NA
	385	7	−5.5b	NA
Brimonidine/timolol^Citation73	385	0	−7.0b	NA
	NA	2	−7.5b	NA
	NA	7	−5.5b	NA
Latanoprost/timolol^Citation67	NA	Diurnald	−3.6b,c,e	NA
Latanoprost/timolol^Citation68	129	Diurnalf	−10.2c	NA
Latanoprost/timolol^Citation71	170	Diurnalf	−10.0c	NA
Latanoprost/timolol^Citation72	140	Diurnald	−2.6c,e	NA
Bimatoprost/timolol^Citation65	533	0	−9.2±3.7	NA
	NA	2	−7.8±4.0	NA
	NA	8	−7.4±4.0	NA
Travoprost/timolol^Citation69	151	0	−8.7±3.2	−34±12
	151	2	−7.8±3.0	−33±11
	151	8	−7.4±3.0	−32±11
Brinzolamide/brimonidine^Citation54	196	0	−6.7c	−24.6b
	194	2	−8.3c	−32.2b
	194	7	−5.4c	−22.1b
Brinzolamide/brimonidine^Citation53	189	0	−7.1c	−26.4b
	189	2	−8.8c	−34.8b
	189	7	−5.7c	−24.1b

Notes:

a Notes: When available;

b approximate values (estimated from graphical data);

c calculated means from values stated in article text or tables;

d diurnal IOP was calculated as the mean of IOP measures at 8 am, 10 am, and 4 pm;

e IOP assessed at 13 weeks;

f mean IOP at 8 am, 10 am, and 4 pm or the mean of non-missing IOP measurements if a measurement was missing.

Abbreviations: IOP, intraocular pressure; NA, not available; SD, standard deviation.

Table 4 Treatment-related adverse events (incidence ≥1% in any group) from a 3-month Phase III trial

Adverse event	BBFC, n (%)(n=214)	Brinzolamide 1%, n (%) (n=226)	Brimonidine 0.2%, n (%) (n=220)
Ocular
Blurred vision	13 (6.1)	14 (6.2)	1 (0.5)
Ocular hyperemia	7 (3.3)	2 (0.9)	9 (4.1)
Eye irritation	6 (2.8)	2 (0.9)	4 (1.8)
Allergic conjunctivitis	4 (1.9)	1 (0.4)	2 (0.9)
Eye pain	3 (1.4)	4 (1.8)	2 (0.9)
Conjunctival hyperemia	3 (1.4)	4 (1.8)	3 (1.4)
Foreign body sensation in eyes	3 (1.4)	2 (0.9)	1 (0.5)
Dry eye	2 (0.9)	2 (0.9)	6 (2.7)
Eye pruritus	2 (0.9)	2 (0.9)	3 (1.4)
Eye allergy	1 (0.5)	0	3 (1.4)
Punctate keratitis	1 (0.5)	1 (0.4)	3 (1.4)
Eye discharge	1 (0.5)	3 (1.3)	0
Nonocular
Dysgeusia	8 (3.7)	14 (6.2)	0
Dry mouth	7 (3.3)	0	6 (2.7)

Notes: Reproduced with permission from Katz G, Dubiner H, Samples J, Vold S, Sall K. Three-month randomized trial of fixed-combination brinzolamide, 1%, and brimonidine, 0.2%. JAMA Ophthalmol. 2013;131(6):724–730.⁵³ Copyright © 2013 American Medical Association. All rights reserved.

Abbreviation: BBFC, brinzolamide 1%/brimonidine 0.2% fixed combination.

Table 5 Treatment-related adverse events (incidence ≥1% in either group) from a 3-month clinical trial with a 3-month safety extension

TRAE	3 months			6 months
	BBFC, n (%)(n=221)	Brinzolamide, n (%) (n=234)	Brimonidine, n (%) (n=235)	BBFC, n (%)(n=221)	Brinzolamide, n (%) (n=234)	Brimonidine, n (%) (n=235)
Ocular
Eye irritation	12 (5.4)	4 (1.7)	6 (2.6)	14 (6.3)	3 (1.3)	8 (3.4)
Blurred vision	10 (4.5)	16 (6.8)	0	10 (4.5)	16 (6.8)	0
Eye allergy	10 (4.5)	0	2 (0.9)	14 (6.3)	1 (0.4)	5 (2.1)
Eye pain	6 (2.7)	4 (1.7)	3 (1.3)	6 (2.7)	4 (1.7)	3 (1.3)
Eye pruritus	5 (2.3)	3 (1.3)	0	7 (3.2)	2 (0.9)	3 (1.3)
Allergic conjunctivitis	4 (1.8)	1 (0.4)	5 (2.1)	8 (3.6)	1 (0.4)	10 (4.3)
Conjunctival hyperemia	4 (1.8)	1 (0.4)	2 (0.9)	5 (2.3)	1 (0.4)	3 (1.3)
Dry eye	4 (1.8)	2 (0.9)	1 (0.4)	4 (1.8)	2 (0.9)	2 (0.9)
Conjunctivitis	4 (1.8)	0	7 (3.0)	11 (5.0)	0	14 (6.0)
Increased lacrimation	3 (1.4)	1 (0.4)	1 (0.4)	3 (1.4)	1 (0.4)	2 (0.9)
Ocular hyperemia	2 (0.9)	1 (0.4)	6 (2.6)	6 (2.7)	1 (0.4)	9 (3.8)
Conjunctival follicles	1 (0.5)	0	3 (1.3)	1 (0.5)	0	4 (1.7)
Nonocular
Dysgeusia	9 (4.1)	24 (10.3)	1 (0.4)	9 (4.1)	24 (10.3)	1 (0.4)
Dry mouth	6 (2.7)	0	5 (2.1)	7 (3.2)	0	5 (2.1)
Fatigue	1 (0.5)	0	4 (1.7)	1 (0.5)	0	4 (1.7)

Notes: 3 months data adapted with permission from Nguyen QH, McMenemy MG, Realini T, Whitson JT, Goode SM. Phase 3 randomized 3-month trial with an ongoing 3-month safety extension of fixed-combination brinzolamide 1%/brimonidine 0.2%. J Ocul Pharmacol Ther. 2013;29(3):290–297.⁵⁴ The publisher for this copyrighted material is Mary Ann Liebert, Inc. publishers. Copyright © 2013. 6 months data is adapted with permission of Dove Medical Press Ltd., from Six-month results from a phase III randomized trial of fixed-combination brinzolamide 1% + brimonidine 0.2% versus brinzolamide or brimonidine monotherapy in glaucoma or ocular hypertension, Whitson JT, Realini T, Nguyen QH, McMenemy MG, Goode SM, 7, 2013.⁵⁶ Copyright © 2013.

Abbreviations: BBFC, brinzolamide 1%/brimonidine 0.2% fixed combination; TRAE, treatment-related adverse event.

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