Fixed-combination intraocular pressure-lowering therapy for glaucoma and ocular hypertension: advantages in clinical practice.

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Biblioteka Uniwersytetu Warszawskiego on 02/19/15 For personal use only.

Review

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Introduction

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Common challenges in glaucoma therapy: outcomes with concomitant therapy versus fixed-combination therapy

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Fixed-combination intraocular pressure-lowering therapy for glaucoma and ocular hypertension: advantages in clinical practice Ga´bor Hollo´†, Fotis Topouzis & Robert D Fechtner †

Semmelweis University, Department of Ophthalmology, Budapest, Hungary

Considerations with fixed-combination glaucoma therapies

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Conclusion

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Expert opinion

Introduction: Several large, randomized, prospective clinical trials have demonstrated that medical therapy to reduce intraocular pressure (IOP) delays the onset and decreases progression of glaucoma. Many patients with glaucoma require more than one ocular hypotensive medication to achieve and maintain their target IOP; however, use of multiple topical glaucoma preparations is associated with factors that may decrease treatment efficacy and increase adverse effects. Areas covered: This article reviews the use of fixed-combination therapies in glaucoma management, the relationship between IOP management and disease progression and challenges associated with glaucoma therapy when multiple instillations are required. Specific topics discussed include IOPlowering efficacy, adherence and persistence, preservative exposure and washout-related risk of diminished IOP reduction. Potential benefits of fixed combinations versus multiple non-fixed medications are reviewed based on a detailed literature search. Expert opinion: Compared with non-fixed combinations, fixed-combination glaucoma therapies provide various demonstrated benefits (similar IOPlowering efficacy with reduced exposure to preservatives and risk of preservative-related ocular surface disease symptoms, elimination of washout associated with insufficient time separation of instillations and reduced number of total instillations). Further, due to simplification of the instillation regimen, fixed combinations may improve treatment adherence and persistence, thereby improving stability of IOP control over time. Keywords: adherence, compliance, cost, fixed-combination therapy, glaucoma, intraocular pressure, medical therapy, ocular hypertension, persistence, preservatives Expert Opin. Pharmacother. (2014) 15(12):1737-1747

1.

Introduction

Glaucoma comprises a collection of progressive diseases with various etiologies that all result in characteristic optic nerve head damage and deterioration of visual function and is a leading cause of blindness worldwide [1,2]. Ocular hypertension, which is characterized by elevated intraocular pressure (IOP) in the absence of glaucomatous optic neuropathy and visual field defects, places patients at increased risk of developing glaucoma [1,3,4]. Glaucomatous optic neuropathy and visual field defects are progressive and associated with uncontrolled or poorly controlled IOP in studies that followed patients for as long as 11 years [4-7]. In patients with glaucoma, quality of life decreases with increasing disease severity, and decreased quality of life correlates with decreased visual acuity and more severe visual field 10.1517/14656566.2014.936850 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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Many patients require more than one topical intraocular pressure (IOP)-lowering agent to reach and maintain the target IOP, particularly after the first year of treatment. Concomitant instillation of non-fixed combination therapy increases treatment complexity and may reduce adherence. Ocular surface disease is common in glaucoma patients and is associated with the cumulative preservative burden of IOP-lowering eye drops. IOP-lowering efficacy of fixed-combination glaucoma therapies is similar to non-fixed combinations. Fixed combinations reduce treatment complexity and exposure to preservatives compared with concomitant use of the component medications. Fixed-combination drugs are suggested to improve adherence, which may improve long-term stability of IOP reduction. In routine clinical practice, for patients with glaucoma or ocular hypertension, fixed-combination medications may be beneficial in terms of convenience of administration, improved long-term adherence and quality of life and may, therefore, lead to improved long-term IOP management.

This box summarizes key points contained in the article.

deterioration [8]. Further, depression is more prevalent with increasing glaucoma severity and with patients’ perceptions of worsening visual function [9]. IOP is currently the only treatable risk factor of optic nerve damage and visual field deterioration in glaucoma. Higher IOP levels are associated with increased risk of glaucomarelated blindness [10]. A meta-analysis of five published studies of patients with open-angle glaucoma found that elevated mean IOP was a significant risk factor for disease progression over 5 years [11]. Mean IOP was 20.0 mmHg for patients with disease progression and 17.1 mmHg for patients who remained stable. Further, only 49% of patients with mean IOP > 18 mmHg maintained stable visual fields and neural rim width, compared with 82% of patients with mean IOP between 13 and 17 mmHg, and 96% of patients with mean IOP < 13 mmHg. These findings are similar to the results of a study comparing two alternative sequences of surgical treatment that found a reduced visual field progression in glaucoma patients who maintained IOP £ 18 mmHg throughout the study [12]. Several large clinical studies (e.g., the Early Manifest Glaucoma Trial, the Ocular Hypertension Treatment Study and the Collaborative Initial Glaucoma Treatment Study) demonstrated that medical therapy delays the onset and progression of glaucomatous optic nerve head damage and visual field defects [4-6,13,14]. Reducing IOP is currently the only way to effectively decrease progression of damage in open-angle glaucoma and progression of ocular hypertension to manifest glaucoma. Maintaining sufficiently low IOP reduces the risk of progression to functionally significant visual field deterioration and improves 1738

functional outcomes even in patients with normal-tension glaucoma [4,15-19]. In addition to measuring IOP during routine office time clinical visits, evaluation of the 24-h IOP is important because IOP can vary significantly over 24 h in patients with glaucoma, and peak IOP often occurs outside of office hours [20]. A retrospective analysis of long-term progression of primary open-angle glaucoma demonstrated that 24-h peak IOP is an independent risk factor for progression and that among patients with similar baseline characteristics, mean 24-h peak IOP was significantly higher in patients who progressed compared with those who did not progress over 5 years [21]. Patients with a 24-h peak IOP of £ 18 mmHg did not progress in approximately 75% of cases [22]. In a separate study, peak IOP monitoring identified the need for changes in glaucoma management in many patients [23]. It has been suggested that large fluctuations in IOP may be associated with optic nerve injury [20]; however, current evidence on the role of peak IOP and IOP fluctuation in glaucoma progression is limited and remains inconsistent [6,24]. Pharmacotherapy, commonly started with a single topical ocular hypotensive agent, is typically the first approach for reducing IOP [18]. These agents decrease IOP either by decreasing aqueous production or increasing aqueous humor outflow via the conventional (trabeculo-canalicular) or uveoscleral pathway or both [25]. Prostaglandin analogs (e.g., latanoprost, tafluprost, travoprost and bimatoprost) and b-blockers (e.g., timolol) are ocular hypotensive agents frequently prescribed as first-line monotherapies to reduce IOP in open-angle glaucoma and ocular hypertension because of their IOP-lowering efficacy and acceptable safety and tolerability profiles. However, for many patients topical IOP reduction with a single IOP-lowering agent does not provide sufficiently low IOP to prevent progression, or treatment with a single IOP-lowering agent is insufficient to achieve and maintain the targeted IOP in the long term [4,14]. In large randomized controlled trials, up to 40% of patients with ocular hypertension required two or more medications to achieve a 20% IOP reduction from baseline [4,26]. In one cohort, monotherapy failed to maintain IOP control in 50% of patients after 2 years [27]. To increase the IOP-lowering efficacy of topical pharmacotherapy, adjunctive IOP-lowering medications are frequently needed. These ocular hypotensive agents, which are typically prescribed in combination with prostaglandin analogs or b-blockers, include topical carbonic anhydrase inhibitors (e.g., brinzolamide and dorzolamide) and a-agonists (e.g., brimonidine). In addition, b-blockers are commonly prescribed in combination with prostaglandin analogs. The aim of this review is to discuss the potential of fixedcombination therapies to improve glaucoma management. Additionally, the relationship between IOP management and disease progression and challenges associated with glaucoma therapy when multiple instillations are required are covered. Specific topics discussed include IOP-lowering

Expert Opin. Pharmacother. (2014) 15(12)

Fixed combinations for glaucoma

efficacy, adherence and persistence, preservative exposure and washout-related risk for diminished IOP reduction.

Common challenges in glaucoma therapy: outcomes with concomitant therapy versus fixed-combination therapy

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Efficacy Combination topical glaucoma therapy comprises the use of IOP-lowering molecules that belong to different pharmacological classes and are additive in IOP-lowering efficacy. The different agents can be administered concomitantly, or when available, in fixed drug combinations. Thus, by definition, the IOP-lowering efficacy of fixed-combination therapies is superior to that of monotherapy with a single component [28-32]. A meta-analysis of randomized clinical trials comparing three fixed combinations of a prostaglandin analog and timolol demonstrated that the fixed-combination therapies provided greater IOP reduction compared with their respective prostaglandin analog or timolol components [33]. Several randomized, double-masked, controlled, prospective clinical studies have shown that, for those fixed-combination medications that have been studied to date, the IOP-lowering efficacy of fixed-combination therapies is comparable to that of the corresponding non-fixed-combination therapies [34-38]. In a meta-analysis of studies of fixed- versus non-fixed-combination therapies or monotherapies comprising prostaglandin analogs and/or b-blockers, fixed combinations were more efficacious than their individual components (mean differences in IOP reduction with fixed combinations versus timolol monotherapy; -2.74 [95% CI: -3.24 to -2.23] for latanoprost/timolol; -1.49 [95% CI: -1.86 to -1.12] for bimatoprost/timolol; -1.93 [95% CI: -2.98 to -0.88] with travoprost/timolol), but less efficacious than their respective non-fixed combinations (mean overall difference in IOP reduction, 0.69 [95% CI: 0.29 -- 1.08]) [39]. The greater efficacy of non-fixed combinations in this analysis may have been due to less-frequent administration of b-blockers with the fixed combinations, given that prostaglandin analog-based fixed combinations are administered once daily, whereas b-blockers are most commonly administered twice daily. Optimal time of administration is an important consideration with fixed- versus non-fixed-combination therapies. IOP fluctuation over a 24-h period has been observed in patients receiving prostaglandin analogs, b-blockers, a-agonists and carbonic anhydrase inhibitors as monotherapy or as components of combination therapy [40,41]. Although there is evidence of circadian IOP regulation [20], 24-h IOP levels may also be influenced by the fact that the IOP-lowering efficacy of b-blockers is diminished at night [41,42]. Further, morning versus evening dosing of glaucoma medications is associated with different levels of IOP reduction. The IOPlowering efficacy of timolol is greatest when administered in the morning, whereas prostaglandin analogs are most effective


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when administered in the evening. Although both morning dosing and evening dosing of travoprost significantly reduced IOP, evening dosing of travoprost was associated with significantly lower 24-h IOP fluctuation and 10.00 h IOP compared with morning dosing [43]. Similarly, evening dosing of latanoprost led to greater IOP reduction compared with morning dosing [44]. Interestingly, overall mean diurnal IOP with evening versus morning administration of concomitant latanoprost/ timolol was similar; however, evening dosing was associated with significantly lower IOP at 06.00 h and a significantly smaller range of 24-h IOP compared with morning dosing [45]. Unfixed combinations enable separate dosing of IOP-lowering eye drops with complementary mechanisms of action at different times of day to optimize their combined IOP-lowering efficacy. This flexibility is not possible with fixed-combination therapies; however, fixed combinations decrease the number of instillations required daily and simplify treatment regimens. Additional studies are needed to establish the optimal time of administration for fixed-combination therapies to achieve optimal IOP reduction [37]. Extrapolation of the IOP-lowering results achieved with concomitant eye drop administration in clinical trials to long-term results in clinical practice may be misleading because the results of short-term clinical trials may not be representative of IOP reduction outside a research setting. In routine clinical practice, nonadherent patients may use their eye drops in the few days before the scheduled office visit; therefore, any periods of nonadherence between visits are not reflected in IOP observed at the clinical visits [46]. Adherence with actual medication regimens, including administering medications at the appropriate time points and separating sequential instillations by a sufficient time interval, decreases with treatment duration [47]. Thus, adherence may be lower in clinical practice than in clinical trials [48]. This phenomenon may cause decreased IOP reduction and reduced stability of IOP in the long term for patients using multiple IOP-lowering medications. Although the IOP-lowering effect of the fixed combinations may also be affected by nonadherence, it is likely that this effect is smaller than with non-fixed combinations because, in general, regimens with fewer instillations are associated with better adherence [49-51]. As discussed in detail later in this article, because of the convenience of administration and the improved adherence associated with fixed-combination therapies in clinical practice [37], it may be reasonable to hypothesize that, in real-life clinical practice, fixed combinations could lead to more stable IOP reduction over time than the corresponding non-fixed combinations; however, long-term, well-controlled studies comparing IOP in patients receiving fixed versus non-fixed combinations are needed to support this hypothesis.

Adherence and persistence to topical glaucoma medications

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Long-term treatment adherence is difficult to study objectively; most studies of adherence rely on patient self-reporting,


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dosing monitors or refill data. Better adherence to glaucoma treatment has been associated with less visual field progression compared with poor adherence or nonadherence [52]. Patients who were at least 90% adherent to their glaucoma medication regimens had no visual field progression, in contrast to 44% of patients with lower adherence rates, who had worsening of visual fields. In general, adherence with glaucoma medications is low [53], possibly because glaucoma and ocular hypertension lack overt symptoms. In addition, insufficient patient education, complexity of treatment regimens, medication-related side effects and technical difficulties associated with drop instillation or opening bottles have been identified as potential barriers to optimal adherence [47,51,54-56]. In a retrospective analysis of adherence of patients in Germany, nonadherence was found to be a cause of unsatisfactory IOP reduction in > 25% of patients [57]. Adding a second medication to initial monotherapy increased the interval between refills for the first medication by an average of 6.7 days; the increase in refill intervals was interpreted as an indication of decreased medication adherence (i.e., more missed doses) [49]. A key factor in patient-reported nonadherence with glaucoma medication is the wish for simpler treatment regimens [56]. Compared with multiple non-fixed therapies supplied in separate bottles that need to be administered at specific time points with specific time intervals between instillations, use of single-bottle medications (i.e., monotherapies or fixed-combination therapies) is associated with higher adherence [50,54,58]. Studies on the frequency of prescription refills suggest that persistence with glaucoma medications (i.e., continuation of prescribed treatment over time) and treatment coverage (i.e., the number of required doses that can be administered based on the prescriptions filled) are low, particularly when multiple medications are required [50,51,59,60]. A recent database analysis of approximately 2500 Japanese patients diagnosed with glaucoma revealed that persistence rates decreased considerably soon after initiation of glaucoma therapy [61]. The rates of persistence were approximately 73% after 3 months, 61% after 1 year and only 53% after 3 years, and the inverse association between decreasing persistence and increasing number of prescribed eye drops was statistically significant [61]. Further, a systematic literature review found that, according to prescription refill records, the medications dispensed in the first year of glaucoma treatment would enable treatment administration for only 56% of days and that at the end of the first year, < 70% of the patients remained persistent with therapy [53]. A retrospective database analysis found that both adherence and persistence were lower for patients receiving one of six different two-bottle concomitant therapy regimens compared with patients receiving either of two fixed-combination therapies [62]. The study results described previously all show that there is a serious need for improvement of adherence and persistence in glaucoma treatment. Fixed-dose combinations reduce the number of daily instillations and, therefore, may support adherence in patients who require more than one IOP-lowering agent [63]. 1740

Risk of washout due to instillation of different IOP-lowering drops with insufficient time separation

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Sequential instillation of multiple IOP-lowering medications introduces the risk of drug washout and decreased drug absorption [64]. The retention volume of the inferior conjunctival sac is approximately 7 µl; therefore, only a small percentage of the instilled volume of the eye drop is retained and absorbed [65,66]. Drug washout due to an insufficient time interval between consecutive instillations may lead to a smaller-than-expected IOP reduction in patients who need to use more than one IOP-lowering drop at the same time of day. When receiving concomitant therapy with multiple medications, patients are frequently instructed to wait for at least 5 min between instillations [67]. However, a survey-based study of patients with glaucoma demonstrated that 12% of the patients instilled a second glaucoma medication within 1 min after the first instillation, and nearly 25% waited < 5 min [66]. In another study, > 20% of the patients reported waiting for < 3 min between instillations [51]. By combining two IOP-lowering agents in the same solution or suspension, fixed-combination eye drops eliminate the risk of drug washout of their components. Exposure to preservatives There is increasing concern about the deleterious effects of preservatives in eye drops and, particularly, in the increased preservative burden associated with multiple-bottle therapy for glaucoma. Use of non-fixed-combination therapy increases the cumulative exposure to preservatives compared with that of fixed-dose combinations. Signs and symptoms of ocular surface disease related to chronic use of IOP-lowering drops preserved with benzalkonium chloride (BAK) are highly prevalent in glaucoma patients and have a negative impact on patients’ quality of life [68-71]. Prevalence of abnormal Ocular Surface Disease Index (OSDI) scores increase with increasing use of BAK-preserved topical glaucoma medications, including increasing number of drops used per day and longer duration of treatment [70-72]. In an observational, cross-sectional study of patients with glaucoma or ocular hypertension, many patients tolerated their first topical medication, but their OSDI scores worsened when receiving two or more medications [69]. This finding supports the concern that the increased preservative burden of multiple individual medications should be avoided or minimized when possible. In clinical practice, chronic exposure to preservatives applied in eye drops, particularly BAK, is associated not only with worse OSDI scores but also with increased prevalence of toxic ocular side effects, including decreased tear film stability and tear film breakup time, increased corneal and conjunctival staining and increased tear film osmolarity [70,72-75]. In animal models, in vivo confocal microscopy showed that exposure to BAK in the concentrations used in glaucoma eye drops pathologically altered the morphology of various corneal and conjunctival layers; immunohistochemical 2.4




assessment showed that the distribution of goblet cells and the expression of several inflammatory markers were abnormal, and impression cytology showed that conjunctival goblet cells were pathologically altered [76]. In vitro studies of various cultured human ocular cell lines found that BAK decreased the viability of the trabecular meshwork cells and was toxic to the epithelial cells [77,78]. The unfavorable effects of BAK increase with higher BAK concentrations, increasing duration of exposure and bedtime administration [74,79,80]. In a crossover study of patients with primary open-angle glaucoma, 14 days of once-daily, bedtime administration of an ocular hypertensive agent preserved with 0.02% BAK was associated with more pronounced ocular surface toxicity than twice-daily administration of medication preserved with 0.01% BAK [80]; signs and symptoms of ocular surface changes attributed to BAK were exacerbated in patients with an existing diagnosis of allergic conjunctivitis. Increased preoperative exposure to BAK-preserved ophthalmic solutions increases the risk of trabeculectomy failure [79]. This effect is proportional to the total amount of BAK applied to the eye before surgery, including lifetime exposure and exposure during the preoperative period [79]. BAK-free formulations have been demonstrated to be noninferior in reducing IOP as the same medications preserved with BAK [73,81-87]. Currently, several BAK-free preserved and preservative-free formulations of ocular hypotensive monotherapies and fixed-dose combinations (e.g., tafluprost, travoprost, bimatoprost, brimonidine, timolol, fixed-combination travoprost/timolol, fixed-combination dorzolamide/timolol) are commercially available. The tolerability and IOP-lowering efficacy of preservative-free fixed-combination tafluprost/ timolol and preservative-free fixed-combination bimatoprost/ timolol were recently demonstrated in two multicenter, Phase III clinical studies that included patients sensitive or allergic to preservatives (bimatoprost/timolol study) [88,89]. Both medications were noninferior to their comparators (preservative-free tafluprost/preservative-free timolol non-fixed concomitant therapy and BAK-preserved, fixed-combination bimatoprost/timolol, respectively). BAK-free travoprost/timolol preserved with polyquaternium-1 was shown to achieve IOP reductions similar to BAK-preserved travoprost/timolol [22]. This is an important finding given that BAK was previously proposed to increase absorption of coadministered medications; BAK-free travoprost/timolol, and possibly other BAKfree fixed combinations, provides IOP-lowering efficacy with potential for reduced risk of BAK-mediated ocular surface toxicity and tolerability issues [22]. A multicenter, cross-sectional epidemiological survey of European patients found that ocular signs and symptoms, including pain or discomfort, stinging or burning, foreign body sensation and dry eye sensation, were all significantly less frequent in patients receiving preservative-free glaucoma medications compared with those treated with IOP-lowering drugs preserved with BAK [90]. Similar results were demonstrated in a prospective, practice-based study of patients treated with one or more glaucoma medications

comprising preserved and preservative-free formulations; the ocular signs and symptoms increased with increasing numbers of preserved medications [91]. Compared with concomitant instillation of preserved IOP-lowering monotherapies, fixed-combination drugs decrease the cumulative exposure to BAK even if they are preserved with BAK [72,92]. This beneficial effect could be further increased if a fixed-dose combination IOP-lowering preparation did not contain BAK (alternatively preserved or preservative-free). It can be hypothesized that this advantage may be maintained even when the BAK-free medication is a part of a complex therapeutic regimen that contains an eye drop preserved with BAK because the total amount of BAK applied to the eye remains reduced. However, this hypothesis needs to be confirmed and quantified in prospective studies. Cost Depending on specific healthcare systems, fixed-combination medications may reduce treatment cost by providing multiple IOP-lowering agents in a single bottle [93,94]. Costs to patients for fixed-combination therapies may be lower than those for concomitant therapy with the separate components because of lower copayments and manufacturing costs (i.e., single prescription versus multiple prescriptions, multiple manufacturing costs versus manufacturing cost of a single bottle). A literature review of four randomized controlled trials conducted in Europe demonstrated improved cost minimization with fixed combinations of brimonidine and timolol or dorzolamide and timolol compared with concomitant therapy with their components in separate bottles [93]. As with branded drugs, cost differences may exist when comparing non-fixed- versus fixed-combination generic drugs. Cost structures vary greatly between countries and even within countries based on insurance and formularies, making generalized cost comparisons difficult. 2.5

Considerations with fixed-combination glaucoma therapies

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Glaucoma medical treatment is usually preferred to start with monotherapy [95-97] because in many patients a single ocular hypotensive agent is sufficient to reduce IOP to the targeted level. Prescribing multiple medications as first-line therapy, whether in fixed or non-fixed combinations, does not allow separate evaluation of the IOP-lowering efficacy and the adverse events attributable to the individual components. However, in one study, 30% (15/50) of ophthalmologists surveyed in the European Union reported prescribing fixedcombination drugs as their first choice and 80% (40/50) as their second choice [98]. Nearly all ophthalmologists surveyed (98%; 49/50) believed that fixed-combination therapies for glaucoma improved patient care through better treatment adherence and patient quality of life [98]. When more than one agent is needed to achieve the target IOP, guidelines propose a stepwise escalation of the treatment regimen; for most


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Table 1. Benefits of fixed-combination glaucoma therapies. Efficacy

Superior to monotherapy with any of the components Noninferior to unfixed combinations of the same two components, with reduced treatment complexity

Treatment adherence

Potential for improved adherence compared with unfixed combinations Higher persistence rates compared with unfixed combinations

Washout risk

No washout effect in contrast to concomitant instillation of the individual components

Preservative exposure

Reduced cumulative exposure to preservatives compared with concomitant use of the components Potential for reduced preservative-related risk of ocular surface disease

Cost

Potential for cost reduction through a single copayment versus multiple copayments for separate bottles containing the individual components Potential long-term direct and indirect cost reduction through improved glaucoma management and decreased glaucoma progression

patients, it is usually not recommended to prescribe medications in more than two individual bottles since multiple instillations increase the risk of decreased adherence [96]. The effectiveness of adding one adjunctive therapy to a fixedcombination therapy has been demonstrated [21,99,100]; this approach reduces the complexity of the treatment regimen (i.e., two bottles versus three bottles) and allows a feasible regimen with a reasonable number of bottles and instillations per day. As discussed, for patients who require multiple medications to achieve and maintain target IOP, fixed-combination ocular hypotensive medications provide a solution to many issues associated with multidrug glaucoma therapy, including increased risk of nonadherence, cumulative exposure to preservatives and potential washout when sequential instillations are not separated by a sufficient time interval. However, a commonly cited limitation of fixed-combination glaucoma medications is that fixed-dose formulations do not allow individualization of treatment in terms of dosing frequency and concentration of the active molecules [92,94]. All current topical fixed combinations are formulated with the highest approved doses of their constituents; altering the number of daily doses or the time of administration is not possible with fixed-combination therapies. However, even monotherapies and concomitant therapies with individual medications are not usually individualized since the concentrations and administration regimens are largely standardized. 4.

Conclusion

Many patients with glaucoma or ocular hypertension require multiple instillations to achieve and maintain their target IOP, but patients’ quality of life may be negatively affected by the side effects associated with administration of multiple concomitant glaucoma medications. Therefore, therapies with powerful IOP-lowering efficacy and simple administration regimens can be prescribed to promote treatment adherence and persistence and to maintain stable IOP control to minimize disease progression and vision loss. Compared 1742

with concomitant therapy comprising multiple individual drugs, use of fixed-combination therapy reduces treatment complexity, may improve treatment adherence, decreases the cumulative exposure to preservatives, reduces the BAKassociated ocular discomfort and ocular surface disease symptoms, decreases the risk of insufficient dosing due to washout and difficulty instilling multiple medications and may contribute to better long-term stability of IOP control (Table 1). As a consequence, fixed-combination glaucoma therapies may offer superior IOP-lowering effects in clinical practice compared with the concomitant administration of their individual components. In conclusion, when more than one medication is needed to achieve target IOP, and the active ingredients are available in fixed-dose combination formulas, prescribing fixedcombination ocular hypotensive drugs may be beneficial for patients with glaucoma or ocular hypertension in terms of long-term treatment effectiveness and convenience. 5.

Expert opinion

The goal of managing glaucoma and ocular hypertension is to maintain vision and vision-related quality of life while minimizing the side effects associated with treatment over the lifespan of treated patients. Patients with glaucoma are reported to experience lower quality of life compared with nonglaucomatous individuals; survey-based assessments suggest that ocular surface disease related to topical IOP-lowering therapies is common in glaucoma patients and negatively affects quality of life. The incidence of glaucoma increases with increasing age, and as such, many patients with glaucoma or ocular hypertension are elderly, have comorbid conditions that require management with multiple medications and may have compromised vision. These unmodifiable conditions represent significant barriers to optimal treatment for glaucoma, even when few instillations per day are prescribed. In addition, if a complex glaucoma treatment regimen is prescribed, the drawbacks of using multiple concomitant individual glaucoma medications (e.g., increased exposure to preservatives and risk




of washout due to insufficient time intervals between sequential instillations) may further decrease adherence to treatment. The elderly may experience increased difficulty in handling a greater number of eye drop bottles and successfully instilling several topical medications; these difficulties may have a cumulative negatively impact on the adherence to glaucoma treatment. Approaches to minimize these difficulties, such as increasing the use of fixed-combination glaucoma therapies, may support adherence, IOP-lowering efficacy and long-term control of glaucoma. A large body of research has established that the IOPlowering efficacy of fixed-combination glaucoma therapies is superior to monotherapy with either of their components. Although published comparisons of fixed versus non-fixed formulations are not available for some existing combination therapies, available studies have demonstrated that IOP reductions achieved with fixed-combination medications are similar to those of the corresponding non-fixed combinations. A limitation of the literature available is that clinical studies have lacked consistency in design, duration and end points; this makes it difficult to directly compare efficacy variables and patient outcomes between the different studies. Further, long-term follow-up studies of patients receiving fixed versus non-fixed formulations would be informative. Such studies could identify potential clinically significant differences in treatment adherence and persistence associated with corresponding fixed and non-fixed combinations. Theoretically, fixed-combination glaucoma therapies may lead to greater IOP reductions over time compared with the corresponding non-fixed combinations because of improved convenience, decreased cumulative exposure to ocular preservatives and risk of adverse side effects. The improved adherence and persistence may result in reduced disease progression and visual field deterioration. A challenge in the accurate quantification of treatment compliance is that adherence to and persistence with Bibliography

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Declaration of interest Ga´bor Hollo´ is a board member, consultant or speaker for Alcon, Allergan, Merck Sharp & Dohme, NicOx and Santen. Fotis Topouzis is a consultant for Novartis, Alcon, Bausch + Lomb, has received speaker honorarium from Alcon and received grants/support from Alcon, Novartis and Pfizer. Robert Fechtner is a consultant for Alcon and Santen. Medical writing support was provided by Heather D. Starkey, PhD, of Complete Healthcare Communications, Inc. (Chadds Ford, PA, USA) and was funded by Alcon. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Affiliation

Ga´bor Hollo´†1 MD PhD DSc, Fotis Topouzis2 MD & Robert D Fechtner3 MD † Author for correspondence 1 Professor of Ophthalmology, Director of Glaucoma Service, Semmelweis University, Department of Ophthalmology, Ma´ria u. 39, 1089; Budapest, Hungary Tel: +003 620 825 8461; Fax: +003 612 100 309; E-mail: [email protected] 2 Associate Professor of Ophthalmology, Aristotle University of Thessaloniki, School of Medicine, American Hellenic Educational Progressive Association (AHEPA) Hospital, Department of Ophthalmology, St. Kiriakidi 1, 54636; Thessaloniki, Greece 3 Professor of Ophthalmology, The State University of New Jersey, Institute of Ophthalmology and Visual Science, New Jersey Medical School Rutgers, 90 Bergen Street, Suite 6100; Newark, NJ 07103, USA

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Postural change of intraocular and blood pressures in ocular hypertension and low tension glaucoma.

HLA antigens in glaucoma and ocular hypertension.

'Glaucoma suspect' or 'ocular hypertension'.

Preservative-free bimatoprost 0.03% in patients with primary open-angle glaucoma or ocular hypertension in clinical practice.

Intraocular pressure-lowering efficacy and safety of bimatoprost 0.03% therapy for primary open-angle glaucoma and ocular hypertension patients in China.

'Ocular hypertension' vs open-angle glaucoma.

Timolol in maintenance treatment of ocular hypertension and glaucoma.

Observations on color vision testing in ocular hypertension and glaucoma.

Pattern discrimination perimetry in patients with glaucoma and ocular hypertension.

The pattern electroretinogram in glaucoma and ocular hypertension.

Norepinephrine in treatment of ocular hypertension and glaucoma.

A lymphatic defect causes ocular hypertension and glaucoma in mice.

Peripheral contrast sensitivity in glaucoma and ocular hypertension.

Glucocorticoid therapy and ocular hypertension.

Drug-Induced Ocular Hypertension and Angle-Closure Glaucoma.

Ocular betaxolol. A review of its pharmacological properties, and therapeutic efficacy in glaucoma and ocular hypertension.

Chronic open-angle glaucoma and ocular hypertension. An epidemiological study.

Steroid glaucoma: corticosteroid-induced ocular hypertension in cats.

Ocular carteolol. A review of its pharmacological properties, and therapeutic use in glaucoma and ocular hypertension.

Corneal hysteresis in patients with glaucoma-like optic discs, ocular hypertension and glaucoma.

Timolol Maleate to Prostaglandin Therapy for Treatment of Ocular Hypertension or Glaucoma.

'Ocular hypertension' vs open-angle glaucoma: a different view.

Macular colour contrast sensitivity in ocular hypertension and glaucoma: evidence for two types of defect.

Are clinical practice guidelines for cataract and glaucoma trustworthy?