A 12 week study comparing the fixed combination of latanoprost and timolol with the concomitant use of the individual components in patients with open angle glaucoma and ocular hypertension

BACKGROUND: To compare the intraocular pressure (IOP) lowering effect and safety of the fixed combination of latanoprost and timolol with that of the concomitant use of the individual components. METHODS: A 12 week, double masked, randomised, crossover, multicentre study of patients with open angle glaucoma or ocular hypertension and IOP controlled on ocular hypotensive treatment (mean < or =21 mmHg). Patients received either a once daily morning dose of the fixed combination of latanoprost 0.005% and timolol 0.5% or once daily evening latanoprost 0.005% and twice daily timolol 0.5% for six weeks and then switched to the other combination. The primary efficacy endpoint was the within-patient difference in diurnal IOP between fixed and unfixed treatment combinations after six weeks of treatment; a one sided 97.5% confidence interval (CI) for the mean difference in IOP <1.0 mmHg indicated the fixed combination was not inferior to the unfixed combination. Adverse events were recorded at each visit. RESULTS: In all, 190 patients were included in observed cases analyses (93 fixed to unfixed combination; 97 unfixed to fixed combination). Mean IOP at baseline was 16.9 mmHg in both groups. The mean diurnal IOP was 17.0 mmHg after fixed combination treatment and 15.9 mmHg after unfixed combination therapy (p<0.0001). The difference in mean within-patient diurnal IOP was 1.1 mmHg favouring the unfixed combination (95% CI 0.8 to 1.4 mmHg). Both treatments were tolerated well. CONCLUSIONS: Although the primary efficacy endpoint was not met, once daily administration of the fixed combination of latanoprost and timolol was found to be safe and effective. The fixed combination provides a convenient alternative to the three instillations required with the individual components.     

Dorzolamide/timolol fixed combination versus latanoprost/timolol fixed combination in patients with primary open-angle glaucoma or ocular hypertension

PURPOSE: The efficacy of dorzolamide/timolol fixed combination (DTFC) versus latanoprost/timolol fixed combination (LTFC) in open-angle glaucoma or ocular hypertensive patients. METHODS: Patients were randomized to DTFC or LTFC for 6 weeks and switched to opposite treatment for Period 2. RESULTS: Thirty-two completed patients had a mean diurnal IOP of 19.5+/-3.2 mmHg for DTFC and 18.9+/-3.4 mmHg for LTFC (p=0.12), with no significant difference found between DTFC and LTFC at any timepoint following a Bonferroni correction (p>or=0.01). CONCLUSIONS: Patients treated with DTFC and LTFC have a statistically similar ocular hypotensive effect.     

Bimatoprost/timolol fixed combination: a 3-month double-masked, randomized parallel comparison to its individual components in patients with glaucoma or ocular hypertension

PURPOSE: To evaluate the safety and efficacy of a fixed combination (FC) of bimatoprost (BIM) and timolol (TIM) compared with each of the active components for 3 months. PATIENTS AND METHODS: Two double-masked, randomized, multicenter parallel studies of FC (once-daily, mornings), BIM (once-daily, evenings), or TIM (twice-daily) were conducted in 1061 patients with glaucoma or ocular hypertension. RESULTS: Mean diurnal decreases from baseline intraocular pressure (IOP) at month 3 were 8.1, 7.9, and 6.4 mm Hg for the FC, BIM, and TIM groups, respectively. The proportion of patients with a mean diurnal percent reduction from baseline in IOP of more than 20% across all visits was 81.8% (436/533), 72.1% (191/265), and 49.8% (131/263) for the FC, BIM, and TIM groups, respectively (P<0.001 for FC vs. BIM and FC vs. TIM). The proportion of patients achieving an IOP of less than 18 mm Hg at all time points was 39.2% (209/533), 28.7% (76/265), and 12.2% (32/263) for the FC, BIM, and TIM groups, respectively (P=0.003 for FC vs. BIM, and P<0.001 for FC vs. TIM). The most commonly reported treatment-related adverse event was conjunctival hyperemia, with the greatest incidence in BIM (38.5%, 102/265), followed by FC (22.7%, 121/533, P<0.0001 vs. BIM) and TIM (6.8%, 18/263; P<0.001 vs. FC). CONCLUSIONS: FC was statistically significantly more effective than BIM or TIM for most comparisons, and safer than BIM with respect to common ocular adverse events. FC represents a convenient, therapeutic advantage over separate bottles.     

Effects of brimonidine timolol fixed combination therapy on anterior ocular segment configuration

Purpose  

To assess the effects of brimonidine and of brimonidine and timolol fixed combination (BTFC) therapy on the pupil and angle structures in both normal subjects and in open angle glaucoma patients.     

拉坦前列素和噻吗心安治疗开角型青光眼、高眼压症的对照研究

目的：观察Ｌａｔａｎｏｐｒｏｓｔ的降眼压效果及安全性。方法：采用随机分组对照组,０．００５％Ｌａｔａｎｏｐｒｏｓｔ每日一次或０．５％Ｔｉｍｏｌｏｌ（噻吗心安）每日２次,治疗原发性开角型青光眼、高眼压症和剥脱性青光眼,共１４例,疗程１２周,观察其眼压及不良反应。结果：Ｌａｔａｎｏｐｒｏｓｔ组和Ｔｉｍｏｌｏｌ组均可有效地降低眼压（Ｐ〈０．０１）,两组间眼压下降值没有差异。两组治疗前后不同时间点眼压下降     

Bimatoprost/timolol fixed combination (BTFC) in patients with primary open angle glaucoma or ocular hypertension in Greece

AIM: To evaluate the efficacy and tolerability of the fixed combination of bimatoprost 0.03% and timolol 0.5% (BTFC) in patients in Greece with primary open angle glaucoma (POAG) or ocular hypertension (OHT) whose previous therapy provided insufficient lowering of intraocular pressure (IOP). METHODS: A multicenter, prospective, open-label, non-interventional, observational study of the use of BTFC in clinical practice was conducted at 41 sites in Greece. The primary endpoint was the reduction in IOP from baseline at study end, approximately 12wk after initiation of BTFC therapy. RESULTS: A total of 785 eligible patients were enrolled in the study and 97.6% completed the study. The mean±SD IOP reduction from baseline at 12wk after initiation of BTFC was 6.3±2.8 mm Hg (n=764; P<0.001). In patients (n=680) who replaced their previous IOP-lowering monotherapy (a single drug, or a fixed combination of 2 drugs in a single ophthalmic drop) with once-daily BTFC, the mean±SD IOP reduction from baseline at 12wk was 6.2±2.8 mm Hg (P<0.001). IOP was reduced from baseline in 99.2% of patients, and 58.0% of patients reached or exceeded their target IOP. Substantial mean IOP reductions were observed regardless of the previous therapy. BTFC was well tolerated, with 96.0% of patients who completed the study rating the tolerability of BTFC as “good” or “very good.” Adverse events were reported in 8.3% of patients; only 0.6% of patients discontinued the study due to adverse events. CONCLUSION: In clinical practice in Greece, BTFC is well tolerated and effectively lower the IOP in patients with POAG or OHT who requires additional IOP lowering on their previous therapy.     

Comparison of fixed combinations of dorzolamide/timolol and brimonidine/timolol in patients with primary open-angle glaucoma

To compare the short-term effectiveness and ocular side-effects of fixed combinations of dorzolamide/timolol (DTFC) and brimonidine/timolol (BTFC) in patients with primary open-angle glaucoma (POAG). Forty-two eyes of 42 patients newly diagnosed with primary open-angle glaucoma were assessed prospectively. One of the two eyes was chosen randomly and treated with DTFC (2 × 1) for 4 weeks. The treatment was then stopped to allow a 4-week wash-out period. Following the wash-out period, the same eye was treated with BTFC (2 × 1) for 4 weeks. Intraocular pressure (IOP) values were measured before and after each treatment at 0800, 1,200 and 1,600 h. Tear function test results and ocular side-effects were also recorded. The mean baseline IOP values for DTFC and BTFC were 24.1 ± 1.8 and 24.6 ± 2.4 mmHg, respectively. The mean IOP values after 4 weeks of treatment with DTFC or BTFC were 17.1 ± 2.9 and 16.9 ± 2.5 mmHg, respectively. Both medications reduced IOP values significantly (P = 0.0000). The effectiveness of both medications was similar (P = 0.7363). Both combinations significantly reduced the amount of tear secretion and tear break-up time (P = 0.0000). Eye burning was more common with DTFC than with BTFC (P = 0.0182). Other adverse effects were observed at similar rates for both combinations. This study demonstrated that the IOP-reducing effects of DTFC and BTFC in patients with POAG are similar. The side-effect profile of BTFC is similar to that of DTFC. Lower occurrence of a burning sensation may improve patient compliance in the BTFC group.     

Long-term effect of latanoprost/timolol fixed combination in patients with glaucoma or ocular hypertension: A prospective,observational, noninterventional study

Background  

Prospective, observational studies that enroll large numbers of patients with few exclusion criteria may better reflect actual ongoing clinical experience than randomized clinical trials. Our purpose was to obtain efficacy and safety information from a cohort of subjects exposed to latanoprost/timolol fixed combination (FC) for ≥18 months using a prospective, observational design.     

Efficacy and safety of the latanoprost/timolol maleate fixed combination vs concomitant brimonidine and latanoprost therapy

AIMS: To evaluate the efficacy and safety of latanoprost/timolol maleate fixed combination (LTFC) given once daily vs the concomitant therapy of brimonidine twice daily and latanoprost once daily in primary open-angle glaucoma or ocular hypertensive subjects. METHODS: A prospective, double-masked, active-controlled comparison in which qualified subjects had all glaucoma medicines discontinued for 1 month and then were randomized to either LTFC or brimonidine and latanoprost concomitant therapy for 6 weeks. They were then switched to the other treatment regimen. The intraocular pressure (IOP) was measured at 0800, 1200, and 1600 h at baseline and at the end of Periods 1 and Period 2. RESULTS: In 32 subjects, the diurnal curve of the untreated IOP of 26.0+/-3.4 decreased to 17.8+/-2.5 on LTFC and 17.2+/-2.8 mmHg on brimonidine and latanoprost (P=0.31). At 0800 and 1600 h, the IOPs were statistically similar between the groups (P>0.05). At 1200 h the latanoprost and brimonidine treatment IOP was statistically lower (16.2+/-3.2) than LTFC (18.0+/-2.8 mmHg). However, the reduced IOP from untreated baseline was not statistically different at each time point and for the diurnal curve for each therapy (P<0.05). Safety was similar between groups for both solicited and unsolicited side effects (P>0.05). CONCLUSION: This study suggests that LTFC and concomitant therapy of brimonidine and latanoprost provide statistically similar diurnal IOP reduction from an untreated baseline.     

A comparison of the fixed combination of latanoprost and timolol with its individual components

PURPOSE: To evaluate the intraocular pressure (IOP)-reducing effect of the fixed combination of 0.005% latanoprost and 0.5% timolol compared with the individual monotherapies. METHODS: A 6-month, randomised, double-masked, controlled multicentre study followed by 6 months of open-label treatment was carried out in patients with glaucoma or ocular hypertension with pre-enrolment IOP >/=25 mmHg on glaucoma medication or >/=30 mmHg if untreated. Following a 2- to 4-week run-in period on timolol twice daily, 436 patients were randomised: 140 to fixed combination therapy once daily in the morning, 147 to latanoprost once daily in the morning and 149 to timolol twice daily. During the open-label extension, patients received fixed combination drug once daily in the morning. RESULTS: The difference in mean change from baseline in diurnal IOP from week 2 to week 26 was -1.2 mmHg between fixed combination and latanoprost (95% confidence interval. CI: -1.8 to -0.5; P<0.001; repeated-measures analysis of covariance). The corresponding difference between fixed combination and timolol was -1.9 mmHg (95% CI -2.5 to -1.2; P<0.001). No long-term drift in IOP was detected in patients treated for 12 months with fixed combination. All treatments were well tolerated with no major differences among groups in the incidence of clinically relevant adverse events. CONCLUSION: The fixed combination of 0.005% latanoprost and 0.5% timolol administered once daily in the morning for 6 months was more effective in reducing IOP than the individual components alone and was effective over 12 months.     

Meta-analysis of randomized controlled trials comparing timolol with brimonidine in the treatment of glaucoma

This paper aims to compare the efficacy and tolerability of timolol versus brimonidine in the treatment of glaucoma. Comprehensive searches were performed using Medline, Embase and the Cochrane Controlled Trials Register for randomized controlled trials comparing timolol and brimonidine. Two reviewers independently assessed trials for eligibility and quality and extracted data. A random effects model was used to combine studies. Outcome was defined as the absolute mean intraocular pressure (IOP) reduction from baseline to end-point for efficacy, and relative risk (RR) for adverse events. Subgroup analysis and meta-regression were used to explore heterogeneity according to trial design and quality. Ten publications reporting on eight trials with 2387 participants were included in the meta-analysis. Two further trials were commented on qualitatively. IOP reduction was not significantly different between timolol and brimonidine. Weighted mean difference (WMD) of IOP reduction was 0.24 mmHg (favouring brimonidine) with a 95% confidence interval of -0.57 to 1.04 mmHg. There was significant heterogeneity between studies (chi(2) (13) = 73.75, P < 0.00001, I(2) = 91%). Subgroup analysis showed no significant WMD for studies where data were analysed from end-points >/=6 months or <6 months. Meta-regression analysis showed increased WMD IOP reduction in favour of brimonidine with increased trial quality (t(3) = -4.58, P = 0.01), but no significant association with trial duration (t(3) = 0.73, P = 0.51) or size (t(3) = -0.59, P = 0.57). The RR of ocular allergy was much lower with timolol than brimonidine (RR = 0.08, 95% confidence interval 0.01 to 0.47). Publication bias was not evident on a funnel plot, although the number of studies was small. The conclusion is that both drugs are equally effective in lowering IOP. Brimonidine is associated with a higher rate of allergy.     

Fixed combination of latanoprost and timolol vs the individual components for primary open angle glaucoma and ocular hypertension:a systematic review and meta-analysis

AIM:To assess the effects of the fixed combination of 0.005% latanoprost and 0.5% timolol (FCLT) vs their individual components for primary open angle glaucoma (POAG) and ocular hypertension (OHT).METHODS:After searched PubMed, EMBASE, the Cochrane Library and SCI, all randomized controlled clinical trials (RCTs) and cross-over studies were included. The control groups were the mono therapy or the concomitant therapy of latanoprost and timolol. The outcomes were visual field defect, optic atrophy, mean intraocular pressure (IOP) and IOP fluctuation. The analysis was carried out in RevMan version 5.1 software.RESULTS:The post-intervention mean IOP of FCLT was significantly lower compared to timolol [mean difference (MD) -2.92, 95%CI -3.28 to -2.55, P<0.00001] and latanoprost (MD -1.11, 95%CI -1.51 to -0.72, P＜0.00001). The post-intervention IOP fluctuation was also significantly lower compared to timolol (MD -0.88, 95%CI -1.23 to -0.53, P<0.00001) and latanoprost (MD -0.63, 95%CI -1.04 to -0.22, P=0.002). The mean IOP was higher in FCLT morning dose group than the one in unfixed combination of 0.005% latanoprost and 0.5% timolol (UFCLT) (MD 1.10, 95%CI 0.81 to 1.39, P<0.00001). Otherwise, there was no difference between FCLT evening dose group and UFCLT (MD 0.34, 95% CI -0.01 to 0.69, P=0.06). There was no statistical difference for the incidence of visual field defect and optic atrophy between FCLT and the monotherapy of components.CONCLUSION:A better IOP lowering effect has been demonstrated for FCLT compared to the mono therapy of components. The IOP lowering effect was worse for FCLT morning dose and almost same for FCLT evening dose compared to the UFCLT. We need more long-term high quality RCTs to demonstrate the outcomes of visual field defect and optic atrophy.     

A double-masked, randomized, parallel comparison of a fixed combination of bimatoprost 0.03%/timolol 0.5% with non-fixed combination use in patients with glaucoma or ocular hypertension

PURPOSE: To compare the safety and efficacy of the fixed combination product with non-fixed combination use of the same active ingredients in separate bottles (bimatoprost once-daily [qd], and timolol twice-daily [bid]). A bimatoprost 0.03% qd treatment arm was used for validation of the study. METHOD: This was a double-masked, randomized, parallel study in 445 patients with open-angle glaucoma or ocular hypertension. They were randomized in a ratio of 2:2:1 to receive bilateral treatment with the fixed combination, non-fixed combination treatment, or bimatoprost alone. RESULTS: Comparing the fixed combination and non-fixed combination, the non-inferiority margin of 1.5 mm Hg was met at all three timepoints for mean intraocular pressure (IOP), and a margin of 1.0 mm Hg for mean diurnal IOP. The incidence of conjunctival hyperemia was statistically significantly lower (p=0.014) in the fixed combination group (8.5%, 15/176) compared with the bimatoprost group (18.9%, 17/90) and the non-fixed combination group (12.5%, 22/176). CONCLUSIONS: The fixed combination of bimatoprost 0.03%/timolol 0.5% administered once daily was comparable in ocular hypotensive efficacy to the non-fixed combination. The lower propensity of the fixed combination to elicit conjunctival hyperemia suggests a superior comparative benefit/risk assessment of the fixed combination in the treatment of elevated IOP.