Clinical effectiveness of brinzolamide 1%-brimonidine 0.2% fixed combination for primary open-angle glaucoma and ocular hypertension.
ABSTRACT: The main first-line treatment strategy for glaucoma is to reduce intraocular pressure (IOP) by topical ocular hypotensive medications, but many patients require multiple medications for adequate IOP control. Fixed-combination therapies provide several benefits, including simplified treatment regimens, theoretical improved treatment adherence, elimination of the potential for washout of the first drug by the second, and the reduction in ocular exposure to preservatives. ?-Adrenoceptor antagonists (particularly 0.5% timolol) are the most commonly used agents in combination with other classes of drugs as fixed-combination eyedrops, but they are contraindicated in many patients, owing to local allergy or systemic side effects. A fixed-combination preparation without a ?-blocker is therefore warranted. This paper reviews the clinical effectiveness of brinzolamide 1% and brimonidine 0.2% fixed combination (BBFC) for use in patients with primary open-angle glaucoma and ocular hypertension. We searched PubMed and the ClinicalTrials.gov registry, and identified three randomized controlled trials comparing BBFC vs its constituents (brimonidine vs brinzolamide), and one comparing BBFC with unfixed brimonidine and brinzolamide. All of the studies demonstrated mean diurnal IOP to be statistically significantly lower in the BBFC group compared with constituent groups and noninferior to that with the concomitant group using two separate bottles. The safety profile of BBFC was consistent with that of its individual components, the most common ocular adverse events being ocular hyperemia, visual disturbances, and ocular allergic reactions. Common systemic adverse effects included altered taste sensation, oral dryness, fatigue, somnolence, and decreased alertness. BBFC seems to be a promising new fixed combination for use in glaucoma patients. However, long-term effects of BBFC on IOP, treatment adherence, and safety need to be determined.
Project description:PURPOSE: To describe pooled efficacy and safety data from two phase 3 studies comparing brinzolamide 1%/brimonidine 0.2% fixed combination (BBFC) with its component medications, brinzolamide and brimonidine, in patients with open-angle glaucoma or ocular hypertension. METHODS: Data were pooled from two nearly identical clinical trials comparing BBFC with its component medications, each given three times daily. The 3-month efficacy outcome was mean intraocular pressure (IOP) at 0800, 1000, 1500, and 1700 hours. Safety outcomes included adverse events (AEs), best-corrected visual acuity, examination of ocular structures, pachymetry, perimetry, and vital signs. RESULTS: A total of 1350 patients were enrolled and included in this analysis (BBFC, n=437; brinzolamide, n=458; brimonidine, n=455). Baseline mean IOP levels were similar among the three treatment groups. At 3 months, mean IOP of the BBFC group was significantly lower than that of either monotherapy group (P<0.0001) at all the four time points. A total of 272 patients (20.1%) experienced at least one treatment-related AE (BBFC, 24.6%; brinzolamide, 18.7%; brimonidine, 17.4%), the majority of which were ocular AEs. One serious AE, moderate intensity chest pain, was considered related to brinzolamide treatment and resulted in study discontinuation. CONCLUSIONS: This analysis strengthens the conclusions drawn from the two individual phase 3 studies showing that, in patients with open-angle glaucoma or ocular hypertension, BBFC had significantly superior IOP-lowering activity compared with either brinzolamide or brimonidine alone and a safety profile consistent with that of its individual components.
Project description:This study compared the intraocular pressure (IOP)-lowering efficacy of fixed-combination brinzolamide 1%/brimonidine 0.2% (BBFC) with that of its component medications, brinzolamide and brimonidine, in patients with open-angle glaucoma or ocular hypertension.In this phase 3, multicenter, double-masked, parallel-group, 3-month study with a 3-month safety extension, eligible patients were randomized 1:1:1 to treatment with BBFC, brinzolamide, or brimonidine thrice daily after a washout period, during which any IOP-lowering medications were discontinued. The primary objectives of this study were to determine whether the IOP-lowering efficacy of BBFC was superior to that of brinzolamide alone and, separately, of brimonidine alone. IOP was assessed at 8:00 AM, 10:00 AM, 3:00 PM, and 5:00 PM at 2 weeks, 6 weeks, and 3 months after study drug initiation.A total of 690 patients were enrolled in the study, and 615 completed the 3-month visit. Baseline mean IOP levels were similar among the 3 treatment groups at each of the 4 time points assessed. At the 3-month primary endpoint, mean IOP of the BBFC group was significantly lower than that of either the brinzolamide group or the brimonidine group (P?0.005) across all time points. At the 2- and 6-week supportive endpoints, mean IOP of the BBFC group was significantly lower at all time points than the mean IOP of either the brinzolamide group (P?0.01) or the brimonidine group (P<0.0001). A total of 143 patients experienced at least 1 treatment-related adverse event (AE; BBFC group, n=58, 26.2%; brinzolamide group, n=44, 18.8%; brimonidine group, n=41, 17.4%), the majority of which were ocular AEs.This study demonstrated that BBFC has significantly superior IOP-lowering activity compared with either brinzolamide 1% or brimonidine 0.2% in patients with open-angle glaucoma or ocular hypertension while providing a safety profile which is consistent with that of the individual components.
Project description:Fixed-combination intraocular pressure (IOP)-lowering medications simplify treatment regimens for patients requiring 2 ocular hypotensive agents to maintain sufficiently low IOP. The aim of this study was to evaluate the safety and efficacy of fixed-combination brinzolamide 1%/brimonidine 0.2% (BBFC) versus concomitant administration of brinzolamide 1% plus brimonidine 0.2% (BRINZ + BRIM) in patients with open-angle glaucoma or ocular hypertension.This was a prospective, phase 3, multicenter, double-masked, 6-month trial. Patients who had insufficient IOP control with monotherapy or who were receiving 2 IOP-lowering medications were randomized 1:1 to receive twice-daily BBFC or BRINZ + BRIM. IOP was assessed at 9 a.m. and 11 a.m. during week 2, week 6, month 3, and month 6 visits. The primary efficacy endpoint was mean diurnal IOP change from baseline to month 3; noninferiority was concluded if the upper limit of the 95% CI of the between-group difference was <1.5 mmHg. Supportive endpoints included mean IOP, IOP change from baseline, and percentage of patients with IOP <18 mmHg. Adverse events were recorded.The mean diurnal IOP change from baseline with BBFC (least squares mean ± standard error -8.5 ± 0.16 mmHg) was noninferior to that with BRINZ + BRIM (-8.3 ± 0.16 mmHg; mean difference -0.1 mmHg; 95% CI -0.5 to 0.2 mmHg). The upper limits of the 95% CIs were <1.5 mmHg at all time points. Decreases from baseline >8 mmHg were observed for least squares mean diurnal IOP in both groups as early as week 2 and continued to the end of the study. The results of all other supportive endpoints were similar to the primary efficacy endpoint. The most common ocular adverse drug reactions were hyperemia of the eye (reported as ocular or conjunctival hyperemia), visual disturbances, ocular allergic reactions, and ocular discomfort. Common systemic adverse drug reactions included dysgeusia, oral dryness, and fatigue/drowsiness.Brinzolamide 1%/brimonidine 0.2% fixed combination was as well tolerated and effective as concomitant therapy with its components. BBFC reduces treatment burden in patients who require multiple IOP-lowering medications.
Project description:Introduction:Maximal medical therapy (MMT) is the use of ?3 classes of topical anti-glaucoma agents to achieve maximal intraocular pressure (IOP) reduction while minimizing adverse effects and compliance challenges. Purpose:To evaluate the additive IOP-lowering effect of twice-daily brinzolamide 1%/brimonidine 0.2% fixed-dose combination (BBFC) used adjunctively with once daily travoprost 0.004%/timolol 0.5% fixed-dose combination (TTFC) in patients with open-angle glaucoma (OAG)/ocular hypertension (OHT). Methods:In this phase IV, double-masked study, patients on TTFC for ?28 days, aged ?18 years, with mean IOP ?19 and ?28 mmHg in at least 1 eye were randomized to receive BBFC+TTFC (n=67) or vehicle+TTFC (n=67) for 6 weeks. The primary endpoint was mean change in diurnal IOP from baseline (BL, averaged over 09:00 and 11:00) at Week 6. Results:The study was terminated prematurely due to recruitment challenges. BL mean IOP was similar in both groups (BBFC+TTFC: 21.6±1.78 mmHg; vehicle+TTFC: 21.8±1.90 mmHg). Mean change in diurnal IOP from BL at Week 6 was greater with BBFC+TTFC (-4.25 mmHg, 95% confidence interval [CI]: -4.7, -3.8) than with vehicle+TTFC (-2.11 mmHg, 95% CI: -2.6, -1.6, treatment difference, -2.15 mmHg (95% CI: -2.8, -1.5; P<0.001). Ocular adverse events (AEs) were reported in 11.9% of patients given BBFC+TTFC and 7.5% of patients given vehicle+TTFC. The AE with highest frequency was punctate keratitis (3%) in the BBFC+TTFC group; eye irritation (3%) in the vehicle+TTFC group. Conclusion:BBFC+TTFC as MMT demonstrated clinically relevant and statistically significant reductions in mean diurnal IOP in patients with OAG/OHT. AEs were consistent with known safety profiles of individual medications.
Project description:Objective:To demonstrate that the intraocular pressure (IOP)-lowering efficacy of a twice-daily brinzolamide 10 mg/mL (BRINZ)/brimonidine 2 mg/mL (BRIM) fixed-dose combination (BBFC) was non-inferior to its individual components (BRINZ+BRIM) dosed concomitantly in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). Safety was also evaluated. Methods and Analysis:This was a Phase III, multicenter, observer-masked study in patients from China, Russia and Taiwan. Patients aged ?18 years with a mean IOP ?21 mmHg and ?36 mmHg in the same eye after washout of other IOP-lowering medications were included. Eligible patients were randomized (1:1) to receive BBFC or BRIZ+BRIM eye drops twice daily for 3 months. The primary endpoint was the mean change in diurnal IOP (averaged over 09:00, +2 h, and +7 h) from baseline to Month 3. Adverse events (AEs) were recorded throughout the study. Results:The per-protocol set included 349 patients (BBFC, n=172; BRINZ+BRIM, n=177). The mean±standard deviation diurnal IOP at baseline was 24.6±2.66 mmHg in both groups. At Month 3, the least square mean±standard error change in diurnal IOP from baseline was -7.2±0.34 mmHg and -7.3±0.34 mmHg with BBFC and BRINZ+BRIM, respectively (between-group difference: 0.1 mmHg [95% CI -0.5, 0.7]). In the BBFC and BRINZ+BRIM groups, 53.3% and 55.0% of patients achieved a diurnal IOP <18 mmHg, and 43.2% and 37.4% of patients, respectively, achieved a mean diurnal IOP reduction >30% from baseline at Month 3. Ocular AEs were reported in 28.7% (BBFC) and 22.5% (BRINZ+BRIM) of patients; conjunctival hyperemia was the most frequent ocular AE (BBFC, 6.4%; BRINZ+BRIM, 6.8%). Non-ocular AEs were reported in 32.4% (BBFC) and 30.4% (BRINZ+BRIM) of patients. Conclusion:The study findings demonstrate that the efficacy of twice-daily BBFC was non-inferior to BRINZ+BRIM in patients with OAG/OHT. The safety profile of BBFC was similar to that of BRINZ+BRIM.
Project description:PurposeTo determine whether intraocular pressure (IOP) lowering with fixed-combination brinzolamide/brimonidine (BBFC) adjunctive to a prostaglandin analog (PGA) was superior to that of vehicle+PGA in patients with open-angle glaucoma or ocular hypertension who were inadequately controlled with PGA monotherapyMethodsThis 6-week, multicenter, randomized, double-masked, parallel-group trial was conducted at 30 clinical sites in the United States between October 2013 and May 2014. Eligible patients were adults with open-angle glaucoma or ocular hypertension and with mean IOP ?21 and <32?mm?Hg, whereas receiving an open-label PGA (latanoprost, bimatoprost, or travoprost). Patients instilled a PGA once-daily in a run-in phase before randomization to masked BBFC or vehicle adjunctive treatment. Masked treatments were instilled 3 times daily for 6 weeks, and patients continued once-daily use of their PGA. The primary efficacy end point was the between-group difference in mean diurnal IOP (average of 0800, 1000, 1500, and 1700 hours time points) at week 6.ResultsAt week 6, mean diurnal IOP with BBFC+PGA was lower than with vehicle+PGA (17.1±0.4?mm?Hg vs 20.5±0.4?mm?Hg; between-group difference, -3.4±0.5?mm?Hg; P<0.0001; 95% confidence interval, -4.5 to -2.4?mm?Hg). BBFC+PGA reduced mean diurnal IOP by 5.7?mm?Hg (25%) from the baseline IOP achieved with PGA monotherapy.ConclusionsTherapy with BBFC produced an additive IOP-lowering effect compared with a PGA alone or in conjunction with vehicle. BBFC may provide an effective treatment option for patients receiving PGA monotherapy who require additional IOP reduction.
Project description:<b>Background:</b> Brinzolamide as a carbonic anhydrase inhibitor could be combined with other intraocular pressure (IOP) lowering drugs for glaucoma and ocular hypertension (OHT), but the efficacy was controversial. So, this study was used to assess the efficacy and safety of brinzolamide as add-on to prostaglandin analogues (PGAs) or ?-blocker in treating patients with glaucoma or OHT who fail to adequately control IOP. <b>Methods:</b> We searched PubMed, Embase, MEDLINE, Cochrane Library, and clinicaltrials.gov from inception to October 4, 2018. Randomized controlled trials of brinzolamide as add-on to PGAs or ?-blocker for glaucoma and OHT were included. Meta-analysis was conducted by RevMan 5.3 software. <b>Results:</b> A total of 26 trials including 5,583 patients were analyzed. Brinzolamide produced absolute reductions of IOP as an adjunctive therapy for patients with glaucoma or OHT. Brinzolamide and timolol were not significantly different in lowering IOP as add-on to PGAs (9 am: <i>P</i> = 0.07; 12 am: <i>P</i> = 0.66; 4 pm: <i>P</i> = 0.66). Likewise, brinzolamide was as effective as dorzolamide in depressing IOP (9 am: <i>P</i> = 0.59; 12 am: <i>P</i> = 0.94; 4 pm: <i>P</i> = 0.95). For the mean diurnal IOP at the end of treatment duration, there were no statistical differences in above comparisons (<i>P</i> > 0.05). Compared with brimonidine (b.i.d.), there was a significant reduction of IOP in brinzolamide (b.i.d.) at 9 am (<i>P</i> < 0.0001); however, the difference was cloudy in thrice daily subgroup (<i>P</i> = 0.44); at 12 am, brinzolamide (b.i.d.) was similar to brimonidine (b.i.d.) in IOP-lowering effect (<i>P</i> = 0.23), whereas brimonidine (t.i.d.) led to a greater effect than brinzolamide (t.i.d.) (<i>P</i> = 0.02). At 4 pm, brinzolamide (b.i.d.) was superior IOP-lowering effect compared with brimonidine (b.i.d.) (<i>P</i> = 0.0003); conversely, the effect in brinzolamide (t.i.d.) was lower than brimonidine (t.i.d.) (<i>P</i> < 0.0001). For the mean diurnal IOP, brinzolamide was lower in twice daily subgroup (<i>P</i> < 0.00001); brimonidine was lower in thrice daily subgroup (<i>P</i> < 0.00001). With regard to the safety, brinzolamide and dorzolamide had a higher incidence of taste abnormality; moreover, brinzolamide resulted in more frequent blurred vision; dorzolamide resulted in more frequent ocular discomfort and eye pain. Timolol resulted in more frequent blurred vision and less conjunctival hyperemia. Brimonidine resulted in more frequent ocular hyperemia. As to other adverse events (AEs) (conjunctivitis, eye pruritus, foreign body sensation in eyes, and treatment-related AEs), brinzolamide was similar to other three active comparators. <b>Conclusions:</b> Brinzolamide, as add-on to PGAs or ?-blocker, significantly decreased IOP of patients with refractory glaucoma or OHT and the AEs were tolerable.
Project description:Fixed-combination glaucoma medications are commonly used to achieve target intraocular pressure (IOP) reduction in patients uncontrolled with monotherapy; however, ocular discomfort associated with eye drops can decrease adherence. This study assessed the efficacy and tolerability of twice-daily fixed-combination brinzolamide 1%/timolol 0.5% (BRINZ/TIM-FC) in Latin American patients transitioned from fixed-combination brimonidine 0.2%/timolol 0.5% (BRIM/TIM-FC) because of insufficient IOP control or treatment intolerance.This 8-week, open-label, prospective study was conducted at six sites in Argentina, Chile, and Mexico. Enrolled patients were aged ≥18 years with open-angle glaucoma (including primary, exfoliative, or pigment-dispersion glaucoma) or ocular hypertension with IOP of 19-35 mmHg in ≥1 eye at baseline (on BRIM/TIM-FC). Patients self-administered BRINZ/TIM-FC to both eyes at 8 a.m. and 8 p.m. daily for 8 weeks. The primary and secondary efficacy endpoints were mean IOP change from baseline at week 8 and percentage of patients achieving target IOP (≤18 mmHg) at week 8, respectively. Exploratory endpoints included patient and investigator preference for treatment at week 8. Adverse events (AEs) were assessed as the safety endpoint.Fifty patients (mean ± SD age, 66.7 ± 11.5 years) received BRINZ/TIM-FC, and 49 were included in the intent-to-treat population. Mean ± SD IOP was significantly reduced from baseline after 8 weeks of treatment with BRINZ/TIM-FC (-3.6 ± 3.0 mmHg; P < 0.0001, Wilcoxon signed-rank test; 17.1% reduction). Overall, 55.3% of patients achieved IOP ≤18 mmHg at week 8. Significantly more patients (89.4%) and investigators (95.7%) preferred BRINZ/TIM-FC to BRIM/TIM-FC (both P < 0.0001, exact binomial test). Of the 13 AEs observed, 8 were related to BRINZ/TIM-FC; the most common treatment-related AEs were eye irritation (n = 4) and abnormal sensation in the eye (n = 2).BRINZ/TIM-FC provides an effective and well-tolerated treatment option for patients transitioned from BRIM/TIM-FC.
Project description:PURPOSE:To determine patient preference of and ocular discomfort with fixed combination brinzolamide/timolol compared with fixed combination dorzolamide/timolol. METHODS:In a prospective, double-masked, randomized, active-controlled, crossover, multicenter study, patients received 1 drop of brinzolamide/timolol and dorzolamide/timolol in both eyes on consecutive days in random order. Ocular discomfort was rated 1 minute after instillation of each medication, and preference was noted on Day 2. Adverse events, if any, were solicited at each visit. RESULTS:127 subjects with ocular hypertension or open-angle glaucoma were included in the intent-to-treat analysis. Of the 106 subjects who expressed a drug preference, 79.2% preferred brinzolamide/timolol (p < 0.0001). Ocular discomfort scores were significantly higher with dorzolamide/timolol than brinzolamide/timolol (2.9 vs 1.4, respectively; p < 0.0001). Significantly more patients reported ocular pain and discomfort after dorzolamide/timolol instillation and transient blurred vision after brinzolamide/timolol instillation. CONCLUSIONS:Patients with ocular hypertension or open-angle glaucoma preferred the brinzolamide/timolol fixed combination over the dorzolamide/timolol fixed combination. This is likely due to the greater ocular discomfort associated with dorzolamide/timolol. The differences in preference, discomfort, and adverse events are likely attributable to formulation differences given the similarities of the active ingredients. Stronger patient preference for brinzolamide/timolol may lead to better therapeutic compliance.
Project description:OBJECTIVE:To evaluate the additive intraocular pressure (IOP)-lowering efficacy and safety of fixed-combination brimonidine 0.2%/timolol 0.5% compared with timolol 0.5% at peak and trough effect when used as therapy adjunctive to latanoprost 0.005% in patients with glaucoma or ocular hypertension who require additional IOP lowering. METHODS:In this prospective, randomized, multicenter, investigator-masked, parallel-group study, patients were treated with latanoprost monotherapy for at least four weeks prior to baseline. At baseline on latanoprost, patients with IOP ?21 mmHg in at least one eye were randomized to twice-daily fixed brimonidine-timolol (n = 102) or timolol (n = 102), each adjunctive to latanoprost for 12 weeks. IOP was measured at 8 am and 10 am at baseline, week 6, and week 12 and evaluated in the per protocol population. The primary efficacy endpoint was peak IOP lowering at 10 am, week 12. Safety measures included adverse events. RESULTS:Baseline mean IOP was similar at 10 am in the treatment groups (brimonidine-timolol 23.4 mmHg; timolol 23.0 mmHg). The mean additional reduction from latanoprost-treated baseline IOP was 8.3 mmHg (35.5%) with fixed brimonidine-timolol and 6.2 mmHg (27.0%) with timolol at 10 am, week 12 (P < 0.001). Patients treated with fixed brimonidine-timolol adjunctive to latanoprost were significantly more likely than patients treated with adjunctive timolol to achieve an IOP <18 mmHg (P = 0.028) and a ?20% reduction in IOP from baseline (P = 0.047) at both 8 am and 10 am in week 12. Adverse events occurred in 14.7% of fixed brimonidine-timolol patients and 12.7% of timolol patients. Biomicroscopy findings were similar between the treatment groups after 12 weeks of treatment. CONCLUSION:Fixed-combination brimonidine-timolol reduced IOP significantly more effectively than timolol when used as adjunctive therapy to latanoprost in patients with glaucoma and ocular hypertension. Both fixed brimonidine-timolol and timolol were well tolerated as agents adjunctive to latanoprost.