From dorzolamide 2%/timolol 0.5% to brinzolamide 1%/timolol 0.5% fixed combination: a 6-month,multicenter, open-label tolerability switch study

Purpose: To assess ocular surface status and tolerability after switching glaucoma patients from dorzolamide/timolol to brinzolamide/timolol fixed combination (FC).

Methods: Six-month, multicenter, open-label, prospective study that switched 72 patients from dorzolamide/timolol to brinzolamide/timolol FC. Intraocular pressure (IOP), tear film break-up-time (TF-BUT), fluorescein staining and Glaucoma Symptom Scale (GSS) questionnaire were recorded at baseline and after 6 months.

Results: Median interquartile range (IQR) IOP was 16 (IQR 15 – 18) mmHg at baseline and 16 (15 – 17) mmHg and 6 months. TF-BUT significantly improved (p < 0.0001); the regression analysis found a negative association between TF-BUT changes and age at baseline and at month 6 (r = ?0.32; p = 0.0082 and r = ?0.31; p = 0.0085). Patients with no corneal fluorescein staining statistically increased after substitution (p = 0.04). Quality of life – as examined by the GSS symptoms (SYMP) score – statistically improved (p < 0.0001), revealing an association between GSS SYMP score and age [coefficient ?0.67, 95% confidence interval (CI) ?1.13 to ?0.21, p = 0.0005), superficial keratitis (coefficient ?8.26, 95% CI ?15.73 to ?0.80, p = 0.031) and TF-BUT (coefficient 4.94, 95% CI 1.71 to 8.17, p = 0.003).

Conclusion: Brinzolamide/timolol FC is associated with reduced topical discomfort and improved signs of ocular surface disease. The good tolerability and comfort of this FC might contribute to good patient adherence.     

Signs and symptoms of ocular surface status in glaucoma patients switched from timolol 0.5% to brinzolamide 1%/timolol 0.5% fixed combination: a 6-month efficacy and tolerability,multicenter, open-label prospective study

Purpose: To examine the impact of switching glaucoma patients from timolol 0.5% to brinzolamide 1%/timolol 0.5% fixed combination (Brinz/Tim FC) on quality of life and on ocular surface status; to assess efficacy after the switch.

Methods: 6-month, multicenter, open-label, prospective, switch study in 119 early to moderate glaucoma patients. Intraocular pressure (IOP), tear film break-up time (TF-BUT), fluorescein staining and Glaucoma Symptom Scale (GSS) questionnaire were recorded at baseline and after 6 months.

Results: Median (interquartile range) IOP significantly decreased from 20 to 16 mmHg, independent of sex and age. Most patients (95.8%) reached an IOP < 18 mmHg. TF-BUT improved, with a negative weak correlation to age at baseline and at 6 months. The percentage of patients with no fluorescein staining improved. The quality of life recorded by GSS also improved, being related both to age and corneal staining.

Conclusion: Brinz/Tim FC is effective and well tolerated. In this study, patients switched to Brinz/Tim FC obtained further reduction in IOP with no effects on ocular surface status and improved quality of life perception: a better quality of life could determine a better adherence to prescribed therapy.     

A comparison of the safety and intraocular pressure lowering of bimatoprost/timolol fixed combination versus latanoprost/timolol fixed combination in patients with open-angle glaucoma*

ABSTRACT

Purpose: To compare the efficacy and tolerability of a once daily evening dose of the latanoprost/timolol fixed combination (LTFC) with that of a once-daily evening dose of the bimatoprost/timolol fixed combination (BTFC) in patients with open-angle glaucoma with elevated intrao­cular pressure (IOP) insufficiently responsive to mono­therapy with prostaglandin analogues/prostamides.

Design: Prospective, randomized, evaluator masked, single-center study.

Participants: 36 patients with a diagnosis of open-angle glaucoma, with or without pseudoexfoliation, and inadequate control of IOP, insufficiently responsive to monotherapy with prostaglandin analogues/prostamides.

Main outcome measure: The primary end-points were the change in IOP at 9:00?am from baseline to week 4, and the difference between treatment groups in the mean diurnal IOP reduction from baseline to week 4.

Results: BTFC provided significantly greater mean diurnal IOP reduction [mean (standard deviation)] 2.8 (0.9)?mmHg, compared with LTFC 2.1 (0.6)?mmHg, p = 0.0214. Both treatments significantly reduced the IOP from baseline at each IOP time-point measured, p < 0.0001, and for the mean diurnal IOP; p = 0.0049 for the LTFC, and p < 0.0001 for the BTFC. There were no significant differences in average hyperemia scores among groups, 1.25 (0.5) vs. 1.62 (0.69), p = 0.3835, for the LTFC and the BTFC, respectively.

Conclusions: The results of this study showed a significantly higher IOP-lowering effect of a once-daily evening dose of the BTFC compared to that of a once-daily evening administration of the LTFC.     

Efficacy and safety of tafluprost 0.0015% and timolol maleate 0.5% fixed combination in patients with ocular hypertension or open-angle glaucoma

Introduction: Lowering intraocular pressure (IOP) is at present the only therapeutic approach to the treatment of glaucoma proven to be successful. The choice of therapy must take into account efficacy, tolerability, safety, quality of life, adherence and cost. Monotherapy fails to achieve a satisfactory IOP reduction in 40 – 75% of glaucoma patients after > 2 years of therapy. So far, three prostaglandin/timolol maleate 0.5% fixed combinations (FCs) are available.

Areas covered: This review provides a background on the tafluprost–timolol FC (TTFC, Santen Oy) and its individual compounds. It summarizes the data on efficacy and safety, including comparative data with prostaglandin/timolol FCs already available.

Expert opinion: Tafluprost is a preservative-free prostaglandin analog with a similar IOP efficacy when compared with other prostaglandin analogs. However, its improved adverse effect profile seems to be beneficial in patients sensitive to preservatives. The preservative-free TTFC has no market authorization yet. Only one Phase III trial was published so far, but results are promising in terms of efficacy, tolerability and safety. It is likely that the TTFC will play a role in the treatment of open-angle glaucoma and ocular hypertension.     

Efficacy,tolerability and safety of the fixed combination of bimatoprost 0.03% and timolol 0.5% in a broad patient population: multicenter,open-label observational study*

ABSTRACT

Objective: To evaluate intraocular pressure (IOP)-lowering efficacy, tolerability, and safety of the fixed combination of bimatoprost 0.03% and timolol 0.5% (Ganfort^?) among German patients.

Methods: Multicenter, observational, open-label study of patients with primary open angle glaucoma or ocular hypertension (n?=?606). As determined by participating physicians, patients had insufficient IOP control and required a medication change. They were switched to once-daily fixed-combination bimatoprost/timolol with no wash-out period. IOP was recorded at treated baseline, 4–6 weeks and 12 weeks after switching. Tolerability was measured using a 4-step scale (excellent, good, moderate, poor) and all adverse events were recorded.

Results: A total of 405 patients switched from monotherapy, 97 switched from other fixed combinations, and 104 switched from non-fixed combinations. Among all patients, 32.5% had used prostaglandin analog (PGA) monotherapy, 8.7% had been using a fixed combination that included a PGA, and 6.9% had been using an adjunctive combination of a PGA and a β-blocker. Mean treated baseline IOP (±SD) for all patients was 20.7?±?3.5?mmHg. Overall, changing medication to fixed-combination bimatoprost/timolol lowered IOP to 16.6?±?2.7?mmHg (p?<?0.001 vs. baseline) after 4–6 weeks and to 16.1?±?2.6?mmHg (p?<?0.001) after 12 weeks; reductions of 19.8% and 22.2%, respectively. Combined bimatoprost/timolol provided an additional IOP reduction versus baseline in most subgroups based on prior treatment. At week 12, patients who had previously used a β-blocker achieved an additional 25.8% decrease from baseline and IOP was reduced by 22.6% in former PGA monotherapy patients. At week 12, 84.6% of all eyes reached a target pressure less than or equal to 18?mmHg. Tolerability of bimatoprost/timolol was rated excellent or good by the physicians for 98.7% of patients and by 96.7% of the patients themselves. Few adverse events occurred during the treatment period.

Conclusions: Although this study was limited by its observational design, our results show that the fixed combination of bimatoprost 0.03%/timolol 0.5% was effective, well tolerated, and safe in a broad patient population.     

Overview of the BAK-free travoprost/timolol BAK-free fixed combination

Introduction: Glaucoma is the second leading cause of blindness globally, representing a significant public health concern. More than 60 million people are affected by glaucoma worldwide; as this population ages, the number is expected to increase. Glaucoma is a collection of heterogeneous diseases sharing common clinical characteristics. The goal of treatment is to prevent significant visual dysfunction through reduction of intraocular pressure (IOP).

Areas covered: This is a review of the current literature about combination therapeutic regimens for the reduction of IOP, focusing on the risk : benefit profile of a fixed-combination therapy using travoprost and timolol.

Expert opinion: Since the debut of prostaglandin analogues in the 1990s, only modest innovation has occurred in glaucoma pharmacology. A growing body of research has established that the preservative benzalkonium chloride (BAK) might not be the benign contributor expected of excipient ingredients. Thus, BAK-free treatments were developed, with the goal of IOP reduction without furthering ocular surface disease symptoms. The BAK-free travoprost/timolol combination represents an important addition to glaucoma medication options and may fill an unmet need in this therapeutic arena.     

Direct and crossover effects of brinzolamide,betaxolol, and latanoprost on choroidal thickness

Purpose: To investigate the acute effects of brinzolamide, betaxolol, and latanoprost (drugs commonly used in the medical management of glaucoma) on choroidal thickness using enhanced depth imaging optical coherence tomography (EDI-OCT).

Methods: Ninety healthy volunteers were evaluated in this prospective study. Participants were randomly divided into 3 groups. Brinzolamide, betaxolol, and latanoprost were administered into the left eyes of the first group (n?=?30), second group (n?=?30), and third group (n?=?30), respectively, and artificial tear (Sodium hyaluronate) was instilled into the right eyes of all participants. Subfoveal choroidal thickness (SFCT) was measured using EDI-OCT before and 45?minutes after administration of the antiglaucomatous drops.

Results: SFCT revealed a significant increase in the left eye (administered antiglaucomatous drop) in the brinzolamide (p?=?0.001) and betaxolol groups (p?=?0.049) and a significant increase also in the right eye (administered artificial drop) in the brinzolamide (p?=?0.001) and betaxolol groups (p?=?0.001). However, SFCT did not reveal a significant increase in the left eye (p?=?0.213) or in the right eye (p?=?0.062) in the latanoprost group.

Conclusion: Brinzolamide and betaxolol caused an increase in SFCT, while latanoprost had no significant effect on SFCT.     

拉坦前列素滴眼液与其复合剂的降眼压作用的比较

目的：评价0.005%拉坦前列素滴眼液＋0.5%噻吗洛尔滴眼液治疗原发性开角形青光眼患者的替代降眼压作用及其安全性。方法应用0.005%拉坦前列素滴眼液单一治疗的原发性开角型青光眼患者31例,给予0.005%拉坦前列素滴眼液＋0.5%噻吗洛尔滴眼液替代治疗。每晚点药1次,每次1滴。将连续点药后4、8、12周的眼压与基线眼压进行比较研究,同时观察血压、心率等全身及局部不良反应。结果0.005%拉坦前列素滴眼液＋0.5%噻吗洛尔滴眼液可以更有效降低眼压。连续点药4、8、12周后,与基线相比,眼压分别额外下降（2.2±1.1）mmHg、（2.0±0.9）mmHg、（2.2±1.0）mmHg,差异均具有统计学意义（P〈0.05）。连续点药4、8、12周后,获得至少2mmHg眼压下降值的患者百分率分别为64.5%、61.3%、64.5%。心动过缓（3.2%）是最严重的不良反应。结论0.005%拉坦前列素＋0.5%噻吗洛尔复方滴眼液能够更加有效的降低目标眼压,可以作为0.005%拉坦前列素滴眼液的替代治疗手段。     

The effect of caffeine on choroidal thickness in young healthy subjects

Background: To investigate the effect of oral caffeine intake on choroidal thickness using optical coherence tomography (OCT).

Methods: Eighteen otherwise healthy caffeine users and 18 controls were enrolled. All participants underwent OCT scanning with high-speed and resolution spectral-domain OCT device (3D OCT 2000, Topcon, Japan) at baseline, and 1 and 3?h following 200-mg oral caffeine intake in the study and after oral placebo in the control group. The measurements were taken in the morning (10–12 am) to avoid diurnal fluctuation.

Results: The median choroidal thickness at the fovea prior to oral caffeine intake was 337.00 (IQR 83.75) μm, which decreased to 311.00 (IQR 79.25) μm at 1?h and 311.00 (IQR 75.00) μm at 3?h following oral caffeine intake (p?=?0.001, 0.002, respectively). The median choroidal thickness was also significantly decreased following oral caffeine intake at other five extrafoveal points (p?p?=?0.552, 0.704, respectively).

Conclusions: Caffeine causes a significant decrease in choroidal thickness following oral intake. This decrease might be a result of reduced ocular blood flow due to its vasoconstrictive effect.     

Observational study of patients switched to the fixed travoprost 0.004%/timolol 0.5% combination in Croatia

The purpose of this study was to assess both the benefits of a 3-month travoprost 0.004%/timolol 0.5%fixed combination (trav/tim) regimen in comparison with previous medications for the control of intraocular pressure (IOP) and the tolerability of these drug regimens in glaucoma patients. An observational, non-interventional, open-label study of 406 eyes with primary open angle glaucoma and ocular hypertension was thus undertaken. One drop of trav/tim fixed combination was administered in the evening for 3 months. Patients were divided into five groups according to previous drug regimens: timolol 0.5% monotherapy; betaxolol 0.5% monotherapy; latanoprost 0.005% monotherapy; travoprost 0.004% monotherapy; and dorzolamide 2%/timolol 0.5% fixed combination. Upon medication substitution, the trav/tim fixed combination provided better IOP control and tolerability in all five patient groups. At the 3-month follow up, the mean IOP changes from previous therapy were as follows: 5.2 ± 2.7 mmHg (20.8% change) in timolol 0.5% group; 5.7 ± 2.2 mmHg (22.5% change) in betaxolol 0.5% group; 3.8 ± 2.6 mmHg (24.5% change) in latanoprost 0.005% group; 4.4 ± 2.8 mmHg (20% change) in travoprost 0.004% group; and 3.4 ± 4.1 mmHg (14.5% change) in dorzolamide 2%/timolol 0.5% fixed combination group. The difference between baseline and trav/tim combination patient satisfaction at the 3-month follow-up was significant. Thus, the trav/tim fixed combination provided better IOP control and tolerability than previous mono- or polytherapies.     

Monitoring adherence rates in glaucoma patients using the Travatan Dosing Aid. A 6-month study comparing patients on travoprost 0.004% and patients on travoprost 0.004%/timolol 0.5% fixed combination

Objective: To assess adherence in glaucoma patients using the Travatan Dosing Aid (TDA); to record differences in adherence by age, sex, therapy, systemic therapies, years from diagnosis, type of therapy and intraocular pressure (IOP).

Research Design and Methods: Sixth-month cohort study; fifty-six Caucasian, primary open-angle glaucoma patients on travoprost (T) or travoprost/timolol fixed combination (TTFC) monotherapy were submitted to four visits: at baseline and months 1, 3 and 6 (M1, M3, M6). Adherence was recorded with TDA and classified as ‘high’ if greater than 90%. Self-reported and physician-presumed adherence data were collected. Kruskall-Wallis and Fisher's exact tests were applied.

Results: Thirty-two patients (54.2%) were treated with T. Age, sex, level of schooling, presence of systemic comorbidities, duration of current therapy and IOP were similar between T and TTFC. Seventeen subjects (30.3%) recorded high adherence at every visit, 13 (23.2%) at two visits, 26 (46.4%) otherwise. Adherence was maintained over time with a slight decrease from month 1 to month 6 without statistical differences within and between groups. Adherence was statistically influenced by age (p = 0.007) and duration of therapy (p = 0.004).

Conclusion: The typical nonadherent patient is elderly. TDA records indicate that only a minority of patients are really adherent: predictive models to screen for poor adherence are needed.     

Effect of topiramate on choroidal thickness and anterior chamber parameters in the treatment of patients with migraine

Objective: To investigate the effects of topiramate on choroidal thickness and anterior chamber parameters using optical coherence tomography in the treatment of patients with migraine.

Methods: A total of 22 eyes of 22 adults (12 females, 10 males) diagnosed with migraine and scheduled to topiramate treatment for pain control were recruited in this prospective study. Choroidal thickness (CT), anterior chamber depth (ACD), anterior chamber angle (ACA), spherical refractive equivalent (SphEq) and intraocular pressure (IOP) measurements were recorded at baseline (prior the topiramate therapy), first and second month visits for the statistical analysis. One-way ANOVA with repeated measures test was used for the statistical evaluation.

Results: Mean age of the patients was 40.2?±?6.5?years. Mean CT at central fovea was 324?±?47?μm initially, 341?±?45?μm in the first month and 344?±?46?μm in the second month, thus first and second month measures were significantly higher than base values (p?p?=?0.001). Baseline ACD (3.66?±?0.22?mm) measures significantly decreased at the first month (3.63?±?0.22?mm) and second month (3.62?±?0.22?mm, p?=?0.009). Also, a significant reduction was detected in the first (36.2?±?4.9°) and second month (35.9?±?5.1°) ACA measures comparing with baseline (39.1?±?5.1°, p?=?0.05). A significant myopic shift was determined in the first and second month SphEq values (?0.08?±?0.6, ?0.10?±?0.6, respectively, p?=?0.05).

Conclusions: The study revealed increased CT and altered anterior chamber parameters and IOP due to topiramate therapy. Therefore, the patients using topiramate should be carefully monitored by an ophthalmologist considering the possible side effects.     

Assessment of macular choroidal thickness,central macular thickness and retinal nerve fiber layer in patients receiving oral isotretinoin treatment

Abstract

Purpose

To investigate the impact of oral isotretinoin therapy in choroidal thickness, central macular thickness (CMT), and retinal nerve fibre layer (RNFL) thickness using optical coherence tomography (OCT).     

Switching from concomitant latanoprost 0.005% and timolol 0.5% to a fixed combination of travoprost 0.004%/timolol 0.5% in patients with primary open-angle glaucoma and ocular hypertension: a 6-month,multicenter, cohort study

Purpose: To assess the usefulness and tolerability of systematically switching glaucoma patients from latanoprost 0.005% and timolol 0.5% (Lat + Tim) to a fixed combination of travoprost 0.004%/timolol 0.5% (TTFC), and to record the effects of this switch on tear-film break-up time (TBUT). Main outcome measures: Intraocular pressure (IOP) reduction, patients reaching IOP < 18 mmHg; the rate of discontinuation; TBUT; and the onset of adverse events (AEs). Methods: Multicenter, observational cohort, 6-month study: 309 patients on concomitant Lat + Tim were switched to TTFC (evening dosage). IOP, TBUT, and AEs were recorded at baseline and after 1 and 6 months. Results: IOP was significantly decreased (from 18.3 ± 2.9 to 16.6 ± 2.7 mmHg) after substitution (p < 0.0001). Many patients (82%) reached an IOP < 18 mmHg (p < 0.0001). TBUT improved significantly (from 8.4 ± 3.6 to 9.2 ± 3.8 s, p < 0.0001). A few patients reported AEs (8.7%), which caused discontinuation in a low percentage (4.5%). Conclusion: TTFC appeared useful in this selected population. In this study, patients who underwent a regimen modification to TTFC obtained further reduction in IOP with a lower exposition to preservative toxicity. The low discontinuation rate at 6 months indicates a good tolerability profile.     

Safety and tolerability of the tafluprost/timolol fixed combination for the treatment of glaucoma

Introduction: The preservative-free (PF) fixed combination (FC) of tafluprost 0.0015%/timolol 0.5% is the newest member of the prostaglandin analogue/timolol FC class.

Areas covered: In this review, we summarize data on safety and tolerability of this FC.

Expert opinion: The intraocular pressure-lowering effect of the tafluprost/timolol FC is approximately 30 – 35%, which is similar to that of the other members of the class. However, in contrast to most similar eye drops the tafluprost/timolol FC is manufactured in a PF, unit-dose pipette formulation. The PF nature eliminates preservative-related ocular surface changes, and improves tolerability. In clinical studies, the tafluprost/timolol FC was well tolerated. The side effects represented the typical side effects of the topical prostaglandin analogue class. The most common side effect, conjunctival hyperemia was mild, and occurred in only 6.4 – 8% of patients during 6 months of treatment. The figures for ocular irritation were also low (7.0 – 12.7%). The other side effects occurred only in very few patients. The frequency and severity of conjunctival hyperemia was lower than those published for most prostaglandin/timolol FCs. Thus, the main clinical advantage of this PF FC is improved tolerability, which may support treatment adherence of glaucoma patients.     

Preservative-free tafluprost/timolol fixed combination: a new opportunity in the treatment of glaucoma

Introduction: Medical therapy of glaucoma aims to maintain the patient’s visual function and quality of life. This generally commences with monotherapy, but it is often difficult to reach the predetermined target pressure with this approach. Fixed combinations (FCs) are therefore selected as the next step of the medical therapy algorithm. By employing a prostaglandin/timolol fixed combination (PTFC) the desired target 24-hour intraocular pressure can be reached in many glaucoma patients with the convenience of once-a-day administration and the associated high rate of adherence.

Areas covered: The current role and value of FCs in the medical therapy of glaucoma is critically appraised. Special attention is paid to the PTFCs and the emerging role of preservative-free PTFCs. This review summarizes existing information on the efficacy and tolerability of the new preservative-free tafluprost/timolol FC (Taptiqom®).

Expert opinion: The preservative-free tafluprost/timolol FC represents a promising stepwise treatment option for those patients whose intraocular pressure is insufficiently controlled with available monotherapy options. This novel FC has the potential to substantially improve glaucoma management and through evolution of the current glaucoma treatment paradigm, to become a core therapeutic option in the future. Nonetheless, future research is needed to better delineate the therapeutic role of current and future preservative-free FCs in glaucoma therapy.     

Brinzolamide/timolol fixed combination: a new ocular suspension for the treatment of open-angle glaucoma and ocular hypertension

For the treatment of open-angle glaucoma, the most frequent cause of irreversible visual loss, fixed combinations of different topical intraocular pressure (IOP) lowering molecules have gained an important role in recent years. The use of fixed combinations reduces the number of daily instillations, which promotes adherence to the prescribed medication and diminishes the exposition of the ocular surface to preservatives. The fixed combination of brinzolamide and timolol was recently approved by the European Medicines Agency (EMEA) and is now available in several countries in Europe. It contains two molecules widely used to treat glaucoma: timolol 0.5% (5 mg/ml) and brinzolamide 1% (10 mg/ml) in ophthalmic suspension formulation. This fixed combination is approved for twice-daily instillation to reduce elevated IOP in open-angle glaucoma and ocular hypertension. The brinzolamide/timolol fixed combination provides an approximately 30 – 33% IOP reduction from the untreated baseline IOP of 25 – 27 mmHg; thus, it is more potent than either of its ingredients alone. It is similarly effective but better tolerated than the dorzolamide/timolol fixed combination, which consists of molecules from the same pharmacological classes. The brinzolamide/timolol fixed combination can be used by itself as a separate therapy, but owing to the additivity of its ingredients to IOP-lowering drugs belonging to other classes, it may also be administered adjunctive to other IOP-reducing molecules, most importantly topical prostaglandin analogues. The ocular and systemic tolerance of the brinzolamide/ timolol fixed combination was reported favorable in Phase III studies, but no long-term clinical experience with this preparation is available at present.