Russian Journal of Clinical Ophthalmology
ISSN 2311-7729 (Print), 2619-1571 (Online)

Comparative analysis of the efficacy and safety of fixed-dose combinations versus their individual components for open-angle glaucoma

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DOI: 10.21689/2311-7729-2019-19-1-13-19
Z.M. Nagornova1, A.V. Kuroyedov2,3, A.V. Seleznev1
1Ivanovo State Medical Academy, Ivanovo, Russian Federation
2 Central Military Clinical Hospital named after P.V. Mandryka, Moscow, Russian Federation
3Pirogov Russian National Research Medical University, Moscow, Russian Federation

Currently, various glaucoma medications are available at the pharmaceutical market. Among them, fixed-dose combinations are of special importance which are considered as first-line agents for some patients (i.e., with advanced glaucoma or high intraocular pressure). Fixed-dose combinations are superior to individual components through the comfortable regimen with less instillations which improves treatment compliance. Moreover, IOP-lowering effect of fixed-dose combinations is similar or even greater than that of individual components due to the lack of washout phenomenon and less toxic effect of preservatives on the ocular surface. However, there are several disadvantages of fixed-dose combinations, e.g., dosing and regimen are inflexible and cannot easily be regulated. The paper discusses the results of clinical trials which compare the efficacy and safety of the most common fixed-dose combinations and their individual components.
Thus, fixed-dose combinations of prostaglandin analogues and timolol maleate demonstrate similar IOP-lowering effect as compared with individual components and less side effects.

Keywords: primary open-angle glaucoma, fixed-dose combination, glaucoma, combined therapy, treatment efficacy.
For citation: Nagornova Z.M., Kuroyedov A.V., Seleznev A.V. Comparative analysis of the efficacy and safety of fixed-dose combinations versus their individual components for open-angle glaucoma. Russian Journal of Clinical Ophthalmology. 2019;19(1):13–19.

Fixed-dose combinations for POAG medical therapy

    The primary goal of the treatment of primary open-angle glaucoma (POAG) and ocular hypertension (OH) is to achieve so-called target intraocular pressure (IOP) which is adequate to prevent the development or progression of glaucoma. According to the current data, IOP lowering is the key mechanism to stabilize vision and to prevent glaucomatous optic neuropathy progression. International studies demonstrate that IOP lowering (therapeutic or surgical) decreases the risk of optic neuropathy progression. Thus, Early Manifest Glaucoma Trial (EMGT) shows that each 1-mm Hg drop of IOP reduces the risk of glaucoma progression by 10-13% [1].

    Russian Glaucoma Society guidelines (2015) postulate that target IOP (measured by tonometry, Pt) is 22-24 mm Hg for early POAG, 19-21 mm Hg for moderate POAG, and 16-18 mm Hg for advanced POAG.

    In general, monotherapy with prostaglandin analogues, non-selective beta blockers, alpha agonists or carbonic anhydrase inhibitors is considered the first-line treatment for POAG irrespective of its stage. However, many patients need more than one agent to achieve target IOP. As a consequence, treatment regimen should include two or more topical glaucoma medications of various classes [2]. Thus, Ocular Hypertensive Treatment Study (OHTS) demonstrates that after 5 years of topical IOP-lowering treatment 40% of patients require two medications and 9% of patients require three or more medications to reduce IOP by 20% [3]. However, this inevitably results in poor adherence to the treatment, e.g., the more medications and instillations are prescribed, the more difficulties are experienced. Therefore, in recent years, fixed-dose combinations containing two or more active ingredients in a single bottle are recommended to reduce IOP in POAG and OH. Fixed-dose combinations are superior to individual components in separate bottles through the more comfortable regimen with less bottles and instillations which improves treatment compliance. Despite few publications which compare treatment adherence when using fixed-dose combinations and individual components, some data demonstrate improved treatment adherence in easier treatment regimens [4]. Thus, retrospective study shows that patients ask for a new prescription less often when the second topical IOP-lowering medication is prescribed [5]. The analysis of treatment compliance in other disorders demonstrates that treatment compliance is higher when several individual components are taken in a single formulation than separately [6].

    In addition, fixed-dose combinations contain active ingredients with different mechanisms of IOP-lowering action which simultaneous use provide additive effect [7].

    Higher clinical efficacy and improved adherence to fixed-dose combinations are also accounted for by the lack of washout phenomenon and no need to wait between instillations. In addition, every drop of an individual component provides unnecessary dose of benzalkonium chloride (BAC), the most commonly used eye drop preservative. BAC stimulates cell apoptosis and inflammation thus resulting in tear film instability, lipid layer thinning, conjunctival goblet cell damage, and poor glaucoma surgery outcomes [8-10]. D.A. Ammar et al. has demonstrated in vitro that BAC reduces trabecular membrane cell survival which is associated with increased matrix metalloproteinase (MMP) 9 level, an enzyme involved in glaucoma pathogenesis [11]. These findings may be of special importance for patients with advanced glaucoma who require multiple medications and, as a result, receive more BAC. Some data suggest that the prevalence of dry eye and other ocular surface disorders is particularly high in glaucoma. 59% of patients with POAG or OH report on dry eye symptoms at least in one eye [12]. Moreover, dry eye is diagnosed in 52.6% of glaucoma patients [13]. Both studies demonstrate that dry eye occurrence directly correlates with the number of glaucoma eye drops containing BAC. Subjective and clinical signs of dry eye (i.e., bulbar conjunctival injection and ocular surface staining) significantly improve in most patients after switching to fixed-dose combinations (including those preservative-free) [14].

    However, there are several disadvantages of fixed-dose combinations, e.g., dosing and regimen are inflexible and cannot easily be regulated. Thus, prostaglandin analogues should be used in the evening while beta blockers should be used in the morning (if prescribed once a day). Therefore, whenever during the day fixed-dose combinations (i.e., prostaglandin analogues and beta blockers) are administered, one of these individual components will provide less benefit than it could be. Nevertheless, if treatment compliance improves due to the easier regimen, this and other advantages of fixed-dose combinations overweight this disadvantage [15, 16]. However, this is IOP-lowering efficacy which determines the choice between individual components or fixed-dose combinations. Considering this, the aim of this paper was to compare IOP-lowering efficacy and safety of fixed-dose combinations and their individual components taken concomitantly which are available at the pharmaceutical market.

    The first fixed-dose combinations invariably included pilocarpine hydrochloride in various concentrations (2% or 4%) and non-selective beta blockers. Clinical studies demonstrated similar IOP-lowering efficacy of fixed-dose combinations containing pilocarpine and timolol maleate 0.5% and individual components taken concomitantly [17, 18]. These medications have not been widely adopted mainly because of pilocarpine adverse effects (blurred vision, conjunctival hyperemia, and headache) which could not be eliminated despite less frequent dosing (twice or thrice daily as compared with 5 times daily instillations of individual components) and challenges in cataract surgery associated with their long-term use. IOP-lowering efficacy of these fixed-dose combinations is similar to that of modern medications (prostaglandin analogues, carbonic anhydrase inhibitors etc.) taken separately [19].

    It is well-known that prostaglandin analogues and prostanoids (as monotherapy or fixed-dose combinations with timolol maleate) are the most effective IOP-lowering agents [20].

Latanoprost/timolol fixed-dose combination

    Fixed-dose combination of latanoprost 0.005% and timolol 0.5% is the most studied one [21]. Double-blind randomized study (195 patients) has demonstrated that latanoprost/timolol fixed-dose combination in the morning (i.e., once a day) is less effective in terms of IOP lowering than latanoprost in the evening plus timolol twice a day [22]. However, 12-week double-blind randomized study (517 patients) has demonstrated that fixed-dose combination in the evening (i.e., once a day) provides similar IOP-lowering effect as compared with individual components taken together [23]. In the course of the study involving 502 patients with POAG, OH, pigmentary and pseudoexfoliation glaucoma, 255 patients received fixed-dose combination and 247 patients received latanoprost plus timolol. At baseline, IOP (P0) was 25.4 mm Hg and 25.2 mm Hg, respectively. After 12 weeks of continuous instillations, 76% of patients in group I and 74% of patients in group II had IOP less than 18 mm Hg (p = 0.52). In patients who receivedlatanoprost/timolol fixed-dose combination, IOP-lowering effect was 0.3-0.7 mm Hg less than in the control group. Therefore, IOP-lowering effect was similar in both groups but latanoprost/timolol fixed-dose combination was superior to the individual components due to the fewer instillations. When comparing safety profiles, local drug-related adverse events (i.e., conjunctival injection and ocular irritation) were less common in patients who received latanoprost/timolol fixed-dose combination (2.3%) than in those who received individual components (7.1% and 4.3%, respectively) [24]. The authors speculate that just one drop of fixed-dose combination but three drops of individual components are instilled in the eye daily thus increasing the amount of excipients. When comparing latanoprost/timolol fixed-dose combination and latanoprost as monotherapy, local adverse reactions were more common in monotherapy group (23.9% and 17.8%, respectively) despite similar dosing regimen. In particular, eye redness was observed in 10.4% of patients who received monotherapy and 7% of patients who received fixed-dose combination [5].

Tafluprost/timolol fixed-dose combination

    Preservative-free fixed-dose combination of tafluprost 0.0015% and timolol 0.5% has higher IOP-lowering efficacy as compared with the separate use of individual components (i.e., preservative-free tafluprost 0.0015% andpreservative-free timolol 0.5%) and similar IOP-lowering efficacy as compared with the combined of these components [25]. In addition, this fixed-dose combination provides significantly less eye redness (the most common adverse reaction resulting in poor treatment compliance) due to the lack of preservatives. N. Pfeifer et al. has reported that in patients who initially received non-fixed dose combination clinical signs (i.e., conjunctival injection and ocular surface staining) improve as compared with the baseline. In particular, by the time of therapy switching, conjunctival injection was observed in 65.5% of patients who received non-fixed dose combination of prostaglandin analogue and beta blocker. At the last visit, conjunctival injection was observed in 49.5% of patients only while the percentage of patients with severe injection reduced from 5% to 0.7%. In addition, switching to the preservative-free fixed-dose combination of tafluprost and timolol reduced conjunctival staining by 7%. 92.7% of patients withdrawn from the study and proceeded to treatment with preservative-free fixed-dose combination. 2.2%, 0.8%, and 0.6% of patients withdrawn due to the inadequate IOP-lowering effect, persistent conjunctival injection, and systemic intolerance, respectively [26]. Japanese study group has demonstrated that after switching from individual components (tafluprost and timolol) to tafluprost/timolol fixed-dose combination treatment compliance improves. Average IOP was 14.8 ± 2.8 mm at baseline and 14,8±3,7 mm Hg after 8 weeks of the treatment with tafluprost/timolol fixed-dose combination. No changes in blood pressure, heart rate, and ocular surface health from baseline were reported in 76% of patients [27].

Bimatoprost/timolol fixed-dose combination

    Bimatoprost is a synthetic prostamide which chemical structure is similar to that of prostaglandinF2α. Bimatoprost/timolol fixed-dose combination (Ganfort) reduces IOP by increasing trabecular outflow facility and uveoscleral outflow and decreasing aqueous humor production.

    In a 3-week double-blind randomized study (n = 445), А. Hommer et al. compared bimatoprost/timolol fixed-dose combination with bimatoprost plus timolol and monotherapy with bimatoprost [28]. Morning instillations of bimatoprost/timolol fixed-dose combination (Ganfort) provide similar IOP-lowering effect as compared with bimatoprost once a day (in the evening) plus timolol twice a day. Clinically relevant conjunctival injection (revealed by slit lamp examination) was significantly less common in patients who received bimatoprost/timolol fixed-dose combination (8.5%) as compared with those who received bimatoprost as monotherapy (18.9%) or non-fixed-dose combination (12.5%).

Travoprost/timolol fixed-dose combination

    Two studies compared efficacy and safety of morning instillations of travoprost/timolol fixed-dose combination and travoprost (once a day in the evening) and timolol (once a day in the morning) [33]. J.S. Schuman et al. have demonstrated that IOP-lowering effect is greater (approx by 1.0 mm Hg) in non-fixed dose combination group as compared with fixed-dose combination group [34]. D.A. Hughes et al. have demonstrated that average IOP is significantly lower (approx by 1.0 mm Hg) in patients who received individual glaucoma medications. Therefore, travoprost/timololfixed-dose combination is less effective than individual components, i.e., travoprost and timolol. L. Quaranta et al. account this phenomenon for the fact that beta blockers are administered twice a day while travoprost/timololfixed-dose combination is used once a day in the morning (in general) [35]. However, IOP-lowering effect was greater in individual component group after one month only (7.7 mm Hg and 8.7 mm Hg, respectively) and almost similar after 12 months (7.4 mm Hg and 7.3 mm Hg, respectively). Treatment adherence was greater in fixed-dose combination group (60% and 43%, respectively). Overall rate of adverse reactions was similar in the groups in all these studies. Meanwhile, J.D. Brandt et al. reported on the significantly lower rate of conjunctival injection in travoprost/timolol fixed-dose combination group (14.3% and 23.4%, respectively) [36].

Dorzolamide/timolol fixed-dose combination 

    4-month randomized double-blind comparative study of the efficacy of dorzolamide/timolol fixed-dose combination and individual components has demonstrated that after two and three months of the treatment the difference between average IOP lowering is less than 0.1 mm Hg. No significant difference in treatment-related adverse reaction rate was revealed, however, ocular pain and superficial corneal lesions were significantly less common in fixed-dose combination group than in individual component group (0% and 4%, p = 0.014; 1% and 7%, p = 0.005, respectively) [37]. In addition, several studies have shown that switching from individual components to fixed-dose combination provides additional IOP lowering [38]. However, К. Strohmaier et al. have demonstrated that in fixed-dose combination group IOP level is 1 mm Hg higher as compared with individual component group. Adverse reaction rate was similar in both groups but ocular pain and discomfort were significantly more common in patients who received fixed-dose combination (6% and 1%, respectively, p = 0.036) [39]. J. Hutzelmann et al.  analyzed economic aspects of combined treatment by calculating cost-effectiveness of fixed-dose combination versus individual components [40]. Both treatments reduced IOP by 24% (on average, by 5.4 ± 3.1 mm Hg). Considering lower cost at baseline, fixed-dose combination is more cost-effective.

Brinzolamide/timolol fixed-dose combination 

    In patients who received brinzolamide/timolol non-fixed dose combination, switching to the fixed combination of brinzolamide 1% and timolol 0.5% resulted in IOP reduction from 25 ± 2 mm Hg at baseline to 21 ± 1 mm Hg. Brinzolamide/timolol fixed-dose combination produced neither adverse reactions nor intolerance [41]. When switching from monotherapy with timolol to brinzolamide/timolol fixed-dose combination or timolol 0.5% plus brinzolamide 1%, IOP reduced by 2.5 to 3.4 mm Hg and 2.7 to 3.3 mm Hg, respectively. The most common adverse reactions were nasopharyngitis (4%) in brinzolamide/timolol fixed-dose combination group and blurred vision (3%), eye redness (2%), and allergic conjunctivitis (2%) in individual component group. Visual field loss (as compared with baseline) was observed in 3% and 7% of patients who received brinzolamide/timolol fixed-dose combination and individual components, respectively [42].

Brimonidin/timolol fixed-dose combination 

    Fixed-dose combination of brimonidin 0.2% and timolol 0.5% (Combigan) is characterized by significant IOP-lowering effect due to the complex action of its ingredients. Brimonidin is a selective alpha2-agonist which provokes neither mydriasis nor microvascular constriction. Brimonidin reduces IOP by decreasing aqueous humor production and improving uveoscleral outflow while timolol reduces IOP by decreasing aqueous humor production.

    Clinical studies have demonstrated that brimonidin/timolol fixed-dose combination is superior to individual components and similar to the combined administration of two medications in terms of IOP lowering [43]. F. Goni compared brimonidin/timolol fixed-dose and non-fixed dose combinations. Total of 371 patients were switched from monotherapy with one individual component to brimonidin/timolol fixed-dose or non-fixed dose combination. After 12 weeks, IOP-lowering effect was similar in both groups. Both brimonidin/timolol fixed-dose combination and individual components were well-tolerated, adverse reaction rate was similar in the groups [44].

Brinzolamide/brimonidin fixed-dose combination 

    A number of data on fixed-dose combination of brinzolamide 1% and brimonidin 0.2% as compared with monotherapies and other fixed-dose combinations are available [46]. However, just one paper on the efficacy of brinzolamide/brimonidin fixed-dose combination as compared with the separate use of individual components was found. 420 patients with POAG and OH received brinzolamide/brimonidin fixed-dose combination and 420 patients received brinzolamide plus timolol. After 3 weeks, IOP reduced by 8.5 ± 0.16 mm Hg and 8.3 ± 0.16 mm Hg, respectively. IOP level less than 18 mm Hg was achieved in 68.9-71.6% and 65.8-71.6% of patients, respectively. The most common adverse reactions were conjunctival injection (5.5% and 6.9%, respectively), blurred vision, and ocular discomfort. The most common systemic adverse reactions were dry mouth and drowsiness [47].

Triple fixed-dose combinations

    Data on triple fixed-dose combinations are also available. Thus, dorzolamide/timolol/brimonidin fixed-dose combination for POAG and OH which was used in Mexico and USA demonstrates less IOP-lowering effect than brinzolamide/brimonidin fixed-dose combination. Tolerability and local adverse reaction rate are similar in both groups [48]. More common triple fixed-dose combination of bimatoprost 0.01%, brimonidin 0.15%, and timolol 0.5% was compared with fixed-dose combinations of brimonidin 0.2% and timolol 0.5% or brinzolamide 2% and timolol 0.5%. Both studies clearly demonstrated better IOP-lowering efficacy of triple fixed-dose combination and similar rate and type of adverse reactions [50]. 

Conclusion 

    Fixed-dose combinations are preferred to the separate use of two individual components mostly due to the improved treatment adherence and more stable IOP-lowering effect. Instillations of eye drops are among major causes of poor treatment adherence. One drop of fixed-dose combination is more comfortable, easier, and faster than two drops from separate bottles. Several studies have demonstrated that many patients (22%) who receive multiple drops do not control time intervals between instillations. As a result, washout effect (which is not typical for fixed-dose combinations) occures. In addition, many clinical studies have shown that available fixed-dose combinations are as effective as individual components used together. Therefore, fixed-dose combinations are an important addition to the available glaucoma medications and provide optimal treatment regimens for patients who require more than one medication to control IOP.

About the authors: 

1Zoya M. Nagornova — Assistant of the Department of Otorhinolaryngology and Ophthalmology; 

2,3Alexander V. Kuroyedov — MD, PhD, Professor of Ophthalmology Department, Head of Ophthalmology Department; 

1Alexey V. Seleznev — MD, PhD, Associate Professor of the Department of Otorhinolaryngology and Ophthalmology. 

1 Ivanovo State Medical Academy. 8, Sheremetevsky Ave., Ivanovo, 153012, Russian Federation. 

2 Central Military Clinical Hospital named after P.V. Mandryka. 8A, B. Olenya str., Moscow, 107014, Russian Federation. 

3 Pirogov Russian National Research Medical University. 1, Ostrovityanova str., Moscow, 117997, Russian Federation. 

Contact information: Alexander V. Kuroyedov, e-mail: akuroyedov@hotmail.com. Financial Disclosure: no author has a financial or property interest in any material or method mentioned. There is no conflict of interests. Received 26.11.2018.

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