Preservative-free treatment in glaucoma

Eur J Ophthalmol 2013; 23 ( 4 ): 518-525

DOI: 10.5301/ejo.5000270

ORIGINAL ARTICLE

Preservative-free treatment in glaucoma: who, when, and why? Ingeborg Stalmans1, Gordana Sunaric Mégevand2, M. Francesca Cordeiro3, Anton Hommer 4, Luca Rossetti5, Francisco Goñi6, Anders Heijl7, Alain Bron8 Department of Ophthalmology, University Hospitals Leuven, Leuven - Belgium Rothschild Memorial, Geneva - Switzerland 3 Glaucoma & Retinal Neurodegeneration Studies, Western Eye Hospital, London - United Kingdom 4 Hera Hospital, Vienna - Austria 5 Eye Clinic San Paolo Hospital, University of Milan, Milan - Italy 6 Servicio Integrado Oftalmologia Valles Oriental (SIOVO), Barcelona - Spain 7 Department of Ophthalmology, Skåne University Hospital, Lund University, Malmö - Sweden 8 Department of Ophthalmology, University Hospital, Dijon - France 1 2

Department of Ophthalmology, University Hospitals Leuven, Leuven - Belgium Rothschild Memorial, Geneva - Switzerland Glaucoma & Retinal Neurodegeneration Studies, Western Eye Hospital, London - United Kingdom Hera Hospital, Vienna - Austria Eye Clinic San Paolo Hospital, University of Milan, Milan - Italy Servicio Integrado Oftalmologia Valles Oriental (SIOVO), Barcelona - Spain Department of Ophthalmology, Skåne University Hospital, Lund University, Malmö - Sweden Department of Ophthalmology, University Hospital, Dijon - France

Purpose: To review and summarize the available literature on the effect of preservatives on the eye, to provide practical guidance for the clinical assessment of the ocular surface in glaucoma patients, and to define patient populations that might benefit from preservative-free topical intraocular pressure (IOP)–lowering agents. Methods: This manuscript is based on a combination of a literature review on preservatives and the eye and expert opinion from glaucoma specialists with an interest in ocular surface disease. Results: There is an increasingly recognized association between eyedrop preservatives and ocular surface disease. Preservative-free therapy is now available for a wide range of active compounds, although there are still some misconceptions regarding their appropriate use. For patients treated topically for glaucoma or ocular hypertension, a rough estimate could be that 20% may need treatment with topical IOP-reducing agents that are free from preservatives. Conclusions: This review provides an up-to-date account of the literature regarding preservatives and the eye, as well as suggestions and recommendations on to when to use preservative-free antiglaucoma treatment. Keywords: Glaucoma, Intraocular pressure–lowering agents, Ocular surface, Preservative Accepted: February 19, 2013

INTRODUCTION Glaucoma is a chronic disease that requires lifetime treatment. For most patients, this means medical treatment. It has long been recognized that the presence of preservatives in topical therapy (Tab. I) may impact ocular surface function and structure. The purpose of this review is to evaluate and discuss the role of preservative-free (PF) an518

tiglaucoma medication in light of its increasing availability and the growing scientific knowledge on the effects of preservatives on the eye. This is based on a comprehensive review of the literature by authoritative specialists in the field (1-3), combined with expert opinions from our group. We attempt to define an appropriate patient population that might benefit from PF antiglaucoma therapy, cognizant that the aim of all glaucoma treatment is to halt

© 2013 Wichtig Editore - ISSN 1120-6721

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TABLE I - MOST FREQUENTLY USED PRESERVATIVES IN OPHTHALMOLOGY Chemical composition

Preservative

Mechanism of action

Ocular treatments containing the preservative

Quaternary ammonium

Benzalkonium

Detergent

Glaucoma, anti-inflammatory, antibiotics, artificial tears

Poly-quaternary ammonium

Polyquad

Detergent

Glaucoma, contact lens solutions, artificial tears

Oxychlorinated complex

Purite

Oxidizing

Glaucoma, artificial tears

Organo-mercurial derivative

Thimerosal

Protein precipitation

Anti-inflammatory, antibiotics

Ionic buffer solution

Sofzia

Oxidizing

Glaucoma

Amidine

Chlorhexidine

Membranolytic

Antibiotics

Alcohol

Chlorobutanol

Lipid permeability increase

Mydriatics, antibiotics, anti-inflammatory

Adapted from Hong J, Bielory L. Allergy to ophthalmic preservatives. Curr Opin Allergy Clin Immunol 2009;9:447-53 (4).

TABLE II - CHARACTERISTICS OF OCULAR TISSUE REACTIONS Type of reaction

Mechanism

Symptoms

Signs

Allergy

Immune

Itching

Redness/chemosis

Toxicity

Direct cell damage

Burning/stinging

Redness, inferior third/corneal epithelium damage

Intolerance

Irritative

Discomfort

Unspecific

Sensitivity

Individual, low response threshold

Discomfort

Unspecific

disease progression, usually through lowering intraocular pressure (IOP).

Definitions of different tissue conditions and responses Allergy can be defined as a hypersensitive state of the immune system, acquired through exposure to a particular allergen. It can be mediated by antibodies (immediate phase response) and/or cells (late-phase response). Allergy is acquired and it can manifest in ocular and periocular tissues. The cardinal symptom is itching; in addition, redness and chemosis can occur (4). Toxicity is the degree to which a substance can damage tissues. It is dependent on the dose, route of administration, and time of exposure. Individuals have different levels of response to substances showing a potentially toxic effect. A suggestive sign of ocular toxicity is the appearance of tissue reaction mainly in the inferior third of the eye, due to concentration of the drug associated with gravity (5). Intolerance to a drug is the inability or difficulty to continue taking a medication because of an adverse side effect that is not immunity-mediated. For example, some people

show intolerance even to “disappearing” preservatives (those supposed to dissipate into basically oxygen and water in contact with the eye) (4). Sensitivity to a drug is the state of reacting to the normal pharmacologic doses of a drug with the symptoms of overdosage (4). ll these conditions (Tab. II) share in common that they can be drug-induced and will result in change or stopping therapy. In the case of benzalkonium (BAK) derivatives (the most frequently used preservatives in glaucoma therapy), toxicity represents probably the main deleterious tissue reaction in the eye, but BAK may also elicit allergic responses (4% to 11% of positive skin tests) (4). Dry eye syndrome is a disorder of the tear film due to tear deficiency or excessive evaporation. It causes damage to the interpalpebral ocular surface and is associated with symptoms of ocular discomfort and the feeling of a dry eye (6).

Effects of preservatives on the eye Preserved glaucoma drops have an important impact on the ocular surface, particularly in patients with preexisting ocular surface disease (OSD). Ocular surface disease


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Preservative-free drugs and glaucoma

encompasses several clinical presentations including dry eye, meibomian gland dysfunction (MGD), and blepharitis (6-8). It is mandatory for clinicians to be aware of the overlap between these clinical entities. Glaucoma patients have a high prevalence of ocular surface disorders including dry eye syndrome as noted in several epidemiologic and observational studies, with a clear relationship to the severity and the duration of the disease as well as the number of antiglaucoma drugs (9-11). Severe dry eye was found in 8.7% and 15% of patients using 2 or 3 topical antiglaucoma drops, respectively (12). In a recent study conducted in 101 American glaucoma patients using preserved antiglaucoma drops, 59% reported symptoms in at least one eye by means of the Ocular Surface Disease Index (OSDI) questionnaire (13), qualified as severe in 27%, whereas 61% showed decreased tear production, and 78% decreased tear break-up time (14). Very recently it was shown that tear osmolarity, a surrogate for dry eye, was increased in glaucoma and ocular hypertensive patients when compared to controls and particularly for those having preserved drops (15). Moreover, it has been shown recently in a Japanese population that glaucoma patients treated with topical prostaglandins or beta-blockers had more alterations in meibomian gland morphology and function than controls (16). Symptoms such as discomfort, burning, stinging, and itching are markedly increased in prevalence and frequency in patients who use preserved compared to unpreserved glaucoma drugs (9), pointing to preservatives, mainly BAK, the most commonly used, as the principal causative factor. A recent article highlighted the impact of OSD on quality of life (QOL) of glaucoma patients treated with topical medication (17). In this series, the proportion of patients with OSD increased with the severity of glaucoma to reach 83.3% in women and 69.2% in men versus 29.4% and 0% for controls. Moreover, a worse score on the QOL questionnaire, or a daily dose of BAK greater than 3 administrations, were predictive of a higher OSDI score (with an odds ratio of 4.14 and 2.47 respectively). Benzalkonium has been recognized as an irritant in dermatologic and allergologic investigations. Allergic reactions such as contact dermatitis are rare (18), and a meta-analysis has shown that withdrawal from randomized clinical trials for allergy occurred at a rate less than 8% (19). On the other hand, several studies have shown that BAK exacerbates ocular surface conditions such as nonal520

lergenic blepharitis, MGD, chronic conjunctival inflammation, tear film instability, and keratitis. Through these toxic and proinflammatory effects, BAK may therefore cause or aggravate dry eye disease (1). Toxicology studies have been performed both in vitro and in vivo to assess the effects of different antiglaucoma drugs and their preservatives on various ocular tissues. These experimental data are summarized in Table III. Taken together, the data indicate that at high doses all preservatives are toxic to ocular surface tissues (with some evidence even of intraocular toxicity). However, BAK, the most commonly used preservative in ophthalmic solutions, is more toxic than most other preservatives, including Polyquad® and Purite® (20, 21). Furthermore, all tested preservatives have some degree of dose-dependent toxicity (20). An association between the number of IOP-lowering drugs, the concentration of preservatives, and the duration of the treatment and the frequency and severity of OSD symptoms and signs is also apparent (22, 23). Of note, very often patients with glaucoma need more than one drug to obtain sufficient IOP control. Clinical studies have indicated that the BAK-induced toxic effects are—at least in part—reversible. A marked improvement of symptoms and signs of intolerance in patients switching from preserved to PF antiglaucoma compounds has been shown in several studies (9, 24). This relates to earlier results from a cytologic impression study showing signs of decreased cytologic and inflammatory processes of the conjunctiva and the cornea in glaucoma patients 3 months after replacement of preserved timolol with PF timolol (25). A marked improvement of ocular surface–related symptoms and signs as well as the tear break-up time has been noted after switching from preserved latanoprost to PF tafluprost (26). Such a reversibility of the lesions at the cessation of IOP-lowering agents has been confirmed on human conjunctival biopsies (27). Chronic use of glaucoma medication has also been linked to an unfavorable outcome of glaucoma surgery (2, 28, 29). The number of inflammatory and fibrotic cells in the conjunctiva correlated with the number of antiglaucoma drops and the duration of the treatment (30). Several studies have illustrated that preoperative anti-inflammatory treatment can reduce the conjunctival cellular infiltration and improve surgical outcome after trabeculectomy (27, 31). These studies provide indirect evidence for a role of preserved glaucoma drops in surgical failure after trabeculectomy,


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TABLE III - EFFECTS OF PRESERVATIVES ON THE OCULAR TISSUES In vitro

In vivo and ex vivo

Ocular surface (overall)

The severity of OSDI score increased with the number of medications (22) Reduced symptoms and signs of OSD after reducing preserved timolol treatment from twice to once daily (24)

Tears

Rabbit: greater reduction in TBUT with BAK-containing versus unpreserved timolol (40) Rabbit: decreased aqueous tear basal secretion after BAK (41) A greater proportion of patients receiving IOP-lowering medications (particularly those on ≥2 drugs) had dry eye than did untreated subjects (12)

Cornea

Human: epithelial cell toxicity with multiple preservatives (20)

Rat: BAK more toxic than polyquaternium-1 for corneal epithelium (42)

Human: dose-dependent toxic effects of BAK on epithelial cells (23)

Rabbit: greater corneal damage with BAK versus Purite (21) Rabbit: more corneal stroma edema with preserved vs unpreserved timolol (40) Rabbit: decrease in corneal epithelial thickness after chronic exposure to BAK-preserved timolol (43) Rabbit: decreased epithelial thickness and increased staining after BAK (41)

Conjunctiva

Human: epithelial cell toxicity with multiple preservatives (20)

Rat: BAK more toxic than polyquaternium-1 for conjunctiva (42)

Human: BAK-containing latanoprost and timolol exhibited higher proapoptotic effects on conjunctival cells, compared with unpreserved timolol (44)

Rabbit: greater inflammatory cell infiltration with BAK versus Purite (21) Rabbit: clinical redness and staining after chronic exposure to BAK-preserved timolol (43) Rabbit: decrease in corneal epithelial thickness, conjunctival goblet cell density, and mucin secretion after BAK (41) Human: epithelial cell apoptosis increased in patients on BAK-preserved IOP-lowering medication (45) Human: squamous metaplasia in patients on BAK-preserved IOP-lowering medication (46)

Intraocular

Human: trabecular cell apoptosis induced by BAK-preserved but not unpreserved IOP-lowering drugs (47)

Human: increased aqueous flare after BAK-containing vs unpreserved timolol (33) Human: possible impact of BAK-containing drops on cataractogenesis (48) Human: possible role of BAK-containing drops on cystoids macular edema (49)

BAK = benzalkonium; IOP = intraocular pressure; OSD = ocular surface disease; OSDI = Ocular Surface Disease Index; TBUT = tear break-up time.


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and for a possible beneficial effect of using PF medications on surgical outcome (32). Importantly, the use of preserved eyedrops has also been correlated to intraocular inflammation. In a recent study, glaucoma drops containing BAK were found to lead to signs of anterior chamber inflammation compared to unpreserved drops with the same active ingredient (33).

Defining patient populations that might benefit from PF topical IOP-lowering agents Rationale. From the literature overview above, it can be seen that chronic use of IOP-lowering medications can induce OSD, with an impact on patients’ QOL, compliance, and surgical success rates. These ocular surface changes are mainly caused by the dose-dependent and cumulative toxic effects of the preservatives, in particular BAK. Therefore, reducing the exposure to preservatives may be of benefit in glaucoma management, particularly in patients who need long-term treatment with multiple medications. Not all glaucoma drugs are available without preservatives. However, many glaucoma patients need more than one drug to obtain sufficient disease control. The toxic effects of preservatives are dose-dependent and cumulative. Therefore, it is recommended to minimize the total dose of preservatives, especially in patients who are on multiple therapies, by choosing PF medications when possible (and combining with preserved medications when needed). Careful consideration of the points above is needed in the decision process for topical therapy in glaucoma patients. Indeed, if we want to delineate those patients who would need PF topical medications we should consider life expectancy, the baseline status of the ocular surface, and those who have a surgical profile based on the severity of glaucoma or the type of glaucoma, before initiating a treatment (Fig. 1). Based on these considerations, we propose 2 groups of patients, possibly representing 20% of the glaucoma population, in whom PF medications are highly recommended or potentially advantageous, respectively.

What population should benefit from PF drops? Group 1: Definitely indicated: known allergy to the preservative, Sjögren or severe dry eye disease (stage 3 and 4) (6), atopic dermatitis and rosacea, children. 522

Fig. 1 - Decision algorithm to treat a patient with preservative-free drops in clinical practice. TFBUT = tear film break-up time.

Group 2: Other populations that may also benefit from PF drops: clinically relevant dry eye disease (stage 2) (6), needing concomitant topical therapy, long life expectancy, blepharitis or MGD, intolerance to the preservative, at high risk of need for surgical intervention.

How to identify these patients The detection of ocular toxicity induced by preservatives can be based on methodology developed for dry eye evaluation. There are 3 methods for detecting and grading dry eye severity: tear function, ocular surface damage, and patient symptomatology. Consensus reports have produced grading systems, taking into account all of them (34, 35). In this section, the methods most frequently used in clinical practice for ocular surface assessment are described.


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Personal history

Clinical assessment of need of PF therapy

Before eye examination, it is advisable to gather a complete history of the different factors that may interfere with ocular surface function. Demographic, occupational, systemic, and ocular factors must be considered (Tab. IV). According to the Dry Eye Workshop (DEWS) guidelines (6), patients should be asked about symptoms included in the definition of dry eye, like discomfort (“recurrent sensation of sand or gravel in the eyes”), visual disturbance, and tear film instability.

Visual function. The presence of any ocular surface disease and mainly dry eye may potentially result in an abnormal tear film that can contribute to a variable degree of visual dysfunction, including contrast sensitivity and visual acuity decrease, and increased optical aberrations (36). Macroscopic evaluation. Before proceeding with more detailed assessment, it is advisable to perform a macroscopic evaluation of both eyes under appropriate light conditions, including ocular surface, lids, and periocular skin, comparing findings between each eye. The tear film meniscus height, presence of apparent hyperemia and predominant location, identification of debris at the level of canthi, and the appearance of periocular skin, mainly at the inferior lids, deserve special consideration. Ocular surface evaluation at the slit lamp. Biomicroscopic examination includes a careful evaluation of those elements contributing to ocular surface health. Lid margins must be evaluated to detect signs suggestive of MGD, meibomitis, and anterior or posterior blepharitis. A correct diagnosis of the different lid margin conditions is relevant for management of secondary tear film changes. In fact, MGD is a frequent cause of evaporative dry eye syndrome (7). The bulbar and tarsal aspects of the conjunctiva may reveal surface abnormalities and follicular or papillary reactions. Corneal surface inhomogeneity may explain an anomalous tear film distribution. The distance between peripheral cornea and the inferior lid border, especially when a scleral show sign is observed, must also be examined. Vital stains. According to patient symptomatology and/or slit-lamp findings, an ocular surface dysfunction can be suspected. At this point, vital stains like fluorescein dye will help to determine both tear film stability and corneal epithelium status. A tear film break-up time shorter than 10 seconds is considered abnormal and represents a most useful tool to diagnose dry eye in clinical practice (37). If present, the amount and distribution of punctate epithelial erosions at the corneal surface inform about significant dry eye. Both methods are used to grade dry eye severity and can help in clinical decision-making, as summarized in the flowchart (Fig. 1).

TABLE IV - MOST RELEVANT ANTECEDENTS IN PATIENT ASSESSMENT WHEN CONSIDERING THE INDICATION OF A CHRONIC, PRESERVATIVE-FREE OCULAR TOPICAL THERAPY Antecedents

Conditions/factors

Demographics and occupational factors

Aging Female sex Professional users of screen/video displayers

Systemic conditions

Collagen vascular diseases Rheumatoid arthritis Wegener granulomatosis Systemic lupus erythematosus Autoimmune diseases Sjögren syndrome associated conditions

Systemic treatments

Antidepressants Antihistamines Beta-blockers Cholino-mimetics Nasal decongestants Oral contraceptives Postmenopausal estrogen therapy Retinoic acid

Ocular conditions

Ocular surface disease Dry eye Chronic/recurrent corneal, conjunctival, or lid disorders Surgical procedures Periocular skin disorders

Ocular topical therapy

Previous use of preserved treatments Ocular hypertension and glaucoma Ocular surface diseases Intraocular inflammatory diseases Documented intolerance/allergy

Symptomatology

Recurrent discomfort Intermittent visual disturbances Tear film instability

CONCLUSIONS The introduction of PF topical therapy is welcomed by the glaucoma community as a major advance in the


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We recommend that PF medication be used in patients with severe OSD (stage 3 and 4 according to DEWS) (6), established preservative allergy, atopic dermatitis and rosacea, and children. We also advise their consideration in patients with stage 2 (according to DEWS) (6) OSD, those with a long life expectancy, and those at high risk of need for surgical intervention. Although difficult to estimate accurately, PF glaucoma topical therapy may be appropriate to consider in around 20% of glaucoma and ocular hypotensive patients.

management of patients. The key goal of therapy in glaucoma is preventing vision loss, and this is currently achieved best by lowering/reducing IOP. Prostaglandin analogues have greatly added to the improvement of IOP control, and are nowadays the most commonly used agents because of proven efficacy (38). Although the toxic effects of preservatives in the eye are well-described, it is important to recognize that not all patients are affected, as identified in European Agency for the Evaluation of Medicinal Products guidelines. Hence, the treatment of over 50 million patients with latanoprost since it became widely available has not led to a direct increase in preservative-related OSD (39). Nevertheless, it is important to define the patients who would benefit from PF antiglaucoma treatment. If cost were not a factor, then we believe that preservative-free medication would be preferred in all glaucoma patients. However, given the higher manufacturing costs associated with PF medication, in the current socioeconomic climate, it is not practical or realistic to recommend that all patients receive PF glaucoma medication. Our aim, therefore, is to define patient populations that would benefit most from PF medications.

Financial Support: Financial support was provided by Allergan for the preparation of the manuscript.

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Conflict of Interest Statement: All the authors are consultants of Allergan. Address for correspondence: Ingeborg Stalmans Ophthalmology Department University Hospitals Leuven Kapucijnenvoer 33 B-3000 Leuven Belgium [email protected]

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