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The only evidence-based way of treating glaucoma is by lowering intraocular pressure (IOP), and the primary way of accomplishing this is through the use of medication in the form of eye drops. Thus, patients’ adherence to their treatment regimen is crucial. However, glaucoma frequently does not cause ocular symptoms, although eye drops do (Figure). Perhaps it is not surprising that many glaucoma patients do not use their drops as prescribed.
How can this problem be addressed? Currently, the most direct approach is the development of new formulations of topical medications that are “easier on the eyes.” Many eye drops are preserved with benzalkonium chloride (BAK), which, despite being an effective preservative, is well known to damage the ocular surface. Ocular signs and symptoms of its effects include tearing, burning, itching, decreased tear breakup time, conjunctival injection, and corneal staining. As the number of drops administered increases, so do signs and symptoms. Patients with allergies to a given drop are particularly vulnerable.
Ocular side effects are not limited to surface irritation. Conjunctival scarring may contribute to trabeculectomy failure. Potential systemic effects of topical glaucoma drops are well established. These include, for beta-blockers, bradycardia; shortness of breath; and bronchospasm; and, for alpha-agonists, fatigue; headache; and drowsiness.
Many glaucoma patients are particularly vulnerable to ocular irritation from their topical drops because the prevalence of both ocular surface disease and glaucoma increase with age. Ocular surface disease has been reported to occur in approximately 15% of the elderly population and 48% to 59% of patients with medically treated glaucoma. Reaction to BAK in drops is frequent in the glaucoma patient population.1
The creation of drops that are more tolerable can be achieved through a variety of mechanisms. This article presents a look at some recently developed “kinder, gentler” topical glaucoma drops that are now available.
REDUCING CONCENTRATION OF ACTIVE INGREDIENT
Some drugs that have been in existence for a number of years have been reformulated with a reduced concentration of active ingredient. Lumigan (bimatoprost; Allergan) is a prostaglandin analogue, a class of drugs that has been associated with conjunctival hyperemia, lash growth, iris darkening, and prostaglandin-associated periorbitopathy. Initially, the drop was available as a solution of 0.03%. In 2010, a reduced concentration of 0.01% was approved. Although the drop actually contains a greater concentration of BAK than in its original form, there seems to be less ocular discomfort with the reduced concentration.2 In a study of patients who were switched to bimatoprost after failing to reach target IOP with other medications, the 0.01% formulation exhibited a more favorable tolerability than the 0.03% formulation.3 In a 2013 comparative study of the two formulations, researchers found that the lower concentration solution was associated with better patient adherence and persistence with treatment.4
For some medications, the active ingredient was not changed, but the drug was reformulated with a milder preservative. The prostaglandin analogue Travatan (travoprost 0.004%; Alcon), as originally formulated, contained BAK. It was reformulated as Travatan Z containing a milder preservative, Sofzia (boric acid, propylene glycol, sorbitol, zinc chloride), to be gentler on the ocular surface. Studies comparing the two formulations have shown mixed results. A 2007 investigation found similarities in the number of adverse events and number of patients discontinuing therapy for both medications. However, adverse events due to hyperemia were greater for the original drug than for the reformulation. The researchers concluded that the two drops were equivalent in safety and efficacy.5
Travatan Z has also been compared to another prostaglandin analogue, latanoprost. Two studies have shown that switching from latanoprost to Travatan Z resulted in a lower incidence of signs and symptoms of ocular surface disease, including conjunctival and corneal inflammation.6,7
The drug Alphagan P (brimonidine tartrate; Allergan) works to reduce irritation by using both mechanisms: using a lower concentration of active ingredient and incorporating a milder preservative. The concentration of the original brimonidine tartrate formulation was 0.2%; Alphagan P is available in concentrations of 0.15% and 0.10%, and the preservative BAK has been replaced by Purite 0.005%.
In a study examining patients who were switched to generic 0.2% brimonidine from Alphagan P 0.15% due to formulary requirements, investigators found that 7.7% of patients developed hypersensitivity to the generic form, a rate similar to those who were not previously exposed to the drug. Most of these patients had to be switched back to the original drug.8
Cantor and colleagues9, in a meta-analysis of two prospective randomized studies comparing the 0.1% and 0.15% formulations with brimonidine 0.2%, found that adverse events were less frequent with both 0.1% and 0.15% compared with the 0.2%. Additionally, while ocular adverse events were similar between 0.1% and 0.15%, overall systemic side effects (oral dryness, headache, asthenia), including those leading to discontinuation of the medication, were less frequent with the 0.1% formulation.
OLD DRUGS IN PRESERVATIVE-FREE FORMULATIONS
Two long-standing glaucoma drops have become available in the past several years in preservative-free unit dosages. Timoptic in Ocudose (timolol maleate; Aton Pharma) is available in 0.25% and 0.50% concentrations. The medication is packaged in 60 individual unit doses. In a prospective clinical trial involving patients who were switched from a twice-daily regimen of timolol .025% or 0.50% to the unpreserved formulations at the same concentrations, researchers found that patients maintained stable IOPs with significant improvement in tolerance, including reduction in conjunctival hyperemia, follicles, and punctate keratitis.10
There has been some concern that preservativecontaining drops may lower IOP more than those without preservatives due to enhanced ocular penetration. However, most studies have shown this not to be the case. In a 2013 summary of the literature investigating preservative-free timolol, Rosin and Bell found that preservative-free unit-dose vials were effective in minimizing toxic adverse effects and useful in patients with ocular surface disease or those who could not tolerate preservative-containing medications.11
Another medication that has been developed in unit dose form is Cosopt PF (timolol maleate 0.5% and dorzolamide 2%; Merck). This formulation is available in packs of 60 or 180 single-use vials. The original combination drug was approved in 1998, and the preservativefree form was approved in 2012.
In a comparison study, the preserved and nonpreserved formulations were equivalent in efficacy with similar tolerability.12 Other studies have found improvement in quality-of-life survey scores among glaucoma patients switched from the preserved to the preservative-free form.13 In patients who were switched to the preservative- free combination drug because of intolerance to preservatives such as BAK, tolerability was significantly improved with the new formulation.14
A NEWER PRESERVATIVE-FREE DRUG
The prostaglandin analogue Zioptan (tafluprost 0.0015%; Merck) was approved in Europe in 2008 and the United States in 2012. It is supplied in packs of 30- or 90-unit doses. This is the only prostaglandin analogue that is formulated preservative-free and in a unit dose. As with other drugs in its class, it lowers IOP by increasing uveoscleral outflow, and side effects can include iris pigmentation changes, conjunctival hyperemia, and lash growth.
In a review of three clinical trials of tafluprost including comparisons with latanoprost and timolol, Swymer et al concluded that the drug is as efficacious as the other agents in managing ocular hypertension and glaucoma.15 However, other studies have shown it to be slightly less effective than Travatan or latanoprost.16,17
In a recent study in patients who were switched from other prostaglandins to tafluprost, there was significant improvement in fluorescein staining without reduction in IOP lowering.18 Other reports have shown the drug to be well-tolerated and to possess a good ocular safety profile in patients with glaucoma and ocular hypertension.19,20
Rescula (unoprostone isopropyl ophthalmic solution 0.15%; Sucampo Pharmaceuticals) is in a class by itself. It is a synthetic docosanoid, developed from a prostaglandin analogue. It was approved in 2000 as a prostaglandin analogue, became unavailable several years later, and was reapproved in 2012 as a docosanoid. It has little affinity for the F2-alpha receptor shown by other prostaglandins, and is believed to work by acting on big potassium and chloride type 2 channels. This results in increased aqueous outflow through the trabecular meshwork as opposed to the uveoscleral pathway, as with other prostanoids. With twice-daily topical dosing, the drug lowers IOP by approximately 3 to 4 mm Hg. Its effect is additive to that of timolol.21
Side effects associated with other prostaglandin analogues, including iris color changes, lash growth, and conjunctival hyperemia, have been reported, but with less severity compared with other prostanoids. This may be due to the drug’s decreased interaction with the prostaglandin F2-alpha receptor. It is generally well-tolerated both ocularly and systemically.22
Perhaps the most significant aspect of unoprostone is evidence of a possible neuroprotective effect and enhancement of ocular blood flow. The proposed mechanism for this is the reduction of endothelium-1 (ET-1), which is thought to play a role in ganglion cell apoptosis and cause constriction of vascular smooth muscle.22,23
COSTS AND BENEFITS
Cost can be a major consideration with the medications described previously. As none of them are yet available in generic forms, they tend to be considerably more expensive than drugs that are available generically. Their use may be limited in patients who have no medical coverage, and they may not appear on insurance plan formularies. Advantages of an improved safety profile must be balanced against the financial burden placed on the patient. In doing so, IOP-lowering capability may be compromised.
There are other potential disadvantages to single-use containers. Drops may be more difficult to insert, particularly for patients with limited dexterity and vision. Also, the single-use vials contain more than one drop, so patients may be inclined to use them more than once to save on cost, potentially increasing the risk of contamination. This risk is increased because these solutions are preservative-free.
CLINICAL DECISION MAKING
How does the availability of these new eye drops help the clinician treat patients who may be negatively impacted by glaucoma medications? Medical therapy must be employed as part of an overall strategy aimed at reducing adverse effects and supporting patient adherence. Patient education regarding drop instillation, including punctal occlusion to maximize efficacy and minimize periocular irritation and systemic absorption, must be stressed. Informing patients about possible adverse reactions, coupled with careful monitoring, can help clinicians to detect changes early, allowing interventions to be made before conditions become more difficult to manage.
Special populations are more likely to benefit from these medications. Patients with conditions associated with ocular inflammation and surface disease such as Sjögren syndrome, thyroid disease, and rosacea, as well as those taking medications known to cause dry eye, must be identified and managed accordingly.
Dosing strategies should be used to maximize effectiveness and reduce side effects. A patient may be able to tolerate only one drug containing BAK, and if additional medications are needed, a gentler drop may be required, despite increased cost. Furthermore, despite recent reports discouraging the use of monocular trials due to their questionable ability to predict IOP, such a strategy may still be useful in assessing side effects by comparing treated and untreated eyes.
Lubricants such as artificial tears, gels, and ointments can be used to manage ocular surface irritation. For more severe reactions, use of mild corticosteroids with close IOP monitoring may be necessary. Temporary discontinuation of glaucoma medications, with evaluation of ocular and systemic effects on and off the drops, may be helpful. Alternative IOP-lowering interventions such as laser trabeculoplasty may have to be employed at an earlier stage of treatment.
As a further step beyond the development of more benign drug formulations, there are other approaches on the horizon to minimize unwanted side effects of glaucoma medications and improve patient adherence. Sustained-release formulations are in various phases of investigation. Delivery methods include subconjunctival, sub-Tenon, and intravitreal approaches, as well as drug release from punctal plugs and contact lenses. Injectable and implantable methods of administration are being studied. Medications under investigation using these modalities include latanoprost, travaprost, bimatoprost, and brimonidine.24
The goal of these investigations is to provide safer means of administration than topical drops and to improve patient adherence. Another potential advantage of these methods is more precise volume control so that the proper amount of medication is delivered.
Other alternatives that would still utilize the eye drop form include the development of additional preservatives that are less toxic than BAK, preservative-free multidose units, and gel-forming solutions.25
Finally, there are new classes of drugs in development. Among the notable ones are rho-kinase or ROCK inhibitors, which target trabecular meshwork outflow. They may have the additional benefits of increasing blood flow to the optic nerve head, retarding ganglion cell death, and reducing bleb scarring following trabeculectomy. Challenges include increased hyperemia and the need to establish a viable selective form of the drug.
The eye care industry has attempted to counter some of the adverse effects of topical glaucoma medications by developing a number of kinder, gentler drops that function through various methods. Each of these formulations is a step toward addressing the ever-present problem of balancing risk and benefit in medical management. Despite the potential advantages enumerated in this article, prohibitive factors such as cost mean that they cannot be used by all patients who may benefit from them at the present time. These options must be used judiciously in conjunction with the rest of the clinician’s therapeutic tools in order to minimize adverse reactions, increase patient adherence, and more effectively manage glaucoma and ocular hypertension.
Leon Nehmad, OD, MSW, is an associate professor at Nova Southeastern University, College of Optometry, Ft. Lauderdale, Florida. He acknowledged no financial interest in the products or companies mentioned herein. Dr. Nehmad may be reached at email@example.com.
- Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma. 2008;17:350-355.
- Figus M, Nardi M, Piaggi P, et al. Bimatoprost 0.01% vs bimatoprost 0.03%: a 12-month prospective trial of clinical and in vivo confocal microscopy in glaucoma patients. Eye (Lond). 2014;28: 422-429.
- Myers JS, Vold S, Zaman F, Williams JM, Hollander DA. Bimatoprost 0.01% or 0.03% in patients with glaucoma or ocular hypertension previously treated with latanoprost: two randomized 12-week trials. Clin Ophthalmol. 2014;8:643-652.
- Campbell JH, Schwartz G, Labounty B, et al. Comparison of adherence and persistence with bimatoprost 0.01% versus bimatoprost 0.03% topical ophthalmic solutions. Curr Med Res Opin. 2013;29:1201-1209.
- Lewis RA, Katz GJ, Weiss MJ, et al. Travoprost 0.004% with and without benzalkonium chloride: a comparison of safety and efficacy. J Glaucoma. 2007;16:98-103.
- Aihara M, Oshima H, Araie M. Effects of SofZia-preserved travoprost and benzalkonium chloride-preserved latanoprost on the ocular surface—a multicentre randomized single-masked study. Acta Ophthalmol. 2013;91:e7-e14.
- Katz G, Springs CL, Craven ER, Montecchi-Palmer M. Ocular surface disease in patients with glaucoma or ocular hypertension treated with either BAK-preserved latanoprost or BAK-free travoprost. Clin Ophthalmol. 2010;4:1253- 1261.
- Sullivan-Mee M, Pensyl D, Alldredge B, et al. Brimonidine hypersensitivity when switching between 0.2% and 0.15% formulations. J Ocul Pharmacol Ther. 2010;26:355-360.
- Cantor LB, Liu CC, Batoosingh AL, Hollander DA. Safety and tolerability of brimonidine purite 0.1% and brimonidine purite 0.15%: a meta-analysis of two phase 3 studies. Curr Med Res Opin. 2009;25:1615-1620.
- Bron A, Chiambaretta F, Pouliquen P, et al. Efficacy and safety of substituting a twice-daily regimen of timolol with a single daily instillation of nonpreserved beta-blocker in patients with chronic glaucoma or ocular hypertension [Article in French]. J Fr Ophthalmol. 2003;26:668-674.
- Rosin LM, Bell NP. Preservative toxicity in glaucoma medication: clinical evaluation of benzalkonium chloride-free 0.5% timolol eye drops. Clin Ophthalmol. 2013;7:2131-2135.
- Shedden A, Adamsons IA, Getson AJ, et al. Comparison of the efficacy and tolerability of preservative-free and preservative-containing formulations of the dorzolamide/timolol fixed combination (COSOPT) in patients with elevated intraocular pressure in a randomized clinical trial. Graefes Arch Clin Exp Ophthalmol. 2010;248:1757-1764.
- Abegao Pinto L, Vandewalle E, Gerlier L, Stalmans I. Improvement in glaucoma patient quality of life by therapy switch to preservative-free timolol/dorzolamide fixed combination. Ophthalmologica. 2014;231:166-171.
- Renieri G, Fuhrer K, Scheithe K, et al. Efficacy and tolerability of preservative-free eye drops containing a fixed combination of dorzolamide and timolol in glaucoma patients. J Ocul Pharmacol Ther. 2010;26:597-603.
- Swymer C, Neville MW. Tafluprost: the first preservative-free prostaglandin to treat open-angle glaucoma and ocular hypertension. Ann Pharmacother. 2012;46:1506-1510.
- Schnober D, Hofmann G, Maier H, et al. Diurnal IOP-lowering efficacy and safety of travoprost 0.004% compared with tafluprost 0.0015% in patients with primary open-angle glaucoma or ocular hypertension. Clin Ophthalmol. 2010;4:1459-1463.
- Uusitalo H, Pillunat LE, Ropo A. Efficacy and safety of tafluprost 0.0015% versus latanoprost 0.005% eye drops in open-angle glaucoma and ocular hypertension: 24-month results of a randomized, double-masked phase III study. Acta Ophthalmol. 2010;88:12-19.
- Kumagami T, Wakiyama H, Kusano M, et al. Comparison of corneal safety and intraocular pressure-lowering effect of tafluprost ophthalmic solution with other prostaglandin ophthalmic solutions. J Ocul Pharmacol Ther. 2014;30:340-345.
- Niwano Y, Iwasawa A, Ayaki M. Ocular surface cytotoxicity and safety evaluation of tafluprost, a recently developed anti-glaucoma prostaglandin analog. Ophthalmol Eye Dis. 2014;6:5-12.
- Lanzl I, Hamacher T, Rosbach K, et al. Preservative-free tafluprost in the treatment of naive patients with glaucoma and ocular hypertension. Clin Ophthalmol. 2013;7:901-910.
- Sowka J, Kabat, AG. Rescula to the rescue? May 15, 2013. Review of Optometry. http://www.revoptom.com/ content/c/40839. Accessed August 10, 2014.
- Fung DS, Whitson JT. An evidence-based review of unoprostone isopropyl ophthalmic solution 0.15% for glaucoma: place in therapy. Clin Ophthalmol. 2014;8:543-554.
- Harms NV, Toris CB. Current status of unoprostone for the management of glaucoma and the future of its use in the treatment of retinal disease. Exp Opin Pharmacother. 2013;14:105-113.
- Franca JR, Foureaux G, Fuscaldi LL, et al. Bimatoprost-loaded ocular inserts as sustained release drug delivery systems for glaucoma treatment: in vitro and in vivo evaluation. PloS One. 2014;9:e95461.
- Baudouin C, Labbe A, Liang H, et al. Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res. 2010;29:312-334.