Drugs 2012; 72 (10): 1355-1371 REVIEW ARTICLE 0012-6667/12/0010-1355/$55.55/0 Adis ª 2012 Springer International Publishing AG. All rights reserved. Intraocular Pressure-Lowering Combination Therapies with Prostaglandin Analogues Florent Aptel,1,2 Christophe Chiquet1,2 and Jean-Paul Romanet1,2 1 Universite´ Joseph Fourier (UJF), Grenoble, France 2 Department of Ophthalmology, University Hospital, CHU Grenoble, Grenoble, France Contents Abstract. 1355 1. Introduction . 1356 1.1 Literature Search Strategy . 1357 2. Combination Therapies with Prostaglandin Analogues (PGAs): Unfixed Combinations . 1357 2.1 PGA–b-Blocker . 1357 – – 2.2 PGA a2-Adrenergic Agonist and PGA Carbonic Anhydrase Inhibitor . 1358 3. Combination Therapies with PGAs: Fixed Combinations . 1360 3.1 Rationale for Using Fixed Combinations . 1360 3.2 Comparative Efficacy and Tolerability vs Monotherapies . 1361 3.3 Comparative Efficacy and Tolerability vs Unfixed Combinations . 1363 3.3.1 Results of Clinical Trials . 1363 3.3.2 Limitations of the Currently Available Clinical Trials . 1363 3.4 Direct Comparisons of the Three PGA–b-Blocker Fixed Combinations. 1364 3.5 Comparative Efficacy and Tolerability with Other b-Blocker-Based Fixed Combinations . 1365 4. Discussion and Conclusions . 1366 5. Key Practical Points for Clinicians. 1367 Abstract Intraocular pressure (IOP) reduction is currently the only therapeutic approach demonstrated to preserve visual function in patients with glauco- ma. The first line of glaucoma treatment consists of topical IOP-lowering medications, usually initiated as monotherapy. A significant proportion of patients require more than one medication to reach a target IOP at which optic nerve damage will not progress. As prostaglandin analogues (PGAs) are the most effective class for reducing IOP, one of the other commonly used classes (b-adrenoceptor antagonist [b-blocker], carbonic anhydrase inhibitor or a2-adrenoceptor agonist) is frequently combined with a PGA. In the last decade, the use of fixed combinations containing two medications in a single bottle has steadily increased. Fixed combinations have the potential to sim- plify the dosing regimen, increase patient adherence, avoid the washout effect of the second drop on the first medication instilled, decrease exposure to preservatives and, sometimes, reduce the cost of treatment. Clinical trials have evaluated PGA-based fixed combinations versus unfixed combinations 1356 Aptel et al. (individual components administered concomitantly) or versus individual monotherapies; however, any advantage that the fixed combinations may have in terms of IOP-lowering efficacy is still debated. For these reasons, the PGA-based fixed combinations are not approved by regulatory authorities in some countries, such as the US. We review the published studies evaluating the efficacy and tolerability of the IOP-lowering unfixed and fixed combi- nation therapies with PGAs. Regarding unfixed combinations, the review shows that a2-adrenergic agonists–PGA and carbonic anhydrase inhibitor–PGA combinations seem to be at least as effective at reducing IOP as the b-blocker–PGA combinations. As for the fixed combinations, the review shows that the three PGA–timolol fixed combinations are more effective than their component medications used separately as monotherapy and are better tolerated than the three respective prostaglandins. The three PGA–timolol fixed combinations are less effective at reducing IOP than the unfixed combinations but are better tolerated. The advantage of the fixed combinations in terms of patient adherence and per- sistence is supported by a very small number of studies and remains to be more accurately determined. Most studies, but not all, seem to show that PGA–timolol fixed combinations are more effective than other available b-blocker fixed combinations (dorzolamide–timolol fixed combinations) at reducing IOP and are similarly tolerated. 1. Introduction open-angle glaucoma. Because of their efficacy, convenience (once-daily application) and minimal Glaucoma is a progressive optic neuropathy systemic side effects, prostaglandin analogues caused by the degeneration and death of retinal (PGAs) launched in the last decade have nowadays ganglion cells and their axons that form the optic become the first line of treatment. Many clinical nerve, causing visual field reduction until blind- trials and meta-analyses have found that PGAs ness.[1] Primary open-angle glaucoma is the most have a greater ability to reduce IOP than the other common form of glaucoma and the second lead- prescribed therapeutic classes, including b-block- ing cause of blindness in developed countries.[2] ers.[7-9] For example, a meta-analysis has shown The biological mechanisms of the retinal ganglion that the three available PGAs can provide an IOP cell degeneration are not precisely known; however, reduction ranging from -31% to -33% at peak and many risk factors of glaucoma occurrence or pro- from -28% to -29% at trough.[7] As a class, the gression have been identified, elevated intraocular PGAswerefoundtobemoreeffectiveatreduc- pressure (IOP) being the only proven treatable risk ing IOP than the other classes of medications factor. Lowering IOP is currently the only ther- (b-blockers, carbonic anhydrase inhibitors, a2- apeutic approach demonstrated to preserve visual adrenoceptor agonist) both at peak and trough. function. Over the past decade, several large clinical For this reason, and also because of the limited studies have proven that IOP reduction can delay systemic side effects and regimen convenience, or prevent the progression of ocular hypertension PGAs are recommended as first-line therapy by to glaucoma and can delay disease worsening in medical society guidelines (European Glaucoma established glaucoma.[3-6] Society guideline,[10] American Academy of For many years, b-adrenoceptor antagonists Ophthalmology preferred practice[11]). (b-blockers) have been the first choice in medical Despite the efficacy of the PGAs, a significant treatment of ocular hypertension and primary proportion of patients require more than one Adis ª 2012 Springer International Publishing AG. All rights reserved. Drugs 2012; 72 (10) Prostaglandin-Based Combination Therapies in Glaucoma 1357 medication to reach an IOP at which optic nerve ‘adrenergic agonist’, ‘combination’, ‘association’ damage will not progress (target IOP). The Ocular and ‘medical treatment’, both alone and in com- Hypertension Study found that almost 40% of binations. All studies were identified using a two- patients required two or more medications to level search strategy: (i) databases in the public reach a given target IOP.[3] Similarly, the results domain were searched using web-based search of the Collaborative Initial Glaucoma Treatment engines; and (ii) relevant studies were identified Study showed that medically treated patients re- through a manual search of secondary sources, quired a median of two medications to control including the references of articles found from the the disease 5 years after treatment initiation.[12] databases and information obtained directly To achieve a better IOP reduction, combination from experts and pharmaceutical companies. All therapy with drugs of differing but complemen- references were downloaded for consolidation, tary mechanisms of action are preferred. As PGAs elimination of duplicates and further scrutiny. are the most effective therapeutic class, one of the Additional searches were conducted for known other classes is frequently combined with a PGA. trial acronyms cited in review articles. Several unfixed drug combinations including a PGA are available. However, unfixed combina- 2. Combination Therapies with tions increase regimen complexity, potentially Prostaglandin Analogues (PGAs): causing decreased adherence and persistence, and Unfixed Combinations require a waiting time between two instillations in order to avoid drug washout.[13-22] For these rea- Four PGAs are currently available: latano- sons, fixed combinations containing two medica- prost (XalatanÒ, Pfizer, New York, NY, USA), tions in a single bottle have been developed and travoprost (TravatanÒ, Alcon, Fort Worth, TX, marketed. Fixed combinations simplify the dos- USA), bimatoprost (LumiganÒ, Allergan, Irvine, ing regimen and may thus improve compliance CA, USA) and tafluprost (TaflotanÒ, Santen, and persistence. Fixed combinations also decrease Osaka, Japan; or SaflotanÒ, Merck, White House the daily exposure to preservatives such as ben- Station, NJ, USA). Tafluprost is only authorized zalkonium chloride, which is known to have toxic in a few countries (Japan and recently some effects for the ocular surface and to increase treat- European countries). To date, tafluprost is not ment side effects.[23] Finally,thecostofafixed available as a fixed combination. To the best of combination is frequently less than the combined our knowledge, only one published study has evalu- cost of the two ingredients prescribed separately. ated the efficacy and tolerability of an unfixed We undertook a review of the published stud- combination of tafluprost with timolol.[24] ies evaluating the efficacy and tolerability of the IOP-lowering unfixed and fixed combina- 2.1 PGA–b-Blocker tion therapies with PGAs. We particularly re- viewed the studies comparing the efficacy and Many previous studies have evaluated the ad- tolerability of the unfixed and fixed combinations ditive effect of combining a b-blocker with a PGA with monotherapies. in an unfixed manner.[25-31]